PARP7 inhibitor and application thereof

Abstract

The invention discloses a PARP7 inhibitor and application thereof, and particularly relates to a compound with a PARP7 inhibiting effect as shown in a formula (I), pharmaceutically acceptable salt, stereoisomer, solvate or prodrug of the compound, application of the compound and a preparation method of the compound. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application 202311125694.7 with an application date of September 1, 2023 and Chinese patent application 202311423018.8 with an application date of October 30, 2023, and this application cites the full text of the above-mentioned Chinese patent applications. Technical Field

[0002] The present disclosure relates to the field of medicine, and in particular to a compound having PARP7 inhibitory effect, and its use and preparation method. Background Art

[0003] Poly-ADP-ribose polymerases (PARPs) are a family of proteins that consist of 17 different members in the human body. They play important roles in different biological processes, including inflammation, viral infection and tumor cell stress. The PARP family can be divided into three categories according to catalytic activity: polyPARPs (4, including PARP1, PARP2, PARP5a, PARP5b) with multiple ADP-ribosylation target proteins, monoPARPs (12, including PARP3, PARP4, PARP6, PARP7, PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15, PARP16) with single ADP-ribosylation target proteins and PARP with no catalytic activity (1, PARP13). Most of the research on PARP is focused on polyPARPs (PARP1, 2, 5a and 5b), especially PARP1 / 2, which has the most research on the role of DNA damage repair. DNA damage refers to the phenomenon that the DNA nucleotide sequence is permanently changed during DNA replication, resulting in changes in genetic characteristics. If DNA damage or abnormal changes in genetic information cannot be corrected, it will affect the function or survival of cells. The repair of DNA damage is a programmed, orderly, multi-stage, and precise process involving multiple factors. PARP is an important protein in the DNA repair process and is involved in a series of important cellular processes including DNA repair and genome stability maintenance. There are 4 PARP inhibitors: niraparib and talazoparib target PARP1 and PARP2; olaparib and rucaparib target PARP1, PARP2, and PARP3. In addition, olaparib (First-in-Class), represented by the PARP1 / 2 inhibitor developed by AstraZeneca, has become a blockbuster drug with significant anti-cancer efficacy, and its indications can be gradually expanded through combination therapy.

[0004] There are relatively few studies on monoPARPs, which are single ADP-ribosylation target proteins. As mentioned above, most members (12) of the PARP family are monoPARPs. In recent years, studies on monoPARPs have found that PARP7 plays an important role in immunity and cancer. Among them, studies suggest that PARP7 is one of the target genes of AHR. PARP7 is part of the negative feedback loop that regulates AHR activity, and AHR can regulate immune function, inflammation, etc., and play a role in cancer. It can be induced by cancer-related stress, such as harmful chemicals in tobacco. Through in-depth studies of lung cancer, esophageal cancer, and head and neck cancer, which are strongly correlated with smoking, it was found that the gene locus where PARP7 is located is amplified and highly expressed. Studies have found that PARP7 is overactive in tumor cells, and many cancer cells rely on PARP7 for cell survival. Studies have shown that PARP7 can enable cancer cells to escape immune attacks by the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells, restore interferon signaling, and reverse immunosuppression. In several cancer models, PARP7 inhibitors have shown persistent tumor growth inhibition and interferon signaling restoration. In summary, PARP7 plays an important role in cancer and immune response and is a potential ideal cancer target. Due to the lack of PARP7-selective chemical probes in previous studies, most of the genetic methods were used to reveal the function of PARP7, so the enzymatic activity and the entire protein and their relationship could not be distinguished. In addition, the lack of mature high-throughput on-target activity screening test methods also hindered the development of corresponding drugs targeting PARP7 targets. In view of the successive reports of PARP7-related research results in recent years, PARP7 has become a relatively ideal anti-cancer target. At present, no PARP7 inhibitor has been approved for marketing. RBN-2397 developed by Ribon is the first compound with strong inhibitory activity and selectivity for PARP7. Therefore, it is of great significance to further study and develop new safe and effective PARP7 inhibitors. In addition, as mentioned above, in addition to playing an important role in tumors, PARP7 also plays a key role in diseases such as inflammation and viral infection. Therefore, in addition to its anti-cancer effect, PARP7 inhibitors are also expected to have potential application value in other diseases such as inflammation, immunity, and viral infection. Summary of the invention

[0005] The purpose of the present invention is to provide a compound having PARP7 inhibitory effect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0006] In one aspect of the present invention, there is provided a compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0007]

[0008] In formula (I),

[0009] Ring A is selected from

[0010] T is selected from CH or N;

[0011] R x Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, -NO2, -NH2, the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0012] p is selected from 0, 1 or 2;

[0013] Ring A is selected from Y1 is selected from -C(R6)(R7)-, m is selected from 1, 2 or 3, q ​​is 1, n is 1, wherein R6 and R7 are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, or R6, R7 and the carbon atom to which they are commonly attached form a 3-6 membered cycloalkyl;

[0014] Or ring A is selected from Y1 is selected from -N(R6)-C 1-3 Alkyl-, m is 1, q is 1, n is 1, wherein R6 is selected from hydrogen or deuterium, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3;

[0015] Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, a 3-10-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom, or a 7-10-membered nitrogen-containing spirocycloalkyl group containing at least one nitrogen atom, wherein R a Selected from hydrogen, deuterium or C 1-3 Alkyl, the -N(R a )-C3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, 3-10-membered nitrogen-containing heterocycloalkyl containing at least one nitrogen atom, 7-10-membered nitrogen-containing spirocycloalkyl containing at least one nitrogen atom, C 1-3 The alkyl group is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0016] Ring B does not exist, the group for

[0017] Or ring B is a 5-8 membered saturated or unsaturated heterocyclic ring, and the ring B is optionally substituted with one or more halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy substituted, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0018] W is selected from C, N, O or S;

[0019] U1, U2, U3, U4 are each independently selected from CH, CH2, N or NH;

[0020] The halogen is selected from fluorine, chlorine and bromine;

[0021] R1, R 1a , R2, R 2a , R3, R 3a , R4, R 4a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, cyano, carboxyl, C 1-3 or any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3, or R1, R 1a Together they form an oxo group, or R2, R 2a Together they form an oxo group, or R3, R 3a Together they form an oxo group, or R4, R 4a Together they form an oxo group;

[0022] n1 R5 are the same or different from each other, n1 is selected from 0, 1, 2 or 3, R5 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 An amide group, an aminoacyl group, a 4-6-membered cyclic aminoacyl group, a 4-6-membered saturated or unsaturated heterocyclic group, a sulfonamide group, a 4-6-membered heterocyclic amino group, or two R5 substituents on the carbon atom adjacent to the ring C and the carbon atom to which they are attached form a 4-6-membered saturated or unsaturated heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Amide, aminoacyl, 4-6 membered cyclic aminoacyl, 4-6 membered saturated or unsaturated heterocyclic group, sulfonamide, 4-6 membered heterocyclic amino group are optionally substituted with one or more halogen, hydroxyl, C 2-6 Ester substitution.

[0023] Another aspect of the present invention provides a compound represented by formula (I'), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0024]

[0025] In formula (I'),

[0026] Ring A is selected from

[0027] T is selected from CH or N;

[0028] R x Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -NO2, -NH2;

[0029] p is selected from 0, 1 or 2;

[0030] Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, a 3-10-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom, or a 7-10-membered nitrogen-containing spirocycloalkyl group containing at least one nitrogen atom, wherein R a is selected from hydrogen or deuterium;

[0031] U1, U2, U3 are each independently selected from CH, CH2, N or NH; the halogen is selected from fluorine, chlorine, bromine;

[0032] R1, R 1a , R2, R 2a , R3, R 3a , R4, R 4a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, cyano, carboxyl, C 1-3 or any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3, or R1, R 1a Together they form an oxo group, or R2, R 2a Together they form an oxo group, or R3, R 3a Together they form an oxo group, or R4, R 4a Together they form an oxo group;

[0033] n1 R5 are the same or different from each other, n1 is selected from 0, 1, 2 or 3, R5 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 The alkynyl group is optionally substituted with one or more halogen, hydroxyl, C 2-6 Ester group, C 1-3 Amide and sulfonamide substitution;

[0034] The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 3-10-membered nitrogen-containing heterocycloalkyl containing at least one nitrogen atom, 7-10-membered nitrogen-containing spirocycloalkyl containing at least one nitrogen atom, C 2-6 Ester group, C 1-3 The amide group is optionally substituted with one or more hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0035] When ring A is selected from When Y1 is selected from -C(R6)(R7)-, m is selected from 0, 1, 2 or 3, q ​​is selected from 0 or 1, n is selected from 0 or 1, and m, n, q are not 0 at the same time, wherein R6 and R7 are each independently selected from hydrogen or deuterium;

[0036] When ring A is selected from When Y1 is selected from -N(R6)-C 1-3 Alkyl-, m is 1, q is 1, n is 1, wherein R6 is selected from hydrogen or deuterium, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3.

[0037] In some embodiments, Selected from

[0038] Preferably, Selected from

[0039]

[0040] Preferably, Ring B is present, Selected from

[0041] Preferably, W is selected from C or O.

[0042] In some embodiments, Ring A is selected from

[0043] Preferably, R x Selected from hydrogen, deuterium, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-6 Haloalkyl, the C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0044] Preferably, p is selected from 1 or 2;

[0045] Preferably, ring A is selected from Y1 is selected from -C(R6)(R7)-, m is 1, q is 1, n is 1, wherein R6 and R7 are each independently selected from hydrogen, deuterium, methyl, or R6, R7 and the carbon atom to which they are commonly attached form a 3-6 membered cycloalkyl group;

[0046] Or ring A is selected from Y1 is selected from -N(R6)-C 1-3 Alkyl-, m is 1, q is 1, n is 1, wherein R6 is selected from hydrogen or deuterium, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1 and 2;

[0047] Preferably, Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, a 3-10-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom, or a 7-10-membered nitrogen-containing spirocycloalkyl group containing at least one nitrogen atom, wherein R a Selected from hydrogen, deuterium or C 1-3 Alkyl, the -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, 3-10-membered nitrogen-containing heterocycloalkyl containing at least one nitrogen atom, 7-10-membered nitrogen-containing spirocycloalkyl containing at least one nitrogen atom, C 1-3 The alkyl group is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0048] Preferably, U1, U2, U3, U4 are each independently selected from CH, CH2, N or NH;

[0049] Preferably, the halogen is selected from fluorine and chlorine;

[0050] Preferably, R1, R 1a , R2, R 2a , R3, R 3a , R4, R 4a are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, or any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1 or 2;

[0051] Preferably, n1 R5 are the same or different from each other, n1 is selected from 0, 1, 2 or 3, and R5 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-3An amide group, an aminoacyl group, a 4-6-membered cyclic aminoacyl group, a 4-6-membered saturated or unsaturated heterocyclic group, a sulfonamide group, a 4-6-membered heterocyclic amino group, or two R5 substituents on the carbon atom adjacent to the ring C and the carbon atom to which they are attached form a 4-6-membered saturated or unsaturated heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-3 The amide group, aminoacyl group, 4-6-membered cyclic aminoacyl group, 4-6-membered saturated or unsaturated heterocyclic group, sulfonamide group, 4-6-membered heterocyclic amino group are optionally substituted by one or more halogens or hydroxyl groups.

[0052] In some embodiments, Ring A is selected from Y1 is selected from -CH2-, -CH(CH3)-, -C(CH3)2- or

[0053] Or ring A is selected from Y1 is selected from -NH-CH(CH3)CH2-, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1 or 2;

[0054] Preferably, Y2 is selected from

[0055] Preferably, Ring B is absent and the group Selected from

[0056]

[0057]

[0058] or Ring B is a 5-8 membered saturated or unsaturated heterocyclic ring, the group Selected from

[0059]

[0060] In some embodiments, the compound, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a compound represented by formula (II), formula (III), formula (IV) or formula (V):

[0061]

[0062] Among them, R x ,p,Y1,Y2,n1,R1,R1a , R2, R 2a , R3, R 3a , R4, R 4a , R5, W, and Ring B are as defined above.

[0063] In a preferred embodiment, the compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is selected from the following groups:

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] Another aspect of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, and at least one pharmaceutically acceptable carrier.

[0070] Another aspect of the present invention provides a use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof or the pharmaceutical composition as described above in the preparation of PARP7 inhibitors or in the treatment of diseases mediated by PARP7;

[0071] Preferably, the PARP7-mediated diseases include cancer, immune diseases, inflammation and viral infection;

[0072] Preferably, the cancer includes PARP7-amplified solid tumors, small cell lung cancer, squamous cell lung cancer, and advanced non-small cell squamous cell lung cancer;

[0073] Preferably, the PARP7-amplified solid tumors include esophageal cancer and head and neck cancer.

[0074] Another aspect of the present invention provides a method for inhibiting PARP7 in a patient in need thereof, comprising administering to the patient the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition as described above.

[0075] Another aspect of the present invention provides a method for inhibiting PARP7 in a biological sample, comprising contacting the biological sample with the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition as described above.

[0076] Another aspect of the present invention provides a method for treating a disorder mediated by PARP7 in a patient in need thereof, comprising administering to the patient the above-mentioned compound, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition as described above;

[0077] Preferably, the PARP7-mediated disorders include cancer, immune diseases, inflammation and viral infection;

[0078] Preferably, the cancer includes PARP7-amplified solid tumors, small cell lung cancer, squamous cell lung cancer, and advanced non-small cell squamous cell lung cancer;

[0079] Preferably, the PARP7-amplified solid tumors include esophageal cancer and head and neck cancer;

[0080] Preferably, the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof or the pharmaceutical composition administered is an effective amount. DETAILED DESCRIPTION

[0081] According to the contents of the present disclosure, in accordance with common technical knowledge and customary means in the art, without departing from the basic technical ideas of the present disclosure, other various forms of modifications, replacements or changes may be made.

[0082] I. Definitions

[0083] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0084] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0085] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. The numerical ranges herein refer to the individual integers in the given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 2-6” means that the group can have 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0086] The term "substituted" means that any one or more hydrogen atoms on a particular atom or group are replaced by a substituent, as long as the valence state of the particular atom or group is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemically achievable.

[0087] In this disclosure, when any variable (such as R n ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-5 R, the group may be optionally substituted with up to 5 R, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0088] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 2,2-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present disclosure.

[0089] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0090] The term "alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0091] The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, the cycloalkyl ring containing at least 3 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0092] The term "heterocycloalkyl" refers to a saturated monocyclic hydrocarbon substituent in which one or more of the ring atoms is selected from nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Non-limiting examples of heterocycloalkyl include pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazacycloheptyl and piperazinyl.

[0093] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0094] The term "heterocycle" or "heterocyclyl" refers to a saturated or unsaturated heterocyclic group in which one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) of heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.

[0095] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0096] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0097] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0098] The term "spirocycloalkyl" refers to an alicyclic hydrocarbon in which two carbon rings in the molecule share one carbon atom. The shared carbon atom is called a "spiro carbon atom".

[0099] The term "amide group" refers to a group in which the hydroxyl group of the carboxyl group in the carboxylic acid molecule is substituted with an amino group or a hydrocarbon amino group [-NHR or -N(R)R].

[0100] The term "aminoacyl" refers to the group remaining after the hydroxyl group is removed from the amino acid molecule.

[0101] The term "cycloaminoacyl" refers to the group remaining after the hydroxyl group is removed from the cyclic amino acid molecule, which is collectively called the cycloaminoacyl group.

[0102] The term "sulfonylamide group" refers to a group in which the hydrogen atom of sulfonylamide is substituted, and the remaining group is generally called a sulfonylamide group.

[0103] The term "heterocyclic amino group" refers to an amino group substituted by a saturated or unsaturated heterocyclic group, and the remaining groups are collectively referred to as heterocyclic amino groups.

[0104] In the present disclosure, "hydroxy" refers to an -OH group; "halogen" refers to fluorine, chlorine, bromine or iodine; "amino" refers to -NH2; "cyano" refers to -CN; "nitro" refers to -NO2; "carbonyl" refers to -C(O)-; and "carboxy" refers to -C(O)OH.

[0105] The hydrogen atoms described in this disclosure may be replaced by their isotope deuterium. Refers to a chemical bond connection. In the present disclosure, "----" refers to a bond or group that may or may not exist.

[0106] NMP: refers to N-methylpyrrolidone;

[0107] EA: refers to ethyl acetate;

[0108] dioxane: refers to dioxane;

[0109] SEMCl: refers to 2-(trimethylsilyl)ethoxymethyl chloride;

[0110] DMF: refers to N,N-dimethylformamide;

[0111] NH2NH2.H2O: refers to hydrated hydrazine;

[0112] NBS: refers to N-bromosuccinimide;

[0113] BPO: refers to dibenzoyl peroxide;

[0114] ACN: refers to acetonitrile;

[0115] n-BuLi: refers to n-butyllithium;

[0116] THF: refers to tetrahydrofuran;

[0117] TEA: refers to triethylamine;

[0118] t-BuOK: refers to potassium tert-butoxide;

[0119] H-Pro-OH: refers to L-proline;

[0120] AlBN: refers to azobisisobutyronitrile;

[0121] AcOH: refers to acetic acid;

[0122] EtOH: refers to ethanol;

[0123] Bn: refers to benzyl;

[0124] Pd(dppf)Cl2: refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0125] MeOH: refers to methanol;

[0126] Boc: refers to tert-butoxycarbonyl;

[0127] Refers to 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane;

[0128] Refers to cyclopropylboronic acid;

[0129] DIPEA or DIEA: refers to N,N-diisopropylethylamine;

[0130] HATU: refers to O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0131] DCM: refers to dichloromethane;

[0132] TFA: refers to trifluoroacetic acid;

[0133] Refers to trimethyl orthoformate;

[0134] NaBH3CN: refers to sodium cyanoborohydride;

[0135] DETA: refers to diethylenetriamine;

[0136] BF3Et2O: refers to boron trifluoride ethyl ether;

[0137] Cs2CO3: refers to cesium carbonate;

[0138] NaOAc: refers to sodium acetate;

[0139] MeOH: refers to methanol;

[0140] PyBOP: refers to 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate.

[0141] Drug or drug composition

[0142] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0143] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without adverse biological effects, such as acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).

[0144] The pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid to prepare.

[0145] The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0146] For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. For oral administration in liquid form, the drug component can be combined with a pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0147] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present disclosure containing the compound of formula I as the active compound can also introduce beads, microspheres or microcapsules, such as those constructed from polyglycolic acid / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

[0148] The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, that is, administered intravenously (iv), intracerebroventricularly (icv), subcutaneously (sc), intraperitoneally (ip), intramuscularly (im), subcutaneously (sd) or intradermally (id), by direct injection, for example, by bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example, in an ampoule or multi-dose container with an added preservative. The composition can be in the shape of an excipient, in the form of a suspension, solution or emulsion in an oil or aqueous vehicle, and can include formulation agents such as anti-settling agents, stabilizers and / or dispersants. Alternatively, the active ingredient can be reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use in powder form.

[0149] The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as a suppository or retention enema (eg, containing a conventional suppository base such as cocoa butter or other glycerides).

[0150] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0151] The terms "reduce," "inhibit," "mitigate," or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0152] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide a desired pharmacological and / or physiological effect. The exact dosage will vary according to a variety of factors, such as variables that the subject depends on (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective amount can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of a subject before or without the administration of a drug or drug combination, or in the case of a drug combination, the combined effect can be compared to the effect of administering only one drug.

[0153] The term "excipient" is used herein to include any other compound that may be contained in or on the microparticles that is not a therapeutic or biologically active compound. Thus, an excipient should be pharmaceutically or biologically acceptable or relevant, e.g., an excipient is generally non-toxic to a subject. An "excipient" includes a single such compound, and is also intended to include a plurality of compounds.

[0154] The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0155] Uses and treatments

[0156] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof amenable to the methods described herein, whether in vitro or in situ. In some non-limiting embodiments, the patient, subject, or individual is a human.

[0157]

[00136] According to the methods of the present disclosure, the compounds or compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease associated with PARP.

[0158] The present disclosure relates to a method of inhibiting PARP in a biological sample, comprising the step of contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

[0159] The term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. Inhibition of enzymes in biological samples can be used to achieve a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioanalysis, gene expression studies, and identification of biological targets.

[0160] The method of inhibiting PARP in a patient disclosed herein comprises the step of administering to the patient a compound disclosed herein or a composition comprising the compound.

[0161] The provided compounds are PARP inhibitors and are therefore useful for treating one or more conditions associated with PARP activity. Thus, in certain embodiments, the present disclosure provides a method for treating a PARP-mediated condition comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0162] As used herein, the term "disorder, disease and / or condition as used herein, "mediated" as used herein means any disease or other deleterious condition in which PARP or a mutant thereof is known to play a role. Therefore, another embodiment of the present disclosure is directed to treating or lessening the severity of one or more diseases in which PARP or a mutant thereof is known to play a role.

[0163] The present disclosure provides a method for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is a proliferative disorder, such as cancer, an inflammatory disorder, or a viral infection.

[0164] In certain embodiments, the present disclosure provides a method of treating cancer or another proliferative disorder, comprising administering a compound or composition of the present disclosure to a patient suffering from cancer or another proliferative disorder. In certain embodiments, the method of treating cancer or another proliferative disorder comprises administering a compound and composition of the present disclosure to a mammal. In certain embodiments, the mammal is a human.

[0165] As used herein, the terms "inhibit cancer" and "inhibit cancer cell proliferation" refer to inhibiting the growth, division, maturation or survival of cancer cells, and / or causing cancer cell death by cytotoxicity, nutrient depletion or induction of apoptosis, either individually or collectively with other cancer cells.

[0166] Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and for which the methods described herein are applicable include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary glands, adrenal glands, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, and stomach.

[0167] The cancer treated by the compounds or compositions of the present disclosure is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma or colon cancer. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

[0168] The compounds of the present disclosure can be used to treat a proliferative disease selected from the group consisting of a benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid; a sarcoma, a glioblastoma, a neuroblastoma, multiple myeloma or a gastrointestinal cancer (particularly a colon cancer or a colorectal adenoma) or a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, an undifferentiated tumor, papillary carcinoma, a seminoma, melanoma, a MYD88 driven disorder, DLBCL, ABC DLBCL, IL-1 driven disorders and rheumatic or indolent multiple myeloma or leukemia.

[0169] Cancers described in the present disclosure include, but are not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myeloid leukemias, acute myeloblastic leukemias, acute promyelocytic leukemias, acute myelomonocytic leukemias, acute monocytic leukemias, acute erythroleukemias, chronic leukemias, chronic myelocytic leukemias, chronic lymphocytic leukemias), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcomas, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mesothelioma, Ewing's tumors, tumor), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal tumor, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0170] In some embodiments, the cancer is a glioma, an astrocytoma, a glioblastoma multiforme (GBM, also known as a glioblastoma), a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, an hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a schwannoma, a neurofibrosarcoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

[0171] In some specific embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low-grade astrocytoma, grade III-pleomorphic astrocytoma, or grade IV-glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or a pediatric patient.

[0172] In another specific embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal tract (stomach, colorectal and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0173] In some embodiments, the cancer is selected from small cell lung cancer, squamous cell lung cancer, advanced non-small cell squamous cell lung cancer, hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic duct cancer or pancreatic cancer; gastrointestinal tract / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0174] The term "primary tumor" is relative to secondary tumor. Primary tumor refers to a tumor that first appears in a certain part of the body such as the lungs, liver, intestines, head, or skin. It can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

[0175] The term "inflammatory disease" includes such autoimmune, allergic and inflammatory disorders, for example selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis, Sjogren's syndrome, and blistering disorders (e.g. pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (cancer or infection primary or secondary). The allergic disorder may be selected in particular from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollens and related allergens, berylliosis. The respiratory disorder may be selected from, inter alia, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension and emphysema, among others.

[0176] The term "viral infection" includes but is not limited to retroviral infection, hepatitis virus infection, COVID-19 novel coronavirus infection, Zika virus infection, dengue virus infection, etc.

[0177] Combination therapy approach

[0178] The present disclosure provides a combination therapy using compounds as described in the present disclosure and other therapeutic drugs. The term "combination therapy" used in the present disclosure includes the administration of these agents in a sequential manner, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents, or at least two agents, is substantially performed simultaneously. The order of each agent, or substantially simultaneous administration, can be affected by any appropriate route, including but not limited to, oral routes, intravenous routes, intramuscular routes, subcutaneous routes, and direct absorption by mucosal tissue. The agents can be administered by the same route or different routes. For example, the first agent can be administered orally, and the second agent can be administered intravenously. In addition, the selected combination can be administered by intravenous injection, and the other agents of the combination can be administered orally. Alternatively, for example, two or more agents can be administered by intravenous or subcutaneous injection.

[0179] II. Embodiment

[0180] The present disclosure is further explained below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present disclosure to the precise form disclosed, and it is clear that many changes and variations can be made according to the teachings of the present disclosure specification. The purpose of selecting and describing exemplary embodiments is to explain the specific principles of the present disclosure and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present disclosure and various different selections and changes.

[0181] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0182] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0183] Experimental instruments and methods:

[0184] Instruments and reagents:

[0185] NMR was measured using an Agilent 400MR DD2 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the solvent, and tetramethylsilane (TMS) as the internal standard. LC-MS: Agilent 1260 Infinity II–InfinityLab LC / MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high pressure liquid chromatograph (Sunfire C18 5μm 150x 4.6mm column). Reagents used are 2-chloro-5-(trifluoromethyl)pyrimidine, N-methylpyrrolidone, piperazine-1-carboxylic acid tert-butyl ester, 3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, ethyl acetate, (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, dioxane hydrochloride solution, 4,5-dibromopyridin-3(2H)-one, N,N dimethylformamide, 3,3,3-trifluoro-2-oxopropionic acid methyl ester, etc. Reagents and starting materials are purchased from Shanghai Bi De Reagent Company, or synthesized using methods known in the art. Unless otherwise specified, all reactions disclosed herein are carried out under continuous magnetic stirring, under dry nitrogen or argon, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.

