CN116925070A

CN116925070A - Substituted aza-fused ring compounds and medical uses thereof

Info

Publication number: CN116925070A
Application number: CN202310435617.5A
Authority: CN
Inventors: 胡涛; 王家尧; 梁慧兴; 罗宏军; 顾阳; 胡嘉俊; 徐浩宇; 张继跃
Original assignee: Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2022-04-24
Filing date: 2023-04-21
Publication date: 2023-10-24

Abstract

The application relates to a compound shown in a formula (I), or a stereoisomer, or a tautomer, or a salt, or a mixture of the compounds and the mixture, a combination medicine composition and application thereof. The compounds are effective in inhibiting ATR kinase activity and are useful in treating ATR kinase mediated hyperproliferative diseases in a patient.

Description

Substituted aza-fused ring compounds and medical uses thereof

Technical Field

The application relates to the technical field of biological pharmacy, in particular to a substituted aza-fused ring compound and medical application thereof, and more particularly relates to a compound with a structure shown in a formula I, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, and a preparation method, a composition, a combined medicine composition and application thereof.

Background

The integrity of the eukaryotic genome is protected by a complex signaling pathway called the DNA Damage Response (DDR) and multiple DNA repair mechanisms. When DNA is damaged in the body, DDR pathway activation results in a cessation of cell cycle, inhibition of global translation, induction of DNA repair, and ultimately cell survival or cell death. Proteins that can directly recognize abnormal DNA structures are ATM (ataxia telangiectasia mutation), ATR (ATM-and Rad 3-related UniProtKB/Swiss-Prot Q13535), DNA-PKcs (DNA-dependent protein kinase), and the like.

ATR belongs to the phosphatidylinositol-3-kinase like kinase (PIKKs) family, and is the major member of the DNA damage checkpoint (cimrich k.a. and cotez d.2008, nature rev. Mol. Cell biol. 9:616-627). After ATR is activated by exogenous or endogenous DNA damage and replication problems (e.g., replication fork pressure, DNA double strand breaks, alkylating agents, etc.), cell cycle progression, stabilization of replication fork, and DNA repair are regulated by phosphorylating various substrates (Chk 1, WRN, MARCAL1, FANCI, etc.), thereby promoting replication pressure and survival of DNA damaged cells (Clin Cancer Res,2015, nov 1;21 (21): 4780-4785). ATR signaling pathway is critical for tumor cells with oncogenic protein abnormalities, many cancer cells lack critical tumor suppressor genes, which can make cancer cells more dependent on ATR pathway to regulate cellular DNA damage repair to promote cell survival than normal cells, thus ATR is a promising cancer therapeutic target. In vitro or in vivo experiments before clinic show that ATR inhibitor is more effective than normal cells in tumor cells, so that various events (such as Ras high expression, ATM deficiency and the like) generated by tumors and ATR inhibition have synthetic lethal effect.

ATR inhibitors can be used for cancer treatment alone or in combination with DNA damaging agents because they cut off the DNA replication mechanism that is more important for cell survival in many cancer cells than in healthy normal cells. In fact, ATR inhibitors have been shown to be effective as single agents in cancer cells and as potent sensitizers for radiotherapy and chemotherapy. At the same time ATR inhibitors may also be used in combination with other DDR related targeting agents, such as PARP inhibitors.

Disclosure of Invention

The present invention aims to solve, at least to some extent, the technical problems existing in the prior art. Therefore, the invention provides a compound shown in the formula I, or a stereoisomer, a tautomer, a salt, a mixture of the stereoisomer and the tautomer, a composition, application and pharmaceutical combination of the compound, and the compound can effectively inhibit ATR kinase activity, can be used for treating ATR kinase-mediated hyperproliferative diseases of patients, and has wide pharmaceutical development prospect.

In one aspect of the present invention, there is provided a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same:

wherein X is ₁ 、X ₂ And X ₃ Each independently is N or CH, and X ₁ 、X ₂ And X ₃ Not both N and CH;

when X is ₂ N, X of a shape of N, X ₃ When CH is, X ₃ Optionally further by R ³ Substitution; r is R ¹ Is a 5 to 7 membered heteroaryl group containing 1-3N; r is R ² Is hydrogen, halogen, -NR ⁴ R ⁵ 、CN、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyloxy, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyl, 4-to 10-membered heterocyclyl C ₂ -C ₃ Alkenyl, phenyl, 4-to 10-membered heteroaryl, - (CO) OR ⁴ 、-(CO)NR ⁴ R ⁵ 、-(SO ₂ )R ⁶ 、-(SO)R ⁶ 、-SR ⁶ 、-(SO ₂ )NR ⁴ R ⁵ 、-NR ⁴ (SO ₂ )R ⁶ 、-((SO)＝NR ⁸ )R ⁷ 、-CR ⁶ R ⁷ (SO ₂ )R ⁿ 、-CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ 、-N＝(SO)R ⁶ R ⁷ 、-(PO)(OR ⁴ ) ₂ 、-(PO)(OR ⁴ )R ⁷ Or- (PO) (R ⁷ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyloxy, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyl, 4-to 10-membered heterocyclyl C ₂ -C ₃ Alkenyl, phenyl or 4 to 10 membered heteroaryl optionally substituted with at least one of the following groups: halogen, -OH, -NR ⁴ R ⁵ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl C ₀ -C ₃ Alkyl, phenyl, - (CO) OR ⁴ 、-(CO)NR ⁴ R ⁵ 、-NR ⁴ (CO)R ⁷ 、-NR ⁵ (CO)OR ⁴ 、-NR ⁵ (CO)NR ⁴ R ⁵ 、-(SO ₂ )R ⁶ 、-(SO)R ⁶ 、-SR ⁶ 、-(SO ₂ )NR ⁴ R ⁵ 、-NR ⁴ (SO ₂ )R ⁶ 、-((SO)＝NR ⁸ )R ⁷ 、-CR ⁶ R ⁷ (SO ₂ )R ⁿ 、-CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ 、-N＝(SO)R ⁶ R ⁷ 、-(PO)(OR ⁴ ) ₂ 、-(PO)(OR ⁴ )R ⁷ 、-(PO)(R ⁷ ) ₂ Furyl or pyrazolyl, wherein the C ₁ -C ₆ Alkyl is optionally substituted with one OR more halogen, -OH, phenyl, - (CO) OR ⁴ 、C ₃ -C ₆ Cycloalkyl, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkoxy substitution; r is R ³ Is hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy or halogen;

R ⁴ and R is ⁵ Each independently is hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl or phenyl, said phenyl optionally substituted with one or more halogens; alternatively, R ⁴ And R is ⁵ Together with the linking atoms form a 4, 5, 6 or 7 membered cyclic amine group, said 4, 5, 6 or 7 membered cyclic amine group optionally being substituted with one or more C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl substitution, said 4, 5, 6 or 7 membered cyclic amine group optionally containing one additional heteroatom selected from O, N and S;

R ⁶ is hydrogen, C ₁ -C ₄ Alkyl or phenyl, said C ₁ -C ₄ Alkyl or phenyl optionally substituted with one or more R ⁹ Substitution;

R ⁷ is hydrogen, C ₁ -C ₄ An alkyl group; alternatively, at CR ⁶ R ⁷ (SO ₂ )R ⁿ 、CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ And-n= (SO) R ⁶ R ⁷ In the case of radicals, R ⁶ And R is ⁷ Together with the linking atoms form C ₃ -C ₇ Cycloalkyl or 3 to 7 membered heterocycloalkyl;

R ⁸ is hydrogen, C ₁ -C ₄ Alkyl, - (CO) OR ⁴ 、-(CO)NR ⁴ R ⁵ Or CN;

R ⁹ is halogen, OH, -NR ⁴ R ⁵ 、CN、NO ₂ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, - (CO) OR ⁴ Or (CO) NR ⁴ R ⁵ ；R ⁿ Is C ₁ -C ₄ Alkyl or C ₃ -C ₇ Cycloalkyl groups.

The inventor finds that the compound can effectively inhibit ATR kinase activity, especially shows good inhibition activity on tumor cells, can be used for treating ATR kinase-mediated hyperproliferative diseases of patients, and has wide drug development prospect.

According to an embodiment of the present invention, the above-mentioned compound, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof may further comprise at least one of the following additional technical features:

according to an embodiment of the present invention, the compound, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, is of the structure represented by formula (Ia), (Ib) or (Ic):

according to an embodiment of the invention, R ¹ At least one selected from the following groups:

according to an embodiment of the invention, R ¹ Is that

According to an embodiment of the invention, R ¹ Is that

According to an embodiment of the invention, R ² Is C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, 4-to 6-membered heterocyclyl C ₁ -C ₃ Alkoxy, 4-to 6-membered heteroaryl, -CR ⁶ R ⁷ (SO ₂ )R ⁿ or-CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ ；

Wherein the C ₁ -C ₃ Alkoxy, 4-to 6-membered heterocyclyl C ₁ -C ₃ Alkoxy or 4 to 6 membered heteroaryl optionally substituted with at least one of the following groups:

-(CO)OR ⁴ 、C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ Alkyl or 3-to 6-membered heterocyclic C ₁ -C ₃ Alkyl, wherein, the C ₁ -C ₃ Alkyl is optionally substituted with one OR more halogens, -OH, - (CO) OR ⁴ 、C ₃ -C ₆ Cycloalkyl, 3-to 5-membered heterocyclyl C ₀ -C ₃ Alkoxy substitution;

R ⁴ is hydrogen or C ₁ -C ₂ An alkyl group;

R ⁶ and R is ⁷ Each independently is hydrogen, C ₁ -C ₂ An alkyl group; alternatively, R ⁶ And R is ⁷ Together with the linking atoms form C ₃ -C ₇ Cycloalkyl;

R ⁸ is hydrogen or C ₁ -C ₂ An alkyl group;

R ⁿ is C ₁ -C ₂ Alkyl or C ₃ -C ₇ Cycloalkyl groups.

According to an embodiment of the invention, the 4-to 10-membered heteroaryl is pyrrolyl, pyrazolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, 1H-pyrrolo [2,3-b ] pyridyl, oxadiazolyl, indolyl, benzothienyl, quinolinyl or isoquinolinyl.

According to an embodiment of the invention, R ² At least one selected from the following groups:

according to an embodiment of the invention, R ² One selected from the following groups:

according to an embodiment of the invention, the compound, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, comprises at least one of the following structures:

In another aspect of the invention, the invention also provides a composition. According to an embodiment of the invention, the composition comprises the above-mentioned compound, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same. The composition prepared from the compound, or the stereoisomer, or the tautomer, or the salt or the mixture thereof can effectively inhibit ATR kinase activity, particularly shows good inhibition activity on tumor cells, can be used for treating ATR kinase-mediated hyperproliferative diseases of patients, and has wide drug development prospect.

According to embodiments of the present invention, the composition may also include other formulations, wherein the two separate formulations may be administered simultaneously or sequentially.

According to an embodiment of the invention, the composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

In a further aspect of the invention, the invention also provides the use of a compound as defined above, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, or a composition as defined above, in the manufacture of a medicament for the prophylaxis or treatment of hyperproliferative diseases. The medicine of the invention can effectively inhibit ATR kinase activity and can be used for treating hyperproliferative diseases of patients.

According to embodiments of the invention, the hyperproliferative diseases include psoriasis, keloids and other skin affecting hyperplasia, benign prostatic hyperplasia, tumors.

According to an embodiment of the invention, the tumor comprises melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer or gallbladder cancer.

In yet another aspect of the invention, the invention further provides a combination composition. According to an embodiment of the present invention, the combination composition is used for preventing or treating hyperproliferative diseases, including the above-mentioned compounds, or stereoisomers thereof, or tautomers thereof, or salts thereof, or mixtures thereof, or the above-mentioned compositions; and other drugs for preventing or treating hyperproliferative diseases. The combination composition of the invention can effectively inhibit ATR kinase activity and can be used for treating hyperproliferative diseases of patients.

