PARP7 inhibitor and use thereof

Abstract

The present invention relates to compounds shown as formula (I) having a PARP7 inhibitory effect, pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, the use thereof, and a preparation method therefor.

Description

PARP7 inhibitors and their applications

[0001] This application claims priority to Chinese patent application No. 202311125694.7, filed on September 1, 2023, and Chinese patent application No. 202311423018.8, filed on October 30, 2023. 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 comprised of 17 distinct members in the human body, each playing a crucial role in diverse biological processes, including inflammation, viral infection, and tumor cell stress. The PARP family can be divided into three categories based on catalytic activity: polyPARPs (four members, including PARP1, PARP2, PARP5a, and PARP5b), which poly-ADP-ribosylate their target proteins; monoPARPs (12 members, including PARP3, PARP4, PARP6, PARP7, PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15, and PARP16), which mono-ADP-ribosylate their target proteins; and catalytically inactive PARPs (one member, PARP13). Most research on PARPs has focused on polyPARPs (PARP1, 2, 5a, and 5b), with PARP1 / 2 being particularly well-researched for their roles in DNA damage repair. DNA damage refers to the phenomenon that the DNA nucleotide sequence is permanently altered during DNA replication, leading to changes in genetic characteristics. If DNA damage or abnormal changes in genetic information cannot be corrected, it will affect the function or survival of the cell. 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, participating in a series of important cellular processes including DNA repair and maintenance of genomic stability. There are four PARP inhibitors available: 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] Relatively little research has been conducted on monoPARPs, which are single ADP-ribosylation target proteins. As mentioned above, most members of the PARP family (12) are monoPARPs. Recent studies on monoPARPs have revealed that PARP7 plays an important role in immunity and cancer. Studies have suggested that PARP7 is a target gene of the AHR and is part of a negative feedback loop that regulates AHR activity. The AHR regulates immune function, inflammation, and plays a role in cancer. It can be induced by cancer-related stressors, such as harmful chemicals in tobacco. In-depth studies of lung, esophageal, and head and neck cancers, which are strongly associated with smoking, have revealed amplification and high expression of the PARP7 gene locus. Studies have shown that PARP7 is overactive in tumor cells, and many cancer cells rely on PARP7 for cell survival. Studies have also shown that PARP7 can enable cancer cells to evade immune attack. Inhibiting PARP7 can effectively inhibit cancer cell growth, restore interferon signaling, and reverse immunosuppression. In several cancer models, PARP7 inhibitors have demonstrated sustained tumor growth inhibition and restoration of interferon signaling. In summary, PARP7 plays a crucial role in cancer and immune responses, making it a promising potential cancer target. Due to the lack of PARP7-selective chemical probes, previous studies have primarily relied on genetic approaches to elucidate PARP7 function, failing to distinguish between enzymatic activity and the entire protein, or their interrelationships. Furthermore, the lack of mature high-throughput on-target activity screening assays has hindered the development of drugs targeting PARP7. In light of the increasing number of PARP7-related research results reported in recent years, PARP7 has become a promising anticancer target. Currently, no PARP7 inhibitors have been approved for marketing. RBN-2397, developed by Ribon, is the first compound with potent and selective PARP7 inhibitory activity. Therefore, further research and development of new, safe, and effective PARP7 inhibitors is of great importance. Furthermore, as mentioned above, in addition to its crucial role in tumorigenesis, PARP7 also plays a key role in diseases such as inflammation and viral infection. Therefore, in addition to its anticancer potential, PARP7 inhibitors are expected to have potential applications in other diseases, including inflammation, immunity, and viral infection.

[0005] Summary of the Invention

[0006] 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.

[0007] 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,

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

[0016] Ring B does not exist, group for

[0017] Or ring B is a 5-8 membered saturated or unsaturated heterocyclic ring, said 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 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 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, 2 or 3, or R1, R 1a Together to form oxo, or R2, R 2a Together to form oxo, or R3, R 3a Together to form oxo, 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 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Amino, aminoacyl, 4-6 membered cyclic aminoacyl, 4-6 membered saturated or unsaturated heterocyclic group, sulfonamide, 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 Halogenated alkyl, 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] In formula (I'),

[0025] Ring A is selected from

[0026] T is selected from CH or N;

[0027] 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;

[0028] p is selected from 0, 1 or 2;

[0029] Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, 3-10 membered nitrogen-containing heterocyclic alkyl containing at least one nitrogen atom, or 7-10 membered nitrogen-containing spirocyclic alkyl containing at least one nitrogen atom, wherein R a selected from hydrogen or deuterium;

[0030] U1, U2, U3 are each independently selected from CH, CH2, N or NH; the halogen is selected from fluorine, chlorine, bromine;

[0031] 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 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, 2 or 3, or R1, R 1a Together to form oxo, or R2, R 2a Together to form oxo, or R3, R 3a Together to form oxo, or R4, R 4a Together they form an oxo group;

[0032] 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 Alkynyl is optionally substituted with one or more halogen, hydroxy, C 2-6 Ester group, C 1-3 Amide and sulfonamide substitution;

[0033] The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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;

[0034] 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;

[0035] 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.

[0036] In some embodiments, Selected from

[0037] Preferably, Selected from

[0038] Preferably, Ring B is present, Selected from

[0039] Preferably, W is selected from C or O.

[0040] In some embodiments, Ring A is selected from

[0041] Preferably, R x Selected from hydrogen, deuterium, C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-6 Halogenated alkyl, 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 hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0042] Preferably, p is selected from 1 or 2;

[0043] Preferably, ring A is selected from Y1 is selected from -C(R6)(R7)-, m is selected from 1, q is selected from 1, and n is selected from 1, wherein R6 and R7 are each independently selected from hydrogen, deuterium, or methyl, or R6, R7 and the carbon atom to which they are attached form a 3-6 membered cycloalkyl group;

[0044] 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;

[0045] Preferably, Y2 is selected from -N(R a )-C 3-7 Cycloalkyl-, -N(R a )-C 6-10 Aryl-, 3-10 membered nitrogen-containing heterocyclic alkyl containing at least one nitrogen atom, or 7-10 membered nitrogen-containing spirocyclic alkyl 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 heterocyclic alkyl containing at least one nitrogen atom, 7-10 membered nitrogen-containing spirocyclic alkyl containing at least one nitrogen atom, C 1-3 The alkyl group is optionally substituted with one or more hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;

[0046] Preferably, U1, U2, U3, U4 are each independently selected from CH, CH2, N or NH;

[0047] Preferably, the halogen is selected from fluorine and chlorine;

[0048] 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;

[0049] Preferably, 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 1-3Amino, aminoacyl, 4-6 membered cyclic aminoacyl, 4-6 membered saturated or unsaturated heterocyclic group, sulfonamide, 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 Halogenated alkyl, 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.

[0050] In some embodiments, Ring A is selected from Y1 is selected from -CH2-, -CH(CH3)-, -C(CH3)2- or

[0051] 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;

[0052] Preferably, Y2 is selected from

[0053] Preferably, ring B is absent and the group Selected from

[0054] Or ring B is a 5-8 membered saturated or unsaturated heterocyclic ring, the group Selected from

[0055] 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):

[0056] Among them, 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 above.

[0057] 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:

[0058] 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.

[0059] Another aspect of the present invention provides a use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or pharmaceutical composition as described above in the preparation of a PARP7 inhibitor or in the treatment of a disease mediated by PARP7;

[0060] Preferably, the PARP7-mediated diseases include cancer, immune diseases, inflammation and viral infection;

[0061] 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;

[0062] Preferably, the PARP7-amplified solid tumors include esophageal cancer and head and neck cancer.

[0063] 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.

[0064] Another aspect of the present invention provides a method for inhibiting PARP7 in a biological sample, comprising contacting the biological sample with the aforementioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition as described above.

[0065] 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;

[0066] Preferably, the PARP7-mediated diseases include cancer, immune diseases, inflammation and viral infection;

[0067] 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;

[0068] Preferably, the PARP7-amplified solid tumors include esophageal cancer and head and neck cancer;

[0069] Preferably, the amount of the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or pharmaceutical composition administered is an effective amount. DETAILED DESCRIPTION

[0070] According to the contents of the present disclosure, in accordance with common technical knowledge and customary means in the field, without departing from the basic technical ideas described in the present disclosure, other various forms of modifications, replacements or changes can be made.

[0071] I. Definition

[0072] 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 forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0073] The compounds of the present disclosure also include tautomeric forms.Tautomeric forms arise from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0074] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. The numerical ranges herein refer to each integer 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.

[0075] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom or group by a substituent, as long as the valence of the particular atom or group is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be any on the basis of chemical practicability.

[0076] 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, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0077] 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 containing 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, with methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred in the present disclosure.

[0078] 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, for example, ethenyl, 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0079] The term "alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0080] The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, wherein the cycloalkyl ring contains at least 3 carbon atoms, preferably contains 3 to 12 carbon atoms, and more preferably contains 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0081] The term "heterocycloalkyl" refers to a saturated monocyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Non-limiting examples of heterocycloalkyl include pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and the like, preferably pyrrolidinyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazacycloheptyl and piperazinyl.

[0082] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0083] The term "heterocycle" or "heterocyclyl" refers to a saturated or unsaturated heterocyclic group in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.

[0084] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings 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- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0085] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0086] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. 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 following groups 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.

[0087] The term "spiroalkyl" refers to an alicyclic hydrocarbon in which two carbon rings share a common carbon atom. The shared carbon atom is called the "spiro carbon atom."

[0088] The term "amide group" refers to a group in which the hydroxyl group of the carboxyl group in a carboxylic acid molecule is substituted by an amino group or a hydrocarbon amino group [-NHR or -N(R)R].

[0089] The term "aminoacyl" refers to the group remaining after the hydroxyl group is removed from the amino acid molecule.

[0090] 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.

[0091] The term "sulfonylamino group" refers to a group in which the hydrogen atom of sulfonylamide is substituted, and the remaining group is generally referred to as a sulfonylamino group.

[0092] 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.

[0093] 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 "carboxyl" refers to -C(O)OH.

[0094] The hydrogen atoms described in this disclosure may be replaced by their isotope deuterium. In this disclosure, "----" refers to a bond or group that may or may not be present.

[0095] NMP: refers to N-methylpyrrolidone;

[0096] EA: refers to ethyl acetate;

[0097] dioxane: refers to dioxane;

[0098] SEMCl: refers to 2-(trimethylsilyl)ethoxymethyl chloride;

[0099] DMF: refers to N,N-dimethylformamide;

[0100] NH2NH2.H2O: refers to hydrated hydrazine;

[0101] NBS: refers to N-bromosuccinimide;

[0102] BPO: refers to dibenzoyl peroxide;

[0103] ACN: refers to acetonitrile;

[0104] n-BuLi: refers to n-butyllithium;

[0105] THF: refers to tetrahydrofuran;

[0106] TEA: refers to triethylamine;

[0107] t-BuOK: refers to potassium tert-butoxide;

[0108] H-Pro-OH: refers to L-proline;

[0109] AlBN: refers to azobisisobutyronitrile;

[0110] AcOH: refers to acetic acid;

[0111] EtOH: refers to ethanol;

[0112] Bn: refers to benzyl;

[0113] Pd(dppf)Cl2: refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0114] MeOH: refers to methanol;

[0115] Boc: refers to tert-butoxycarbonyl;

[0116] Refers to 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane;

[0117] Refers to cyclopropylboronic acid;

[0118] DIPEA or DIEA: refers to N,N-diisopropylethylamine;

[0119] HATU: refers to O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0120] DCM: refers to dichloromethane;

[0121] TFA: refers to trifluoroacetic acid;

[0122] Refers to trimethyl orthoformate;

[0123] NaBH3CN: refers to sodium cyanoborohydride;

[0124] DETA: refers to diethylenetriamine;

[0125] BF3Et2O: refers to boron trifluoride etherate;

[0126] Cs2CO3: refers to cesium carbonate;

[0127] NaOAc: refers to sodium acetate;

[0128] MeOH: refers to methanol;

[0129] PyBOP: refers to 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate.

[0130] Drug or pharmaceutical composition

[0131] 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.

[0132] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects, such as acid addition salts (including organic acids and inorganic acids) or base addition salts (including organic bases and inorganic bases).

[0133] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0134] 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. The oral route is generally desirable. The active agent can be administered orally in the form of capsules, tablets, and the like (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0135] 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, polyvinylpyrrolidone 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 (e.g., 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 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.

[0136] Tablets comprising the active compound can be coated by methods well known in the art. The compositions of the present disclosure comprising the compound of formula I as the active compound can also be introduced into beads, microspheres or microcapsules, for example, 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.

[0137] 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, through rapid 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 form of an excipient, a suspension, a solution or an 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.

[0138] The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter or other glycerides).

[0139] 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.

[0140] The terms "reduce," "inhibit," "alleviate," 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.

[0141] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, suppress 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 the variables on which the subject depends (e.g., age, immune system health, etc.), the disease or illness, and the treatment being 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 the subject before or without administration of the 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.

[0142] The term "excipient" is used herein to include any other compound that may be included 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. "Excipient" includes a single such compound and is also intended to include a plurality of compounds.

