CDK9 inhibitor as well as preparation method and application thereof

Abstract

The invention provides a CDK9 inhibitor as well as a preparation method and application thereof, and belongs to the field of medicinal chemistry. The compound provided by the invention is an effective cyclin dependent kinase (CDK) inhibitor and has a structure as shown in a formula I. The compound disclosed by the invention has an excellent inhibition effect on CDK9 / cyclin T1, and has a wide application prospect in the aspect of preparing a CDK9 inhibitor.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a CDK9 inhibitor, its preparation method, and its uses. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are a class of protein kinases that play a crucial role in cell cycle regulation. They regulate various stages of the cell cycle by binding to cyclins to form complexes. CDK activity is regulated by cyclins, as well as through phosphorylation and dephosphorylation processes.

[0003] Since most aberrant CDK expression is associated with cancer progression, the development of CDK inhibitors as targeted anticancer drugs has attracted great attention from the academic community. Current research has identified several CDK family members, such as CDK1, CDK4 / 6, CDK9, and CDK12, which have different functions and mechanisms of action in different types of tumors. In recent years, although dozens of CDK-targeting drugs have been studied in clinical trials, only a very small number have been approved for clinical treatment. In the early stages of research, most discovered CDK inhibitors were pan-CDK inhibitors and multi-CDK inhibitors. While they can effectively inhibit multiple CDKs or other kinases, the significant side effects they exhibit have hindered their market entry and clinical application. Among them, CDK9 inhibitors are a class of drugs targeting cyclin-dependent kinase 9 (CDK9), and they have shown potential in the field of antitumor therapy. CDK9 plays a crucial role in RNA transcription and is a subunit of positive transcription elongation factor b (P-TEFb). It triggers RNA elongation by phosphorylating the Ser2 residue in the C-terminal domain of RNA polymerase II (Pol II). Inhibiting CDK9 can downregulate the overexpression of the anti-apoptotic factor MCL-1, thereby inhibiting tumor growth.

[0004] Currently, several CDK9 inhibitors have entered clinical research stages. For example, AZD-4573 and KB-0742 have entered Phase 2 clinical trials. AZD-4573 is a CDK9 inhibitor introduced by AstraZeneca, with indications including hematologic malignancies. KB-0742 is a highly selective CDK9 inhibitor that reduces the expression of the oncogene MYC and is being used in Phase 1 / 2 clinical trials to treat patients with solid tumors carrying MYC amplification. Fadraciclib is a highly selective and potent CDK2 / 9 inhibitor, and preclinical data show it may benefit patients with certain cyclin E addiction or MYC amplification in solid tumors. SYHX1903 is a highly selective CDK9 inhibitor with potential in the treatment of hematologic malignancies and solid tumors. QHRD107 is a CDK9 inhibitor independently developed by Qianhong Pharmaceutical. Phase 1 clinical studies showed good safety in AML patients and demonstrated some anti-leukemia activity. SNS-032 is an effective and selective CDK9 inhibitor with an IC50 value of 100%. 50 It has a value of 4nM and also has anti-tumor effects.

[0005] Although many CDK inhibitor compounds have been disclosed, there is still a need to seek more types of CDK inhibitors (especially selective CDK9 inhibitors) for clinical treatment of CDK-related diseases. Summary of the Invention

[0006] The purpose of this invention is to provide a CDK9 inhibitor, its preparation method, and its uses.

[0007] This invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, or their enantiomers, diastereomers, racemates, solvates, crystal forms, prodrugs, or isotopic variants thereof:

[0008]

[0009] Wherein, L is selected from none, carbonyl, C 1-4 Alkylene;

[0010] Ring A is selected from benzene rings, 3-8 membered heteroaromatic rings, 3-8 membered saturated cycloalkyl groups, and 3-8 membered saturated heterocyclic groups;

[0011] m is selected from 0, 1, 2, 3 or 4;

[0012] R a Each is independently selected from halogen, methanesulfonyl, amino, C 1-6 Alkyl, L1C 1-6 Alkyl group, COR1, NHCOR2, unsubstituted or substituted with one or more R groups a1Substituted 3-8 membered saturated heterocyclic groups; L1 is selected from none, C 1-4 Alkylene;

[0013] R1 is selected from those that have not been replaced or are replaced by one or more R1s. a1 Substituted 3-8 membered saturated heterocyclic groups;

[0014] R2 is selected from C 1-6 alkyl;

[0015] R a1 Each is independently selected from carbonyl, C 1-6 Alkyl, NR a2 R a3 3-6 saturated cycloalkyl groups, R a2 Selected from hydrogen, C 1-6 Alkyl, R a3 Selected from hydrogen, C 1-6 alkyl;

[0016] R b Selected from H, -C(O)R b1 -C(O)OR b1 -C(O)NR b2 R b3 C 1-6 Alkyl groups, unsubstituted or C-shaped compounds substituted with one or more halogens 1-6 Alkyl, 3-7 membered saturated cycloalkyl, 3-7 membered saturated heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0017] R b1 Selected from hydrogen, -C 0-6 Alkylene-CN, -C 0-6 Alkylene-NO2, -C 0-6 Alkylene-OR', -C 0-6 Alkylene-SR', -C 0-6 Alkylene-NR”R”'、-C 0-6 Alkylene-C(O)R', -C 0-6 Alkylene-C(O)OR', -C 0-6 Alkylene-C(O)NR”R”'、-C 0-6 Alkylene-S(O) n R'、-C 0-6 Alkylene-S(O) n OR'、-C 0-6 Alkylene-S(O) n NR”R”'、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, unsubstituted or substituted C with one or more halogens 1-6Alkyl, -C 0-6 Alkylene-C 1-6 Alkyl, -C 0-6 Alkylene-3-7 saturated heterocyclic groups, -C 0-6 Alkylene-C 6-10 Aryl or -C 0-6 alkylene-5-10-membered heteroaryl;