According to an embodiment of the present invention, the "combination composition" may be a single compound preparation, or a composition of two or more separate preparations, wherein the two separate preparations may be administered simultaneously or sequentially, wherein the effect of using the two or more separate preparations is remarkable due to the effect of using one or part of the separate preparations alone.

According to an embodiment of the present invention, the other agents for preventing or treating hyperproliferative diseases include at least one of the following anticancer agents: cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, carboplatin, camptothecine, irinotecan, topotecan, doxorubicin, mitoxantrone, methylhydroxy ellipticine, mindapippine, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2' -deoxyuridine, fludarabine, cytarabine, pramipexole, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, pertuzumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, you Tuozhu monoclonal antibody, famuzumab, rituximab, alemtuzumab Tilmimumab, tositumomab, bentuximab, darimumab, erltuzumab, ofatumumab, denotuximab (Dinutuximab), bei Lintuo European monoclonal antibody (Blinatemomab), avadine, herceptin, mevalhua, imatinib, gefitinib, erlotinib, octenib, afatinib, ceritinib, ai Leti ni, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temozolomide, vorinostat, luo Mi Decine, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoxantrone, oxydol, oxygenitalide, retinoic acid, ruba, zoledronic acid, bortemide, carfiltinib, 84, izomib, triazomib, dimidide, gezomib, salvamide, lenalidomide, pomalidomide, valinatock (vennetoclax), recombinant human interleukin-2 (Aldesleukin), sipueucel-T (prostate cancer treatment vaccine), palbociclib, olaparib, nilaparib (Niraparib), racaparib (Rucaparib), and talazopanib (talazopanib).

In yet another aspect of the present invention, the present invention also provides the use of the aforementioned combination composition for the preparation of a medicament for the prevention or treatment of hyperproliferative diseases.

In yet another aspect of the invention, the invention also provides a method of preventing or treating a hyperproliferative disorder. According to an embodiment of the invention, it comprises: administering to a subject a pharmaceutically acceptable amount of the above compound, the above composition, or the above pharmaceutical combination. The method can inhibit the activity of ATR kinase in a subject and effectively treat the hyperproliferative diseases of the patient.

Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.

In the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more.

As used herein, the term "halogen atom", "halo- (halo-)" or "halo- (Hal-)" refers to a fluorine, chlorine, bromine or iodine atom.

Herein, the term "C ₁ -C _n Alkyl "refers to a straight or branched saturated monovalent hydrocarbon group having 1,2, 3, 4, 5, … …, or n carbon atoms. The term "C ₁ -C ₆ Alkyl "refers to a straight or branched saturated monovalent hydrocarbon group having 1,2, 3, 4, 5, or 6 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl and 1, 2-dimethylbutylA group, or an isomer of the above group. In particular, the radicals may have 1,2, 3 or 4 carbon atoms ("C ₁ -C ₄ Alkyl "), for example: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl; more particularly, the groups may have 1,2 or 3 carbon atoms ("C ₁ -C ₃ Alkyl "), for example: methyl, ethyl, n-propyl or isopropyl.

Herein, the term "C ₁ -C ₆ Haloalkyl "means C ₁ -C ₆ One or more hydrogen atoms of the alkyl group being replaced by identical or different halogen atoms, i.e. one halogen atom being independent of the other, wherein "C ₁ -C ₆ Alkyl "is as defined above. In particular, the halogen atom is F, for example: the C is ₁ -C ₆ Haloalkyl can be-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CF ₂ CF ₃ or-CH ₂ CF ₃ 。

Herein, the term "C ₁ -C ₄ Hydroxyalkyl "means C ₁ -C ₄ -one or more hydrogen atoms in the alkyl group being replaced by a hydroxyl group, wherein the term "C ₁ -C ₄ Alkyl "is as defined above. For example: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 1, 3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl.

Herein, the term "C ₁ -C ₆ Alkoxy "and" C ₁ -C ₆ Alkyloxy "means C containing the formula" -O-alkyl ₁ -C ₆ Alkyl, wherein the term "alkyl" is as defined above. For example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy and n-hexoxy, or isomers of the foregoing. In particular, the "C ₁ -C ₆ Alkoxy "may contain 1, 2, 3, 4 or 5 carbon atoms (" C ₁ -C ₅ Alkoxy "),preferably, it may contain 1, 2, 3 or 4 carbon atoms ("C ₁ -C ₄ Alkoxy ").

Herein, the term "C ₁ -C ₆ Haloalkoxy "means C ₁ -C ₆ One or more hydrogen atoms in the alkoxy group being replaced by identical or different halogen atoms, wherein the term "C ₁ -C ₆ Alkoxy "is as defined above. In particular, the halogen atom is F, for example: the C is ₁ -C ₆ The haloalkoxy group may be-OCF ₃ 、-OCHF ₂ 、-OCH ₂ F、-OCF ₂ CF ₃ or-OCH ₂ CF ₃ 。

Herein, the term "C ₂ -C ₆ Alkenyl "means C ₂ -C ₆ Alkoxy groups containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, or 2, 3 or 4 carbon atoms ("C ₂ -C ₄ Alkenyl "), in particular 2 or 3 carbon atoms (" C ₂ -C ₃ Alkenyl "), it is understood that where the alkenyl group contains more than one double bond, the double bonds may be separate from each other or conjugated to each other. For example: vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, homoallyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylpropan-1-enyl, 3-methylbutan-3-enyl, 2-methylbutan-3-enyl, 1-methylbutan-3-enyl, 3-methylbutan-2-enyl, (E) -2-methylbutan-2-enyl, (Z) -2-methylbutan-2-enyl, (E) -1-methylbutan-2-enyl, (Z) -1-methylbutan-2-enyl, (E) -3-methylbutan-1-enyl, (Z) -3-methylbutan-1-enyl, (E) -2-methylbutan-1-enyl, (Z) -2-methylbutan-1-enyl, (E) -1-methylbutan-1-enyl, (Z) -1-methylbutan-1-enyl -alkenyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E) -3-methylpent-3-enyl, (Z) -3-methylpent-3-enyl, (E) -2-methylpent-3-enyl, (Z) -2-methylpent-3-enyl, (E) -1-methylpent-3-enyl, (Z) -1-methylpent-3-enyl, (E) -4-methylpent-2-enyl, (Z) -4-methylpent-2-enyl, (E) -3-methylpent-2-enyl, (Z) -3-methylpent-2-enyl, (E) -3-methylpent-2-E) -2-methylpent-2-yl, (Z) -1-methylpent-2-enyl, (Z) -1-methylpent-2-yl, (E) -4-methylpent-1-enyl, (Z) -4-methylpent-1-enyl, (E) -3-methylpent-1-enyl, (Z) -3-methylpent-1-enyl, (E) -2-methylpent-1-enyl, (Z) -2-methylpent-1-enyl, (E) -1-methylpent-1-enyl, (Z) -1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E) -3-ethylbut-2-enyl, (Z) -3-ethylbut-2-enyl, (E) -2-ethylbut-2-enyl, (Z) -2-ethylbut-2-enyl, (E) -1-ethylbut-2-enyl, (Z) -1-ethylbut-2-enyl, (E) -3-ethylbut-1-enyl, (Z) -3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (Z) -1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E) -2-propylprop-1-enyl, (Z) -2-propylprop-1-enyl, (E) -1-propylprop-1-enyl, (Z) -1-propylprop-1-enyl, (E) -2-isopropylprop-1-enyl, (Z) -2-isopropylprop-1-enyl, (E) -1-isopropylprop-1-enyl, (Z) -1-isopropylprop-1-enyl, (E) -3, 3-dimethylprop-1-enyl, (Z) -3, 3-dimethylprop-1-enyl, 1- (1, 1-dimethylethyl) vinyl, but-1, 3-dienyl, pent-1, 4-dienyl, hex-1, 5-dienyl or methylhexdienyl. In particular vinyl or allyl.

Herein, the term "C ₃ -C ₇ Cycloalkyl "or" 3-to 7-membered cycloalkyl "refers to a saturated monovalent mono-or bicyclic hydrocarbon ring containing 3, 4, 5, 6, or carbon atoms. The C is ₃ -C ₇ Cycloalkyl is a monocyclic hydrocarbon ring, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptylThe method comprises the steps of carrying out a first treatment on the surface of the The C is ₃ -C ₁₀ Cycloalkyl is a bicyclic hydrocarbon ring, for example: perhydro cyclopentadiene or decalin ring. In particular, the rings contain 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ Cycloalkyl "), preferably cyclopropyl.

Herein, the term "3 to 10 membered heterocyclyl C ₀ -C ₃ Alkyl "means C ₀ -C ₃ The alkyl groups being substituted by 3-to 10-membered heterocyclic groups, i.e., - (C) ₀ -C ₃ Alkyl) -R, wherein R is a 3 to 10 membered heterocyclyl. The 3-to 10-membered heterocyclic group C ₀ -C ₃ The alkyl group may be monocyclic, but is not limited thereto, and may be, for example, a 4-membered ring (e.g., azetidinyl, oxetanyl), or a 5-membered ring (e.g., tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl), or a 6-membered ring (e.g., tetrahydropyranyl, piperidinyl, morpholinyl, dithiocyclohexenyl, thiomorpholinyl, piperazinyl, or trithianyl), or a 7-membered ring (e.g., diazepinyl ring). Optionally, the heterocycloalkyl group may be benzo-fused. Preferably tetrahydrofuranyl, tetrahydropyranyl or piperazinyl.

The 3-to 10-membered heterocyclic group C ₀ -C ₃ The alkyl group may be bicyclic, but is not limited thereto, and may be, for example, a 5, 5-membered ring (e.g., hexahydrocyclopenta [ c ]]Pyrrol-2 (1H) -yl ring), or 5, 6-membered bicyclo (e.g., hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl ring).

As described above, for example, the nitrogen atom-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, a 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydro-oxazolyl, or 4H- [1,4] thiazinyl ring; for example, benzo-fused; for example, but not limited to, a dihydroisoquinolinyl ring.

Herein, the term "3 to 10 membered heterocyclyl C ₀ -C ₃ Alkyloxy "means C ₀ -C ₃ The alkyl groups in the alkyloxy groups being substituted by 3-to 10-membered heterocyclic groups, i.e. -O- (C) ₀ -C ₃ Alkyl) -R, wherein R is a 3 to 10 membered heterocyclyl, for example: pyrrolidinyloxyA group, tetrahydrofuranyloxy, or tetrahydropyranoyloxy.

Herein, the term "3 to 10 membered heterocyclyl C ₀ -C ₃ Alkyl "means C ₀ -C ₃ Alkyl groups are substituted with 3 to 10 membered heterocyclyl groups.

Herein, the term "4-to 10-membered heterocyclyl C ₂ -C ₃ Alkenyl "means C ₂ -C ₃ Alkenyl groups are substituted with 4 to 10 membered heterocyclyl groups.

Herein, the terms "alkyloxy" and "alkoxy" are synonymous.

It is noted that, in this context, heteroaryl or heteroarylene generally and unless otherwise indicated, includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term "pyridinyl" or "pyridylene" includes pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; or the term thienyl or thienylene includes thiophen-2-yl, thienylene-2-yl, thiophen-3-yl and thienylene-3-yl.

In this context, the terms "-OR", "-NRR", etc. refer to the R group being attached singly to an oxygen OR nitrogen atom.

In this context, the terms "-C (O) R", "-S (O) ₂ The oxygen atom in R' and the like is doubly bonded to a carbon atom or a sulfur atom.

