Compound used as CDK7 kinase inhibitor and application thereof

Abstract

The invention relates to a compound used as a CDK7 kinase inhibitor and application thereof, and belongs to the field of medicines. The compound is a compound as shown in a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, polymorphic substance, co-crystal substance, optical isomer, raceme, isotope derivative or prodrug of the compound as shown in the formula (I), and the compound can be used for inhibiting CDK7 kinase activity or preventing and / or treating related diseases caused by abnormal increase of CDK7 kinase activity. The medicine activity is good. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicines, and in particular relates to a compound used as a CDK7 kinase inhibitor and an application thereof. Background Art

[0002] Cyclin dependent kinases (CDKs) are a class of serine / threonine kinases that play a key role in cell cycle regulation and cell transcription. Twenty CDKs have been discovered, divided into two subfamilies: one is cell cycle-related CDKs, including CDK1-7 and 14-18; the other is transcription-related CDKs, including CDK7-13, 19 and 20. CDKs need to form a complex with cell cycle proteins to regulate the cell cycle and other biological functions.

[0003] CDK7 is the most unique member of the CDK family, with dual functions of regulating cell cycle and transcription. On the one hand, CDK7, Cyclin H, and MAT1 form CDK-activated kinase (CAK), which regulates the cell cycle by phosphorylating CDK1, 2, 4, and / or 6. On the other hand, CDK7 can phosphorylate Ser5 and Ser7 sites on the C-terminal domain (CTD) of RNA polymerase II, and can also phosphorylate and activate CDK9, thereby phosphorylating the Ser2 site of CTD. Therefore, CDK7 directly or indirectly participates in regulating the initiation and elongation of intracellular transcription by phosphorylating the CTD domain. The unique dual function of CDK7 makes it play an important role in the occurrence and development of tumors, and it is a potential target for anti-tumor drugs. Studies have confirmed that CDK7 inhibitors can inhibit the dual mechanism of oncogene transcription and cell cycle progression to exert anti-tumor effects, and have shown significant anti-tumor activity in vitro and in vivo against a variety of malignant tumors such as triple-negative breast cancer, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, and acute myeloid leukemia. In addition, preclinical studies have found that CDK7 inhibitors are effective against breast cancer that is resistant to CDK4 / 6 inhibitors. These studies suggest that CDK7 inhibitors have great potential as anti-tumor drugs, especially in the field of tumor diseases with huge clinical needs, such as triple-negative breast cancer, pancreatic cancer, castration-resistant prostate cancer, and colon cancer. Therefore, the development of new CDK7 inhibitors is particularly important.

[0004] Although some CDK7 inhibitors have been reported, CDK7 inhibitors with rapid research progress (such as SY-5609 and CT7001) are still in the early clinical stage, and no CDK7 inhibitor has been approved for clinical treatment. Therefore, there is still an urgent need for more effective small molecule CDK7 inhibitors to enrich the clinical pipeline and solve unmet clinical needs. In view of this, the present invention provides a series of CDK7 inhibitors with novel structures and excellent activity, and is used for the treatment of CDK7-related diseases, including but not limited to tumors. Summary of the invention

[0005] The present invention provides a compound or a pharmaceutical composition thereof used as a CDK7 kinase inhibitor, and further relates to the use of the compound or the pharmaceutical composition thereof in the preparation of a drug, i.e., for inhibiting CDK7 kinase activity or preventing and / or treating diseases related to abnormally elevated CDK7 kinase activity, and has good pharmaceutical activity.

[0006] In the first aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, optical isomer, racemate, isotope derivative and prodrug of the compound represented by formula (I),

[0007]

[0008] in, is a single bond or a double bond;

[0009] A1 and A2 are each independently selected from C, CH, and N;

[0010] Ring B is selected from a substituted or unsubstituted saturated or unsaturated 5-, 6-, 7- or 8-membered carbocyclic ring, or a substituted or unsubstituted saturated or unsaturated 5-, 6-, 7- or 8-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0011] R1 is selected from substituted or unsubstituted C1-C6 alkyl (e.g. substituted or unsubstituted C1 alkyl, substituted or unsubstituted C2 alkyl, substituted or unsubstituted C3 alkyl, substituted or unsubstituted C4 alkyl, substituted or unsubstituted C5 alkyl, substituted or unsubstituted C6 alkyl), substituted or unsubstituted C3-C8 cycloalkyl (e.g. substituted or unsubstituted C3 cycloalkyl, substituted or unsubstituted C4 cycloalkyl, substituted or unsubstituted C5 cycloalkyl, substituted or unsubstituted C6 cycloalkyl, substituted or unsubstituted C7 cycloalkyl, substituted or unsubstituted C8 cycloalkyl), substituted or unsubstituted C6-C 10 Aryl (e.g., substituted or unsubstituted C6 aryl, substituted or unsubstituted C7 aryl, substituted or unsubstituted C8 aryl, substituted or unsubstituted C9 aryl, substituted or unsubstituted C 10substituted or unsubstituted 4-12 membered heterocyclyl (e.g., substituted or unsubstituted 4 membered heterocyclyl, substituted or unsubstituted 5 membered heterocyclyl, substituted or unsubstituted 6 membered heterocyclyl, substituted or unsubstituted 7 membered heterocyclyl, substituted or unsubstituted 8 membered heterocyclyl, substituted or unsubstituted 9 membered heterocyclyl, substituted or unsubstituted 10 membered heterocyclyl, substituted or unsubstituted 11 membered heterocyclyl, substituted or unsubstituted 12 membered heterocyclyl), substituted or unsubstituted 5-9 membered heterobridged cycloalkyl (e.g., substituted or unsubstituted 5 membered heterobridged cycloalkyl, substituted or unsubstituted 6 membered heterobridged cycloalkyl, substituted or unsubstituted 7 membered heterocycloalkyl, substituted or unsubstituted 5-9 membered bridged cycloalkyl (e.g. substituted or unsubstituted 5-membered bridged cycloalkyl, substituted or unsubstituted 6-membered bridged cycloalkyl, substituted or unsubstituted 7-membered bridged cycloalkyl, substituted or unsubstituted 8-membered bridged cycloalkyl, substituted or unsubstituted 9-membered bridged cycloalkyl), substituted or unsubstituted 6-10 membered heterospirocycloalkyl (e.g. substituted or unsubstituted 6-membered heterospirocycloalkyl, substituted or unsubstituted 7-membered heterospirocycloalkyl, substituted or unsubstituted 8-membered heterospirocycloalkyl, substituted or unsubstituted 9-membered substituted or unsubstituted 10-membered heterospirocycloalkyl), substituted or unsubstituted 6-10-membered spirocycloalkyl (e.g. substituted or unsubstituted 6-membered spirocycloalkyl, substituted or unsubstituted 7-membered spirocycloalkyl, substituted or unsubstituted 8-membered spirocycloalkyl, substituted or unsubstituted 9-membered spirocycloalkyl, substituted or unsubstituted 10-membered spirocycloalkyl), substituted or unsubstituted 6-10-membered heterocycloalkyl (e.g. substituted or unsubstituted 6-membered heterocycloalkyl, substituted or unsubstituted 7-membered heterocycloalkyl, substituted or unsubstituted 8-membered heterocycloalkyl, substituted or unsubstituted 9-membered heterocycloalkyl, substituted or unsubstituted substituted or unsubstituted 10-membered heterocycloalkyl), substituted or unsubstituted 6-10-membered cycloalkyl (e.g., substituted or unsubstituted 6-membered cycloalkyl, substituted or unsubstituted 7-membered cycloalkyl, substituted or unsubstituted 8-membered cycloalkyl, substituted or unsubstituted 9-membered cycloalkyl, substituted or unsubstituted 10-membered cycloalkyl), substituted or unsubstituted 5-10-membered heteroaryl (e.g., substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 7-membered heteroaryl, substituted or unsubstituted 8-membered heteroaryl, substituted or unsubstituted 9-membered heteroaryl, substituted or unsubstituted 10-membered heteroaryl);

[0012] X is selected from -(CH2) n1 -、-(CH2) n1 O-, -(CH2) n2 C(R 5a )(R 5b )(CH2) n3 -, -CH=CH-;

[0013] R 5a , R5b are each independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkynyl, or R 5a , R 5b Together with the adjacent carbon atoms, they form a C3-C6 cycloalkyl group.

[0014] n1 is selected from 1, 2, 3, 4 or 5;

[0015] L is selected from NH, N(C1-C6 alkylene).

[0016] In some embodiments, the substituted or unsubstituted 4-12 membered heterocyclic group in R1 contains 1-11 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0017] In some embodiments, the substituted or unsubstituted 5-9 membered heterobridged cycloalkyl in R1 contains 1-8 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0018] In some embodiments, the substituted or unsubstituted 6-10 membered heterospirocycloalkyl in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0019] In some embodiments, the substituted or unsubstituted 6-10 membered heterocycloalkyl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0020] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0021] In some embodiments, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

[0022] In some embodiments, R 5a , R 5b The substitution in the substituted or unsubstituted is that one or more hydrogen atoms are independently replaced by methyl. 5a , R 5b is selected from hydrogen or methyl.