[0143] The term "pharmaceutical composition" means a composition comprising a compound of 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.

[0144] Uses and treatments

[0145] 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.

[0146]

[00146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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 administering a compound of the present disclosure or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0151] As used herein, the term "mediated" disorder, disease, and / or condition as used herein refers to any disease or other deleterious condition in which PARP or a mutant thereof is known to play a role. Thus, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which PARP or a mutant thereof is known to play a role.

[0152] 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.

[0153] 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 or composition of the present disclosure to a mammal. In certain embodiments, the mammal is a human.

[0154] 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 the death of cancer cells, either individually or collectively with other cancer cells, by cytotoxicity, nutrient depletion or induction of apoptosis.

[0155] 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, testicle, 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.

[0156] 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).

[0157] 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, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer (particularly colon cancer or colorectal adenoma) or tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, 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, undifferentiated tumor, papillary carcinoma, seminoma, melanoma, MYD88 driven disorders, DLBCL, ABC DLBCL, IL-1 driven disorders and rheumatic or indolent multiple myeloma or leukemia.

[0158] Cancers described herein include, but are not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myelocytic 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 diseases, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcomas, myxosarcomas, liposarcomas, chondrosarcomas, osteogenic sarcomas, chordomas, angiosarcomas, endotheliosarcomas, lymphangiosarcomas, lymphoendotheliosarcomas, synoviomas, mesotheliomas, Ewing's tumors, and sarcomas). 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 cancer, 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.

[0159] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0160] In some 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.

[0161] 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, stomach 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, cancer of the endocrine system, 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 ureteral 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.

[0162] 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, epithelial ovarian 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 / 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.

[0163] 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.

[0164] The term "inflammatory disease" includes 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 particularly selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, berylliosis. The respiratory disorder may be selected from among 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.

[0165] 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.

[0166] Combination therapy

[0167] 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 administering these agents in a sequential manner, i.e., each therapeutic agent is administered at different times, and administering these therapeutic agents, or at least two agents, substantially simultaneously. The order of each agent, or substantially simultaneous administration, can be affected by any appropriate route, including but not limited to, oral route, intravenous route, intramuscular route, subcutaneous route, 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, while the second agent can be administered intravenously. In addition, the combination of agents selected can be administered by intravenous injection, while 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.

[0168] II. Examples

[0169] The present disclosure is further illustrated below with reference to the examples. The descriptions of specific exemplary embodiments of the present disclosure are for the purpose of illustration and description. These descriptions are not intended to limit the present disclosure to the precise form disclosed, and it is apparent that many changes and variations are possible based on the teachings of this disclosure. The exemplary embodiments are selected and described for the purpose of explaining the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to realize and utilize the various exemplary embodiments of the present disclosure and various options and variations.

[0170] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0171] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0172] Experimental instruments and methods:

[0173] Instruments and reagents:

[0174] NMR measurements were performed using an Agilent 400MR DD2 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard. LC-MS was performed using an Agilent 1260 Infinity II–InfinityLab LC / MSD mass spectrometer. HPLC was performed using an Agilent 1260 Infinity II high-pressure liquid chromatograph (Sunfire C18 5 μm, 150 x 4.6 mm 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 Co., Ltd., or synthesized using methods known in the art. Unless otherwise specified, all reactions of the present disclosure are carried out under continuous magnetic stirring, under dry nitrogen or argon, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0175] intermediates

[0176] Intermediate I-1: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1)

[0177] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-1-a)

[0178] Dissolve 2-chloro-5-(trifluoromethyl)pyrimidine (1825 mg, 10 mmol) in N-methylpyrrolidone (30 ml), add tert-butyl piperazine-1-carboxylate (1862 mg, 10 mmol) and potassium carbonate (2764 mg, 20 mmol), and react at 80°C for 1 hour. Add water (100 ml), collect the solid by filtration, and dry in vacuo to obtain the desired product, tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-1-a, 2.9 g, 87% yield).

[0179] Step 2: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1)

[0180] Dissolve tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-1-a, 332 mg, 1 mmol) in 4M hydrochloric acid and ethyl acetate (5 ml) and allow to react at room temperature for 2 hours. Filter the reaction mixture, and wash the solid with petroleum ether to obtain the desired product, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 289 mg, 94% yield). 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).

[0181] Intermediate I-2: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-2)

[0182] Step 1: Preparation of tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (I-2-a)

[0183] 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) and stir at 0°C for 30 minutes. The precipitated solid is collected by filtration, washed with water, and dried 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

[0184] Step 2: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-2)

[0185] 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 in dioxane (10 ml) and react at room temperature for 3 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to obtain the desired product, 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-2, 232 mg, 90.6% yield). ESI [M+H] + =259.2

[0186] Intermediate I-3: Preparation of (R)-2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-3)

[0187] Step 1: Preparation of tert-butyl (R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-3-a)

[0188] To a solution of (R)-tert-butyl 2-methylpiperazine-1-carboxylate (100 mg, 0.499 mmol) in N-methylpyrrolidone (10 ml) were added potassium carbonate (138 mg, 0.999 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (91 mg, 0.499 mmol) at room temperature, and the reaction mixture was stirred at 80°C overnight. The reaction was quenched by the addition of 20 mL of water and extracted with 3 × 10 mL of ethyl acetate. 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)-tert-butyl 2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-3-a, 110 mg, yield 63.61%). ESI [M+H] + =347.3

[0189] Step 2: Preparation of (R)-2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-3)

[0190] At room temperature, a 4M hydrochloric acid solution in dioxane (3 mL) was added to a solution of (R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-3-a, 110 mg, 0.318 mmol) in ethyl acetate (3 mL). 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

[0191] Intermediate I-4: Preparation of (S)-2-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4)

[0192] Step 1: Preparation of tert-butyl (S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-4-a)

[0193] Dissolve (S)-tert-butyl 3-methylpiperazine-1-carboxylate (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) and stir at 0°C for 30 minutes. The precipitated solid is collected by filtration, washed with water, and dried at 70°C to obtain the target product, (S)-tert-butyl 3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-4-a, 276 mg, yield 79.8%). ESI [M+H-56] + =291.0ESI[M+H-100]+ =247.1

[0194] Step 2: Preparation of (S)-2-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4)

[0195] Dissolve (S)-tert-butyl 3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (I-4-a, 276 mg, 0.797 mmol) in ethyl acetate (5 ml), add 4M hydrochloric acid in dioxane (5 ml), and react at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with ethyl acetate, and then evaporated under reduced pressure to obtain the desired product, (S)-2-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4, 220 mg, yield 97.8%). ESI [M+H] + =247.2

[0196] Intermediate I-5: Preparation of 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5)

[0197] Step 1: Preparation of 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-a)

[0198] Under ice-cooling, 4,5-dibromopyridin-3(2H)-one (20 g, 78.78 mmol) was dissolved in N,N-dimethylformamide (200 mL). 60% sodium hydride (4.0 g, 94.54 mmol) was slowly added. After stirring at room temperature for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (14.4 g, 86.66 mmol) was added dropwise under ice-cooling. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. Under ice-cooling, the reaction solution was quenched with water (200 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was washed with brine (100 mL*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

[0199] Step 2: Preparation of 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5-b)

[0200] 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) was added lithium chloride (1.93 g, 45.30 mmol), and the resulting solution was stirred at 95 ° C for 4 hours. Then 250 mL of water was added to the reaction, and the mixture was extracted with 3×250 mL of ethyl acetate, 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 product of 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

[0201] Step 3: Preparation of 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-5)

[0202] 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. The reaction was quenched by addition of 250 mL of water 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 give 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

[0203] Intermediate I-6: Preparation of 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (I-6)

[0204] Step 1: Preparation of methyl 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (I-6-a)

[0205] Methyl 3,3,3-trifluoro-2-oxopropanoate (10 g, 64.08 mmol) was dissolved in acetone (5.2 ml) and stirred at 100°C in a sealed tube for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the target product, methyl 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (I-6-a, 12.84 g, yield 93.65%). ESI [M+H] + =215.05

[0206] Step 2: Preparation of 6-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-b)

[0207] Dissolve methyl 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (I-6-a, 12.13 g, 56.68 mmol) in acetic acid (35 ml). Add hydrazine hydrate (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)pyridazin-3(2H)-one (I-6-b, 6.55 g, yield 64.88%). ESI [M+H] + =179.04

[0208] Step 3: Preparation of 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c)

[0209] Dissolve 6-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-b, 6.55 g, 36.8 mmol) in carbon tetrachloride (190 ml). Add N-bromosuccinimide (9.82 g, 55.17 mmol) and dibenzoyl peroxide (1.78 g, 7.35 mmol) sequentially. Allow to react at 80°C overnight. Add saturated brine and extract with ethyl acetate. The organic phase is concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 91:9) to obtain the desired product, 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 4.7 g, 49.91% yield). ESI [M+H] + =256.95

[0210] Step 4: Preparation of 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carboxaldehyde (I-6)

[0211] 6-(Bromomethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-6-c, 500 mg, 1.95 mmol) was dissolved in acetonitrile (5 ml), and N-methylmorpholine-N-oxide (803 mg, 6.84 mmol) and potassium iodide (32.4 mg, 0.195 mmol) were added under ice-cooling. After reacting at room temperature for 2 hours, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain the target product 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carbaldehyde (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).

[0212] Intermediate I-7: Preparation of 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7)

[0213] 5-Bromo-3-(trifluoromethyl)pyridin-2(1H)-one (2 g, 0.826 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml) and stirred at -80°C under nitrogen for 20 minutes. After that, n-butyllithium (9.9 ml, 2.479 mmol) was slowly added dropwise and the reaction continued at -80°C for 3 hours. N,N-dimethylformamide (1.53 ml, 19.824 mmol) was added dropwise again and the reaction continued for 1 hour. Saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate and then dichloromethane. The organic phase was concentrated under reduced pressure. The aqueous phases were filtered and combined under reduced pressure. The crude product was purified by column chromatography (petroleum ether to ethyl acetate: 0-70%) to obtain the desired product, 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 1.01 g, yield 63.96%). ESI [M+H] + =192.1

[0214] Intermediate I-8: Preparation of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8)

[0215] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-8-a)

[0216] 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, filter, collect the solid, and dry in vacuo to obtain the desired product, tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-8-a, 520 mg, 58.46% yield).

[0217] Step 2: Preparation of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8)

[0218] Dissolve tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-8-a, 520 mg, 1.57 mmol) in 4M hydrochloric acid and ethyl acetate (6 ml) and allow to react at room temperature for 2 hours. Filter the reaction mixture, and wash the solid with petroleum ether to obtain the desired product, 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-8, 400 mg, yield 95.22%). ESI [M+H] + =232.0

[0219] Intermediate I-9: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]octane hydrochloride (I-9)

[0220] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate (I-9-a)

[0221] 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-cooling. After reacting at 80°C for 4 hours, add water (50 ml) under ice-cooling to the reaction solution. Filter and wash the filter cake with water. The filter cake is collected and concentrated under reduced pressure to obtain the target product, tert-butyl 4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate (I-9-a, 880 mg, yield 96.8%). ESI[M-56+H] + =277.2

[0222] Step 2: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine hydrochloride (I-9)

[0223] Dissolve tert-butyl 4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate (I-9-a, 880 mg, 2.61 mmol) in ethyl acetate (10 ml). Add 4M hydrochloric acid in ethyl acetate (10 ml) under ice-cooling. After reacting at room temperature for 2 hours, concentrate under reduced pressure to obtain the target 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine hydrochloride (I-9, 638 mg, yield 89.6%). ESI [M+H] + =233.2

[0224] 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)

[0225] Step 1: Preparation of tert-butyl (R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (I-10-a)

[0226] Dissolve (R)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (100 mg, 0.434 mmol) in N,N-dimethylformamide (3 ml), add 2,3-difluoro-5-(trifluoromethyl)pyridine (100 mg, 0.564 mmol) and triethylamine (270 μl, 1.95 mmol), and heat to 85°C to react overnight. Cool the reaction mixture, add water, and extract with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure and purified by flash column chromatography (ethyl acetate:petroleum ether = 0-27%) to obtain the desired product, tert-butyl (R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (I-10-a, 136 mg, yield 79.62%). ESI [M-100+H] + =294.3,ESI[M+H] + =394.3

[0227] Step 2: Preparation of tert-butyl (R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxaindene-9-carboxylate (I-10-b)

[0228] 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 evaporated under reduced pressure, then dissolved in ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (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]pyrido[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

[0229] 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)

[0230] To tert-butyl (R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxaindene-9-carboxylate (I-10-b, 102 mg, 0.273 mmol) was added 4M hydrochloric acid ethyl ethyl solution (3 ml) at room temperature. The reaction solution was stirred at room temperature for 1 hour, and then 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]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-10, 96 mg, yield 113.46%). ESI [M+H] + =274.3

[0231] 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)

[0232] Step 1: Preparation of tert-butyl (S)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (I-11-a)