[0018] R b2 and R b3 Independently selected from hydrogen, -C 0-6 Alkylene-CN, -C 0-6 Alkylene-NO2, -C 0-6 Alkylene-OR', -C 0-6 Alkylene-SR', -C 0-6 Alkylene-NR”R”'、-C 0-6 Alkylene-C(O)R', -C 0-6 Alkylene-C(O)OR', -C 0-6 Alkylene-C(O)NR”R”'、-C 0-6 Alkylene-S(O) n R'、-C 0-6 Alkylene-S(O) n OR'、-C 0-6 Alkylene-S(O) n NR”R”'、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, unsubstituted or substituted C with one or more halogens 1-6 Alkyl, -C 0-6 Alkylene-C 1-6 Alkyl, -C 0-6 Alkylene-3-7 saturated heterocyclic groups, -C 0-6 Alkylene-C 6-10 Aryl or -C 0-6 alkylene-5-10-membered heteroaryl; or, R b1 R b2 Together with the N atom, they form 3-7 membered saturated heterocyclic groups;

[0019] R' is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, unsubstituted or substituted C with one or more halogens 1-6 Alkyl, 3-7 membered saturated heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0020] R” and R”' are independently selected from hydrogen, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 Alkyne group, unsubstituted or substituted C with one or more halogens 1-6 Alkyl, 3-7 membered saturated heterocyclic groups, C 6-10 Aryl or 5-10 membered heteroaryl; or, R”, R”’ together with N atom to form 3-7 membered saturated heterocyclic group;

[0021] n represents 0, 1, or 2.

[0022] Furthermore, the L is selected from the group with no carbonyl group;

[0023] Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring, 5-6 membered saturated cycloalkyl group, and 5-6 membered saturated heterocyclic group;

[0024] m is selected from 1 or 2;

[0025] R a Each is independently selected from halogen, methanesulfonyl, amino, C 1-3 Alkyl, L1C 1-3 Alkyl group, COR1, NHCOR2, unsubstituted or substituted with one or more R groups a1 Substituted 5-6 membered saturated heterocyclic groups; L1 is selected from none, C 1-2 Alkylene;

[0026] R1 is selected from those that have not been replaced or are replaced by one or more R1s. a1 Substituted 5-6 membered saturated heterocyclic groups;

[0027] R2 is selected from C 1-3 alkyl;

[0028] R a1 Each is independently selected from carbonyl, C 1-3 Alkyl, NR a2 R a3 3-4 saturated cycloalkyl groups, R a2 Selected from C 1-3 Alkyl, R a3 Selected from C 1-3 alkyl;

[0029] R b Selected from C 1-4 Alkyl groups, unsubstituted or C-shaped compounds substituted with one or more halogens 1-4 Alkyl groups, 3-6 saturated cycloalkyl groups.

[0030] Furthermore, the structure of the compound is shown in Formula II:

[0031]

[0032] Among them, R3 is selected from halogens, C 1-3Alkyl, C 1-3 Alkyl group, unsubstituted or with one or more R groups a1 Substituted 5-6 membered saturated heterocyclic groups;

[0033] R a1 Selected from carbonyl, C 1-3 Alkyl groups, 3-4 membered saturated cycloalkyl groups;

[0034] R4 is selected from hydrogen, halogens, and C. 1-3 alkyl;

[0035] R b Selected from C 1-3 Alkyl groups, unsubstituted or C-shaped compounds substituted with one or more halogens 1-3 alkyl.

[0036] Furthermore, the structure of the compound is shown in Formula III:

[0037]

[0038] Among them, R3 is selected from halogens, C 1-3 Alkyl, C 1-3 Alkyl group, unsubstituted or with one or more R groups a1 Substituted 5-6 membered saturated heterocyclic groups;

[0039] R a1 Selected from carbonyl, C 1-3 Alkyl groups, 3-4 membered saturated cycloalkyl groups;

[0040] R4 is selected from hydrogen, halogens, and C. 1-3 alkyl;

[0041] Preferably, the structure of the compound is shown in Formula IV:

[0042]

[0043] R5 is selected from hydrogen and carbonyl groups;

[0044] R6 is selected from hydrogen, C 1-3 Alkyl groups, ternary saturated cycloalkyl groups;

[0045] R7 is selected from hydrogen, C 1-3 alkyl;

[0046] R8 is selected from hydrogen, C 1-3 alkyl.

[0047] Furthermore, the structure of the compound is shown in Formula VI:

[0048]

[0049] R9 is selected from NHCOR2;

[0050] R2 is selected from C 1-3 alkyl.

[0051] Furthermore, the compound is selected from one of the following compounds:

[0052]

[0053]

[0054]

[0055] The present invention also provides a pharmaceutical composition comprising a formulation prepared by adding pharmaceutically acceptable excipients to a compound as an active ingredient, such as any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemic mixture thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof.

[0056] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or their enantiomers, or their diastereomers, or their racemic mixtures, or their solvates, or their crystal forms, or their prodrugs, or their isotopic variants, in the preparation of CDK inhibitors.

[0057] Furthermore, the CDK is CDK9.

[0058] Furthermore, the CDK inhibitor is a drug for the prevention and / or treatment of acute myeloid leukemia, hepatocellular carcinoma, prostate cancer, hematologic malignancies, diffuse large B-cell lymphoma, and mantle cell lymphoma.

[0059] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0060] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C 1～6 Alkyl groups are straight-chain or branched alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms; and so on.

[0061] "alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. The alkyl group can be straight or branched, and may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, and propyl (n-propyl and isopropyl).

[0062] "Alkoxy" refers to the aforementioned alkyl group having a specific number of carbon atoms connected by an oxygen bridge, unless otherwise specified. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0063] "Heterocyclic group" refers to a cyclic group containing one or more heteroatoms. "Heteroaromatic ring" refers to a heteroaromatic group containing one or more heteroatoms. Heteratoms referred to here include, but are not limited to, oxygen, sulfur, and nitrogen. For example, a 3-8 membered saturated heterocyclic group refers to a saturated heterocycle containing 3, 4, 5, 6, 7, or 8 ring atoms; a 3-8 membered heteroaromatic ring refers to a heteroaromatic ring containing 3, 4, 5, 6, 7, or 8 ring atoms.

[0064] Halogens are fluorine, chlorine, bromine or iodine.