[0186] Intermediates

[0187]

[0188]

[0189]

[0190]

[0191] Intermediate I-1: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1)

[0192]

[0193] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-1-a)

[0194] 2-Chloro-5-(trifluoromethyl)pyrimidine (1825 mg, 10 mmol) was dissolved in N-methylpyrrolidone (30 ml), and tert-butyl piperazine-1-carboxylate (1862 mg, 10 mmol) and potassium carbonate (2764 mg, 20 mmol) were added, and the mixture was reacted at 80°C for 1 hour. Water (100 ml) was added, and the solid was collected by filtration and dried in vacuo to obtain the target product tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-1-a, 2.9 g, yield 87%).

[0195] Step 2: Preparation of 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1)

[0196] Dissolve tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-1-a, 332 mg, 1 mmol) in 4M hydrochloric acid ethyl acetate (5 ml) and react at room temperature for 2 hours. Filter the reaction solution and wash the solid with petroleum ether to obtain the target product 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 289 mg, yield 94%). ESI [M+H] + =233.1 1 H NMR(400MHz,DMSO-d6)NMR(400MHz,DMSO--d6)δ9.48(S,2H),8.78(S,2H),4.06(S,4H),3.18(S,4H).

[0197] Intermediate I-2: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-2)

[0198]

[0199] Step 1: Preparation of tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2-a)

[0200] Dissolve tert-butyl 3,8-diazacyclo[3.2.1]octane-8-carboxylate (200 mg, 0.942 mmol) in N-methylpyrrolidone (5 ml), add 2-chloro-5-(trifluoromethyl)pyrimidine (172 mg, 0.942 mmol) and potassium carbonate (260 mg, 1.88 mmol), and react at 80°C for 5 hours. Add water (20 ml), stir at 0°C for 30 minutes, collect the precipitated solid by filtration, wash with water, and dry at 70°C to obtain the target product tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2-a, 312 mg, yield 92.6%). ESI[M+H-56] + =303.1

[0201] Step 2: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-2)

[0202] Dissolve tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2-a, 312 mg, 0.871 mmol) in ethyl acetate (5 ml), add 4M hydrochloric acid dioxane solution (10 ml), and react at room temperature for 3 hours. Collect the precipitated solid by filtration, wash with ethyl acetate to obtain the target product 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-2, 232 mg, yield 90.6%). ESI[M+H] + =259.2

[0203] Intermediate I-3: Preparation of (R)-2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-3)

[0204]

[0205] Step 1: Preparation of (R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-3-a)

[0206] Potassium carbonate (138 mg, 0.999 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (91 mg, 0.499 mmol) were added to a solution of (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.499 mmol) in N-methylpyrrolidone (10 ml) at room temperature, and the reaction solution was stirred at 80°C overnight. 20 mL of water was added to quench the reaction, and 3×10 mL of ethyl acetate were used for extraction. The organic layers were combined, washed with 3×10 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-3-a, 110 mg, yield 63.61%). ESI[M+H] + =347.3

[0207] Step 2: Preparation of (R)-2-(3-methylpiperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-3)

[0208] At room temperature, 4M hydrochloric acid dioxane solution (3 mL) was added to a solution (3 mL) of ethyl acetate (R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-3-a, 110 mg, 0.318 mmol), and the reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain a crude product (R)-2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-3, 100 mg). ESI[M+H] + =247.2

[0209] Intermediate I-4: Preparation of (S)-2-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4)

[0210]

[0211] Step 1: Preparation of (S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-4-a)

[0212] Dissolve (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol) in N-methylpyrrolidone (5 ml), add 2-chloro-5-(trifluoromethyl)pyrimidine (183 mg, 1 mmol) and potassium carbonate (276 mg, 2 mmol), and react at 100°C for 2 hours. Add water (20 ml), stir at 0°C for 30 minutes, collect the precipitated solid by filtration, wash with water, and dry at 70°C to obtain the target product (S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-4-a, 276 mg, yield 79.8%). ESI[M+H-56] +=291.0ESI[M+H-100] + =247.1

[0213] Step 2: Preparation of (S)-2-(2-methylpiperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4)

[0214] Dissolve (S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-4-a, 276 mg, 0.797 mmol) in ethyl acetate (5 ml), add 4M hydrochloric acid dioxane solution (5 ml), and react at room temperature for 3 hours. Collect the precipitated solid by filtration, wash with ethyl acetate, and then distill under reduced pressure to obtain the target product (S)-2-(2-methylpiperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4, 220 mg, yield 97.8%). ESI[M+H] + =247.2

[0215] Intermediate I-5: Preparation of 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5)

[0216]

[0217] Step 1: Preparation of 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-a)

[0218] Under ice bath, 4,5-dibromopyridin-3(2H)-one (20g, 78.78mmol) was dissolved in N,N-dimethylformamide (200mL), 60% sodium hydride (4.0g, 94.54mmol) was slowly added, and stirred at room temperature for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (14.4g, 86.66mmol) was added dropwise under ice bath, and after the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Under ice bath, the reaction solution was quenched with water (200mL), extracted with ethyl acetate (100mL*3), and the organic phase was washed with brine (100mL*3), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-a, 18.6 g, yield: 61.46%, colorless oil). ESI [M+H] + =355.1,357.1

[0219] Step 2: Preparation of 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-b)

[0220] Lithium chloride (1.93 g, 45.30 mmol) was added to a solution of compound 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-a, 17.4 g, 45.30 mmol) in N-methylpyrrolidone (100 mL), and the resulting solution was stirred at 95 ° C for 4 hours. Then 250 mL of water was added to the reaction, and 3×250 mL of ethyl acetate were extracted, and the organic layers were combined. The organic layer was washed with 3×250 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-b, 13 g), which was used directly in the next step. ESI[M+H] + =311.2,313.2

[0221] Step 3: Preparation of 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5)

[0222] To a solution of compound 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-b, 13 g, 38.27 mmol) in N-methylpyrrolidone (80 mL) was added iodide (1.47 g, 7.66 mmol) at room temperature, followed by dropwise addition of compound 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (22.17 g, 114.8 mmol). The resulting solution was stirred at 80° C. for 2 hours. 250 mL of water was added to quench the reaction, and extracted with 3×250 mL of ethyl acetate. The organic layers were combined and washed with 3×250 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:99) to obtain compound 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5, 9.4 g, yield 53.95%). ESI [2M + Na] + =679.1

[0223] Intermediate I-6: Preparation of 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6)

[0224]

[0225] Step 1: Preparation of methyl 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (I-6-a)

[0226] Dissolve 3,3,3-trifluoro-2-oxopropionic acid methyl ester (10 g, 64.08 mmol) in acetone (5.2 ml) and stir at 100°C for 16 hours. Concentrate the reaction solution under reduced pressure to obtain the target product, 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoic acid methyl ester (I-6-a, 12.84 g, yield 93.65%). ESI [M+H] + =215.05

[0227] Step 2: Preparation of 6-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-b)

[0228] Dissolve methyl 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (I-6-a, 12.13 g, 56.68 mmol) in acetic acid (35 ml). Add hydrated hydrazine (5.67 g, 113.26 mmol) and react at 110°C overnight. Add saturated brine, extract with ethyl acetate, and purify by column chromatography (petroleum ether: ethyl acetate = 88%: 12%) to obtain the target product 6-methyl-4-(trifluoromethyl)pyridazine-3(2H)-one (I-6-b, 6.55 g, yield 64.88%). ESI[M+H] + =179.04

[0229] Step 3: Preparation of 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c)

[0230] Dissolve 6-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-b, 6.55 g, 36.8 mmol) in carbon tetrachloride solution (190 ml). Add N-bromosuccinimide (9.82 g, 55.17 mmol) and dibenzoyl peroxide (1.78 g, 7.35 mmol) in sequence, and react at 80°C overnight. Add saturated brine, extract with ethyl acetate, concentrate the organic phase under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 91:9) to obtain the target product 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 4.7 g, yield 49.91%). ESI[M+H] + =256.95

[0231] Step 4: Preparation of 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carboxaldehyde (I-6)

[0232] Dissolve 6-(bromomethyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (I-6-c, 500 mg, 1.95 mmol) in acetonitrile (5 ml), add N-methylmorpholine-N-oxide (803 mg, 6.84 mmol) and potassium iodide (32.4 mg, 0.195 mmol) under ice bath, react at room temperature for 2 hours, concentrate under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain the target product 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carboxaldehyde (I-6, 270 mg, yield 72%). (ESI)[M+H] + =193.02 1 HNMR(600MHz,DMSO-d6)δ14.45(S,1H),9.74(S,1H),8.04(S,1H).

[0233] Intermediate I-7: Preparation of 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7)

[0234]

[0235] Dissolve 5-bromo-3-(trifluoromethyl)pyridin-2(1H)-one (2g, 0.826mmol) in anhydrous tetrahydrofuran solution (3ml), stir at -80℃ under nitrogen protection for 20 minutes, slowly add n-butyl lithium (9.9ml, 2.479mmol) and continue to react at -80℃ for 3 hours, then add N,N-dimethylformamide (1.53ml, 19.824mmol) again and react for 1 hour. Add saturated ammonium chloride aqueous solution to quench, extract with ethyl acetate, then extract with dichloromethane, and concentrate the organic phase under reduced pressure. The aqueous phase is filtered and combined after distillation under reduced pressure, and the crude product is purified by column chromatography (petroleum ether-ethyl acetate: 0-70%) to obtain the target product 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxaldehyde (I-7, 1.01g, yield 63.96%). ESI[M+H] + =192.1

[0236] Intermediate I-8: Preparation of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8)

[0237]

[0238] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-8-a)

[0239] Dissolve 2-chloro-5-(trifluoromethyl)pyridine (500 mg, 2.68 mmol) in N-methylpyrrolidone (13 ml), add tert-butyl piperazine-1-carboxylate (2.82 mg, 10 mmol) and potassium carbonate (557 mg, 4.02 mmol), and react at 80°C for 3 hours. Add water (150 ml), stir and filter to collect the solid, and vacuum dry to obtain the target product tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-8-a, 520 mg, yield 58.46%).

[0240] Step 2: Preparation of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8)

[0241] Dissolve 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-8-a, 520 mg, 1.57 mmol) in 4M hydrochloric acid ethyl acetate (6 ml) and react at room temperature for 2 hours. Filter the reaction solution and wash the solid with petroleum ether to obtain the target product 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8, 400 mg, yield 95.22%). ESI [M + H] + =232.0

[0242] Intermediate I-9: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-9)

[0243]

[0244] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyrazine-2-yl)piperazine-1-carboxylate (I-9-a)

[0245] Dissolve tert-butyl piperazine-1-carboxylate (486 mg, 2.61 mmol) in N-methylpyrrolidone (20 ml), add 2-chloro-5-(trifluoromethyl)pyrazine (500 mg, 2.74 mmol) and potassium carbonate (757 mg, 5.22 mmol) under ice bath, react at 80°C for 4 hours, add water (50 ml) to the reaction solution under ice bath, filter, wash the filter cake with water, collect the filter cake and concentrate under reduced pressure to obtain the target product tert-butyl 4-(5-(trifluoromethyl)pyrazine-2-yl)piperazine-1-carboxylate (I-9-a, 880 mg, yield 96.8%). ESI[M-56+H] + =277.2

[0246] Step 2: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine hydrochloride (I-9)

[0247] Dissolve tert-butyl 4-(5-(trifluoromethyl)pyrazine-2-yl)piperazine-1-carboxylate (I-9-a, 880 mg, 2.61 mmol) in ethyl acetate (10 ml), add 4M hydrochloric acid ethyl acetate solution (10 ml) under ice bath, react at room temperature for 2 hours, and concentrate under reduced pressure to obtain the target 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrazine hydrochloride (I-9, 638 mg, yield 89.6%). ESI[M+H] + =233.2

[0248] Intermediate I-10: Preparation of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-10)

[0249]

[0250] Step 1: Preparation of (R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-10-a)

[0251] Dissolve (R)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.434 mmol) in N,N-dimethylformamide (3 ml), add 2,3-difluoro-5-(trifluoromethyl)pyridine (100 mg, 0.564 mmol), triethylamine (270 μl, 1.95 mmol) and heat to 85 ° C to react overnight. Cool the reaction solution and add water, then extract with ethyl acetate, combine the organic phases and wash with saturated brine, dry the organic phase with anhydrous sodium sulfate and filter. The filtrate is concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0-27%) to obtain the target product (R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-10-a, 136 mg, yield 79.62%). ESI[M-100+H] + =294.3,ESI[M+H] + =394.3

[0252] Step 2: Preparation of tert-butyl (R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaindene-9-carboxylate (I-10-b)

[0253] Dissolve (R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-10-a, 136 mg, 0.345 mmol) in tert-butanol (4 ml), add potassium tert-butoxide (117 mg, 1.04 mmol) and react at 120°C for 3 hours. After cooling, the reaction solution was distilled under reduced pressure, and then ethyl acetate was added to dissolve and filter. The filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0-43%) to obtain the target product tert-butyl (R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaindene-9-carboxylate (I-10-b, 102 mg, yield 79.02%). ESI[M-100+H] + =274.3,ESI[M+H] + =374.4

[0254] Step 3: Preparation of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-10)

[0255] 4M hydrochloric acid ethyl acetate solution (3 ml) was added to tert-butyl (R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaindene-9-carboxylate (I-10-b, 102 mg, 0.273 mmol) at room temperature. After the reaction solution was stirred at room temperature for 1 hour, ethyl acetate was added several times and concentrated under reduced pressure to obtain crude (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine hydrochloride (I-10, 96 mg, yield 113.46%). ESI[M+H] + =274.3

[0256] Intermediate I-11: Preparation of (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-11)

[0257]

[0258] Step 1: Preparation of (S)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-11-a)

[0259] (S)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.868 mmol) and 2,3-difluoro-5-(trifluoromethyl)pyridine (183 mg, 0.999 mmol) were dissolved in N,N-dimethylformamide (6 ml), triethylamine (540 μl, 3.91 mmol) was added, and the mixture was reacted at 85°C in a sealed tube overnight, quenched with water (10 ml), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product (S)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-11-a, 287 mg, yield 67.2%). ESI[M+H] + =394.4,ESI[M-56+H] + =338.2

[0260] Step 2: Preparation of tert-butyl (S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaindene-9-carboxylate (I-11-b)

[0261] Dissolve (S)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-11-a, 237 mg, 0.603 mmol) in tert-butanol (8 ml), add potassium tert-butoxide (203 mg, 1.81 mmol), react in a sealed tube at 120°C for 2 hours, filter, and concentrate the filtrate under reduced pressure to obtain the target product tert-butyl (S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaindene-9-carboxylate (I-11-b, 260 mg, crude product). ESI[M-56+H] + =318.3

[0262] Step 3: Preparation of (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-11)

[0263] (S)-3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaindene-9-carboxylate (I-11-b, 260 mg, 0.697 mmol) was dissolved in ethyl acetate (2 ml), and 4M hydrochloric acid ethyl acetate solution (4 ml) was added. After reacting at room temperature for 2 hours, the target product (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine hydrochloride (I-11, 280 mg, crude product) was obtained after concentration under reduced pressure. ESI[M+H] + =274.4

[0264] Intermediate I-12: Preparation of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-12)

[0265]

[0266] Step 1: Preparation of (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-a)

[0267] Dissolve (R)-3-(Hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.62 mmol) in N,N-dimethylformamide (15 ml), add 2-chloro-5-(trifluoromethyl)nicotinate (1.11 g, 4.62 mmol), potassium carbonate (1.28 g, 9.25 mmol), react at 80°C overnight, add the reaction solution dropwise into water (150 ml), solid precipitates, filter, and concentrate the filter cake under reduced pressure to obtain the target product (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-a, 1.0 g, yield 55.9%). ESI[M-56+H] + =332.4

[0268] Step 2: Preparation of (R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-b)

[0269] Dissolve (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-a, 800 mg, 2.07 mmol) in tetrahydrofuran (15 ml), add sodium borohydride (210.9 mg, 5.58 mmol) and boron trifluoride ether solution (293 ml) under ice bath. g, 2.07mmol), reacted at 50°C for 4 hours under nitrogen protection, the reaction solution was concentrated under reduced pressure and purified by normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product (R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-b, 110mg, yield 11.4%). ESI[M+H] + =374.4,ESI[M-56+H] + =318.4

[0270] Step 3: Preparation of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-12)

[0271] Dissolve (R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-b, 110 mg, 0.295 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (4 ml), react at room temperature for 2 hours, and concentrate under reduced pressure to obtain the target product (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazepine hydrochloride (I-12, 110 mg, crude product). ESI[M+H] + =274.4

[0272] Intermediate I-13: Preparation of (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-13)

[0273]

[0274] Step 1: Synthesis of (S)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-13-a)

[0275] (S)-3-(Hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.31 mmol) and 2-chloro-5-(trifluoromethyl)nicotinate (554 mg, 2.31 mmol) were dissolved in N,N-dimethylformamide (10 ml), and potassium carbonate (639 mg, 4.62 mmol) was added and the temperature was raised to 80°C for overnight reaction. After the reaction was completed, the reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0% to 35%) to obtain the target product (S)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-13-a, 800 mg, yield 62%). ESI[M+H] + =332.2

[0276] Step 2: (S)-3-(Trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9

[0277] Preparation of (7H)-tert-butyl carboxylate (I-13-b)

[0278] Dissolve (S)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-13-a, 730 mg, 1.88 mmol) in tetrahydrofuran (8 ml), add sodium borohydride (187 mg, 4.71 mmol) and boron trifluoride ether solution (267 mg, 4.71 mmol) under ice bath. 1.88mmol), reacted at 50℃ for 4 hours under nitrogen protection, the reaction solution was concentrated under reduced pressure and purified by normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product (S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-13-b, 100mg, yield 14.2%). ESI[M+H] + =374.4,ESI[M-56+H] + =318.4

[0279] Step 3: Preparation of (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-13)

[0280] Dissolve (S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-13-b, 100 mg, 0.241 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (4 ml), react at room temperature for 2 hours, and concentrate under reduced pressure to obtain the target product (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazepine hydrochloride (I-13, 110 mg, crude product). ESI[M+H] + =274.4

[0281] Intermediate I-14: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile hydrochloride (I-14)

[0282]

[0283] Step 1: tert-Butyl 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-14-a)

[0284] 2-Chloro-5-(trifluoromethyl)nicotinonitrile (200 mg, 0.968 mmol) and tert-butyl piperazine-1-carboxylate (178.6 mg, 0.959 mmol) were dissolved in N-methylpyrrolidone (3 ml), potassium carbonate (199 mg, 1.44 mmol) was added, and the mixture was reacted at 80°C for 3 hours. Water (10 ml) was added dropwise to the reaction solution, and a white solid was precipitated. The solid was filtered, and the filter cake was washed with water. The filter cake was collected and concentrated under reduced pressure to obtain the target product tert-butyl 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-14-a, 350 mg, yield 97.6%). ESI[M-100+H] + =257.4,ESI[M-56+H] + =301.5

[0285] Step 2: Preparation of 2-(piperazine-1-yl)-5-(trifluoromethyl)nicotinonitrile hydrochloride (I-14)

[0286] Dissolve tert-butyl 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-14-a, 350 mg, 0.983 mmol) in ethyl acetate (3 ml), add 4M hydrochloric acid ethyl acetate solution (4 ml), react at room temperature for 4 hours, and concentrate under reduced pressure to obtain the target product 2-(piperazine-1-yl)-5-(trifluoromethyl)nicotinonitrile hydrochloride (I-14, 310 mg, crude product). ESI[M+H] + =257.2

[0287] Intermediate I-15: Preparation of 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15)

[0288]

[0289] Step 1: Preparation of tert-butyl 4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-15-a)

[0290] Dissolve piperazine-1-carboxylic acid tert-butyl ester (301 mg, 1.62 mmol) and 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine (156 mg, 0.737 mmol) in N-methylpyrrolidone (4 ml), add potassium carbonate (153 mg, 1.11 mmol), and react in a sealed tube at 85°C for 4 hours. After cooling, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 10:1) to obtain the target product 4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-15-a, 153 mg, yield 57.42%). ESI[M+H] + =362.6

[0291] Step 2: 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15)

[0292] 4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-15-a, 153 mg, 0.423 mmol) was added to 4M hydrochloric acid ethyl acetate solution (3 ml), and reacted at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate several times and concentrated under reduced pressure to obtain the target product, 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15, 114 mg, crude product). ESI[M+H] + =262.5

[0293] Intermediate I-16: Preparation of 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16)

[0294]

[0295] Step 1: Preparation of methyl 2-hydroxy-3-oxo-2-(trifluoromethyl)pentanoate (I-16-a)

[0296] Methyl 3,3,3-trifluoro-2-oxopropanoate (5 g, 32.0 mmol) and butan-2-one (11.5 ml, 129 mmol) were dissolved in N,N-dimethylformamide (10 ml), and L-proline (1.1 g, 12.8 mmol) was added. After reacting at room temperature for 48 hours, water (20 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product, methyl 2-hydroxy-3-oxo-2-(trifluoromethyl)pentanoate (I-16-a, 7 g, yield 95%).

[0297] Step 2: Preparation of 6-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16-b)

[0298] Dissolve 2-hydroxy-3-oxo-2-(trifluoromethyl)pentanoic acid methyl ester (I-16-a, 7 g, 30.7 mmol) in acetic acid (20 ml), add hydrazine hydrate (3 ml, 256 mmol), react overnight at 110 ° C, and the reaction solution is concentrated under reduced pressure and purified by normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 6-ethyl-4-(trifluoromethyl) pyridazine-3(2H)-one (I-16-b, 2.2 g, yield 37.3%). ESI [M + H] + =193.4

[0299] Step 3: Preparation of 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16)

[0300] Dissolve 6-ethyl-4-(trifluoromethyl)pyridazine-3(2H)-one (I-16-b, 1 g, 5.21 mmol) in carbon tetrachloride (10 ml), add N-bromosuccinimide (927 mg, 5.21 mmol) and azobisisobutyronitrile (85.5 mg, 0.521 mmol), react overnight at 80°C, concentrate the reaction solution under reduced pressure and purify it with a normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (I-16, 1.1 g, yield 70.1%). ESI[M+H] + =298.3,300.3

[0301] Intermediate I-17: Preparation of 6-(2-bromopropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17)

[0302]

[0303] The first step: Preparation of methyl 2-hydroxy-5-methyl-4-oxo-2-(trifluoromethyl)hexanoate (I-17-a)

[0304] 3,3,3-trifluoro-2-oxopropionic acid methyl ester (3g, 0.019mmol), 3-methylbutan-2-one (6.6g, 0.076mmol) were dissolved in N,N-dimethylformamide (10ml), and L-proline (0.66g, 0.0058mmol) was added to the reaction mixture and stirred at room temperature for 3 minutes, and then reacted at 40°C overnight. After the reaction was completed, the mixture was cooled to room temperature, the reaction mixture was quenched by adding water, and then extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 2-hydroxy-5-methyl-4-oxo-2-(trifluoromethyl)hexanoic acid methyl ester (I-17-a, 3g, crude product).

[0305] Step 2: Preparation of 6-isopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17-b)

[0306] Dissolve 2-hydroxy-5-methyl-4-oxo-2-(trifluoromethyl)hexanoic acid methyl ester (I-17-a, 3g, 0.012mmol) in ethanol (10ml), then add hydrated hydrazine (1.2ml, 0.024mmol) under stirring, seal the tube and heat to 110℃ to react overnight. After the reaction is completed, add water to quench, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 6-isopropyl-4-(trifluoromethyl)pyridazine-3(2H)-one (I-17-b, 250mg, yield 9.8%). ESI[M+H] + =207.03

[0307] Step 3: Preparation of 6-(2-bromopropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17)

[0308] Dissolve 6-isopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17-b, 150 mg, 0.728 mmol) in carbon tetrachloride (6 ml), add N-bromosuccinimide (140 mg, 0.80 mmol) and azobisisobutyronitrile (12 mg, 0.072 mmol), seal the tube and heat to 80°C to react overnight. After the reaction is completed, cool to room temperature, concentrate the filtrate under reduced pressure, and purify it with a Flash column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 6-(2-bromopropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 70 mg, yield 25.4%). ESI[M+H] + =285.2,287.2 Intermediate I-18: Preparation of 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18)

[0309]

[0310] Step 1: Preparation of 6-(benzyloxy)-3-chloro-4-(trifluoromethyl)pyridazine (I-18-a)

[0311] Benzyl alcohol (262 mg, 2.42 mmol) was dissolved in tetrahydrofuran (10 ml), placed in an ice bath, and 60% sodium hydride (138 mg, 3.46 mmol) was added under nitrogen protection and stirred for 15 minutes, and then 3,6-dichloro-4-(trifluoromethyl)pyridazine (500 mg, 2.3 mmol) was added and the mixture was heated to room temperature for 4 hours. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (ethyl acetate: petroleum ether = 0-10%) to obtain the target product 6-(benzyloxy)-3-chloro-4-(trifluoromethyl)pyridazine (I-18-a, 597 mg, yield 89.75%).