[0233] (S)-tert-Butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (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), and triethylamine (540 μl, 3.91 mmol) was added. The mixture was reacted at 85°C overnight in a sealed tube, quenched with water (10 ml), 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 normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product, tert-butyl (S)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (I-11-a, 287 mg, yield 67.2%). ESI [M+H] + =394.4,ESI[M-56+H] + =338.2

[0234] Step 2: Preparation of tert-butyl (S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxaindene-9-carboxylate (I-11-b)

[0235] 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), and react in a sealed tube at 120°C for 2 hours. The mixture is filtered and the filtrate is concentrated 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). ESI[M-56+H] + =318.3

[0236] 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)

[0237] (S)-3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[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 mixture was concentrated under reduced pressure to obtain the target product (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, 280 mg, crude product). ESI[M+H] + =274.4

[0238] 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)

[0239] Step 1: Preparation of (R)-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-12-a)

[0240] Dissolve (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 4.62 mmol) in N,N-dimethylformamide (15 ml), add methyl 2-chloro-5-(trifluoromethyl)nicotinate (1.11 g, 4.62 mmol) and potassium carbonate (1.28 g, 9.25 mmol), and react at 80°C overnight. Add the reaction solution dropwise to water (150 ml). Solid precipitates and is filtered. The filter cake is concentrated under reduced pressure to obtain the target product, (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylate (I-12-a, 1.0 g, yield 55.9%). ESI[M-56+H] + =332.4

[0241] Step 2: Preparation of (R)-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-12-b)

[0242] 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, 2.07 mmol), reacted at 50 ° C under nitrogen protection for 4 hours, and 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]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylic acid tert-butyl ester (I-12-b, 110 mg, yield 11.4%). ESI [M+H] + =374.4,ESI[M-56+H] + =318.4

[0243] 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)

[0244] Dissolve (R)-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-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]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-12, 110 mg, crude product). ESI[M+H] + =274.4

[0245] 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)

[0246] Step 1: Synthesis of tert-butyl (S)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylate (I-13-a)

[0247] (S)-tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate (500 mg, 2.31 mmol) and methyl 2-chloro-5-(trifluoromethyl)nicotinate (554 mg, 2.31 mmol) were dissolved in N,N-dimethylformamide (10 ml). Potassium carbonate (639 mg, 4.62 mmol) was added and the mixture was heated to 80°C and allowed to react overnight. After completion of the reaction, the reaction solution was filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure and purified on a 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]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylate (tert-butyl ester, I-13-a, 800 mg, yield 62%). ESI [M+H] + =332.2

[0248] Step 2: Preparation of tert-butyl (S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9(7H)-carboxylate (I-13-b)

[0249] 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, The reaction mixture was concentrated under reduced pressure and purified by normal phase column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (S)-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-b, 100 mg, yield 14.2%). ESI [M+H] + =374.4,ESI[M-56+H] + =318.4

[0250] 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)

[0251] Dissolve (S)-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-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]pyrido[2,3-e][1,4]oxazepine hydrochloride (I-13, 110 mg, crude product). ESI[M+H] + =274.4

[0252] Intermediate I-14: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile hydrochloride (I-14)

[0253] Step 1: tert-Butyl 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-14-a)

[0254] 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 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, 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

[0255] Step 2: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile hydrochloride (I-14)

[0256] 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-(piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile hydrochloride (I-14, 310 mg, crude product). ESI [M+H] + =257.2

[0257] Intermediate I-15: Preparation of 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15)

[0258] Step 1: Preparation of tert-butyl 4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-15-a)

[0259] 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) were dissolved in N-methylpyrrolidone (4 ml), and potassium carbonate (153 mg, 1.11 mmol) was added. The mixture was reacted in a sealed tube at 85°C for 4 hours. The reaction mixture was cooled and quenched with water. The mixture was 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 flash chromatography (10 g silica gel column, petroleum ether:ethyl acetate = 10:1) to obtain the desired product, tert-butyl 4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-15-a, 153 mg, yield 57.42%). ESI [M+H] + =362.6

[0260] Step 2: 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-15)

[0261] 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 a 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). ESI [M+H] + =262.5

[0262] Intermediate I-16: Preparation of 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16)

[0263] Step 1: Preparation of methyl 2-hydroxy-3-oxo-2-(trifluoromethyl)pentanoate (I-16-a)

[0264] 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%).

[0265] Step 2: Preparation of 6-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16-b)

[0266] Methyl 2-hydroxy-3-oxo-2-(trifluoromethyl)pentanoate (I-16-a, 7 g, 30.7 mmol) was dissolved in acetic acid (20 ml), hydrazine hydrate (3 ml, 256 mmol) was added, and the mixture was reacted at 110°C overnight. The reaction solution was concentrated under reduced pressure and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product 6-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16-b, 2.2 g, yield 37.3%). ESI [M+H] + =193.4

[0267] Step 3: Preparation of 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16)

[0268] 6-Ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16-b, 1 g, 5.21 mmol) was dissolved in carbon tetrachloride (10 ml), and N-bromosuccinimide (927 mg, 5.21 mmol) and azobisisobutyronitrile (85.5 mg, 0.521 mmol) were added. The mixture was reacted at 80°C overnight. The reaction solution was concentrated under reduced pressure and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product 6-(1-bromoethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-16, 1.1 g, yield 70.1%). ESI [M+H] + =298.3,300.3

[0269] Intermediate I-17: Preparation of 6-(2-bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17)

[0270] Step 1: Preparation of methyl 2-hydroxy-5-methyl-4-oxo-2-(trifluoromethyl)hexanoate (I-17-a)

[0271] Methyl 3,3,3-trifluoro-2-oxopropanoate (3 g, 0.019 mmol) and 3-methylbutan-2-one (6.6 g, 0.076 mmol) were dissolved in N,N-dimethylformamide (10 ml). L-proline (0.66 g, 0.0058 mmol) was added to the reaction mixture and stirred at room temperature for 3 minutes. The mixture was then allowed to react overnight at 40°C. After completion of the reaction, the mixture was cooled to room temperature, quenched with water, and 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, methyl 2-hydroxy-5-methyl-4-oxo-2-(trifluoromethyl)hexanoate (I-17-a, 3 g, crude).

[0272] Step 2: Preparation of 6-isopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17-b)

[0273] Methyl 2-hydroxy-5-methyl-4-oxo-2-(trifluoromethyl)hexanoate (I-17-a, 3 g, 0.012 mmol) was dissolved in ethanol (10 ml) and hydrated hydrazine (1.2 ml, 0.024 mmol) was added with stirring. The mixture was sealed and heated to 110°C overnight. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate. 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 = 3:1) to obtain the desired product, 6-isopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17-b, 250 mg, 9.8% yield). ESI [M+H] + =207.03

[0274] Step 3: Preparation of 6-(2-bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17)

[0275] 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 for overnight reaction. After completion of the reaction, cool to room temperature. The filtrate is concentrated under reduced pressure and purified on a flash column (petroleum ether:ethyl acetate = 3:1) to obtain the desired product, 6-(2-bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 70 mg, 25.4% yield). ESI [M+H] + =285.2,287.2 Intermediate I-18: Preparation of 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18)

[0276] Step 1: Preparation of 6-(benzyloxy)-3-chloro-4-(trifluoromethyl)pyridazine (I-18-a)

[0277] Benzyl alcohol (262 mg, 2.42 mmol) was dissolved in tetrahydrofuran (10 ml) and placed in an ice bath. Under nitrogen, 60% sodium hydride (138 mg, 3.46 mmol) was added and stirred for 15 minutes. 3,6-dichloro-4-(trifluoromethyl)pyridazine (500 mg, 2.3 mmol) was then added and the mixture was allowed to warm to room temperature for 4 hours. The reaction mixture was quenched with water and 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. The mixture was then purified on a flash column (ethyl acetate:petroleum ether = 0-10%) to afford the desired product, 6-(benzyloxy)-3-chloro-4-(trifluoromethyl)pyridazine (I-18-a, 597 mg, 89.75% yield).

[0278] Step 2: Preparation of 6-(benzyloxy)-3-methyl-4-(trifluoromethyl)pyridazine (I-18-b)

[0279] 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 then the temperature was raised to 110 ° C for 5 hours. After the reaction, water was added to quench the reaction, followed by extraction 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 on a 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

[0280] Step 3: Preparation of 6-methyl-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18-c)

[0281] 6-(Benzyloxy)-3-methyl-4-(trifluoromethyl)pyridazine (I-18-b, 300 mg, 1.12 mmol) was dissolved in methanol (5 ml) and purged with nitrogen. 5% palladium on carbon (20 mg) was added and the atmosphere was replaced with hydrogen three times. The reaction mixture was allowed to react under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the desired product, 6-methyl-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18-c, 195 mg, yield 97.99%). ESI [M+H] + =179.1

[0282] Step 4: Preparation of 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18)

[0283] Dissolve 6-methyl-5-(trifluoromethyl)pyridazin-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, cool to room temperature, concentrate the filtrate under reduced pressure, and purify on a flash column (ethyl acetate:petroleum ether = 0-36%) to obtain the desired product, 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18, 59 mg, 21% yield). ESI [M+H] + =256.8,258.8

[0284] Intermediate I-19: Preparation of 6-(bromomethyl)-5-cyclobutoxypyridazin-3(2H)-one (I-19)

[0285] Step 1: Preparation of 6-chloro-4-cyclobutoxy-3-methylpyridazine (I-19-a)

[0286] 4,6-Dichloro-3-methylpyridazine (500 mg, 3.07 mmol) was dissolved in tetrahydrofuran (15 ml), and potassium tert-butoxide (517 mg, 4.61 mmol) and cyclobutanol (265 μl, 3.37 mmol) were added. After reacting at room temperature for 2 hours, the mixture 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. The crude product was purified by normal phase column chromatography (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

[0287] Step 2: Preparation of 5-cyclobutoxy-6-methylpyridazin-3(2H)-one (I-19-b)

[0288] Dissolve 6-chloro-4-cyclobutoxy-3-methylpyridazine (I-19-a, 340 mg, 1.51 mmol) in acetic acid (8 ml), add water (2 ml) and potassium acetate (257.4 mg, 3.03 mmol), and react at 100°C for 5 hours. After concentration under reduced pressure, the crude product is purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product 5-cyclobutoxy-6-methylpyridazin-3(2H)-one (I-19-b, 257 mg, yield 83.2%). ESI [M+H] + =361.1

[0289] Step 3: Preparation of 6-(bromomethyl)-5-cyclobutoxypyridazin-3(2H)-one (I-19)

[0290] 5-Cyclobutoxy-6-methylpyridazin-3(2H)-one (I-19-b, 120 mg, 0.666 mmol) was dissolved in carbon tetrachloride (2 ml), N-bromosuccinimide (118.6 mg, 0.666 mmol), and benzoyl peroxide (16 mg, 0.067 mmol). The reaction was allowed to proceed overnight at 80°C. After concentration under reduced pressure, the crude product was purified by normal phase column chromatography (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

[0291] Intermediate I-20: Preparation of 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20)

[0292] Step 1: Preparation of 2-chloro-3-ethoxy-5-trifluoromethylpyridine (I-20-a)

[0293] 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. The mixture was reacted in a sealed tube at 90°C for 1 hour. The reaction mixture was cooled and quenched with water. The mixture was 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 Flash chromatography (10 g silica gel column, petroleum ether:ethyl acetate = 6:1) to obtain the desired product, 2-chloro-3-ethoxy-5-trifluoromethylpyridine (I-20-a, 220 mg, yield 77.04%). ESI [M+H] + =225.9

[0294] Step 2: Preparation of tert-butyl 4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-20-b)

[0295] 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) were dissolved in N-methylpyrrolidone (8 ml), and potassium carbonate (203 mg, 1.47 mmol) was added. The mixture was reacted in a sealed tube at 80°C overnight. The reaction mixture was cooled and quenched with water. The mixture was 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 flash chromatography (10 g silica gel column, petroleum ether:ethyl acetate = 6:1) to obtain the desired product, tert-butyl 4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-20-b, 120 mg, yield 32.69%). ESI [M+H] + =366.0

[0296] Step 3: Preparation of 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20)

[0297] Dissolve tert-butyl 4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-20-b, 115 mg, 0.31 mmol) in 4M hydrochloric acid and ethyl acetate (3 ml) and react at room temperature for 2 hours, then 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

[0298] Intermediate I-21: Preparation of 1-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-21)

[0299] Step 1: Preparation of tert-butyl 4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-21-a)

[0300] 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 mixture 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%).

