A class of pyridazinone compounds, their preparation and applications

Abstract

The present invention discloses a class of pyridazinone compounds, their preparation and applications, specifically a pyridazinone compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, a preparation method thereof and pharmaceutical applications thereof, wherein the definitions of each group are as described in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, it relates to a class of pyridazinone compounds, which have good PARP7 inhibitory activity and can be used to prepare therapeutic and prophylactic drugs for treating diseases related to PARP7 activity, expression or mutation. Background Art

[0002] PARP stands for poly-ADP-ribose polymerase, that is, poly ADP-ribose polymerase, which participates in a series of cellular processes including DNA repair, genomic stability, etc. This protein family consists of 17 members, all of which contain a common catalytic domain of about 230 amino acids. Four members of the family (PARP1, 2, 5a and 5b) can attach to their target substrates and catalyze the synthesis of poly ADP-ribose (PAR) chains, and the remaining members are called monoPARP. Except for PARP13, they can only transfer a single ADP-ribose (MAR) moiety, while PARP13 seems to lack ADP-ribosyltransferase activity.

[0003] Lynparza (olaparib) is the world's first marketed PARP inhibitor based on the DNA damage response (DDR) mechanism, and was first acceleratedly approved by the FDA in December 2014. Currently, there are 4 PARP inhibitors marketed globally. In addition to olaparib, they also include rucaparib, niraparib, and talazoparib. In terms of indications, the diseases for which PARP inhibitors have been approved and are under research include multiple solid tumors such as ovarian cancer, pancreatic cancer, fallopian tube cancer, castration-resistant prostate cancer, urothelial cancer, small cell lung cancer, breast cancer, peritoneal cancer, etc. However, among the approved PARP inhibitors, currently more are concentrated in BRCA-mutated tumor types.

[0004] The MonoPARP protein family plays a role in various stress responses associated with the development of cancer, inflammatory diseases, and neurodegenerative diseases. Its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival. Studies have found that many cancer cells rely on PARP7 for intrinsic cell survival, and PARP7 enables cancer cells to "hide" from the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively releasing the "brakes" that cancer uses to avoid the immune system and inhibit innate and adaptive immune mechanisms. In several preclinical cancer models, PARP7 inhibitors have shown persistent tumor growth inhibition, effective anti-proliferative activity, and restoration of interferon signaling. Ribon Therapeutics' PARP7 inhibitor RBN2397 has already initiated a Phase I clinical trial.

[0005] Therefore, there is an urgent need for more therapeutics with unique mechanisms, high efficiency, and low toxicity to enter the clinic for PARP7-dependent tumors. Discovering and finding highly efficient, low-toxic, and structurally novel PARP7-targeted drugs is a hot area in the industry. Summary of the Invention

[0006] One of the technical problems to be solved by the present invention is to provide a novel PARP7 inhibitor for preparing anti-tumor drugs.

[0007] The solution to the above technical problem is as follows:

[0008] In the first aspect of the present invention, there is provided a pyridazinone compound represented by the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph, or prodrug thereof,

[0009]

[0010] wherein: X is independently selected from hydrogen, halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, C1-C6 alkylthio, 3-6 membered cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-6 membered cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl may be optionally substituted by one or more R x substituents, and R x is independently selected from deuterium, halogen, amino, hydroxy, cyano, mono-C1-C3 alkylamino, bis-C1-C3 alkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C1-C6 alkyl, and the number of substituents is one or more;

[0011] Y 1 、Y2 and Y 3 are each independently selected from O, S(O) p , NR y , C(=O), C(=O)O, C(=O)NR y , S(O) p NR y , NR y C(=O)NR y , wherein R y is independently selected from hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, and said R y may optionally be substituted by one or more R y1 groups, and R y1 is independently selected from deuterium, halogen, amino, hydroxy, cyano, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl-C1-C3 alkyl-; p is 0, 1 or 2;

[0012] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8Each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-10 membered cycloalkyl-C1-C3 alkyl-, 3-10 membered heterocycloalkyl-C1-C3 alkyl-, 6-12 membered aryl-C1-C3 alkyl-, 5-12 membered heteroaryl-C1-C3 alkyl-, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkyl acyl, -C(=O)O-, -C(=O)NH-, sulfonamido, sulfonylimide, ureido, sulfonylurea, guanidino, amidino, carbamate, mono-C1-C3 alkyl substituted amino, di-C1-C3 alkyl substituted amino; the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-10 membered cycloalkyl-C1-C3 alkyl-, 3-10 membered heterocycloalkyl-C1-C3 alkyl-, 6-12 membered aryl-C1-C3 alkyl-, 5-12 membered heteroaryl-C1-C3 alkyl-, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkyl acyl may be substituted by one or more substituents selected from the group consisting of: halogen, deuterium, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, 3-10 membered cycloalkyl;

[0013] Or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Any two groups among them may form a 3-10 membered saturated or unsaturated or partially unsaturated ring system through a carbon chain or a heteroatom;

[0014] Or, R 1 Or R 2 Together with Ry and the atoms to which they are attached form a 4-10 membered heterocycloalkyl, that is, R 1 Or R 2 Together with the atoms to which they are attached and Y1 form a 4-10 membered heterocycloalkyl;

[0015] m and n are each independently selected from integers of 1-3;

[0016] Cy 1 Independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered spirocyclic group, 4-12 membered bridged cyclic group, 4-12 membered fused cyclic group;

[0017] Cy 2Independently selected from 6-10-membered aryl-fused 4-10-membered saturated or partially unsaturated ring systems or 5-10-membered heteroaryl-fused 4-10-membered saturated or partially unsaturated ring systems;

[0018] R 9 and R 10 are each independently selected from one or more of carbonyl, hydrogen, halogen, C1-C3 alkyl or halo-C1-C3 alkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 alkylcarbonyl, 3-6-membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;

[0019] One or more (e.g., 1, 2, 3, 4, 5) hydrogen atoms on any of the above groups may be substituted with substituents selected from the group consisting of, but not limited to, deuterium, halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6-membered cycloalkyl or 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkylalkyl; wherein the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, the ring system contains saturated or partially unsaturated ring systems such as spiro rings, bridged rings, fused rings, annulated rings, etc.; the saturated or partially unsaturated ring system may optionally contain 1-3 heteroatoms selected from the group consisting of N, O, P or S; the saturated or partially unsaturated ring system includes, but is not limited to, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl.

[0020] In some preferred embodiments, the compound of general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, is preferably a compound represented by general formula (IIa-IIf),

[0021]

[0022] wherein ring D is independently selected from: 5-12-membered monocyclic or polycyclic groups, and the ring system includes, but is not limited to

[0023]

[0024] wherein the *a end is connected to Y 3 connected;

[0025] Ring E is independently selected from: wherein the *a end is connected to the parent pyridazine ring end;

[0026] Ring F and ring G are each independently selected from 5-12-membered cycloalkyl or heterocycloalkyl, 5-10-membered aryl or heteroaryl;

[0027] R 15 、R 16 、R 17 are each independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 alkylcarbonyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;

[0028] In some preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, Cy 2 is

[0029] wherein Z 1 and Z 2 are each independently selected from N and CR 11 , M1, M2, M3 are each independently selected from -(CR 12 R 13 )t-, -NR 14 , -C(O)-, -O-, -S(O)q- or -CH=CH-;

[0030] R 11 is independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 alkylcarbonyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;

[0031] R 12 and R 13 are each independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 alkylcarbonyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;

[0032] R 14 is independently selected from hydrogen, C1-C3 haloalkyl, C1-C3 alkoxyC1-C3 alkyl, C1-C3 hydroxyalkyl, substituted or unsubstituted amino-C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the substituents in the substituted amino-C1-C3 alkyl are independently selected from one or more of the following groups: halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylC1-C3 alkyl;

[0033] t is independently selected from integers of 1 - 3; q is independently selected from integers of 0 - 2.

[0034] In some preferred embodiments, the compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, is preferably of the general formula shown in (III - 1) or (III - 2),

[0035]

[0036] wherein X is preferably F, Cl, Br, CH3, CF3; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are each independently preferably selected from hydrogen, deuterium, fluorine, methyl, ethyl; a is preferably an integer of 0 - 6; Z 1 is preferably CH, C - F, C - Me, N.

[0037] In some preferred embodiments, the compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, is preferably as shown in (IV - 1), (IV - 2), (IV - 3), (IV - 4), (IV - 5) or (IV - 6)

[0038]

[0039]

[0040] wherein X, R 10 , Z 1 and a are as described above.

[0041] In some preferred embodiments, when X is C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 alkylthio, C2 - C6 alkenyl, C2 - C6 alkynyl, it is preferably C1 - C3 alkyl, C1 - C3 alkoxy, C1 - C3 alkylthio, vinyl, ethynyl; more preferably methyl, methoxy, methylthio;

[0042] In some preferred embodiments, when R 1 , R 2 , R 3 , R 4, R 5 , R 6 , R 7 , R 8 When independently selected from 3- to 10-membered cycloalkyl or heterocycloalkyl, 5- to 12-membered aryl or heteroaryl, 3- to 10-membered cycloalkyl-C1-C3-alkyl-, 3- to 10-membered heterocycloalkyl-C1-C3-alkyl-, 6- to 12-membered aryl-C1-C3-alkyl-, 5- to 12-membered heteroaryl-C1-C3-alkyl-, it is preferably 3- to 6-membered cycloalkyl or heterocycloalkyl, 5- to 8-membered aryl or heteroaryl, 3- to 6-membered cycloalkyl-C1-C3-alkyl-, 3- to 6-membered heterocycloalkyl-C1-C3-alkyl-, 6- to 10-membered aryl-C1-C3-alkyl-, 5- to 8-membered heteroaryl-C1-C3-alkyl-;

[0043] In some preferred embodiments, R 1 or R 2 When together with Ry and the atoms to which they are attached form a 4- to 10-membered heterocycloalkyl, the 4- to 10-membered heterocycloalkyl is a 5- to 8-membered heterocycloalkyl.

[0044] In some preferred embodiments, R 1 or R 2 When together with Ry and the atoms to which they are attached form a 4- to 10-membered heterocycloalkyl, it is preferably where the *a end is connected to the parent pyridazine ring and the *b end is connected to the chain end.

[0045] In some preferred embodiments, Cy 1 is preferably a 5- to 8-membered cycloalkyl, 5- to 8-membered heterocycloalkyl, 5- to 8-membered spirocyclic group, 5- to 8-membered bridged cyclic group, 5- to 8-membered fused cyclic group; more preferably

[0046]

[0047] where the *b end is connected to Y 3 and the *a end is connected to Cy 2 ;

[0048] In some preferred embodiments, Cy 2 is preferably selected from 6- to 10-membered aryl-fused 5- to 8-membered saturated or partially unsaturated ring systems or 5- to 10-membered heteroaryl-fused 5- to 8-membered saturated or partially unsaturated ring systems; more preferably 6- to 10-membered aryl-fused 5- to 8-membered cycloalkyl, 6- to 10-membered aryl-fused 5- to 8-membered heterocycloalkyl, 6- to 10-membered aryl-fused 5- to 8-membered cycloalkenyl, 5- to 10-membered heteroaryl-fused 5- to 8-membered cycloalkyl, 5- to 10-membered heteroaryl-fused 5- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl-fused 5- to 8-membered cycloalkenyl; further preferably

[0049] In some preferred embodiments, R 9 is independently preferably selected from 1 - 3 of H, F, -CF3, CN, CH3CH2-, CH3-, CH3O-, -CH2CN, and the number is preferably 1 - 3.