[0065] Experimental results show that the compound of this invention is an effective inhibitor of cyclin-dependent kinase (CDK) and has excellent inhibitory effect on CDK9 / cyclin T1, and has broad application prospects in the preparation of CDK9 inhibitors.

[0066] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0067] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0068] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0069] The "room temperature" referred to in this invention is 25±5℃.

[0070] Example 1: Preparation of Compound I-1 of the Present Invention

[0071] Compound I-1 was prepared according to the following synthetic route:

[0072]

[0073] 1): Ethyl 2-(2-hydroxy-6-oxocyclohex-1-en-1-yl)ethyl acetate (2)

[0074] At room temperature, ethyl bromoacetate (105 mL, 0.89 mol, 1.0 eq) was added dropwise to a solution of 1,3-cyclohexanedione 1 (100 g, 0.89 mol, 1.0 eq) in sodium acetate (20% ethanol solution) (380 mL). After the addition was complete, the temperature was raised to 90 °C and the reaction was allowed to proceed for 4 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, dissolved in 1 N NaOH solution, extracted with diethyl ether (3 × 300 mL), and the pH of the aqueous layer was adjusted to approximately 5 with 4 N HCl. The aqueous layer was then allowed to crystallize at 0 °C for 12 h and filtered to obtain a white solid, which was the title compound 2 (70.0 g, 0.35 mol, 39%). 1 H NMR (400MHz, Chloroform-d) δ 10.04 (s, 1H), 4.18 (q, J = 7.1Hz, 2H), 3.47 (s, 2H), 2.45 (d, J = 47.3Hz, 4H), 1.94 (p, J = 6.4Hz, 2H), 1.28 (t, J = 7.1Hz, 3H).

[0075] 2): 2-(6-oxo-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-en-1-yl)ethyl acetate (3)

[0076] Compound 2 (70 g, 0.38 mol, 1.0 eq.) was dissolved in dichloromethane (500 mL) at -78 °C. N,N-diisopropylethylamine (DIPEA) (160 mL, 0.11 mol, 3.0 eq) and Tf₂O (133 mL, 0.95 mol, 2.5 eq) were added sequentially. After reacting for 30 min, the aqueous phase was extracted with dichloromethane (3 × 300 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a pale yellow oily liquid, which was the title compound 3 (100.0 g, 0.3 mol, 79%). 1 H NMR (400MHz, Chloroform-d) δ4.14(q,J=7.1Hz,2H),3.38(s,2H),2.84(t,J=6.2Hz,2H),2.58–2.47(m,2H),2.14(p,J=6.4Hz,2H),1.25(t,J=7.1Hz,3H).

[0077] 3): Ethyl 2-(2-(acetoxymethyl)-6-oxocyclohex-1-en-1-yl)ethyl acetate (4)

[0078] At room temperature, 3 (50 g, 0.15 mol, 1.0 eq) was dissolved in tetrahydroTHF (1 L), and then Bu3SnCH2OAc (60 g, 0.18 mol, 1.2 eq), Pd(OAc)2 (6.79 g, 30 mmol, 0.2 eq), and Ph3P (15.7 g, 60 mmol, 0.4 eq) were added sequentially. Argon gas was replaced, and the mixture was heated to 65 °C and reacted for 3 h. After cooling the reaction solution to room temperature, it was filtered, concentrated, and the resulting residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give a pale yellow oily liquid 4 (24.7 g, 97.5 mmol, 65%). 1 H NMR (400MHz, Chloroform-d) δ4.75(s,2H),4.11(q,J=7.1Hz,2H),3.42(s,2H),2.51–2.43(m,4H),2.09(s,3H),2.05–1.98(m,2H),1.24(t,J=7.1Hz,3H).

[0079] 4): 4,6,7,8-Tetrahydro-1H-isochrom-3,5-dione (5)

[0080] At room temperature, compound 4 (24.7 g, 97 mmol, 1.0 eq) was dissolved in a mixed solvent of THF / EtOH / H2O (1000 mL), and LiOH·2H2O (9.36 g, 0.15 mol, 1.6 eq) was added. The reaction was allowed to proceed for 30 min, and the pH was adjusted to 2 with 4N HCl. The reaction was continued for another 30 min, and the mixture was extracted with EA (3 × 300 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2 / 1) to obtain a pale yellow oily liquid, which was the title compound 5 (24.7 g, 64 mmol, 65%). 1 H NMR(400MHz,Chloroform-d)δ4.94(td,J=2.6,1.3Hz,2H),3.27(p,J=2.5Hz,2H),2.49( dd,J=7.5,6.0Hz,2H),2.33(td,J=5.4,4.5,2.5Hz,2H),2.15–2.06(m,2H),1.25(s,3H).

[0081] 5): N-benzyl-2-(2-(hydroxymethyl)-6-oxocyclohex-1-en-1-yl)acetamide (6)

[0082] Compound 6 (10 g, 60 mmol, 1.0 eq.) was dissolved in THF (500 mL) at room temperature, followed by the addition of DIPEA (34 g, 0.36 mol, 6.0 eq.) and BnNH2 (150 mL, 0.14 mol, 24.0 eq.). The reaction was carried out for 30 min, followed by extraction with EA (3 × 300 mL). The organic phase was then washed successively with 1 N HCl and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by rapid silica gel column chromatography (dichloromethane:methanol = 50 / 1) to obtain a pale yellow oily liquid, which was the title compound 6 (10.5 g, 38.4 mmol, 64%). 1 HNMR(400MHz,Chloroform-d)δ7.25–7.12(m,5H),4.30(d,J=5.8Hz,2H),4.23(s,2H) ,3.32(s,2H),2.44(t,J=6.1Hz,2H),2.35(dd,J=7.5,6.0Hz,2H),1.95–1.88(m,2H).