[0023] In some embodiments, n2 and n3 are selected from: n2 is 1, n3 is 0, 1, 2, or 3. In some embodiments, n2 and n3 are selected from: n2 is 2 or 3, n3 is 0 or 1. In some embodiments, n2 and n3 are selected from: n2 is 4, n3 is 0.

[0024] In some embodiments, R1 is selected from:

[0025]

[0026]

[0027]

[0028] wherein p1 is selected from 0, 1, 2 or 3, p2 is selected from 0 or 1, and p3 is selected from 1, 2 or 3;

[0029] R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ;

[0030] R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl;

[0031] R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent to them together constitute a C3-C6 cycloalkyl group.

[0032] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0033] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0034] In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

[0035] In some embodiments,

[0036] Ring B is selected from:

[0037]

[0038] wherein A4 is independently selected from NH, NR6, O, S, CH, CR7;

[0039] A5, A6, A7, A8 or A9 are each independently selected from CR8;

[0040] Rb and Rc are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7,

[0041] Ra is selected from halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7,

[0042] R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring.

[0043] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra, Rb, and Rc contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0044] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl group in Ra, Rb, and Rc contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0045] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0046] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0047] In some embodiments,

[0048] Ring B is selected from:

[0049]

[0050] wherein A3 is selected from NH, NR6, O, S, CH, CR7;

[0051] Ra and Rb are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, And Ra and Rb are not hydrogen at the same time;

[0052] R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring.

[0053] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra and Rb contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0054] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl group in Ra and Rb contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0055] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0056] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0057] In some embodiments, X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -(CH2)4-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CF2CH2-, -CH=CH-,

[0058] In some embodiments, X is selected from -CH2CH2-, -CH2CH2CH2-, -C(CH3)2CH2-.

[0059] In some embodiments, L is -NH-.

[0060] In some embodiments, the compound represented by formula (I) is selected from the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or the compound represented by formula (V),

[0061]

[0062] wherein Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-;

[0063] R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ;

[0064] R 2a, R 2b Each is independently selected from hydrogen or C1-C6 alkyl;

[0065] R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent thereto together form a C3-C6 cycloalkyl group;

[0066] A4 is selected from NH, NR6, O, S, CH, CR7;

[0067] A5, A6, A7, A8 or A9 are each independently selected from CR8;

[0068] Rb and Rc are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7,

[0069] Ra is selected from halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7,

[0070] R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11'、R 12 , R 12 'are each independently selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring.

[0071] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0072] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0073] In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

[0074] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra, Rb, and Rc contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0075] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl group in Ra, Rb, and Rc contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0076] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0077] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0078] In some embodiments, the compound represented by formula (I) is selected from the compound represented by formula (VI) or the compound represented by formula (VII),

[0079]

[0080] wherein Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-;

[0081] R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ;

[0082] R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl;

[0083] R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent thereto together form a C3-C6 cycloalkyl group;

[0084] A3 is selected from NH, NR6, O, S, CH, CR7;

[0085] Ra and Rb are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, And Ra and Rb are not hydrogen at the same time;

[0086] R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring.

[0087] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0088] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0089] In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

[0090] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra and Rb contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0091] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl group in Ra and Rb contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0092] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0093] In some embodiments, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0094] In some embodiments, the compound represented by formula (I) is selected from the compound represented by formula (VIII) or the compound represented by formula (IX),

[0095]

[0096] wherein Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-;

[0097] p1 is selected from 0, 1, 2 or 3;

[0098] A4 is selected from NH, NR6, O, S, CH, CR7;

[0099] A5 is selected from CR8;

[0100] R6, R7, and R8 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring.

[0101] In some embodiments, the 5-10 membered heteroaryl group in R6, R7, and R8 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0102] In some embodiments, the 3-8 membered heterocycloalkyl group in R6, R7, and R8 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0103] In some embodiments, the compound represented by formula (I) is selected from the compound represented by formula (X), the compound represented by formula (XI), the compound represented by formula (XII), the compound represented by formula (XIII) or the compound represented by formula (XIV),

[0104]

[0105]

[0106] wherein Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-;

[0107] Ra and Rb are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted 5-10 membered heteroaryl, -C(=O)-R 13 ; R7, R9, R9', R 12 , R 12 ' are each independently selected from C1-C6 alkyl, R 13 Selected from C1-C6 alkylamino groups,

[0108] Rd is selected from C1-C6 alkyl,

[0109] Ra and Rb are not hydrogen at the same time, or, when Rb is absent, Ra is not hydrogen;

[0110] R1 is selected from:

[0111]

[0112]

[0113]

[0114] wherein p1 is selected from 0, 1, 2 or 3, p2 is selected from 0 or 1, and p3 is selected from 1, 2 or 3;

[0115] R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ; R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent to them together constitute a C3-C6 cycloalkyl.

[0116] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra and Rb contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0117] In some embodiments, the substitution in the substituted or unsubstituted in Ra and Rb is that one or more hydrogen atoms are independently replaced by C1-C6 alkyl. In some embodiments, the substitution in the substituted or unsubstituted in Ra and Rb is that one or more hydrogen atoms are independently replaced by methyl.

[0118] In some embodiments, R7, R9, R9', R 12 , R 12 ' are each independently methyl.

[0119] In some embodiments, R 13 It is a methylamino group.

[0120] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0121] In some embodiments, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0122] In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3 membered cycloalkyl). In some embodiments, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

[0123] In some embodiments, R1 is selected from a substituted or unsubstituted 4-12 membered heterocyclyl, a substituted or unsubstituted 5-10 membered heteroaryl, and a substituted or unsubstituted C1-C6 hydroxyalkyl.

[0124] In some embodiments, the substituted or unsubstituted 4-12 membered heterocyclic group in R1 contains 1-11 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0125] In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0126] In some embodiments, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by C1-C6 alkyl. In some embodiments, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by methyl.

[0127] In some embodiments, R1 is selected from 2,2-dimethylpiperidinyl, piperidinyl, C3-C5 hydroxyalkyl. In some embodiments, R1 is selected from 2,2-dimethylpiperidin-5-yl, piperidin-3-yl, 2-hydroxy-1-methylethyl, 3-hydroxy-1-methylpropyl, 3-hydroxy-3-methylbutyl.

[0128] In some embodiments, Ring B is selected from:

[0129]

[0130] Wherein, Ra is selected from hydrogen, methyl, cyano, methylaminocarbonyl, 3,5-dimethylisoxazol-4-yl, methylsulfonyl, dimethylphosphonyl, N-methyl-N-methylsulfonylamino, Rb is selected from hydrogen, methyl, cyano, fluorine, Rd is selected from methyl, Ra and Rb are not hydrogen at the same time, or, when Rb is not present, Ra is not hydrogen.

[0131] In some embodiments, the compound is a compound represented by formula (XV) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, optical isomer, racemate, isotope derivative or prodrug thereof of the compound represented by formula (XV).

[0132]

[0133] wherein R1 is selected from 2,2-dimethylpiperidin-5-yl, piperidin-3-yl, 2-hydroxy-1-methylethyl, 3-hydroxy-1-methylpropyl, 3-hydroxy-3-methylbutyl;

[0134] Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-;

[0135] Ring B is selected from

[0136] Ra is selected from hydrogen, methyl, cyano, methylaminocarbonyl, 3,5-dimethylisoxazol-4-yl, methanesulfonyl, dimethylphosphonyl, N-methyl-N-methylsulfonylamino, Rb is selected from hydrogen, methyl, cyano, fluorine, Rd is selected from methyl, Ra and Rb are not hydrogen at the same time, or, when Rb is not present, Ra is not hydrogen.

[0137] In some embodiments, the compound comprises one of the following compounds:

[0138]

[0139]

[0140]

[0141] In a second aspect, the present invention relates to a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.

[0142] In a third aspect, use of the compound described in the first aspect or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a drug, wherein the drug is used to inhibit CDK7 kinase activity or prevent and / or treat diseases related to abnormally elevated CDK7 kinase activity.

[0143] In some embodiments, in the use described in the present invention, the disease related to abnormally elevated CDK7 kinase activity is selected from one or more of cancer, inflammation, cardiovascular disease, infectious disease, immune disease, and metabolic disease.

[0144] In some embodiments, the use described in the present invention, wherein the cancer is selected from one or more of breast cancer, ovarian cancer, colorectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, pancreatic cancer, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.

[0145] In some embodiments, the use described in the present invention, wherein the cancer is selected from one or both of estrogen receptor (ER)-positive breast cancer and triple-negative breast cancer.