[0050] In some preferred embodiments, R 10 is independently preferably selected from 1 - 3 of H, F, -CF3, CN, CH3CH2-, CH3-, CH3O-, -CH2CN.

[0051] The present invention provides a method for preparing a compound of formula I, which method generates an amide compound through a condensation reaction of an acid and an amine:

[0052]

[0053] Preferably, the steps are carried out in respective solvents, and the solvents are selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0054] Preferably, the combination of condensing agents is selected from the group consisting of: DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), CDI (carbonyldiimidazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole), BOP (Carter's reagent), PyBOP (1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate), HATU (2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), etc., or a combination thereof.

[0055] Preferably, the inorganic bases are selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic bases are selected from the group consisting of: pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), hexamethyldisilazide lithium, hexamethyldisilazide sodium, dimethylpyridine, or a combination thereof.

[0056] Preferably, the acids are selected from the group consisting of: hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or a combination thereof.

[0057] A class of preferred compounds of general formula (I) provided by the present invention includes, but is not limited to, the following structures:

[0058]

[0059]

[0060]

[0061] Another object of the present invention is to provide a drug and its composition for treating or preventing tumors. The technical solutions for achieving the above object are as follows:

[0062] A pharmaceutical composition for treating tumors, which is composed of the pyridazinone compound represented by the above general formula (I), or its pharmaceutically acceptable salt, or its enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug and a pharmaceutically acceptable carrier.

[0063] Another object of the present invention is to provide a use of the above compound. The technical solutions for achieving the above object are as follows:

[0064] The pyridazinone compound represented by the general formula (I), or its pharmaceutically acceptable salt, or its enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug is used for preparing a drug for treating diseases related to PARP7 mutation, activity or expression level, especially a therapeutic drug for tumors. The tumors are independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

[0065] The present invention relates to compounds having the structural characteristics of general formula (I), which can inhibit a variety of tumor cells, especially can efficiently kill tumors related to abnormal PARP7 protein signaling pathway, and are a class of therapeutic drugs with a completely new mechanism of action.

[0066] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed implementation mode

[0067] After long-term and in-depth research, the inventors prepared a novel class of pyridazinone compounds with the structure shown in Formula I, and found that they have good inhibitory activity against PARP7 protein. Moreover, the compounds can specifically inhibit PARP7 protein at extremely low concentrations (as low as less than 20 nM), and have excellent inhibitory activity against the proliferation of cells related to the PARP7 pathway (such as H1373) (IC50 is less than 100 nM). Therefore, they can be used to treat related diseases such as tumors caused by PARP7 mutations or abnormal activity or expression levels. Based on the above findings, the inventors completed the present invention.

[0068] The term

[0069] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter pertains. All patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference unless otherwise indicated.

[0070] It should be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that, unless clearly stated otherwise in the text, the singular forms used in this specification and the claims include the plural forms of the indicated items. It should also be noted that, unless otherwise indicated, the terms "or" or "either...or" mean "and / or". In addition, the term "comprising" and other forms, such as "comprises", "including", and "contains", are not restrictive.

[0071] Unless otherwise indicated, conventional methods within the scope of those skilled in the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods. Unless specifically defined, the terms used in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutics and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions provided by the manufacturer for the kits can be utilized, or the reactions and purifications can be carried out in a manner well-known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in the various general and more specific documents cited and discussed in this specification, in accordance with the conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0072] When a substituent is described by a conventional chemical formula written from left to right, the substituent also equally includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0073] The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals of operations, and theses, are hereby incorporated by reference in their entirety.

[0074] In front of certain chemical groups defined herein, the total number of carbon atoms present in the group is represented by a simplified symbol. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbol does not include the carbon that may be present in the substituents of the group.

[0075] Except as otherwise provided above, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings set forth below.

[0076] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine; "hydroxyl" refers to the -OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted by a hydroxyl (-OH) group; "carbonyl" refers to the -C(=O)- group; "nitro" refers to -NO2; "cyano" refers to -CN; "amino" refers to -NH2; "substituted amino" refers to an amino group substituted by one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, or heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylacylamino, aralkylamino, heteroaralkylamino; "carboxyl" refers to -COOH.

[0077] In this application, as a group or as part of another group (e.g., used in groups such as halogen-substituted alkyl), the term "alkyl" means a straight-chain or branched-chain hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the remainder of the molecule by a single bond. Examples of alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl, etc.

[0078] In this application, as a group or as part of another group, the term "alkenyl" means a straight-chain or branched-chain hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and connected to the remainder of the molecule by a single bond, such as but not limited to vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0079] In the present application, as a group or as part of another group, the term "alkynyl" means a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the remainder of the molecule by a single bond, such as but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.

[0080] In the present application, as a group or as part of another group, the term "cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and being saturated or unsaturated and being linked to the remainder of the molecule by a single bond through any suitable carbon atom. Unless otherwise specifically indicated in the present specification, the carbon atoms in the cycloalkyl may be optionally oxidized. Examples of cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro-naphthalenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methano-1H-indenyl and octahydro-2,5-methano-s-indacenyl, etc.

[0081] In the present application, the terms "heterocyclic group" and "heterocycloalkyl group" are used interchangeably as a group or as part of another group, and mean a stable 3- to 20-membered non-aromatic cyclic group composed of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the present specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more-ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; the nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized; the nitrogen atoms may be optionally quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be linked to the rest of the molecule via a carbon atom or a heteroatom by a single bond. In a heterocyclic group containing fused rings, one or more rings may be an aryl group or a heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4- to 8-membered (e.g., 4, 5, 6, 7, 8-membered) non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 (e.g., 1, 2, 3) heteroatoms selected from nitrogen, oxygen and sulfur, wherein the nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinuclidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, etc.

[0082] In the present application, the term "heterocyclic group alkyl" means an alkyl group as defined above substituted by a heterocyclic group as defined above.

[0083] In the present application, as a group or as part of another group, the term "aryl group" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms). For the purposes of the present invention, the aryl group may be a monocyclic, bicyclic, tricyclic or more-ring ring system, and may also be fused with a cycloalkyl group or a heterocyclic group as defined above, provided that the aryl group is linked to the rest of the molecule via an atom on the aromatic ring by a single bond. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.

[0084] In the present application, the term "arylalkyl" means an alkyl group as defined above substituted by an aryl group as defined above.

[0085] In the present application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in this specification, the heteroaryl can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with the cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. For the purposes of the present invention, the heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include but are not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, phenanthrolinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0086] In the present application, the term "heteroarylalkyl" means an alkyl group as defined above substituted by a heteroaryl group as defined above.

[0087] In the present application, the terms "amido" and "acylamino" include - alkyl-CONH2 as defined above or -CONH-alkyl as defined above or -CON(alkyl)2 as defined above. In the present application, "optional" or "optionally" means that the subsequent described event or condition may or may not occur, and this description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and this description includes both the substituted aryl and the unsubstituted aryl.

[0088] As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.

[0089] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention will cover various stereoisomers and their mixtures.

[0090] When the compounds of the present invention contain an olefin double bond, unless otherwise specified, the compounds of the present invention are intended to include E- and Z-geometric isomers.

[0091] "Tautomers" refer to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention will also be included within the scope of the present invention.

[0092] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms, and thus enantiomers, diastereomers and other stereoisomeric forms may be produced. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can use racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0093] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.

[0094] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0095] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, etc. These salts can be prepared by methods known in the art.

[0096] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt, etc. Preferred inorganic salts are ammonium salt, sodium salt, potassium salt, calcium salt and magnesium salt. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0097] "Polymorphs" refer to different solid crystalline phases of certain compounds of the present invention in the solid state due to the existence of two or more different molecular arrangements. Some compounds of the present invention can exist in more than one crystal form, and the present invention aims to include various crystal forms and their mixtures.

[0098] Generally, crystallization results in solvates of the compounds of the present invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. The compounds of the present invention can form true solvates, but in some cases, they can also retain only indeterminate water or a mixture of water plus some indeterminate solvent. The compounds of the present invention can react in a solvent or precipitate or crystallize out from a solvent. The solvates of the compounds of the present invention are also included within the scope of the present invention.

[0099] The present invention also includes prodrugs of the above-mentioned compounds. In the present application, the term "prodrug" refers to a compound that can be converted into the bioactive compound of the present invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. When administered to an individual in need, the prodrug may be inactive, but is converted into the active compound of the present invention in vivo. Prodrugs are generally rapidly converted in vivo to produce the parent compound of the present invention, for example, by hydrolysis in the blood. Prodrugs generally provide the advantages of solubility, tissue compatibility, or slow release in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups.

[0100] In the present application, a "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). This medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0101] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any of the components contained in the composition.

[0102] In the present application, "pharmaceutically acceptable carriers" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities for use in humans or livestock.

[0103] As used herein, "tumor", "disease related to abnormal cell proliferation", etc. include, but are not limited to, diseases such as leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc.

[0104] As used herein, the terms "preventive", "prevent" and "prevent from" include reducing the likelihood of the occurrence or worsening of a disease or disorder in a patient.

[0105] As used herein, the terms "treat" and other similar synonyms include the following meanings:

[0106] (i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder;

[0107] (ii) Inhibiting a disease or disorder, i.e., curbing its development;

[0108] (iii) Alleviating a disease or disorder, i.e., causing the state of the disease or disorder to subside; or

[0109] (iv) Relieving the symptoms caused by the disease or disorder.

[0110] As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to the amount of at least one agent or compound that, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated. The result can be the reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant alleviation of the disorder clinically. Techniques such as dose escalation trials can be used to determine the effective amount suitable for any individual case.

[0111] As used herein, the terms "administer", "administering", "administration", etc. refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical administration and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0112] As used herein, the terms "drug combination", "drug co-administration", "combination therapy", "administering an additional therapy", "administering an additional therapeutic agent", etc. refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, co-administration, or sequential administration at variable intervals to a patient of at least one compound described herein and at least one synergistic agent in the form of separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0113] Those skilled in the art should also understand that in the methods described hereinafter, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino, and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R'' (where R'' is alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0114] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The protecting group can also be a polymer resin.

[0115] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only for illustrating the present invention and not for limiting the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0116] Preparation of Intermediates

[0117] Intermediate A1: 5-Chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

[0118]

[0119] Step 1: Under ice-bath cooling, sodium hydride (7.56 g, 189.1 mmol) was added to 4,5-dibromopyridazin-3(2H)-one (40.0 g, 157.6 mmol) in N,N-dimethylformamide (300 mL). The reaction mixture was reacted at room temperature for 1 hour. Then, under ice-bath cooling, 2-(trimethylsilyl)ethoxymethyl chloride (28.91 g, 173.4 mmol) was added. The reaction mixture was continued to react at room temperature for 2 hours. LCMS detected that the raw materials were completely converted. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a light yellow solid intermediate compound (45 g). LCMS (ESI) m / z: 384.9 / 386.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 5.49 (s, 2H), 3.76 - 3.69 (m, 2H), 1.00 - 0.93 (m, 2H), 0.01 (s, 9H).