It should be noted that the term "C" is used herein ₁ -C ₆ ", e.g., in" C ₁ -C ₆ Alkyl "," C ₁ -C ₆ Haloalkyl "," C ₁ -C ₆ Alkoxy "or" C ₁ -C ₆ Haloalkoxy "in the context of the definition of" haloalkoxy "refers to an alkyl group having 1 to 6 carbon atoms of a limited number, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is further understood that the term "C ₁ -C ₆ "should be construed as including any subrange therein, e.g. C ₁ -C ₆ 、C ₂ -C ₅ 、C ₃ -C ₄ 、C ₁ -C ₂ 、C ₁ -C ₃ 、C ₁ -C ₄ 、C ₁ -C ₅ The method comprises the steps of carrying out a first treatment on the surface of the In particular C ₁ -C ₂ 、C ₁ -C ₃ 、C ₁ -C ₄ 、C ₁ -C ₅ 、C ₁ -C ₆ The method comprises the steps of carrying out a first treatment on the surface of the More particularly C ₁ -C ₄ The method comprises the steps of carrying out a first treatment on the surface of the In "C ₁ -C ₆ -haloalkyl "or" C ₁ -C ₆ In the case of haloalkoxy ", more particularly C ₁ -C ₂ 。

Similarly, as used herein, the term "C" is used throughout ₂ -C ₆ ", e.g., in" C ₂ -C ₆ Alkenyl groups "and" C ₂ -C ₆ In the context of the definition of alkynyl "is understood to mean alkenyl or alkynyl groups having from 2 to 6 carbon atoms in a limited number, i.e. 2, 3, 4, 5 or 6 carbon atoms. It is further understood that the term "C ₂ -C ₆ "should be construed as including any subrange therein, e.g., C ₂ -C ₆ 、C ₃ -C ₅ 、C ₃ -C ₄ 、C ₂ -C ₃ 、C ₂ -C ₄ 、C ₂ -C ₃ The method comprises the steps of carrying out a first treatment on the surface of the In particular C ₂ -C ₃ 。

Further, the term "C" is used throughout ₃ -C ₆ ", e.g., in" C ₃ -C ₆ Cycloalkyl "in the context of the definition of cycloalkyl" is understood to mean cycloalkyl having 3 to 6 carbon atoms of a limited number, i.e. 3, 4, 5 or 6 carbon atoms. It is further understood that the term "C3-C6" is to be interpreted as any sub-interval included therein, e.g., C ₃ -C ₆ 、C ₄ -C ₅ 、C ₃ -C ₅ 、C ₃ -C ₄ 、C ₄ -C ₆ 、C ₅ -C ₆ The method comprises the steps of carrying out a first treatment on the surface of the In particular C ₃ -C ₆ 。

Further, as used herein, the term "C" is used throughout ₂ -C ₄ ", e.g., in" C ₂ -C ₄ In the context of the definition of "alkenyl", it is understood to mean alkenyl having from 2 to 4 carbon atoms of limited number, i.e. 2, 3 or 4 carbon atoms. It is further understood that the term "C ₂ -C ₄ "should be construed as any sub-interval included therein, e.g., C ₂ -C ₄ 、C ₂ -C ₃ 、C ₃ -C ₄ 。

In the description of the radicals according to the inventionAre used to describe the positions of substitution of groups.

In this context, the term "substituted" means that one or more hydrogens on the designated atom are replaced with a selection from the indicated groups, provided that: no more than the normal valency of the atom specified in the prior art, and this substitution results in a stable compound. Substituents and/or variables may be combined so long as such combination can result in a stable compound.

The term "stabilizing compound" or "stabilizing structure" as used herein refers to a compound that is sufficiently stable to withstand separation from the reaction mixture to an effective purity, and can be formulated as an effective therapeutic agent.

Herein, the term "optionally substituted" or "optionally substituted" means optionally substituted with a particular group, radical or moiety. Ring system substitution refers to a substituent attached to an aromatic or non-aromatic ring system, for example, that replaces available hydrogen on the ring system.

The "group is optionally substituted with a plurality of substituents" may be the case where the same group may be substituted with the same substituent a plurality of times, or may be the case where each group may be substituted with a different substituent.

In this context, the term "may be further substituted" means that "substitution" may, but need not, occur, and that the description includes situations where this occurs or does not occur.

The term "one or more" (e.g., in the definition of substituents of compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, more especially one or two".

It should be noted that the number of the substrates,the compounds of the present invention also include all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are defined as: compounds of the present invention in which at least one atom is replaced by an atom of the same atomic number but an atomic weight different from the atomic weight normally or predominantly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include the following isotopes, respectively: hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example: ² h (deuterium), ³ H (tritium), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² P、 ³³ P、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁹ I and ¹³¹ I. certain isotopic variations of the compounds of the present invention, for example, the incorporation of one or more radioisotopes (e.g.: ³ h or ¹⁴ C) For drug and/or substrate tissue distribution studies. Tritium and carbon 14 are particularly preferred (i.e., ¹⁴ c) Isotopes, because of their ease of preparation and detection.

Further, substitution with isotopes (e.g., deuterium) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, or reduced dosage requirements, and may be preferred in some circumstances. Isotopic variations of the compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, for example, by using the illustrative methods or preparations described in the examples below, using suitable reagents.

It is noted that the compounds of the present invention may contain one or more asymmetric centers, depending on the position and nature of the various substituents of interest. The asymmetric carbon atoms may be present in either the (R) or (S) configuration, forming a racemic mixture in the case of a single asymmetric center and a mixture of diastereomers in the case of multiple asymmetric centers. In some cases, asymmetry may also be present due to the anti-rotation effect around a given bond, e.g., a central bond connecting two substituted aromatic rings of a particular compound.

It is noted that the compounds of the present invention may also contain an asymmetric sulfur atom, for example, an asymmetric sulfoxide or sulfoximine (sulfoximine) group of the following structure:

wherein, represents an atom that can bond to the rest of the molecule. Substituents on the ring may also be present in cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the invention.

Further, the compound of the present invention may be a preferable compound. The term "preferred compounds" refers to those compounds that result in more desirable biological activity. For example, isolated, purified or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

For example, the racemic mixture may be resolved according to conventional methods to obtain the pure stereoisomers. For example, the use of optically active acids or bases, the formation of diastereoisomeric salts, or the formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their single non-corresponding isomers based on their physical and/or chemical differences using methods well known to those skilled in the art, such as chromatography or fractional crystallization. Optically active bases or acids are then released from the separated diastereomeric salts. Different methods for separating optical isomers include: chiral chromatography (e.g., chiral HPLC columns) is preferably selected to substantially separate the enantiomers with or without conventional derivatization. Daicel produces suitable chiral HPLC columns, e.g., chiracel OD and Chiracel OJ, as well as many other chiral HPLC columns, which are commonly selectable columns. Enzymatic isolation is also used with or without derivatization. Similarly, the optically active compound of the present invention can be obtained by chiral synthesis using an optically active starting material.

To limit isomers which differ in type from one another, reference is made to IUPAC Rules Section E (Pure Appl Chem 45,11-30, 1976).

It is noted that the compounds of the present invention may also include all possible stereoisomers of the compounds of the present invention, either as single stereoisomers, or as any ratio of said stereoisomers, such as the (R) or (S) isomers, or as any mixture of the (E) or (Z) isomers. Using any suitable method described in the art, for example: chromatography, particularly chiral chromatography, may allow separation of individual stereoisomers of the compounds of the invention, for example: separation of single enantiomers or single diastereomers.

Further, the compounds of the present invention may exist as tautomers. For example, any of the compounds of the invention comprising a pyrazole moiety as heteroaryl group, for example, may exist in the form of a 1H tautomer or a 2H tautomer or a mixture of any number of both tautomers, or comprise a triazole moiety, for example, may exist in the form of a 1H tautomer, a 2H tautomer or a 4H tautomer or even a mixture of any number of said 1H, 2H and 4H tautomers, i.e.:

It is noted that the compounds of the present invention may also include all possible tautomers of the compounds of the present invention, as a single tautomer, or any mixture of any proportions of said tautomers.

Further, the compounds of the present invention may exist in the form of an N-oxide, which is defined as: at least one nitrogen of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

It is noted that the compounds of the present invention also relate to useful forms of the compounds disclosed herein, e.g., metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.

Further, the compounds of the present invention may exist in the form of a hydrate or solvate, wherein the compounds of the present invention contain a polar solvent, especially water, methanol or ethanol, for example, as a structural element of the crystal lattice of the compound. The polar solvent, in particular the amount of water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, such as hydrates, it may be a half (part), one and one half, two, three, four, five solvates or hydrates, respectively, and so on. The present invention includes all such hydrates or solvates.

Further, the compounds of the present invention may exist in free form, e.g., as a free base or free acid or zwitterionic, or may exist in salt form. The salt may be any salt commonly used in pharmacy, organic or inorganic addition salts, in particular any pharmaceutically acceptable organic or inorganic addition salt.

As used herein, the terms "salt" and "pharmaceutically acceptable salt" refer to a compound or stereoisomer thereof, and acid and/or base salts formed with relatively non-toxic inorganic and/or organic acids and bases of the compound or stereoisomer thereof, as well as zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium. Suitable pharmaceutically acceptable salts of the compounds of the invention may be acid addition salts of basic compounds carrying a nitrogen atom in the chain or ring. In view of the foregoing, one of skill in the art will further recognize that acid addition salts of the claimed compounds can be prepared by any of a number of known methods, by reaction of the compounds with a suitable inorganic or organic acid.

The present invention includes all possible salts of the compounds of the present invention, either as a single salt, or any mixture of the salts in any proportion.

Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, as a single polymorph, or as a mixture of any proportion of more than one polymorph. When substituted for a group in a compound of the invention, the group may be mono-or polysubstituted, unless otherwise indicated. In the context of the present invention, all groups which occur more than once are defined independently of one another. Preferably by one, two or three identical or different substituents.

The disclosure herein also relates to compounds of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof (especially a pharmaceutically acceptable salt), or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of hyperproliferative diseases. Herein, the term "hyperproliferative diseases" includes, but is not limited to, for example: psoriasis, keloids and other skin affecting hyperplasia, benign Prostatic Hyperplasia (BPH), tumors, such as breast cancer, respiratory tract cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distal metastases thereof. Those diseases also include lymphomas, sarcomas, and leukemias.

The present disclosure further relates herein to compounds of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof (especially a pharmaceutically acceptable salt), or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of tumors. The term "tumor" includes, but is not limited to, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.

As used herein, the term "treating" includes inhibiting, delaying, examining, alleviating, attenuating, limiting, reducing, suppressing, counteracting, or curing a disease (the term "disease" includes but is not limited to a condition, disorder, injury, or health problem), or the development, progression, or progression of such a condition and/or symptoms of such a condition. The term "therapy" is understood herein as synonymous with the term "treatment".

The terms "prevention", "prevention" or "prevention" are used synonymously in the context of the present invention and refer to avoiding or reducing the risk of infection, experiencing, suffering from or having a disease or the development or progression of such a condition and/or symptoms of such a condition. Treatment or prevention of a disease may be partial or complete.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Detailed Description

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

General synthetic method 1:

when R is ¹ Is thatR ² Is->In this case, the compound (Ia) can be synthesized by referring to the following steps:

Firstly, reacting the compound 1 with ethylene glycol and pyridine p-toluenesulfonate to obtain a compound 2; reacting the compound 2 with 1,1' -bis-diphenylphosphino ferrocene palladium dichloride and triethylamine under the protection of carbon monoxide to obtain a compound 3; reacting the compound 3 with m-chloroperoxybenzoic acid and methylene dichloride to obtain a compound 4; combining compound 4 with a compound containing R ² Borate esters of radicals, pd (dppf) Cl ₂ 、K ₂ CO ₃ Reacting under the protection of nitrogen to obtain a compound 5; combining Compound 5 with triethylamine, POCl ₃ Reacting to obtain a compound 6; compound 6 is reacted with NH ₂ NH ₂ ·H ₂ O is reacted and freeze-dried to obtain a compound 7; reacting the compound 7 with N, N-diisopropylethylamine and di-tert-butyl dicarbonate to obtain a compound 8; reacting the compound 8 with 3-methylmorpholine under the microwave condition to obtain a compound 9; combining Compound 9 with POCl ₃ Carrying out the reaction to obtain a compound 10; combining compound 10 with a compound containing R ¹ Boric acid of group, pd (dppf) Cl ₂ 、K ₂ CO ₃ Reacting under the protection of nitrogen to obtain a compound 11; the compound 11 is reacted with trifluoromethanesulfonic acid and trifluoroacetic acid to obtain a compound represented by the formula (Ia).