[0301] Step 2: Preparation of 1-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-21)

[0302] Dissolve tert-butyl 4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (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

[0303] Intermediate I-22: Preparation of 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22)

[0304] Step 1: Preparation of tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-22-a)

[0305] Dissolve 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (300 mg, 1.5 mmol) in N-methylpyrrolidone (10 ml), then add tert-butyl piperazine-1-carboxylate (336 mg, 1.8 mmol) and potassium carbonate (415.6 mg, 3.01 mmol). The mixture was reacted overnight in an oil bath at 80°C. After completion of the reaction, the filtrate was concentrated under reduced pressure and purified via a flash column (petroleum ether:ethyl acetate = 4:1) to obtain the desired product, tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-22-a, 450 mg, 82% yield). ESI [M+H] + =366.0,368.0

[0306] Step 2: Preparation of 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22-b)

[0307] Dissolve tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-22-a, 450 mg) in ethyl acetate (4 ml), then add hydrogen chloride in ethyl acetate (4 ml) and allow to react overnight at room temperature. After the reaction is complete, concentrate the reaction mixture under reduced pressure, dissolve it in dichloromethane, and concentrate it again under reduced pressure. Repeat this process 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

[0308] Step 3: Preparation of 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22)

[0309] 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 the mixture was 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 three times 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 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-22, 390 mg, crude product). ESI [M+H] + =246.3

[0310] Intermediate I-23: Preparation of 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-23)

[0311] Step 1: Preparation of tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-a)

[0312] 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) were dissolved in N-methylpyrrolidone (10 ml), and potassium carbonate (416 mg, 3.01 mmol) was added. The mixture was reacted in a sealed tube at 80°C for 2 hours. The reaction mixture was cooled and quenched with water. The mixture was 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 flash chromatography (25 g silica gel column, petroleum ether:ethyl acetate = 8:1) to obtain the desired product, tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-a, 600 mg, yield 82.02%). ESI [M+H] + =366.0

[0313] Step 2: Preparation of tert-butyl 4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-b)

[0314] 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 cyclopropylboronic 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 under nitrogen protection for 80 minutes. After concentration under reduced pressure, the crude product was flash chromatography (25 g silica gel column, 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

[0315] Step 3: Preparation of 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine (I-23)

[0316] Dissolve tert-butyl 4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-23-b, 290 mg, 0.78 mmol) in 4M hydrochloric acid and 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, and extract with (dichloromethane:methanol = 10:1). The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to give 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

[0317] Intermediate I-24: Preparation of 1-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-24)

[0318] Step 1: Preparation of tert-butyl 4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-24-a)

[0319] 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) were dissolved in N-methylpyrrolidone (5 ml), and potassium carbonate (147 mg, 1.06 mmol) was added. The mixture was reacted in a sealed tube at 80°C overnight. The reaction mixture was cooled and quenched with water. The mixture was 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 flash chromatography (10 g silica gel column, petroleum ether:ethyl acetate = 8:1) to obtain the desired product, tert-butyl 4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-24-a, 140 mg, yield 54.64%). ESI [M+H] + =362.0

[0320] Step 2: Preparation of 1-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-24)

[0321] tert-Butyl 4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-24-a, 140 mg, 0.39 mmol) was dissolved in 4M hydrochloric acid and ethyl acetate (2 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure. Water (1 ml) was added, and the pH was adjusted to 8 with NaHCO₃. The mixture was extracted with (dichloromethane:methanol = 10:1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated 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

[0322] Intermediate I-25: Preparation of N-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (I-25)

[0323] Step 1: Preparation of tert-butyl 4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-25-a)

[0324] 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), and react at 80°C for 1 hour. Quench the reaction mixture with water and extract with ethyl acetate. The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 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

[0325] Step 2: Preparation of tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-25-b)

[0326] 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

[0327] Step 3: Preparation of N-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (I-25)

[0328] Tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-25-b, 110 mg, 0.318 mmol) and potassium carbonate (132 mg, 0.953 mmol) were added to N,N-dimethylformamide (3 ml). Acetyl chloride (37 mg, 0.476 mmol) was added dropwise under nitrogen and the temperature was raised to 100°C for 2 hours. The reaction solution was cooled and quenched with water, then extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product, N-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (I-25, 400 mg, purity 25%, yield 109.23%). ESI [M+H] + =289.1

[0329] Intermediate I-26: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-26)

[0330] Step 1: Preparation of tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-26-a)

[0331] Dissolve tert-butyl 4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-14-a, 550 mg, 1.54 mmol) in ethanol (15 ml), add water (5 ml), potassium carbonate (640 mg, 4.63 mmol), and 30% hydrogen peroxide (3.3 ml). After reacting at room temperature for 5 hours, the solvent was removed by concentration under reduced pressure, water (15 ml) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product, tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-26-a, 256 mg, yield 44.3%). ESI [M+H] + =375.2

[0332] Step 2: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-26)

[0333] 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-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-26, 194 mg, yield 91.5%). ESI [M+H] + =275.1

[0334] Intermediate I-27: Preparation of 6-(2-chloropropan-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-27)

[0335] 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 for overnight reaction. After completion of the reaction, cool to room temperature. The filtrate is concentrated under reduced pressure and purified on a flash column (petroleum ether:ethyl acetate = 3:1) to obtain the desired 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

[0336] Intermediate I-28: Preparation of 7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-28)

[0337] Step 1: Preparation of 7-bromo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-28-a)

[0338] 2-Bromo-3-nitro-5-(trifluoromethyl)pyridine (500 mg, 1.78 mmol) was dissolved in tetrahydrofuran (15 ml), the atmosphere was replaced with nitrogen, and vinylmagnesium bromide (11 ml, 10.7 mmol) was added dropwise at -78°C. The mixture was then stirred at -20°C for 1 hour. After the reaction was completed, the mixture was returned to room temperature and quenched with saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate. The organic phase was collected, 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 = 4:1) to obtain the desired product, 7-bromo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-28-a, 130 mg, 26.5% yield). ESI [M+H] + =266.2

[0339] Step 2: Preparation of tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-28-b)

[0340] 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). N,N-diisopropylethylamine (325 μl, 1.96 mmol) and tert-butyl piperazine-1-carboxylate (275 mg, 1.47 mmol) were added with stirring. The mixture was sealed and heated to 135°C overnight. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. 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, tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (1-28-b, 180 mg, 98% yield). ESI[M+H] + =371.4

[0341] Step 3: Preparation of 7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-28)

[0342] Dissolve tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-28-b, 80 mg, 0.22 mmol) in ethyl acetate (2 ml), then 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-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-28, 70 mg, crude product). ESI [M+H] + =271.4

[0343] Intermediate I-29: Preparation of 1-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-29)

[0344] 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)

[0345] tert-Butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-28-b, 30 mg, 0.081 mmol) was dissolved in N,N-dimethylformamide (2 ml). Potassium iodide (4.3 μl, 0.081 mmol) and potassium carbonate (16.8 mg, 0.121 mmol) were added with stirring and allowed to react at room temperature overnight. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. 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 = 4:1) to obtain the desired product, tert-butyl 4-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-29-a, 30 mg, 96% yield). 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)

[0346] Dissolve tert-butyl 4-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-29-a, 30 mg, 0.078 mmol) in ethyl acetate (1 ml), then 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-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-29, 30 mg, crude product). ESI [M+H] + =285.4

[0347] Intermediate I-30: Preparation of (2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (I-30)

[0348] Step 1: Preparation of tert-butyl 4-(3-(methoxycarbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-a)

[0349] Methyl 2-chloro-5-(trifluoromethyl)nicotinate (500 mg, 2.087 mmol) and tert-butyl piperazine-1-carboxylate (408 mg, 2.194 mmol) were dissolved in N-methylpyrrolidone (15 ml), and potassium carbonate (432 mg, 3.13 mmol) was added. The mixture was reacted at 80°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered. The filter cake was washed with water and dried 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

[0350] Step 2: Preparation of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b)

[0351] 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) were dissolved in methanol (20 ml) and water (4 ml) and reacted overnight at room temperature. After monitoring, the reaction was completed and acetic acid was added to adjust the pH to 7. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product, 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b, 820 mg, crude). ESI [M+H] + =376.3

[0352] Step 3: Preparation of tert-butyl 4-(3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-c)

[0353] 2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinic acid (I-30-b, 200 mg, 0.533 mmol) was dissolved in dichloromethane (10 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg, 0.526 mmol) was added and stirred for 10 minutes. N,N-diisopropylethylamine (279 μl, 1.578 mmol) and tetrahydropyrrole (44 μl, 0.53 mmol) were added and the reaction was allowed to react at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by Flash chromatography (10 g silica gel column, petroleum ether:ethyl acetate = 1:1) to obtain the target product, tert-butyl 4-(3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-30-c, 180 mg, yield 71.72%). ESI [M+H] + =429.0

[0354] Step 4: Preparation of (2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (I-30)

[0355] Dissolve tert-butyl 4-(3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-1-c, 180 mg, 0.42 mmol) in 4M hydrochloric acid and ethyl acetate (3 ml) and react at room temperature for 2 hours, then concentrate under reduced pressure to obtain the target product (2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (I-30, 190 mg, crude). ESI [M+H] + =329.0

[0356] Intermediate I-31: Preparation of N-methyl-2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-31)

[0357] Step 1: Preparation of tert-butyl 4-(3-(methylcarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-31-a)

[0358] 2-(4-(tert-Butoxycarbonyl)piperazin-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. N,N-diisopropylethylamine (279 μl, 1.578 mmol) and methylamine hydrochloride (36 mg, 0.53 mmol) were then added. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by Flash chromatography (10 g silica gel column, petroleum ether:ethyl acetate = 1:1) to obtain the desired product, tert-butyl 4-(3-(methylcarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-31-a, 220 mg, yield 106.38%). ESI[M+H] + =389.0

[0359] Step 2: Preparation of N-methyl-2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-31)

[0360] Dissolve tert-butyl 4-(3-(methylcarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-31-a, 220 mg, 0.567 mmol) in 4M hydrochloric acid and ethyl acetate (3 ml) and react at room temperature for 2 hours, then concentrate under reduced pressure to obtain the target product, N-methyl-2-(piperazin-1-yl)-5-(trifluoromethyl)nicotinamide hydrochloride (I-31, 193 mg, yield 105.46%). ESI [M+H] + =289.0

[0361] Intermediate I-32: Preparation of 2-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-32)

[0362] Step 1: Preparation of 7-chloro-2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-32-a)

[0363] 2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (250 mg, 1.10 mmol) was dissolved in tetrahydrofuran (12 ml), the atmosphere was replaced with nitrogen, and isopropenylmagnesium bromide (6.62 ml, 6.62 mmol) was added dropwise at -78°C. The mixture was then stirred at -20°C for 1 hour. After the reaction was completed, the mixture was returned to room temperature and quenched with saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate. The organic phase was collected, 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 = 4:1) to obtain the desired product, 7-chloro-2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (I-32-a, 90 mg, 34.75% yield). ESI [M+H] + =235.8

[0364] 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)

[0365] 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 then 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, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. 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 = 3:1) to obtain the target product, tert-butyl 4-(2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-32-b, 80 mg, yield 54.4%). ESI [M+H] + =385.3

[0366] Step 3: Preparation of 2-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-32)

[0367] Dissolve tert-butyl 4-(2-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (I-32-b, 80 mg, 0.21 mmol) in ethyl acetate (1 ml), add 4M hydrochloric acid in ethyl acetate (3 ml), and react at room temperature for 2 hours. After the reaction, concentrate under reduced pressure, dissolve in dichloromethane, and spin dry twice to obtain the target product, 2-methyl-7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (I-32, 100 mg, crude). ESI [M+H] + =285.3

[0368] Intermediate I-33: Preparation of 3-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole trifluoroacetate (I-33)

[0369] Step 1: Preparation of tert-butyl 4-(3-(N'-hydroxycarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-a)

[0370] 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) and sodium ethoxide (43 mg, 0.63 mmol), and react at 100°C overnight. The reaction solution is concentrated under reduced pressure, and the crude product is purified by Flash column chromatography (10 g silica gel column, 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

[0371] 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)

[0372] Dissolve tert-butyl 4-(3-(N'-hydroxycarbamoyl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-a, 50 mg, 0.13 mmol) in trimethyl orthoformate (5 ml), add trifluoroacetic acid (0.5 ml), and react at 70°C for 1 hour. The reaction solution is concentrated under reduced pressure to obtain the target product, tert-butyl 4-(3-(1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (I-33-b, 60 mg, crude product). ESI[M+H] + =400.1

[0373] Step 3: Preparation of 3-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole trifluoroacetate (I-33)

[0374] 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), and react at room temperature for 0.5 hour, then concentrate under reduced pressure to obtain the target product, 3-(2-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole trifluoroacetate (I-33, 110 mg, crude product). ESI [M+H] + =300.1

[0375] 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)

[0376] 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)

[0377] (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 monitoring the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC on silica gel plates (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

[0378] 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)

[0379] 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) was dissolved in a 4 mol / L hydrogen chloride solution in ethyl acetate and allowed to react overnight at room temperature. After monitoring the reaction for completion, the mixture was concentrated 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, 149% yield). ESI [M+H] + =370.2

[0380] 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)

[0381] (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 at room temperature overnight. After monitoring the reaction completion, water was added to quench the reaction, 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 chromatography [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22min] to give 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, 1.46 mg, 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).