[0312] Step 2: Preparation of 6-(benzyloxy)-3-methyl-4-(trifluoromethyl)pyridazine (I-18-b)

[0313] Under nitrogen protection, 6-(benzyloxy)-3-chloro-4-(trifluoromethyl)pyridazine (I-18-a, 547 mg, 1.9 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriazolinone (360 mg, 2.84 mmol), cesium carbonate (1.85 g, 5.68 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (69 mg, 0.095 mmol) were dissolved in dioxane (21 ml) and water (3 mL), and the temperature was raised to 110 ° C for reaction for 5 hours. After the reaction, water was added to quench, and then extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Flash column (ethyl acetate: petroleum ether = 0-10%) to obtain the target product 6-(benzyloxy)-3-methyl-4-(trifluoromethyl)pyridazine (I-18-b, 300 mg, yield 59.06%). ESI [M+H] + =269.0

[0314] Step 3: Preparation of 6-methyl-5-(trifluoromethyl)pyridazine-3(2H)-one (I-18-c)

[0315] 6-(Benzyloxy)-3-methyl-4-(trifluoromethyl)pyridazine (I-18-b, 300 mg, 1.12 mmol) was dissolved in methanol (5 ml), nitrogen was introduced, 5% palladium carbon (20 mg) was added, and hydrogen was replaced three times. The reaction solution was reacted in a hydrogen atmosphere at room temperature for 2 hours. After the reaction was completed, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and then purified by thin layer chromatography preparation plate (petroleum ether: ethyl acetate = 1: 1) to obtain the target product 6-methyl-5-(trifluoromethyl)pyridazine-3(2H)-one (I-18-c, 195 mg, yield 97.99%). ESI [M+H] + =179.1

[0316] Step 4: Preparation of 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18)

[0317] Dissolve 6-methyl-5-(trifluoromethyl)pyridazine-3(2H)-one (I-18-c, 195 mg, 1.095 mmol) in carbon tetrachloride (10 ml), add N-bromosuccinimide (877 mg, 4.928 mmol) and azobisisobutyronitrile (54 mg, 0.329 mmol), seal the tube and heat to 85°C to react overnight. After the reaction is completed, cool to room temperature, concentrate the filtrate under reduced pressure, and purify it with a Flash column (ethyl acetate: petroleum ether = 0-36%) to obtain the target product 6-(bromomethyl)-5-(trifluoromethyl)pyridazine-3(2H)-one (I-18, 59 mg, yield 21%). ESI[M+H] + =256.8,258.8

[0318] Intermediate I-19: Preparation of 6-(bromomethyl)-5-cyclobutoxypyridazin-3(2H)-one (I-19)

[0319]

[0320] Step 1: Preparation of 6-chloro-4-cyclobutoxy-3-methylpyridazine (I-19-a)

[0321] Dissolve 4,6-dichloro-3-methylpyridazine (500 mg, 3.07 mmol) in tetrahydrofuran (15 ml), add potassium tert-butoxide (517 mg, 4.61 mmol), cyclobutanol (265 μl, 3.37 mmol), react at room temperature for 2 hours, quench with water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and purify the crude product with a normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 6-chloro-4-cyclobutoxy-3-methylpyridazine (I-19-a, 340 mg, yield 55.9%). ESI[M+H] + =199.1,201.1

[0322] Step 2: Preparation of 5-cyclobutoxy-6-methylpyridazine-3(2H)-one (I-19-b)

[0323] Dissolve 6-chloro-4-cyclobutoxy-3-methylpyridazine (I-19-a, 340 mg, 1.51 mmol) in acetic acid (8 ml), add water (2 ml), potassium acetate (257.4 mg, 3.03 mmol), react at 100 ° C for 5 hours, concentrate under reduced pressure, and purify the crude product by normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 5-cyclobutoxy-6-methylpyridazine-3 (2H) -one (I-19-b, 257 mg, yield 83.2%). ESI [M + H] + =361.1

[0324] Step 3: Preparation of 6-(bromomethyl)-5-cyclobutoxypyridazine-3(2H)-one (I-19)

[0325] Dissolve 5-cyclobutoxy-6-methylpyridazin-3(2H)-one (I-19-b, 120 mg, 0.666 mmol) in carbon tetrachloride (2 ml), N-bromosuccinimide (118.6 mg, 0.666 mmol), and benzoyl peroxide (16 mg, 0.067 mmol), and react overnight at 80°C. After concentration under reduced pressure, the crude product is purified by normal phase column (petroleum ether: ethyl acetate = 1:1) to obtain the target product 6-(bromomethyl)-5-cyclobutoxypyridazin-3(2H)-one (I-19, 62 mg, yield 36.1%). ESI[M+H]+ =259.2,261.2

[0326] Intermediate I-20: Preparation of 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20)

[0327]

[0328] Step 1: Preparation of 2-chloro-3-ethoxy-5-trifluoromethylpyridine (I-20-a)

[0329] 2-Chloro-5-(trifluoromethyl)pyridin-3-ol (250 mg, 1.27 mmol) and iodoethane (203 μl, 2.53 mmol) were dissolved in N,N-dimethylformamide (15 ml), and cesium carbonate (619 mg, 1.89 mmol) was added, and the mixture was reacted at 90°C in a sealed tube for 1 hour. After the reaction solution was cooled, water was added to quench it, and it was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 6:1) to obtain the target product 2-chloro-3-ethoxy-5-trifluoromethylpyridine (I-20-a, 220 mg, yield 77.04%). ESI [M+H] + =225.9

[0330] Step 2: Preparation of tert-butyl 4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-20-b)

[0331] Dissolve piperazine-1-carboxylic acid tert-butyl ester (218 mg, 1.17 mmol) and 2-chloro-3-ethoxy-5-trifluoromethylpyridine (I-20-a, 220 mg, 0.98 mmol) in N-methylpyrrolidone (8 ml), add potassium carbonate (203 mg, 1.47 mmol), and react overnight at 80°C in a sealed tube. After cooling, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 6:1) to obtain the target product 4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-20-b, 120 mg, yield 32.69%). ESI[M+H] + =366.0

[0332] Step 3: Preparation of 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20)

[0333] Dissolve 4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-20-b, 115 mg, 0.31 mmol) in 4M hydrochloric acid ethyl acetate (3 ml) and react at room temperature for 2 hours and concentrate under reduced pressure to obtain the target product 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20, 110 mg, yield 115.79%). ESI [M + H] + =276.0

[0334] Intermediate I-21: Preparation of 1-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-21)

[0335]

[0336] Step 1: Preparation of tert-butyl 4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-21-a)

[0337] 2-Chloro-3,5-bis(trifluoromethyl)pyridine (100 mg, 0.359 mmol) and tert-butyl piperazine-1-carboxylate (73.6 mg, 0.355 mmol) were dissolved in N-methylpyrrolidone (2 ml), potassium carbonate (92.3 mg, 0.533 mmol) was added, and the mixture was reacted at 80°C for 3 hours. Water (10 ml) was added dropwise to the reaction solution, and a white solid precipitated. The solid was filtered and the filter cake was washed with water. The filter cake was collected and concentrated under reduced pressure to obtain the target product, tert-butyl 4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-21-a, 155 mg, yield 96.9%).

[0338] Step 2: Preparation of 1-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-21)

[0339] Dissolve 4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-21-a, 155 mg, 0.388 mmol) in ethyl acetate (3 ml), add 4M hydrochloric acid ethyl acetate solution (4 ml), react at room temperature for 4 hours, and concentrate under reduced pressure to obtain the target product 1-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-21, 150 mg, crude product). ESI[M+H] + =300.1

[0340] Intermediate I-22: Preparation of 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22)

[0341]

[0342] Step 1: Preparation of tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-22-a)

[0343] 3-Chloro-2-fluoro-5-(trifluoromethyl)pyridine (300 mg, 1.5 mmol) was dissolved in N-methylpyrrolidone (10 ml), and then tert-butyl piperazine-1-carboxylate (336 mg, 1.8 mmol) and potassium carbonate (415.6 mg, 3.01 mmol) were added, and the mixture was reacted overnight at 80°C in an oil bath. After the reaction, the filtrate was concentrated under reduced pressure and purified by a Flash column (petroleum ether: ethyl acetate = 4:1) to obtain the target product tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-22-a, 450 mg, yield 82%). ESI[M+H] + =366.0,368.0

[0344] Step 2: Preparation of 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22-b)

[0345] Dissolve 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-22-a, 450 mg) in ethyl acetate solution (4 ml), then add hydrogen chloride ethyl acetate solution (4 ml) and react at room temperature overnight. After the reaction is completed, the reaction solution is concentrated under reduced pressure, dissolved in dichloromethane and concentrated again under reduced pressure, and repeated twice to obtain the target product 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22-b, 420 mg, crude product). ESI[M+H] + =266.0,268.0

[0346] Step 3: Preparation of 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22)

[0347] 1-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22-b, 340 mg, 1.28 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane (193 mg, 1.54 mmol), cesium carbonate (836 mg, 2.57 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.022 mmol) were dissolved in dioxane (7 ml) and water (1 ml), and reacted in a sealed reaction bottle at 110°C in an oil bath under nitrogen protection overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate three times. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22, 390 mg, crude product). ESI[M+H] + =246.3

[0348] Intermediate I-23: Preparation of 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-23)

[0349]

[0350] Step 1: Preparation of tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-a)

[0351] Dissolve piperazine-1-carboxylic acid tert-butyl ester (448 mg, 2.41 mmol) and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (400 mg, 2.01 mmol) in N-methylpyrrolidone (10 ml), add potassium carbonate (416 mg, 3.01 mmol), and react at 80°C in a sealed tube for 2 hours. After cooling, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by Flash (silica gel column 25 g, petroleum ether: ethyl acetate = 8:1) to obtain the target product 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-23-a, 600 mg, yield 82.02%). ESI[M+H] + =366.0

[0352] Step 2: Preparation of tert-butyl 4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-b)

[0353] Dissolve tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-a, 530 mg, 1.45 mmol) in acetonitrile (15 ml), add cyclopropylboric acid (166 mg, 1.93 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (53 mg, 0.07 mmol) and potassium phosphate (923 mg, 4.35 mmol). Microwave reaction was carried out at 100 ° C for 80 minutes under nitrogen protection. After concentration under reduced pressure, the crude product was flashed (silica gel column 25 g, petroleum ether: ethyl acetate = 5:1) to obtain the target product tert-butyl 4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-b, 290 mg, yield 47.62%). ESI [M + H] + =372.2

[0354] Step 3: Preparation of 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-23)

[0355] Dissolve 4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-23-b, 290 mg, 0.78 mmol) in 4M hydrochloric acid ethyl acetate (4 ml) and react at room temperature for 2 hours, then concentrate under reduced pressure, add water (1 ml), adjust the pH to 8 with NaHCO3, extract with (dichloromethane: methanol = 10:1), dry the organic phase over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the target product 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-23, 310 mg, yield 129.17%). ESI[M+H] + =272.6

[0356] Intermediate I-24: Preparation of 1-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-24)

[0357]

[0358] Step 1: Preparation of tert-butyl 4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-24-a)

[0359] Dissolve piperazine-1-carboxylic acid tert-butyl ester (158 mg, 0.85 mmol) and 2-chloro-4-methoxy-5-(trifluoromethyl)pyridine (150 mg, 0.71 mmol) in N-methylpyrrolidone (5 ml), add potassium carbonate (147 mg, 1.06 mmol), and react overnight at 80°C in a sealed tube. After cooling, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 8:1) to obtain the target product 4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-24-a, 140 mg, yield 54.64%). ESI[M+H] + =362.0

[0360] Step 2: Preparation of 1-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-24)

[0361] Dissolve 4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-24-a, 140 mg, 0.39 mmol) in 4M hydrochloric acid ethyl acetate (2 ml) and react at room temperature for 2 hours, then concentrate under reduced pressure, add water (1 ml), adjust the pH to 8 with NaHCO3, extract with (dichloromethane: methanol = 10:1), dry the organic phase over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the target product 1-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-24, 144 mg, yield 125.22%). ESI[M+H] + =262.0

[0362] Intermediate I-25: Preparation of N-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (I-25)

[0363]

[0364] Step 1: Preparation of tert-butyl 4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-25-a)

[0365] Dissolve 2-bromo-3-nitro-5-(trifluoromethyl)pyridine (100 mg, 0.369 mmol) and tert-butyl piperazine-1-carboxylate (76 mg, 0.406 mmol) in N-methylpyrrolidone (3 ml), add potassium carbonate (153 mg, 1.107 mmol), react at 80°C for 1 hour, add water to the reaction solution to quench, extract with ethyl acetate, combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product tert-butyl 4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-25-a, 120 mg, yield 86.41%). ESI[M+H-100] + =277.0,ESI[M+H-56] + =321.3

[0366] Step 2: Preparation of tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-25-b)

[0367] 4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-25-a, 120 mg, 0.319 mmol) and iron powder (356 mg, 6.377 mmol) were added to acetic acid (4 ml) and reacted at 80°C for 2 hours. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-25-b, 110 mg, yield 99.61%). ESI [M + H] + =347.9

[0368] Step 3: Preparation of N-(2-(piperazine-1-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (I-25)

[0369] 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-25-b, 110 mg, 0.318 mmol) and potassium carbonate (132 mg, 0.953 mmol) were added to N,N-dimethylformamide (3 ml), and acetyl chloride (37 mg, 0.476 mmol) was added dropwise under nitrogen protection and the temperature was raised to 100°C for 2 hours. After the reaction solution was cooled, water was added to quench it, and then extracted with ethyl acetate. The organic phases were combined, washed with brine, dried and filtered with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the target product N-(2-(piperazine-1-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (I-25, 400 mg, purity 25%, yield 109.23%). ESI[M+H] + =289.1

[0370] Intermediate I-26: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-26)

[0371]

[0372] Step 1: Preparation of tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-26-a)

[0373] Dissolve 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-14-a, 550 mg, 1.54 mmol) in ethanol (15 ml), add water (5 ml), potassium carbonate (640 mg, 4.63 mmol), 30% hydrogen peroxide (3.3 ml), react at room temperature for 5 hours, concentrate under reduced pressure to remove the solvent, add water (15 ml), extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and purify the crude product with a normal phase column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-26-a, 256 mg, yield 44.3%). ESI[M+H] + =375.2

[0374] Step 2: Preparation of 2-(piperazine-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-26)

[0375] Dissolve tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-26-a, 256 mg, 0.684 mmol) in ethyl acetate (4 ml), add 4M hydrochloric acid ethyl acetate solution (4 ml), react at room temperature for 3 hours, and concentrate under reduced pressure to obtain the target product 2-(piperazine-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-26, 194 mg, yield 91.5%). ESI[M+H] + =275.1

[0376] Intermediate I-27: Preparation of 6-(2-chloropropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-27)

[0377]

[0378] Dissolve 6-isopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17-b, 2.28 g, 11.06 mmol) in chloroform (70 ml), add N-chlorosuccinimide (2.22 g, 16.59 mmol) and azobisisobutyronitrile (1.82 g, 11.06 mmol), seal the tube and heat to 80°C to react overnight. After the reaction is completed, cool to room temperature, concentrate the filtrate under reduced pressure, and purify it with a Flash column (petroleum ether: ethyl acetate = 3:1) to obtain the target product 6-(2-chloropropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-27, 2.9 g, yield 109.02%). ESI[M+H] + =241.0,243.0 Intermediate I-28: Preparation of 7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-28)

[0379]

[0380] Step 1: Preparation of 7-bromo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-28-a)

[0381] Dissolve 2-bromo-3-nitro-5-(trifluoromethyl)pyridine (500 mg, 1.78 mmol) in tetrahydrofuran (15 ml), replace with nitrogen, add vinylmagnesium bromide (11 ml, 10.7 mmol) dropwise at -78 °C, and then stir at -20 °C for 1 hour. After the reaction is completed, return to room temperature, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate, collect the organic phase, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify with Flash column (petroleum ether: ethyl acetate = 4:1) to obtain the target product 7-bromo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-28-a, 130 mg, yield 26.5%). ESI[M+H] + =266.2

[0382] Step 2: Preparation of tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-28-b)

[0383] 7-Bromo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-28-a, 130 mg, 0.49 mmol) was dissolved in N-methylpyrrolidone (6 ml), and N,N-diisopropylethylamine (325 μl, 1.96 mmol) and tert-butyl piperazine-1-carboxylate (275 mg, 1.47 mmol) were added under stirring, and the temperature was raised to 135°C to react overnight. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (petroleum ether: ethyl acetate = 1:1) to obtain the target product 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (1-28-b, 180 mg, yield 98%). ESI[M+H] + =371.4

[0384] Step 3: Preparation of 7-(piperazine-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-28)

[0385] Dissolve 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (I-28-b, 80 mg, 0.22 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (2 ml), and react at room temperature overnight. After the reaction is completed, concentrate under reduced pressure, add dichloromethane solution and spin dry twice to obtain the target product 7-(piperazine-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-28, 70 mg, crude product). ESI[M+H] + =271.4

[0386] Intermediate I-29: Preparation of 1-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-29)

[0387]

[0388] Step 1: Preparation of tert-butyl 4-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-29-a)

[0389] Dissolve 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (I-28-b, 30 mg, 0.081 mmol) in N,N-dimethylformamide (2 ml), add potassium iodide (4.3 μl, 0.081 mmol) and potassium carbonate (16.8 mg, 0.121 mmol) under stirring, and react at room temperature overnight. After the reaction is completed, dilute with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify with Flash column (petroleum ether: ethyl acetate = 4:1) to obtain the target product 4-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (I-29-a, 30 mg, yield 96%). ESI[M+H] + =385.4 Step 4: Preparation of 1-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-29)

[0390] Dissolve 4-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (I-29-a, 30 mg, 0.078 mmol) in ethyl acetate (1 ml), add 4M hydrochloric acid ethyl acetate solution (1 ml), and react at room temperature overnight. After the reaction is completed, concentrate under reduced pressure, add dichloromethane solution and spin dry twice to obtain the target product 1-methyl-7-(piperazine-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-29, 30 mg, crude product). ESI[M+H] + =285.4

[0391] Intermediate I-30: Preparation of (2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (I-30)

[0392]

[0393] Step 1: Preparation of tert-butyl 4-(3-(methoxycarbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-a)

[0394] Dissolve 2-chloro-5-(trifluoromethyl)nicotinate (500 mg, 2.087 mmol) and tert-butyl piperazine-1-carboxylate (408 mg, 2.194 mmol) in N-methylpyrrolidone (15 ml), add potassium carbonate (432 mg, 3.13 mmol), react at 80°C for 2 hours, add water to the reaction solution, precipitate solid, filter, wash the filter cake with water, and dry at 70°C for 1.5 hours to obtain the target product tert-butyl 4-(3-(methoxycarbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-a, 764 mg, yield 93.81%). ESI[M+H] + =376.3

[0395] Step 2: Preparation of 2-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b)

[0396] Dissolve tert-butyl 4-(3-(methoxycarbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-a, 740 mg, 1.9 mmol) and lithium hydroxide (146 mg, 3.476 mmol) in methanol (20 ml) and water (4 ml) and react overnight at room temperature. After monitoring, add acetic acid to adjust the pH to 7, extract with ethyl acetate three times, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 2-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b, 820 mg, crude product). ESI[M+H] + =376.3

[0397] Step 3: Preparation of tert-butyl 4-(3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-c)

[0398] Dissolve 2-(4-(tert-Butyloxycarbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b, 200 mg, 0.533 mmol) in dichloromethane (10 ml), add O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg, 0.526 mmol) and stir for 10 minutes, then add N,N-diisopropylethylamine (279 μl, 1.578 mmol) and tetrahydropyrrole (44 μl, 0.53 mmol) and react at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 1:1) to obtain the target product 4-(3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl (I-30-c, 180 mg, yield 71.72%). ESI [M+H] + =429.0

[0399] Step 4: Preparation of (2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (I-30)

[0400] Dissolve 4-(3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl (I-1-c, 180 mg, 0.42 mmol) in 4M hydrochloric acid ethyl acetate (3 ml) and react at room temperature for 2 hours and then concentrate under reduced pressure to obtain the target product (2-(piperazine-1-yl)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (I-30, 190 mg, crude product). ESI [M+H] + =329.0

[0401] Intermediate I-31: Preparation of N-methyl-2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-31)

[0402]

[0403] Step 1: Preparation of tert-butyl 4-(3-(methylcarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-31-a)

[0404] 2-(4-(tert-Butyloxycarbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b, 200 mg, 0.533 mmol) was dissolved in dichloromethane (10 ml), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg, 0.526 mmol) was added and stirred for 10 minutes, and then N,N-diisopropylethylamine (279 μl, 1.578 mmol) and methylamine hydrochloride (36 mg, 0.53 mmol) were added and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 1:1) to obtain the target product 4-(3-(methylcarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-31-a, 220 mg, yield 106.38%). ESI[M+H] + =389.0

[0405] Step 2: Preparation of N-methyl-2-(piperazine-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-31)

[0406] Dissolve 4-(3-(methylcarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-31-a, 220 mg, 0.567 mmol) in 4M hydrochloric acid ethyl acetate (3 ml) and react at room temperature for 2 hours and concentrate under reduced pressure to obtain the target product N-methyl-2-(piperazine-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-31, 193 mg, yield 105.46%). ESI [M+H] + =289.0

[0407] Intermediate I-32: Preparation of 2-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-32)

[0408]

[0409] Step 1: Preparation of 7-chloro-2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-32-a)

[0410] 2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (250 mg, 1.10 mmol) was dissolved in tetrahydrofuran (12 ml), replaced with nitrogen, and isopropenylmagnesium bromide (6.62 ml, 6.62 mmol) was added dropwise at -78 °C, and then stirred at -20 °C for 1 hour. After the reaction was completed, the room temperature was restored, and the reaction was quenched with a saturated ammonium chloride solution, and then extracted with ethyl acetate. The organic phase was collected, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (petroleum ether: ethyl acetate = 4:1) to obtain the target product 7-chloro-2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-32-a, 90 mg, yield 34.75%). ESI[M+H] + =235.8

[0411] Step 2: Preparation of tert-butyl 4-(2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-32-b)

[0412] Dissolve 7-chloro-2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-1-a, 90 mg, 0.38 mmol) in N-methylpyrrolidone (4 ml), and add N,N-diisopropylethylamine (254 μl, 1.53 mmol) and tert-butyl piperazine-1-carboxylate (214 mg, 1.15 mmol) under stirring. Seal the tube and heat to 135°C to react overnight. After the reaction, cool to room temperature, dilute with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 4-(2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (I-32-b, 80 mg, yield 54.4%). ESI[M+H] + =385.3

[0413] Step 3: Preparation of 2-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-32)

[0414] Dissolve 4-(2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (I-32-b, 80 mg, 0.21 mmol) in ethyl acetate (1 ml), add 4M hydrochloric acid ethyl acetate solution (3 ml), and react at room temperature for 2 hours. After the reaction is completed, concentrate under reduced pressure, add dichloromethane to dissolve and spin dry twice to obtain the target product 2-methyl-7-(piperazine-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-32, 100 mg, crude product). ESI[M+H] + =285.3

[0415] Intermediate I-33: Preparation of 3-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole trifluoroacetate (I-33)

[0416]

[0417] Step 1: Preparation of tert-butyl 4-(3-(N'-hydroxycarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-a)

[0418] Dissolve tert-butyl 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-14-a, 100 mg, 0.28 mmol) in ethanol (5 ml), add hydroxylamine hydrochloride (29 mg, 0.42 mmol), sodium ethoxide (43 mg, 0.63 mmol), react at 100°C overnight, concentrate the reaction solution under reduced pressure, and purify the crude product by Flash (silica gel column 10 g, petroleum ether: ethyl acetate = 0-40%) to obtain the target product tert-butyl 4-(3-(N'-hydroxycarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-a, 50 mg, yield 45.9%). ESI[M+H] + =390.1

[0419] Step 2: Preparation of tert-butyl 4-(3-(1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-b)

[0420] Dissolve 4-(3-(N'-hydroxycarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-33-a, 50 mg, 0.13 mmol) in trimethyl orthoformate (5 ml), add trifluoroacetic acid (0.5 ml), react at 70°C for 1 hour, and then concentrate the reaction solution under reduced pressure to obtain the target product 4-(3-(1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-33-b, 60 mg, crude product). ESI[M+H] + =400.1

[0421] Step 3: Preparation of 3-(2-(piperazine-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole trifluoroacetate (I-33)

[0422] Dissolve tert-butyl 4-(3-(1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-b, 60 mg, 0.15 mmol) in dichloromethane (3 ml), add trifluoroacetic acid (0.6 ml), react at room temperature for 0.5 hours and then concentrate under reduced pressure to obtain the target product 3-(2-(piperazine-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole trifluoroacetate (I-33, 110 mg, crude product). ESI[M+H] + =300.1

[0423] Example 1: Preparation of 3-trifluoromethyl-5-((1S,3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopentyl)amino)methyl)pyridin-2(1H)one (1)

[0424]

[0425] Step 1: Preparation of tert-butyl ((1S,3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopentyl)carbamate (1-a)

[0426] (1S,3S)-3-(tert-Butyloxycarbonyl)amino)cyclopentane-1-carboxylic acid (50 mg, 0.218 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (99.6 mg, 0.262 mmol), and N,N-diisopropylethylamine (184 mg, 1.42 mmol) were dissolved in N,N-dimethylformamide (2 ml), and finally 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane (I-2, 64.9 mg, 0.221 mmol) was added and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC silica gel plate (ethyl acetate: petroleum ether = 1:1) to obtain the target product tert-butyl ((1S, 3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopentyl)carbamate (1-a, 67.6 mg, yield 66.1%). ESI [M+H] + =470.2

[0427] Step 2: Preparation of (1S, 3S)-3-aminocyclopentyl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (1-b)

[0428] Dissolve tert-butyl ((1S, 3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopentyl)carbamate (1-a, 67.6 mg, 0.144 mmol) in 4 mol / L hydrogen chloride in ethyl acetate solution and react overnight at room temperature. After monitoring the reaction completion, concentrate under reduced pressure to obtain the target product (1S, 3S)-3-aminocyclopentyl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (1-b, 76.4 mg, yield 149%). ESI [M+H] + =370.2

[0429] Step 3: Preparation of 3-trifluoromethyl-5-((1S,3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopentyl)amino)methyl)pyridin-2(1H)one (1)

[0430] (1S, 3S)-3-aminocyclopentyl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (1-b, 30 mg, 0.0739 mmol) and 6-oxo-5-trifluoromethyl-1,6-dihydropyridazine-3-carbaldehyde (I-6, 16.9 mg, 0.088 mmol) were dissolved in methanol (2 ml) under ice bath, and sodium acetate (3 μl) was added dropwise. After stirring under ice bath for 20 minutes, sodium cyanoborohydride (13.9 mg, 0.221 mmol) was added and the reaction was allowed to react overnight at room temperature. After monitoring the reaction completion, water was added to quench, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-50%over22min] to obtain 3-trifluoromethyl-5-((1S,3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopentyl)amino)methyl)pyridin-2(1H)one (1,1.46mg, yield 3.30%), ESI[M+H] + =545.2 1H NMR(400MHz,DMSO-d6)δ8.72(S,2H),8.29(S,1H),7.94(S,1H),7.58(S,1H),4.64(d, J=6.4Hz,1H),4.49(t,J=12.6Hz,2H),3.59(d,J=6.4Hz,1H),3.46(S,1H),3.16–3.01 (m,3H),2.07(S,1H),1.83(ddd,J=21.6,15.6,8.8Hz,5H),1.69–1.56(m,2H),1.54(d ,J=8.0Hz,1H),1.44–1.34(m,1H),1.23(S,1H),1.19–1.09(m,1H),1.08–0.98(m,1H).