[0146] In some embodiments, the use described in the present invention, wherein the prostate cancer is castration-resistant prostate cancer.

[0147] Beneficial Effects

[0148] Compared with the prior art, the present invention has at least one of the following technical effects:

[0149] (1) The compounds provided by the present invention have excellent CDK7 kinase inhibitory activity and can be used to inhibit CDK7 kinase activity or prevent and / or treat diseases related to abnormally elevated CDK7 kinase activity.

[0150] (2) The compounds provided by the present invention have excellent anti-tumor activity, especially excellent inhibitory activity against the proliferation of human colorectal cancer and human chronic myeloid leukemia cells.

[0151] Definition of terms

[0152] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

[0153] "Compounds of the present invention" means compounds of formula I or pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates thereof. Similarly, the phrase "compounds of formula I" means compounds of the formula and pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates thereof.

[0154] In the present invention, expressions such as "compound I" and "compound represented by formula I" refer to the same compound.

[0155] "V / V" means volume ratio. IC50 means half inhibitory concentration.

[0156] "wt%" means percent by mass.

[0157] The terms "plurality" or "several" mean at least 2, for example 2, 3, 4 or 5, etc.

[0158] In the present invention, the meanings of the atoms in the compound structure are as follows: F represents fluorine, Cl represents chlorine, and D represents deuterium.

[0159] The term "and / or" should be understood to mean any one of the optional items or a combination of any two or more of the optional items.

[0160] The term "optional", "optional" or "optionally" means that the event or situation described later may but does not necessarily occur. For example, "optionally, the heteroatom in the heterocycle includes at least one selected from nitrogen, oxygen, and sulfur" means that the situation of "the heteroatom in the heterocycle includes at least one selected from nitrogen, oxygen, and sulfur" may exist or not exist.

[0161] In the present invention, "room temperature" refers to ambient temperature, which is from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C; in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0162] "Alkyl" is a hydrocarbon containing positive carbon atoms, secondary carbon atoms, tertiary carbon atoms, or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to -8 carbon atoms (i.e., C1-C8 alkyl) or 1 to -6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH (CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 or octyl (-(CH2)7CH3).

[0163] The term "alkylene" means a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group contains 1-3 carbon atoms; in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like. The alkylene group is optionally substituted with one or more substituents described herein.

[0164] The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Bicyclic or tricyclic ring systems may include fused rings, bridged rings and spirocyclic rings. Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In one embodiment, the carbocyclyl contains 3-10 carbon atoms, such as C 3- C 10 In another embodiment, the carbocyclic group contains 3-8 carbon atoms, such as C 3- C8 carbocyclyl; In another embodiment, the carbocyclyl contains 3-6 carbon atoms, such as C 3- In another embodiment, the monocyclic carbocyclic group contains 4-8 carbon atoms, such as C 4- C8 monocyclic carbocyclic group; In another embodiment, the monocyclic carbocyclic group contains 4-6 carbon atoms, such as C 4-C6 monocyclic carbocyclic radical.The example of carbocyclic radical group further comprises, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.Described carbocyclic radical group is optionally substituted by one or more substituents described in the present invention. The example of carbocyclyl group further includes, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.When the structure clearly needs a linking group, the Markush variable listed for the group should be understood as a linking group.For example, if the structure needs a linking group and the Markush group definition for the variable lists "carbocyclyl", it should be understood that the subcarbocyclyl group connected by the "carbocyclyl" representative.

[0165] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. The bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. In one embodiment, the cycloalkyl contains 3 to 10 carbon atoms, such as C 3- C 10 In another embodiment, the cycloalkyl group contains 3-8 carbon atoms, such as C 3- C8 cycloalkyl; In another embodiment, the cycloalkyl contains 3-6 carbon atoms, such as C 3- C6 cycloalkyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0166] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0167] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0168] An "alkenyl group" is a group containing at least one unsaturated site, i.e., a carbon-carbon sp 2 For example, an alkenyl group can have 2 to 10 carbon atoms (C2-C 10 alkenyl), 2 to 12 carbon atoms (C2-C 12 The alkenyl group may be optionally substituted with one or more substituents as described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7) 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0169] "Alkynyl" is a hydrocarbon containing a positive carbon atom, a secondary carbon atom, a tertiary carbon atom or a ring carbon atom having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. The alkynyl group may be optionally substituted with one or more substituents described herein. For example, an alkynyl group may have 2 to 10 carbon atoms (C2-C 10 Alkynyl), 2 to 12 carbon atoms (C2-C 12 Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C=CH), propargyl (-CH2C=CH), or the like.

[0170] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbon ring system containing 6-20 ring atoms, or 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups can include groups derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. The aryl group is optionally substituted by one or more substituents described herein.

[0171] "Arylalkyl" refers to a radical in which the 3 The term "arylalkyl" refers to an alkyl radical having a carbon atom (carbon atom) and a cycloalkyl radical having a carbon atom (carbon atom). The term "arylalkyl" refers to an alkyl radical having a carbon atom (carbon atom) and a cycloalkyl radical having a carbon atom (carbon atom). Typical arylalkyl includes, but is not limited to, benzyl, 2-phenyl second-1-yl, naphthylmethyl, 2-naphthyl second-1-yl, naphthobenzyl, 2-naphthophenyl second-1-yl and analogue. Arylalkyl can comprise 7 to 20 carbon atoms, for example, alkyl moiety is 1 to 6 carbon atom, and aryl moiety is 6 to 14 carbon atoms.

[0172] The term "substituted" refers to alkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, "substituted C1-C 10 Alkyl", "substituted C6-C 20 Aryl", "substituted arylalkyl", "substituted C1-C 20 "Heterocycle" and "substituted carbocyclyl" refer to C1-C2-1, C1-C3-1, C1-C4-1, C1-C6-1, C1-C7-1, C1-C8-1, C1-C9-1, C1-C1 ... 10 Alkyl, C6-C 20 Aryl, Arylalkyl, C1-C 20 Heterocycle, alkylamino, carbocyclyl. Unless otherwise indicated, when the term "substituted" is used in conjunction with a group having two or more moieties capable of substitution, such as arylalkyl, the substituents may be attached to the aryl portion, the alkyl portion, or both.

[0173] The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is independently substituted with one or two alkyl groups, wherein the alkyl group has the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like. The alkylamino group is optionally substituted with one or more substituents as described herein.

[0174] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; such examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl and the like.

[0175] The term "jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k, and any natural number between the two. For example, "3-8 atoms" or "3-8-membered", "3-6 atoms" or "3-6-membered", "5-10 atoms" or "5-10-membered", "5-6 atoms" or "5-6-membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For another example, piperidinyl is a 6-atom heterocyclic group or a 6-membered heterocyclic group, and pyridinyl is a 6-atom heteroaryl group or a 6-membered heteroaryl group.

[0176] The term "jk pieces", "jk yuan" or "C j -C k " wherein j and k are independently any non-zero natural numbers, and k>j; for example, "1-4" means 1, 2, 3 or 4, "4-6 yuan" means 4 yuan, 5 yuan or 6 yuan; "C3-C6" means C3, C4, C5 or C6. And so on.

[0177] The terms "(alkoxy)-alkylene", "(alkylamino)-alkylene", "(cycloalkyl)-alkylene", "(heterocyclyl)-alkylene", "(aryl)-alkylene", "(heteroaryl)-alkylene" mean that the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently connected to the rest of the molecule through an alkylene, wherein the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene have the meanings described in the present invention. For example, examples of (cycloalkyl)-alkylene include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, etc. For another example, examples of (aryl)-alkylene include, but are not limited to, phenylmethylene, phenylethylidene, phenylpropylene, etc. The (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclyl)-alkylene, (aryl)-alkylene, (heteroaryl)-alkylene are each independently optionally substituted with one or more substituents described herein.

[0178] The term "prodrug" refers to any compound that, when administered to a biological system, produces a drug, i.e., an active ingredient, due to spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.

[0179] "Heterocycle" or "heterocyclic radical" include, by way of example and without limitation, those described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28 and J. Am. Chem. Soc. (1960) 82:5566. In a particular embodiment of the invention, "heterocycle" includes "carbocycles" as defined herein, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N or S). The term "heterocycle" or "heterocyclic radical" includes saturated rings, partially unsaturated rings and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyl groups include, for example, heterocycles substituted with any of the substituents disclosed herein including carbonyl.

[0180] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-8 ring atoms (1-7 carbon atoms and 1-4 heteroatoms selected from N, O, P or S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2); in another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-6 ring atoms (1-5 carbon atoms and 1-4 heteroatoms selected from N, O, P or S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7-12 ring atoms (1-11 carbon atoms and 1-4 heteroatoms selected from N, O, P or S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2). The heterocyclyl groups are optionally substituted by one or more substituents described herein.