[0120] Step 2: Under ice-bath cooling, lithium chloride (567 mg, 13.51 mmol) was added to the above intermediate (5.16 g, 13.51 mmol) in N-methylpyrrolidone (20 mL). The reaction mixture was reacted at 95 °C for 4 hours. TLC detected that the reaction was basically complete. Ethyl acetate (200 mL) was added to the reaction solution, and then the organic phase was washed with saturated brine (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white oily compound (4.35 g). LCMS (ESI) m / z: 341 / 339 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 5.50 (s, 2H), 3.78 - 3.63 (m, 2H), 1.02 - 0.88 (m, 2H), 0.01 (s, 9H).

[0121] Step 3: At room temperature, cuprous iodide (4.51 g, 23.67 mmol) and methyl 2,2-difluoro-2-fluorosulfonylacetate (68.15 g, 335.04 mmol) were added to N-methylpyrrolidone (200 mL) of the above intermediate compound (40 g, 118.35 mmol). The reaction mixture was reacted at 100 °C for 2 hours. The reaction solution was diluted with ethyl acetate (500 mL), and the organic phase was washed with saturated brine (300 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain white oily intermediate A1 (26 g). LCMS (ESI) m / z: 329.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 5.46 (s, 2H), 3.81 - 3.63 (m, 2H), 1.01 - 0.88 (m, 2H), 0.00 (s, 9H).

[0122] Intermediate A2: (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) isopropoxy) propionic acid

[0123]

[0124] Step 1: At room temperature, methyl acrylate (8.6 g, 99.93 mmol) was added to a solution of (S)-1-hydroxy-2-carbamoyl tert-butyl ester (3.5 g, 19.99 mmol) and cesium carbonate (13.02 g, 39.97 mmol) in acetonitrile (100 mL). The reaction mixture was reacted at room temperature for 16 hours. TLC detected that the reaction product was the main one. The reaction solution was diluted with dichloromethane (100 mL), and the reaction solution was washed with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a colorless oily intermediate compound (2.17 g). LCMS (ESI) m / z: 262.2 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 6.61 (d, J = 7.3 Hz, 1H), 3.65 - 3.53 (m, 6H), 3.29 - 3.26 (m, 1H), 3.14 (m, 1H), 2.53 (m, 2H), 1.37 (s, 9H), 0.97 (d, J = 6.7 Hz, 3H).

[0125] Step 2: Hydrochloric acid / methanol solution (4 M, 5 mL, 20 mmol) was added to a methanol (30 mL) solution of the above intermediate (2.1 g, 8.04 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of light yellow solid compound (1.5 g). LCMS (ESI) m / z: 162.0 [M+H] + .

[0126] Step 3: At room temperature, N,N-diisopropylethylamine (1.4 g, 10.8 mmol) was added to a solution of the above intermediate (1.3 g, 8.02 mmol) and intermediate A1 (2.63 g, 8.02 mmol) in ethanol (10 mL). The reaction mixture was reacted at 70 °C for 2 hours. The reaction product was detected mainly by LCMS. The reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain an anhydrous oily intermediate (1.8 g). LCMS (ESI) m / z: 454.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 5.83 (m, 1H), 5.41 - 5.34 (m, 2H), 3.94 (m, 1H), 3.78 - 3.60 (m, 7H), 3.49 - 3.45 (m, 1H), 2.59 - 2.56 (t, J = 6.0 Hz, 2H), 1.31 (d, J = 7.2 Hz, 3H), 0.97 (m, 2H), 0.01 (s, 9H).

[0127] Step 4: At room temperature, trifluoroacetic acid (5 mL) was added to a solution of the above intermediate compound (1.8 g, 3.97 mmol) in dichloromethane (20 mL). The reaction mixture was reacted at 20 °C for 2 hours. Trifluoroacetic acid was removed by concentration under reduced pressure. The residue was dissolved in 1,4-dioxane (5 mL), and then an aqueous potassium carbonate solution (4 M, 3 mL, 12 mmol) was added. The reaction mixture was further heated and stirred at 60 °C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white solid intermediate compound (500 mg). LCMS (ESI) m / z: 454.2 [M+H] + .

[0128] Step 5: At room temperature, an aqueous solution (1.5 mL) of lithium hydroxide (89 mg, 3.869 mmol) was added to methanol (1.5 mL) of the above intermediate compound (250 mg, 0.774 mmol). The reaction mixture was reacted at 20 °C for 1 hour. LCMS detected that the reaction was complete. The solvent was removed by concentration under reduced pressure, and the crude product was separated by HPLC preparative separation to obtain the white solid intermediate compound A2 (200 mg). LCMS (ESI) m / z: 310.1 [M+H] + 。

[0129] Intermediate A3: (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrol-2-yl)methoxy)propanoic acid

[0130]

[0131] Step 1: At room temperature, (S)-2-(hydroxymethyl)pyrrole-1-carboxylic acid tert-butyl ester (20 g, 99.37 mmol), methyl acrylate (43 g, 496.85 mmol), and cesium carbonate (97 g, 298.11 mmol) were dissolved in acetonitrile (200 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The separated organic phase was concentrated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (10 g). LCMS (ESI) m / z: 288.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3) δ 3.99–3.80 (m, 1H), 3.77–3.65 (m, 5H), 3.57 (d, J = 12.6 Hz, 1H), 3.38–3.23 (m, 3H), 2.56 (t, J = 6.3 Hz, 2H), 1.93–1.79 (m, 4H), 1.46 (s, 9H).

[0132] Step 2: Hydrochloric acid / 1,4-dioxane (20 mL) was added to methanol (100 mL) of the above intermediate compound (10 g, 34.80 mmol). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected that the product was the main component. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain a brown solid intermediate compound (8.0 g). LCMS (ESI) m / z: 188.2 [M+H] + 。

[0133] Step 3: At room temperature, N,N - diisopropylethylamine (885 mg, 6.84 mmol) was added to a solution of the above intermediate compound (1.1 g, 5.57 mmol) and intermediate compound A1 (2.2 g, 6.84 mmol) in ethanol (10 mL). The reaction mixture was reacted at 70 °C for 2 hours. LCMS detected that the reaction was complete. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain a colorless oily intermediate compound (1 g). LCMS (ESI) m / z: 480.2 [M + H] + . 1 HNMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 5.45 (d, J = 9.8 Hz, 1H), 5.31 (d, J = 9.8 Hz, 1H), 4.37 (dd, J = 6.9, 4.3 Hz, 1H), 3.74 - 3.56 (m, 9H), 3.49 - 3.33 (m, 2H), 2.51 (t, J = 6.1 Hz, 2H), 2.29 - 2.19 (m, 1H), 2.08 - 1.93 (m, 1H), 1.76 - 1.61 (m, 2H), 0.97 (m, 2H), -0.00 (s, 9H).

[0134] Step 4: At room temperature, trifluoroacetic acid (5 mL) was added to a solution of the above intermediate compound (1 g, 2.09 mmol) in dichloromethane (10 mL). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected that the reaction was complete. Trifluoroacetic acid was removed by concentration under reduced pressure, and the resulting residue was dissolved in 1,4 - dioxane (3 mL), and then ammonia water (3 mL) was added. The reaction mixture was heated and stirred at 60 °C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white solid intermediate compound (700 mg). LCMS (ESI) m / z: 350.0 [M + H] + .

[0135] Step 5: An aqueous solution (10 mL) of lithium hydroxide (180 mg, 4.3 mmol) was added dropwise to a solution of the above intermediate compound (300 mg, 0.86 mmol) in methanol (10 mL). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected that the raw materials had completely reacted, and the solvent was removed by concentration under reduced pressure to obtain a crude light yellow solid intermediate compound A3 (280 mg). LCMS (ESI) m / z: 336.1 [M + H] + .

[0136] Preparation method of the example

[0137] Example 1: (S)-5-((1-(3-(4-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0138]

[0139] Step 1: At room temperature, zinc powder (5.5 g, 84.6 mmol) was added to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (4.0 g, 21.2 mmol) and ammonia water (14 mL, 105.8 mmol) in ethanol (30 mL). The reaction mixture was reacted at 60 °C for 16 hours. LCMS detected that the raw materials had completely reacted. The reaction solution was diluted with ethyl acetate (50 mL), then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (1.7 g). LCMS (ESI) m / z: 155.1 [M+H] + . 1 1H NMR (400 MHz, DMSO): δ 8.53 (m, 1H), 2.92 (m, 4H), 2.16 - 2.03 (m, 2H).

[0140] Step 2: At room temperature, N-Boc-piperazine (4.23 g, 22.7 mmol) was added to the above intermediate compound (500 mg, 3.25 mmol) and N,N-diisopropylethylamine (2.94 g, 22.7 mmol) in tetrahydrofuran (8 mL). The reaction mixture was reacted at 70 °C for 2 hours. LCMS detected that the reaction was complete. The organic solvent was removed by concentration under reduced pressure, and then the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain a white solid intermediate compound (500 mg). LCMS (ESI) m / z: 305.2 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 3.84 - 3.70 (m, 4H), 3.55 - 3.41 (m, 4H), 2.80 (m, 4H), 2.15 - 2.01 (m, 2H), 1.49 (s, 9H).

[0141] Step 3: At room temperature, add hydrochloric acid / 1,4-dioxane (1M, 10 mL) to a 1,4-dioxane solution (10 mL) of the above intermediate compound (500 mg, 1.64 mmol). The reaction mixture was reacted at room temperature for 4 hours. The reaction was detected to be complete by LC-MS. The 1,2-dioxane solvent was removed by concentration under reduced pressure, and the residue was triturated with ether (10 mL), and the solid product was filtered out. After drying the obtained solid product, a light yellow solid intermediate compound (380 mg) was obtained. LCMS (ESI) m / z: 205.1 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 9.41 (s, 2H), 8.25 (s, 1H), 4.01 - 3.95 (m, 4H), 3.15 (s, 4H), 2.80 (m, 4H), 2.03 (m, 2H).

[0142] Step 4: At room temperature, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg, 0.58 mmol) to a N,N-dimethylformamide solution (3 mL) of the above intermediate compound (70 mg, 0.29 mmol), intermediate A2 (90 mg, 0.29 mmol), 1-hydroxybenzotriazole (79 mg, 0.58 mmol) and N,N-diisopropylethylamine (75 mg, 0.58 mmol). The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by HPLC preparation to obtain a white solid compound of Example 1 (4.1 mg). LCMS (ESI) m / z: 496.2 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 6.26 (m, 1H), 4.15 (m, 1H), 3.77 - 3.61 (m, 6H), 3.48 (m, 6H), 2.81 - 2.72 (m, 4H), 2.58 (m, 2H), 1.99 (m, 2H), 1.15 (d, J = 6.5 Hz, 3H).

[0143] Example 2: (S)-6-methyl-2-(4-(3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one

[0144]

[0145] Step 1: At room temperature, liquid bromine (2.72 g, 17.0 mmol) was added to a solution of ethyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate (4.0 g, 18.9 mmol) in acetic acid (30 mL). The reaction mixture was heated to 60 °C and reacted for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by reverse-phase chromatography column to obtain a white solid compound (3.54 g). LCMS (ESI) m / z: 292.9 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 4.86 (s, 2H), 4.36 (m, 2H), 2.59 (s, 3H), 1.35 (m, 3H).