[0083] 6): 2-Benzyl-2,6,7,8-Tetrahydroisoquinoline-3,5-dione (7)

[0084] At room temperature, compound 6 (10 g, 37 mmol, 1.0 eq.) was dissolved in DCM (300 mL), followed by the addition of DMP (24 g, 56 mmol, 1.5 eq) and PTSA (630 mg, 3.7 mmol, 0.1 eq). The reaction was carried out for 20 min, and the reaction was quenched with saturated sodium thiosulfate solution. The mixture was extracted with dichloromethane (3 × 200 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 50 / 1) to obtain a deep yellow solid, which was the title compound 7 (8.0 g, 31.6 mmol, 85%). 1 H NMR (400MHz, Chloroform-d) δ7.26(qd,J=7.2,5.7,2.9Hz,5H),7.16(s,1H),7.12(s,1H),5.08(s,2H),2.55(dt,J=12.6,6.3Hz,4H),1.96(p,J=6.4Hz,2H).

[0085] 7): 7-Benzyl-1-isopropyl-1,4,5,7-tetrahydro-8H-[1,2,3]triazolo[4,5-f]isoquinoline-8-one (8)

[0086] Compound 7 (7.7 g, 21 mmol, 1.0 eq) was dissolved in toluene (200 mL). Then, p-nitroazide (6.4 g, 39.2 mmol, 1.3 eq), 4A molecular sieve (7.7 g), CH3COOH (0.35 mL, 9 mmol, 0.3 eq), and isopropylamine (6.6 mL, 90.3 mmol, 3.0 eq) were added sequentially at room temperature. The reaction mixture was heated to 100 °C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 50 / 1) to obtain a deep yellow solid, which was the title compound 8 (5.12 g, 16 mmol, 76%). 1 H NMR(400MHz,Chloroform-d)δ7.34(q,J=7.1,6.6Hz,5H),7.20(s,1H),6.77(s,1H),5.14(s,2 H), 4.96 (h, J = 6.6Hz, 1H), 2.94 (t, J = 7.0Hz, 2H), 2.70 (t, J = 7.0Hz, 2H), 1.70 (d, J = 6.6Hz, 6H).

[0087] 8): 1-Isopropyl-1,4,5,7-tetrahydro-8H-[1,2,3]triazolo[4,5-f]isoquinoline-8-one (9)

[0088] Compound 8 (3.66 g, 11.4 mmol, 1.0 eq.) was dissolved in MeOH (100 mL), and 10% Pd-C (1.2 g) and ClCH2CHCl2 (1.2 mL, 12.7 mmol, 1.1 eq.) were added sequentially to replace the hydrogen gas. The mixture was heated to 60 °C and reacted for 12 h. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 35 / 1) to give a white solid, which was the title compound 9 (2.28 g, 9.9 mmol, 87%). 1 H NMR (400MHz, DMSO-d6) δ11.58(s,1H),7.40(s,1H),6.57(s,1H),5.08(p,J=6.5 Hz,1H),2.85–2.77(m,2H),2.70(dd,J=8.1,5.8Hz,2H),1.57(d,J=6.5Hz,6H).

[0089] 9): 1-Isopropyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-f]isoquinoline-8-trifluoromethanesulfonate (10)

[0090] Compound 9 (2.28 g, 9.9 mmol, 1.0 eq.) was dissolved in DCM (100 mL), and pyridine (4.6 mL, 56 mmol, 2.5 eq.) and trifluoromethanesulfonic anhydride (9.4 mL, 56 mmol, 2.5 eq.) were added under ice bath conditions. The reaction was carried out for 30 min. After the reaction was completed, saturated NH4Cl was added to quench the reaction. The mixture was extracted with dichloromethane (3 × 100 mL), washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was subjected to rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3 / 1) to give a white solid, which was the title compound 10 (3.2 g, 8.6 mmol, 87%). 1 HNMR (400MHz, Chloroform-d) δ8.32(s,1H),7.20(s,1H),4.94(h,J=6.6Hz,1H),3.07(s,4H),1.77(d,J=6.6Hz,6H).

[0091] 10): 1-Isopropyl-1H-[1,2,3]triazolo[4,5-f]isoquinoline-8-yltrifluoromethanesulfonate (11)

[0092] Compound 10 (3.2 g, 8.6 mmol, 1.0 eq) was dissolved in toluene (100 mL), and MnO2 (15 g, 0.17 mol, 20.0 eq) was added. The mixture was heated to 60 °C and reacted overnight. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 35 / 1) to give a white solid, which was the title compound 11 (2.5 g, 7.1 mmol, 82%). 1 H NMR (400MHz, Chloroform-d) δ9.21 (s, 1H), 8.23 ​​(d, J = 9.0Hz, 1H), 8.01 (s, 1H), 7.91 (d, J = 9.0Hz, 1H), 5.41 (p, J = 6.6Hz, 1H), 1.93 (d, J = 6.6Hz, 6H).

[0093] 11): 4-(4-fluoro-6-((1-isopropyl-1H-[1,2,3]triazolo[4,5-f]isoquinoline-8-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (I-1a)

[0094] At room temperature, 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12a (160 mg, 0.6 mmol, 2.0 eq.) were added to a dry test tube, followed by 1,4-dioxane (5 mL), Pd2(bda)3 (20 mg, 0.001 mmol, 0.05 eq.), BINAP (20 mg, 0.02 mmol, 0.075 eq.), and CsCO3 (180 mg, 0.6 mmol, 2.0 eq.). The atmosphere was replaced with argon gas, and the mixture was heated to 100 °C and reacted for 3 h. The mixture was filtered, concentrated, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 35 / 1) to obtain a yellow solid, which was the title compound I-1a (121 mg, 0.24 mmol, 82%). LC-MS (ESI), C 26 H 32 N8FO2[M+H] + :m / z=507.3.

[0095] 12): N-(4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)-1-isopropyl-1H-[1,2,3]triazolo[4,5-f]isoquinoline-8-amine (I-1)

[0096] HCl (4M in EA, 0.6mL, 2.4mmol, 10eq) was added dropwise to a mixed solution of dichloromethane / methanol (9:1, 4mL) of I-1a at room temperature. After the addition was complete, the mixture was stirred for 2 hours, concentrated under reduced pressure, and the pH of the aqueous phase was adjusted to >10 with NaOH aqueous solution (4N). The aqueous phase was then extracted with dichloromethane (20mL × 3). The organic phases were combined and washed successively with saturated brine (20mL) and H2O (20mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid, namely, title compound I-1 (83mg, 0.2mmol, 85%). 1 H NMR(400MHz, Methanol-d4)δ9.17(s,1H),9.04(s,1H),8.29(s,1H),7.76(q,J=9.10Hz ,2H),7.08(s,1H),5.65–5.55(m,1H),3.42(d,J=7.12Hz,8H),1.88(d,J=6.32Hz,6H).