[0431] Example 2: Preparation of 4-(trifluoromethyl)-5-(((2S)-1-((3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (2)

[0432]

[0433] Step 1: Preparation of tert-butyl (3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate (2-a)

[0434] (R)-1-(tert-Butyloxycarbonyl)pyrrolidine-3-carboxylic acid (50 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (88.5 mg, 0.23 mmol) and N,N-diisopropylethylamine (120 μl, 0.696 mmol) were added in sequence and reacted at 0° C. for 20 minutes. 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (I-2, 69.6 mg, 0.238 mmol) was then added and stirring was continued for 4 hours. Add 10 times the volume of water to the reaction solution, stir for 10 minutes and filter, then rinse the filter cake with ethyl acetate solution, and concentrate the filtrate under reduced pressure to obtain the target product (3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2-a, 97 mg, yield 91.60%). ESI [M+H] + =456.21

[0435] Step 2: Preparation of ((R)-pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (2-b)

[0436] Hydrogen chloride-ethyl acetate solution (4M) (1 ml) was slowly added dropwise to tert-butyl (3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate (2-a, 97 mg, 0.213), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the target product, crude ((R)-pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (2-b, 131 mg). ESI[M+H] + =356.16

[0437] Step 3: Preparation of tert-butyl (2S)-1-(3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)carbamate (2-c)

[0438] ((R)-pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (2-b, 131 mg, 0.37 mmol) was dissolved in methanol (7 ml). Then, (S)-tert-butyl(1-oxopropan-2-yl)carbamate (76.5 mg, 0.44 mmol) was added, sodium acetate (62.84 mg, 1.10 mmol) was added at 0°C and stirred at 0°C for 20 minutes, and sodium cyanoborohydride (15.1 mg, 0.18 mmol) was added at 0°C. The reaction was allowed to proceed overnight at room temperature. Saturated brine was added, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain the target product (2S)-1-(3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)carbamic acid tert-butyl ester (2-c, 82 mg, yield 43.47%). ESI [M+H] + =513.27

[0439] Step 4: Preparation of ((R)-1-((S)-2-aminopropyl)pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (2-d)

[0440] Hydrogen chloride-ethyl acetate solution (4M) (0.8 ml) was slowly added dropwise to tert-butyl (2S)-1-(3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)carbamate (2-c, 82 mg, 0.16 mmol) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude target product ((R)-1-((S)-2-aminopropyl)pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (2-d, 80 mg). ESI[M+H] + =413.27

[0441] Step 5: Preparation of 4-(trifluoromethyl)-5-(((2S)-1-((3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2-e)

[0442] ((R)-1-((S)-2-aminopropyl)pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (2-d, 80 mg, 0.194 mmol) was dissolved in ethanol (8 ml). 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5, 95.6 mg, 0.291 mmol) and triethylamine (14.7 mg, 0.144 mmol) were added in sequence and stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate) to obtain the target product 4-(trifluoromethyl)-5-(((2S)-1-((3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2-e, 56 mg, yield 40.97%). ESI [M+H] + =705.31

[0443] Step 6: Preparation of 4-(trifluoromethyl)-5-(((2S)-1-((3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (2)

[0444] 4-(Trifluoromethyl)-5-(((2S)-1-((3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2-e, 28 mg, 0.04 mmol) was dissolved in acetonitrile (3 ml). Boron trifluoride etherate (33.9 mg, 0.239 mmol) was added at -10°C, and the mixture was stirred at -10°C for 1 hour. Diethylenetriamine (14.4 mg, 0.14 mmol) and 1M sodium hydroxide solution (84 μl) were added in sequence, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and then purified using HPLC [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 10%-70%over22min] to obtain the target product 4-(trifluoromethyl)-5-(((2S)-1-((3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (2, 13 mg, yield 57.01%). ESI[M+H] + =575.22 1 H NMR(600MHz,DMSO-d6)δ12.44(d,J=9.5Hz,1H),8.71(S,2H),8.18(S,1H),7.91(S, 1H),4.64(t,J=6.6Hz,1H),4.54–4.44(m,3H),3.06(dt,J=27.1,13.8Hz,3H),2.93 (dt,J=30.2,8.7Hz,1H),2.71(dt,J=13.5,7.8Hz,2H),2.62(dt,J=19.7,10.0Hz,2 H),2.04–1.84(m,4H),1.81–1.65(m,2H),1.63–1.49(m,2H),1.18(d,J=6.2Hz,3H).

[0445] Example 3: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (3)

[0446]

[0447] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)carbamate (3-a)

[0448] (1R, 3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (60 mg, 0.279 mmol) was dissolved in dichloromethane (2 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.279 mmol), N,N-diisopropylethylamine (108 mg, 0.837 mmol) and 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (I-2, 55 mg, 0.223 mmol) were added and reacted at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure, and then purified on a preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product tert-butyl ((1R, 3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)carbamate (3-a, 81 mg, yield 63.8%). ESI [M+H] + =456.4ESI[M+H-56] + =456.4ESI[2M+H] + =911.6

[0449] Step 2: Preparation of (((1R, 3R)-3-aminocyclobutyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (3-b)

[0450] Hydrogen chloride-ethyl acetate solution (4M) (2 ml) was slowly added dropwise to tert-butyl ((1R, 3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)carbamate (3-a, 81 mg, 0.178 mmol) and stirred at room temperature for 1 hour. The reaction solution was added with 4 ml of ethyl acetate and filtered. The filter cake was dried to obtain the target product crude product ((1R, 3R)-3-aminocyclobutyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (3-b, 76 mg, yield 109.07%). ESI [M+H] + =356.3ESI[2M+H] + =711.5

[0451] Step 3: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (3)

[0452] ((1R, 3R)-3-aminocyclobutyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (3-b, 30 mg, 0.084 mmol) was dissolved in methanol (0.5 ml) and dichloromethane (0.5 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6, 24 mg, 0.127 mmol) was added. Sodium acetate (3.5 mg, 0.042 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (16 mg, 0.252 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1). Then, the product was purified by high performance liquid chromatography [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-70% over 22min] to obtain the target product 4-(trifluoromethyl)-6-((((1R, 3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (3, 10 mg, yield 22.29%). ESI [M+H] + =532.4 1 HNMR (400MHz, DMSO-d6) δ8.71(S,2H),8.38(S,1H),7.94(S,1H),4.64(d,J=6.5Hz,1H),4.46(d,J=12.9Hz,1H),4.24(d,J=6.0Hz,1H),4.10(S,2H),3 .57(S,2H),3.28–3.18(m,2H),3.05(dd,J=12.5,5.1Hz,2H),2.36(S,1H), 2.19(S,1H),2.03–1.80(m,3H),1.74(d,J=15.6Hz,1H),1.63–1.44(m,2H).

[0453] Example 4: Preparation of 3-(trifluoromethyl)-5-((((1R,3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (4)

[0454]

[0455] ((1R, 3R)-3-aminocyclobutyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (3-a, 50 mg, 0.141 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 40 mg, 0.211 mmol) was added, sodium acetate (5.7 mg, 0.071 mmol) was added at 0°C and stirred at 0°C for 20 minutes, and sodium cyanoborohydride (16 mg, 0.252 mmol) was added at 0°C and reacted at room temperature overnight. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified using a thin layer silica gel plate (dichloromethane: methanol = 10: 1) and then purified using a high performance liquid chromatography [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-70% over 22min] to obtain the target product 3-(trifluoromethyl)-5-((((1R, 3R)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (4, 1.23 mg, yield 1.65%). ESI [M+H] + =531.30 1 HNMR(400MHz,DMSO-d6)δ8.71(S,2H),8.34(S,1H),7.92(S,1H),7.55(S,1H),4.64(d ,J=6.4Hz,1H),4.46(d,J=12.9Hz,2H),4.24(d,J=6.0Hz,1H),3.25–3.16(m,3H),3.0 5(dd,J=12.4,6.4Hz,2H),2.38(dd,J=7.1,3.7Hz,1H),2.21(dd,J=7.0,3.7Hz,1H),1 .94(dd,J=26.4,15.0Hz,4H), 1.74(d,J=10.5Hz,2H), 1.57(dd,J=28.0,11.8Hz,3H).

[0456] Example 5: Preparation of 4-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (5)

[0457]

[0458] Step 1: Preparation of tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (5-a)

[0459] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (1 g, 4.97 mmol) was dissolved in dichloromethane (50 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.89 g, 4.97 mmol), N,N-diisopropylethylamine (2.6 ml, 14.91 mmol) and 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 1.6 g, 5.96 mmol) were added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure, and then purified by Flash (petroleum ether: ethyl acetate = 1:1) column to obtain the target product tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (5-a, 2.041 g, yield 98.86%). ESI[M+H-56] + =360.0ESI[2M+H] + =831.3

[0460] Step 2: Preparation of azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (5-b)

[0461] Dissolve tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (5-a, 2.041 g, 4.91 mmol) in ethyl acetate (20 ml) and slowly drop hydrogen chloride-ethyl acetate solution (4M) (40 ml) and stir at room temperature for 4 hours. The reaction solution is directly distilled under reduced pressure to obtain the target product crude azetidine-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (5-b, 2 g, yield 99.52%). ESI [M+H] + =316.1, ESI[2M+H] + =631.4

[0462] Step 3: Preparation of 4-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (5)

[0463] Azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (5-b, 50 mg, 0.159 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6, 37 mg, 0.19 mmol) was added. Sodium acetate (6.5 mg, 0.08 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (30 mg, 0.477 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified using a thin layer silica gel plate (dichloromethane: methanol = 10: 1) and then purified using a high performance liquid chromatography [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-70% over 22min] to obtain the target product 4-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (5, 1.27 mg, yield 1.63%). ESI [M+H] + =492.30 1 HNMR(400MHz,DMSO-d6)δ8.72(S,2H),7.79(S,1H),3.81(d,J=4.8Hz,4H),3 .54(d,J=7.2Hz,3H),3.50(S,2H),3.47(d,J=8.0Hz,2H),3.28–3.23(m,4H).

[0464] Example 6: Preparation of 4-trifluoromethyl-5-(2S)-1-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)one (6)

[0465]

[0466] Step 1: Preparation of tert-butyl (3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate (6-a)

[0467] (S)-1-(tert-Butyloxycarbonyl)pyrrolidine-3-carboxylic acid (0.1 g, 0.465 mmol) was dissolved in N,N-dimethylformamide (4 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.177 g, 0.465 mmol) and N,N-diisopropylethylamine (243 μL, 1.395 mmol) were added under ice-cooling. After stirring for 30 minutes under ice-cooling, 3-(5-(trifluoromethyl)pyrimidin-2-yl)-1-nitrobenzotriazole was added. )-3,8-diazabicyclo[3.2.1]octane hydrochloride (I-2, 0.15 g, 0.581 mmol), react at room temperature for 3 hours, add the reaction solution dropwise into water (40 mL) with stirring, filter and concentrate the filter cake under reduced pressure to obtain the target product (3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6-a, 0.1 g, yield 47.26%). (ESI)[M+H] + =456.6

[0468] Step 2: Preparation of ((S)-pyrrolidin-3-yl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (6-b)

[0469] (3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6-a, 0.1 g, 0.219 mmol) was added to 4M hydrochloric acid ethyl acetate solution (2 mL), reacted at room temperature for 3 hours, and concentrated under reduced pressure to obtain the target product crude product (3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester hydrochloride (6-b, 0.1 g). (ESI)[M+H] + =356.5

[0470] Step 3: Preparation of tert-butyl (2S)-1-(3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)carbamate (6-c)

[0471] (S)-Pyrrolidin-3-yl-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (6-b, 50 mg, 0.14 mmol) and (S)-tert-butyl(1-oxopropane-2-yl)carbamate (29.5 mg, 0.17 mmol) were dissolved in methanol (3 ml), and then sodium acetate (6 mg, 0.07 mmol) was added under ice bath and stirred for 20 minutes. Finally, sodium cyanoborohydride (26.5 mg, 0.42 mmol) was slowly added and the reaction was allowed to react at room temperature for 3 hours. After monitoring the reaction completion, water was added to quench, and the mixture was extracted with dichloromethane. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC silica gel plate (dichloromethane / methanol=10:1) to obtain tert-butyl (2S)-1-(3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)carbamate (6-c, 39 mg, yield 54%), ESI[M+H] + =513.5.

[0472] Step 4: Preparation of (S)-1-(S)-2-aminopropylpyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (6-d)

[0473] Dissolve (2S)-1-(3S)-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)carbamic acid tert-butyl ester (6-c, 39 mg, 0.076 mmol) in 4 mol / L hydrogen chloride ethyl acetate solution and react at room temperature for 1 hour. After monitoring the completion of the reaction, concentrate under reduced pressure to obtain the target product (S)-1-(S)-2-aminopropylpyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (6-d, 45 mg, yield 143%). ESI[M+H] + =413.7

[0474] Step 5: Preparation of 4-trifluoromethyl-5-((2S)-1-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)one (6-e)

[0475] (S)-1-(S)-2-aminopropylpyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (6-d, 45 mg, 0.109 mmol), 5-chloro-4-trifluoromethyl-2-(2-(trimethylsilyl)ethoxy)methylpyridazin-3(2H)one (I-5, 49.4 mg, 0.15 mmol), and triethylamine (30.4 mg, 0.30 mmol) were dissolved in ethanol (2 ml) and heated to 80°C for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by TLC silica gel plate (pure ethyl acetate) to obtain the target product 4-trifluoromethyl-5-((2S)-1-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)one (6-e, 32 mg, yield 41.6%). ESI [M+H] + =705.6

[0476] Step 6: Preparation of 4-trifluoromethyl-5-(2S)-1-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)one (6)

[0477] 4-Trifluoromethyl-5-((2S)-1-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)one (6-e, 32 mg, 0.045 mmol) was dissolved in acetonitrile (3 ml), and boron trifluoride etherate (38.5 mg, 0.27 mmol) was slowly added dropwise at -10°C. After monitoring showed that the reaction was complete to the intermediate, 1 mol / L sodium hydroxide aqueous solution (9 ml) and diethylenetriamine (16.4 mg, 0.159 mmol) were slowly added dropwise in sequence, and the reaction was stirred from -10°C to room temperature to overnight. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 5%-50% over 22min] to obtain the target product 4-trifluoromethyl-5-(2S)-1-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)one (6, 8.2 mg, yield 31.4%). ESI [M+H] + =575.4 1 H NMR (400MHz, DMSO-d6) δ12.44(S,1H),8.72(S,2H),8.17(S,1H),7.92(S,1H),4.47(d,J=13.0Hz,2H),3.40(S,2H),3.16–2.98(m,4H),2.98– 2.84(m,2H),2.65–2.55(m,2H),2.43(d,J=8.3Hz,2H),1.93(dd,J=23.9,14.7Hz,4H),1.57(dd,J=22.2,10.5Hz,2H),1.18(d,J=6.2Hz,3H).

[0478] Example 7: Preparation of 3-(trifluoromethyl)-5-(((4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl)amino)methyl)pyridin-2(1H)-one (7)

[0479]

[0480] Step 1: Preparation of tert-butyl (4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl)carbamate (7-a)

[0481] Dissolve 4-(tert-Butyloxycarbonyl)amino)benzoic acid (100 mg, 0.421 mmol) in dichloromethane (5 ml), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg, 0.421 mmol), N,N-diisopropylethylamine (220 μl, 1.263 mmol) and 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (I-2, 130 mg, 0.505 mmol), and react at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure, and then purified by Flash (petroleum ether: ethyl acetate = 1:1) column to obtain the target product (tert-butyl 4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl)carbamate (7-a, 176 mg, yield 87.45%). ESI [M+H] + =478.2ESI[2M+H] + =955.5

[0482] Step 2: Preparation of (4-aminophenyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (7-b)

[0483] Hydrogen chloride-ethyl acetate solution (4M) (3 ml) was slowly added dropwise to tert-butyl (4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl)carbamate (7-a, 176 mg, 0.369 mmol) and stirred at room temperature for 2 hours. The reaction solution was added with 10 ml of ethyl acetate and filtered. The filter cake was directly distilled under reduced pressure to obtain the target product crude (4-aminophenyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (7-b, 164 mg). ESI[M+H] + =378.2ESI[2M+H] + =755.5

[0484] Step 3: Preparation of 3-(trifluoromethyl)-5-(((4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl)amino)methyl)pyridin-2(1H)-one (7)

[0485] (4-Aminophenyl)(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (7-b, 74 mg, 0.196 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 49 mg, 0.255 mmol) was added. Sodium acetate (8 mg, 0.098 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (25 mg, 0.588 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. Saturated brine was added, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified using a thin layer silica gel plate (dichloromethane: methanol = 10: 1) and then purified using a thin layer silica gel plate (pure ethyl acetate) to obtain the target product 3-(trifluoromethyl)-5-(((4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl)amino)methyl)pyridin-2(1H)-one (7, 4.04 mg, yield 3.73%). ESI[M+H] + =553.40 1 HNMR (400MHz, DMSO-d6) δ8.71(S,2H),7.97(S,1H),7.68(S,1H),7.35(d,J=8.4Hz,2H),6.66(dd,J=17.7,7.3Hz,3H) ,4.49(d,J=12.6Hz,3H), 4.11(d,J=5.6Hz,2H), 3.23(d,J=12.3Hz,3H), 1.80(d,J=4.0Hz,2H), 1.56(d,J=7.4Hz,2H).

[0486] Example 8: Preparation of 5-((((1R,3R)-3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (8)

[0487]

[0488] Step 1: Preparation of tert-butyl ((1R, 3R)-3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (8-a)

[0489] Dissolve (1R, 3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (80 mg, 0.372 mmol) in dichloromethane (4 ml), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (141 mg, 0.372 mmol), N,N-diisopropylethylamine (198 μl, 1.116 mmol) and (R)-2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-3, 100 mg, 0.409 mmol), and react at room temperature for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and then purified by Flash (petroleum ether: ethyl acetate = 1:1) column to obtain the target product tert-butyl ((1R, 3R)-3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (8-a, 138 mg, yield 83.73%). ESI [M+H] + =444.7ESI[M+H-56] + =388.6

[0490] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (8-b)

[0491] Hydrogen chloride-ethyl acetate solution (4M) (3 ml) was slowly added dropwise to tert-butyl ((1R, 3R)-3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (8-a, 138 mg, 0.311 mmol) and stirred at room temperature for 1.5 hours. The reaction solution was added with 4 ml of ethyl acetate and filtered. The filter cake was dried to obtain the target product crude product ((1R, 3R)-3-aminocyclobutyl)((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (8-b, 157 mg, yield 132.84%). ESI [M+H] + =344.6

[0492] Step 3: Preparation of 5-((((1R,3R)-3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (8)

[0493] ((1R, 3R)-3-aminocyclobutyl)((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (8-b, 100 mg, 0.263 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 60 mg, 0.316 mmol) was added, and sodium acetate (11 mg, 0.132 mmol) was added at 0°C, and stirred at 0°C for 20 minutes, and sodium cyanoborohydride (50 mg, 0.79 mmol) was added at 0°C, and the reaction was allowed to react at room temperature overnight. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified using a thin layer silica gel plate (dichloromethane: methanol = 8: 1) and then purified using a high performance liquid chromatography [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-70% over 22min] to obtain the target product 5-((((1R, 3R)-3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (8, 2.63 mg, yield 1.93%). ESI [M+H] + =519.20

[0494] Example 9: Preparation of 3-trifluoromethyl-5-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)one (9)

[0495]

[0496] (S)-pyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (6-b, 30 mg, 0.0845 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 24.2 mg, 0.127 mmol) were dissolved in dichloromethane (1.5 ml), and acetic acid (2.5 mg, 0.0417 mmol) was added to the reaction at 0 degrees Celsius. After stirring for 20 minutes, sodium cyanoborohydride (15.9 mg, 0.253 mmol) was added and the reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-50%over 22min] to obtain 3-trifluoromethyl-5-(3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)one (9, 1.24 mg, yield 3.05%). ESI[M+H] + =531.2 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.72(s,2H),7.92(d,J=6.5Hz,1H),7.84(s,1H),7.70(d,J= 5.5Hz,1H),7.59(s,1H),6.30(t,J=6.7Hz,1H),4.64(d,J=5.8Hz,1H),4.55–4.42(m,2H),3.06(dd, J=27.3,14.6Hz,2H),2.85–2.75(m,1H),2.67–2.59(m,1H),2.59–2.52(m,1H),2.45(d,J=8.2Hz,1 H),2.42–2.31(m,1H),2.00(s,1H),1.94–1.78(m,2H),1.74(s,1H),1.56(dd,J=20.8,11.0Hz,2H).

[0497] Example 10: Preparation of 3-trifluoromethyl-5-((3R)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)one (10)

[0498]

[0499] (R)-pyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone hydrochloride (2-b, 30 mg, 0.0845 mmol) and 6-oxo-5-trifluoromethyl-1,6-dihydropyridine-3-carbaldehyde (I-7, 24.2 mg, 0.127 mmol) were dissolved in methanol (1.5 ml) under ice bath, and acetic acid (2.5 mg) was added dropwise. After stirring under ice bath for 20 minutes, sodium cyanoborohydride (15.9 mg, 0.253 mmol) was added and the reaction was allowed to react overnight at room temperature. After monitoring the reaction completion, water was added to quench, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-50%over22min] to obtain 3-trifluoromethyl-5-((3R)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)one (10, 1.01 mg, yield 2.25%). ESI[M+H] + =531.2 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.72(s,2H),7.84(s,1H),7.59(s,1H),4.64(d,J=6 .2Hz,1H),4.54–4.44(m,1H),4.02(dd,J=14.2,7.1Hz,1H),3.60(s,4H),3.10–3.00(m,1H) ,2.83(dd,J=20.1,11.4Hz,1H),2.64(d,J=21.0Hz,1H),2.41–2.32(m,1H),1.99(s,1H),1 .76(s,4H),1.58(dd,J=14.5,7.5Hz,1H),1.16(dd,J=14.3,7.1Hz,1H),0.88–0.80(m,1H).

[0500] Example 11: Preparation of 4-trifluoromethyl-6-((3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)methyl)pyridazin-3(2H)one (11)

[0501]

[0502] (S)-pyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (6-b, 50 mg, 0.141 mmol), 6-bromomethyl-4-trifluoromethylpyridazin-3(2H)one (I-6-c, 43.3 mg, 0.169 mmol), and cesium carbonate (137.6 mg, 0.422 mmol) were dissolved in N,N-dimethylformamide (2 ml) and the reaction was carried out at room temperature for 2 hours. After monitoring the completion of the reaction, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22min] to obtain 4-trifluoromethyl-6-((3S)-3-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidin-1-yl)methyl)pyridazin-3(2H)one (11, 1.61 mg, yield 2.15%), ESI [M+H] + =532.1 1 H NMR (400MHz, DMSO-d6) δ8.73(S,2H),8.21(S,1H),7.99(S,1H),4.66(S,1H),4.49(d,J=13.7Hz,2H),3.10(dd,J=28.3,12.7Hz,3H),2.93(td,J =14.0,7.1Hz,2H),1.91(S,3H),1.76(S,2H),1.60(dd,J=23.9,11.4Hz,3H),1.38(S,1H),1.25(dd,J=10.7,4.5Hz,1H),1.16(t,J=7.3Hz,1H).

[0503] Example 12: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (12)

[0504]

[0505] Step 1: Preparation of tert-butyl ((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (12-a)

[0506] Dissolve ((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (1 g, 4.65 mmol) in N,N-dimethylformamide (10 ml), add O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.77 g, 4.65 mmol) and N,N-diisopropylethylamine (2.44 mL, 13.95 mmol) under ice-cooling, stir under ice-cooling for 30 minutes, and then add 2- (Piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (1.26 g, 4.65 mmol) was reacted at room temperature for 3 hours, and then the reaction solution was added dropwise to water (100 mL) with stirring. After filtration, the filter cake was concentrated under reduced pressure to obtain the target product ((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (12-a, 1.7 g, yield 85.4%). (ESI)[M+H] + =430.2.

[0507] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (12-b)

[0508] Dissolve tert-butyl ((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (12-a, 1.7 g, 3.96 mmol) in ethyl acetate (10 ml), add 4M hydrochloric acid ethyl acetate solution (20 mL) under ice bath, react at room temperature for 3 hours, and concentrate under reduced pressure to obtain the target product ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (12-b, 1.7 g, crude product). (ESI)[M+H] + =330.2.

[0509] Step 3: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (12)

[0510] ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (12-b, 500 mg, 1.37 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6, 368 mg, 1.91 mmol) were dissolved in methanol (5 ml) and dichloromethane (10 ml), acetic acid (78 μL) was added under ice bath, and stirred under ice bath for 30 minutes. , sodium cyanoborohydride (257.8 mg, 4.10 mmol) was added, and the reaction was continued at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, purified by column chromatography, and the crude product was slurried with ethyl acetate to obtain the target product 4-(trifluoromethyl)-6-((((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazine-3(2H)-one (12, 150.25 mg, yield 21.7%). ESI[M+H] + =506.2. 1 H NMR (400MHz, CDCl3) δ8.51(s,2H),7.71(s,1H),3.90(s,4H),3.72(s,4H),3.56–3.39(m,3H),3.30(s,2H),2.60(s,2H),2.05(d,J=10.5Hz,2H).