[0382] 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)

[0383] 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)

[0384] (R)-1-(tert-Butoxycarbonyl)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 sequentially. The mixture was 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. Rinse the filter cake with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the target product, 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, yield 91.60%). ESI [M+H] + =456.21

[0385] 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)

[0386] 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) was slowly added dropwise a hydrogen chloride-ethyl acetate solution (1 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude target product ((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

[0387] 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)

[0388] ((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). Tert-butyl (S)-(1-oxopropan-2-yl)carbamate (76.5 mg, 0.44 mmol) was added, followed by sodium acetate (62.84 mg, 1.10 mmol) at 0°C and stirring at 0°C for 20 minutes. Sodium cyanoborohydride (15.1 mg, 0.18 mmol) was then added at 0°C. The reaction was allowed to proceed 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 column chromatography (dichloromethane:methanol = 10:1) to obtain the target product, 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, yield 43.47%). ESI [M+H] + =513.27

[0389] 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)

[0390] 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) was slowly added dropwise a 4M hydrogen chloride-ethyl acetate solution (0.8 ml) 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

[0391] 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)

[0392] ((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 the mixture was stirred at 80° C. for 2 hours. The reaction mixture 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

[0393] 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)

[0394] 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 then added in sequence, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified using HPLC (Pack Column 20 ID*250 mm*10 μm; A: H2O (0.1% FA), B: ACN, B%: 10%-70% over 22 min) to obtain the desired 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).

[0395] 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)

[0396] 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)

[0397] (1R,3R)-3-((tert-Butyloxycarbonyl)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 the reaction was allowed to react at room temperature overnight. The reaction mixture was filtered, 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

[0398] 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)

[0399] 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) was slowly added dropwise a 4M hydrogen chloride-ethyl acetate solution (2 ml) and stirred at room temperature for 1 hour. The reaction mixture was added with 4 ml of ethyl acetate and filtered. The filter cake was dried to obtain the crude target 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

[0400] 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)

[0401] ((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 then 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 thin-layer silica gel chromatography (dichloromethane:methanol = 10:1). The product was then purified using high-performance liquid chromatography (HPLC) [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-70% over 22 min] to obtain the desired 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),2.3 6(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).

[0402] 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)

[0403] ((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. Sodium cyanoborohydride (16 mg, 0.252 mmol) was then 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 thin-layer silica gel chromatography (dichloromethane:methanol = 10:1). The product was then purified using high-performance liquid chromatography (HPLC) [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-70% over 22 min] to obtain the desired 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).

[0404] 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)

[0405] Step 1: Preparation of tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (5-a)

[0406] 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-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 1.6 g, 5.96 mmol) were added. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was filtered, concentrated under reduced pressure, and purified by flash column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the desired 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

[0407] Step 2: Preparation of azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (5-b)

[0408] 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 add 4M hydrogen chloride-ethyl acetate solution (40 ml) dropwise. Stir at room temperature for 4 hours. The reaction mixture is directly distilled under reduced pressure to obtain the target product, crude azetidin-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

[0409] 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)

[0410] 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 then 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 thin-layer silica gel chromatography (dichloromethane:methanol = 10:1). The product was then purified using high-performance liquid chromatography (HPLC) [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-70% over 22 min] to obtain the desired 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).

[0411] 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)

[0412] 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)

[0413] (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) was reacted at room temperature for 3 hours, and the reaction solution was added dropwise to water (40 mL) with stirring. After filtration, the filter cake was concentrated 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

[0414] 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)

[0415] (3S)-tert-butyl 3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate (6-a, 0.1 g, 0.219 mmol) was added to a 4M hydrochloric acid ethyl acetate solution (2 mL). After reacting at room temperature for 3 hours, the mixture was concentrated under reduced pressure to obtain the crude target product, (3S)-tert-butyl 3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate hydrochloride (6-b, 0.1 g). (ESI) [M+H] + =356.5

[0416] 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)

[0417] (S)-Pyrrolidin-3-yl-(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (6-b, 50 mg, 0.14 mmol) and (S)-tert-butyl(1-oxopropan-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 completion of the reaction, water was added to quench the reaction, 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 on silica gel plates (dichloromethane / methanol = 10:1) to give 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.

[0418] 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)

[0419] 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, 0.076 mmol) was dissolved in a 4 mol / L hydrogen chloride solution in ethyl acetate and allowed to react at room temperature for 1 hour. After monitoring the reaction for completion, the mixture was concentrated under reduced pressure to yield the desired 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, 143% yield). ESI [M+H] + =413.7

[0420] 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)

[0421] (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 monitoring the reaction, the reaction 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

[0422] 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)

[0423] 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 overnight. After monitoring the reaction completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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 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).

[0424] 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)

[0425] 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)

[0426] 4-(tert-Butyloxycarbonyl)amino)benzoic acid (100 mg, 0.421 mmol) was dissolved in dichloromethane (5 ml), and 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) were added and the reaction was allowed to proceed at room temperature overnight. The reaction mixture was filtered, concentrated under reduced pressure, and then purified by Flash column chromatography (petroleum ether:ethyl acetate = 1:1) 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

[0427] 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)

[0428] 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) was slowly added dropwise a 4M hydrogen chloride-ethyl acetate solution (3 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to 10 ml of ethyl acetate and filtered. The filter cake was directly distilled under reduced pressure to obtain the crude target product, (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

[0429] 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)

[0430] (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 then added at 0°C and the reaction was allowed to proceed 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 thin-layer silica gel chromatography (dichloromethane:methanol = 10:1). Purification was then performed again using thin-layer silica gel chromatography (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, 3.73% yield). 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).

[0431] 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)

[0432] 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)

[0433] (1R,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (80 mg, 0.372 mmol) was dissolved in dichloromethane (4 ml), and 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) were added and reacted at room temperature for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, and then purified by Flash column chromatography (petroleum ether:ethyl acetate = 1:1) 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

[0434] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (8-b)

[0435] 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) was slowly added dropwise a 4M hydrogen chloride-ethyl acetate solution (3 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was added with 4 ml of ethyl acetate and filtered. The filter cake was dried to obtain the crude target product, ((1R,3R)-3-aminocyclobutyl)((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (8-b, 157 mg, yield 132.84%). ESI [M+H] + =344.6

[0436] 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)

[0437] ((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. Sodium acetate (11 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 then 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 thin-layer silica gel chromatography (dichloromethane:methanol = 8:1). The product was then purified using high-performance liquid chromatography (HPLC) [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-70% over 22 min] to obtain the desired 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

[0438] 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)

[0439] (S)-pyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methanone hydrochloride (6-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 dichloromethane (1.5 ml) and the reaction was stirred at 0 degrees Celsius. Acetic acid (2.5 mg, 0.0417 mmol) was added and stirred for 20 minutes before sodium cyanoborohydride (15.9 mg, 0.253 mmol). The reaction was stirred at room temperature overnight. After monitoring the reaction for completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol = 10:1. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22 min] to afford 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).

[0440] 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)

[0441] (R)-pyrrolidin-3-yl)(3-(5-trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-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 at room temperature overnight. After monitoring the reaction for completion, the product was quenched with water and extracted with dichloromethane:methanol = 10:1. The product was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography (Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22 min) to afford 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, 2.25% yield). 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).

[0442] 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)

[0443] (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. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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 give 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).

[0444] 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)

[0445] Step 1: Preparation of tert-butyl ((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (12-a)

[0446] ((1R,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (1 g, 4.65 mmol) was dissolved in N,N-dimethylformamide (10 ml), and 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) were added under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (1.26 g, 4.65 mmol) was reacted at room temperature for 3 hours, and 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, tert-butyl ((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (12-a, 1.7 g, yield 85.4%). (ESI) [M+H] + =430.2.

[0447] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (12-b)

[0448] 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 in ethyl acetate (20 mL) under ice-cooling. After reacting at room temperature for 3 hours, concentrate under reduced pressure to obtain the target product, ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (12-b, 1.7 g, crude product). (ESI) [M+H] + =330.2.

[0449] 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)

[0450] ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (12-b, 500 mg, 1.37 mmol) and 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-cooling and stirred for 30 minutes. Sodium cyanoborohydride (257.8 mg, 4.10 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was then concentrated under reduced pressure and purified by column chromatography. The crude product was then 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)pyridazin-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).

[0451] 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)

[0452] Step 1: Preparation of tert-butyl (1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (13-a)

[0453] (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 monitoring the reaction, ice water was added and stirred thoroughly, and the mixture was filtered to collect the filter cake to obtain the target product, tert-butyl (1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (13-a, 85.6 mg, yield 85.9%). ESI [M+H] + =430.2

[0454] Step 2: Preparation of (1R, 3R)-3-aminocyclobutyl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (13-b)

[0455] Tert-butyl (1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (13-a, 85.6 mg, 0.199 mmol) was dissolved in a 4 mol / L hydrogen chloride solution in ethyl acetate and allowed to react overnight at room temperature. After monitoring the reaction for completion, the mixture was concentrated under reduced pressure to yield the desired product, (1R,3R)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (13-b, 94.6 mg, 144% yield). ESI [M+H] + =330.1

[0456] 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)

[0457] (1R, 3R)-3-aminocyclobutyl) 4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazine-1-methanone (13-b, 30 mg, 0.0739 mmol) and 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 the reaction, and the mixture was extracted with dichloromethane:methanol = 10:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22min] to give 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).

[0458] 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)

[0459] Azetidin-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-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 then 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 thin-layer silica gel chromatography (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, 3.45% yield). 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).

[0460] 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)

[0461] Step 1: Preparation of tert-butyl ((1R, 4R)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (15-a)

[0462] (1R, 4R)-4-((tert-Butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (100 mg, 0.411 mmol) was dissolved in dichloromethane (5 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156 mg, 0.411 mmol) and N,N-diisopropylethylamine (216 μl, 1.233 mmol) were added and reacted for 20 minutes. Then, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 133 mg, 0.493 mmol) was added and reacted at room temperature for 3 hours. The reaction mixture was filtered, concentrated under reduced pressure, and then purified by Flash column chromatography (petroleum ether:ethyl acetate = 1:1) 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

[0463] Step 2: Preparation of ((1R,4R)-4-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (15-b)

[0464] 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 mixture was diluted with 4 ml of ethyl acetate and concentrated under reduced pressure to obtain the crude target product, ((1R,4R)-4-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (15-b, 244 mg, crude). ESI [M+H] + =358.7

[0465] 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)

[0466] ((1R, 4R)-4-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-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 then 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 twice using thin-layer silica gel chromatography (dichloromethane:methanol = 8:1) to obtain the desired 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).

[0467] 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)

[0468] Step 1: Preparation of tert-butyl (1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (16-a)

[0469] (1S,3S)-3-((tert-Butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (100 mg, 0.411 mmol) was dissolved in dichloromethane (5 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156 mg, 0.411 mmol) and N,N-diisopropylethylamine (216 μl, 1.233 mmol) were added and reacted for 20 minutes. Then, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 133 mg, 0.493 mmol) was added and the reaction was allowed to proceed at room temperature overnight. The reaction mixture was filtered, concentrated under reduced pressure, and then purified by Flash column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the target tert-butyl (1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (16-a, 208 mg, yield 110%). ESI [M+H] + =458.1,ESI[M+H-56] + =401.9

[0470] Step 2: Preparation of ((1S,3S)-3-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (16-b)

[0471] To tert-butyl (1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclohexyl)carbamate (16-a, 208 mg, 0.455 mmol) was slowly added dropwise a 4M hydrogen chloride-ethyl acetate solution (3 ml) and stirred at room temperature for 2 hours. The reaction mixture was diluted with 4 ml of ethyl acetate and concentrated under reduced pressure to obtain the crude target product, ((1S,3S)-3-aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (16-b, 240 mg, crude). ESI [M+H] + =358.2,ESI[2M+H] + =715.2

[0472] 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)

[0473] ((1S,3S)-3-Aminocyclohexyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-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 then 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 twice using thin-layer silica gel chromatography (dichloromethane:methanol = 8:1) to obtain the desired 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).

[0474] 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)

[0475] Step 1: Preparation of tert-butyl (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (17-a)

[0476] (S)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (100 mg, 0.436 mmol) was dissolved in dichloromethane (5 ml), and 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 reacted for 20 minutes. Then, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-1, 141 mg, 0.523 mmol) was added and reacted at room temperature for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, and then purified by Flash column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain the target (S)-tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (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

[0477] Step 2: Preparation of (S)-piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (17-b)

[0478] 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) was slowly added dropwise a 4M hydrogen chloride-ethyl acetate solution (3 ml) and stirred at room temperature for 2 hours. The reaction mixture was diluted with 4 ml of ethyl acetate and concentrated under reduced pressure to obtain the crude target product, (S)-piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (17-b, 194 mg, crude). ESI [M+H] + =344.2

[0479] 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)

[0480] (S)-Piperidin-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-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 then added at 0°C and the reaction was allowed to react at room temperature overnight. 0.1 ml of water was added and filtered. The organic phase was concentrated under reduced pressure and purified using thin-layer silica gel chromatography (dichloromethane:methanol = 8:1). High-performance liquid chromatography (HPLC) [Pack Column 20 ID*250 mm*10 μm; A: H2O (0.1% FA), B:ACN, B%: 10%-70% over 22 min] was used to obtain the desired 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, 4.16% yield). 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).