[0181] The ring atoms of the heterocyclic group can be carbon groups or heteroatom groups. In which the -CH2- group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group is optionally substituted by one or more substituents described herein.

[0182] Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthyl, indolyl, indolene, quinolyl, isoquinolyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenolic flavinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl pyridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatoacyl, and bis-tetrahydrofuranyl.

[0183] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring consisting of 5-7 atoms. The heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted by one or more substituents described in the present invention. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all those aromatic rings listed in the definition of "heterocyclyl", including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazolyl, etc. In one embodiment, the heteroaryl group consisting of 5-10 ring atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S or N.

[0184] Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0185] "Prodrug moiety" refers to an unstable functional group that is separated from an active inhibitory compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, 113-191 pages). Prodrug moieties can be used to enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy.

[0186] The prodrug moiety may include an active metabolite or the drug itself.

[0187] The compound shown in Formula I or its pharmaceutically acceptable salt can exist as different polymorphs or pseudopolymorphs. Crystal polymorphism used herein refers to the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can be derived from differences in crystal packing (stacking polymorphism) or packing differences between different conformers of the same molecule (conformational polymorphism). Crystal pseudopolymorphism used herein refers to the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention can exist due to differences in crystal packing (stacking pseudopolymorphism) or due to packing differences between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of Formula I-III compounds and their pharmaceutically acceptable salts.

[0188] The compound shown in formula I or its pharmaceutically acceptable salt can also exist as an amorphous solid. Amorphous solids used herein are such solids, wherein there is no long-range order in the positions of the atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives including solvents can be used to establish the amorphous form of the present invention. The present invention includes all amorphous forms of compounds of formula I-III and their pharmaceutically acceptable salts.

[0189] The term "treat", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing the condition or disorder, or one or more symptoms of such condition or disorder, to which the term applies. The term "treat", as used herein, refers to the act of treating, as "treating" is defined immediately above.

[0190] The compounds described herein also include reference to their physiologically acceptable salts, examples of which include salts derived from suitable bases, such as alkali metals or alkaline earth metals (e.g., Na + , Li + , K + , Ca +2 and Mg +2 ), ammonium and NR4 +(wherein R is as defined herein). Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene, and the like. (c) salts with elemental anions, such as chlorine, bromine and iodine. Physiologically acceptable salts of hydroxy compounds include salts of the anions of the compounds with hydroxy groups, such as sodium + and NR4 + A combination of appropriate cations.

[0191] For therapeutic use, the salts of the active ingredients of the compounds of the invention are physiologically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts that are not physiologically acceptable acids or bases may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the present invention.

[0192] The compounds described in formula I may have chiral centers, such as chiral carbons. The compounds described in formula I therefore include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds described in the present invention include optical isomers enriched or separated at any or all asymmetric chiral atoms. In other words, chiral centers similar to the description are provided in the form of chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures, as well as separate or synthesized, substantially free of their enantiomers or diastereomeric partners, are within the scope of the present invention. Racemic mixtures are separated into their separate, substantially optically pure isomers by known techniques, such as separation of diastereomeric salts formed with optically active auxiliary agents (such as acids or bases), which are then converted back to optically active substances. In most cases, starting from the appropriate stereoisomers of the desired raw materials, the desired optical isomers are synthesized by stereospecific reactions.

[0193] Whenever a compound described herein is represented by more than one of the same designated group (e.g., "R" or "R 1”), it is to be understood that these groups may be the same or different, i.e., each group is independently selected.

[0194] Pharmaceutical preparations

[0195] The compounds of the present invention are formulated with conventional carriers and excipients, which will be selected in accordance with conventional practice. Although the active ingredients can be administered alone, it is preferred that they are formulated into pharmaceutical preparations. The preparations of the present invention, whether for veterinary or human use, contain at least one active ingredient as defined above and one or more acceptable carriers therefor, and optionally contain other therapeutic ingredients, especially those additional therapeutic ingredients as disclosed herein. The carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is physiologically harmless to its recipient.

[0196] Preparations include those suitable for the above-mentioned routes of administration. Preparations can be conveniently prepared into unit dosage forms, and can be prepared by any method well-known in the pharmaceutical field. Technology and preparations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA.). Such methods include the step of mixing the active ingredient with a carrier constituting one or more auxiliary components. In general, the preparation is prepared as follows: by uniformly and closely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, the product is shaped.

[0197] The invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0198] Veterinary carriers are substances useful for the purpose of the veterinary composition and may be solid, liquid or gaseous substances which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0199] Route of Administration:

[0200] One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual) and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. It should be understood that the preferred route may vary, for example, depending on the condition of the recipient. DETAILED DESCRIPTION

[0201] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0202] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0203] In the present invention, nM means nanomole per liter, μM means micromole per liter, mmol means millimole, equiv means equivalent, and EA means ethyl acetate.

[0204] Example 1: Preparation of Compound 1

[0205] Step 1-1:

[0206]

[0207] Methyl acetoacetate (5 g, 43.1 mmol) was dissolved in glacial acetic acid (6 mL), cooled to -10 °C, and a cold aqueous solution (6 mL) of sodium nitrite (3.4 g, 50 mmol) was added dropwise, and then warmed to room temperature. After three hours, a saturated sodium bicarbonate solution was added to make it alkaline. Ethyl acetate was added for extraction (10 mL × 3), and the organic phases were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography to obtain methyl 2-(hydroxyimino)-3-oxobutanoate (light yellow oily liquid, 5 g, 34.48 mmol, yield: 80%).

[0208] Characterization data of methyl 2-(hydroxyimino)-3-oxobutanoate:

[0209] 1 H NMR (400MHz, Chloroform-d) δ10.02(s,1H),3.90(s,3H),2.40(s,3H).

[0210] 13 C NMR (101MHz, CDCl3) δ193.69,161.99,151.05,52.80,25.36.

[0211] Step 1-2:

[0212]

[0213] Dissolve 2-(hydroxyimino)-3-oxobutyric acid methyl ester (725 mg, 5 mmol) and 1,3-cycloheptanedione (630 mg, 5 mmol) in glacial acetic acid (10 mL), add sodium acetate (1.23 g, 15 mmol) and heat to 90 ° C. Slowly add activated zinc powder (815 mg, 12.5 mmol), reflux for 4 hours and filter while hot. Add water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash the combined organic phases with saturated sodium chloride and dry with anhydrous sodium sulfate. After concentration, the residue is purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 5: 1) to obtain 3-methyl-4-oxo-1,4,5,6,7,8-hexahydrocycloheptane [b] pyrrole-2-carboxylic acid methyl ester (light yellow solid, 800 mg, 3.62 mmol, yield: 72.4%).

[0214] Characterization data of 3-methyl-4-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylic acid methyl ester:

[0215] 1 H NMR (400MHz, Chloroform-d) δ9.34(s,1H),3.86(s,3H),2.92(dd,J=7.0,5.0Hz,2H),2.67(dd,J=7.1,4.7Hz,2H),2.56(s,3H),1.94-1.85(m,4H).

[0216] 13 C NMR (101MHz, CDCl3) δ198.87,162.47,142.92,131.09,123.25,118.34,51.48,42.94,26.99,24.38,21.98,11.88.

[0217] Steps 1-3:

[0218]

[0219] Dissolve 3-methyl-4-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylic acid methyl ester (210 mg, 0.95 mmol) in anhydrous tetrahydrofuran (8 mL), cool to 0°C and add a tetrahydrofuran solution of potassium tert-butoxide (1 M, 1.42 mL, 1.42 mmol) dropwise. After 30 minutes, add 2-(trimethylsilyl)ethoxymethyl chloride (340 μL, 1.9 mmol) dropwise and stir at room temperature for 12 h. After TLC detection, add saturated ammonium chloride solution (20 mL) dropwise at 0°C to quench the reaction, remove tetrahydrofuran from the solution by rotary evaporator, add ethyl acetate for extraction (20 mL×3), combine the organic phases, wash the combined organic phases with saturated sodium chloride and dry them with anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 10:1) to give 3-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylic acid methyl ester (light yellow solid, 330 mg, 0.94 mmol, yield: 99%).

[0220] Characterization data of 3-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylic acid methyl ester:

[0221] 1 H NMR(400MHz,Chloroform-d)δ5.76(s,2H),3.85(s,3H),3.52(t,J=8.1Hz,2H),2.96(t,J=7.1,5.1Hz, 2H), 2.67(t,J=7.1,5.4Hz,2H),2.51(s,3H),1.94-1.83(m,4H),0.87(t,J=8.3Hz,2H),-0.03(s,9H).