[0146] Step 2: At room temperature, a solution of methylamine in tetrahydrofuran (2 M, 22.6 mL, 45.2 mmol) was added to a solution of the above intermediate compound (3.54 g, 12.2 mmol) in tetrahydrofuran (20 mL). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected that the reaction was complete. The solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1 to 1:1) to obtain a white solid intermediate compound (960 mg). LCMS (ESI) m / z: 196.1 [M+H] + 。 1 HNMR (400 MHz, DMSO) δ 8.88 (s, 1H), 4.53 (s, 2H), 3.06 (s, 3H), 2.59 (s, 3H).

[0147] Step 3: At room temperature, m-chloroperoxybenzoic acid (978 mg, 5.67 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (850 mg, 4.36 mmol). The reaction mixture was reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. After the reaction solution was diluted with dichloromethane (20 mL), it was washed twice with sodium sulfite solution (20 mL). Then it was washed once with saturated aqueous sodium bicarbonate solution. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 1,4-dioxane (10 mL) and directly used for the next reaction. At room temperature, N-Boc piperazine (1.62 g, 8.72 mmol) was added to the 1,4-dioxane solution of the previously prepared crude compound. The reaction mixture was heated to 50 °C and reacted for 1 hour. LC-MS detected the reaction solution, and most of the raw materials were converted into the desired product. The reaction solution was diluted with dichloromethane (50 mL) and then washed with saturated aqueous sodium chloride solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain a pale yellow solid intermediate compound (155 mg). LCMS (ESI) m / z: 334.1 [M+H] + 。 1 HNMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 4.21 (s, 2H), 3.97 - 3.84 (m, 4H), 3.55 - 3.50 (m, 4H), 3.13 (s, 3H), 1.49 (s, 9H).

[0148] Step 4: At room temperature, trifluoroacetic acid (2 mL) was added to dichloromethane (5 mL) of the above intermediate compound (153 mg, 0.459 mmol). The reaction mixture was reacted at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with dichloromethane (20 mL) and then washed twice with saturated aqueous sodium bicarbonate solution (20 mL). The separated organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain a white solid compound (80 mg). LCMS (ESI) m / z: 234.1 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 4.21 (s, 2H), 3.98 - 3.88 (m, 4H), 3.13 (s, 3H), 3.00 - 2.88 (m, 4H).

[0149] Step 5: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.69 mmol) was added to a N,N-dimethylformamide solution (3 mL) of the above intermediate compound (80 mg, 0.34 mmol), intermediate compound A2 (106 mg, 0.34 mmol), N,N-diisopropylethylamine (89 mg, 0.69 mmol) and 1-hydroxybenzotriazole (93 mg, 0.69 mmol). The reaction mixture was stirred overnight at room temperature. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to give the white solid Compound of Example 2 (3.9 mg). LCMS (ESI) m / z: 525.1 [M+H] + 。 1 HNMR (400 MHz, DMSO) δ 12.42 (s, 1H), 8.62 (s, 1H), 7.90 (s, 1H), 7.38 - 6.94 (m, 2H), 6.26 (m, 1H), 4.36 (s, 2H), 4.22 - 4.09 (m, 1H), 3.83 (m, 4H), 3.74 - 3.66 (m, 2H), 3.57 - 3.52 (m, 4H), 2.99 (s, 3H), 2.59 (t, J = 6.4 Hz, 2H), 1.15 (d, J = 6.5 Hz, 3H).

[0150] Example 3: (S)-2-(4-(3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

[0151]

[0152] Step 1: At room temperature, N-bromosuccinimide (3.05 g, 17.13 mmol) and azobisisobutyronitrile (0.256 g, 1.56 mmol) were added to a 1,2-dichloroethane solution (80 mL) of 2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.15 g, 15.58 mmol). The reaction mixture was reacted at 80 °C for 2 hours. The reaction was detected to be complete by LCMS, and the reaction mixture was concentrated under reduced pressure. The obtained crude product was directly used in the next step.

[0153] Step 2: The crude product concentrated in the previous step was dissolved in ethylene glycol dimethyl ether (60 mL), and then silver carbonate (8.6 g, 31.19 mmol) and water (3 mL) were added. The reaction mixture was further heated to 70 °C and reacted for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 1:1) to obtain a light yellow solid compound (1.3 g). LCMS (ESI) m / z: 171.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 5.39 (t, J = 6.0 Hz, 1H), 3.17 (m, 1H), 2.94 (m, 1H), 2.68 - 2.56 (m, 1H), 2.20 (m, 1H), 2.12 - 2.00 (m, 1H).

[0154] Step 3: At room temperature, potassium fluoride (4.44 g, 76.5 mmol) was added to a DMSO solution (20 mL) of the above intermediate compound (1.3 g, 7.65 mmol) and N-boc piperazine (2.85 g, 15.29 mmol). The reaction mixture was reacted at 120 °C for 2 hours. LCMS detected that the reaction was basically complete. Ethyl acetate (100 mL) was added to the reaction solution, and then it was washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain a white solid compound (1.77 g). LCMS (ESI) m / z: 321.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 5.23 (s, 1H), 3.90 - 3.78 (m, 4H), 3.54 - 3.45 (m, 4H), 3.00 (m, 1H), 2.72 (m, 1H), 2.45 (m, 1H), 1.96 (m, 1H), 1.83 (m, 1H), 1.49 (s, 9H).

[0155] Step 4: At room temperature, manganese dioxide (2.88 g, 33.13 mmol) was added to a dichloromethane solution (50 mL) of the above intermediate compound (1.71 g, 5.34 mmol). The reaction mixture was reacted at 40 °C for 16 hours. LCMS detected that the reaction was complete. After filtering the reaction solution through diatomaceous earth, it was washed with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 20:1) to obtain a white solid compound (1.3 g). LCMS (ESI) m / z: 319.2 [M+H]+ . 1 HNMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 4.02 - 3.95 (m, 4H), 3.57 - 3.48 (m, 4H), 3.02 - 2.94 (m, 2H), 2.66 - 2.61 (m, 2H), 1.50 (s, 9H).

[0156] Step 5: At room temperature, a hydrochloric acid / 1,4 - dioxane solution (1 M, 4 mL) was added to a 1,4 - dioxane solution (10 mL) of the above intermediate compound (0.37 g, 1.16 mmol). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected that the reaction was substantially complete. The reaction solution was concentrated under reduced pressure, and the residue was triturated with diethyl ether (5 mL). The solid filtered out was dried to obtain a white crude intermediate compound (0.28 g). LC - MS (ESI) m / z: 219.0 [M + H] + . 1 HNMR (400 MHz, DMSO): δ 9.67 (s, 2H), 8.69 (s, 1H), 4.25 - 4.10 (m, 4H), 3.19 (s, 4H), 3.03 - 2.93 (m, 2H), 2.67 - 2.55 (m, 2H).

[0157] Step 6: At room temperature, 1 - (3 - dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride (520 mg, 2.72 mmol) was added to an N,N - dimethylformamide solution (10 mL) of intermediate compound A2 (280 mg, 0.91 mmol), the above intermediate compound (264 mg, 0.91 mmol) and 1 - hydroxybenzotriazole (367 mg, 2.72 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by HPLC preparative method to obtain a white solid, Compound of Example 3 (42 mg). LCMS (ESI) m / z: 510.4 [M + H] + . 1HNMR(400MHz, DMSO): δ 12.43 (s, 1H), 8.65 (s, 1H), 7.91 (s, 1H), 6.27 (m, 1H), 4.21 - 4.10 (m, 1H), 3.96 - 3.80 (m, 4H), 3.74 - 3.62 (m, 2H), 3.60 - 3.53 (m, 4H), 3.49 (d, J = 5.4 Hz, 2H), 3.00 - 2.90 (m, 2H), 2.60 (t, J = 6.4 Hz, 2H), 2.57 - 2.52 (m, 2H), 1.15 (d, J = 6.5 Hz, 3H). Example 4: (S)-5-((1-(3-(4-(5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)-3-isopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0158]

[0159] Step 1: At room temperature, zinc powder (2.6 g, 38.64 mmol) was added to a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (2.0 g, 9.66 mmol) and ammonia water (4.6 g, 38.64 mmol) in ethanol (10 mL). The reaction mixture was reacted at 60 °C for 16 hours. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain a white solid intermediate compound (1.42 g). LCMS (ESI) m / z: 173.1 [M + H] + 。

[0160] Step 2: Under nitrogen protection, the above intermediate compound (1.05 g, 6.08 mmol), N-boc piperazine (2.3 g, 12.16 mmol), and potassium fluoride (3.5 g, 60.8 mmol) were dissolved in dimethyl sulfoxide (10 mL). The reaction mixture was reacted at 100 °C for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (1.3 g). LCMS (ESI) m / z: 323.1 [M + H] + 。 11H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 3.78 - 3.72 (m, 4H), 3.51 - 3.46 (m, 4H), 3.32 (m, 2H), 3.18 (m, 2H), 1.48 (s, 9H).

[0161] Step 3: Under nitrogen protection, m-chloroperbenzoic acid (69 mg, 10.1 mmol) was added to dichloromethane (15 mL) of the above intermediate compound (1.3 g, 4.0 mmol). The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was washed with saturated aqueous sodium carbonate solution, then washed with aqueous sodium thiosulfate solution, and finally washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain a white solid intermediate compound (1.1 g). LCMS (ESI) m / z: 355.1 [M + H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 3.97 - 3.90 (m, 4H), 3.50 (m, 6H), 3.26 (m 2H), 1.49 (s, 9H).

[0162] Step 4: At room temperature, hydrochloric acid / 1,4-dioxane solution (1 M, 5 mL, 5 mmol) was added to dichloromethane solution (5 mL) of the above intermediate compound (1.1 g, 3.10 mmol). The reaction mixture was reacted at room temperature for 4 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with anhydrous ether (10 mL). The filtered solid was dried to obtain a white solid intermediate compound (800 mg). LCMS (ESI) m / z: 255.1 [M + H] + 。 1 1H NMR (400 MHz, DMSO): δ 9.42 (s, 1H), 8.91 (s, 1H), 4.16 - 3.98 (m, 4H), 3.61 (t, J = 7.1 Hz, 2H), 3.29 (t, J = 7.1 Hz, 2H), 3.18 (s, 4H).

[0163] Step 5: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.61 mmol) was added to a solution of the above intermediate compound (250 mg, 0.31 mmol), intermediate compound A2 (151 mg, 0.46 mmol), and 1-hydroxybenzotriazole (62 mg, 0.46 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the white solid Example 4 compound (61 mg). LCMS (ESI) m / z: 546.3 [M+H] + 。 1 H NMR (400 MHz, DMSO): δ 12.44 (s, 1H), 8.84 (s, 1H), 7.91 (s, 1H), 6.27 (m, 1H), 4.15 (m, 1H), 3.83 (m, 4H), 3.69 - 3.56 (m, 8H), 3.26 (t, J = 7.1 Hz, 2H), 2.59 (m, 2H), 1.15 (d, J = 6.5 Hz, 3H).