General synthetic method 2:

when R is ¹ Is thatR ² Is-> In this case, the compound (Ia) can be synthesized by referring to the following steps: />

First, compound 9 (for synthesis of compound 9, see compound 9 of general synthetic method 2) was combined with POCl ₃ Reacting to obtain a compound 10; compound 10 was reacted with triethylamine, pd (dppf) Cl ₂ Reacting under the protection of carbon monoxide to obtain a compound 11; reacting the compound 11 with methanol and ammonia gas to obtain a compound 12; compound 12 and (MeO) ₂ CHNMe ₂ Reacting to obtain a compound 13; compound 13 is reacted with NH ₂ NH ₂ ·H ₂ O and acetic acid to obtain the compound shown in the formula (Ia).

General synthetic method 3:

when R is ¹ Is thatR ² Is->In this case, the compound (Ib) may be synthesized by referring to the following steps:

first, compound 0 is reacted with a compound containing R ¹ Boric acid, K of a radical ₂ CO ₃ 、Pd(dppf)Cl ₂ Reacting under the protection of nitrogen to obtain a compound 1; compound 1 was reacted with Pd (dppf) Cl ₂ Triethylamine and methanol react under the condition of nitric oxide pressurization to obtain a compound 2; reacting the compound 2 with acetic anhydride to obtain a compound 3; reacting the compound 3 with tetrahydrofuran and potassium tert-butoxide under the protection of nitrogen to obtain a compound 4; combining Compound 4 with POCl ₃ Reacting to obtain a compound 5; reacting the compound 5 with 3-methylmorpholine and N-methylpyrrolidone under the microwave condition to obtain a compound 6; combining compound 6 with a compound containing R ² Boric acid esters of radicals, K ₂ CO ₃ 、Pd(dppf)Cl ₂ Reacting under the protection of nitrogen to obtain a compound 7; the compound 7 is reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain a compound represented by the formula (Ib).

General synthetic method 4:

when R is ¹ Is thatR ² Is->In this case, the compound (Ib) may be synthesized by referring to the following steps: />

First, compound 6 (compound 6 of general Synthesis method 3, see Compound 6 for Synthesis of Compound 6) was reacted with Compound a, potassium carbonate, pd (dppf) Cl ₂ Reacting dioxane under the protection of nitrogen to obtain a compound 7; reacting the compound 7 with methanol and hydrochloric acid at normal temperature to obtain a compound 8; compound 8 and compound b, cesium carbonate, CH ₃ CN is mixed, replaced by nitrogen and then reacted to obtain a compound 9; the compound 9 is reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain a compound represented by the formula (Ib).

General synthesis method 5:

1) When R is ¹ Is thatR ² Is->In this case, the compound (Ib) may be synthesized by referring to the following steps:

first, compound 1 is reacted with pinacol boric acidEsters in CuSO ₄ Reacting in an aqueous solution to obtain a compound 2; compound 2 was reacted with SM2 (4- (1- (4-methoxybenzyl) -1H-pyrazol-3-yl) -6-chloropyrimidin-5-amine), K ₂ CO ₃ And Pd (dppf) Cl ₂ In 1, 4-dioxane, under the protection of nitrogen, reacting to obtain a compound 3; reacting the compound 3 with sodium ethoxide to obtain a compound 4; combining Compound 4 with POCl ₃ Carrying out the reaction to obtain a compound 5; reacting the compound 5 with 3-methylmorpholine and N-methylpyrrolidone under the microwave condition to obtain a compound 6; compound 6 and 1, 4-dioxane, seO ₂ Reacting to obtain a compound 7; compound 7 was reacted with methanol, naBH ₄ Reacting at room temperature to obtain a compound 8; reacting the compound 8 with triethylamine and 4-toluenesulfonyl chloride at room temperature to obtain a compound 9; reacting the compound 9 with sodium metabisulfite and dimethylformamide at room temperature to obtain a compound 10; reacting the compound 10 with 1, 2-dibromoethane, tetrabutylammonium bromide and toluene in an alkaline environment to obtain a compound 11; the compound 11 is reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain a compound represented by the formula (Ib). The structural formula of SM2 is as follows:

2) When R is ¹ Is thatR ² Is->In this case, the compound Ib can also be synthesized by referring to the following steps:

reacting the compound 10 in the step 1) with 1, 4-dibromoethane, tetrabutylammonium bromide and toluene in an alkaline environment to obtain a compound 11; the compound 11 is reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain a compound represented by the formula (Ib).

General synthetic method 6:

first, compound 8 (compound 8 of general synthetic method 5 for synthesis see compound 8) was reacted with phosphorus tribromide in anhydrous dichloromethane at room temperature to give compound 9; reacting the compound 9 with sodium mercaptide containing alkyl and dimethylformamide at room temperature to obtain a compound 10; reacting the compound 10 with sodium periodate, ethyl acetate and methanol at room temperature to obtain a compound 11; compound 11 was combined with trifluoroacetamide, phI (AcO) ₂ 、MgO、Rh ₂ (OAc) ₄ Reacting under the protection of nitrogen to obtain a compound 12; the compound 12 is reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain a compound represented by the formula (Ib).

General synthetic method 7:

First, compound 1 is reacted with a compound containing R ² Boric acid esters of radicals, potassium carbonate, pd (dppf) Cl ₂ Reacting under the protection of nitrogen to obtain a compound 2; reacting compound 2 with dimethyl sulfoxide, potassium tert-butoxide/tetrahydrofuran in oxygen environment to obtain the compound of formula (Ib)) The compounds shown.

General synthetic method 8:

when R is ¹ Is thatR ² Is->In this case, the compound (Ic) can be synthesized by referring to the following steps:

firstly, reacting the compound 1 with benzyl bromide, cesium carbonate and MeCN to obtain a compound 2; compound 2 was combined with compound 3, pd (PPh ₃ ) ₂ Cl ₂ Mixing cesium carbonate and MeCN, and reacting after nitrogen substitution to obtain a compound 4; compound 4 is reacted with NH ₃ Reacting methanol at room temperature to obtain a compound 5; reacting the compound 5 with triphosgene to obtain a compound 6; compound 6 was combined with POCl ₃ Reacting with diisopropylethylamine to obtain a compound 7; combining compound 7 with a compound containing R ² Alkyl of radicals, alCl ₃ Reacting with dichloromethane and N-methylpyrrole to obtain a compound 8; reacting the compound 8 with 3-methylmorpholine, diisopropylethylamine and N-methylpyrrolidone to obtain a compound 9; and (3) reacting the compound 9 with dimethyl sulfoxide and potassium tert-butoxide/tetrahydrofuran in an oxygen environment to obtain the compound shown in the formula (Ic).

Example 1: preparation of Compound A-3

The specific preparation steps of the compound A-3 are as follows:

compound 1 (24.5 g,0.14 mol), ethylene glycol (87 g,1.4 mol), pyridine p-toluenesulfonate (PPTS) (3.5 g,0.014 mol) and 100mL of toluene were charged into a 250mL single-neck flask, reacted at 50℃for 16 hours,concentration and column chromatography (PE: ea=8:1) gave 30g of product 2 as a colourless oil in 97% yield. The retention time of the product in LC-MS 01 was 2.125min, M/z (ESI) =221.1 (M+H) ⁺ 。

Compound 2 (30 g,0.14 mol) was dissolved in 100mL of methanol (MeOH) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (Pd (dppf) Cl) was added ₂ ) (3.1 g,4.2 mmol) and Triethylamine (TEA) (28.5 g,0.28 mol) were reacted overnight at 60℃under the protection of carbon monoxide (CO), concentrated and chromatographed (PE: EA=5:1) to give 29g of product 3 as a white solid in 87% yield. The retention time of the product in LC-MS 02 was 1.952min, M/z (ESI) = 243.8 (M+H) ⁺ 。

Compound 3 (29 g,0.12 mol) was dissolved in 100mL of Dichloromethane (DCM), m-chloroperoxybenzoic acid (m-CPBA) (41 g,0.24 mol) was added and reacted overnight at 25℃filtered and column chromatography (PE: EA=3:1) afforded 30g of product 4 as a white solid in 96% yield. The retention time of the product in LC-MS 03 was 2.088min, M/z (ESI) =259.8 (M+H) ⁺ 。

Compound 4 (30 g,0.12 mol) and boric acid ester (50 g,0.24 mol) were dissolved in 200mL of Dioxane (Dioxane) and 20mL of H ₂ In O, add Pd (dppf) Cl ₂ (2.6 g,3.6 mmol) and K ₂ CO ₃ (33 g,0.24 mol) under nitrogen (N) ₂ ) Under the protection of (2), the reaction is carried out at 100 ℃ for 2 hours. The reaction was filtered, concentrated and column chromatographed (PE: ea=3:1) to give 20g of product 5 as a yellow solid in 55% yield. The retention time of the product in LC-MS 04 was 1.783min, M/z (ESI) =305.8 (M+H) ⁺ 。

Compound 5 (20 g,62.6 mmol) and TEA (63 g,626 mmol) were dissolved in 100mL DCM and POCl was added under ice-bath conditions ₃ (50 g,323 mmol) was reacted overnight at 25℃and the pH of the reaction solution was adjusted to 8-9 by adding TEA, concentrated and chromatographed (PE: EA=5:1) to give 4g of product 6 as a yellow solid in 20% yield. The retention time of the product in LC-MS 05 was 2.164min, M/z (ESI) =323.8 (M+H) ⁺ 。

Compound 6 (4 g,12.4 mmol) was dissolved in 15mL ethanol (EtOH) and NH was added ₂ NH ₂ ·H ₂ O (6.2 g,124 mmol), overnight at 25℃and the reaction solution was lyophilized to give 3g of product 7 as a yellow solid with a yield of 75%. The retention time of the product in LC-MS 06 was 1.614min, M/z (ESI) = 323.7 (M+H) ⁺ 。

Compound 7 (3 g,9.3 mmol) and N, N-Diisopropylethylamine (DIEA) (2.4 g,18.6 mmol) were dissolved in 20mL DCM and di-tert-butyl dicarbonate ((Boc) was added ₂ O) (4.1 g,18.6 mmol), at 25℃overnight. 10mL of H was added ₂ O, DCM extraction, drying, concentration, column chromatography (PE: EA=2:1) gave 2.5g of product 8 as a yellow solid in 63% yield.