[0222] Steps 1-4:

[0223]

[0224] 3-Methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6,7,8-hexahydrocycloheptyl[b]pyrrole-2-carboxylic acid methyl ester (350 mg, 1 mmol) was dissolved in anhydrous toluene (10 mL), and ethyl formate (400 μL, 5 mmol) and sodium hydride (60%, 120 mg, 3 mmol) were added in sequence at 0°C. After the reaction was completed as monitored by TLC, a saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and ethyl acetate was added for extraction (20 mL×3), and the organic phases were combined, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removing the solvent by rotary evaporator, the crude product of ethyl 5-(hydroxymethylene)-3-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylate was directly used in the next reaction.

[0225] The crude product of 5-(hydroxymethylene)-3-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6,7,8-hexahydrocycloheptyl[b]pyrrole-2-carboxylic acid ethyl ester obtained in the previous step was dissolved in anhydrous ethanol (10 mL), and morpholine (870 μL, 10 mmol) was added, and the mixture was refluxed at 90° C. for 1 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, and crude product of (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (5 mmol) and sodium methoxide (270 mg, 5 mmol) were added in sequence, and the mixture was refluxed at 90° C. for 16 hours. After the reaction was completed as monitored by mass spectrometry, the solvent was removed by rotary evaporator, and water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After spin drying, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 3:1) to give (S)-2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid ethyl ester (light yellow oily liquid, 295 mg, 0.493 mmol, 2-step yield: 49.3%).

[0226] (S)-2-((1-(tert-Butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid ethyl ester Characterization data: MS (ESI): [M+H] + =600;

[0227] Steps 1-5:

[0228]

[0229] To (S)-2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrrolo[2',3':6,7]cycloheptane[1,2-d]pyrimidine-9-carboxylic acid ethyl ester (60 mg, 0.1 mmol) was added 4 mol / L hydrochloric acid-1,4-dioxane solution (3 mL), and the mixture was heated at 60° C. for 12 h to react. The solvent was removed by a rotary evaporator to obtain a crude product of (S)-10-methyl-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptane[1,2-d]pyrimidine-9-carboxylic acid ethyl ester.

[0230] Aqueous methylamine solution (25 wt% to 30 wt%, 3 mL) was added to the crude (S)-10-methyl-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid ethyl ester obtained in the previous step, and the mixture was heated in a microwave oven at 95°C for 12 h. After the reaction was complete as monitored by mass spectrometry, the solvent was removed by rotary evaporation, and the residue was purified by preparative HPLC to obtain compound 1.

[0231] Characterization data of compound 1:

[0232] MS(ESI):[M+H] + =355;

[0233] 1 H NMR(400MHz, Methanol-d4)δ7.96(s,1H),4.50-4.40(m,1H),3.57-3.52(m,1H),3.38-3.31(m,1H),3.17-3.10(m,2H),3.0 1(t,J=7.1Hz,2H),2.91(s,3H),2.70-2.63(m,2H),2.60(s,3H),2.26-2.18(m,1H),2.17-2.00(m,3H),1.91-1.75(m,2H).

[0234] Example 2: Biological Activity Test

[0235] (1) CDK7 kinase inhibitory activity assay

[0236] Diluent: It consists of an aqueous solution containing 24 mM MES (pH 6.75), 0.012% Tween 20, 0.06 mg / mL BSA and 7.2 mM MgCl2.

[0237] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein the blank control group was added with 2 μL of diluent, the test group was added with 2 μL of diluted test compound, and the positive control group was added with 2 μL of diluted staurosporine, and then all groups were added with 5 μL of CDK7 / Cyclin H / MAT1 enzyme solution (Promega Company), incubated for 30 minutes, and 5 μL of CDK7tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 minutes, and 4 μL of 150mM ethylenediaminetetraacetic acid solution was added to terminate the reaction, and the plate was read on the EZ readerII instrument. IC50 was calculated by GraphPadPrism 8 software, and the results are shown in Table 1.

[0238] Table 1: IC50 values ​​(nM) of compounds inhibiting CDK7 kinase

[0239]

[0240] Conclusion: Compound 1 has excellent CDK7 kinase inhibitory activity.

[0241] (2) Cell proliferation inhibitory activity

[0242] The following experiment is used to determine the inhibitory activity of the compounds of the present invention on tumor cell proliferation under in vitro conditions. The inhibitory activity of the compounds can be expressed by IC50 values.

[0243] The experimental scheme is briefly described as follows: tumor cells are suspended in a medium containing 10% FBS at an appropriate cell density (such as 15,000-50,000 cells / mL culture medium), then inoculated on a 96-well plate, and cultured in a cell culture incubator at 37°C and 5% carbon dioxide for 12 hours. A blank control group and a test group are set up respectively. The test compound is first dissolved with DMSO, then diluted with a medium without FBS to the concentration required for the experiment (generally 9 concentration points are set for each compound), and added to a 96-well plate as a test group. The blank control group is added to a 96-well plate with an equal volume of culture medium without the test compound, and cultured for 72 hours at 37°C and 5% carbon dioxide. Thereafter, the inhibitory activity of the compound on cell proliferation is determined by the CCK8 method. The IC50 value of the compound can be obtained by numerically calculating the inhibitory value of the compound on cell proliferation at different concentrations, and the IC50 value is calculated using GraphPadprism 8 software. Human colorectal cancer cells HCT116 and human chronic myeloid leukemia cells K562 were respectively tested according to the above operation, wherein the culture medium in the test of human colorectal cancer cells HCT116 was DMEM culture medium; the culture medium in the test of human chronic myeloid leukemia cells K562 was IMDM culture medium. The results are shown in Table 2.

[0244] Table 2: IC50 values ​​of compounds for inhibiting tumor cell proliferation (μM)

[0245]

[0246] Conclusion: Compound 1 exhibits excellent tumor cell proliferation inhibitory activity against human colorectal cancer cells HCT116 and human chronic myeloid leukemia cells K562, respectively.

[0247] Example 3: Preparation of Compounds 16 to 21

[0248] Compounds 16 to 21 were prepared by the preparation method of Reference Example 1:

[0249] 3.1 The difference between the preparations of Compound 16 to Compound 19 is that Steps 1 to 5 in Example 1 are replaced by the following synthetic strategy.

[0250]

[0251] Step 3-1: Dissolve (S)-2-((1-(tert-butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid ethyl ester (1 mmol) in a mixed solution of tetrahydrofuran, ethanol and water (10 mL, V / V / V=4 / 2 / 1). After adding lithium hydroxide monohydrate (20 mmol), seal the tube and heat at 85°C for about 16 hours until the reaction is complete as monitored by TLC and LC-MS. Cool the reaction to room temperature and add 10 mL of water to the sealed tube bottle. Then adjust the pH value of the reaction solution to about 3 with 1M hydrochloric acid aqueous solution. After extracting three times with ethyl acetate, combine the organic phases and wash once with saturated brine, and then dry the organic phase over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain (S)-2-((1-(tert-butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid, which was used directly in the next step without further purification. MS (ESI): [M+H] + =600;

[0252] Step 3-2: The (S)-2-((1-(tert-butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid (0.088 mmol) obtained in step 3-1 was dissolved in anhydrous N,N-dimethylformamide (1 mL), and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 105 mmol) and N,N-diisopropylethylamine (DIPEA, 0.42 mmol) were added in sequence. After ten minutes of reaction at room temperature, different amine solutions were added according to the different synthesized compounds (dimethylamine hydrochloride (0.126mmol) was added to prepare compound 16, ammonium chloride (0.126mmol) was added to prepare compound 17, cyclopropylamine (0.126mmol) was added to prepare compound 18, and 3-oxetane hydrochloride (0.126mmol) was added to prepare compound 19). After about 12 hours of reaction at room temperature, the reaction was complete as monitored by TLC and LC-MS. After adding ethyl acetate (10mL) to dilute the reaction solution, the organic phase was washed three times with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by a rotary evaporator, and the crude product was directly used in the next step without further purification;

[0253] Step 3-3: Add the crude product obtained in step 3-2 above to a dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 20 minutes, remove the solvent using a rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and dropwise add ethylenediamine (400 μL). React at room temperature until complete conversion is monitored by mass spectrometry. Remove the solvent using a rotary evaporator, and purify the residue by preparative HPLC to obtain the target compound (the corresponding compounds 16-19 are obtained according to the different amine solutions added in step 2).