[0097] The following are the structural and characterization data of compounds I-1 to I-21:

[0098] Table 1 Examples I-1 to I-21

[0099]

[0100]

[0101]

[0102]

[0103] Example 2: Preparation of Compound I-2 of the Present Invention

[0104] Following the synthesis method of I-1a in Example 1, compound I-2 (76 mg, 195 μmol, 65%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12b (1107 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),7.70(d,J=8.9Hz,1H),7.57(d,J=8.9Hz,1H),7.03(s,1H),5.36(p,J=6.6Hz,1H),4.78(d,J=7.9Hz,1H),4.1 1–3.98(m,1H),3.80(dt,J=12.5,4.2Hz,2H),3.49(s,1H),3.06–2.95(m,2H ), 2.84 (s, 3H), 2.31–2.22 (m, 2H), 1.86 (d, J = 6.6Hz, 6H), 1.73–1.67 (m, 2H).

[0105] Example 3: Preparation of Compound I-3 of the Present Invention

[0106] Following the synthetic method of I-1a in Example 1, compound I-3 (85 mg, 213 μmol, 71%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12c (116 mg, 0.6 mmol, 2.0 eq). 1 H NMR (400MHz, Chloroform-d) δ9.2 (s, 1H), 9.0 (s, 1H), 8.0 (s, 1H), 7.8 (d, J = 8.8Hz, 1H), 7.7–7.6 (m, 2H), 6. 9 (s, 1H), 5.6 (p, J = 6.7Hz, 1H), 3.9 (d, J = 4.6Hz, 4H), 3.0 (t, J = 4.5Hz, 4H), 2.3 (s, 3H), 2.0 (d, J = 6.5Hz, 6H).

[0107] Example 4: Preparation of compound I-4 of the present invention

[0108] Following the synthesis method of I-1a in Example 1, compound I-4 (60 mg, 186 μmol, 62%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12d (67 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.2(s,1H),9.0(s,1H),8.2(d,J=3.05Hz,1H),7.9(d,J=8.79Hz,1H),7.7(d,J=8.94 Hz, 1H), 7.4 (td, J = 8.42, 3.15Hz, 1H), 7.1 (dd, J = 9.21, 3.54Hz, 1H), 5.6 (p, J = 6.69Hz, 1H), 1.9 (d, J = 6.64Hz, 6H).

[0109] Example 5: Preparation of compound I-5 of the present invention

[0110] Following the synthesis method of I-1a in Example 1, compound I-5 (75 mg, 225 μmol, 75%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12e (67 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.16(s,1H),9.00(s,1H),8.02(d,J=3.05Hz,1H),7.84(d,J=8.89Hz,1H),7.66(d,J=8.92Hz ,1H),7.29(dd,J=8.97,3.11Hz,1H),7.04(d,J=8.99Hz,1H),5.58(p,J=6.68Hz,1H),3.89(s,3H),1.94(d,J=6.58Hz,6H).

[0111] Example 6: Preparation of compound I-6 of the present invention

[0112] Following the synthesis method of I-1a in Example 1, compound I-6 (97 mg, 228 μmol, 76%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12f (131 mg, 0.6 mmol, 2.0 eq.). 1H NMR(400MHz,Chloroform-d)δ9.14(s,1H),8.99(s,1H),8.00(d,J=2.93Hz,1H),7.8 2(d,J=8.91Hz,1H),7.64(d,J=8.95Hz,1H),7.33(dd,J=8.91,2.98Hz,1H),7.00(d,J =8.93Hz,1H),5.57(h,J=6.61Hz,1H),3.48(s,1H),3.13(t,J=5.02Hz,4H),2.87–2.7 7(m,4H),1.93(d,J=6.64Hz,6H),1.71(ddd,J=8.46,6.65,3.82Hz,1H),0.49(m,4H).

[0113] Example 7: Preparation of Compound I-7 of the Present Invention

[0114] Following the synthesis method of I-1a in Example 1, compound I-7 (71 mg, 222 μmol, 74%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12 g (65 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.34(s,1H),9.01(s,1H),8.16(s,1H),7.86(d,J=8.90Hz,1H),7.67(d,J=8.92Hz,1H) ,7.47(dd,J=8.34,2.26Hz,1H),6.96(d,J=8.38Hz,1H),5.61(h,J=6.71Hz,1H),2.32(s,3H),1.95(d,J=6.61Hz,6H).

[0115] Example 8: Preparation of Compound I-8 of the Present Invention

[0116] Following the synthesis method of I-1a in Example 1, compound I-8 (79 mg, 189 μmol, 63%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12h (103 mg, 0.6 mmol, 2.0 eq.). 1H NMR(400MHz,Chloroform-d)δ9.25(s,1H),9.03(s,1H),8.38(d,J=2.46Hz,1H),7.90(d,J=8.92H z,1H),7.75–7.66(m,2H),6.98(d,J=8.79Hz,1H),5.57(p,J=6.62Hz,1H),1.96(d,J=6.61Hz,6H).

[0117] Example 9: Preparation of Compound I-9 of the Present Invention

[0118] Following the synthesis method of I-1a in Example 1, compound I-9 (74 mg, 195 μmol, 65%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12i (101 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),9.10(s,1H),8.73(s,1H),8.04(d,J=8.94Hz,1H),7.76(d,J=8.93 Hz, 1H), 6.84 (s, 1H), 5.59 (p, J = 6.59Hz, 1H), 4.50 (s, 2H), 4.27 (s, 3H), 3.44 (s, 3H), 1.95 (d, J = 6.59Hz, 6H).