[0511] Example 13: Preparation of 3-trifluoromethyl-5-((1R,3R)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)cyclobutyl)amino)methyl)pyridin-2(1H)one (13)

[0512]

[0513] Step 1: Preparation of tert-butyl (1R, 3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (13-a)

[0514] (1R, 3R)-3-(tert-Butyloxycarbonylamino)cyclobutane-1-carboxylic acid (50 mg, 0.232 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (88.5 mg, 0.232 mmol), and diisopropylethylamine (89.89 mg, 0.696 mmol) were dissolved in N,N-dimethylformamide (2 ml), and finally 2-piperazine-1-yl-5-trifluoromethylpyrimidine (I-1, 63 mg, 0.234 mmol) was added and the reaction was stirred at room temperature for 3 hours. After the reaction is completed, ice water is added and stirred thoroughly, filtered, and the filter cake is collected to obtain the target product (1R, 3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (13-a, 85.6 mg, yield 85.9%). ESI [M+H] + =430.2

[0515] Step 2: Preparation of (1R, 3R)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (13-b)

[0516] Dissolve (1R, 3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (13-a, 85.6 mg, 0.199 mmol) in 4 mol / L hydrogen chloride ethyl acetate solution and react overnight at room temperature. After monitoring the reaction completion, concentrate under reduced pressure to obtain the target product (1R, 3R)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (13-b, 94.6 mg, yield 144%). ESI [M+H] + =330.1

[0517] Step 3: Preparation of 3-trifluoromethyl-5-((1R, 3R)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)cyclobutyl)amino)methyl)pyridin-2(1H)one (13)

[0518] (1R, 3R)-3-aminocyclobutyl) 4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazine-1-methanone (13-b, 30 mg, 0.0739 mmol), 6-oxo-5-trifluoromethyl-1,6-dihydropyridazine-3-carbaldehyde (I-7, 18.8 mg, 0.098 mmol) were dissolved in methanol (2 ml) under ice bath, and sodium acetate (4 μl) was added dropwise. After stirring under ice bath for 20 minutes, sodium cyanoborohydride (15.5 mg, 0.246 mmol) was added and the reaction was allowed to react at room temperature overnight. After monitoring the reaction completion, water was added to quench, and the product was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-50%over 22min] to obtain 3-trifluoromethyl-5-((1R,3R)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)cyclobutyl)amino)methyl)pyridin-2(1H)one (13, 1.59 mg, yield 3.46%), ESI[M+H] + =505.1 1 H NMR (400MHz, DMSO-d6) δ8.72(S,2H),8.27(S,1H),7.92(S,1H),7.55(S,1H),3.82(d,J=4.3Hz,2H),3.55(S,2H),3 .39(S,4H),3.27(S,3H),3.15(dd,J=13.8,6.9Hz,2H),2.31(dd,J=10.3,5.7Hz,2H),1.94(dd,J=18.1,9.7Hz,2H).

[0519] Example 14: Preparation of 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (14)

[0520]

[0521] Azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (5-b, 100 mg, 0.317 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 73 mg, 0.381 mmol) was added. Sodium acetate (13 mg, 0.159 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (60 mg, 0.951 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. Saturated brine was added, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified using thin layer chromatography on silica gel (dichloromethane: methanol = 10: 1) to obtain the target product 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (14, 5.37 mg, yield 3.45%). ESI [M+H] + =491.30 1 HNMR(400MHz,CD3OD)δ8.58(S,2H),7.96(S,1H),7.59(S,1H),4.56(S,2H),3.96–3.88(m,4H),3. 69–3.64(m,2H),3.57(t,J=7.6Hz,2H),3.47(d,J=5.4Hz,1H),3.45(S,2H),3.37(t,J=7.2Hz,2H).

[0522] Example 15: Preparation of 3-(trifluoromethyl)-5-((((1R,4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)amino)methyl)pyridin-2(1H)-one (15)

[0523]

[0524] Step 1: Preparation of tert-butyl ((1R, 4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (15-a)

[0525] Dissolve (1R, 4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (100 mg, 0.411 mmol) in dichloromethane (5 ml), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156 mg, 0.411 mmol), N,N-diisopropylethylamine (216 μl, 1.233 mmol) and react for 20 minutes, then add 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 133 mg, 0.493 mmol) and react at room temperature for 3 hours. The reaction solution was filtered, concentrated under reduced pressure, and then purified by Flash (petroleum ether: ethyl acetate = 1:1) column to obtain the target tert-butyl ((1R, 4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (15-a, 202 mg, yield 107.45%). ESI [M+H] + =458.7,ESI[M+H-56] + =402.6

[0526] Step 2: Preparation of ((1R, 4R)-4-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (15-b)

[0527] 4M hydrogen chloride-ethyl acetate solution (6 ml) was slowly added dropwise to tert-butyl ((1R, 4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (15-a, 202 mg, 0.442 mmol) and stirred at room temperature for 1.5 hours. The reaction solution was diluted with 4 ml of ethyl acetate and concentrated under reduced pressure to obtain the target crude product ((1R, 4R)-4-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (15-b, 244 mg, crude product). ESI [M+H] + =358.7

[0528] Step 3: Preparation of 3-(trifluoromethyl)-5-((((1R,4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)amino)methyl)pyridin-2(1H)-one (15)

[0529] ((1R, 4R)-4-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (15-b, 100 mg, 0.255 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 58 mg, 0.305 mmol) was added. Sodium acetate (10 mg, 0.127 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (48 mg, 0.764 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. 0.1 ml of water was added and filtered, and the organic phase was concentrated under reduced pressure and purified twice using thin layer chromatography on silica gel plates (dichloromethane: methanol = 8: 1) to obtain the target product 3-(trifluoromethyl)-5-((((1R, 4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)amino)methyl)pyridin-2(1H)-one (15, 2.43 mg, yield 1.79%). ESI [M+H] + =533.2,ESI[2M+H] + =1065.3 1 HNMR (400MHz, CDCl3) δ8.51(s,1H),8.10(s,1H),7.92(s,1H),7.56(s,1H),3.92(d,J=20.8Hz,2H),3.78–3.67(m,2H),3.63–3.55(m,1H),2. 60(dd,J=63.0,17.2Hz,3H),2.10(d,J=5.2Hz,2H),1.86(d,J=12.7Hz,2H),1.73–1.67(m,2H),1.42(d,J=6.6Hz,3H),1.30(d,J=8.7Hz,4H).

[0530] Example 16: Preparation of 3-(trifluoromethyl)-5-(((1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)amino)methyl)pyridin-2(1H)-one (16)

[0531]

[0532] Step 1: Preparation of tert-butyl (1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (16-a)

[0533] Dissolve (1S, 3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (100 mg, 0.411 mmol) in dichloromethane (5 ml), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156 mg, 0.411 mmol) and N,N-diisopropylethylamine (216 μl, 1.233 mmol) and react for 20 minutes, then add 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 133 mg, 0.493 mmol) and react at room temperature overnight. The reaction solution was filtered, concentrated under reduced pressure, and then purified by Flash (petroleum ether: ethyl acetate = 1:1) column to obtain the target (1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamic acid tert-butyl ester (16-a, 208 mg, yield 110%). ESI [M+H] + =458.1,ESI[M+H-56] + =401.9

[0534] Step 2: Preparation of ((1S, 3S)-3-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (16-b)

[0535] Hydrogen chloride-ethyl acetate solution (4M) (3 ml) was slowly added dropwise to tert-butyl (1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (16-a, 208 mg, 0.455 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with 4 ml of ethyl acetate and concentrated under reduced pressure to obtain the target crude product ((1S, 3S)-3-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (16-b, 240 mg, crude product). ESI [M+H] + =358.2,ESI[2M+H] + =715.2

[0536] Step 3: Preparation of 3-(trifluoromethyl)-5-(((1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)amino)methyl)pyridin-2(1H)-one (16)

[0537] ((1S, 3S)-3-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (16-b, 100 mg, 0.254 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 58 mg, 0.305 mmol) was added. Sodium acetate (10 mg, 0.127 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (48 mg, 0.764 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. 0.1 ml of water was added and filtered, and the organic phase was concentrated under reduced pressure and purified twice using thin layer chromatography on silica gel plates (dichloromethane: methanol = 8: 1) to obtain the target product 3-(trifluoromethyl)-5-(((1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)amino)methyl)pyridin-2(1H)-one (16, 2.67 mg, yield 1.97%). ESI [M+H] + =533.1,ESI[2M+H] + =1065.3 1 HNMR(400MHz,DMSO-d6)δ8.73(s,2H),8.29(s,1H),7.99(s,1H),7.64(s,1H),3.83(d,J=25.5Hz,4 H),3.56(s,6H),3.11–3.02(m,2H),2.91(s,1H),1.61(dd,J=19.6,13.6Hz,4H),1.50–1.28(m,4H).

[0538] Example 17: Preparation of (S)-3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)pyridin-2(1H)-one (17)

[0539]

[0540] Step 1: Preparation of tert-butyl (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (17-a)

[0541] (S)-1-(tert-Butyloxycarbonyl)piperidine-3-carboxylic acid (100 mg, 0.436 mmol) was dissolved in dichloromethane (5 ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (166 mg, 0.436 mmol) and N,N-diisopropylethylamine (229 μl, 1.308 mmol) were added and the reaction was continued for 20 minutes. Then 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 141 mg, 0.523 mmol) was added and the reaction was continued at room temperature for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and then purified by Flash (ethyl acetate: petroleum ether = 0-50%) column to obtain the target (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (17-a, 187.8 mg, yield 96.95%). ESI [M+H] + =444.2,ESI[M+H-56] + =388.1,ESI[M+H-100] + =344.2

[0542] Step 2: Preparation of (S)-piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (17-b)

[0543] Hydrogen chloride-ethyl acetate solution (4M) (3 ml) was slowly added dropwise to tert-butyl (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (17-a, 187.8 mg, 0.423 mmol) and stirred at room temperature for 2 hours. The reaction solution was diluted with 4 ml of ethyl acetate and concentrated under reduced pressure to obtain the target product, crude (S)-piperidin-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (17-b, 194 mg, crude product). ESI [M+H] + =344.2

[0544] Step 3: Preparation of (S)-3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)pyridin-2(1H)-one (17)

[0545] (S)-Piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (17-b, 100 mg, 0.263 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 60 mg, 0.316 mmol) was added. Sodium acetate (10 mg, 0.132 mmol) was added at 0°C and stirred at 0°C for 20 minutes. Sodium cyanoborohydride (50 mg, 0.79 mmol) was added at 0°C and the reaction was allowed to react overnight at room temperature. 0.1 ml of water was added and filtered. The organic phase was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 8: 1). Then, the target product (S)-3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)pyridin-2(1H)-one (17, 5.68 mg, yield 4.16%) was prepared and purified by high performance liquid chromatography [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-70% over 22min]. ESI [M+H] + =519.1,ESI[2M+H] + =1037.2 1 HNMR (400MHz, DMSO-d6) δ8.72(s,2H),7.83(s,1H),7.57(s,1H),3.80(d,J=10.8Hz,4H),3.55(d,J=20.2Hz,4H),3.27(s,2H),2.78(dd,J=20.9,11. 2Hz,3H),2.01(t,J=10.7Hz,1H),1.87(t,J=10.6Hz,1H),1.73(d,J=12.1H z,1H),1.64(d,J=12.6Hz,1H),1.57–1.46(m,1H),1.27(d,J=15.3Hz,1H).

[0546] Example 18: Synthesis of 3-(trifluoromethyl)-5-((4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-2(1H)-one (18)

[0547]

[0548] Step 1: Preparation of tert-butyl 4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (18-a)

[0549] 1-(tert-Butyloxycarbonyl)piperidine-4-carboxylic acid (100 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (3.5 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) and N,N-diisopropylethylamine (228 μl) were added in sequence, and stirred at 0°C for 20 minutes. 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (69.6 mg, 0.24 mmol) was then added, and the reaction solution was stirred at room temperature for 4 hours. Add 10 times the volume of water to the reaction solution, stir for 15 minutes under ice bath, filter, and then rinse the filter cake with a mixed solution of petroleum ether: ethyl acetate = 1:1. Concentrate the filtrate under reduced pressure to obtain the target product tert-butyl 4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (18-a, 128 mg, yield 66.25%). ESI[M+H] + =444.2

[0550] Step 2: Preparation of piperidin-4-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone (18-b)

[0551] Dissolve tert-butyl 4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (18-a, 128 mg, 0.29 mmol) in 4M hydrogen chloride-ethyl acetate solution (1.3 ml). React at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the target product, crude piperidin-4-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone (18-b, 54 mg, crude product). ESI[M+H] + =344.16

[0552] Step 3: Preparation of 3-(trifluoromethyl)-5-((4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-2(1H)-one (18)

[0553] Piperidin-4-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone (18-b, 54 mg, 0.16 mmol) was dissolved in methanol (1.5 ml). 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxaldehyde (I-7, 36 mg, 0.19 mmol) was added and stirred for 10 minutes. Sodium acetate (11 mg, 0.13 mmol) was added at 0°C. After stirring for 20 minutes, sodium cyanoborohydride (49 mg, 0.78 mmol) was added. The reaction was allowed to react overnight at room temperature. The reaction solution was added to a small amount of water, and ethyl acetate was added for extraction. The filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane: methanol = 10: 1). Finally, the target product 3-(trifluoromethyl)-5-((4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-2(1H)-one (18, 8 mg, yield 9.81%) was purified using preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 10%-70%over 22min]. + =519.19 1 H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.73(s,2H),7.95(s,1H),7.71(s,1 H),4.42(s,2H),3.91–3.77(m,8H),2.45–2.30(m,4H),2.05–1.93(m,5H).

[0554] Example 19: Preparation of 3-trifluoromethyl-5-(((1S,3S)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (19)

[0555]

[0556] Step 1: Preparation of tert-butyl (1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (19-a)

[0557] (1S,3S)-3-(tert-Butyloxycarbonylamino)cyclobutane-1-carboxylic acid (100 mg, 0.304 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (181 mg, 0.476 mmol), and N,N-diisopropylethylamine (179.3 mg, 1.39 mmol) were dissolved in N,N-dimethylformamide (3 ml), and finally 2-piperazine-1-yl-5-trifluoromethylpyrimidine hydrochloride (I-1, 127 mg, 0.472 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was added dropwise to ice water with stirring, the precipitated solid was filtered, the filter cake was collected, and finally the target product (1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (19-a, 190 mg, yield 95.4%) was obtained by vacuum concentration. ESI [M+H] + =430.2

[0558] Step 2: Preparation of (1S, 3S)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (19-b)

[0559] Dissolve (1S, 3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (19-a, 190 mg, 0.443 mmol) in 4M hydrogen chloride ethyl acetate solution (3 ml) and react overnight at room temperature. After monitoring the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the target product (1S, 3S)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (19-b, 215 mg, yield 147.2%). ESI [M+H] + =330.2

[0560] Step 3: Preparation of 3-trifluoromethyl-5-(((1S,3S)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (19)

[0561] (1S, 3S)-3-aminocyclobutyl) 4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazine-1-methanone hydrochloride (19-b, 100 mg, 0.304 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 87 mg, 0.455 mmol) were dissolved in dichloromethane (3 ml), and acetic acid (9.1 mg, 0.151 mmol) was added to the reaction at 0°C. After stirring for 20 minutes, sodium cyanoborohydride (57.3 mg, 0.912 mmol) was added and the reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-50%over 22min] to obtain 3-trifluoromethyl-5-(((1S,3S)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (19, 1.87mg, yield 1.22%). ESI[M+H] + =505.2 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 2H), 8.70 (s, 1H), 8.35 (s, 1H), 7.98 (s, 1H), 4.22 (d, J = 4.3Hz, 1H), 4.03 (s, 3H), 3.9 5(d,J=4.4Hz,1H),3.50–3.44(m,1H),3.40–3.29(m,2H),2.93(s,4H),2.67(s,1H),2.33(s,1H),2.20–2.16(m,3H).

[0562] Example 20: Preparation of 4-(trifluoromethyl)-6-(((1S,3S)-3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (20)

[0563]

[0564] (1S, 3S)-3-aminocyclobutyl) 4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazine-1-methanone hydrochloride (19-b, 190 mg, 0.521 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6, 120 mg, 0.625 mmol) were dissolved in dichloromethane (2 ml) and methanol (2 ml), and sodium acetate (21 mg, 0.26 mmol) was added to the reaction at 0°C. After stirring for 30 minutes, sodium cyanoborohydride (97 mg, 1.56 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was quenched by adding a small amount of water and filtered, and then concentrated under reduced pressure and purified twice by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1) to obtain 4-(trifluoromethyl)-6-(((1S, 3S)-3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazine-3(2H)-one (20, 43.25 mg, yield 16.43%). ESI [M+H] + =506.3,ESI[2M+H] + =1011.5 1 HNMR (400MHz, DMSO-d6) δ8.72(s,2H),7.95(s,1H),3.79(d,J=4.1Hz,4H),3.56(s,2H),3.54–3.50(m,2H),3.44(d,J=4.3Hz, 3H), 3.04(dt,J=15.7,8.0Hz,1H), 2.93(dt,J=17.7,9.0Hz,1H), 2.25(dd,J=15.6,7.8Hz,2H), 1.82(dd,J=19.4,9.9Hz,2H).

[0565] Example 21: Preparation of 3-(trifluoromethyl)-5-((6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-yl)methyl)pyridin-2(1H)-one (21)

[0566]

[0567] Step 1: Preparation of tert-butyl 6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (21-a)

[0568] 2-(tert-Butyloxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (100 mg, 0.413 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (161 mg, 0.424 mmol), and N,N-diisopropylethylamine (216 μl, 1.24 mmol) were dissolved in N,N-dimethylformamide (3 ml), and finally 2-piperazine-1-yl-5-trifluoromethylpyrimidine hydrochloride (I-1, 113.6 mg, 0.423 mmol) was added, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was dropped into ice water with stirring, the precipitated solid was filtered, the filter cake was collected, and finally the target product 6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (21-a, 176 mg, yield 93.6%) was obtained by vacuum concentration. ESI [M+H] + =456.4

[0569] Step 2: Preparation of (2-azaspiro[3.3]heptane-6-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone trifluoroacetate (21-b)

[0570] 6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (21-a, 176 mg, 0.387 mmol) was dissolved in dichloromethane (3 ml), and trifluoroacetic acid (0.3 ml) was added to react at room temperature for 4 hours. After monitoring the completion of the reaction, the target product (2-azaspiro[3.3]heptane-6-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone trifluoroacetate (21-b, 220 mg) was obtained by concentration under reduced pressure. ESI[M+H] + =356.4

[0571] Step 3: Preparation of 3-(trifluoromethyl)-5-((6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-yl)methyl)pyridin-2(1H)-one (21)

[0572] (2-Azaspiro[3.3]heptane-6-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone trifluoroacetate (21-b, 30 mg, 0.085 mmol) and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 24.2 mg, 0.127 mmol) were dissolved in tetrahydrofuran (1 ml), and sodium acetate (3.5 mg, 0.043 mmol) was added to the reaction at 0°C. After stirring for 20 minutes, sodium cyanoborohydride (15.9 mg, 0.261 mmol) was added and the reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-50%over 22min] to obtain 3-(trifluoromethyl)-5-((6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-yl)methyl)pyridine-2(1H) (21, 0.73 mg, yield 1.63%). ESI[M+H] + =531.4 1 HNMR(400MHz,DMSO-d6)δ8.72(s,2H),8.37(s,1H),7.78(s,1H),7.53(s,1H),3.79(s,2H) ,3.26(s,6H),3.15(s,3H),2.98(s,3H),2.67(s,2H),2.33(s,1H),2.25(d,J=8.3Hz,2H).

[0573] Example 22: Preparation of (R)-3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)pyridin-2(1H)-one (22)

[0574]

[0575] Step 1: Preparation of tert-butyl (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (22-a)

[0576] (R)-1-(tert-Butyloxycarbonyl)piperidine-3-carboxylic acid (100 mg, 0.436 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (169.1 mg, 0.445 mmol), and N,N-diisopropylethylamine (168.7 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (3 ml), and finally 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (119.5 mg, 0.445 mmol) was added, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was added to ice water, the precipitated solid was filtered, the filter cake was collected, and the target product (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (22-a, 184 mg, yield 95.3%) was obtained after concentration under reduced pressure. ESI [M+H] + =444.19

[0577] Step 2: Preparation of (R)-piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (22-b)

[0578] Dissolve (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (22-a, 184 mg, 0.415 mmol) in 4M hydrogen chloride ethyl acetate solution (2 ml) and react overnight at room temperature. After monitoring the reaction completion, concentrate under reduced pressure to obtain the target product crude (R)-piperidin-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (22-b, 213.2 mg, yield 150%). ESI [M+H] + =343.2

[0579] Step 3: Preparation of (R)-3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)pyridin-2(1H)-one (22)

[0580] (R)-Piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (22-b, 100 mg, 0.263 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 60 mg, 0.316 mmol) were dissolved in dichloromethane (2 ml) and methanol (2 ml). Sodium acetate (10 mg, 0.132 mmol) was added to the reaction at 0°C. After stirring for 30 minutes, sodium cyanoborohydride (48 mg, 0.789 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was quenched by adding a small amount of water and filtered, and then concentrated under reduced pressure and purified twice by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1) to obtain 4 (R) -3- (trifluoromethyl) -5- (3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazine-1-carbonyl) piperidin-1-yl) methyl) pyridin-2 (1H) -one (22, 4.32 mg, yield 3.16%). ESI [M + H] + =519.4 1 H NMR (400MHz, DMSO-d6) δ8.72(s,2H),7.84(s,1H),7.57(s,1H),3.93–3.70(m,4H),3.54(d,J=20.4Hz,4H),3.27(s,2 H),2.78(dd,J=21.0,11.2Hz,3H),2.02(t,J=10.8Hz,1H),1.92–1.82(m,1H),1.61(ddd,J=37.3,31.0,12.2Hz,4H).

[0581] Example 23: Preparation of 5-(((1S,3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-3-(trifluoromethane)pyridin-2(1H)-one (23)

[0582]

[0583] Step 1: Preparation of tert-butyl (1S, 3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (23-a)

[0584] (1R, 3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (80 mg, 0.372 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (141 mg, 0.372 mmol), and N,N-diisopropylethylamine (198 μl, 1.116 mmol) were dissolved in dichloromethane (3 ml) and reacted for 30 minutes. Finally, (S)-2-(2-methylpiperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4, 97 mg, 0.391 mmol) was added and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash (petroleum ether: ethyl acetate = 0-50%) column to obtain the target product (1S, 3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (23-a, 156 mg, yield 94.65%). ESI [M+H] + =444.3,ESI[2M+H] + =887.6

[0585] Step 2: Preparation of ((1R, 3S)-3-aminocyclobutyl)((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (23-b)

[0586] Dissolve (1S, 3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (23-a, 156 mg, 0.352 mmol) in 4 mol / L hydrogen chloride ethyl acetate solution (3 ml) and react at room temperature for 2 hours. After monitoring the completion of the reaction, concentrate under reduced pressure to obtain the target crude product ((1R, 3S)-3-aminocyclobutyl)((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (23-b, 156 mg). ESI [M+H] + =344.3,ESI[2M+H] + =687.5

[0587] Step 3: Preparation of 5-(((1S,3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-3-(trifluoromethane)pyridin-2(1H)-one (23)

[0588] ((1R, 3S)-3-aminocyclobutyl)((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (23-b, 156 mg, 0.411 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 70 mg, 0.411 mmol) were dissolved in dichloromethane (1 ml) and methanol (2 ml), and sodium acetate (17 mg, 0.206 mmol) was added to the reaction at 0°C. After stirring for 30 minutes, sodium cyanoborohydride (77 mg, 1.233 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was quenched by adding a small amount of water and filtered, and then concentrated under reduced pressure and purified by Flash (methanol: dichloromethane = 0-10%) column twice to obtain 5-(((1S, 3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-3-(trifluoromethane)pyridin-2(1H)-one (23, 11.73 mg, yield 5.51%). ESI [M+H] + =519.3,ESI[2M+H] + =1037.5 1 H NMR (400MHz, DMSO-d6) δ8.73(s,2H),8.24(s,1H),7.96(s,1H),7.1H),4.46(d,J=12.5Hz,1H),4.27(t,J=14.1Hz,1H ),3.40–3.10(m,2.85–2.76(m,1H),2.40–2.22(m,2H),2.06(dd,J=15.6,10.0Hz,2H),1.09(dd,J=21.8,6.7Hz,3H).

[0589] Example 24: Preparation of (R)-3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)-one (24)

[0590]

[0591] Step 1: Preparation of tert-butyl (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (24-a)

[0592] (R)-1-(tert-Butyloxycarbonyl)pyrrolidine-3-carboxylic acid (100 mg, 0.465 mmol) was dissolved in N,N-dimethylformamide (6 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (176.7 mg, 0.465 mmol) and N,N-diisopropylethylamine (244 μl, 1.39 mmol) were added under ice-cooling, and stirred for 30 minutes under ice-cooling. , 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (124 mg, 0.465 mmol), react at room temperature for 3 hours, add the reaction solution dropwise into water (12 mL) with stirring, filter and concentrate the filter cake under reduced pressure to obtain the target product (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (24-a, 130 mg, yield 65.2%). ESI[M-56+H] + =374.4

[0593] Step 2: Preparation of (R)-pyrrolidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (24-b)

[0594] Dissolve (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (24-a, 130 mg, 0.303 mmol) in 4M hydrogen chloride ethyl acetate solution (3 ml) and react at room temperature for 2 hours. After monitoring the reaction completion, add ethyl acetate several times and concentrate under reduced pressure to obtain the target product crude (R)-pyrrolidin-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (24-b, 137 mg, crude product). ESI [M+H] + =330.2,ESI[2M+H] + =659.5

[0595] Step 3: Preparation of (R)-3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)-one (24)

[0596] (R)-pyrrolidin-3-yl (4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl)methanone hydrochloride (24-b, 137 mg, 0.375 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 72 mg, 0.375 mmol) were dissolved in dichloromethane (1 ml) and methanol (2 ml), and sodium acetate (15 mg, 0.187 mmol) was added to the reaction at 0°C. After stirring for 30 minutes, sodium cyanoborohydride (71 mg, 1.125 mmol) was added, and the reaction was stirred at room temperature overnight. After adding 0.3 ml of water, the mixture was concentrated under reduced pressure and filtered. The filtrate was purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1) and then purified by preparative liquid chromatography [Pack Column 20 ID * 250 mm * 10 μm; A: H2O (0.1% FA), B: ACN, B%: 5%-50% over 22 min] to obtain (R)-3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)pyridin-2(1H)-one (24, 2.17 mg, yield 1.15%). ESI [M+H] + =505.3 1 H NMR(600MHz,DMSO-d6)δ8.72(s,2H),7.84(s,1H),7.58(s,1H),3.82(dd,J= 13.1,4.4Hz,4H),3.61–3.53(m,4H),3.28(dd,J=15.9,8.0Hz,2H),2.77(t,J =8.7Hz,1H),2.60(dd,J=13.2,7.1Hz,1H),2.56–2.52(m,1H),2.38(dd,J=1 5.4,7.9Hz,1H),1.99(dd,J=20.5,9.2Hz,2H),1.91(dd,J=11.8,6.0Hz,1H).