[0254] The structures and characterization data of the obtained compounds 16-19 are as follows:

[0255]

[0256] Compound 16: 1 H NMR (500MHz, Methanol-d4) δ7.96 (s, 1H), 4.47 (s, 1H), 3.58 (dd, J = 12.5, 4.1Hz, 1H), 3. 37(d,J=4.2Hz,1H),3.18-3.15(m,1H),3.12(s,6H),3.10-3.06(m,3H),2.73(td,J=8.4 ,3.0Hz,2H),2.43(s,3H),2.24(dd,J=13.4,4.6Hz,1H),2.12(ddd,J=14.1,6.5,4.1Hz, 2H),2.08-2.03(m,1H),1.89(ddt,J=14.5,7.4,3.7Hz,1H),1.83-1.76(m,1H).MS(ESI):

[0257] [M+H] + =369;

[0258]

[0259] Compound 17: 1 H NMR(500MHz, Methanol-d4)δ8.02(s,1H),4.48-4.40(m,1H),3.58(dd,J=12.4,4.0Hz,1H),3.37-3.35(m,1H),3.17-3.12(m,1H),3.11-3.06(m,1H),3. 04-3.00(m,2H),2.69(dd,J=7.6,4.2Hz,2H),2.67(s,3H),2.27-2.21(m,1H ),2.17-2.07(m,3H),1.93-1.86(m,1H),1.84-1.77(m,1H).MS(ESI):[M+H]+ = 341;

[0260]

[0261] Compound 18: 1 H NMR(500MHz, Methanol-d4) δ8.00(s, 1H), 4.44(s, 1H), 3.58(dd, J = 12.5, 4.1Hz, 1H), 3.37(d, J = 4.2Hz, 1H), 3.16 - 3.06(m, 2H), 3.01(t, J = 7.1Hz, 2H), 2.84(tt, J = 7.3, 3.9Hz, 1H), 2.72 - 2.65(m, 2H), 2.63(s, 3H), 2.27 - 2.20(m, 1H), 2.11(dddp, J = 18.1, 10.9, 6.9, 3.7Hz, 3H), 1.93 - 1.85(m, 1H), 1.81(ddd, J = 13.5, 9.9, 3.3Hz, 1H), 0.84(td, J = 7.1, 4.9Hz, 2H), 0.63(dt, J = 7.1, 4.7Hz, 2H). MS(ESI): [M + H] + = 381;

[0262]

[0263] Compound 19: 1 H NMR(500MHz, Methanol-d4) δ8.17(s, 1H), 5.08(td, J = 9.5, 3.6Hz, 1H), 4.97(ddd, J = 9.0, 6.0, 4.3Hz, 1H), 4.68 - 4.63(m, 1H), 4.39(s, 1H), 3.90(ddt, J = 12.0, 2.8, 1.3Hz, 1H), 3.77(dd, J = 12.1, 3.3Hz, 1H), 3.57(dd, J = 12.4, 4.0Hz, 1H), 3.37(d, J = 4.1Hz, 1H), 3.16 - 3.07(m, 2H), 3.06 - 3.00(m, 2H), 2.73(d, J = 1.1Hz, 3H), 2.65(tt, J = 8.3, 4.0Hz, 2H), 2.19(dqd, J = 14.6, 7.5, 6.4, 4.2Hz, 3H), 2.12(dt, J = 13.7, 4.6Hz, 1H), 1.95 - 1.86(m, 1H), 1.80(tdd, J = 13.2, 8.6, 5.1Hz, 1H). MS(ESI): [M + H] + = 397.

[0264] 3.2 Preparation of Compound 20-Compound 21

[0265] The difference in the preparation of compound 20-compound 21 is that the (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester in the last step of steps 1-4 of Example 1 is replaced by materials of corresponding structures, such as (S)-1-(4-hydroxybutan-2-yl)guanidine (7.47 mmol) is used in the preparation of compound 20; (S)-1-(1-hydroxypropan-2-yl)guanidine (7.47 mmol) is used in the preparation of compound 21, and the rest of the operations are the same as the preparation method in Example 1.

[0266] The structures and characterization data of the obtained compounds 20-21 are as follows:

[0267]

[0268] Compound 20: 1 H NMR (500MHz, Methanol-d4) δ7.89(s,1H),4.50(br,1H),3.71(td,J=6.2,2.3Hz,2H),3.04(td,J=7.0,2.3Hz,2H),2.93(d,J=2.3Hz,3H),2.68(t,J= 5.7Hz,2H),2.62(d,J=2.2Hz,3H),2.09(dtd,J=9.2,5.8,4.7,2.1Hz,2H),1.87(qd,J=6.4,2.2Hz,2H),1.35(dd,J=6.6,2.3Hz,3H).MS(ESI):[M+H] + =344;

[0269]

[0270] Compound 21: 1 H NMR (500MHz, Methanol-d4) δ7.80 (s, 1H), 4.50 (br, 1H), 3.72 (t, J = 6.2, 2H), 3.68 (d, J = 5.7Hz, 2H), 3.04 (t ,J=6.2,2H),3.02(d,J=2.3Hz,3H),2.62(d,J=2.2Hz,3H),2.09(m,2H),1.35(d,J=6.6,3H).MS(ESI):[M+H] + =330.

[0271] Example 4: Preparation of Compound 22

[0272] Step 4-1:

[0273]

[0274] (S)-2-((1-(tert-butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidine-9-carboxylic acid (1 mmol) was dissolved in 25 mL of a mixed solution of 1,2-dichloroethane and water (V:V=1:1), followed by addition of an aqueous solution (7.5 mL) of sodium bicarbonate (2.7 mmol), potassium iodide (1.41 mmol) and iodine (0.8 mmol). The tube was sealed at 85°C for 12 h to react. After TLC monitoring of the reaction was complete, a saturated sodium sulfite solution was added to quench the reaction, followed by extraction with EA three times (30 ml×3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1 (V / V)) to give a yellow solid (S)-tert-butyl 3-((9-iodo-10-methyl-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (0.594 mmol, yield 59.4%)

[0275] 1 H NMR(400MHz,Chloroform-d)δ7.98(s,1H),5.33(s,2H),5.12-5.06(m,1H),4. 04(s,1H),3.93-3.84(m,1H),3.59(t,2H),3.30-3.14(m,2H),3.00(t,J=7.0H z,2H),2.54(t,J=5.8Hz,2H),2.41(s,3H),2.10-1.99(m,3H),1.82-1.74(m,1 H),1.64-1.58(m,2H),1.42(s,9H),0.94(t,2H),0.02(s,9H).MS(ESI):[M+H] + =654;

[0276] Step 4-2:

[0277]

[0278] (S)-3-((9-iodo-10-methyl-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.1mmol), palladium acetate (0.031mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062mmol) and potassium phosphate (0.31mmol) were added to a microwave tube, and the argon gas was replaced three times, and then deoxygenated dimethylphosphine (0.31mmol) in N,N-dimethylformamide (1mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered to obtain crude (S)-3-((9-(dimethylphosphoryl)-10-methyl-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. MS (ESI): [M+H] + =604;

[0279] Step 4-3:

[0280]

[0281] To the crude product of ((S)-3-((9-(dimethylphosphoryl)-10-methyl-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester, add dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 20 minutes, remove the solvent by rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and add ethylenediamine (400 μL) dropwise. Reaction at room temperature until complete conversion is monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain (S)-dimethyl (10-methyl-2- (piperidin-3-ylamino) -5,6,7,8-tetrahydropyrrolo [2', 3': 6,7] cycloheptyl [1,2-d] pyrimidin-9-yl) phosphine oxide (Compound 22). The obtained Compound 22 was tested for mass spectrum and hydrogen spectrum, and the results were as follows:

[0282] Compound 22: MS (ESI): [M+H]+=474. 1H NMR (400MHz, Methanol-d4) δ8.00 (s, 1H), 4.49-4.40 (m, 1H), 3.56 (dd, J = 12.1, 3.9Hz, 1H),3.34(d,J=4.6Hz,1H),3.12(dd,J=12.6,9.9Hz,1H),3.05(t,J=7.0Hz,3H),2.67( td,J=6.9,4.4Hz,2H),2.62(d,J=1.7Hz,3H),2.25-2.19(m,1H),2.10(dtt,J=14.4,7. 1,3.3Hz,3H),1.88(t,J=3.1Hz,1H),1.85(s,3H),1.82(s,3H),1.76(d,J=2.9Hz,1H).

[0283] Example 5: Preparation of Compound 15

[0284]

[0285] Synthesis of compound 9: After dissolving ethyl 4-methyl-1H-pyrrole-3-carboxylate (6.54 mmol) in 15 mL of anhydrous N,N-dimethylformamide, the reaction was cooled to 0°C, followed by the addition of solid sodium hydride (60%, 288 mg, 7.2 mmol). After half an hour, ethyl 4-bromobutyrate (1.4 mL, 9.8 mmol) was added dropwise and the reaction was gradually restored to room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction was quenched with saturated ammonium chloride solution (30 mL) at 0°C. The mixture was extracted three times with EA, washed three times with water, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and finally concentrated by rotary evaporation. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 10:1) to give colorless oily liquid 1-(4-ethoxy-4-oxobutyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (Compound 9) (367 mg, 1.37 mmol, yield 21%).

[0286] Characterization data of compound 9:

[0287] 1H NMR(400MHz,Chloroform-d)δ7.21(d,J=2.5Hz,1H),6.37(dd,J=2.4,1.1Hz,1H),4.25(q,J=7.1Hz,2H),4.13(q,J=7.1Hz,2H), 3.87(t,J=6.8Hz,2H),2.27(t,J=7.3Hz,2H),2.25(s,3H),2.06(p,J=7.0Hz,2H),1.33(t,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H).