Compound 8 (2.5 g,5.9 mmol) was placed in a microwave tube and morpholine (3 mL) was added and reacted in the microwave at 150℃for 4h, the reaction was lyophilized and column chromatographed (DCM: meOH=40:1) to give 800mg of product 9 as a yellow solid in 41% yield. The retention time of the product in LC-MS 09 was 1.950min, M/z (ESI) = 326.9 (M+H) ⁺ 。

Compound 9 (200 mg,0.61 mmol) was dissolved in POCl ₃ (10 mL), reacted at 100℃for 2 hours, concentrated, and then directly subjected to the next reaction. The retention time of the product in LC-MS 10 was 2.475min, M/z (ESI) = 344.8 (M+H) ⁺ 。

Unpurified Compound 10 was dissolved in 20mL of Dioxane and K was added ₂ CO ₃ (1.7 g,12.2 mmol) and 2mL H ₂ O, ensuring that the reaction solution is alkaline, adding boric acid (283 mg,1.22 mmol) and Pd (dppf) Cl ₂ (44 mg,0.06 mmol). Under the protection of nitrogen, the reaction is carried out for 2 hours at 100 ℃. Concentration, column chromatography (DCM: meoh=40:1) afforded 150mg of product 11 as a yellow solid in 49% yield in two steps. The retention time of the product in LC-MS 11 was 2.53 min, M/z (ESI) =497.2 (M+H) ⁺ 。

Compound 11 (150 mg,0.30 mmol) was dissolved in trifluoroacetic acid (TFA) (2.5 mL), and then trifluoromethanesulfonic acid (TfOH) (0.5 mL) was added thereto, reacted at 45℃for 4 hours, and saturated sodium bicarbonate solution was added thereto to adjust the pH of the reaction solution to 8-9, extracted with DCM, dried and concentrated. Pre-HPLC purification yielded 30mg of product A-3 as a yellow solid in 27% yield. The retention time of the product in LC-MS was 1.640 min, M/z (ESI) = 376.8 (M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ δ13.77(s,1H),8.96(s,1H),7.81–7.62(m,3H),7.49(s,1H),6.70(d,J＝1.6Hz,1H),4.73(s,1H),4.36(d,J＝13.3Hz,1H),4.04(t,J＝11.4Hz,1H),3.83(s,4H),3.71(d,J＝10.7Hz,1H),3.62–3.50(m,2H),1.33(d,J＝6.5Hz,3H)。

Example 2: preparation of Compound A-2

The specific preparation steps of the compound A-2 are as follows:

compound 9 (see example 1 for preparation of Compound 9) (350 mg,1.07 mmol) was dissolved in POCl ₃ (10 mL), reacted at 100℃for 2 hours, concentrated, and then directly subjected to the next reaction. The retention time of the product in LCMS-1 was 2.475min, M/z (ESI) = 344.8 (M+H) ⁺ 。

Unpurified Compound 10 was dissolved in 10mL MeOH, TEA (2 mL) was added to ensure that the reaction was basic, and Pd (dppf) Cl was added ₂ (78 mg,0.11 mmol). Reaction for 16h at 60℃under protection of carbon monoxide, concentration and column chromatography (DCM: meOH=60:1) gave 270mg of product 11 as a yellow solid in 68% yield in two steps. LCMS-2 retention time of 1.912min, M/z (ESI) = 368.8 (M+H) ⁺ 。

Compound 11 (270 mg,0.73 mol) was dissolved in 7M NH ₃ MeOH (10 mL) was placed in a lock tube and reacted at 40℃for 16h, and concentrated to give 240mg of crude product 12 as a white solid in 93% yield. The retention time of the product in LCMS-3 was 1.952min, M/z (ESI) =353.8 (M+H) ⁺ 。

Compound 12 (240 mg,0.68 mmol) was dissolved in 0.5mL (MeO) ₂ CHNMe ₂ Placing in a tube for sealing, reacting for 15min at 95 ℃, and concentrating to obtain 200mg of crude product 13, white solid, and the yield is 72%. The retention time of the product in LCMS-4 was 1.596min, M/z (ESI) = 408.8 (M+H) ⁺ 。

Compound 13 (200 mg,0.49 mmol) was dissolved in 2mL CH ₃ In COOH, NH is added ₂ NH ₂ ·H ₂ O (49 mg,0.98 mmol), at 90℃for 1.5h. Pre-HPLC purification gave 60mg of product A-2 as a yellow solid in 33% yield. The retention time of the product in LCMS was 1.961min, M/z (ESI) = 378.2 (M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ14.47(s,1H),9.14–8.95(m,1H),8.44(s,1H),7.76–7.55(m,2H),6.76–6.69(m,1H),4.64(s,1H),4.40(d,J＝11.8Hz,1H),4.03–3.92(m,1H),3.89–3.82(m,3H),3.76(d,J＝11.7Hz,1H),3.64(dd,J＝11.5,2.8Hz,1H),3.49(td,J＝11.9,2.7Hz,1H),3.25(d,J＝12.6Hz,1H),1.24(d,J＝6.7Hz,3H)。

Preparation of Compounds A-4, A-5, A-6, A-7, A-8 and A-9 reference was made to the synthesis of Compound A-3 of example 1. The structural formulas and the nuclear magnetic characterization results of the compounds A-4, A-5, A-6, A-7, A-8 and A-9 are shown in Table 1.

Table 1: structural formulas and nuclear magnetic characterization results of Compounds A-4, A-5, A-6, A-7, A-8 and A-9

Example 3: preparation of Compound B-2/B-2a

The specific preparation steps of the compound B-2/B-2a are as follows:

compound 0 (10 g,61 mmol), (1- (4-methoxybenzyl) -1H-pyrazol-3-yl) boronic acid (21 g,92 mmol), K ₂ CO ₃ (17 g,122 mmol) and Pd (dppf) Cl ₂ (450 mg) was put into a 200mL one-necked flask, 5mL of water was further added thereto, and N was added at 100 ℃ ₂ The reaction was protected overnight, monitored by LC-MS, and purified by column chromatography (PE: ea=6:1) to give 9g (47% yield) of the product as a yellow oil. M/z (ESI) = 315.8 (m+h) ⁺ 。

1 (5.8 g,18.4 mmol), pd (dppf) Cl ₂ (135 mg,0.18 mmol) and TEA (3.7 g,37 mmol) were dissolved in 100mL anhydrous MeOH, CO displaced and reacted overnight at 50℃under CO pressure, the reaction monitored by LC-MS and the column chromatography (PE: EA=1:1) separated and purified to give 3.2g of product (yield 51.34%). M/z (ESI) = 339.9 (m+h) ⁺ 。

Compound 2 (3 g,8.85 mmol) was dissolved in 20mL of acetic anhydride and reacted overnight at 100℃and the reaction was monitored by LC-MS, and the product was isolated and purified by column chromatography (PE: EA=2:1) to yield 2.7g (yield 72.13%). M/z (ESI) =423.7 (m+h) ⁺ 。

Compound 3 (2.7 g,6.4 mmol) was dissolved in 30ml of anhydrous Tetrahydrofuran (THF), followed by the addition of potassium tert-butoxide (t-BuOK) (2.2 g,19.2 mmol), N ₂ The reaction was carried out at 80℃for 3h under protection, monitored by LC-MS, and purified by column chromatography (DMC: meOH=10:1) to give 1.5g (yield 67.34%). M/z (ESI) =350.1 (m+h) ⁺ 。

Compound 4 (1.5 g,4.3 mmol) was dissolved in 20mL of POCl ₃ In the reaction, the reaction was carried out at 100℃for 3h, and the reaction was monitored by LC-MS, and the product was isolated and purified by column chromatography (DMC: meOH=10:1) to give 1g (yield 60.3%). M/z (ESI) = 385.7 (m+h) ⁺ 。

Compound 5 (1 g,2.6 mmol) was dissolved in 2mL of 3-methylmorpholine, a small amount of N-methylpyrrolidone (NMP) was added to aid dissolution, the reaction was microwaved at 100℃for 3h, LC-MS was monitored, the reaction solution was freeze-dried to remove NMP and 3-methylmorpholine and then column chromatography (PE: EA=2:1) was used to separate and purify the product 6+6a in 500mg (yield 42.83%). Molecular weight 450.8 on LC-MS was the product peak, peak time 2.3min was product 6, and peak time 2.55min was product 6a.

Compounds 6 and 6a were combined in 500mg (1.11 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) -1H-pyrazole (700 mg,3.33 mmol), K ₂ CO ₃ (300 mg,2.22 mmol) and Pd (dppf) Cl ₂ (73 mg,0.1 mmol) in 10mL of 1, 4-dioxane and 2mL of water, N ₂ The reaction was carried out overnight at 100℃under protection, and the reaction was monitored by LC-MS, and the product was isolated and purified by column chromatography (PE: EA=1:1) to give Compound 7 (140 mg) +Compound 7a (60 mg) (overall yield 36.3%), M/z (ESI) =497 (M+H) ⁺ 。

Compound 7 (140 mg) was dissolved in 2.5mL of trifluoroacetic acid (TFA), added to 0.5mL of trifluoromethanesulfonic acid (TfOH), and reacted at 40℃for 3h, followed by LC-MS monitoring of the reaction completion, saturated NaHCO ₃ The solution is prepared into neutral, extracted by DCM, distilled under reduced pressure to remove DCM and then dissolved in dimethyl sulfoxide (DMSO) to prepare and purify the solution in liquid phase to obtain 20mg (yield 18.9%) of target product B-2。1H NMR(400MHz,CDCl ₃ )δ9.11(s,1H),7.77(d,J＝1.8Hz,1H),7.65(d,J＝1.8Hz,1H),7.47(d,J＝1.9Hz,1H),7.37(s,1H),6.51(d,J＝1.9Hz,1H),4.44(dd,J＝6.7,2.3Hz,1H),4.19(dd,J＝11.5,3.7Hz,1H),4.05(dd,J＝12.8,2.2Hz,1H),3.94(d,J＝11.6Hz,1H),3.86(dd,J＝11.6,3.0Hz,1H),3.82(d,J＝3.6Hz,3H),3.73(td,J＝11.8,3.0Hz,1H),3.58(td,J＝12.5,3.9Hz,1H),1.48(d,J＝6.8Hz,3H)。

Compound 7a (60 mg) was dissolved in 2.5mL of TFA, added to 0.5mL of TfOH, reacted at 40℃for 3h, and then LC-MS monitored for completion of the reaction, saturated NaHCO ₃ The solution was prepared to be neutral, extracted with DCM, distilled under reduced pressure to remove DCM, and then dissolved in DMSO to prepare and purify the target product B-2a in liquid phase by 10mg (yield 21.9%). ¹ H NMR(400MHz,CDCl3)δ9.20(s,1H),7.75(d,J＝1.9Hz,1H),7.62(d,J＝1.9Hz,1H),7.49(t,J＝2.2Hz,1H),7.11(s,1H),6.67(dd,J＝6.2,2.0Hz,1H),5.29(s,1H),4.25–4.22(m,3H),4.14–4.05(m,2H),3.88(ddd,J＝25.5,17.2,7.1Hz,3H),3.67(td,J＝12.2,3.6Hz,1H),1.32(t,J＝5.8Hz,4H)。

Example 4: preparation of Compound B-3

The specific preparation steps of the compound B-3 are as follows:

compound 1 (25 g,255 mmol) and pinacol borate (44 g,173 mmol) were dissolved in 1.3mg/mL CuSO ₄ To an aqueous solution (408 mg,2.55 mmol) was added 4-methylpyridine (1.2 g,12.75 mmol), and after heating to 50℃the biphenol borate (44 g,173 mmol) was added thereto, and the reaction was stirred at 50℃for 3 hours. After completion of the reaction, TLC was followed by EA extraction to give 55g (yield 57.28%) (60% purity).

Compound 2 (55 g,243 mmol), SM2 (26 g,81 mmol), K ₂ CO ₃ (22 g,162 mmol) and Pd (dppf) Cl ₂ (600 mg,0.81 mmol) in 200mL 1, 4-dioxane at N ₂ The reaction is carried out overnight at 100 ℃ under protection, LC-MS monitors the reaction, and column chromatography (petroleum ether (PE): ethyl Acetate (EA) =2:1) is carried out to obtain 35g (yield 63.2%) of product with m/z (ESI) = 380.2%M+H) ⁺ 。

Compound 3 (35 g,92 mmol) was dissolved in 200mLEtOH, sodium ethoxide (EtONa) (8 g,116 mmol) was added and reacted overnight at 80℃and the reaction monitored by LC-MS, column chromatography (PE: EA=1:1) to give 25g (yield 78.02%) of product, M/z (ESI) =347.8 (M+H) ⁺ . Compound 4 (25 g,72 mmol) was dissolved in 100ml POCl ₃ In the reaction for 3 hours at 100 ℃, the majority of POCl is removed by reduced pressure distillation ₃ After that, saturated NaHCO is slowly added in ice bath ₃ The solution was prepared to be neutral, and purified by column chromatography (PE: ea=1:1) to give 17g (yield 64.57%) of a yellow solid.