[0597] Example 25: Preparation of 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)amino)methyl)pyridin-2(1H)-one (25)

[0598]

[0599] Step 1: Preparation of tert-butyl (3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate (25-a)

[0600] 3-((tert-Butyloxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 0.440 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (167 mg, 0.440 mmol), and N,N-diisopropylethylamine (230 μl, 1.32 mmol) were dissolved in dichloromethane (4 ml) and reacted for 30 minutes. Finally, 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 142 mg, 0.528 mmol) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash (ethyl acetate: petroleum ether = 0-50%) column to obtain the target product (3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamic acid tert-butyl ester (25-a, 190 mg, yield 97.81%). ESI [M+H] + =442.1

[0601] Step 2: Preparation of (3-aminobicyclo[1.1.1]pentan-1-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (25-b)

[0602] Dissolve tert-butyl (3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate (25-a, 190 mg, 0.43 mmol) in 4M hydrogen chloride in ethyl acetate solution (3 ml) and react at room temperature for 2 hours. After monitoring the reaction completion, add ethyl acetate several times and concentrate under reduced pressure to obtain the target product crude product (3-aminobicyclo[1.1.1]pentan-1-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (25-b, 190 mg, crude product). ESI[M+H] + =342.2

[0603] Step 3: Preparation of 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)amino)methyl)pyridin-2(1H)-one (25)

[0604] (3-Aminobicyclo[1.1.1]pentan-1-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (25-b, 90 mg, 0.241 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 46 mg, 0.241 mmol) were dissolved in dichloromethane (1 ml) and methanol (2 ml), and sodium acetate (10 mg, 0.121 mmol) was added to the reaction at 0°C. After stirring for 30 minutes, sodium cyanoborohydride (45 mg, 0.723 mmol) was added and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1) and then purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 5%-70% over 22min] and lyophilized to obtain 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)amino)methyl)pyridin-2(1H)-one (25, 0.67 mg, yield 0.54%). ESI [M+H] + =517.3,ESI[2M+H] + =1033.5 1 HNMR (600MHz, DMSO-d6) δ8.72(s,2H),7.92(s,1H),7.59(s,1H),3.81(d,J=20.4Hz,4H),3.63(s,2H),3.52(s,3H),3.49(s,2H),1.99(s,6H).

[0605] Example 26: Preparation of (S)-5-((3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (26)

[0606]

[0607] Step 1: Preparation of (S)-tert-butyl 3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (26-a)

[0608] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (100 mg, 0.497 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (189 mg, 0.497 mmol), and N,N-diisopropylethylamine (260 μl, 1.491 mmol) were dissolved in dichloromethane (4 ml) and reacted for 20 minutes. Finally, (S)-2-(2-methylpiperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4, 135 mg, 0.547 mmol) was added and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash (ethyl acetate: petroleum ether = 0-50%) column to obtain the target product (S)-3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (26-a, 185 mg, yield 86.85%). ESI [M+H-56] + =374.2,ESI[M+H-100] + =330.1

[0609] Step 2: Preparation of (S)-azetidin-3-yl(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (26-b)

[0610] (S)-3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (26-a, 185 mg, 0.431 mmol) was dissolved in 4 mol / L hydrogen chloride ethyl acetate solution (3 ml) and reacted at room temperature for 2 hours. After monitoring the reaction completion, dichloromethane was added and the mixture was concentrated under reduced pressure several times to obtain the target product crude product (S)-azetidine-3-yl (3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (26-b, 171 mg, crude product). ESI[M+H] + =330.2

[0611] Step 3: Preparation of (S)-5-((3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (26)

[0612] (S)-azetidin-3-yl(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (26-b, 171 mg, 0.479 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 89 mg, 0.479 mmol) were dissolved in dichloromethane (2 ml) and methanol (2 ml). Sodium acetate (19 mg, 0.24 mmol) was added to the reaction at 0°C. After stirring for 30 minutes, sodium cyanoborohydride (87 mg, 1.437 mmol) was added and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and purified twice by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1) to obtain (S)-5-((3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (26, 4.74 mg, yield 2.0%). ESI [M+H] + =505.3 1 H NMR(600MHz,DMSO-d6)δ8.72(s,2H),7.81(s,1H),7.57(s,1H),4.86(d,J=53.8Hz, 1H),4.46(dd,J=18.2,15.2Hz,1H),4.25(dd,J=30.3,13.1Hz,1H),3.68(d,J=12.7H z,1H),3.60–3.53(m,1H),3.51–3.42(m,3H),3.31(d,J=3.0Hz,2H),3.17(dd,J=16. 5,10.0Hz,2H),3.14–3.07(m,1H),2.95–2.76(m,1H),1.08(dd,J=19.2,6.7Hz,3H).

[0613] Example 27: Preparation of 3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (27)

[0614]

[0615] Step 1: Preparation of tert-butyl 3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (27-a)

[0616] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (100 mg, 0.497 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (189 mg, 0.497 mmol), and N,N-diisopropylethylamine (260 μl, 1.491 mmol) were dissolved in dichloromethane (4 ml) and reacted for 20 minutes. Finally, 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8, 146 mg, 0.646 mmol) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash column chromatography (petroleum ether: ethyl acetate = 0-50%) to obtain the target product tert-butyl 3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (27-a, 161 mg, yield 78.17%). ESI [M+H-56] + =359.2

[0617] Step 2: Preparation of azetidin-3-yl(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (27-b)

[0618] Dissolve tert-butyl 3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (27-a, 161 mg, 0.388 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (4 ml) under ice bath, react at room temperature for 2 hours, concentrate under reduced pressure, and purify by thin layer chromatography (dichloromethane: methanol = 15: 1) to obtain the target product heterocyclobutane-3-yl (4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone hydrochloride (27-b, 60 mg, yield 49.2%). ESI [M+H] + =315.2

[0619] Step 3: Preparation of 3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (27)

[0620] Heterocyclobutane-3-yl(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (27-b, 60 mg, 0.172 mmol) was dissolved in dichloromethane (4 ml) and methanol (2 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 42.7 mg, 0.223 mmol) and sodium acetate (7 mg, 0.0860 mmol) were added under ice bath, and stirred under ice bath for 20 min. After 3 minutes, sodium cyanoborohydride (32.4 mg, 0.516 mmol) was added, and the reaction was continued at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (dichloromethane: methanol = 10: 1) to obtain the target product 3-(trifluoromethyl)-5-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (27, 3.97 mg, yield 4.72%). ESI [M+H] + =490.2 1 H NMR(600MHz,DMSO-d6)δ12.21(s,1H),8.42(s,1H),7.80(s,2H),7.57(s,1H),6.96(d,J=20.6Hz,1 H),5.73(s,2H),5.33(s,1H),3.61(d,J=5.5Hz,5H),3.58–3.49(m,3H),3.17(s,2H),3.16(s,2H).

[0621] Example 28: Preparation of 3-(trifluoromethyl)-5-(((1R,3R)-3-(4-(5-(trifluoromethane)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (28)

[0622]

[0623] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (28-a)

[0624] (1R, 3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (100 mg, 0.465 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol), and diisopropylethylamine (245 μl, 1.395 mmol) were dissolved in dichloromethane (4 ml) and reacted for 20 minutes. Finally, 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8, 137 mg, 0.511 mmol) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Flash (ethyl acetate: petroleum ether = 0-50%) column to obtain the target product tert-butyl ((1R, 3R)-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (28-a, 153 mg, yield 76.86%). ESI [M+H] + =429.3

[0625] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (28-b)

[0626] Tert-butyl ((1R, 3R)-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (28-a, 153 mg, 0.357 mmol) was dissolved in ethyl acetate (2 ml), and 4M hydrochloric acid ethyl acetate solution (4 ml) was added under ice bath. After reacting at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone hydrochloride (28-b, 110 mg, yield 85.3%). ESI [M+H] + =329.2

[0627] Step 3: Preparation of 3-(trifluoromethyl)-5-(((1R,3R)-3-(4-(5-(trifluoromethane)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (28)

[0628] Dissolve ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (28-b, 110 mg, 0.303 mmol) in dichloromethane (4 ml) and methanol (2 ml), add 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 75.3 mg, 0.394 mmol) and sodium acetate (12.5 mg, 0.152 mmol) under ice bath, and then add 4-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 75.3 mg, 0.394 mmol) and sodium acetate (12.5 mg, 0.152 mmol) under ice bath. After stirring for 20 minutes, sodium cyanoborohydride (57 mg, 0.909 mmol) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC preparation plate (dichloromethane: methanol = 10: 1) to obtain the target product 3-(trifluoromethyl)-5-(((1R, 3R)-3-(4-(5-(trifluoromethane)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (28, 1.03 mg, yield 0.67%). ESI [M+H] + =504.8 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.18(s,1H),8.01–7.75(m,2H),7.56(s,1H),7.21(s,1H),6.96(d,J=8.7Hz,1H),6.68(s,1H),5.76(s ,2H),5.32(d,J=3.2Hz,1H),3.92(ddd,J=174.5,96.7,25.2Hz,6H),3.14(d,J=16.4Hz,2H),2.31(d,J=11.0Hz,2H),1.97(t,J=13.0Hz,2H).

[0629] Example 29: Preparation of 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrazin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (29)

[0630]

[0631] Step 1: Preparation of tert-butyl 3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (29-a)

[0632] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (100 mg, 0.497 mmol) was dissolved in N,N-dimethylformamide (6 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (189 mg, 0.497 mmol) and N,N-diisopropylethylamine (261 μl, 1.49 mmol) were added under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (Piperazine-1-yl)-5-(trifluoromethyl)pyrazine hydrochloride (I-9, 133.5 mg, 0.497 mmol), react at room temperature for 3 hours, then add the reaction solution dropwise into water (12 mL) with stirring, filter and concentrate the filter cake under reduced pressure to obtain the target product 3-(4-(5-(trifluoromethyl)pyrazine-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (29-a, 161 mg, yield 78.2%). ESI[M-56+H] + =359.3

[0633] Step 2: Preparation of azetidin-3-yl(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)methanone hydrochloride (29-b)

[0634] Dissolve tert-butyl 3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (29-a, 161 mg, 0.389 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (4 mL) under ice bath, react at room temperature for 3 hours, concentrate under reduced pressure, and purify the crude product by thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain the target product azetidine-3-yl (4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-yl)methanone hydrochloride (29-b, 80 mg, 65.3%). ESI [M + H] + =316.3

[0635] Step 3: Preparation of 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrazin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (29)

[0636] Azetidin-3-yl(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)methanone hydrochloride (29-b, 80 mg, 0.228 mmol) was dissolved in dichloromethane (4 ml) and methanol (2 ml), and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 57 mg, 0.296 mmol) and sodium acetate (10 mg, 0.114 mmol) were added under ice bath, and stirred under ice bath for 20 min. After 3 minutes, sodium cyanoborohydride (43 mg, 0.684 mmol) was added, and the reaction was continued at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by thin layer preparation plate (dichloromethane: methanol = 10: 1) to obtain the target product 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrazine-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridin-2(1H)-one (29, 5.65 mg, yield 5.06%). ESI [M+H] + =491.8 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.42(s,1H),8.25(s,1H),7.80(s,1H),7.58(s,1H),5 .76(s,1H),3.89(d,J=12.4Hz,2H),3.70(s,4H),3.58(d,J=1.9Hz,4H),3.43–3.29(m,4H).

[0637] Example 30: Preparation of 6-(((R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (30)

[0638]

[0639] Step 1: Preparation of tert-butyl (R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (30-a)

[0640] (R)-1-(tert-Butyloxycarbonyl)pyrrolidine-3-carboxylic acid (100 mg, 0.465 mmol) was dissolved in dichloromethane (4 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) and N,N-diisopropylethylamine (244 μL, 1.395 mmol) were added under ice bath. After stirring under ice bath for 30 minutes, (S)-2-(2-methylpiperazine-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4, 144 mg, 0.512 mmol) was added and reacted at room temperature for 1.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then purified by Flash (petroleum ether: ethyl acetate = 0-50%) column to obtain the target product (R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-a, 190 mg, yield 92.22%). ESI [M+H] + =444.8,ESI[M+H-100] + =344.6

[0641] Step 2: Preparation of ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)((R)-pyrrolidin-3-yl)methanone hydrochloride (30-b)

[0642] (R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-a, 0.19 g, 0.428 mmol) was dissolved in 4M hydrochloric acid ethyl acetate solution (4 mL), reacted at room temperature for 4 hours, and concentrated under reduced pressure to obtain the target product ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)((R)-pyrrolidin-3-yl)methanone hydrochloride (30-b, 120 mg, crude product). ESI[M+H] + =344.8

[0643] Step 3: Preparation of ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)((R)-pyrrolidin-3-yl)methanone (30-c)

[0644] ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)((R)-pyrrolidin-3-yl)methanone hydrochloride (30-b, 120 mg, 0.315 mmol) was dissolved in water (1 ml), sodium bicarbonate (29 mg, 0.347 mmol) was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the target product ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)((R)-pyrrolidin-3-yl)methanone (30-c, 73 mg, yield 67.6%).

[0645] Step 4: Preparation of 6-(((R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (30)

[0646] ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)((R)-pyrrolidin-3-yl)methanone (30-c, 73 mg, 0.213 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 27 mg, 0.106 mmol) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (dichloromethane:methanol=10:1) to give the target product 6-(((R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (30, 6.16 mg, yield 5.6%). ESI[M+H] + =520.5 1 H NMR(400MHz,DMSO-d6)δ13.56(s,1H),8.73(s,2H),7.84(s,1H),4.97–4.78(m,1H) ,4.47(d,J=11.0Hz,1H),4.28(t,J=11.7Hz,1H),4.11–3.95(m,1H),3.88(d,J=13. 5Hz,1H),3.63–3.49(m,2H),3.27–3.12(m,2H),2.86(dd,J=37.0,15.7Hz,2H),2.7 3–2.53(m,2H),2.20–1.91(m,2H),1.90–1.72(m,1H),1.09(dd,J=25.0,6.6Hz,3H).

[0647] Example 31: Preparation of (R)-4-(trifluoromethyl)-6-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)pyridazin-3(2H)-one (31)

[0648]

[0649] (R)-pyrrolidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (23-b, 120 mg, 0.365 mmol) was dissolved in dichloromethane / methanol (4 ml / 2 ml), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6, 98 mg, 0.510 mmol) and sodium acetate (15 mg, 0.182 mmol) were added under ice-bath, and stirred for 2 h under ice-bath. After 0 minutes, sodium cyanoborohydride (69 mg, 1.09 mmol) was added, and the reaction was continued at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC preparation plate (dichloromethane: methanol = 10: 1) to obtain the target product (R)-4-(trifluoromethyl)-6-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)methyl)pyridazin-3(2H)-one (31, 2.73 mg, yield 1.48%). ESI [M+H] + =506.8 1 H NMR (400MHz, DMSO-d6) δ13.56 (s, 1H), 8.73 (s, 2H), 7.84 (s, 1H), 3.82 (d, J = 5.1Hz, 4H), 3.55 (s,4H),3.30(d,J=7.7Hz,2H),2.82(t,J=8.6Hz,1H),2.69–2.57(m,2H),2.05–1.86(m,4H).

[0650] Example 32: Preparation of 4-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (32)

[0651]

[0652] Azetidine-3-yl (4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone hydrochloride (27-b, 120 mg, 0.382 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (I-6-c, 48 mg, 0.191 mmol) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (dichloromethane: methanol = 10: 1) to obtain the target product 4-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-yl)methyl)pyridazine-3(2H)-one (32, 6.07 mg, yield 3.24%). ESI [M+H] + =491.5 1 H NMR (400MHz, DMSO-d6) δ13.56(s,1H),8.42(s,1H),8.15(s,1H),7.80(s,1H),6.96(d,J=9.1Hz,1H),3.6 1(s,4H),3.55(d,J=6.0Hz,4H),3.50(s,2H),3.46(d,J=7.6Hz,2H),3.27(d,J=6.8Hz,2H),3.16(s,1H).

[0653] Example 33: Preparation of ((1R,3R)-3-(((6-methoxy-5-(trifluoromethyl)pyridazin-3-yl)methyl)(methyl)amino)cyclobutyl)(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazin-1-yl)methanone (33)

[0654]

[0655] 4-(Trifluoromethyl)-6-((((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (12, 30 mg, 0.0595 mmol) was dissolved in acetonitrile (1 ml), potassium carbonate (29 mg, 0.0893 mmol) and iodomethane (8 μl, 0.119 mmol) were added and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (ethyl acetate) to give the target product ((1R,3R)-3-(((6-methoxy-5-(trifluoromethyl)pyridazin-3-yl)methyl)(methyl)amino)cyclobutyl)(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazin-1-yl)methanone (33, 5.33 mg, yield 16.8%). ESI[M+H] + =534.7 1H NMR(400MHz,DMSO-d6)δ8.73(s,2H),7.84(s,1H),3.83(s,4H),3.69(s,3H),3.57(s,2H),3.42( s,2H),3.31(s,2H),3.22(s,1H),2.93(dd,J=17.8,10.7Hz,1H),2.34–2.11(m,4H),1.98(s,3H).

[0656] Example 34: Preparation of 6-((methyl((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (34)

[0657]

[0658] Step 1: Preparation of ((1R, 3R)-3-(methylamino)cyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (34-a)

[0659] ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (100 mg, 0.274 mmol) was dissolved in acetonitrile (2 ml), cesium carbonate (133.7 mg, 0.410 mmol) and potassium iodide (6 μl, 0.274 mmol) were added, and the mixture was reacted at room temperature for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-(methylamino)cyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (34-a, 100 mg, crude product). ESI[M+H] + =344.5

[0660] Step 2: Preparation of 6-((methyl((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (34)

[0661] ((1R, 3R)-3-(Methylamino)cyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (34-a, 100 mg, 0.292 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 37 mg, 0.146 mmol) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, purified by thin layer chromatography (dichloromethane: methanol = 10: 1), and then purified by high performance liquid chromatography [Pack Column 20ID*250mm*10μm; A: H2O (0.1% NH4HCO3), B: ACN, B%: 10%-100% over 25min] Preparation and purification to obtain the target product 6-((methyl((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (34, 0.56 mg, yield 0.37%). ESI [M+H] + =520.4 1 H NMR(400MHz,DMSO-d6)δ13.56(s,1H),8.74(s,2H),7.82(s,1H),3.83(s,4H),3.57(s,2H),3 .42(s,2H),3.22(s,2H),2.94(s,2H),2.22(dd,J=54.5,18.5Hz,4H),2.00(d,J=16.9Hz,3H).

[0662] Example 35: Preparation of 4-(trifluoromethyl)-6-(1-(((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)ethyl)pyridazin-3(2H)-one and 4-(trifluoromethyl)-6-(1-(((1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)ethyl)pyridazin-3(2H)-one (35-P1, 35-P2)

[0663]

[0664] (3-Aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (120 mg, 0.363 mmol) was dissolved in dichloromethane (2 ml), and 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16, 54 mg, 0.182 mmol) was added. After reacting at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure and purified by thin layer preparation (dichloromethane: methanol = 20: 1) and then chiral resolution to obtain the target product 4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone. methyl)-6-(1-(((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)ethyl)pyridazin-3(2H)-one (35-P1, 10.55 mg) and the target product 4-(trifluoromethyl)-6-(1-(((1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)ethyl)pyridazin-3(2H)-one (35-P2, 10.86 mg). ESI [M+H] + =520.4 1 H NMR(400MHz,DMSO-d6)δ13.49(s,1H),8.73(s,2H),7.98(s,1H),3.80(s,4H),3.74–3.40(m,4H),3 .19(s,1H),3.03(s,1H),2.67(s,1H),2.38–1.87(m,4H),1.89–1.72(m,1H),1.23(d,J=5.1Hz,3H).

[0665] Example 36: Preparation of (R)-4-(trifluoromethyl)-6-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)ethyl)pyridazin-3(2H)-one and (S)-4-(trifluoromethyl)-6-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)ethyl)pyridazin-3(2H)-one (36-P1, 36-P2)

[0666]

[0667] Azetidine-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone (5-b, 160 mg, 0.508 mmol) was dissolved in dichloromethane (10 ml), and 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (I-16, 75.4 mg, 0.254 mmol) was added. After reacting at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure and purified by thin layer preparation (dichloromethane: methanol = 20: 1) and then chiral separation was performed to obtain the target The product (R)-4-(trifluoromethyl)-6-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)ethyl)pyridazin-3(2H)-one (36-P1, 7.99 mg) and the target product (S)-4-(trifluoromethyl)-6-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)ethyl)pyridazin-3(2H)-one (36-P2, 7.71 mg). ESI [M+H] + =506.5 1 H NMR (400MHz, DMSO-d6) δ13.61(s,1H),8.72(s,2H),7.77(s,1H),3.80(s,4H),3.51(d,J=2 2.6Hz, 4H), 3.29 (d, J = 6.2Hz, 1H), 3.23 (s, 1H), 3.15–3.04 (m, 1H), 1.14 (d, J = 6.4Hz, 3H).

[0668] Example 37: Preparation of (R)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (37)

[0669]

[0670] Step 1: Preparation of tert-butyl (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxadiazine-9-carbonyl)azetidine-1-carboxylate (37-a)

[0671] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (51 mg, 0.252 mmol), (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine hydrochloride (I-10, 60 mg, 0.194 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (121 mg, 0.322 mmol) were dissolved in N,N-dimethylformamide (5 ml), and triethylamine (81 μl, 0.423 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with water, and then extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0-45%) to obtain the target product (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxadiazine-9-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (37-a, 75 mg, yield 84.81%). ESI [M+H] + =457.3,ESI[M+H-56] + =401.3

[0672] Step 2: Preparation of (R)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxetane-9-yl)methanone hydrochloride (37-b)

[0673] (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxetane-9-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (37-a, 75 mg, 0.164 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (2 ml) and reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product (R)-azetidine-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxetane-9-yl)methanone hydrochloride (37-b, 74 mg, yield 114.66%). ESI[M+H] + =357.4

[0674] Step 3: Preparation of (R)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxetane-9-yl)methanone (37-c)

[0675] (R)-azetidin-3-yl (3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxetane-9-yl)methanone hydrochloride (37-b, 74 mg, 0.188 mmol) was dissolved in water (2 ml) and sodium bicarbonate (19 mg, 0.226 mmol) was added to react at room temperature for 5 minutes. After monitoring pH = 8-9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane:methanol = 10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to give the target product (R)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxetane-9-yl)methanone (37-c, 57 mg, yield 84.91%).

[0676] Step 4: Preparation of (R)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (37)

[0677] (R)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxetane-9-yl)methanone (37-c, 57 mg, 0.16 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 37 mg, 0.192 mmol) were dissolved in methanol (0.9 ml) and acetic acid (0.1 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (20 mg, 0.32 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified twice by thin layer chromatography on silica gel plates (dichloromethane:methanol=10:1) to obtain (R)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxadiazine-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (37, 4.04 mg, yield 4.74%). ESI[M+H] + =533.3 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.14(s,1H),7.79(s,1H),7.34(d,J=7.3Hz,1H),4.33–4.20(m,2H),3.97(s,1H),3.89–3.79(m,2H),3.73(d ,J=12.3Hz,1H),3.67–3.58(m,2H),3.53(d,J=6.7Hz,1H),3.49(s,2H),3 .44(d,J=19.3Hz,2H),3.29–3.18(m,2H),2.09(s,1H),1.94–1.83(m,1H).

[0678] Example 38: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-((R)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (38)

[0679]

[0680] Step 1: Preparation of tert-butyl ((1R, 3R)-3-((R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (38-a)

[0681] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (83 mg, 0.387 mmol), (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine hydrochloride (I-10, 100 mg, 0.323 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (202 mg, 0.387 mmol) were dissolved in N,N-dimethylformamide (5 ml), and triethylamine (135 μl, 0.969 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was added with water, and then extracted with ethyl acetate, the combined organic phases were washed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0-57%) to obtain the target product tert-butyl ((1R, 3R)-3-((R)-3-(trifluoromethyl)-7,7a, 8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (38-a, 120 mg, yield 79%). ESI [M+H] + =471.4

[0682] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)methanone hydrochloride (38-b)

[0683] Tert-butyl ((1R, 3R)-3-((R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (38-a, 120 mg, 0.255 mmol) was dissolved in 4M hydrochloric acid and ethyl acetate (3 ml) and reacted at room temperature for 1.5 hours. After monitoring the reaction completion, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepin-9-yl)methanone hydrochloride (38-b, 120 mg, yield 115.65%). ESI [M+H] + =371.3

[0684] Step 3: Preparation of ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)methanone (38-c)

[0685] Dissolve ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxirane-9-yl)methanone hydrochloride (38-b, 120 mg, 0.295 mmol) in water (2 ml) and add sodium bicarbonate (30 mg, 0.355 mmol) to react at room temperature for 5 minutes. After monitoring pH=8-9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane:methanol=10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to give the target product ((1R,3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)methanone (38-c, 99 mg, yield 90.62%).

[0686] Step 4: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-((R)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (38)

[0687] ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepin-9-yl)methanone (38-c, 99 mg, 0.267 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 62 mg, 0.321 mmol) were dissolved in methanol (1.8 ml) and acetic acid (0.2 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (34 mg, 0.535 mmol) was added. The reaction was stirred at room temperature for 3 hours. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column (methanol:dichloromethane=0-8%) to obtain 4-(trifluoromethyl)-6-((((1R,3R)-3-((R)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine-9-carbonyl)cyclobutyl)amino)methyl)pyridazine-3(2H)-one (38, 16.65 mg, yield 11.40%). ESI[M+H] + =547.3 1 H NMR (600MHz, CDCl3) δ8.11(d,J=5.6Hz,1H),7.72(d,J=3.6Hz,1H),7.23(d,J=9.3Hz,1H) ,4.32(dd,J=30.4,7.3Hz,2H),4.05(dd,J=13.6,3.7Hz,1H),4.01–3.86(m,2H),3.77(d,J =6.8Hz,2H),3.75–3.59(m,2H),3.58–3.49(m,2H),3.37(dd,J=13.5,5.9Hz,1H),3.31(dd ,J=9.1,4.5Hz,1H),2.64–2.54(m,2H),2.12(dd,J=16.3,11.2Hz,3H),2.05–1.92(m,1H).