[0119] Example 10: Preparation of Compound I-10 of the Present Invention

[0120] Following the synthesis method of I-1a in Example 1, compound I-10 (90 mg, 207 μmol, 69%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12j (136 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.03(d,J=17.00Hz,2H),8.03(s,1H),7.85(d,J=8.90Hz,1H),7.65(d,J=8.97Hz,1H),7.36(dd,J= 8.94, 2.90Hz, 1H), 7.12 (d, J = 9.00Hz, 1H), 5.55 (p, J = 6.69Hz, 1H), 3.76–3.68 (m, 4H), 3.26–3.16 (m, 4H), 1.93 (d, J = 6.58Hz, 6H).

[0121] Example 11: Preparation of Compound I-11 of the Present Invention

[0122] Following the synthesis method of I-1a in Example 1, compound I-11 (90 mg, 216 μmol, 72%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12k (124 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.32(s,1H),9.02(s,1H),8.29(d,J=2.63Hz,1H ),7.94(s,1H),7.87(d,J=8.92Hz,1H),7.67(d,J=9.02Hz,1H),7.56(dd,J=8.7 7,2.66Hz,1H),7.04(d,J=8.76Hz,1H),5.56(p,J=6.62Hz,1H),3.77–3.70(m, 2H), 3.32 (s, 2H), 2.83 (t, J = 5.41Hz, 2H), 2.44 (s, 3H), 1.93 (d, J = 6.56Hz, 6H).

[0123] Example 12: Preparation of Compound I-12 of the Present Invention

[0124] Following the synthesis method of I-1a in Example 1, compound I-12 (78 mg, 177 μmol, 59%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12l (140 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.04(s,1H),7.85(d,J=9.01Hz,1H),7.73(s,1H),7 .67(d,J=8.98Hz,1H),7.59(d,J=8.29Hz,2H),7.46(d,J=8.32Hz,2H),5.31(p,J= 6.59Hz,1H),4.03–3.52(m,4H),2.90(d,J=33.96Hz,1H),2.38(d,J=21.18Hz,6H) ,2.22(t,J=7.67Hz,1H),2.02(d,J=13.60Hz,1H),1.85(dd,J=6.61,2.00Hz,6H).

[0125] Example 13: Preparation of Compound I-13 of the Present Invention

[0126] Following the synthesis method of I-1a in Example 1, compound I-13 (76 mg, 186 μmol, 62%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12t (64 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.03(d,J=17.0Hz,2H),8.03(s,1H),7.85(d,J=8.9Hz,1H),7.65(d,J=9.0Hz,1H),7.36(dd,J =8.9, 2.9Hz, 1H), 7.12 (d, J = 9.0Hz, 1H), 5.55 (p, J = 6.7Hz, 1H), 3.76–3.68 (m, 4H), 3.26–3.16 (m, 4H), 1.93 (d, J = 6.6Hz, 6H).

[0127] Example 14: Preparation of compound I-14 of the present invention

[0128] Following the synthesis method of I-1a in Example 1, compound I-14 (65 mg, 165 μmol, 55%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12v (110 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.24(s,1H),9.07(s,1H),8.63(s,1H),8.00(d,J=8.95Hz,1H),7.74(d,J=8.96Hz,1H),5.53(dq,J=14.31,7.85 ,7.23Hz,2H),3.91(m,1H),2.61–2.51(m,1H),2.43–2.33(m,1H),1.99 (s,3H),1.90(dd,J=6.60,2.69Hz,6H),1.77(s,2H),1.63–1.40(m,4H).

[0129] Example 15: Preparation of Compound I-15 of the Present Invention

[0130] Following the synthetic method of I-1 in Example 1, compound I-15 (66 mg, 159 μmol, 53%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12m (184 mg, 0.6 mmol, 2.0 eq.). 1H NMR (400MHz, Methanol-d4) δ8.94(s,1H),8.90(s,1H),7.94(d,J=2.89Hz,1H),7.73–7.60(m,2H),7.44(dd,J=8.98,2.95Hz,1H),7. 20(d,J=8.98Hz,1H),5.53(p,J=6.62Hz,1H),3.32(s,2H),3.28(t,J=1.68Hz,2H),3.15(s,2H),1.85(d,J=6.55Hz,6H),1.52(s,6H).

[0131] Example 16: Preparation of Compound I-16 of the Present Invention

[0132] Following the synthetic method of I-1 in Example 1, compound I-16 (66 mg, 165 μmol, 55%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12n (175 mg, 0.6 mmol, 2.0 eq.). 1 H NMR (400MHz, Methanol-d4) δ9.39(s,1H),9.03(s,1H),7.82–7.69(m,2H),7.55(d,J=8.68Hz,1H),7.10(d,J=8.6 9Hz, 1H), 5.82–5.70 (m, 1H), 3.36 (d, J = 5.59Hz, 4H), 3.14 (t, J = 4.99Hz, 4H), 2.60 (s, 3H), 1.89 (d, J = 6.60Hz, 6H).

[0133] Example 17: Preparation of Compound I-17 of the Present Invention

[0134] Following the synthetic method of I-1 in Example 1, compound I-17 (70 mg, 174 μmol, 58%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12 (175 mg, 0.6 mmol, 2.0 eq.). 1H NMR(400MHz,Methanol-d4)δ9.01(d,J=7.97Hz,2H),8.01(d,J=3.02Hz,1H),7.7 7(d,J=9.01Hz,1H),7.71(d,J=9.00Hz,1H),7.51(dd,J=9.05,2.99Hz,1H),7.28( d,J=9.06Hz,1H),5.62(p,J=6.56Hz,1H),3.69(d,J=12.43Hz,2H),2.86(td,J=1 2.32, 2.43Hz, 2H), 2.19–2.13 (m, 2H), 1.90 (d, J = 6.57Hz, 6H), 1.86–1.80 (m, 2H).

[0135] Example 18: Preparation of Compound I-18 of the Present Invention

[0136] Following the synthetic method of I-1 in Example 1, compound I-18 (57 mg, 147 μmol, 49%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12p (279 mg, 0.6 mmol, 2.0 eq). 1 H NMR(400MHz, Methanol-d4)δ9.11(s,1H),8.99(s,1H),7.90–7.70(m,3H),7.49(d,J=9.77Hz,1H) ,5.71(p,J=6.62Hz,1H),3.81(t,J=5.29Hz,4H),3.35(d,J=3.55Hz,4H),1.90(d,J=6.51Hz,6H).