[0164] Example 5: 2-(4-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carbonitrile

[0165]

[0166] Step 1: At room temperature, potassium cyanide (800 mg, 12.3 mmol) was added to a solution of 5-bromo-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1 g, 4.28 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 60 °C and stirred overnight. The reaction was monitored by LCMS for safety. The reaction solution was diluted with ethyl acetate (100 mL), washed twice with water (50 mL), and once with saturated brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude white solid intermediate compound (330 mg). LCMS (ESI) m / z: 180.0 [M+H] + 。

[0167] Step 2: At room temperature, dissolve the above intermediate compound (330 mg, 1.84 mmol), N-boc piperazine (685 mg, 3.68 mmol), potassium fluoride (1.07 g, 18.4 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture is reacted at 100 °C for 2 hours. Dilute the reaction solution with ethyl acetate (100 mL), and wash the organic phase with sodium chloride solution. The separated organic phase is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (220 mg). LCMS (ESI) m / z: 330.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ8.31 (s, 1H), 4.04 (m, 1H), 3.84 - 3.81 (m, 4H), 3.51 - 3.47 (m, 4H), 3.02 - 2.81 (m, 2H), 2.58 - 2.36 (m, 2H), 1.49 (s, 9H).

[0168] Step 3: At room temperature, add hydrochloric acid / 1,4-dioxane solution (1 M, 3 mL, 3 mmol) to the dichloromethane solution (5 mL) of the above intermediate compound (210 mg, 0.64 mmol). The reaction mixture is reacted at room temperature for 2 hours. LCMS detects that the reaction is complete. Concentrate the reaction solution under reduced pressure, and the crude product is slurried with anhydrous ether (10 mL). The filtered solid is dried to obtain a white solid intermediate compound (89 mg). LCMS (ESI) m / z: 230.3 [M+H] + . 1 HNMR (400 MHz, CDCl3): δ8.31 (s, 1H), 4.05 - 4.01 (m, 1H), 3.96 - 3.79 (m, 4H), 3.04 - 2.97 (m, 4H), 2.88 - 2.81 (m, 4H), 2.55 (m, 1H), 2.44 - 2.32 (m, 1H).

[0169] Step 4: At room temperature, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (149 mg, 0.78 mmol) to the above intermediate compound (89 mg, 0.39 mmol), intermediate compound A2 (317 mg, 0.59 mmol), 1-hydroxybenzotriazole (118 mg, 0.87 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture is reacted for 16 hours. Concentrate the reaction solution under reduced pressure, and the residue is purified by HPLC preparation to obtain a white solid Example 5 compound (23 mg). LCMS (ESI) m / z: 521.2 [M+H] + .1 1H NMR (400 MHz, DMSO): δ 12.34 (s, 1H), 8.38 (s, 1H), 7.91 (s, 1H), 6.28 - 6.25 (m, 1H), 4.38 - 4.34 (m, 1H), 4.14 (m, 1H), 3.75 - 3.65 (m, 6H), 3.50 - 3.48 (m, 7H), 2.90 - 2.82 (m, 2H), 2.61 - 2.53 (m, 2H), 2.49 - 2.22 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H).

[0170] Example 6: (S)-5-((1-(3-oxo-3-(4-(5,6,7,8-tetrahydroquinazolin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0171]

[0172] Step 1: At room temperature, zinc powder (1.28 g, 19.7 mmol) was added to a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1 g, 4.92 mmol) and ammonia water (4 mL, 24.6 mmol) in ethanol (25 mL). Under nitrogen protection, the reaction mixture was reacted at 60 °C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was diluted with methanol (50 mL), filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (700 mg).

[0173] LCMS (ESI) m / z: 169.2 [M + H] + . 1 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 2.88 (m, 2H), 2.74 (m, 2H), 1.86 (m, 4H).

[0174] Step 2: At room temperature, potassium fluoride (3.64 g, 62.6 mmol) was added to a dimethyl sulfoxide (25 mL) solution of the above intermediate compound (0.7 g, 4.17 mmol) and N-Boc piperazine (2.33 g, 12.5 mmol). The reaction mixture was reacted at 120 °C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white solid intermediate compound (1.02 g). LCMS (ESI) m / z: 319.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 3.80 - 3.61 (m, 4H), 3.54 - 3.40 (m, 4H), 2.62 (m, 4H), 1.85 - 1.74 (m, 4H), 1.48 (s, 9H).

[0175] Step 3: At room temperature, hydrochloric acid / 1,4-dioxane solution (2 M, 5 mL, 10 mmol) was added to a dichloromethane (5 mL) solution of the above intermediate compound (1.02 g, 3.204 mmol). The reaction mixture was reacted at room temperature for 2 hours. LCMS detection showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain the compound (700 mg). LCMS (ESI) m / z: 219.3 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 8.27 (s, 1H), 4.52 (m, 4H), 3.84 - 3.69 (m, 4H), 2.83 - 2.69 (m, 4H), 1.65 (m, 4H).

[0176] Step 4: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (581 mg, 3.03 mmol) was added to N,N-dimethylformamide (10 mL) of the above intermediate compound (220 mg, 1.01 mmol), intermediate A2 (313 mg, 1.01 mmol), and 1-hydroxybenzotriazole (410 mg, 3.03 mmol). The reaction mixture was stirred overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and then it was washed twice with water (20 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to obtain the white solid Example 6 compound (24 mg). LCMS (ESI) m / z: 510.2 [M+H] +。 1 1H NMR (400 MHz, DMSO): δ 12.3 (br.s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 6.27 (m, 1H), 4.14 (m, 1H), 3.67 (m, 6H), 3.48 (m, 6H), 2.66 - 2.52 (m, 7H), 1.72 (m, 4H), 1.15 (d, J = 6.4 Hz, 3H).

[0177] Example 7: 5-Fluoro-2-(4-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carbonitrile

[0178]

[0179] Step 1: At room temperature, anhydrous aluminum trichloride (21 mg, 0.16 mmol) was added to a solution of tert-butyl 4-(5-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperazine-1-carboxylate (258 mg, 0.81 mmol) in anhydrous dichloromethane (20 mL). Then the mixture was cooled to 0 °C, and trimethylcyanosilane (201 mg, 2.03 mmol) was slowly added dropwise. Under nitrogen protection, the reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by LCMS and was found to be complete. The reaction mixture was added to saturated aqueous sodium bicarbonate (30 mL), and the separated organic phase was washed once with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain a white solid intermediate compound (150 mg). LCMS (ESI) m / z: 346.2 [M + H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 4.05 - 3.93 (m, 4H), 3.57 - 3.48 (m, 4H), 3.05 - 2.91 (m, 2H), 2.61 - 2.53 (m, 2H), 1.49 (s, 9H).

[0180] Step 2: At room temperature, diethylaminosulfur trifluoride (350 mg, 2.17 mmol) was added to a dichloromethane solution (20 mL) of the above intermediate compound (150 mg, 0.43 mmol). The reaction mixture was reacted at 60 °C for 5 h. LCMS detection showed that the reaction was complete. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate solution (30 mL), and then extracted twice with ethyl acetate (60 mL). The combined organic phases were washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain a white solid intermediate compound (80 mg). LCMS (ESI) m / z: 348.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.79 (s, 1H), 4.03 - 3.91 (m, 4H), 3.55 - 3.46 (m, 4H), 3.15 - 2.93 (m, 2H), 2.65 - 2.53 (m, 2H), 1.49 (s, 9H).

[0181] Step 3: At room temperature, hydrochloric acid / 1,4-dioxane solution (2 M, 0.5 mL, 1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (80 mg, 0.23 mmol). The reaction mixture was reacted at room temperature for 30 min. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude intermediate compound (40 mg). LCMS (ESI) m / z: 248.2 [M+H] + 。

[0182] Step 4: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol) was added to N,N-dimethylformamide (5 mL) of the above intermediate compound (40 mg, 0.16 mmol), intermediate compound A2 (75 mg, 0.23 mmol), and 1-hydroxybenzotriazole (25 mg, 0.18 mmol). The reaction mixture was reacted for 16 h. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparative to obtain a white solid Example 7 compound (7 mg). LCMS (ESI) m / z: 539.2 [M+H] + 。 1HNMR(400MHz, DMSO): δ 12.3 (s, 1H), 8.85 (s, 1H), 7.93 (s, 1H), 6.25 (m, 1H), 4.15 (m, 1H), 3.85 - 3.81 (m, 4H), 3.65 - 3.58 (m, 6H), 3.56 (m, 2H), 3.26 (m, 2H), 2.59 (m, 2H), 1.15 (d, J = 6.4 Hz, 3H).

[0183] Example 8: 5 - (((2S)-1-(3-(4-(5 - fluoro - 5 - (trifluoromethyl)-6,7 - dihydro - 5H - cyclopenta[d]pyrimidin - 2 - yl)piperazin - 1 - yl)-3 - oxopropoxy)propan - 2 - yl)amino)-4 - (trifluoromethyl)pyridazin - 3(2H)-one

[0184]

[0185] Step 1: At room temperature, tetrabutylammonium fluoride (1 M in THF, 0.5 mL, 0.5 mmol) was slowly added to an anhydrous THF solution (20 mL) of tert - butyl 4-(5 - oxo - 6,7 - dihydro - 5H - cyclopenta[d]pyrimidin - 2 - yl)piperazine - 1 - carboxylate (318 mg, 1.0 mmol) and (trifluoromethyl)trimethylsilane (356 mg, 2.5 mmol). Under nitrogen protection, the reaction mixture was reacted at room temperature for 6 hours. The reaction was detected to be complete by LCMS. The reaction mixture was added to saturated aqueous sodium bicarbonate (30 mL), and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain a white solid intermediate compound (110 mg). LCMS (ESI) m / z: 389.2 [M + H] + 。 1 HNMR(400MHz, CDCl3): δ 8.68 (s, 1H), 4.05 - 3.93 (m, 4H), 3.57 - 3.48 (m, 4H), 3.11 - 2.95 (m, 2H), 2.65 - 2.58 (m, 2H), 1.49 (s, 9H).

[0186] Step 2: At room temperature, diethylaminosulfur trifluoride (350 mg, 2.17 mmol) was added to a dichloromethane solution (20 mL) of the above intermediate compound (100 mg, 0.26 mmol). The reaction mixture was reacted at 80 °C for 5 h. LCMS detection showed that the reaction was complete. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate solution (30 mL), and then extracted with ethyl acetate (100 mL). The separated organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (60 mg). LCMS (ESI) m / z: 391.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.79 (s, 1H), 4.05 - 3.91 (m, 4H), 3.53 - 3.46 (m, 4H), 3.15 - 2.95 (m, 2H), 2.71 - 2.58 (m, 2H), 1.51 (s, 9H).

[0187] Step 3: At room temperature, hydrochloric acid / 1,4-dioxane solution (2 M, 0.5 mL, 1 mmol) was added to a dichloromethane (5 mL) solution of the above intermediate compound (60 mg, 0.15 mmol). The reaction mixture was reacted at room temperature for 30 min. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude intermediate compound (40 mg). LCMS (ESI) m / z: 291.0 [M+H] + 。

[0188] Step 4: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) was added to a N,N-dimethylformamide (5 mL) solution of the above intermediate compound (40 mg, 0.14 mmol), intermediate compound A2 (75 mg, 0.23 mmol), and 1-hydroxybenzotriazole (20 mg, 0.15 mmol). The reaction mixture was reacted for 12 h. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparative purification to obtain a white solid Example 8 compound (2 mg). LCMS (ESI) m / z: 539.2 [M+H] + 。 11H NMR (400 MHz, DMSO): δ 12.3 (s, 1H), 8.85 (s, 1H), 7.93 (s, 1H), 6.25 (m, 1H), 4.13 (m, 1H), 3.85 - 3.81 (m, 4H), 3.68 - 3.58 (m, 6H), 3.56 (m, 2H), 3.26 (m, 2H), 2.58 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H).