Compound 5 (17 g,46.6 mmol) was dissolved in 20mL of 3-methylmorpholine, a small amount of NMP was added to assist dissolution, the reaction was monitored by LC-MS at 130℃for 2H, 3-methylmorpholine and NMP were removed by freeze-drying, and the product was purified by column chromatography (DMC: meOH=20:1) to give 12g (yield 59.98%), M/z (ESI) = 385.7 (M+H) ⁺ 。。

Compound 6 (12 g,28 mmol) was dissolved in 100mL of 1, 4-dioxane and SeO was added ₂ (6.2 g,56 mmol) at 100deg.C overnight, monitoring the formation of the desired product by LC-MS, and simultaneously with a small amount of carboxylic acid, column chromatography (PE: EA=1:1) gives 8g (yield 64.57%) of the product, M/z (ESI) = 444.8 (M+H) ⁺ 。

Compound 7 (8 g,18 mmol) was dissolved in 100mL MeOH and NaBH was added slowly under ice-bath ₄ (2 g,54 mmol), 3H at room temperature, LC-MS monitoring the reaction, column chromatography (PE: EA=1:1) to give 5g (yield 62.22%), M/z (ESI) =446 (M+H) ⁺ 。

Compound 8 (5 g,11.2 mmol) and TEA (2.3 g,22.4 mmol) were dissolved in 30mL of DCM and 4-toluenesulfonyl chloride (TsCl) (3.2 g,16.8 mmol) was added and reacted at room temperature for 3h and the reaction monitored by LC-MS. Quenching with water, extracting with saturated NaHSO ₄ Washing with NaCl solution, anhydrous MgSO ₄ The product after drying was 3.8g (yield 56.49%).

Compound 9 (3.8 g,6.3 mmol) and sodium metabisulfite (1.3 g,12.6 mmol) were dissolved in 20mL of Dimethylformamide (DMF), reacted overnight at room temperature, LC-MS monitored the reaction, column chromatography (DCM: meOH=10:1) after removal of DMF by distillation under reduced pressure was isolated and purified to yield 2.1g (65.27%) of product.

Compound 10 (300 mg,0.6 mmol), 1, 2-dibromoethane (222 mg,1.2 mmol) and tetrabutylammonium bromide (TBAB) (40 mg,0.12 mmol) were dissolved in 3mL of toluene, 1mL of 50% NaOH solution was added thereto and reacted overnight at 60℃to monitor the reaction, toluene and water were removed by distillation under reduced pressure, and 200mg (yield 63.42%) of the purified product was isolated by column chromatography (PE: EA=1:1).

After compound 11 (200 mg) was dissolved in TFA (2.5 mL) and TfOH (0.5 mL) and reacted at 40℃for 3h, LCMS monitored the reaction was complete. Saturated NaHCO under ice bath ₃ The solution was prepared to be neutral, extracted with DCM, dried by spin-drying and then dissolved in DMSO to prepare and isolate 31.04mg (yield 19.99%) of B-3 product in liquid phase. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.09(s,1H),7.85(s,1H),7.71(s,1H),7.58(s,1H),4.63(s,1H),4.23(d,J＝13.1Hz,1H),4.07(d,J＝8.2Hz,1H),3.84(d,J＝11.5Hz,1H),3.72(d,J＝9.3Hz,1H),3.57(t,J＝10.5Hz,1H),3.38(s,1H),3.02(s,3H),1.86(q,J＝5.2Hz,2H),1.52(s,2H),1.30(d,J＝6.6Hz,3H)。

Example 5: preparation of Compound B-4

The specific preparation steps of the compound B-4 are as follows:

compound 1 (see compound 8 in example 4 for preparation) (3.2 g) was dissolved in 20mL of anhydrous dichloromethane. Phosphorus tribromide (4.0 mL) was slowly added dropwise under ice bath conditions, and after the addition, the temperature was naturally raised to room temperature and stirred for 3 hours. LCMS monitored reaction was complete, the reaction was poured into 100ml ice water and the solution was pH adjusted to 7-8 by slow addition of sodium carbonate solids. After extraction with dichloromethane (100 ml×2), the organic phases were combined and dried, filtered and rotary distilled to give 4.2g of crude oil which was used directly in the next step.

Compound 2 (4.2 g, crude) was dissolved in 25mL of DMF, 1.7g of sodium methyl mercaptide was added under ice bath conditions, and the mixture was stirred overnight (16 hours) after naturally warming to room temperature. After the reaction solution was extracted with dichloromethane (100 ml×2), the organic phases were combined and dried, filtered, and rotary distilled to obtain a crude product, which was purified by column (EA/pe=100/0-0/100) to obtain 900mg of compound 3 as a yellow solid in a two-step yield of 26.35%.

Compound 3 (450 mg) was dissolved in ethyl acetate (4 mL), methanol (2 mL) and water (2 mL), and sodium periodate (202 mg,1.0 eq) was added. After the addition, the mixture was stirred at room temperature for 3 hours. LCMS monitored completion of the reaction, the reaction was filtered through celite, the filtrate was extracted with dichloromethane (50 ml×2), the organics combined and dried, filtered, and rotary distilled to give crude product which was purified by column (DCM/meoh=100/0-90/10, 20 min) to give 350mg of compound 4 as a yellow solid in 75.3% yield

Compound 4 (380 mg,0.77 mmol), trifluoroacetamide (174 mg,1.54 mmol), phI (AcO) ₂ (2793 mg,0.85 mmol), mgO (124 mg,3.08 mmol) and Rh ₂ (OAc) ₄ (10.2 mg,0.023 mmol) was dissolved in 8mL dry dichloromethane. Stirring was carried out at room temperature for 16 hours under nitrogen, LCMS monitors that half of starting material remained. The reaction solution was spin-dried and purified by passing through a neutral alumina column (pure ethyl acetate) to give 210mg of compound 5, 40% pure, which was used directly in the next step.

Compound 5 (210 mg,40% purity) was placed in a 100mL single-port bottle, and trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (1 mL) were added. Sealed, stirred at 50℃for 2 hours. LCMS monitoring showed complete reaction, the reaction was poured into 100ml ice water and the solution was pH adjusted to 7-8 by slow addition of sodium carbonate solid. After extraction with dichloromethane (50 mL. Times.2), the organic phases were combined and dried, filtered and rotary distilled to give crude product, which was purified by liquid phase preparation to give 10mg of compound B-4 as a pale yellow solid in 18.6% yield. ¹ H NMR(400MHz,CDCl ₃ )δ12.70(s,1H),9.09(s,1H),7.76(d,J＝1.9Hz,1H),7.60(s,1H),7.44(d,J＝1.9Hz,1H),5.08(dd,J＝13.2,6.6Hz,1H),4.88(dd,J＝13.2,6.7Hz,1H),4.44(d,J＝6.6Hz,1H),4.17(dd,J＝11.5,3.8Hz,1H),4.05(d,J＝12.8Hz,1H),3.93(d,J＝11.6Hz,1H),3.85(dd,J＝11.6,3.0Hz,1H),3.71(td,J＝12.0,3.1Hz,1H),3.59–3.50(m,1H),2.96(s,3H),2.91–2.77(m,1H),1.46(d,J＝6.8Hz,3H)。

Example 6: preparation of Compound B-8

The specific preparation steps of the compound B-8 are as follows:

compound 1 (25 g,71.5 mmol) was taken up in POCl ₃ (150 ml) and Diisopropylethylamine (DIPEA) (10 drops) were added to a 500ml single-necked flask, reacted at 110 ℃ for 3 hours, monitored by LC-MS for reaction, dried DCM was stirred, and PE/ea=3:1 was purified to give product 2 (20 g, 72.36%) as a yellow powder, M/z (ESI) =386 (m+h) ⁺ 。

Compound 2 (3.5 g,9 mmol) was added to DIEA (12 ml), 3- (S) -3-methylmorpholine (3 ml) was added, the reaction vessel was a microwave tube, the reaction was monitored by LC-MS after nitrogen displacement at 120℃for 2 hours, the reaction solution was extracted with DCM/saturated ammonium chloride solution, and PE: EA=2:1 gave product 3 (1.5 g, 36.7%) as a yellow powder. The position of the peak in LC-MS was 2.72min, M/z (ESI) =451 (M+H) ⁺ 。

Compound 3 (1.5 g,3.3 mmol) was dissolved in dioxane (15 ml) and purified water (2 ml), starting material 4 (900 mg,5 mmol), potassium carbonate (920 mg,6.6 mmol) and Pd (dppf) Cl2 (120 mg,0.16 mmol) were added and stirred overnight at 100℃under nitrogen, the reaction was monitored by LC-MS and spin-dry PE/EA=1:1 purified by column chromatography to give product 5 (700 mg, 37.1%). The position of the peak in LC-MS was 2.98min, M/z (ESI) =567 (M+H) ⁺ 。

Compound 5 (300 mg) was dissolved in methanol hydrochloride (5 ml) and added to a 50ml single-necked flask, stirred at room temperature overnight, dried by DCM extraction, dried and filtered to give crude product 6 (250 mg) which was directly used in the next reaction.

Compound 6 (250 mg,0.51 mmol) was added to CH ₃ To CN (6 ml), starting material 7 (294 mg,1.04 mmol) and cesium carbonate (500 mg,1.55 mmol) were added to a 50ml single-necked flask, and the flask was heated to 40℃overnight after displacement with nitrogen, monitored for reaction by LC-MS, filtered and dried, and PE: EA=10:1 gave product 8 (120 mg, 36.1%) as a yellow powder. The position of the peak in LC-MS was 3.18min, M/z (ESI) =640 (M+H) ⁺ 。

Raw material 8 (120 mg,0.18 mmol), trifluoroacetic acid (2.5 ml) and trifluoromethanesulfonic acid (0.5 ml) were charged into a 50ml single-necked flask, reacted at 40℃for 1.5 hours,LC-MS monitored reaction, saturated sodium bicarbonate solution neutralized reaction, extracted with DCM and purified by HPLC to give product B-8 (20 mg, 26.28%) as a yellow powder. ¹ H NMR(400MHz,CDCl ₃ )δ8.99(s,1H),7.84(s,1H),7.66(d,J＝1.8Hz,1H),7.52(d,J＝2.2Hz,1H),7.39(d,J＝2.2Hz,1H),7.32(d,J＝1.8Hz,1H),4.39(d,J＝4.7Hz,1H),4.32–4.26(m,2H),4.10(dd,J＝11.5,3.6Hz,1H),4.05–4.00(m,2H),3.95(dd,J＝12.8,2.2Hz,1H),3.86(d,J＝11.5Hz,1H),3.81(d,J＝2.8Hz,1H),3.65(d,J＝2.9Hz,1H),3.45(d,J＝3.9Hz,1H),1.37(d,J＝6.8Hz,3H)；m/z(ESI)＝323(M+H) ⁺ 。

Example 7: preparation of Compound B-18

The specific preparation steps of the compound B-18 are as follows:

compound 10 (cf. Synthesis of Compound B-3) (200 mg,0.4 mmol) and 1, 4-dibromobutane (169 mg,0.8 mmol) and TBAB (25 mg,0.08 mmol) were dissolved in 2mL of toluene, and then 50% NaOH solution 1mL was added thereto for reaction at 60℃overnight, and the peak of the product was monitored by LC-MS. Toluene and water were removed by distillation under the reduced pressure, and 110mg (yield 49.71%) of the purified product was isolated by column chromatography (PE: ea=1:1).