[0688] Example 39: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-((R)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepane-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (39)

[0689]

[0690] Step 1: Preparation of tert-butyl ((1R, 3R)-3-((R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (39-a)

[0691] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (24 mg, 0.127 mmol), (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-12, 29 mg, 0.106 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (58 mg, 0.127 mmol) were dissolved in N,N-dimethylformamide (2 ml), and triethylamine (38 μl, 0.318 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was added with water, and then extracted with ethyl acetate, the combined organic phases were washed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by Flash column (ethyl acetate: petroleum ether = 0-51%) to obtain the target product tert-butyl ((1R, 3R)-3-((R)-3-(trifluoromethyl)-7,7a, 8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (39-a, 56 mg, yield 112.15%). ESI [M+H] + =471.3,ESI[M+H-56] + =415.2

[0692] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazin-9(7H)-yl)methanone hydrochloride (39-b)

[0693] Tert-butyl ((1R, 3R)-3-((R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (39-a, 56 mg, 0.119 mmol) was dissolved in 4M hydrochloric acid and ethyl acetate (2 ml) and reacted at room temperature for 3 hours. After monitoring the reaction completion, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-7a, 8,10,11-tetrahydro-5H-pyrazine[2,1-c]pyridin[2,3-e][1,4]oxazine-9(7H)-yl)methanone hydrochloride (39-b, 58 mg, yield 119.78%). ESI [M+H] + =371.2,ESI[2M+H] + =741.4

[0694] Step 3: Preparation of ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazin-9(7H)-yl)methanone (39-c)

[0695] Dissolve ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazin-9(7H)-yl)methanone hydrochloride (39-b, 58 mg, 0.143 mmol) in water (1.5 ml) and add sodium bicarbonate (24 mg, 0.286 mmol) to react at room temperature for 5 minutes. After monitoring pH = 8 to 9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane:methanol = 10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to give the target product ((1R,3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazin-9(7H)-yl)methanone (39-c, 52 mg, yield 98.31%).

[0696] Step 4: Preparation of 4-(trifluoromethyl)-6-((((1R,3R)-3-((R)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepane-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (39)

[0697] ((1R, 3R)-3-aminocyclobutyl)((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazine[2,1-c]pyridin[2,3-e][1,4]oxazinepin-9(7H)-yl)methanone (39-c, 52 mg, 0.211 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 40.5 mg, 0.14 mmol) were dissolved in methanol (0.9 ml) and acetic acid (0.1 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (18 mg, 0.281 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane: methanol = 10:1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column (methanol: dichloromethane = 0-8%), and then purified by thin layer chromatography silica gel plate (dichloromethane: methanol = 10:1), and then purified by preparative liquid phase [Pack Column 20ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 22min] was purified to give 4-(trifluoromethyl)-6-((((1R,3R)-3-((R)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazepane-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (39, 2.44 mg, yield 3.18%). ESI [M+H] + =547.3,ESI[2M+H] + =1093.5

[0698] Example 40: Preparation of (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (40)

[0699]

[0700] Step 1: Preparation of tert-butyl (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepane-9-carbonyl)azetidine-1-carboxylate (40-a)

[0701] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (260 mg, 0.743 mmol) was dissolved in N,N-dimethylformamide (10 ml), and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (463.9 mg, 0.891 mmol), (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-11, 230 mg, 0.473 mmol), triethylamine (310 μl, 2.23mmol), reacted at room temperature for 2 hours, the reaction solution was quenched with water (15ml), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and purified by normal phase column (petroleum ether: ethyl acetate = 1:8) to obtain the target product (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepane-9-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (40-a, 177mg, yield 42.96%). ESI[M-56+H] + =401.3

[0702] Step 2: Preparation of (S)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazolidin-9-yl)methanone (40-b)

[0703] (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxirane-9-carbonyl)azepine-1-carboxylic acid tert-butyl ester (40-a, 177 mg, 0.381 mmol) was dissolved in ethyl acetate (2 ml), 4 M hydrochloric acid ethyl acetate solution (3 ml) was added, the mixture was reacted at room temperature for 3 hours, and then concentrated under reduced pressure, water (1 ml) was added, and NaHCO 3 Adjust the pH to 8, extract with dichloromethane: methanol = 8: 1, dry the organic phase over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure and purify it with a normal phase column (dichloromethane: methanol = 8: 1) to obtain the target product (S)-azetidin-3-yl (3-(trifluoromethyl)-6,7,7,7a, 8,10,11-hexahydro-9H-pyrazino [1,2-d] pyridino [3,2-b] [1,4] oxazolidin-9-yl) ketone (40-b, 50 mg, yield 36.7%). ESI [M+H] + =357.3.

[0704] Step 3: Preparation of (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (40)

[0705] (S)-azetidin-3-yl (3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazolidin-9-yl)methanone (40-b, 50 mg, 0.195 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 17.5 mg, 0.098 mmol) was added. After reacting at room temperature for 3 hours, the mixture was purified by TLC preparation (dichloromethane: methanol = 10:1) and purified by HPLC [Pack Column 20ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 10%-100%over25min] prepared and purified to obtain the target product (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (40, 1.51mg, yield 3.17%). ESI[M+H] + =533.4 1 H NMR (400MHz, DMSO-d6) δ13.59(s,1H),8.15(s,1H),7.80(s,1H),7.35(d,J=14.3Hz,1H),4.34–4.18(m,2H),3.98(dd,J=17.1,12.3Hz,2H),3.81( dd,J=13.7,3.6Hz,2H),3.69–3.55(m,2H),3.49(d,J=7.3Hz,4H),3.25(d ,J=7.0Hz,1H),3.18–3.11(m,1H),2.21–1.98(m,2H),1.97–1.75(m,2H).

[0706] Example 41: Preparation of 4-(trifluoromethyl)-6-((((1S,3R)-3-((S)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxa-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (41)

[0707]

[0708] Step 1: Preparation of tert-butyl ((1S, 3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (41-a)

[0709] (1R,3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (139 mg, 0.646 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (403.4 mg, 0.775 mmol), (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-11, 200 mg, 0.646 mmol), triethylamine (269 μM) were added. l, 1.94mmol), reacted at room temperature for 2 hours, the reaction solution was quenched with water (15ml), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and purified by normal phase column (petroleum ether: ethyl acetate = 1:8) to obtain the target product tert-butyl ((1S, 3R)-3-((S)-3-(trifluoromethyl)-7,7a, 8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (41-a, 201mg, yield 66.2%). ESI [M+H] + =471.3,ESI[M-56+H] + =415.3

[0710] Step 2: Preparation of (((1R,3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxacyclohexan-9-yl)methanone (41-b)

[0711] Tert-butyl ((1S, 3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (41-a, 201 mg, 0.447 mmol) was dissolved in ethyl acetate (2 ml), 4 M hydrochloric acid ethyl acetate solution (2 ml) was added, the mixture was reacted at room temperature for 3 hours, and then concentrated under reduced pressure, water (1 ml) was added, and N aHCO3 was used to adjust the pH to 8, and the mixture was extracted with dichloromethane:methanol=8:1. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (((1R,3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxa-oxa-9-yl)methanone (41-b, 96 mg, yield 60.6%). ESI[M+H] + =371.4

[0712] Step 3: Preparation of 4-(trifluoromethyl)-6-((((1S,3R)-3-((S)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxaoxazol-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (41)

[0713] (((1R, 3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxa-oxa-9-yl)methanone (41-b, 96 mg, 0.259 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 33.2 mg, 0.130 mmol) was added. After reacting at room temperature for 3 hours, the mixture was purified by TLC preparation (dichloromethane: methanol = 10:1) and purified by HPLC [Pack Column 20 ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 25min] Preparation and purification to obtain the target product (4-(trifluoromethyl)-6-((((1S,3R)-3-((S)-3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxa-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (41, 6.57 mg, yield 4.76%). ESI [M+H] + =547.21 H NMR (600MHz, DMSO-d6) δ13.40(s,1H),8.14(s,1H),7.91(s,1H),7.32(s,1H),4.26(d,J=30.7Hz,2H),3.90(dd,J =97.5,13.2Hz,2H),3.65(dd,J=57.8,22.5Hz,6H),3.17(t,J=45.3Hz,4H),2.27(s,2H),1.92(d,J=25.7Hz,2H).

[0714] Example 42: Preparation of (R)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (42)

[0715]

[0716] Step 1: Preparation of tert-butyl (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxadiazine-9-carbonyl)azetidine-1-carboxylate (42-a)

[0717] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (71.5 mg, 0.355 mmol) was dissolved in N,N-dimethylformamide (3 ml), and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (222 mg, 0.426 mmol), (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-12, 110 mg, 0.355 mmol), triethylamine (148 μl, 1.07mmol), reacted at room temperature for 2 hours, the reaction solution was quenched with water (10ml), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and purified by normal phase column (petroleum ether: ethyl acetate = 1:8) to obtain the target product tert-butyl (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxadiazine-9-carbonyl)azetidine-1-carboxylate (42-a, 110mg, yield 67.9%). ESI[M-56+H] + =401.2

[0718] Step 2: Preparation of (R)-azetidin-3-yl(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone (42-b)

[0719] To tert-butyl (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9-carbonyl)azetidine-1-carboxylate (42-a, 110 mg, 0.241 mmol) was added 4M hydrochloric acid dioxane solution (4 ml), reacted at room temperature for 3 hours, and then concentrated under reduced pressure, water (1 ml) was added, and the mixture was washed with water. The pH was adjusted to 8 with NaHCO3, and the mixture was extracted with dichloromethane:methanol=8:1. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (R)-azetidin-3-yl (3-(trifluoromethyl)-7a, 8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone (42-b, 100 mg, crude product). ESI[M+H] + =357.3

[0720] Step 3: Preparation of (R)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (42)

[0721] (R)-azetidin-3-yl (3-(trifluoromethyl)-7a, 8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone (42-b, 100 mg, 0.382 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 75.3 mg, 0.382 mmol) was added. After reacting at room temperature for 3 hours, the mixture was purified by normal phase column (dichloromethane: methanol = 10:1) and purified by high performance liquid chromatography [Pack Column 20 ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 22min] Preparation and purification of the target product (R)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxadiazole-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (42, 3.16 mg, yield 1.58%). ESI[M+H] + =533.2 1 H NMR (400MHz, DMSO-d6) δ13.99(s,1H),8.43(d,J=13.2Hz,1H),7.99(s,1H),7.82( d,J=23.0Hz,1H),4.88(dd,J=23.3,12.2Hz,2H),4.57(s,1H),4.55(d,J=14.5Hz,1 H),4.45(dd,J=29.0,9.0Hz,2H),4.34(dd,J=32.1,10.3Hz,2H),4.24(dd,J=24.9, 16.6Hz, 2H), 4.05 (dd, J=25.9, 21.6Hz, 2H), 3.97–3.74 (m, 4H), 3.38–3.21 (m, 2H).

[0722] Example 43: Preparation of 4-(trifluoromethyl)-6-((((1S,3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (43)

[0723]

[0724] Step 1: Preparation of tert-butyl ((1S, 3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (43-a)

[0725] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (46 mg, 0.213 mmol), (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-13, 55 mg, 0.178 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (111 mg, 0.213 mmol) were dissolved in N,N-dimethylformamide (4 ml), and triethylamine (74 μl, 0.533 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was added with water, and then extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column (ethyl acetate: petroleum ether = 0-51%) to obtain the target product tert-butyl ((1S, 3R)-3-((S)-3-(trifluoromethyl)-7,7a, 8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (43-a, 72 mg, yield 86.18%). ESI [M+H] + =471.4

[0726] Step 2: Preparation of ((1R, 3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-yl)methanone hydrochloride (43-b)

[0727] Tert-butyl ((1S, 3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (43-a, 72 mg, 0.153 mmol) was dissolved in 4M hydrochloric acid and ethyl acetate (2 ml) and reacted at room temperature for 1 hour. After monitoring the reaction completion, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product ((1R, 3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-7a, 8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-yl)methanone hydrochloride (43-b, 67 mg, yield 107.62%). ESI [M+H] + =371.2

[0728] Step 3 Preparation of ((1R, 3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-yl)methanone (43-c)

[0729] Dissolve ((1R, 3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-yl)methanone hydrochloride (43-b, 67 mg, 0.165 mmol) in water (2 ml) and add sodium bicarbonate (28 mg, 0.329 mmol) to react at room temperature for 5 minutes. After monitoring pH=8-9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane:methanol=10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to give the target product ((1R,3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-yl)methanone (43-c, 51 mg, yield 83.61%).

[0730] Step 4: Preparation of 4-(trifluoromethyl)-6-((((1S,3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (43)

[0731] ((1R, 3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9(7H)-yl)methanone (43-c, 51 mg, 0.137 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 40 mg, 0.207 mmol) were dissolved in methanol (1.8 ml) and acetic acid (0.2 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (17 mg, 0.275 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane: methanol = 10:1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1), and then purified by preparative liquid phase [Pack Column 30ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 22min] purified to give 4-(trifluoromethyl)-6-((((1S,3R)-3-((S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (43, 11.23 mg, yield 14.92%), ESI [M+H] + =547.7 1 HNMR (400MHz, DMSO-d6) δ8.40(s,1H),7.94(s,1H),7.79(s,1H),4.88(dd,J=13.9,10.1Hz,1H),4.53(d,J=14.2Hz,1H),4.00(dt,J=16 .3,9.9Hz,2H),3.91–3.77(m,2H),3.75–3.58(m,4H),3.56(s,2H),3.31–3.11(m,4H),2.24(d,J=11.2Hz,2H),1.90(t,J=12.2Hz,2H).

[0732] Example 44: Preparation of (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (44)

[0733]

[0734] Step 1: Preparation of tert-butyl (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxadiazine-9-carbonyl)azetidine-1-carboxylate (44-a)

[0735] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (43 mg, 0.213 mmol), (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-13, 55 mg, 0.178 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (111 mg, 0.213 mmol) were dissolved in N,N-dimethylformamide (4 ml), and triethylamine (74 μl, 0.533 mmol) was added. The reaction was stirred at room temperature for 3 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and passed through a Flash silica gel column (ethyl acetate: petroleum ether

[0736] =0~51%) was purified by column to obtain the target product tert-butyl (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxadiazine-9-carbonyl)azetidine-1-carboxylate (44-a, 65 mg, yield 80.19%). ESI

[0737] [M+H] + =457.2,ESI[M+H-56] + =401.2

[0738] Step 2: Preparation of (S)-azetidin-3-yl(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone hydrochloride (44-b)

[0739] Tert-butyl (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9-carbonyl)azetidine-1-carboxylate (44-a, 65 mg, 0.142 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (2 ml) and reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product (S)-azetidine-3-yl(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone hydrochloride (44-b, 60 mg, yield 107.27%). ESI[M+H] + =357.2

[0740] Step 3 Preparation of (S)-azetidin-3-yl (3-(trifluoromethyl)-7a, 8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone (44-c)

[0741] (S)-azetidin-3-yl (3-(trifluoromethyl)-7a, 8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone hydrochloride (44-b, 60 mg, 0.152 mmol) was dissolved in water (2 ml) and sodium bicarbonate (27 mg, 0.305 mmol) was added to react at room temperature for 5 minutes. After monitoring pH = 8-9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane: methanol = 10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to give the target product (S)-azetidin-3-yl(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxetane-9(7H)-yl)methanone (44-c, 46 mg, yield 84.51%).

[0742] Step 4: Preparation of (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethane)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (44)

[0743] (S)-azetidin-3-yl(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxetane-9(7H)-yl)methanone (44-c, 46 mg, 0.129 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 37 mg, 0.193 mmol) were dissolved in methanol (1.8 ml) and acetic acid (0.2 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (16 mg, 0.258 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the reaction completion, a large amount of water was added, and the mixture was extracted with dichloromethane: methanol = 10:1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plates (dichloromethane: methanol = 10:1), and then purified by preparative liquid phase [Pack Column 30ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 22min] to obtain (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxirane-9-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (44, 4.75 mg, yield 6.91%), ESI [M+H] + =533.7 1 HNMR (400MHz, DMSO-d6) δ8.41(d,J=6.2Hz,1H),7.80(s,2H),4.87(t,J=13.4Hz,1H),4.53(dd,J=14.2,4.9Hz,1H),4. 08–3.94(m,2H),3.94–3.76(m,3H),3.75–3.57(m,3H),3.50(s,4H),3.42(dd,J=13.7,7.1Hz,1H),3.31–3.17(m,3H).

[0744] Example 45: Preparation of 6-((((1R,3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (45)

[0745]

[0746] Step 1: Preparation of tert-butyl (1R, 3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (45-a)

[0747] (1R, 3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (64 mg, 0.299 mmol) was dissolved in dichloromethane (5 ml), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.299 mmol) was added and stirred for 10 minutes, and N,N-diisopropylethylamine (157 μl, 0.897 mmol) and 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15, 89 mg, 0.299 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by flash silica gel column (ethyl acetate: petroleum ether = 0-49%) to obtain the target product (1R, 3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (45-a, 114 mg, yield 83.17%). ESI [M+H] + =459.0

[0748] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (45-b)

[0749] Tert-butyl (1R, 3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (45-a, 114 mg, 0.249 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (3 ml) and reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone hydrochloride (45-b, 118 mg, yield 120.20%).

[0750] Step 3 Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (45-c)

[0751] Dissolve ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (45-b, 118 mg, 0.299 mmol) in water (2 ml) and add sodium bicarbonate (51 mg, 0.598 mmol) to react at room temperature for 5 minutes. After monitoring pH=8-9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane:methanol=10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (45-c, 106 mg, yield 98.97%).

[0752] Step 4: Preparation of 6-((((1R,3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (45)

[0753] ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (45-c, 106 mg, 0.296 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 85 mg, 0.444 mmol) were dissolved in methanol (1.8 ml) and acetic acid (0.2 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (37 mg, 0.592 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the completion of the reaction, a large amount of water was added, and the product was extracted with dichloromethane:methanol=10:1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative liquid phase [Pack Column 30ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-80% over 22min], and then purified twice by Flash (silica gel column 8g, dichloromethane:methanol=10:1) to obtain 6-((((1R,3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (45, 38.58 mg, yield 30.43%), ESI [M+H] + =535.2 1HNMR(400MHz,DMSO-d6)δ8.11(s,1H),7.94(s,1H),7.44(d,J=1.6Hz,1H),4.03(dd,J=14.2,7.1Hz,1H),3.88(s,3H),3.56(s,4H),3.45(s,4 H),3.40(d,J=5.1Hz,2H),3.23(ddd,J=13.9,9.4,4.6Hz,1H),3.14(dt,J=13.9,6.9Hz,1H),2.32–2.23(m,2H),1.92(dd,J=18.5,9.4Hz,2H).

[0754] Example 46: Preparation of 6-((3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (46)

[0755]

[0756] Step 1: Preparation of tert-butyl 3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (46-a)

[0757] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (60 mg, 0.299 mmol) was dissolved in dichloromethane (5 ml), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.299 mmol) was added and stirred for 10 minutes, then N,N-diisopropylethylamine (157 μl, 0.897 mmol) and 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15, 89 mg, 0.299 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by Flash silica gel column (ethyl acetate: petroleum ether = 0-50%) to obtain the target product tert-butyl 3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (46-a, 119 mg, yield 89.56%). ESI [M+H] + =445.0

[0758] Step 2: Preparation of azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone hydrochloride (46-b)

[0759] 3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (46-a, 119 mg, 0.268 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (3 ml) and reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was diluted with dichloromethane several times and then concentrated under reduced pressure to obtain the target product azetidine-3-yl (4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone hydrochloride (46-b, 119 mg, yield 116.72%).

[0760] Step 3: Preparation of azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (46-c)

[0761] Azetidine-3-yl (4- (3-methoxy-5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) ketone hydrochloride (46-b, 119 mg, 0.313 mmol) was dissolved in water (2 ml) and sodium bicarbonate (53 mg, 0.626 mmol) was added to react at room temperature for 5 minutes. After monitoring pH = 8-9, the reaction solution was concentrated under reduced pressure, and the crude product was added with a solution of dichloromethane: methanol = 10:1 and ultrasonically dissolved and filtered. The filtrate was concentrated under reduced pressure to obtain the target product azetidine-3-yl (4- (3-methoxy-5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) ketone (46-c, 103 mg, yield 95.72%).

[0762] Step 4: Preparation of 6-((3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (46)

[0763] Azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (46-c, 103 mg, 0.299 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-6, 86 mg, 0.449 mmol) were dissolved in methanol (1.8 ml) and acetic acid (0.2 ml). The reaction was stirred at room temperature for 1.5 hours, and then sodium cyanoborohydride (38 mg, 0.598 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the completion of the reaction, a large amount of water was added, extracted with dichloromethane: methanol = 10: 1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative liquid phase [Pack Column 30ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 22min], and then purified twice by Flash (silica gel column 8g, dichloromethane: methanol = 10: 1) to obtain 6-((3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (46, 9.83mg, yield 6.31%), ESI [M+H] + =521.3 1 HNMR (400MHz, DMSO-d6) δ13.54(s,1H),8.11(s,1H),7.79(s,1H),7.44(d,J=1.7Hz,1H),3.88(s,3H),3.55( d,J=5.6Hz,2H),3.50(d,J=9.1Hz,3H),3.46(d,J=7.8Hz,5H),3.37(d,J=3.2Hz,3H),3.25(t,J=6.6Hz,2H).

[0764] Example 47: Preparation of 2-(4-((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (47)

[0765]

[0766] Step 1: Preparation of tert-butyl ((1R,3R)-3-(4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (47-a)

[0767] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (73.6 mg, 0.342 mmol) was dissolved in N,N-dimethylformamide (3 ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 0.342 mmol) and N,N-diisopropylethylamine (179 μl, 1.03 mmol) were added, and the mixture was stirred for 20 minutes under ice bath, and 2-(piperazine-1-yl)- 5-(Trifluoromethyl)nicotinonitrile hydrochloride (I-14, 100 mg, 0.342 mmol), reacted at room temperature for 4 hours, water (20 ml) was added dropwise to the reaction solution, a white solid precipitated, filtered, the filter cake was washed with water, the filter cake was collected, and concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-(4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (47-a, 131 mg, yield 84.5%). ESI [M-56+H] + =398.2

[0768] Step 2: Preparation of 2-(4-((1R, 3R)-3-aminocyclobutane-1-carbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinonitrile (47-b)

[0769] Dissolve tert-butyl (1R, 3R)-3-(4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (47-a, 131 mg, 0.289 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (3 ml), react at room temperature for 3 hours, and then concentrate under reduced pressure. Add water (1 ml), adjust the pH to 8 with NaHCO3, extract with dichloromethane:methanol=8:1, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 2-(4-((1R, 3R)-3-aminocyclobutane-1-carbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinonitrile (47-b, 118 mg, crude product). ESI[M+H] + =354.3

[0770] Step 3: Preparation of 2-(4-((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (47)

[0771] 2-(4-((1R, 3R)-3-aminocyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (47-b, 118 mg, 0.303 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 17.5 mg, 0.098 mmol) was added. After reacting at room temperature for 3 hours, the mixture was purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) and purified by high performance liquid chromatography [Pack Column 30 ID*250 mm*10 μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 25min] Preparation and purification to obtain the target product 2-(4-((1R, 3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (47, 1.51 mg, yield 3.17%). ESI [M+H] + =530.0 1 H NMR (400MHz, DMSO-d6) δ13.40(s,1H),8.69(s,1H),8.53(s,1H),7.94(s,1H),3.81(t,J=9.6Hz,4H),3.64–3.59(m,2 H),3.57(s,2H),3.49(s,2H),3.28–3.21(m,1H),3.14(dd,J=8.5,5.4Hz,1H),2.36–2.24(m,2H),1.99–1.88(m,2H).

[0772] Example 48: Preparation of 4-(trifluoromethyl)-6-(2-(((1R,3R)-3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)pyridazin-3(2H)-one (48)

[0773]

[0774] 6-(2-bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 40 mg-50%, 0.14 mmol), ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (23 mg, 0.14 mmol) were dissolved in dichloromethane (3 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure and purified by silica gel preparation plate (dichloromethane: methanol = 10: 1) to obtain the target product 4-(trifluoromethyl)-6-(2-(((1R, 3R)-3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)pyridazin-3(2H)-one (48, 14.23 mg, yield 18.92%). ESI[M+H] + =534.80 1 H NMR (600MHz, DMSO-d6) δ13.87(s,1H),9.14(s,2H),8.54(s,1H),4.22(d,J=3.0Hz,4H),3.98–3.93(m,2H),3.43 (ddt,J=20.7,13.8,8.2Hz,3H),2.93(dt,J=3.4,1.7Hz,2H),2.63–2.58(m,2H),2.37–2.30(m,2H),1.70(s,6H).

[0775] Example 49: Preparation of 4-(trifluoromethyl)-6-(2-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)propan-2-yl)pyridazin-3(2H)-one (49)

[0776]

[0777] 6-(2-Bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 30 mg, purity 50%, 0.11 mmol), azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (5-b, 19 mg, 0.11 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature overnight for 1 h. No obvious product was produced. The pH was adjusted to weak alkalinity with sodium bicarbonate aqueous solution and the reaction was continued overnight. After the reaction, the filtrate was concentrated under reduced pressure and purified once by silica gel preparation plate (dichloromethane: methanol = 10: 1), and then purified for the second time by preparative liquid phase [Pack Column 30ID*250mm*15um; A: H2O (0.1% FA), B: CAN, B%: 10%-95% over 25min] to obtain the target product 4-(trifluoromethyl)-6-(2-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)propan-2-yl)pyridazin-3(2H)-one (49, 5.11 mg, yield 9.4%). ESI [M+H] + =520.1 1 H NMR (400MHz, DMSO-d6) δ13.51(s,1H),8.72(s,2H),7.95(s,1H),3.80(s,5H),3.50(d,J=31.5Hz,8H),1.22(s,6H).