[0481] 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)

[0482] Step 1: Preparation of tert-butyl 4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (18-a)

[0483] 1-(tert-Butoxycarbonyl)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 sequentially, and the mixture was 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 mixture was stirred at room temperature for 4 hours. The reaction mixture was added with 10 times the volume of water, stirred under ice for 15 minutes, and then filtered. The filter cake was then rinsed with a mixture of petroleum ether and ethyl acetate (1:1). The filtrate was concentrated 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

[0484] Step 2: Preparation of piperidin-4-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (18-b)

[0485] 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 mixture under reduced pressure to obtain the target crude product, piperidin-4-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (18-b, 54 mg, crude). ESI [M+H] + =344.16

[0486] 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)

[0487] Dissolve piperidin-4-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (18-b, 54 mg, 0.16 mmol) in methanol (1.5 ml). Add 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 36 mg, 0.19 mmol) and stir for 10 minutes. Then, add sodium acetate (11 mg, 0.13 mmol) at 0°C. Stir for 20 minutes, then add sodium cyanoborohydride (49 mg, 0.78 mmol). Allow to react overnight at room temperature. The reaction mixture was added to a small amount of water and extracted with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1). Finally, the product was purified using preparative liquid chromatography (Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-70% over 22 min) to obtain the desired 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%). ESI [M+H] + =519.19 1 H NMR(400MHz,DMSO-d6)δ11.72(s,1H), 8.73(s,2H),7.95(s,1H),7.71(s,1H),4.42(s,2H),3.91–3.77(m,8H),2.45–2.30(m,4H),2.05–1.93(m,5H).

[0488] 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)

[0489] Step 1: Preparation of tert-butyl (1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (19-a)

[0490] (1S,3S)-3-(tert-Butoxycarbonylamino)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 monitoring the reaction, the reaction solution was added dropwise to ice water with stirring. The precipitated solid was filtered, and the filter cake was collected. 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 concentration under reduced pressure. ESI [M+H] + =430.2

[0491] Step 2: Preparation of (1S,3S)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (19-b)

[0492] Tert-butyl (1S,3S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (19-a, 190 mg, 0.443 mmol) was dissolved in a 4M hydrogen chloride solution in ethyl acetate (3 ml) and allowed to react overnight at room temperature. After monitoring the reaction for completion, the reaction solution was concentrated under reduced pressure to obtain the desired product, (1S,3S)-3-aminocyclobutyl)4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-methanone hydrochloride (19-b, 215 mg, 147.2% yield). ESI [M+H] + =330.2

[0493] 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)

[0494] (1S, 3S)-3-aminocyclobutyl) 4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazine-1-methanone hydrochloride (19-b, 100 mg, 0.304 mmol) and 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbaldehyde (I-7, 87 mg, 0.455 mmol) were dissolved in dichloromethane (3 ml) and the reaction was added with acetic acid (9.1 mg, 0.151 mmol) 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 for completion, a large amount of water was added, and the mixture was extracted with dichloromethane:methanol = 10:1. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22 min] to afford 3-trifluoromethyl-5-(((1S,3S)-3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridin-2(1H)-one (19, 1.87 mg, 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).

[0495] 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)

[0496] (1S, 3S)-3-aminocyclobutyl) 4-(5-(trifluoromethyl) pyrimidin-2-yl) piperazine-1-methanone hydrochloride (19-b, 190 mg, 0.521 mmol) and 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). Sodium acetate (21 mg, 0.26 mmol) was added to the reaction mixture 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 product was quenched with a small amount of water and filtered, then concentrated under reduced pressure and purified twice by thin-layer silica gel chromatography (dichloromethane:methanol = 10:1) to afford 4-(trifluoromethyl)-6-(((1S,3S)-3-(4-(5-(trifluoromethane)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (20, 43.25 mg, 16.43% yield). 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).

[0497] 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)

[0498] 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)

[0499] 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-piperazin-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 monitoring the reaction, the reaction solution was added dropwise to ice water with stirring. The precipitated solid was filtered, the filter cake was collected, and finally concentrated under reduced pressure to obtain the target product, tert-butyl 6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (21-a, 176 mg, yield 93.6%). ESI [M+H] + =456.4

[0500] Step 2: Preparation of (2-azaspiro[3.3]heptane-6-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone trifluoroacetate (21-b)

[0501] 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. The mixture was reacted at room temperature for 4 hours. After monitoring the reaction completion, 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

[0502] 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)

[0503] (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 the reaction was stirred at 0°C. Sodium acetate (3.5 mg, 0.043 mmol) was added and stirred for 20 minutes before sodium cyanoborohydride (15.9 mg, 0.261 mmol). 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. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography [Pack Column 20 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-50% over 22 min] 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 H NMR(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).

[0504] 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)

[0505] Step 1: Preparation of tert-butyl (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (22-a)

[0506] (R)-1-(tert-Butoxycarbonyl)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-(piperazin-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 monitoring the reaction, the reaction solution was added to ice water, the precipitated solid was filtered, the filter cake was collected, and the mixture was concentrated under reduced pressure to obtain 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%). ESI [M+H] + =444.19

[0507] Step 2: Preparation of (R)-piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (22-b)

[0508] Dissolve (R)-tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (22-a, 184 mg, 0.415 mmol) in a 4M solution of hydrogen chloride in ethyl acetate (2 ml) and allow to react overnight at room temperature. After monitoring the reaction for completion, concentrate under reduced pressure to obtain the crude target product, (R)-piperidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (22-b, 213.2 mg, 150% yield). ESI [M+H] + =343.2

[0509] 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)

[0510] (R)-Piperidin-3-yl (4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (22-b, 100 mg, 0.263 mmol) and 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 mixture 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 reaction mixture was quenched with a small amount of water and filtered, then concentrated under reduced pressure and purified twice by thin-layer chromatography on silica gel (dichloromethane:methanol = 10:1) to give 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, 3.16% yield). 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).

[0511] 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)

[0512] 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)

[0513] (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-methylpiperazin-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 monitoring the reaction, 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 (1S,3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (23-a, 156 mg, yield 94.65%). ESI [M+H] + =444.3,ESI[2M+H] + =887.6

[0514] Step 2: Preparation of ((1R,3S)-3-aminocyclobutyl)((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (23-b)

[0515] Tert-butyl (1S,3R)-3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (23-a, 156 mg, 0.352 mmol) was dissolved in a 4 mol / L hydrogen chloride solution in ethyl acetate (3 ml) and allowed to react at room temperature for 2 hours. After monitoring the reaction for completion, the mixture was concentrated under reduced pressure to obtain the crude target product, ((1R,3S)-3-aminocyclobutyl)((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (23-b, 156 mg). ESI [M+H] + =344.3,ESI[2M+H] + =687.5

[0516] 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)

[0517] ((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) and 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). Sodium acetate (17 mg, 0.206 mmol) was added to the reaction at 0°C, stirred for 30 minutes, and then sodium cyanoborohydride (77 mg, 1.233 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a small amount of water and filtered, then concentrated under reduced pressure and purified twice by Flash column chromatography (methanol:dichloromethane = 0-10%) to give 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, 5.51% yield). 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).

[0518] 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)

[0519] Step 1: Preparation of tert-butyl (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (24-a)

[0520] (R)-1-(tert-Butoxycarbonyl)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 the mixture was stirred under ice-cooling for 30 minutes. , 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (124 mg, 0.465 mmol), reacted at room temperature for 3 hours, and then the reaction solution was added dropwise to water (12 mL) with stirring. After filtration, the filter cake was concentrated 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

[0521] Step 2: Preparation of (R)-pyrrolidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (24-b)

[0522] Dissolve (R)-tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (24-a, 130 mg, 0.303 mmol) in a 4M hydrogen chloride solution in ethyl acetate (3 ml) and allow to react at room temperature for 2 hours. After monitoring the reaction for 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)piperazin-1-yl)methanone hydrochloride (24-b, 137 mg, crude). ESI [M+H] + =330.2,ESI[2M+H] + =659.5

[0523] 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)

[0524] (R)-Pyrrolidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (24-b, 137 mg, 0.375 mmol) and 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). Sodium acetate (15 mg, 0.187 mmol) was added to the mixture 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. 0.3 ml of water was added, the mixture was concentrated under reduced pressure, and then filtered. The filtrate was purified by thin-layer chromatography on silica gel (dichloromethane:methanol = 10:1) and then 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 afford (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, 1.15% yield). 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).

[0525] 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)

[0526] 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)

[0527] 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-(piperazin-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 monitoring the reaction, the reaction solution was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain the target product (tert-butyl 3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate (25-a, 190 mg, yield 97.81%). ESI [M+H] + =442.1

[0528] 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)

[0529] 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 a 4M hydrogen chloride solution in ethyl acetate (3 ml) and allow to react at room temperature for 2 hours. After monitoring the reaction for completion, add ethyl acetate several times and concentrate under reduced pressure to obtain the crude target product, (3-aminobicyclo[1.1.1]pentan-1-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (25-b, 190 mg, crude). ESI [M+H] + =342.2

[0530] 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)

[0531] (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) and 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). Sodium acetate (10 mg, 0.121 mmol) was added to the reaction mixture 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 mixture was concentrated under reduced pressure and purified by thin-layer chromatography on silica gel (dichloromethane:methanol = 10:1). The mixture was then purified and lyophilized by preparative liquid chromatography (Pack Column 20 ID*250 mm*10 μm; A: H2O (0.1% FA), B:ACN, B%: 5%-70% over 22 min) to afford 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, 0.54% yield). ESI [M+H] + =517.3,ESI[2M+H] + =1033.5 1 H NMR (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).

[0532] 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)

[0533] Step 1: Preparation of tert-butyl (S)-3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (26-a)

[0534] 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-methylpiperazin-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 monitoring the reaction, the reaction solution was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain the target product (S)-tert-butyl 3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (26-a, 185 mg, yield 86.85%). ESI [M+H-56] + =374.2,ESI[M+H-100] + =330.1

[0535] Step 2: Preparation of (S)-azetidin-3-yl(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (26-b)

[0536] (S)-tert-Butyl 3-(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (26-a, 185 mg, 0.431 mmol) was dissolved in a 4 mol / L hydrogen chloride solution in ethyl acetate (3 ml) and allowed to react at room temperature for 2 hours. After monitoring the reaction completion, dichloromethane was added and concentrated under reduced pressure several times to obtain the target product, crude (S)-azetidin-3-yl(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-yl)methanone hydrochloride (26-b, 171 mg, crude). ESI [M+H] + =330.2

[0537] 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)

[0538] (S)-azetidin-3-yl(3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone hydrochloride (26-b, 171 mg, 0.479 mmol) and 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 mixture at 0°C, stirred for 30 minutes, and then sodium cyanoborohydride (87 mg, 1.437 mmol) was added. The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified twice by thin-layer silica gel chromatography (dichloromethane:methanol=10:1) to give (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, 2.0% yield). 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).

[0539] 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)

[0540] Step 1: Preparation of tert-butyl 3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (27-a)

[0541] 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 monitoring the reaction, 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

[0542] Step 2: Preparation of azetidin-3-yl(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (27-b)

[0543] 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 4 M hydrochloric acid in ethyl acetate (4 ml) under ice-cooling. After reacting at room temperature for 2 hours, the reaction solution is concentrated under reduced pressure and purified by thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain the target product, heterocyclobutane-3-yl(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (27-b, 60 mg, yield 49.2%). ESI [M+H] + =315.2

[0544] 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)

[0545] 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). 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 for 20 min. After 3 minutes, sodium cyanoborohydride (32.4 mg, 0.516 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 preparative thin-layer chromatography (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).

[0546] 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)

[0547] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (28-a)

[0548] (1R, 3R)-3-((tert-Butyloxycarbonyl)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 monitoring the reaction, the reaction solution was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate:petroleum ether = 0-50%) 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

[0549] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (28-b)

[0550] 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). 4 M hydrochloric acid in ethyl acetate (4 ml) was added under ice-cooling. 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)piperazin-1-yl)methanone hydrochloride (28-b, 110 mg, yield 85.3%). ESI [M+H] + =329.2

[0551] 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)

[0552] ((1R, 3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (28-b, 110 mg, 0.303 mmol) was dissolved in dichloromethane (4 ml) and methanol (2 ml), and 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) were added under ice-cooling. 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 plate preparation (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).

[0553] 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)

[0554] Step 1: Preparation of tert-butyl 3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (29-a)

[0555] 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- (Piperazin-1-yl)-5-(trifluoromethyl)pyrazine hydrochloride (I-9, 133.5 mg, 0.497 mmol) was reacted at room temperature for 3 hours, and the reaction solution was added dropwise to water (12 mL) with stirring. After filtration, the filter cake was concentrated under reduced pressure to obtain the target product, tert-butyl 3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (29-a, 161 mg, yield 78.2%). ESI [M-56+H] + =359.3

[0556] Step 2: Preparation of azetidin-3-yl(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)methanone hydrochloride (29-b)

[0557] 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 4 M hydrochloric acid in ethyl acetate (4 mL) under ice-cooling. After reacting at room temperature for 3 hours, the reaction solution is concentrated under reduced pressure. The crude product is purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the desired product, azetidin-3-yl(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)methanone hydrochloride (29-b, 80 mg, 65.3%). ESI [M+H] + =316.3

[0558] 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)

[0559] 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). 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. After stirring for 20 minutes under ice-bath, sodium cyanoborohydride (43 mg, 0.684 mmol) was added. After 3 hours of reaction at room temperature, the reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC plate preparation (dichloromethane:methanol = 10:1) to obtain the target product 3-(trifluoromethyl)-5-((3-(4-(5-(trifluoromethane)pyrazin-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).