After compound 11 (110 mg) was dissolved in TFA (2.5 mL) and TfOH (0.5 mL) and reacted at 40℃for 3h, LCMS monitored the reaction was complete. Saturated NaHCO under ice bath ₃ The solution was prepared to neutrality, extracted with DCM, dried by spin-drying and then dissolved in DMSO for liquid phase preparation to isolate 26mg (30.0% yield) of product. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.05(s,1H),7.71(s,1H),7.60(s,1H),7.56(s,1H),4.61(d,J＝4.9Hz,1H),4.20(d,J＝12.2Hz,1H),4.07(d,J＝8.8Hz,1H),3.84(d,J＝11.4Hz,1H),3.73(dd,J＝12.5,3.3Hz,1H),3.58(dd,J＝11.7,9.3Hz,1H),3.38(dd,J＝7.5,3.7Hz,1H),3.10(dd,J＝13.3,7.2Hz,2H),2.86(s,3H),2.81–2.66(m,2H),1.98–1.87(m,2H),1.69(d,J＝2.1Hz,2H),1.28(d,J＝6.7Hz,3H)。

Example 8: preparation of Compound B-1

The specific preparation steps of the compound B-1 are as follows:

to a mixed solution of dioxane (10 mL) and water (1 mL) was added compound 1 (75 mg,0.17 mmoL), followed by potassium carbonate (47 mg,0.34 mmoL), pd (dppf) Cl2 (62 mg,0.08 mmoL), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) -1H-pyrazole (71 mg,0.34 mmoL). The reaction was carried out at 100℃for 3 hours under nitrogen protection. After completion of the reaction, the mixture was purified by spin-dry column chromatography (DCM: meoh=30:1) to give the product as a yellow solid (50 mg, 61%). (ESI) M/z=480.3 (m+h) ⁺ ,t＝2.443min(215nm)。

Compound 2 (50 mg,0.10 mmoL) was dissolved in t-BuOK/THF (2 ml) at a concentration of 1M, and DMSO (1.5 ml) was added to the above mixture in a 100ml three-necked flask. Oxygen is blown in for about 10min while stirring, the reaction is monitored by an LC-MS, DMSO and t-BuOK/THF with the concentration of 1M are added, the oxygen is blown in for 10min, the raw materials are reduced and the products are increased after the LC-MS is monitored, but the raw materials are still unreacted, and a yellow solid product (5 mg, 13%) is obtained after spin drying. ¹ H NMR(400MHz,CDCl ₃ )δ7.76(s,1H),7.63(s,1H),7.46(s,1H),7.33(s,1H),6.49(s,1H),5.72(s,2H),4.41(d,J＝6.3Hz,1H),4.18(dd,J＝11.4,3.1Hz,1H),4.01(d,J＝12.7Hz,1H),3.93(d,J＝11.5Hz,1H),3.87(s,1H),3.83(d,J＝0.8Hz,3H),3.76–3.67(m,1H),3.55(td,J＝12.5,3.4Hz,1H),2.80(s,3H),1.46(d,J＝6.8Hz,4H).(ESI)m/z＝391.2(M+H) ⁺ ,t＝1.896min(215nm)。

The preparation of the compounds B-5, B-6, B-7, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-19, B-20, B-21, B-22, B-23, B-24, B-25 and B-26 refer to the synthesis of the compound B-2 of example 3, and their structural formulae and the results of the nuclear magnetic characterization are shown in Table 2.

Table 2: results of structural formula and nuclear magnetic characterization of each Compound

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Example 9: preparation of Compound C-1

The specific preparation steps of the compound C-1 are as follows:

compound 1 (2 g), benzyl bromide (1.3 ml), cesium carbonate (10.1 g) and 80ml MeCN were added to a 250ml single neck flask, reacted at 100℃for 2 hours, and the reaction was monitored by LC-MS and used directly for the next reaction without treatment.

Compound 3 (3-amino-2-chloro-pyridine-4-carboxylic acid methyl ester) (1.5 g), pd (PPh) ₃ ) ₂ Cl ₂ (723 mg) and 3ml of water were added to the reaction mixture in the first step, nitrogen substitution was performed, the reaction was monitored by LC-MS, and the reaction was dried by spin-drying with DCM, and PE: EA=10:1, yielding 1.0g of Compound 4 in 31.5% yield, M/z (ESI) =308 (M+H) ⁺ 。

Compound 4 (3 g) and 30ml of NH at a concentration of 7M ₃ MeOH was added to a 48ml tube seal and reacted for 3 days, and LC-MS monitoring showed that most of the starting material did not participate in the reaction, column chromatography (PE/EA) separated the product from the starting material, and the starting material was continuously fed with NH at a concentration of 7M ₃ Reaction with MeOH finally gave Compound 5 (708 mg) as a yellow solid in 27.33% yield.

Compound 5 (500 mg) and triphosgene (506 mg) were added to 30ml of THF, reacted overnight at 70℃in a 100ml single flask, monitored by LC-MS for completion of the reaction, and spin-dried to give 624mg of crude compound 6, M/z (ESI) =319 (M+H) ⁺ Directly used in the next step.

Compound 6 (400 mg), POCl ₃ (6 ml) and DIPEA (4 drops) were added to a 10ml microwave tubeIn the reaction, the reaction is carried out at 110 ℃ overnight, and the product is extremely unstable and can react with water or alcohol, so the product is directly spin-dried and put into the next reaction.

Compound 7 (400 mg), alCl ₃ (360 mg) was added to 30ml of DCE, the reaction vessel was a three-necked flask, 1.6ml of N-methylpyrrole was added dropwise after the displacement with nitrogen, the reaction was completed at 80℃for 4 hours, the reaction was monitored by LC-MS, the reaction solution was extracted with DCM, and PE: EA=5:1 was purified by column to give 200mg of Compound 8 as a product, the yield of the above three steps was 29.27%.

Compound 8 (200 mg), 3-methylmorpholine (200 mg), DIPEA (0.1 ml) and NMP (5 ml) were put into a 20ml microwave tube and reacted at 150 ℃ for 1h, and the reaction was completed as monitored by LC-MS, PE: ea=1: 1 column purification gave 150mg of compound 9 as a yellow solid in 64.58% yield, M/z (ESI) =465 (m+h) ⁺ 。

Compound 9 (100 mg) was dissolved in DMSO (1.5 ml), and 1.0-M t-BuOK/THF (2 ml) was added to the above mixture. Oxygen is blown in for about 10min while stirring, LC-MS monitors the reaction conversion to about 50%, DMSO and t-BuOK/THF with the concentration of 1.0M are added, oxygen is blown in for 10min, the raw materials are reduced and the products are increased after LC-MS monitors, but the raw materials are still unreacted, and the 15mg yellow solid compound C-1 is prepared by spin drying and liquid phase feeding, and the yield is 18.60%. ¹ H NMR(400MHz,CDCl ₃ )δ8.40(d,J＝5.5Hz,1H),7.91(d,J＝5.5Hz,1H),7.72(d,J＝1.7Hz,1H),7.30(d,J＝1.7Hz,1H),6.97(s,1H),6.84(dd,J＝3.8,1.5Hz,1H),6.33(dd,J＝3.8,2.7Hz,1H),4.82(d,J＝4.2Hz,1H),4.43(d,J＝12.6Hz,1H),4.12(dd,J＝11.2,3.3Hz,1H),4.00(s,3H),3.90(d,J＝11.4Hz,1H),3.80(dd,J＝11.4,2.9Hz,1H),3.66(td,J＝11.8,2.8Hz,1H),3.58–3.46(m,1H),1.46(d,J＝6.8Hz,3H)。

Preparation of Compounds C-2, C-3, C-4, C-5, C-6, C-7 and C-8 reference was made to the synthesis of Compound C-1 of example 9. The structural formulas and the nuclear magnetic characterization results of the compounds C-2, C-3, C-4, C-5, C-6, C-7 and C-8 are shown in Table 3.

Table 3: structural formulas and nuclear magnetic characterization results of compounds C-2, C-3, C-4, C-5, C-6, C-7 and C-8

Biological evaluation test example 1: inhibition of ATR enzyme by Compounds the purpose of this assay is by assaying IC ₅₀ The inhibitory activity of the test compounds on ATR kinase in humans was evaluated. 1. Experimental materials:

2. test instrument

Chinese name	English name	Model number	Manufacturer' s
				Kinase detector/microfluidic system	Caliper	EZ ReaderII	Perkin Elmer

3. Experimental procedure

The specific experimental procedure for the mobility shift analysis (Mobility shift assay) detection experiment is as follows:

All compounds were formulated with 100% dmso to initial concentrationsTransfer 40. Mu.L into 384 well Echo plates (Labcyte PP-0200); dilutions were made with 100% DMSO and 40 μl of 100% DMSO was transferred to two empty wells as controls without compound and without enzyme. 60nL of compound was transferred into 384 well reaction plates using Echo 550 (Corning 3573). Transfer 10. Mu.L of the sample with 1-fold kinase buffer (50mM HEPES pH 7.5,10mM MnCl) ₂ 1mM DTT and 0.0055% Brij-35) configured ATR (final concentration of 5 nM) in 2-fold kinase solution to 384-well plates, negative control wells were added with 1-fold kinase buffer. Incubating for 10 minutes at room temperature after uniformly mixing; FAM-labeled polypeptide (final concentration: 3000nM, 5-FAM-AK-17), ATP (final concentration: 2. Mu.M) was added to 1-fold kinase buffer to form a 2-fold substrate solution; transferring 10 mu L of the 2-fold substrate solution to a 384-well plate reaction plate to initiate reaction; the reaction was stopped by adding 25. Mu.L of stop solution (100mM HEPES pH 7.5, 50mM EDTA,0.2% Coating Reagent #3and 0.015% Brij-35) to 384-well plates after incubation at 28℃for 240 min.

Conversion data were read on a calipers z Reader ii. Conversion to inhibition data Percent inhibition = [ (MA-X)/(MA-MI) ]X 100%. "MI" is the control well reading for the reaction without enzyme; "MA" is the control well reading with DMSO added; "X" is the compound's reading from different wells. Fitting IC with XLFIT exceladd-in version 5.4.0.8 ₅₀ Values. Fitting formula y=bottom+ (Top-Bottom)/(1+ (IC) ₅₀ /X)^HillSlope)

4. The experimental results are shown in table 4:

table 4: IC of compound ₅₀ Value of

In Table 4, the positive control BAY1895344 had the structure ofa represents IC ₅₀ Between 10 and 100nM, b represents IC ₅₀ Greater than 100nM and less than or equal to 1000nM, c represents greater than 1000nM.

5. Conclusion of the test

This experiment shows that the ATR enzyme activity of many of the compounds of the examples is superior or comparable to the positive control BAY 1895344.

Test example 2: compound for killing colon cancer cell

By detecting intracellular ATP content, the method is based on IC ₅₀ Size evaluation the inhibitory effect of the compounds of the present disclosure on HT29 and LoVo cell proliferation. The specific experimental method is as follows:

1. experimental materials and instruments:

LoVo (human colon cancer cells), HT29 (human colon adenocarcinoma cells), fetal Bovine Serum (FBS) (BI, 04-002-1A), F-12K medium (Gibco, 21127-022), moCoy's 5A medium (Gibco, 16600-082), sodium pyruvate (Invitrogen, 11360-070), DMSO (Sigma, 276855-1L), penicillin-streptomycin (Hyclone, SV 30010), cellTite-Glo kit (Promega, G7571), 96-well Cell culture plates (corn, 3903), 0.25% pancreatin-EDTA (Invitrogen, 25200-072), XLFIT software (IDBS, version 5.5.0.5), enzyme-labeled instrument (EnSpire), and Cell counter (Vi-Cell XR).

2. Experimental conditions:

3. the experimental steps are as follows:

LoVo and HT29 cells were resuscitated separately, and a third generation of cell lines with good growth status were selected. The cells were collected, the cell suspension was adjusted to the appropriate concentration, added to a 96-well plate, 100. Mu.L/well, and the culture plate was placed at 37℃with 5% CO ₂ The incubator was left overnight. Compounds were added to corresponding well plates using an automated dosing instrument at a final concentration of 10 μm, 3-fold dilution, 3-fold wells, 9 concentrations in comparison to 0.3% DMSO. 37 ℃ 5% CO ₂ Incubators were incubated for 72h. The CellTiter-Glo Buffer was thawed at room temperature and the lyophilized CellTiter Glo substrate equilibrated to room temperature. Adding CellTiter-Glo BufferInto CellTiter Glo substrate and thoroughly mixed. The cell plates were taken out and equilibrated to room temperature, 100. Mu.L of the well-mixed CellTiter Glo reagent was added to each well, shaken for 30min in the absence of light, and incubated for 30min. Placing the culture plate into an enzyme-labeled instrument reading plate, recording the reading result, calculating the inhibition rate, drawing a drug effect inhibition rate curve by using XLFIT, and calculating the IC ₅₀ Values.