[0189] Example 9: (S)-5-((1-(3-(4-7H-cyclopenta[d]pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0190]

[0191] Step 1: At room temperature, 1,8-diazabicycloundec-7-ene (600 mg, 3.94 mmol) was added to a solution of 5-bromo-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (250 mg, 1.07 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 80 °C and stirred overnight. The reaction was monitored by LCMS and was found to be safe. The reaction solution was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude white solid intermediate compound (130 mg). LCMS (ESI) m / z: 153.0 [M + H] + 。

[0192] Step 2: At room temperature, potassium fluoride (500 mg, 8.6 mmol) was added to a solution of the above intermediate compound (130 mg, 0.86 mmol) and N-Boc piperazine (484 mg, 2.6 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was reacted at 120 °C for 1 hour. The reaction was monitored by LCMS and was found to be complete. The reaction solution was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white solid intermediate compound (80 mg). LCMS (ESI) m / z: 303.2 [M + H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 6.57 - 6.52 (m, 1H), 6.23 - 6.03 (m, 1H), 3.80 - 3.61 (m, 4H), 3.54 - 3.40 (m, 4H), 3.22 (m, 2H), 1.53 (s, 9H).

[0193] Step 3: At room temperature, add hydrochloric acid / 1,4-dioxane solution (2M, 0.5 mL, 1 mmol) to dichloromethane (5 mL) of the above intermediate compound (80 mg, 0.26 mmol). The reaction mixture is reacted at room temperature for 30 minutes. LCMS detection shows that the reaction is complete. The reaction solution is concentrated under reduced pressure to obtain a crude yellow solid intermediate compound (40 mg). LCMS (ESI) m / z: 203.2 [M+H] + 。

[0194] Step 4: At room temperature, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol) to N,N-dimethylformamide (5 mL) of the above intermediate compound (40 mg, 0.20 mmol), intermediate compound A2 (100 mg, 0.32 mmol), and 1-hydroxybenzotriazole (40 mg, 0.30 mmol). The reaction mixture is reacted for 12 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by HPLC preparation to obtain a white solid compound of Example 9 (10 mg). LCMS (ESI) m / z: 494.2 [M+H] + 。 1 HNMR (400 MHz, DMSO) δ 12.4 (s, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 6.65 - 6.56 (m, 1H), 6.26 - 6.13 (m, 2H), 4.15 (m, 1H), 3.78 - 3.62 (m, 6H), 3.48 - 3.45 (m, 6H), 2.71 - 2.62 (m, 2H), 1.15 (d, J = 6.5 Hz, 3H).

[0195] Example 10: (S)-5-((1-(3-(4-(5,5-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0196]

[0197] Step 1: At room temperature, a reaction mixture of tert-butyl 4-(5-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-1-carboxylate (318 mg, 1.0 mmol) and diethylaminosulfur trifluoride (1.2 g, 7.44 mmol) was heated to 80 °C and reacted for 10 hours. LCMS detection showed that the reaction was complete. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate solution (100 mL), and then extracted with ethyl acetate (100 mL). The separated organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (65 mg). LCMS (ESI) m / z: 341.2 [M+H] + . 1 HNMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 3.89 - 3.87 (m, 4H), 3.53 - 3.48 (m, 4H), 2.94 - 2.92 (m, 2H), 2.57 - 2.54 (m, 2H), 1.49 (s, 9H).

[0198] Step 2: At room temperature, hydrochloric acid / 1,4-dioxane solution (2 M, 0.5 mL, 1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (61 mg, 0.18 mmol). The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude yellow solid intermediate compound (43 mg). LCMS (ESI) m / z: 241.0 [M+H] + .

[0199] Step 3: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol) was added to N,N-dimethylformamide (5 mL) of the above intermediate compound (40 mg, 0.17 mmol), intermediate compound A2 (75 mg, 0.23 mmol), and 1-hydroxybenzotriazole (25 mg, 0.18 mmol). The reaction mixture was reacted for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparation to obtain a white solid compound of Example 10 (4 mg). LCMS (ESI) m / z: 532.2 [M+H] + . 11H NMR (400 MHz, DMSO): δ 12.3 (s, 1H), 8.55 (s, 1H), 7.93 (s, 1H), 6.25 (m, 1H), 4.13 (m, 1H), 3.85 - 3.81 (m, 4H), 3.68 (m, 2H), 3.60 - 3.58 (m, 4H), 3.56 (m, 2H), 3.26 (m, 2H), 2.59 (m, 2H), 1.15 (d, J = 6.4 Hz, 3H).

[0200] Example 11: 5 - ((((2S)-1-(3-(4-(5 - fluoro - 6,7 - dihydro - 5H - cyclopenta[d]pyrimidin - 2 - yl)piperazin - 1 - yl)-3 - oxopropoxy)propan - 2 - yl)amino)-4-(trifluoromethyl)pyridazin - 3(2H)-one

[0201]

[0202] Step 1: At room temperature, silver fluoride (315 mg, 2.5 mmol) was added to a solution of 5 - bromo - 2 - chloro - 6,7 - dihydro - 5H - cyclopenta[d]pyrimidine (250 mg, 1.07 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction was monitored by LCMS to ensure safety. The reaction solution was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude white solid intermediate compound (60 mg). LCMS (ESI) m / z: 173.0 [M + H] + 。

[0203] Step 2: At room temperature, potassium fluoride (100 mg, 1.7 mmol) was added to a solution of the above intermediate compound (60 mg, 0.35 mmol) and N - Boc piperazine (130 mg, 0.7 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was reacted at 120 °C for 1 hour. The reaction was monitored by LCMS to show completion. The reaction solution was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white solid intermediate compound (20 mg). LCMS (ESI) m / z: 323.2 [M + H] + 。

[0204] Step 3: At room temperature, add hydrochloric acid / 1,4-dioxane solution (2M, 0.5 mL, 1 mmol) to dichloromethane (5 mL) of the above intermediate compound (20 mg, 0.06 mmol). The reaction mixture was reacted at room temperature for 10 minutes. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude yellow solid intermediate compound (12 mg). LCMS (ESI) m / z: 223.0 [M+H] + 。

[0205] Step 4: At room temperature, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 0.06 mmol) to N,N-dimethylformamide (5 mL) of the above intermediate compound (12 mg, 0.05 mmol), intermediate compound A2 (31 mg, 0.1 mmol), and 1-hydroxybenzotriazole (10 mg, 0.07 mmol). The reaction mixture was reacted for 10 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparative to obtain the white solid compound of Example 11 (2 mg). LCMS (ESI) m / z: 514.2 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 12.3 (s, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 6.25 (m, 1H), 4.58 (m, 1H), 4.13 (m, 1H), 3.85 - 3.81 (m, 4H), 3.68 - 3.58 (m, 6H), 3.56 (m, 2H), 3.26 (m, 2H), 2.59 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H).

[0206] Example 12: (S)-5-((1-(3-(4-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0207]

[0208] Step 1: At room temperature, sodium hydride (60% oil dispersion, 200 mg, 5.0 mmol) was added to a solution of 5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine (300 mg, 2.14 mmol) and N-Boc-N,N-bis(2-bromoethyl)amine (702 mg, 2.14 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding ice water (50 mL), and the reaction solution was extracted with ethyl acetate (100 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (230 mg). LCMS (ESI) m / z: 310.2 [M+H] + 。

[0209] Step 2: At room temperature, hydrochloric acid / 1,4-dioxane solution (2 M, 0.5 mL, 1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (130 mg, 0.42 mmol). The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude intermediate compound (150 mg). LCMS (ESI) m / z: 210.0 [M+H] + 。

[0210] Step 3: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol) was added to N,N-dimethylformamide (10 mL) of the above intermediate compound (60 mg, 0.29 mmol), intermediate compound A2 (155 mg, 0.5 mmol), and 1-hydroxybenzotriazole (46 mg, 0.34 mmol). The reaction mixture was reacted for 10 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparation to obtain a white solid compound of Example 12 (8 mg). LCMS (ESI) m / z: 501.2 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 12.5 (s, 1H), 7.91 (s, 1H), 6.27 (m, 1H), 4.60 (m, 1H), 4.15 - 4.06 (m, 2H), 3.65 - 3.33 (m, 8H), 2.99 (m, 1H), 2.76 - 2.40 (m, 7H), 1.77 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H).

[0211] Example 13: (S)-5-((1-(3-(4-(5,5-difluoro-5H-cyclopenta[d]pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0212]

[0213] Step 1: Under nitrogen protection, the reaction mixture of tert-butyl 4-(5-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-1-carboxylate (500 mg, 1.56 mmol) and diethylaminosulfur trifluoride (1.2 g, 7.44 mmol) was heated to 70 °C and reacted for 16 hours. LCMS detection showed that the reaction was complete. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate solution (50 mL), and then extracted with ethyl acetate (100 mL). The separated organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain a white solid intermediate compound (27 mg). LCMS (ESI) m / z: 339.2 [M+H] + 。 1 HNMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 6.71 (m, 1H), 6.64 (m, 1H), 3.91 - 3.89 (m, 4H), 3.52 - 3.49 (m, 4H), 1.49 (s, 9H).

[0214] Step 2: At room temperature, hydrochloric acid / 1,4-dioxane solution (2 M, 0.5 mL, 1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (25 mg, 0.07 mmol). The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude intermediate compound (10 mg). LCMS (ESI) m / z: 239.0 [M+H] + 。

[0215] Step 3: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 mg, 0.05 mmol) was added to a solution of the above intermediate compound (10 mg, 0.04 mmol), intermediate compound A2 (23 mg, 0.07 mmol), and 1-hydroxybenzotriazole (8 mg, 0.06 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparative chromatography to obtain the white solid of Example 13 compound (2.5 mg). LCMS (ESI) m / z: 530.2 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 12.3 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.04 - 6.99 (m, 2H), 6.29 - 6.25 (m, 1H), 4.16 (m, 1H), 3.84 - 3.66 (m, 6H), 3.54 - 3.48 (m, 6H), 2.59 - 2.57 (m, 2H), 1.15 (d, J = 6.4 Hz, 3H).

[0216] Example 14: (S)-5-((1-(3-(4-(5,6-Dihydrofuro[2,3-d]pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0217]

[0218] Step 1: At room temperature, potassium fluoride (200 mg, 3.4 mmol) was added to a solution of 2-chloro-5,6-dihydrofuro[2,3-d]pyrimidine (200 mg, 1.28 mmol) and N-Boc piperazine (280 mg, 1.5 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was heated at 120 °C for 1 hour. LCMS analysis showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the white solid intermediate compound (100 mg). LCMS (ESI) m / z: 307.2 [M+H] + 。

[0219] Step 2: At room temperature, add hydrochloric acid / 1,4-dioxane solution (2 M, 0.5 mL, 1 mmol) to dichloromethane (5 mL) of the above intermediate compound (50 mg, 0.16 mmol). The reaction mixture is reacted at room temperature for 10 minutes. LCMS detection shows that the reaction is complete. The reaction solution is concentrated under reduced pressure to obtain a crude yellow solid intermediate compound (30 mg). LCMS (ESI) m / z: 207.0 [M+H] + 。

[0220] Step 3: At room temperature, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) to N,N-dimethylformamide (5 mL) of the above intermediate compound (30 mg, 0.15 mmol), intermediate compound A2 (100 mg, 0.32 mmol), and 1-hydroxybenzotriazole (27 mg, 0.20 mmol). The reaction mixture is reacted for 10 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by HPLC preparative to obtain the white solid compound of Example 14 (5 mg). LCMS (ESI) m / z: 514.2 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 12.44 (s, 1H), 8.64 (s, 1H), 7.92 (s, 1H), 6.25 (m, 1H), 4.15 (m, 1H), 3.83 (m, 4H), 3.69 - 3.56 (m, 8H), 3.26 (t, J = 7.1 Hz, 2H), 2.69 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H).