[0137] Example 19: Preparation of compound I-19 of the present invention

[0138] Following the synthetic method of I-1 in Example 1, compound I-19 (68 mg, 168 μmol, 56%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12q (292 mg, 0.6 mmol, 2.0 eq.). 1H NMR(400MHz, Methanol-d4)δ9.06(d,J=13.86Hz,2H),8.05(d,J=2.95Hz,1H),7.79(d, J=9.03Hz,1H),7.73(d,J=8.94Hz,1H),7.52(dd,J=8.89,2.93Hz,1H),7.31(d,J=9.02 Hz,1H),5.65(p,J=6.64Hz,1H),3.63(t,J=13.49Hz,3H),3.35(s,3H),3.24–3.16(m,2 H), 2.94 (dd, J = 13.38, 10.54Hz, 1H), 2.66 (t, J = 11.35Hz, 1H), 1.92 (d, J = 6.50Hz, 6H).

[0139] Example 20: Preparation of Compound I-20 of the Present Invention

[0140] Following the synthetic method of I-1 in Example 1, compound I-20 (69 mg, 177 μmol, 59%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12r (167 mg, 0.6 mmol, 2.0 eq.). 1 H NMR(400MHz,Chloroform-d)δ9.16(s,1H),8.99(s,1H),8.00(d,J=2.93Hz,1H),7.84(d,J=8.99Hz,1H),7.65(d,J=9.21Hz,2H) ,7.34(dd,J=8.95,2.93Hz,1H),7.03(d,J=9.01Hz,1H),5.58(p,J=6.75Hz,1H),3.13(d,J=7.67Hz,8H),1.95(d,J=6.55Hz,6H).

[0141] Example 21: Preparation of compound I-21 of the present invention

[0142] Following the synthesis method of I-1 in Example 1, compound I-21 (54 mg, 135 μmol, 45%) was prepared from compound 11 (100 mg, 0.3 mmol, 1.0 eq.) and side chain 12S (175 mg, 0.6 mmol, 2.0 eq). 1H NMR(400MHz,Chloroform-d)δ9.33(s,1H),9.03(s,1H),8.31(d,J=2.65Hz,1H),7.88(d,J=8.93Hz,1H),7.84(s,1H),7.68(d,J=8.93Hz,1H),7. 59(dd,J=8.79,2.66Hz,1H),7.04(d,J=8.80Hz,1H),5.57(p,J=6.60Hz,1H),3.77–3.71(m,4H),3.27(t,J=5.43Hz,2H),1.94(d,J=6.56Hz,6H).

[0143] The following experimental examples demonstrate the beneficial effects of the present invention.

[0144] Experimental Example 1: Kinase Activity Test of the Compounds of the Present Invention

[0145] 1. Experimental Methods

[0146] CDK / cyclin catalyzes substrate phosphorylation, which consumes ATP and produces ADP. The inhibition rate (%) in the presence of small molecule inhibitors is assessed by detecting the amount of ADP generated in the reaction. The test compound is vortexed thoroughly and then diluted with DMSO to a concentration 100×100 times higher than the detection concentration. The solution is then pipetted using a nanoliter pipetting system. (SYSTEM) Transfer 40 nL of the compound to a 384 assay plate. Prepare a 2× kinase solution using 1× kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij 35, 2 mM DTT). Transfer 2 μL of the kinase solution to the 384 assay plate, centrifuge at 1000 rpm for 60 seconds using a microplate centrifuge, and incubate at 25°C for 10 minutes. Prepare a 2× substrate and ATP mixture using kinase reaction buffer, add 2 μL of the substrate and ATP mixture to the 384 assay plate, centrifuge at 1000 rpm for 60 seconds using a microplate centrifuge, and incubate at 25°C for 60 minutes. Add 4 μL of ADP-Glo ​​Reagent (product number: V9103, manufacturer: Promega) incubated at 25°C in a biochemical incubator to each well of a 384 detection plate, centrifuge at 1000 rpm for 60 seconds using a microplate centrifuge, and incubate at 25°C in a biochemical incubator for 40 minutes. Add 8 μL of Detection Reagent incubated at 25°C in a biochemical incubator to each well of the 384 detection plate, centrifuge at 1000 rpm for 60 seconds using a microplate centrifuge, and incubate at 25°C in a biochemical incubator for 40 minutes. Finally, read the chemiluminescence signal using a multi-mode microplate reader (model: PHERAstar FSX, manufacturer: BMG). Calculate the IC50 using GraphPad Prism software with a non-linear fitting of the concentration-response curve. 50 value.

[0147] 2. Experimental Results

[0148] The compounds of this invention were tested in a kinase activity assay, and it was found that they exhibited good inhibitory activity against CDK9 / cyclin T1. The results of the enzyme inhibitory activities of the most representative compounds of this invention are shown in Table 2 below.

[0149] Table 2 shows the results of the enzyme inhibitory activities of the compounds.

[0150]

[0151]

[0152] The results above show that the compounds of the present invention have an inhibitory effect on the CDK9 / cyclin C complex. Among them, compounds I-4, I-5, I-8, I-11, I-14, I-15, I-19, and I-21 were found to have CDK9 inhibitory activities that were comparable to or even better than those of the positive control SNS-032.

[0153] In summary, this invention provides a CDK9 inhibitor, its preparation method, and its uses. The compound of this invention is an effective inhibitor of cyclin-dependent kinase 9 (CDK9), exhibiting excellent inhibitory activity against CDK9 / cyclin T1, and has broad application prospects in the preparation of CDK9 inhibitors.