4. Experimental data: measured IC ₅₀ The values are shown in Table 5.

Table 5: IC of compound to cell proliferation experiments ₅₀ Value of

Compounds of formula (I)	HT29 IC ₅₀ (μM)	LoVo IC ₅₀ (μM)
			A-3	0.852	0.141
A-6	0.305	0.045
			A-7	0.331	0.081
B-2	0.705	0.165
			B-3	0.103	0.016
B-11	0.319	0.043
			C-3	0.218	0.024
C-4	0.321	0.056
			BAY1895344	0.456	0.103

Test example 3: metabolic stability experiments of Compounds in liver microsomes

The test was performed to evaluate the metabolic stability of the test compounds when incubated with human, rat, mouse, dog, monkey liver microsomes.

1. Experimental materials and instruments:

name of the name	Suppliers of goods	Lot number
			Acetonitrile	Sigma	WXBD5828V
DMSO	Amresco	21A2756279
			Water and its preparation method	Baby haha	NA
NADPH	MCE	93125

2. Experimental conditions:

instrument for measuring and controlling the intensity of light	Suppliers of goods	Model number
			-20 ℃/4 ℃ low-temperature refrigerator	Sea Er	BCD-269WDGB
Centrifuge (6000 rpm)	ThermoFisher	Heraeus X3R
			Electronic balance	METTLER TOLEDO	XS104
Constant temperature water bath oscillator	Shanghai Yiheng	DK-8AX
			PH meter	METTLER TOLEDO	FE28-STANDARD
Microplate oscillator	IKA	MTS 2/4
			Ultralow temperature preservation box (-80 ℃)	Thermo Fisher	FDE40086FV
Vortex oscillator	Hangzhou ao Sheng	MX100-4A

3. The experimental steps are as follows:

3.1 preparation of buffer C:

buffer a:1.0L of 0.1M potassium dihydrogen phosphate buffer (containing 1.0mM EDTA);

buffer B:1.0L of 0.1M dipotassium hydrogen phosphate buffer (containing 1.0mM EDTA);

buffer C: buffer a was added to 700mL of buffer B and stopped when pH reached 7.4.

3.2 Preparation of 10mM stock solution:

test compounds and controls were dissolved in DMSO to prepare 10mM stock solutions.

3.3 preparation of dosing solution:

500 μm solution: mu.L of 10mM stock solution was added to 190. Mu.L of ACN;

1.5. Mu.M dosing solution (dissolved in liver microsome solution):

18.75. Mu.L of 20mg/mL liver microsomes were added to 479.75. Mu.L of buffer C, followed by 1.5. Mu.L of 500. Mu.M solution, and mixed with gentle shaking.

3.4 Preparation of 6mM NADPH solution:

NADPH was weighed and then an appropriate amount of buffer C was added to prepare a 6mM NADPH solution.

3.5 30. Mu.L of 1.5. Mu.M dosing solution was added to wells set at different time points (0 min, 5 min, 15 min, 30 min, 45 min) on 96-well plates, with a duplicate number of 2.

3.6 preparation of 0 min samples: mu.L of ACN (with internal standard) was added to the 0 min well followed by 15. Mu.L of 6mM NADPH solution.

3.7 96-well plates containing 1.5. Mu.M dosing solution and NADPH solution were pre-heated in a 37℃water bath for 5 minutes.

3.8 the pre-warmed 15. Mu.L of 6mM NADPH solution was added to the wells set at 5 minutes, 15 minutes, 30 minutes, 45 minutes, the reaction was started and timing was started.

3.9 the reaction was terminated by adding 135. Mu.L of ACN (with internal standard) at the time of 5 minutes, 15 minutes, 30 minutes and 45 minutes indicated by the timer. Vortex for 10 min and centrifuge the samples on a centrifuge (Thermo multiplex. Times.3R) using 5594 Xg for 15 min.

3.10 50. Mu.L of supernatant from the centrifuged sample was transferred to a 96 well sample plate to which 50. Mu.L of water had been added, mixed and finally the sample was sent to LC-MS/MS analysis.

4. Experimental data:

description: HLM: human liver microsomes; RLM: rat liver microsomes; MLM: mouse liver microsomes; DLM: dog liver microsomes; MKLM: monkey liver microsomes. T (T) _1/2 (min) is half-life in minutes. The results are shown in the following table:

5. Conclusion of experiment:

most of the compounds of the examples of the present invention had better hepatic microsomal metabolic stability than the control compounds.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

The embodiment numbering is for each particular embodiment only and does not result in structural interrelationships between the various embodiments.

Claims

1. A compound of the structure shown in formula (I), or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof:

when X is ₂ N, X of a shape of N, X ₃ Is CIn H, X ₃ Optionally further by R ³ Substitution; r is R ¹ Is a 5 to 7 membered heteroaryl group containing 1-3N; r is R ² Is hydrogen, halogen, -NR ⁴ R ⁵ 、CN、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyloxy, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyl, 4-to 10-membered heterocyclyl C ₂ -C ₃ Alkenyl, phenyl, 4-to 10-membered heteroaryl, - (CO) OR ⁴ 、-(CO)NR ⁴ R ⁵ 、-(SO ₂ )R ⁶ 、-(SO)R ⁶ 、-SR ⁶ 、-(SO ₂ )NR ⁴ R ⁵ 、-NR ⁴ (SO ₂ )R ⁶ 、-((SO)＝NR ⁸ )R ⁷ 、-CR ⁶ R ⁷ (SO ₂ )R ⁿ 、-CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ 、-N＝(SO)R ⁶ R ⁷ 、-(PO)(OR ⁴ ) ₂ 、-(PO)(OR ⁴ )R ⁷ Or- (PO) (R ⁷ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyloxy, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkyl, 4-to 10-membered heterocyclyl C ₂ -C ₃ Alkenyl, phenyl or 4 to 10 membered heteroaryl optionally substituted with at least one of the following groups: halogen, -OH, -NR ⁴ R ⁵ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl C ₀ -C ₃ Alkyl, phenyl, - (CO) OR ⁴ 、-(CO)NR ⁴ R ⁵ 、-NR ⁴ (CO)R ⁷ 、-NR ⁵ (CO)OR ⁴ 、-NR ⁵ (CO)NR ⁴ R ⁵ 、-(SO ₂ )R ⁶ 、-(SO)R ⁶ 、-SR ⁶ 、-(SO ₂ )NR ⁴ R ⁵ 、-NR ⁴ (SO ₂ )R ⁶ 、-((SO)＝NR ⁸ )R ⁷ 、-CR ⁶ R ⁷ (SO ₂ )R ⁿ 、-CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ 、-N＝(SO)R ⁶ R ⁷ 、-(PO)(OR ⁴ ) ₂ 、-(PO)(OR ⁴ )R ⁷ 、-(PO)(R ⁷ ) ₂ Furyl or pyrazolyl, wherein the C ₁ -C ₆ Alkyl is optionally substituted with one OR more halogen, -OH, phenyl, - (CO) OR ⁴ 、C ₃ -C ₆ Cycloalkyl, 3-to 10-membered heterocyclyl C ₀ -C ₃ Alkoxy substitution; r is R ³ Is hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy or halogen;

R ⁹ is halogen, OH, -NR ⁴ R ⁵ 、CN、NO ₂ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, - (CO) OR ⁴ Or (CO) NR ⁴ R ⁵ ；

R ⁿ Is C ₁ -C ₄ Alkyl or C ₃ -C ₇ Cycloalkyl groups.

2. The compound of claim 1, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein the compound is of formula (Ia), (Ib) or (Ic):

3. A compound according to claim 1 or 2, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, wherein R ¹ At least one selected from the following groups:

4. a compound according to claim 3, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein R ¹ At least one selected from the following groups:

5. a compound according to any one of claims 14, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein R ¹ Is that

6. A compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein R ² Is C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, 4-to 6-membered heterocyclyl C ₁ -C ₃ Alkoxy, 4-to 6-membered heteroaryl, -CR ⁶ R ⁷ (SO ₂ )R ⁿ or-CR ⁶ R ⁷ ((SO)＝NR ⁸ )R ⁿ ；

-(CO)OR ⁴ 、C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ Alkyl or 3-to 6-membered heterocyclic C ₀ -C ₃ Alkyl, wherein, the C ₁ -C ₃ Alkyl is optionally substituted with one OR more halogens, -OH, - (CO) OR ⁴ 、C ₃ -C ₆ Cycloalkyl, 3-to 5-membered heterocyclyl C ₀ -C ₃ Alkoxy substitution;

R ⁴ is hydrogen or C ₁ -C ₂ An alkyl group;

R ⁸ is hydrogen or C ₁ -C ₂ An alkyl group;

R ⁿ is C ₁ -C ₂ Alkyl or C ₃ -C ₇ Cycloalkyl groups.

7. The compound of any one of claims 1-5, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein the 4-to 10-membered heteroaryl is pyrrolyl, pyrazolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, 1H-pyrrolo [2,3-b ] pyridyl, oxadiazolyl, indolyl, benzothienyl, quinolinyl, or isoquinolinyl.

8. A compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein R ² Having at least one of the following groups:

9. the compound of claim 8, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, wherein R ² One selected from the following groups:

10. the compound of any one of claims 1-9, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, comprising at least one of the following structures:

11. A composition comprising a compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a salt thereof, or a mixture thereof.

12. Use of a compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, or a composition according to claim 11, for the manufacture of a medicament for the prophylaxis or treatment of hyperproliferative diseases.

13. The use according to claim 12, wherein the hyperproliferative diseases include psoriasis, keloids and other skin affecting hyperplasia, benign prostatic hyperplasia, tumors.

14. The use according to claim 13, wherein the tumour comprises melanoma, brain tumour, oesophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumour, multiple myeloma, B-cell lymphoma, polycythemia vera, leukaemia, thyroid tumour, bladder cancer or gall bladder cancer.

15. A combination composition comprising a compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture of same, or a composition according to claim 11; and other drugs for preventing or treating hyperproliferative diseases.

16. The combination composition of claim 15, wherein the additional agent for preventing or treating hyperproliferative diseases comprises at least one of the following anticancer agents:

cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, carboplatin, camptothecine, irinotecan, topotecan, doxorubicin, mitoxantrone, methylhydroxy ellipticine, mindapippine, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2' -deoxyuridine, fludarabine, cytarabine, pralafadromide, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, nivolumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, you Tuozhu monoclonal antibody, famuzumab, rituximab, alemtuzumab, irauzumab, irinotecan, cabazithromycin Toxomomab, bentuximab, darinamide, erltuzumab, ofatuzumab, denotuximab, bei Lintuo outuzumab, avastin, herceptin, mevalonate, imatinib, gefitinib, erlotinib, octenib, afatinib, ceritinib, ai Leti ni, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temozol, everolimus, vorinostat, luo Mi digoxin, panitustat, belinostat, tamoxifen, letrozole, fulvestrant, migazone, octreotide, retinoic acid, ruba, zoledronic acid, bortezomib, carfilomide, irinotecan, sha Zuomi, sorafenib, dieldomide, salvoxamine, lenalidomide, pontine, ponamine, recombinant human interleukin-2, recombinant interleukin-2 Sipueucel-T, paboscalid, olaparib, nilapatinib, ruicarpabab, and Taraxazopanib.

17. Use of a combination composition according to claim 15 or 16 for the manufacture of a medicament for the prevention or treatment of hyperproliferative diseases.