[0221] Example 15: (S)-2-(4-(3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)furo[2,3-d]pyrimidin-5(6H)-one

[0222]

[0223] Step 1: At room temperature, sodium hydride (60%, 280 mg, 7.0 mmol) was added to a solution of ethyl 2-hydroxyacetate (677 mg, 6.51 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at room temperature for 30 minutes. Under ice-bath cooling, a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.5 g, 6.47 mmol) in tetrahydrofuran (10 mL) was added to the reaction solution. The reaction mixture was stirred at room temperature for 4 hours. LCMS detection showed that the reaction was complete. The reaction was quenched by adding ice water (100 mL), and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain a white solid intermediate compound (1.6 g). LCMS (ESI) m / z: 301.0 [M+H] + .

[0224] Step 2: Under ice-bath cooling, m-chloroperoxybenzoic acid (1.08 g, 6.26 mmol) was added to a solution of the above intermediate (1.6 g, 5.33 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 3 hours. LC-MS detection showed that the reaction was complete. A saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution. The separated organic phase was washed once with saturated brine, saturated aqueous sodium thiosulfate solution, and water in sequence. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude light yellow solid intermediate compound (1.2 g). LCMS (ESI) m / z: 317.0 [M+H] + .

[0225] Step 3: At room temperature, potassium fluoride (771 mg, 13.4 mmol) was added to a solution of the above intermediate compound (1.2 g, 3.80 mmol) and N-Boc piperazine (707 mg, 3.8 mmol) in dimethyl sulfoxide (20 mL). The reaction mixture was reacted at 120 °C for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (200 mL) and washed twice with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain a white solid intermediate compound (1.4 g). LCMS (ESI) m / z: 439.2 [M+H] + .

[0226] Step 4: Under ice-bath cooling, potassium tert-butoxide (673 mg, 6.0 mmol) was added to N,N-dimethylformamide (20 mL) of the above intermediate (1.3 g, 2.97 mmol). The reaction mixture was stirred at zero degree for 30 minutes. The reaction was detected to be complete by LC-MS. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and then it was extracted with ethyl acetate (150 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain a white solid intermediate compound (540 mg). LCMS (ESI) m / z: 393.2 [M+H] + 。

[0227] Step 5: Under ice-bath cooling, concentrated hydrochloric acid (5 mL) was added to methanol (10 mL) of the above intermediate (540 mg, 1.38 mmol). The reaction mixture was stirred at 60 degree for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain a crude white solid intermediate compound (260 mg). LCMS (ESI) m / z: 221.0 [M+H] + 。

[0228] Step 6: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added to N,N-dimethylformamide (5 mL) of the above intermediate compound (100 mg, 0.45 mmol), intermediate compound A2 (250 mg, 0.81 mmol), and 1-hydroxybenzotriazole (68 mg, 0.51 mmol). The reaction mixture was reacted for 10 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparation to obtain a white solid compound of Example 15 (18 mg). LCMS (ESI) m / z: 512.2 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 12.3 (s, 1H), 8.64 (s, 1H), 7.98 (s, 1H), 6.27 (m, 1H), 5.28 (s, 2H), 4.17 (m, 1H), 3.85 (m, 4H), 3.75 - 3.36 (m, 8H), 1.15 (d, J = 6.8 Hz, 3H).

[0229] Referring to the synthesis methods of Examples 1-15, raw materials with different substituents were used to replace 2-(piperazin-1-yl)cyclopentano[d]pyrimidine to synthesize the following example compounds.

[0230]

[0231] Example 21: (S)-2-(4-(3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrol-2-yl)methoxy)propanoyl)piperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

[0232]

[0233] Step 1: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (483 mg, 2.52 mmol) was added to a solution of Intermediate A3 (280 mg, 0.84 mmol), 2-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one hydrochloride (183 mg, 0.84 mmol), and 1-hydroxybenzotriazole (340 mg, 2.52 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (100 mL) and washed twice with water (30 mL). The separated organic phase was concentrated under reduced pressure, and the resulting crude product was purified by HPLC preparative purification to obtain the white solid compound of Example 21 (15 mg). LCMS (ESI) m / z: 536.2 [M+H] + 。 1 HNMR (400 MHz, DMSO): δ 12.35 (s, 1H), 8.66 (s, 1H), 8.01 (s, 1H), 4.52 (m, 1H), 3.89 (m, 4H), 3.64 (m, 2H), 3.53 (m, 6H), 3.39 - 3.18 (m, 2H), 2.95 (m, 2H), 2.57 - 2.53 (m, 4H), 2.08 (m, 1H), 1.88 (m, 1H), 1.63 (m, 2H).

[0234] Referring to the synthesis method of Example 21, starting materials with different substituents were used instead of 2-(piperazin-1-yl)cyclopenta[d]pyrimidine to synthesize the following example compounds.

[0235]

[0236]

[0237] Referring to the synthesis methods of Examples 1 - 15, starting materials with different substituents were used instead of 2-(piperazin-1-yl)cyclopenta[d]pyrimidine to synthesize the following example compounds.

[0238]

[0239]

[0240] Referring to the synthesis method of Example 21, raw materials with different substituents were used instead of 2-(piperazin-1-yl)cyclopentano[d]pyrimidine to synthesize the following example compounds.

[0241]

[0242]

[0243] Referring to the synthesis methods of Examples 1-15, raw materials with different substituents were used instead of 2-(piperazin-1-yl)cyclopentano[d]pyrimidine to synthesize the following example compounds.

[0244]

[0245]

[0246] Referring to the synthesis method of Example 21, raw materials with different substituents were used instead of 2-(piperazin-1-yl)cyclopentano[d]pyrimidine to synthesize the following example compounds.

[0247]

[0248]

[0249] Example 61: (S)-5-((1-(3-(4-(7,7-Dimethyl-7H-pyrano[2,3-d]pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0250]

[0251] Step 1: At room temperature, sodium hydride (60%, 280 mg, 7.0 mmol) was added to a solution of ethyl 3-hydroxy-3-methylbutyrate (951 mg, 6.50 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at room temperature for 30 minutes. Under ice-bath cooling, a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.5 g, 6.47 mmol) in tetrahydrofuran (10 mL) was added to the reaction solution. The reaction mixture was stirred at room temperature for 4 hours. LCMS detection showed that the reaction was complete. The reaction was quenched by adding ice water (100 mL), and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain a white solid intermediate compound (1.3 g). LCMS (ESI) m / z: 343.0 [M+H] + 。

[0252] Step 2: Under ice bath cooling, add m-chloroperoxybenzoic acid (0.54 g, 3.13 mmol) to a dichloromethane solution (50 mL) of the above intermediate (1.3 g, 2.92 mmol). The reaction mixture was stirred at room temperature for 3 hours. LC-MS detected that the reaction was complete. Add saturated aqueous sodium bicarbonate solution (50 mL) to the reaction solution. The separated organic phase was washed once with saturated brine, saturated aqueous sodium thiosulfate solution, and water successively. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude light yellow solid intermediate compound (920 mg). LCMS (ESI) m / z: 359.0 [M+H] + 。

[0253] Step 3: At room temperature, add potassium fluoride (771 mg, 13.4 mmol) to a dimethyl sulfoxide (20 mL) solution of the above intermediate compound (0.92 g, 2.57 mmol) and N-benzylpiperazine (460 mg, 2.61 mmol). The reaction mixture was reacted at 120 °C for 2 hours. LCMS detection showed that the reaction was complete. Dilute the reaction solution with ethyl acetate (200 mL) and wash it twice with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain a white solid intermediate compound (0.85 g). LCMS (ESI) m / z: 471.2 [M+H] + 。

[0254] Step 4: Under ice bath cooling, add potassium tert-butoxide (673 mg, 6.0 mmol) to a N,N-dimethylformamide (20 mL) solution of the above intermediate (0.85 g, 1.81 mmol). The reaction mixture was stirred at zero degree for 30 minutes. LC-MS detected that the reaction was complete. Add saturated aqueous ammonium chloride solution (100 mL) to the reaction solution, and then extract it with ethyl acetate (150 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain a white solid intermediate compound (550 mg). LCMS (ESI) m / z: 425.2 [M+H] + 。

[0255] Step 5: Under ice bath cooling, add concentrated hydrochloric acid (5 mL) to an ethanol (10 mL) solution of the above intermediate (450 mg, 1.17 mmol). The reaction mixture was stirred at 60 °C for 1 hour. Concentrate the reaction solution under reduced pressure and dry it to obtain a crude white solid intermediate compound (280 mg). LCMS (ESI) m / z: 353.0 [M+H] + 。

[0256] Step 6: Under ice bath cooling, sodium borohydride (61 mg, 1.6 mmol) was added to ethanol (10 mL) of the above intermediate (280 mg, 0.79 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL), washed twice with water (5 mL), and the separated organic phase was concentrated under reduced pressure to obtain a crude white solid intermediate compound (240 mg). LCMS (ESI) m / z: 355.0 [M+H] + 。

[0257] Step 7: p-Toluenesulfonic acid monohydrate (21 mg, 0.11 mmol) was added to a toluene solution (20 mL) of the above intermediate (240 mg, 0.68 mmol). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL), washed with water (5 mL). The separated organic phase was concentrated under reduced pressure to obtain a crude white solid intermediate compound (160 mg). LCMS (ESI) m / z: 337.0 [M+H] + 。

[0258] Step 8: At room temperature, 1-chloroethyl chloroformate (100 mg, 1.05 mmol) was added to dichloromethane (4 mL) of the above intermediate compound (160 mg, 0.47 mmol), and the reaction mixture was reacted at 40 °C for 2 hours. After the reaction solution was concentrated, it was dissolved in methanol (5 mL) and continued to react at 50 °C for 2 hours. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain a white solid intermediate compound (55 mg). LCMS (ESI) m / z: 247.1 [M+H] + 。

[0259] Step 9: At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol) was added to N,N-dimethylformamide (5 mL) of the above intermediate compound (55 mg, 0.22 mmol), intermediate compound A2 (123 mg, 0.4 mmol), and 1-hydroxybenzotriazole (32 mg, 0.26 mmol). The reaction mixture was reacted for 10 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by HPLC preparation to obtain a white solid compound of Example 61 (15 mg). LCMS (ESI) m / z: 538.2 [M+H] + 。 1HNMR(400MHz, DMSO) δ 12.35 (s, 1H), 8.63 (s, 1H), 7.91 (s, 1H), 6.36 (m, 1H), 6.27 (m, 1H), 5.93 - 5.77 (m, 1H), 4.25 - 4.04 (m, 1H), 3.70 - 3.49 (m, 8H), 2.71 (m, 2H), 2.58 (m, 2H), 2.36 (m, 2H), 1.15 (d, J = 6.4 Hz, 3H), 0.96 (s, 6H).

[0260] Referring to the synthesis methods of Reference Example 61 or Example 21, raw materials with different substituents were used to replace 2-(piperazin-1-yl)-cyclopentano[d]pyrimidine to synthesize the compounds of the following examples.