[0288] 13 C NMR (101MHz, CDCl3) δ172.55,165.31,126.54,121.76,120.17,114.35,60.58,59.18,48.76,30.80,26.28,14.50,14.18,11.70.

[0289] Synthesis of compound 10: Compound 9 (367 mg, 1.37 mmol) was dissolved in anhydrous dichloromethane (6.5 mL) and the reaction was cooled to 0°C, followed by dropwise addition of 1 M dichloromethane solution of boron tribromide (1.37 mL, 1.37 mmol). After TLC monitoring of the reaction was complete, a saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction. After extraction with EA three times, the mixture was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 10:1) to obtain a light yellow solid 1-methyl-8-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylic acid ethyl ester (compound 10) (261 mg, 1.18 mmol, yield 86.1%).

[0290] Characterization data of compound 10:

[0291] 1 H NMR(400MHz,Chloroform-d)δ7.37(s,1H),4.28(q,J=7.0Hz,2H),4.12-4.05(m,2H ),2.67(s,3H),2.60(t,J=6.4Hz,2H),2.24(p,J=6.2Hz,2H),1.34(t,J=7.2Hz,3H).

[0292] 13C NMR (101MHz, CDCl3) δ188.52,164.52,131.53,129.04,127.88,115.78,59.80,45.88,37.13,23.06,14.44,11.82.

[0293] Synthesis of compound 11: After preparing a sufficient amount of compound 10 by repeating the above steps for several times, compound 10 (330 mg, 1.49 mmol) was dissolved in anhydrous toluene (12 ml), cooled to 0°C, and ethyl formate (360 μL, 4.38 mmol) and 1 mol / L potassium tert-butoxide tetrahydrofuran solution (4.48 mL, 4.48 mmol) were added. After TLC monitoring of the reaction was complete, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and ethyl acetate was added for extraction (20 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and spin-dried to obtain crude ethyl 7-(hydroxymethyl)-1-methyl-8-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate (compound 11), which was directly used in the next step.

[0294] Synthesis of compound 12: Dissolve the crude compound 11 in anhydrous ethanol (7.5 mL), add morpholine (1.3 mL, 14.9 mmol), and heat to 90°C. After one hour, cool the reaction to room temperature, add crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (7.47 mmol) and sodium methoxide (386 mg, 7.14 mmol), and heat to 90°C for 12 h. After the reaction was completed by mass spectrometry, the ethanol was dried and water (20 mL) and ethyl acetate (20 mL×3) were added for extraction. The organic phases were combined, dried and then dried. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=2.5:1) to give ((S)-2-((1-(tert-butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-5,6-dihydropyrimido[5,4-g]indolizine-9-carboxylic acid ethyl ester (Compound 12) (352 mg, 0.77 mmol, yield: 52%).

[0295] Characterization data of compound 12:

[0296] 1H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.36(s,1H),5.21-5.12(m,1H),4.29 (q,J=7.1Hz,2H),4.05(t,J=6.5Hz,2H),4.02-3.97(m,1H),3.54-3.47(m,1H),3. 39-3.20(m,2H),2.89(t,J=6.5Hz,2H),2.79(s,3H),2.03-1.96(m,1H),1.80-1. 72(m,1H),1.70-1.62(m,1H),1.61-1.55(m,1H),1.42(s,9H),1.36-1.33(m,3H). MS(ESI):[M+H] + =456;

[0297] Synthesis of compound 13: Compound 12 (80 mg, 0.176 mmol) was dissolved in a THF / H2O / MeOH mixed solution (4 mL, V / V / V = 4:2:1), and then lithium hydroxide monohydrate (73.8 mg, 1.76 mmol) was added. The reaction was sealed at 85°C for 12 h. After the reaction was complete as monitored by TLC, the reaction was cooled to 0°C and the pH value was adjusted to 3. Then EA was extracted three times, the organic phases were combined, dried, and then spin-dried to obtain the crude product of ((S)-2-((1-(tert-butyloxycarbonyl)piperidin-3-yl)amino)-10-methyl-5,6-dihydropyrimido[5,4-g]indolizine-9-carboxylic acid (compound 13), which was directly used in the next step. Characterization data of compound 13: MS (ESI): [M+H] - =426.

[0298] Synthesis of compound 14: The crude compound 13 (60 mg, 0.14 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.2 mL), and then HATU (160 mg, 0.42 mmol) and DIPEA (120 μL, 0.7 mmol) were added in sequence. After reacting at room temperature for 10 minutes, methylamine hydrochloride (28.4 mg, 0.42 mmol) was added, and then reacted at room temperature for 12 hours. After LC-MS monitoring, water (10 mL) was added to quench the reaction, and then EA was extracted three times (10 mL×3). The organic phases were combined and washed three times with water, washed once with saturated sodium chloride aqueous solution, dried, and then spin-dried to obtain (S)-3-((10-methyl-9-(methylcarbamoyl)-5,6-dihydropyrimido[5,4-g]indolizine-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 14) crude product. Characterization data of compound 14: MS (ESI): [M+H] + =441.

[0299] Synthesis of compound 15: The crude compound 14 was added to a dioxane hydrochloride solution (4 mol / L, 3 mL), reacted at room temperature for 10 minutes, and then the solvent was removed by a rotary evaporator. The residue was purified by preparative HPLC to obtain (S)-N,10-dimethyl-2-(piperidin-3-ylamino)-5,6-dihydropyrimido[5,4-g]indolizine-9-carboxamide.

[0300] Characterization data of compound 15:

[0301] 1H NMR (600MHz, Methanol-d4) δ8.02 (s, 1H), 7.52 (s, 1H), 4.36 (p, J = 5.8Hz, 1H), 4.22-4.17 (m, 2H), 3.5 8(dd,J=11.0,3.3Hz,1H),3.33(t,J=5.1Hz,1H),3.18(dd,J=12.5,9.3Hz,1H),3.09(ddd,J=13.1,10 .4,3.4Hz,1H),3.03(t,J=6.6Hz,2H),2.86(s,3H),2.77(s,3H),2.26-2.18(m,1H),2.11(dt,J=12.7 ,4.0Hz,1H),1.87(dtt,J=13.8,9.8,3.4Hz,1H),1.80(qd,J=9.8,4.9Hz,1H).MS(ESI):[M+H]+=341.

[0302] Example 6: Biological Activity Test

[0303] Diluent: It consists of an aqueous solution containing 24 mM MES (pH 6.75), 0.012% Tween 20, 0.06 mg / mL BSA and 7.2 mM MgCl2.

[0304] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein the blank control group was added with 2 μL of diluent, the test group was added with 2 μL of diluted test compound, and the positive control group was added with 2 μL of diluted staurosporine, and then all groups were added with 5 μL of CDK7 / Cyclin H / MAT1 enzyme solution (Promega Company), incubated for 30 minutes, and 5 μL of CDK7tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 minutes, and 4 μL of 150mM ethylenediaminetetraacetic acid solution was added to terminate the reaction, and the plate was read on the EZ readerII instrument. The inhibition rate was calculated by GraphPadPrism 8 software, and the results are shown in Table 3.

[0305] Table 3. Compounds inhibiting CDK7 activity

[0306] Target compound <![CDATA[CDK7 kinase inhibition rate a > Compound 15 78％ Compound 16 95％ Compound 17 95％ Compound 18 97％ Compound 19 97％ Compound 20 93％ Compound 21 92％ Compound 22 88％

[0307] a The inhibition rate of the compound on CDK7 kinase at 1 μM concentration.

[0308] Conclusion: The compounds provided by the present invention have good CDK7 kinase inhibitory activity.

[0309] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0310] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, optical isomer, racemate, isotope derivative or prodrug thereof, in, is a single bond or a double bond; A1 and A2 are each independently selected from C, CH, and N; Ring B is selected from a substituted or unsubstituted saturated or unsaturated 5-, 6-, 7- or 8-membered carbocyclic ring, or a substituted or unsubstituted saturated or unsaturated 5-, 6-, 7- or 8-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S; R1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 4-12 membered heterocyclyl, substituted or unsubstituted 5-9 membered heterobridged cycloalkyl, substituted or unsubstituted 5-9 membered bridged cycloalkyl, substituted or unsubstituted 6-10 membered heterospirocycloalkyl, substituted or unsubstituted 6-10 membered spirocycloalkyl, substituted or unsubstituted 6-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl; X is selected from -(CH2) n1 -、-(CH2) n1 O-, -(CH2) n2 C(R 5a )(R 5b )(CH2) n3 -, -CH=CH-; R 5a , R 5b are each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkynyl, or R 5a , R 5b Together with the carbon atoms adjacent to them, they form a C3-C6 cycloalkyl group; n1 is selected from 1, 2, 3, 4 or 5; n2 and n3 are selected from: (1) n2 is 1, n3 is 0, 1, 2 or 3; or (2) n2 is 2 or 3, and n3 is 0 or 1; or (3) n2 is 4, n3 is 0; L is selected from NH, N(C1-C6 alkylene); Optionally, the substituted or unsubstituted 4-12 membered heterocyclic group in R1 contains 1-11 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 5-9 membered heterobridged cycloalkyl in R1 contains 1-8 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 6-10 membered heterospirocycloalkyl in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 6-10 membered heterocycloalkyl in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl); or the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH( R1 is substituted with -CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3-membered cycloalkyl); preferably, the substitution in the substituted or unsubstituted R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl; Optionally, R 5a , R 5b The substitution in the substituted or unsubstituted is that one or more hydrogen atoms are independently replaced by methyl; preferably, R 5a , R 5b is selected from hydrogen or methyl.