[0778] Example 50: Preparation of 2-(4-((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (50)

[0779]

[0780] Step 1: Preparation of tert-butyl (1R, 3R)-3-(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (50-a)

[0781] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (96.2 mg, 0.447 mmol) was dissolved in N,N-dimethylformamide (5 ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170 mg, 0.447 mmol) and N,N-diisopropylethylamine (235 μl, 1.34 mmol) were added, and stirred for 20 minutes under ice bath, and 1-(3,5-bis( After 4 hours of reaction at room temperature, water (20 ml) was added dropwise to the reaction solution to precipitate a white solid. The solid was filtered and the filter cake was washed with water. The filter cake was collected and concentrated under reduced pressure to obtain the target product (1R, 3R)-3-(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (50-a, 80 mg, yield 36.2%). ESI[M-56+H] + =441.2

[0782] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (50-b)

[0783] Dissolve (1R, 3R)-3-(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (50-a, 80 mg, 0.161 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (3 ml), react at room temperature for 3 hours, and then concentrate under reduced pressure. Add water (1 ml), adjust the pH to 8 with NaHCO3, extract with dichloromethane:methanol=8:1, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (50-b, 78 mg, crude product). ESI[M+H] + =397.2

[0784] Step 3: Preparation of 2-(4-((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (50)

[0785] ((1R, 3R)-3-aminocyclobutyl)(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (50-b, 78 mg, 0.188 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 54 mg, 0.188 mmol) was added. After reacting at room temperature for 3 hours, the mixture was purified by thin layer chromatography on silica gel plates (dichloromethane: methanol = 10:1) and purified by high performance liquid chromatography [Pack Column 30 ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 25min] Preparation and purification to obtain the target product 2-(4-((1R, 3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (50, 7.26 mg, yield 6.75%). ESI [M+H] + =573.0 1 H NMR(400MHz,DMSO-d6)δ13.99(s,1H),8.84–8.76(m,1H),8.37(d,J=1.4Hz,1H),8 .01(s,1H),4.12(s,2H),3.90–3.56(m,4H),3.55–3.39(m,6H),2.48–2.31(m,4H).

[0786] Example 51: Preparation of 5-cyclobutoxy-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (51)

[0787]

[0788] Azetidine-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone (5-b, 75.7 mg, 0.240 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-5-cyclobutoxypyridazine-3(2H)-one (I-19, 31 mg, 0.120 mmol) was added. After reacting at room temperature for 1 hour, the mixture was purified by thin layer chromatography on silica gel (dichloromethane: methanol = 10:1) and purified by high performance liquid chromatography [Pack Column 30 ID * 250 mm * 10 μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 30 min] Preparation and purification of the target product 5-cyclobutoxy-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (51, 1.11 mg, yield 6.75%). ESI [M+H] + =494.2 1 H NMR (600MHz, DMSO-d6) δ12.48(s,1H),8.72(s,2H),5.94(s,1H),4.78–4.68(m,2H),3.79(d,J=17.0H z,4H),3.61–3.46(m,6H),2.05(dd,J=28.2,15.2Hz,4H),1.83–1.75(m,2H),1.64(d,J=22.7Hz,2H).

[0789] Example 52: Preparation of 5-cyclobutyloxy-6-(((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (52)

[0790]

[0791] ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (79.1 mg, 0.240 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-5-cyclobutyloxypyridazin-3(2H)-one (I-19, 31 mg, 0.120 mmol) was added. After reacting at room temperature for 1 hour, the product was purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) and purified by high performance liquid chromatography [Pack Column 30 ID*250 mm*10 μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 30min] Preparation and purification of the target product 5-cyclobutyloxy-6-(((1R, 3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (52, 2.29 mg, yield 3.76%). ESI [M+H] + =508.2 1 H NMR(600MHz,DMSO-d6)δ12.91(s,1H),8.72(s,2H),6.09(s,1H),4.80(dd, J=14.0,7.0Hz,1H),3.98(s,2H),3.84(s,4H),3.79–3.72(m,1H),3.62–3.5 4(m,2H),3.49–3.40(m,4H),2.46(dd,J=14.9,8.2Hz,5H),2.12(dd,J=18. 8,9.0Hz,2H),1.82(dd,J=20.5,10.1Hz,1H),1.65(dd,J=18.9,9.6Hz,1H).

[0792] Example 53: Preparation of 6-((((1R,3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (53)

[0793]

[0794] Step 1: Preparation of tert-butyl (1R, 3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (53-a)

[0795] (1R, 3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (245 mg, 1.138 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (433 mg, 1.138 mmol) were dissolved in dichloromethane (10 mL) and stirred for 10 minutes. N,N-diisopropylethylamine (595 μl, 3.41 mmol) was added, 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22, 335 mg, 1.36 mmol) was dissolved in dichloromethane (5 ml) and added to the reaction, and the reaction was allowed to react overnight at room temperature. After the reaction, the reaction solution was concentrated under reduced pressure and then purified by Flash column (petroleum ether: ethyl acetate = 1:1) to obtain the target product (1R, 3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (53-a, 330 mg, yield 54%). ESI [M+H] + =443.4

[0796] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (53-b)

[0797] Dissolve (1R, 3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamic acid tert-butyl ester (53-a, 300 mg) in ethyl acetate solution (4 ml), then add hydrogen chloride ethyl acetate solution (4 mL), and react at room temperature overnight. After the reaction is completed, the reaction solution is concentrated under reduced pressure, dissolved in dichloromethane and concentrated again under reduced pressure. After repeating twice, sodium bicarbonate aqueous solution is slowly added to pH = 7-9, filtered, and the solution is partially concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (53-b, 300 mg, crude product). ESI[M+H] + =343.4

[0798] Step 3: Preparation of 6-((((1R,3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (53)

[0799] ((1R, 3R)-3-aminocyclobutyl)(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (53-b, 150 mg, 0.44 mmol), 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6, 143 mg, 0.48 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours. After the reaction, the filtrate was concentrated under reduced pressure and purified by silica gel preparation plate (dichloromethane: methanol = 10: 1), and then the liquid phase [Pack Column 30ID*250mm*15μm; A: H2O (0.1% FA), B: ACN, B%: 10%-95% over 25min] Purification twice to obtain the target product 6-((((1R,3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (53, 2.88 mg, yield 1.3%). ESI [M+H] + =519.41 1 H NMR (600MHz, DMSO-d6) δ8.43(s,1H),8.39(s,1H),7.94(s,1H),7.85(s,1H),3.58(d,J=19.9Hz,4H),3.41(d,J=19.8H z,3H),3.28–3.22(m,2H),3.18(d,J=14.4Hz,4H),2.31(d,J=6.9Hz,3H),2.28(s,2H),1.92(dd,J=17.0,10.0Hz,2H).

[0800] Example 54: Preparation of 5-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (54)

[0801]

[0802] Dissolve azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (5-b, 39 mg, 0.124 mmol) in dichloromethane (2 ml), add 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18, 29 mg, 0.113 mmol) and react at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by TLC plate (dichloromethane: methanol = 10:1), and then purified by HPLC [Pack Column 30 ID * 250 mm * 10 μm; A: H2O (0.1% FA), B: ACN, B%: 10%-60% over 30 min] to obtain the target product 5-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)pyridazin-3(2H)-one (54, 0.8 mg, yield 1.44%). ESI [M+H] + =492.5 1 H NMR (600MHz, DMSO-d6) δ8.72(s,2H),7.33(s,1H),3.80(d,J=4.2Hz,3H),3.55–3.52(m,4H),3.50–3.47(m,4H),3.29–3.25(m,4H).

[0803] Example 55: Preparation of 5-(trifluoromethyl)-6-((((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (55)

[0804]

[0805] Dissolve ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (41 mg, 0.124 mmol) in dichloromethane (2 ml), add 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18, 29 mg, 0.113 mmol), and react at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by TLC plate (dichloromethane: methanol = 10:1) and then by high performance preparative liquid chromatography [Pack Column 30ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-60% over 30min] to obtain the target product 5-(trifluoromethyl)-6-((((1R, 3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (55, 1.34 mg, yield 2.35%). ESI [M+H] + =506.5 1 H NMR(600MHz,DMSO-d6)δ8.72(s,2H),7.33(s,1H),3.81(s,4H),3.63(s,2H),3.55(s, 2H),3.47–3.33(m,3H),3.28–3.18(m,2H),2.30(d,J=4.3Hz,2H),2.01–1.86(m,2H).

[0806] Example 56: Preparation of 6-(((1R,3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (56)

[0807]

[0808] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (56-a)

[0809] Dissolve (1R, 3R)-3-(tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (202 mg, 1.01 mmol) in dichloromethane (14 ml), add O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (384 mg, 1.25 mmol) and stir for 10 minutes, then add N,N-diisopropylethylamine (528 μl, 3.03 mmol), 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-23, 310 mg, 1.01 mmol), and the reaction is stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and flash (silica gel column 25 g, petroleum ether: ethyl acetate = 2:1) to obtain the target product tert-butyl ((1R, 3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (56-a, 185 mg, yield 79.02%). ESI [M+H] + =469.8

[0810] Step 2: Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (56-b)

[0811] Tert-butyl ((1R, 3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (56-a, 185 mg, 0.39 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (3 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure, added with water (1 ml), adjusted the pH to 8 with NaHCO3, extracted with (dichloromethane: methanol = 10:1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product ((1R, 3R)-3-aminocyclobutyl)(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (56-b, 135 mg, yield 92.75%). ESI [M+H] + =369.4

[0812] Step 3: Preparation of 6-(((1R,3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (56)

[0813] (1R, 3R)-3-aminocyclobutyl)(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (56-b, 80 mg, 0.22 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 67 mg, 0.26 mmol) was added. The reaction was stirred at room temperature for 1 hour and purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 10: 1), and then purified by preparative liquid phase [Pack Column 30 ID * 250 mm * 10 μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 25min] purification to obtain the target product 6-(((1R,3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (56, 1.48 mg, yield 1.25%), ESI [M+H] + =545.2 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.03(s,1H),7.50(s,1H),4.09(s,2H),3.75(s,1H),3.66(s,2H),3.48( s,2H),3.44(s,1H),2.42(d,J=45.4Hz,4H),2.02–1.96(m,4H),1.07(d,J=7.6Hz,2H),0.86(d,J=5.8Hz,3H).

[0814] Example 57: Preparation of 6-(3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (57)

[0815]

[0816] Step 1: Preparation of tert-butyl 3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (57-a)

[0817] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (97 mg, 0.48 mmol) was dissolved in dichloromethane (8 ml), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (184 mg, 0.48 mmol) was added and stirred for 10 minutes, and N,N-diisopropylethylamine (254 μl, 1.45 mmol) and 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-24, 310 mg, 1.01 mmol) were added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and flashed (silica gel column 10 g, petroleum ether: ethyl acetate = 2:1) to obtain the target product tert-butyl 3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (57-a, 205 mg, yield 95.21%). ESI [M+H] + =445.0

[0818] Step 2: Preparation of azetidin-3-yl(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (57-b)

[0819] Tert-butyl 3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (57-a, 205 mg, 0.46 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (3 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure, added water (1 ml), adjusted the pH to 8 with NaHCO3, extracted with (dichloromethane: methanol = 10:1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product azetidine-3-yl (4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (57-b, 150 mg, yield 94.34%). ESI [M+H] + =345.2

[0820] Step 3: Preparation of 6-(3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (57)

[0821] Azetidine-3-yl (4- (4-methoxy-5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl)methanone (57-b, 78 mg, 0.21 mmol) was dissolved in dichloromethane (2 ml), and 6- (bromomethyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (I-6-c, 63 mg, 0.25 mmol) was added. The reaction was stirred at room temperature overnight and then purified by thin layer chromatography on silica gel plates (dichloromethane: methanol = 10: 1), and then purified by preparative liquid phase [Pack Column 30 ID * 250 mm * 10 μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 25min] purification to give 6-(3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (57, 2.76 mg, yield 2.59%), ESI [M+H] + =521.0 1 H NMR(400MHz,DMSO-d6)δ13.96(s,1H),8.18(s,1H),7.99(s,1H),6.46(s,1H),4.51–4.15( m,6H),3.99(s,1H),3.92(s,3H),3.89–3.79(m,1H),3.71(d,J=47.4Hz,5H),3.60(s,2H).

[0822] Example 58: Preparation of 6-(2-(((1R,3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)-4-(trifluoromethane)pyridazin-3(2H)-one (58)

[0823]

[0824] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (58-a)

[0825] Dissolve (1R, 3R)-3-(tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (100 mg, 0.32 mmol) in dichloromethane (6 ml), add O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123 mg, 0.32 mmol) and stir for 10 minutes, then add N,N-diisopropylethylamine (169 μl, 0.97 mmol), 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20, 100 mg, 0.32 mmol), and the reaction is stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and flash (silica gel column 10 g, petroleum ether: ethyl acetate = 1:1) to obtain the target product tert-butyl ((1R, 3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (58-a, 160 mg, yield 91.43%). ESI [M+H] + =473.0

[0826] Step 2: Preparation of (1R, 3R)-3-aminocyclobutyl)(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (58-b)

[0827] Tert-butyl ((1R, 3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (58-a, 160 mg, 0.34 mmol) was dissolved in 4M hydrochloric acid ethyl acetate (3 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure, added with water (1 ml), adjusted the pH to 8 with NaHCO3, extracted with (dichloromethane: methanol = 10:1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (1R, 3R)-3-aminocyclobutyl) (4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (58-b, 120 mg, yield 95.24%). ESI [M+H] + =373.2

[0828] Step 3: Preparation of 6-(2-(((1R,3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)-4-(trifluoromethane)pyridazin-3(2H)-one (58)

[0829] (1R, 3R)-3-aminocyclobutyl)(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (58-b, 10 mg, 27.36 μmol) was dissolved in dichloromethane (3 ml), and 6-(2-bromopropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 100 mg, purity 6%, 21.05 umol) was added. After reacting at room temperature for 1.5 hours, the reaction solution was distilled under reduced pressure and the crude product was purified by TLC preparation plate (dichloromethane: methanol = 10:1), and then purified by HPLC [Pack Column 30ID*250mm*10μm; A: H2O (0.1% FA), B: ACN, B%: 10%-100% over 45min] to obtain the target product 6-(2-(((1R, 3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)-4-(trifluoromethane)pyridazin-3(2H)-one (58, 1.47 mg, yield 12.11%). ESI [M+H] + =577.4 1 HNMR(600MHz, DMSO-d6)δ8.29(s,1H),8.11(s,1H),7.40(d,J=1.5Hz,1H),4.12(q,J=6.9Hz,2H),3.55–3.52(m,2H),3.48–3.43(m,6H),3 .06(t,J=9.5Hz,1H),2.99(dt,J=15.9,8.1Hz,2H),2.20–2.14(m,2H),1.89(dd,J=20.0,9.6Hz,2H),1.36(t,J=6.9Hz,3H),1.27(s,6H).

[0830] Example 59: Preparation of 6-(2-(((1R,3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)-4-(trifluoromethane)pyridazin-3(2H)-one (59)

[0831]

[0832] ((1R,3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (45-c, 10 mg, 27.9 μmol), 6-(2-bromopropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 30 mg, 0.103 mmol) were dissolved in dichloromethane (1 ml) and the reaction was stirred at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative liquid phase [Pack Column 30 ID*250 mm*10 μm; A: H2O (0.1% TFA), B: ACN, B%: 10%-80% over 40 min] and lyophilized to obtain 6-(2-(((1R, 3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)propan-2-yl)-4-(trifluoromethane)pyridazin-3(2H)-one (59, 2.29 mg, yield 14.59%), ESI [M+H] + =563.7 1 HNMR(600MHz,DMSO-d6)δ8.12(s,2H),7.45(s,1H),3.88(s,3H),3.79(s,2H),3 .57(s,3H),3.46(d,J=2.8Hz,6H),2.43(dd,J=27.5,19.4Hz,4H),1.59(s,6H).

[0833] Example 60: Preparation of 2-(4-((1R,3R)-3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)propan-2-yl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinamide (60)

[0834]

[0835] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(3-carbamoyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (60-a)

[0836] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (69.4 mg, 0.323 mmol) was dissolved in N,N-dimethylformamide (5 ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123 mg, 0.323 mmol) and N,N-diisopropylethylamine (170 μl, 0.968 mmol) were added, and the mixture was stirred for 20 minutes under ice bath, and 2-(piperazine-1-yl)-5-( After reacting for 4 hours at room temperature, water (20 ml) was added dropwise to the reaction solution to precipitate a white solid, which was filtered and washed with water. The filter cake was collected and concentrated under reduced pressure to obtain the target product, tert-butyl ((1R, 3R)-3-(4-(3-carbamoyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (60-a, 120 mg, yield 78.8%). ESI [M+H] + =472.2

[0837] Step 2: Preparation of 2-(4-((1R, 3R)-3-aminocyclobutane-1-carbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinamide (60-b)

[0838] Dissolve ((1R, 3R)-3-(4-(3-aminoformyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (60-a, 120 mg, 0.255 mmol) in ethyl acetate (2 ml), add 4M hydrochloric acid ethyl acetate solution (3 ml), react at room temperature for 3 hours, and then concentrate under reduced pressure. Add water (1 ml), adjust the pH to 8 with NaHCO3, extract with dichloromethane:methanol=8:1, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 2-(4-((1R, 3R)-3-aminocyclobutane-1-carbonyl)piperazine-1-yl)-5-(trifluoromethyl)nicotinamide (60-b, 40 mg, yield 43%). ESI[M+H] + =372.1

[0839] Step 3: Preparation of 2-(4-((1R,3R)-3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)propan-2-yl)amino)cyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinamide (60)

[0840] 6-(2-bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 10 mg, 0.0352 mmol) was dissolved in dichloromethane (2 ml), and 2-(4-((1R, 3R)-3-aminocyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinamide (60-b, 24 mg, 0.0634 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the crude product was purified by a normal phase column (dichloromethane: meth...

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof, In formula (I), Ring A is selected from T is selected from CH or N; R x Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, -NO2, -NH2, the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; p is selected from 0, 1 or 2; Ring A is selected from Y1 is selected from -C(R6)(R7)-, m is selected from 1, 2 or 3, q ​​is 1, n is 1, wherein, R6 and R7 are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, or R6, R7 and the carbon atom to which they are commonly attached form a 3-6 membered cycloalkyl; Or ring A is selected from Y1 is selected from -N(R6)-C 1-3 Alkyl-, m is 1, q is 1, n is 1, wherein R6 is selected from hydrogen or deuterium, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3; Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, a 3-10-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom, or a 7-10-membered nitrogen-containing spirocycloalkyl group containing at least one nitrogen atom, wherein R a Selected from hydrogen, deuterium or C 1-3 Alkyl, the -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, 3-10-membered nitrogen-containing heterocycloalkyl containing at least one nitrogen atom, 7-10-membered nitrogen-containing spirocycloalkyl containing at least one nitrogen atom, C 1-3 The alkyl group is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; Ring B does not exist, the group Or ring B is a 5-8 membered saturated or unsaturated heterocyclic ring, and the ring B is optionally substituted with one or more halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy substituted, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; W is selected from C, N, O or S; U1, U2, U3, U4 are each independently selected from CH, CH2, N or NH; The halogen is selected from fluorine, chlorine and bromine; R1, R 1a , R2, R 2a , R3, R 3a , R4, R 4a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, cyano, carboxyl, C 1-3 or any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3, or R1, R 1a Together they form an oxo group, or R2, R 2a Together they form an oxo group, or R3, R 3a Together they form an oxo group, or R4, R 4a Together they form an oxo group; n1 R5 are the same or different from each other, n1 is selected from 0, 1, 2 or 3, R5 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 An amide group, an aminoacyl group, a 4-6-membered cyclic aminoacyl group, a 4-6-membered saturated or unsaturated heterocyclic group, a sulfonamide group, a 4-6-membered heterocyclic amino group, or two R5 substituents on the carbon atom adjacent to the ring C and the carbon atom to which they are attached form a 4-6-membered saturated or unsaturated heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Amide, aminoacyl, 4-6 membered cyclic aminoacyl, 4-6 membered saturated or unsaturated heterocyclic group, sulfonamide, 4-6 membered heterocyclic amino group are optionally substituted with one or more halogen, hydroxyl, C 2-6 Ester substitution.

2. A compound represented by formula (I'), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, In formula (I'), Ring A is selected from T is selected from CH or N; R x Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -NO2, -NH2; p is selected from 0, 1 or 2; Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, a 3-10-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom, or a 7-10-membered nitrogen-containing spirocycloalkyl group containing at least one nitrogen atom, wherein R a is selected from hydrogen or deuterium; U1, U2, U3 are each independently selected from CH, CH2, N or NH; the halogen is selected from fluorine, chlorine, bromine; R1, R 1a , R2, R 2a , R3, R 3a , R4, R 4a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, cyano, carboxyl, C 1-3 or any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -,in, n2 is selected from 1, 2 or 3, or R1, R 1a Together they form an oxo group, or R2, R 2a Together they form an oxo group, or R3, R 3a Together they form an oxo group, or R4, R 4a Together they form an oxo group; n1 R5 are the same or different from each other, n1 is selected from 0, 1, 2 or 3, R5 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 The alkynyl group is optionally substituted with one or more halogen, hydroxyl, C 2-6 Ester group, C 1-3 Amide and sulfonamide substitution; The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 3-10 membered nitrogen-containing heterocycloalkyl containing at least one nitrogen atom, 7-10 membered nitrogen-containing spirocycloalkyl containing at least one nitrogen atom, C 2-6 Ester group, C 1-3 The amide group is optionally substituted with one or more hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; When ring A is selected from When Y1 is selected from -C(R6)(R7)-, m is selected from 0, 1, 2 or 3, q ​​is selected from 0 or 1, n is selected from 0 or 1, and m, n, q are not 0 at the same time, wherein R6 and R7 are each independently selected from hydrogen or deuterium; When ring A is selected from When Y1 is selected from -N(R6)-C 1-3 Alkyl-, m is 1, q is 1, n is 1, wherein R6 is selected from hydrogen or deuterium, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1, 2 or 3.

3. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein: Selected from Selected from Ring B exists, Selected from W is selected from C or O.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein: Ring A is selected from R x Selected from hydrogen, deuterium, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-6 haloalkyl, the C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; p is selected from 1 or 2; Ring A is selected from Y1 is selected from -C(R6)(R7)-, m is 1, q is 1, n is 1, wherein R6 and R7 are each independently selected from hydrogen, deuterium, methyl, or R6, R7 and the carbon atom to which they are commonly attached form a 3-6 membered cycloalkyl group; Or ring A is selected from Y1 is selected from -N(R6)-C 1-3 Alkyl-, m is 1, q is 1, n is 1, wherein R6 is selected from hydrogen or deuterium, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1 and 2; Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, a 3-10-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom, or a 7-10-membered nitrogen-containing spirocycloalkyl group containing at least one nitrogen atom, wherein R a Selected from hydrogen, deuterium or C 1-3 Alkyl, the -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, 3-10-membered nitrogen-containing heterocycloalkyl containing at least one nitrogen atom, 7-10-membered nitrogen-containing spirocycloalkyl containing at least one nitrogen atom, C 1-3 The alkyl group is optionally substituted with one or more of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; U1, U2, U3, U4 are each independently selected from CH, CH2, N or NH; The halogen is selected from fluorine and chlorine; R1, R 1a , R2, R 2a , R3, R 3a , R4, R 4a are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, or any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1 or 2; n1 R5 are the same or different from each other, n1 is selected from 0, 1, 2 or 3, R5 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-3 An amide group, an aminoacyl group, a 4-6-membered cyclic aminoacyl group, a 4-6-membered saturated or unsaturated heterocyclic group, a sulfonamide group, a 4-6-membered heterocyclic amino group, or two R5 substituents on the carbon atom adjacent to the ring C and the carbon atom to which they are attached form a 4-6-membered saturated or unsaturated heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-3 The amide group, aminoacyl group, 4-6-membered cyclic aminoacyl group, 4-6-membered saturated or unsaturated heterocyclic group, sulfonamide group, 4-6-membered heterocyclic amino group are optionally substituted with one or more halogens or hydroxyl groups.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein: Ring A is selected from Y1 is selected from -CH2-, -CH(CH3)-, -C(CH3)2- or Or ring A is selected from Y1 is selected from -NH-CH(CH3)CH2-, and any two of R1, R2, R3, and R4 are connected to each other to form -(CH2) n2 -, wherein n2 is selected from 1 or 2; Y2 is selected from Ring B does not exist, the group Selected from or Ring B is a 5-8 membered saturated or unsaturated heterocyclic ring, the group Selected from 6. A compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which has a compound represented by formula (II), formula (III), formula (IV) or formula (V): in, R x ,p,Y1,Y2,n1,R1,R 1a , R2, R 2a , R3, R 3a , R4, R 4a , R5, W, and Ring B are as defined in claims 1-5.

7. The following compounds, their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, and at least one pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition according to claim 8 in the preparation of a PARP7 inhibitor or in the treatment of a disease mediated by PARP7; Preferably, the PARP7-mediated diseases include cancer, immune diseases, inflammation and viral infection; Preferably, the cancer includes PARP7-amplified solid tumors, small cell lung cancer, squamous cell lung cancer, and advanced non-small cell squamous cell lung cancer; Preferably, the PARP7-amplified solid tumors include esophageal cancer and head and neck cancer.

10. A method of inhibiting PARP7 in a patient in need thereof, comprising administering to the patient a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to claim 8.

11. A method for inhibiting PARP7 in a biological sample, comprising contacting the biological sample with the compound of any one of claims 1 to 7, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition of claim 8.

12. A method for treating a disorder mediated by PARP7 in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1 to 7, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of claim 8; Preferably, the PARP7-mediated disorders include cancer, immune diseases, inflammation and viral infection; Preferably, the cancer includes PARP7-amplified solid tumors, small cell lung cancer, squamous cell lung cancer, and advanced non-small cell squamous cell lung cancer; Preferably, the PARP7-amplified solid tumors include esophageal cancer and head and neck cancer.

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