[0560] 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)

[0561] 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)

[0562] (R)-1-(tert-Butoxycarbonyl)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-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-4, 144 mg, 0.512 mmol) was added and the reaction was carried out at room temperature for 1.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then purified by Flash column chromatography (petroleum ether:ethyl acetate = 0-50%) to obtain the target product, (R)-tert-butyl 3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (30-a, 190 mg, yield 92.22%). ESI [M+H] + =444.8,ESI[M+H-100] + =344.6

[0563] Step 2: Preparation of ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)((R)-pyrrolidin-3-yl)methanone hydrochloride (30-b)

[0564] Dissolve (R)-tert-butyl 3-((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (30-a, 0.19 g, 0.428 mmol) in 4M hydrochloric acid and ethyl acetate solution (4 mL). After reacting at room temperature for 4 hours, concentrate under reduced pressure to obtain the target product ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)((R)-pyrrolidin-3-yl)methanone hydrochloride (30-b, 120 mg, crude product). ESI [M+H] + =344.8

[0565] Step 3: Preparation of ((S)-3-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)((R)-pyrrolidin-3-yl)methanone (30-c)

[0566] ((S)-3-Methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-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)piperazin-1-yl)((R)-pyrrolidin-3-yl)methanone (30-c, 73 mg, yield 67.6%).

[0567] 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)

[0568] ((S)-3-Methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-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).

[0569] 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)

[0570] (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), and 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-cooling, and the mixture was stirred for 2 min under ice-cooling. After 10 minutes, sodium cyanoborohydride (69 mg, 1.09 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 thin layer 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).

[0571] 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)

[0572] Azetidin-3-yl(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (27-b, 120 mg, 0.382 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-4-(trifluoromethyl)pyridazin-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 give the target product, 4-(trifluoromethyl)-6-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)azetidin-1-yl)methyl)pyridazin-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).

[0573] 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)

[0574] 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 the mixture was 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-(trifluoromethyl)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).

[0575] 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)

[0576] Step 1: Preparation of ((1R,3R)-3-(methylamino)cyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (34-a)

[0577] ((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), and cesium carbonate (133.7 mg, 0.410 mmol) and potassium iodide (6 μl, 0.274 mmol) were added. 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

[0578] 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)

[0579] ((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 and purified by thin layer chromatography (dichloromethane:methanol=10:1). The product was purified by high performance liquid chromatography [Pack Column 20 ID*250 mm*10 μm; A:H2O(0.1%NH4HCO3), B:ACN, B%: 10%-100% over 25min] Preparation and purification gave 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).

[0580] 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)

[0581] (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 preparative chromatography (dichloromethane: methanol = 20:1) and then subjected to chiral separation 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).

[0582] 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)

[0583] Azetidine-3-yl (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl)methanone (5-b, 160 mg, 0.508 mmol) was dissolved in dichloromethane (10 ml), and 6- (1-bromoethyl) -4- (trifluoromethyl) pyridazin-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 preparative plate (dichloromethane: methanol = 20: 1) and then subjected to chiral separation 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).

[0584] 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)

[0585] 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]oxirane-9-carbonyl)azetidine-1-carboxylate (37-a)

[0586] 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]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-10, 60 mg, 0.194 mmol), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (121 mg, 0.322 mmol) were dissolved in N,N-dimethylformamide (5 ml). Triethylamine (81 μl, 0.423 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (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]pyrido[3,2-b][1,4]oxirane-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

[0587] Step 2: Preparation of (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 hydrochloride (37-b)

[0588] (R)-tert-Butyl 3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxetane-9-carbonyl)azetidine-1-carboxylate (37-a, 75 mg, 0.164 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, (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 hydrochloride (37-b, 74 mg, yield 114.66%). ESI[M+H] + =357.4

[0589] Step 3: Preparation of (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)

[0590] Dissolve (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 hydrochloride (37-b, 74 mg, 0.188 mmol) in water (2 ml) and add sodium bicarbonate (19 mg, 0.226 mmol). Allow to react at room temperature for 5 minutes. After monitoring the pH between 8 and 9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a 10:1 solution of dichloromethane:methanol by ultrasonication 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%).

[0591] 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)

[0592] (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) and 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. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified twice by thin-layer silica gel chromatography (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]pyrido[3,2-b][1,4]oxirane-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).

[0593] 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)

[0594] 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)

[0595] (1R,3R)-3-((tert-Butoxycarbonyl)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]pyrido[3,2-b][1,4]oxazepine hydrochloride (I-10, 100 mg, 0.323 mmol), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (202 mg, 0.387 mmol) were dissolved in N,N-dimethylformamide (5 ml). Triethylamine (135 μl, 0.969 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was added to water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (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]pyrido[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (38-a, 120 mg, yield 79%). ESI [M+H] + =471.4

[0596] 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)

[0597] 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 4 M 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]pyrido[3,2-b][1,4]oxazepin-9-yl)methanone hydrochloride (38-b, 120 mg, yield 115.65%). ESI [M+H] + =371.3

[0598] 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)

[0599] Dissolve ((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]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). Allow to react at room temperature for 5 minutes. After monitoring the pH between 8 and 9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a 10:1 solution of dichloromethane:methanol by ultrasonication 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%).

[0600] 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)

[0601] ((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) and 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, and 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. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column chromatography (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]pyrido[3,2-b][1,4]oxazepine-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-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).

[0602] 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)

[0603] 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)

[0604] (1R,3R)-3-((tert-Butoxycarbonyl)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), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (58 mg, 0.127 mmol) were dissolved in N,N-dimethylformamide (2 ml). Triethylamine (38 μl, 0.318 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was added to water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (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]pyrido[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

[0605] 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)

[0606] 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 4 M 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-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazin-9(7H)-yl)methanone hydrochloride (39-b, 58 mg, yield 119.78%). ESI [M+H] + =371.2,ESI[2M+H] + =741.4

[0607] 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)

[0608] 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). Allow to react at room temperature for 5 minutes. After monitoring the pH between 8 and 9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a 10:1 solution of dichloromethane:methanol by ultrasonication 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%).

[0609] 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)

[0610] ((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, 0.211 mmol) and 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 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%-80% over 22min] purification to give 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, 2.44 mg, yield 3.18%). ESI [M+H] + =547.3,ESI[2M+H] + =1093.5

[0611] 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)

[0612] 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)

[0613] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (260 mg, 0.743 mmol) was dissolved in N,N-dimethylformamide (10 ml), and 1H-benzotriazol-1-yloxytripyrrolidinyl 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, After reacting for 2 hours at room temperature, the reaction solution was quenched with water (15 ml) 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 normal phase column chromatography (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]pyrido[3,2-b][1,4]oxazepane-9-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (40-a, 177 mg, yield 42.96%). ESI[M-56+H] + =401.3

[0614] Step 2: Preparation of (S)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazolidin-9-yl)methanone (40-b)

[0615] (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[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, and the mixture was reacted at room temperature for 3 hours, 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 on 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]pyrido[3,2-b][1,4]oxazolidin-9-yl)methanone (40-b, 50 mg, yield 36.7%). ESI [M+H] + =357.3.

[0616] Step 3: 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)

[0617] (S)-azetidin-3-yl(3-(trifluoromethyl)-6,7,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[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 product was purified by TLC (dichloromethane:methanol=10:1) and purified by HPLC [Pack Column 20 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 (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, 1.51 mg, 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).

[0618] 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]oxazo[9-carbonyl]cyclobutyl)amino)methyl)pyridazin-3(2H)-one (41)

[0619] 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)

[0620] (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-yloxytripyrrolidinyl 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 μg, 400 μmol) were added. l, 1.94 mmol), reacted at room temperature for 2 hours, the reaction solution was quenched with water (15 ml), 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 chromatography (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]pyrido[3,2-b][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (41-a, 201 mg, yield 66.2%). ESI [M+H] + =471.3,ESI[M-56+H] + =415.3

[0621] Step 2: Preparation of (((1R,3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxathiophene-9-yl)methanone (41-b)

[0622] 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, and the mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure, water (1 ml) was added, and the mixture was washed with N The pH was adjusted to 8 with aHCO3 solution, and the mixture was extracted with dichloromethane:methanol = 8:1. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the target product (((1R,3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazoxazone-9-yl)methanone (41-b, 96 mg, yield 60.6%). ESI [M+H] + =371.4

[0623] 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]pyrido[3,2-b][1,4]oxazoline-9-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (41)

[0624] (((1R,3S)-3-aminocyclobutyl)((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxathiophen-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 product was purified by TLC (dichloromethane:methanol=10:1) and purified by HPLC [Pack Column 20 ID*250 mm*10 μm; A:H2O(0.1% FA), B:ACN, B%: 10%-100% over 25min] Preparation and purification to give 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]oxazoline-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).

[0625] 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)

[0626] Step 1: Preparation of tert-butyl (R)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidine-1-carboxylate (42-a)

[0627] 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-yloxytripyrrolidinyl 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, After reacting for 2 hours at room temperature, the reaction solution was quenched with water (10 ml) 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 normal phase column chromatography (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]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidine-1-carboxylate (42-a, 110 mg, yield 67.9%). ESI[M-56+H] + =401.2

[0628] Step 2: Preparation of (R)-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 (42-b)

[0629] 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]pyrido[2,3-e][1,4]oxetane-9(7H)-yl)methanone (42-b, 100 mg, crude). ESI[M+H] + =357.3

[0630] 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)

[0631] (R)-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 (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 product was purified by normal phase column chromatography (dichloromethane:methanol=10:1) and purified by high performance liquid chromatography [Pack Column 20 ID*250 mm*10 μm; 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]pyrido[2,3-e][1,4]oxirane-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).

[0632] 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)

[0633] 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)

[0634] (1R,3R)-3-((tert-Butoxycarbonyl)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), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (111 mg, 0.213 mmol) were dissolved in N,N-dimethylformamide (4 ml). Triethylamine (74 μl, 0.533 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was added to water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (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]pyrido[2,3-e][1,4]oxathiophene-9-carbonyl)cyclobutyl)carbamate (43-a, 72 mg, yield 86.18%). ESI [M+H] + =471.4

[0635] 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)

[0636] 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 4 M 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]pyrido[2,3-e][1,4]oxirane-9(7H)-yl)methanone hydrochloride (43-b, 67 mg, yield 107.62%). ESI [M+H] + =371.2

[0637] Step 3 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 (43-c)

[0638] Dissolve ((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, 67 mg, 0.165 mmol) in water (2 ml) and add sodium bicarbonate (28 mg, 0.329 mmol). Let react at room temperature for 5 minutes. After monitoring the pH between 8 and 9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a 10:1 solution of dichloromethane:methanol by ultrasonication 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%).

[0639] 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)

[0640] ((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 plates (dichloromethane:methanol=10:1), and then purified by preparative liquid chromatography [Pack Column 30ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-80% over 22min] purification to give 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, 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).

[0641] 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)

[0642] Step 1: Preparation of tert-butyl (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidine-1-carboxylate (44-a)

[0643] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (43 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), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (111 mg, 0.213 mmol) were dissolved in N,N-dimethylformamide (4 ml). Triethylamine (74 μl, 0.533 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction solution was added to water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, 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 (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxirane-9-carbonyl)azetidine-1-carboxylate (44-a, 65 mg, yield 80.19%). ESI [M+H] + =457.2,ESI[M+H-56] + =401.2

[0644] Step 2: Preparation of (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 hydrochloride (44-b)

[0645] Tert-butyl (S)-3-(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxetane-9-carbonyl)azetidine-1-carboxylate (44-a, 65 mg, 0.142 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, (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 hydrochloride (44-b, 60 mg, yield 107.27%). ESI[M+H] + =357.2

[0646] 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)

[0647] Dissolve (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 hydrochloride (44-b, 60 mg, 0.152 mmol) in water (2 ml) and add sodium bicarbonate (27 mg, 0.305 mmol). Allow to react at room temperature for 5 minutes. After monitoring the pH between 8 and 9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a 10:1 solution of dichloromethane:methanol by ultrasonication 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%).

[0648] 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)

[0649] (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 chromatography [Pack Column 30ID*250mm*10μm; A:H2O(0.1%FA), B:ACN, B%: 5%-80% over 22min] purification to give (S)-4-(trifluoromethyl)-6-((3-(3-(trifluoromethyl)-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, 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).