[0261]

[0262]

[0263] Test Example 1: Test for inhibitory activity of H1373 cell proliferation

[0264] 1), Digest the well-conditioned NCI-H1373 cells (ATCC), centrifuge, resuspend, count and inoculate them into a 96-well plate (Corning), with 1000 cells per well.

[0265] 2), After pre-culturing in an incubator for 24 h (37 °C, 5% CO2), treat with compounds of different concentrations for 144 h; both the experimental group and the control group were set with 6 replicates, and a control well with DMSO solvent added and a blank well without cells (pure medium) were set.

[0266] 3), After drug treatment, use CellTiter- luminescence method to detect cell viability. Balance the culture plate to room temperature before measurement, add 50 μL of CellTiter- reagent (Promega) to each well, mix on an orbital shaker for 2 minutes to induce cell lysis, continue to incubate at room temperature for 60 minutes to stabilize the luminescence signal, and then record the luminescence value on an Envision (PerkinElmer).

[0267] 4), Calculate the cell viability inhibition rate (%) = [A (DMSO) - A (加药) / [A (DMSO) - A (空白) × 100%. (A (加药) : Absorbance of the well with cells and drug solution; A (空白) : Absorbance of the well with medium but without cells; A (DMSO): Absorbance of the wells seeded with cells and added with DMSO). Three repeated experiments were performed and statistically analyzed using Graghpad software.

[0268] Results: Compounds of most of the examples of the present invention have strong cell proliferation inhibitory activity, with IC50 less than 1 μM, and the IC50 of the cell proliferation inhibitory activity of compounds of some of the examples is even less than 100 nM. The specific results are shown in the following table:

[0269]

[0270]

[0271] (The strength of compound activity in the table is represented by letters: A indicates IC50 ≤ 100 nM, B indicates 100 nM < IC50 ≤ 1000 nM, and C indicates IC50 > 1000 nM)

[0272] Test Example 2: Biochemical assay of PARP7

[0273] Biochemical experiment protocol:

[0274] 1. Coating: Coat a 384-well plate with 25 μl / well of 1xhistone overnight.

[0275] 2. Blocking: Wash the 384-well plate with PBST and add 50 μl / well of blocking solution to block at room temperature for 1 hour.

[0276] 3. Compound dilution: Dilute the compound at a ratio of 1:3 to 10 concentrations, with the starting concentration of 100 nM.

[0277] 4. Enzyme reaction: Add the enzyme, Biotin-NAD + , different concentrations of the compound, incubate the reaction under certain conditions, and then wash the 384-well plate with PBST.

[0278] 5. Luminescence reading: Add 25 μL of Stre-HRP and incubate at room temperature for 1 hour, wash 3 times with PBS, then add QuantaRed Enhancer and incubate for 10 minutes to terminate the reaction, and quickly read with a microplate reader at Ex550 / Em620.

[0279] IC 50 : Refers to the compound concentration when the PARP7 enzyme activity is inhibited by 50%.

[0280] Results: Compounds of most of the examples of the present invention have strong PARP7 enzyme activity inhibitory activity, with IC50 less than 10 nM, and the IC50 of the cell proliferation inhibitory activity of compounds of some of the examples is even less than 1 nM. The specific results are shown in the following table:

[0281] Number IC50 Number IC50 Number IC50 Control RBN-2397 0.74 nM 1 0.76 nM 3 0.77 nM 4 0.94 nM 6 1.28 nM 11 0.75 nM 14 1.2 nM 15 1.3 nM 22 0.75 nM 27 0.79 nM 33 0.98 nM 34 0.95 nM 35 0.87 nM 37 1.1 nM 38 0.62 nM 41 1.0 nM 42 0.81 nM 46 0.82 nM

[0282] Test Example 3: ADMET Test of Example Compounds

[0283] (1) Metabolic Stability Test: The metabolic stability was incubated at a temperature using liver microsomes with a system volume of 150 μL (final concentration 0.5 mg / mL). The system contained NADPH (final concentration 1 mM), 1 μM test compound, and positive control midazolam or negative control atenolol. The reaction was terminated with acetonitrile containing tinidazole at 0 min, 5 min, 10 min, 20 min, and 30 min, vortexed for 10 min, centrifuged at 15000 rmp for 10 min, and 50 μL of the supernatant was injected into a 96-well plate. The metabolic stability of the compound was calculated by measuring the relative reduction of the parent drug.

[0284] Results: The compounds of the examples of the present invention have high stability in liver microsomes of various species (rats, mice, dogs, monkeys, humans), with a half-life greater than 30 min, such as Example Compounds 6, 34, etc.

[0285]

[0286] Test Example 4: Pharmacokinetic Parameter Test of Example Compounds in Mice

[0287] Six male SPF-grade Balb c mice (Shanghai SIPPR-BK Lab Animal) were divided into two groups. The test compound was formulated into a suitable solution or suspension; one group was administered by intravenous injection and the other group was administered orally. Blood was collected by jugular vein puncture, and about 0.2 mL / time point was collected for each sample, anticoagulated with sodium heparin. The blood collection time points were as follows: before dosing and at 5, 15, and 30 min, 1, 2, 4, 6, 8, and 24 h after dosing; after the blood samples were collected, they were placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 8000 revolutions per minute, 6 minutes, 2 - 8 °C). The collected plasma was stored at -80 °C before analysis. The plasma samples were analyzed by LC-MS / MS.

[0288] Based on the blood concentration data of the drug, the pharmacokinetic calculation software WinNonlin 5.2 was used to calculate the pharmacokinetic parameters AUC 0-t 、AUC 0-∞ 、MRT 0-∞ 、C max 、T max 、T 1 / 2 and V d and other parameters, as well as their averages and standard deviations. In addition, the bioavailability (F) will be calculated using the following formula.

[0289]

[0290] For samples with concentrations below the lower limit of quantification, when calculating pharmacokinetic parameters, samples taken before reaching Cmax should be calculated as zero values, and samples at sampling points after reaching C max should be calculated as not quantifiable (BLQ).

[0291] The PK data results of the mice in Example 6 are as follows

[0292]

[0293] : F = (AUC INF-PO *Dose IV ) / (SUC INF-IV *Dose PO ) * 100%

[0294] All documents mentioned in the present invention are cited herein by reference as if each individual document was cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A pyridazinone compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, wherein, X is independently selected from C1-C6 alkyl; the C1-C6 alkyl may optionally be substituted by one or more R x substituted, R x is independently selected from deuterium, halogen; Y 1 independently selected from NR y , wherein R y is independently selected from hydrogen, C1-C6 alkyl; Y 2 independently selected from O; R 1 independently selected from C1-C6 alkyl; R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 are each independently selected from hydrogen; Alternatively, R 1 or R 2 together with R y and the atoms connected thereto form a 4- to 10-membered heterocycloalkyl group; Cy 2 independently selected from 5- to 10-membered heteroaryl fused to a 4- to 10-membered saturated or partially unsaturated ring system; R 9 independently selected from one or more of hydrogen, halogen, C1-C3 alkyl or halo-C1-C3 alkyl; R 10 independently selected from one or more of carbonyl, hydrogen, halogen, C1-C3 alkyl, halo-C1-C3 alkyl or cyano; 1, 2, 3, 4, or 5 hydrogen atoms on any of the above groups may be substituted by substituents selected from the following group: deuterium, halogen, hydroxyl, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl C1-C3 alkyl; wherein, the heteroaryl contains 1-3 heteroatoms selected from the following group: N, O, P, or S, the heterocycloalkyl contains 1-3 heteroatoms selected from the following group: N, O, P, or S, and the ring system contains a saturated or partially unsaturated ring system of spiro ring, bridged ring, fused ring, or annulated ring.

2. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: wherein Z 1 , Z 2 are each independently selected from N and CR 11 , M1, M2, M3 are each independently selected from -(CR 12 R 13 )t-, -NR 14 , -C(O)-, -O-, -S(O)q- or -CH=CH-; R 11 independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 alkylcarbonyl, 3-6 membered cycloalkyl, 3-6 membered hetero cycloalkyl, vinyl, ethynyl; R 12 、R 13 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 alkylcarbonyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, vinyl or ethynyl; R 14 independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C3 hydroxyalkyl, substituted or unsubstituted amino-C1-C3 alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; the substituents in the substituted amino-C1-C3 alkyl are independently selected from one or more of the following groups: halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl C1-C3 alkyl; t independently represents an integer from 1 to 3; q independently represents an integer from 0 to 2.

3. The pyridazine compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The pyridazinone compound represented by the formula (I) has the general formula shown in (III-1) or (III-2) below, wherein X is CH3, CF3; R 1 , R 9 are each independently selected from methyl, ethyl; R 10 is selected from hydrogen, deuterium, fluorine, methyl, ethyl; a is an integer from 0 to 6; Z 1 is CH, C-F, C-Me, N.

4. The pyridazine compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of the formula (I) has the general formula shown in (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), or (IV-6) below, where a is an integer from 0 to 6; Z 1 is CH, C-F, C-Me, N.

5. The pyridazine compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, When X is a C1-C6 alkyl group, it is a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkylthio group, vinyl, or ethynyl; Alternatively, when R 1 together with Ry and the atoms connected thereto form a 4- to 10-membered heterocycloalkyl group, the 4- to 10-membered heterocycloalkyl group is a 5- to 8-membered heterocycloalkyl group; Alternatively, R 1 when, together with Ry and the atoms attached thereto, form a 4- to 10-membered heterocycloalkyl group, the 4- to 10-membered heterocycloalkyl group is wherein the *a end is connected to the parent pyridazine ring and the *b end is connected to the chain end; Alternatively, R 9 is H, CH3CH2-, CH3-, CH3O-, -CH2CN; Alternatively, Cy 2 is selected from 5- to 10-membered heteroaryl-fused 5- to 8-membered saturated or partially unsaturated ring systems; Alternatively, R 10 is selected from H, F, -CF3, CN, CH3CH2-, CH3-, CH3O-, -CH2CN.

6. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, When X is a C1-C6 alkyl group, X is methyl, methoxy, or methylthio; Alternatively, Cy 2 is selected from 5- to 10-membered heteroaryl-fused 5- to 8-membered saturated or partially unsaturated ring systems.

7. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Cy 2 selected from 5- to 10-membered heteroaryl-fused 5- to 8-membered cycloalkyl, 5- to 10-membered heteroaryl-fused 5- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl-fused 5- to 8-membered cycloalkenyl.

8. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Cy 2 selected from 9. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Cy 2 -R 10 selected from 10. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, is any of the following compounds:

11. A method for preparing a pyridazinone compound represented by formula (I) according to any one of claims 1-10, characterized in that, It includes the following steps: in a solvent, through the condensation reaction of an acid and an amine, an amide compound is formed, wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Cy 2 as described in any one of claims 1 - 10.

12. A pharmaceutical composition comprising the pyridazinone compound represented by the formula (I) according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of the pyridazinone compound represented by the formula (I) according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the preparation of a PARP7 inhibitor and in the preparation of a drug for treating diseases related to PARP7 mutation, activity, or expression level.

14. Use of a pyridazinone compound represented by formula (I) as described in any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 12, in the preparation of a PARP7 inhibitor and in the preparation of a therapeutic drug for treating tumors related to PARP7 mutation, activity or expression level; the tumors are independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer.

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