2. According to the compound of claim 1, R1 is selected from: in, p1 is selected from 0, 1, 2 or 3, p2 is selected from 0 or 1, and p3 is selected from 1, 2 or 3; R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ; R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl; R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent thereto together form a C3-C6 cycloalkyl group; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl); or the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH( R2 is substituted with -CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3-membered cycloalkyl); preferably, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

3. A compound according to any one of claims 1 to 2, Ring B is selected from: in, A4 is each independently selected from NH, NR6, O, S, CH, CR7; A5, A6, A7, A8 or A9 are each independently selected from CR8; Rb and Rc are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, Ra is selected from halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra, Rb, Rc contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl group in Ra, Rb, and Rc contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; or Ring B is selected from: wherein A3 is selected from NH, NR6, O, S, CH, CR7; Ra and Rb are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, And Ra and Rb are not hydrogen at the same time; R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra and Rb contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in Ra and Rb contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

4. A compound according to any one of claims 1 to 3, X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -(CH2)4-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CF2CH2-, -CH=CH-, 5. A compound according to any one of claims 1 to 4, X is selected from -CH2CH2-, -CH2CH2CH2-, -C(CH3)2CH2-.

6. A compound according to any one of claims 1 to 5, L is -NH-.

7. The compound according to any one of claims 1 to 6, wherein the compound represented by formula (I) is selected from the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or the compound represented by formula (V), in, Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-; R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ; R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl; R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent thereto together form a C3-C6 cycloalkyl group; A4 is selected from NH, NR6, O, S, CH, CR7; A5, A6, A7, A8 or A9 are each independently selected from CR8; Rb and Rc are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, Ra is selected from halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl); or the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH( R2 is substituted with -CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3-membered cycloalkyl); preferably, the substitution in the substituted or unsubstituted R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra, Rb, Rc contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl group in Ra, Rb, and Rc contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; or The compound represented by formula (I) is selected from the compound represented by formula (VI) or the compound represented by formula (VII), wherein Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-; R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ; R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl; R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent thereto together form a C3-C6 cycloalkyl group; A3 is selected from NH, NR6, O, S, CH, CR7; Ra and Rb are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR6-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R7, -C(=O)-R7, And Ra and Rb are not hydrogen at the same time; R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 'are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl); or the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH( R2 is substituted with -CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3-membered cycloalkyl); preferably, the substitution in the substituted or unsubstituted R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra and Rb contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in Ra and Rb contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; or The compound represented by formula (I) is selected from the compound represented by formula (VIII) or the compound represented by formula (IX), wherein Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-; p1 is selected from 0, 1, 2 or 3; A4 is selected from NH, NR6, O, S, CH, CR7; A5 is selected from CR8; R6, R7, and R8 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C 10 Aryl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, or R9, R9' and their adjacent P are connected to form a 4-6 membered ring; Optionally, the 5-10 membered heteroaryl group in R6, R7, and R8 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the 3-8 membered heterocycloalkyl group in R6, R7 and R8 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

8. According to any one of claims 1 to 6, the compound represented by formula (I) is selected from the compound represented by formula (X), the compound represented by formula (XI), the compound represented by formula (XII), the compound represented by formula (XIII) or the compound represented by formula (XIV), in, Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-; Ra and Rb are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted 5-10 membered heteroaryl, -C(=O)-R 13 ; R7, R9, R9', R 12 , R 12 ' are each independently selected from C1-C6 alkyl; preferably, R7, R9, R9', R 12 , R 12 ' are each independently methyl; R 13 is selected from C1-C6 alkylamino groups; preferably, R 13 Methylamino, Rd is selected from C1-C6 alkyl, Ra and Rb are not hydrogen at the same time, or, when Rb is absent, Ra is not hydrogen; R1 is selected from: wherein p1 is selected from 0, 1, 2 or 3, p2 is selected from 0 or 1, and p3 is selected from 1, 2 or 3; R2 is selected from hydrogen, amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -C(=O)-NR 2a R 2b ; R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl; R3 and R4 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3, R4 and the carbon atoms adjacent thereto together form a C3-C6 cycloalkyl group; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in Ra and Rb contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in Ra and Rb contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 5-10 membered heteroaryl group contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, R6, R7, R8, R9, R9', R 10 , R 10 '、R 11 , R 11 '、R 12 , R 12 The 3-8 membered heterocycloalkyl group contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in Ra and Rb is that one or more hydrogen atoms are independently replaced by C1-C6 alkyl; preferably, the substitution in the substituted or unsubstituted in Ra and Rb is that one or more hydrogen atoms are independently replaced by methyl; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R2 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl in R2 contains 1-7 carbon atoms and 1, 2 or 3 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl or -NH-(3-6 membered cycloalkyl); or the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, methyl, ethyl, -CH2CH2CH3, -CH( R2 is substituted with -CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl or -NH-(3-membered cycloalkyl); preferably, the substitution in the substituted or unsubstituted in R2 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

9. A compound according to any one of claims 1 to 8, R1 is selected from a substituted or unsubstituted 4-12 membered heterocyclic group, a substituted or unsubstituted 5-10 membered heteroaryl group, or a substituted or unsubstituted C1-C6 hydroxyalkyl group; Optionally, the substituted or unsubstituted 4-12 membered heterocyclic group in R1 contains 1-11 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by C1-C6 alkyl; preferably, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by methyl.

10. The compound according to any one of claims 1 to 9, R1 is selected from 2,2-dimethylpiperidinyl, piperidinyl, C3-C5 hydroxyalkyl; or R1 is selected from 2,2-dimethylpiperidin-5-yl, piperidin-3-yl, 2-hydroxy-1-methylethyl, 3-hydroxy-1-methylpropyl, 3-hydroxy-3-methylbutyl.

11. A compound according to any one of claims 1 to 10, Ring B is selected from in, Ra is selected from hydrogen, methyl, cyano, methylaminocarbonyl, 3,5-dimethylisoxazol-4-yl, methanesulfonyl, dimethylphosphonyl, N-methyl-N-methylsulfonylamino, Rb is selected from hydrogen, methyl, cyano, fluorine, Rd is selected from methyl, Ra and Rb are not hydrogen at the same time, or, when Rb is not present, Ra is not hydrogen.

12. The compound according to any one of claims 1 to 11, which is a compound represented by formula (XV) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, optical isomer, racemate, isotopic derivative or a prodrug thereof of the compound represented by formula (XV), in, R1 is selected from 2,2-dimethylpiperidin-5-yl, piperidin-3-yl, 2-hydroxy-1-methylethyl, 3-hydroxy-1-methylpropyl, 3-hydroxy-3-methylbutyl; Y is selected from -CH2-, -CH2CH2-, -C(CH3)2-, -CH2C(CH3)2-; Ring B is selected from: Ra is selected from hydrogen, methyl, cyano, methylaminocarbonyl, 3,5-dimethylisoxazol-4-yl, methanesulfonyl, dimethylphosphonyl, N-methyl-N-methylsulfonylamino, Rb is selected from hydrogen, methyl, cyano, fluorine, Rd is selected from methyl, Ra and Rb are not hydrogen at the same time, or, when Rb is not present, Ra is not hydrogen.

13. A compound according to any one of claims 1 to 12, comprising one of the following compounds:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, and a pharmaceutically acceptable excipient, diluent or carrier.

15. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a drug for inhibiting CDK7 kinase activity or a drug for preventing and / or treating diseases related to abnormally elevated CDK7 kinase activity; Optionally, the disease associated with abnormally elevated CDK7 kinase activity is selected from one or more of cancer, inflammation, cardiovascular disease, infectious disease, immune disease, and metabolic disease; Optionally, the cancer is selected from one or more of breast cancer, ovarian cancer, colorectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, pancreatic cancer, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer; Optionally, the cancer is selected from one or both of estrogen receptor (ER)-positive breast cancer or triple-negative breast cancer; Optionally, the prostate cancer is castration-resistant prostate cancer.

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