[0650] 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)

[0651] Step 1: Preparation of tert-butyl (1R,3R)-3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (45-a)

[0652] (1R, 3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (64 mg, 0.299 mmol) was dissolved in dichloromethane (5 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.299 mmol) was added and stirred for 10 minutes. 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)-tert-butyl 3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (45-a, 114 mg, yield 83.17%). ESI [M+H] + =459.0

[0653] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (45-b)

[0654] 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 and ethyl acetate (3 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,3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (45-b, 118 mg, yield 120.20%).

[0655] Step 3 Preparation of ((1R, 3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (45-c)

[0656] ((1R,3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (45-b, 118 mg, 0.299 mmol) was dissolved in water (2 ml) and sodium bicarbonate (51 mg, 0.598 mmol) was added. The mixture was allowed to react at room temperature for 5 minutes. After monitoring the pH at 8-9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a solution of dichloromethane:methanol (10:1) by ultrasonication and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product, ((1R,3R)-3-aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (45-c, 106 mg, 98.97% yield).

[0657] 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)

[0658] ((1R,3R)-3-Aminocyclobutyl)(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (45-c, 106 mg, 0.296 mmol) and 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. The product was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by preparative liquid phase [Pack Column 30 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 5%-80% over 22min], and then purified twice by Flash chromatography (silica gel column 8g, dichloromethane:methanol = 10:1) to give 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).

[0659] 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)

[0660] Step 1: Preparation of tert-butyl 3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (46-a)

[0661] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (60 mg, 0.299 mmol) was dissolved in dichloromethane (5 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.299 mmol) was added and stirred for 10 minutes. 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

[0662] Step 2: Preparation of azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (46-b)

[0663] Tert-butyl 3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (46-a, 119 mg, 0.268 mmol) was dissolved in 4M hydrochloric acid and ethyl acetate (3 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, azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (46-b, 119 mg, yield 116.72%).

[0664] Step 3: Preparation of azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (46-c)

[0665] Azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone hydrochloride (46-b, 119 mg, 0.313 mmol) was dissolved in water (2 ml) and sodium bicarbonate (53 mg, 0.626 mmol) was added. The mixture was allowed to react at room temperature for 5 minutes. After monitoring the pH at 8-9, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in a solution of dichloromethane:methanol (10:1) by ultrasonication and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product, azetidin-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (46-c, 103 mg, 95.72% yield).

[0666] 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)

[0667] Azetidine-3-yl(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methanone (46-c, 103 mg, 0.299 mmol) and 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, 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 give 6-((3-(4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)methyl)-4-(trifluoromethane)pyridazin-3(2H)-one (46, 9.83 mg, 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).

[0668] 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)

[0669] Step 1: Preparation of tert-butyl ((1R,3R)-3-(4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (47-a)

[0670] (1R,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (73.6 mg, 0.342 mmol) was dissolved in N,N-dimethylformamide (3 ml), and 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. After stirring in an ice bath for 20 minutes, 2-(piperazin-1-yl)- 5-(Trifluoromethyl)nicotinonitrile hydrochloride (I-14, 100 mg, 0.342 mmol) was reacted at room temperature for 4 hours. Water (20 ml) was then 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 give the target product, tert-butyl ((1R,3R)-3-(4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (47-a, 131 mg, yield 84.5%). ESI [M-56+H] + =398.2

[0671] Step 2: Preparation of 2-(4-((1R,3R)-3-aminocyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (47-b)

[0672] 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) was dissolved in ethyl acetate (2 ml), and a 4M 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 the pH was adjusted to 8 with NaHCO₃. The mixture was extracted with dichloromethane:methanol in a ratio of 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, 2-(4-((1R,3R)-3-aminocyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinonitrile (47-b, 118 mg, crude product). ESI [M+H] + =354.3

[0673] 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)

[0674] 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 product 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 25min] Preparation and purification gave 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).

[0675] 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)

[0676] 6-(2-Bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 40 mg - 50%, 0.14 mmol) and ((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 completion of the reaction, the filtrate was concentrated under reduced pressure and purified on a 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)prop-2-yl)pyridazin-3(2H)-one (48, 14.23 mg, 18.92% yield). 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).

[0677] 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)

[0678] 6-(2-Bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 30 mg, purity 50%, 0.11 mmol) and 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 hour. No obvious product was produced after the reaction. The pH was adjusted to weak alkalinity with aqueous sodium bicarbonate solution and the reaction was continued overnight. After the reaction, the filtrate was concentrated under reduced pressure and purified once on a silica gel preparative plate (dichloromethane:methanol = 10:1), followed by a second purification on a preparative liquid phase [Pack Column 30 ID*250 mm*15 μm; A: H2O (0.1% FA), B:CAN, B%: 10%-95% over 25 min] to afford the desired 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 mg, 5.11 mg, 9.4% yield). 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).

[0679] 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)

[0680] Step 1: Preparation of tert-butyl (1R,3R)-3-(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (50-a)

[0681] (1R, 3R)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (96.2 mg, 0.447 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 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. After stirring for 20 minutes under ice bath, 1-(3,5-bis( After reacting for 4 hours 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, tert-butyl (1R,3R)-3-(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (50-a, 80 mg, yield 36.2%). ESI [M-56+H] + =441.2

[0682] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (50-b)

[0683] Dissolve tert-butyl (1R,3R)-3-(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (50-a, 80 mg, 0.161 mmol) in ethyl acetate (2 ml). Add 4M hydrochloric acid in ethyl acetate (3 ml). The mixture is reacted at room temperature for 3 hours and then concentrated under reduced pressure. Water (1 ml) is added and the pH is adjusted to 8 with NaHCO₃. Extraction is performed with dichloromethane:methanol = 8:1. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to obtain the target product ((1R,3R)-3-aminocyclobutyl)(4-(3,5-bis(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (50-b, 78 mg, crude). ESI [M+H] + =397.2

[0684] 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)

[0685] ((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 product 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 25min] Preparation and purification gave 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).

[0686] 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)

[0687] Azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (5-b, 75.7 mg, 0.240 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-5-cyclobutoxypyridazin-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 (dichloromethane: methanol = 10:1) and then 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 gave 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).

[0688] Example 52: Preparation of 5-cyclobutoxy-6-(((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (52)

[0689] ((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 (dichloromethane: methanol = 10:1) and then 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 gave the target product 5-cyclobutoxy-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).

[0690] 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)

[0691] Step 1: Preparation of tert-butyl (1R,3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (53-a)

[0692] (1R,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (245 mg, 1.138 mmol) and 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 then 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. The reaction was allowed to proceed at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure and then purified using a flash column (petroleum ether:ethyl acetate = 1:1) to obtain the target product, tert-butyl (1R,3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (53-a, 330 mg, yield 54%). ESI [M+H] + =443.4

[0693] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (53-b)

[0694] Tert-butyl (1R,3R)-3-(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (53-a, 300 mg) was dissolved in ethyl acetate (4 ml), and then hydrogen chloride in ethyl acetate (4 mL) was added. The mixture was allowed to react at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and concentrated again under reduced pressure. This was repeated twice, and then aqueous sodium bicarbonate was slowly added to a pH of 7-9. After filtration, the solution was partially concentrated under reduced pressure to obtain the target product, ((1R,3R)-3-aminocyclobutyl)(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (53-b, 300 mg, crude). ESI [M+H] + =343.4

[0695] 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)

[0696] ((1R,3R)-3-aminocyclobutyl)(4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (53-b, 150 mg, 0.44 mmol) and 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 was prepared [Pack Column 30 ID*250 mm*15 μm; A: H2O (0.1% FA), B: ACN, B%: 10%-95% over The reaction mixture was purified twice to give 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).

[0697] 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)

[0698] Azetidin-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (5-b, 39 mg, 0.124 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18, 29 mg, 0.113 mmol) was added and the reaction was allowed to proceed at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by TLC preparative plate (dichloromethane:methanol = 10:1). High-performance liquid chromatography (HPLC) [Pack Column 30 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-60% over 30 min] was used to obtain the desired 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, 1.44% yield). 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).

[0699] 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)

[0700] ((1R,3R)-3-aminocyclobutyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone (41 mg, 0.124 mmol) was dissolved in dichloromethane (2 ml), and 6-(bromomethyl)-5-(trifluoromethyl)pyridazin-3(2H)-one (I-18, 29 mg, 0.113 mmol) was added and the reaction was allowed to react at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by TLC plate (dichloromethane:methanol = 10:1) followed by high performance preparative liquid chromatography (HPLC) [Pack Column 30 ID*250 mm*10 μm; A: H2O (0.1% FA), B:ACN, B%: 10%-60% over 30 min] to afford the desired product, 5-(trifluoromethyl)-6-((((1R,3R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclobutyl)amino)methyl)pyridazin-3(2H)-one (55 mg, 1.34 mg, 2.35% yield). ESI [M+H] + =506.51 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).

[0701] 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)

[0702] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (56-a)

[0703] (1R, 3R)-3-(tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (202 mg, 1.01 mmol) was dissolved in dichloromethane (14 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (384 mg, 1.25 mmol) was added and stirred for 10 minutes. N,N-diisopropylethylamine (528 μl, 3.03 mmol) and 1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-23, 310 mg, 1.01 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 chromatography (25 g silica gel column, 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

[0704] Step 2: Preparation of ((1R,3R)-3-aminocyclobutyl)(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (56-b)

[0705] 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 and ethyl acetate (3 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure. Water (1 ml) was added, and the pH was adjusted to 8 with NaHCO₃. The mixture was extracted with (dichloromethane:methanol = 10:1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product ((1R,3R)-3-aminocyclobutyl)(4-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (56-b, 135 mg, yield 92.75%). ESI [M+H] + =369.4

[0706] 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)

[0707] (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 then purified by thin layer chromatography on silica gel (dichloromethane: methanol = 10:1). The reaction mixture was purified by preparative liquid chromatography [Pack Column 30 ID*250 mm*10 μm; A: H2O (0.1% FA), B: ACN, B%: 5%-80% over 25min] purification to give 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).

[0708] 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)

[0709] Step 1: Preparation of tert-butyl 3-(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (57-a)

[0710] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (97 mg, 0.48 mmol) was dissolved in dichloromethane (8 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (184 mg, 0.48 mmol) was added and stirred for 10 minutes. 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 purified by Flash chromatography (10 g silica gel column, 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

[0711] Step 2: Preparation of azetidin-3-yl(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (57-b)

[0712] 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 and ethyl acetate (3 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure. Water (1 ml) was added, and the pH was adjusted to 8 with NaHCO₃. The mixture was extracted with (dichloromethane:methanol = 10:1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product, azetidin-3-yl(4-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (57-b, 150 mg, yield 94.34%). ESI [M+H] + =345.2

[0713] 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)

[0714] Azetidin-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 (dichloromethane: methanol = 10:1). The product was then purified by preparative liquid chromatography [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).

[0715] 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)

[0716] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (58-a)

[0717] (1R, 3R)-3-(tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (100 mg, 0.32 mmol) was dissolved in dichloromethane (6 ml), and O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123 mg, 0.32 mmol) was added and stirred for 10 minutes. N,N-diisopropylethylamine (169 μl, 0.97 mmol) and 1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-20, 100 mg, 0.32 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 chromatography (10 g silica gel column, 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

[0718] Step 2: Preparation of (1R, 3R)-3-aminocyclobutyl)(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (58-b)

[0719] 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 and ethyl acetate (3 ml) and reacted at room temperature for 2 hours, then concentrated under reduced pressure. Water (1 ml) was added, and the pH was adjusted to 8 with NaHCO3. The mixture was extracted with (dichloromethane:methanol = 10:1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (1R,3R)-3-aminocyclobutyl)(4-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (58-b, 120 mg, yield 95.24%). ESI [M+H] + =373.2

[0720] 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)

[0721] (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-bromoprop-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (I-17, 100 mg, purity 6%, 21.05 μmol) was added. After 1.5 hours of reaction at room temperature, the reaction mixture was evaporated under reduced pressure and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) and then purified by HPLC (Pack Column 30 ID*250mm*10μm; A:H2O (0.1% FA), B:ACN, B%: 10%-100% over 45 min) to obtain the desired 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 mg, 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).

[0722] 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)

[0723] ((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-bromoprop-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 chromatography [Pack Column 30 ID*250 mm*10 μm; A: H2O (0.1% TFA), B: ACN, B%: 10%-80% over 40 min] and lyophilized to give 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).

[0724] 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)

[0725] Step 1: Preparation of tert-butyl ((1R, 3R)-3-(4-(3-carbamoyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (60-a)

[0726] (1R, 3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (69.4 mg, 0.323 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 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. After stirring for 20 minutes under ice bath, 2-(piperazin-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. 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 ((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

[0727] Step 2: Preparation of 2-(4-((1R,3R)-3-aminocyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinamide (60-b)

[0728] ((1R,3R)-3-(4-(3-carbamoyl-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)cyclobutyl)carbamate (60-a, 120 mg, 0.255 mmol) was dissolved in ethyl acetate (2 ml), and a 4M 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 the pH was adjusted to 8 with NaHCO3. 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, 2-(4-((1R,3R)-3-aminocyclobutane-1-carbonyl)piperazin-1-yl)-5-(trifluoromethyl)nicotinamide (60-b, 40 mg, 43% yield...

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 for 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- The 3-aminoacyl 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 halogen 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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