Claims

1. A compound of Formula I: ###0001### Formula I or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof. wherein L is selected from the group consisting of nothing, carbonyl, C 1-4 alkylene; A ring is selected from a phenyl ring, a 3-8 membered heteroaromatic ring, a 3-8 membered saturated cycloalkyl, a 3-8 membered saturated heterocyclyl; m is selected from 0, 1, 2, 3 or 4; R a Each is independently selected from halogen, methanesulfonyl, amino, C 1-6 Alkyl, L1C 1-6 Alkyl group, COR1, NHCOR2, unsubstituted or substituted with one or more R groups a1 Substituted 3-8 membered saturated heterocyclic groups; L1 is selected from none, C 1-4 Alkylene; R1is selected from the group consisting of unsubstituted or substituted 3-8 membered saturated heterocyclyl; a1 substituted 3-8 membered saturated heterocyclyl; R2is selected from C 1-6 alkyl; R a1 each independently selected from carbonyl, C 1-6 alkyl, NR a2 R a3 , 3-6 membered saturated cycloalkyl, R a2 selected from hydrogen, C 1-6 alkyl, R a3 selected from hydrogen, C 1-6 alkyl; R b selected from H, -C(0)R b1 , -C(0)OR b1 , -C(0)NR b2 R b3 , C 1-6 alkyl, C 1-6 alkyl, 3-7 membered saturated cycloalkyl, 3-7 membered saturated heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; R b1 selected from hydrogen, -C 0-6 alkylene-CN, -C 0-6 alkylene-NO2, -C 0-6 alkylene-OR', -C 0-6 alkylene-SR', -C 0-6 alkylene-NR"R"', -C 0-6 alkylene-C(O)R', -C 0-6 alkylene-C(O)OR', -C 0-6 alkylene-C(O)NR"R"', -C 0-6 alkylene-S(O) n R', -C 0-6 alkylene-S(O) n OR', -C 0-6 alkylene-S(O) n NR"R"', C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, -C 0-6 alkylene-C 1-6 alkyl, -C 0-6 alkylene-3-7 membered saturated heterocyclyl, -C 0-6 alkylene-C 6-10 aryl or -C 0-6 alkylene-5-10 membered heteroaryl; R b2 and R b3 are independently selected from the group consisting of hydrogen, -C 0-6 alkylene-CN, -C 0-6 alkylene-NO2, -C 0-6 alkylene-OR', -C 0-6 alkylene-SR', -C 0-6 alkylene-NR"R"', -C 0-6 alkylene-C(O)R', -C 0-6 alkylene-C(O)OR', -C 0-6 alkylene-C(O)NR"R"', -C 0-6 alkylene-S(O) n R', -C 0-6 alkylene-S(O) n OR', -C 0-6 alkylene-S(O) n NR"R"', C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, -C 0-6 alkylene-C 1-6 alkyl, -C 0-6 alkylene-3-7 membered saturated heterocyclyl, -C 0-6 alkylene-C 6-10 aryl, or -C 0-6 alkylene-5-10 membered heteroaryl; or, R b1 and R b2 together with the N atom form a 3-7 membered saturated heterocyclyl; R' is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, 3-7 membered saturated heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; R" and R'" are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, 3-7 membered saturated heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R", R'" and the N atom together form a 3-7 membered saturated heterocyclyl; n represents 0, 1, or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof, characterized in that, L is selected from nothing, a carbonyl group; A ring is selected from a phenyl ring, a 5-6 membered heteroaromatic ring, a 5-6 membered saturated cycloalkyl, a 5-6 membered saturated heterocyclyl; m is selected from 1 or 2; R a each independently selected from the group consisting of halogen, methylsulfonyl, amino, C 1-3 alkyl, L1C 1-3 alkoxy, COR1, NHCOR2, unsubstituted or substituted with one or two or more R a1 substituted 5-6 membered saturated heterocyclyl; L1is selected from the group consisting of nothing, C 1-2 alkylene; R1is selected from the group consisting of unsubstituted or substituted 5-6 membered saturated heterocyclyl; a1 substituted 5-6 membered saturated heterocyclyl; R2is selected from C 1-3 alkyl; R a1 each independently selected from carbonyl, C 1-3 alkyl, NR a2 R a3 , 3-4 membered saturated cycloalkyl, R a2 selected from C 1-3 alkyl, R a3 selected from C 1-3 alkyl; R b selected from C 1-4 alkyl, C1-6alkyl unsubstituted or substituted with one or two or more halogen 1-4 alkyl, 3-6 membered saturated cycloalkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof, wherein, The structure of the compound is shown in Formula II: wherein R3is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, unsubstituted or substituted with one or two or more R a1 substituted 5-6 membered saturated heterocyclyl; R a1 selected from carbonyl, C 1-3 alkyl, 3-4 membered saturated cycloalkyl; R4is selected from hydrogen, halogen, C 1-3 alkyl; R b Selected from C 1-3 Alkyl groups, unsubstituted or C-shaped compounds substituted with one or more halogens 1-3 alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof, wherein, The structure of the compound is shown in Formula III: wherein R3is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, unsubstituted or substituted with one or two or more R a1 substituted 5-6 membered saturated heterocyclyl; R a1 selected from carbonyl, C 1-3 alkyl, 3-4 membered saturated cycloalkyl; R4is selected from hydrogen, halogen, C 1-3 alkyl; Preferably, the structure of the compound is shown in Formula IV: R5 is selected from hydrogen, a carbonyl group; R6is selected from hydrogen, C 1-3 alkyl, 3-membered saturated cycloalkyl; R7is selected from hydrogen, C 1-3 alkyl; R8is selected from hydrogen, C 1-3 alkyl.

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof, wherein, The structure of the compound is shown in Formula VI: R9 is selected from NHCOR2; R2is selected from C 1-3 alkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof, wherein, The compound is selected from one of the following compounds: 。 7. A pharmaceutical composition, characterized by, The pharmaceutical composition is prepared by using the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof as an active ingredient, and adding a pharmaceutically acceptable adjuvant.

8. Use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or an isotopic variant thereof for preparing a CDK inhibitor.

9. Use according to claim 8, characterized in that, The CDK is CDK9.

10. Use according to claim 8 or 9, characterized in that, The CDK inhibitor is a drug for preventing and / or treating acute myeloid leukemia, hepatocellular carcinoma, prostate cancer, hematological malignancies, diffuse large B-cell lymphoma, mantle cell lymphoma.

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