Pyridazinopyridone derivatives and uses thereof

Abstract

Relates to the technical field of medicines, in particular to a pyridazinopyridone derivative used as an SOS1 protein inhibitor and application of the pyridazinopyridone derivative. The compound provided by the invention has an obvious inhibition effect on the activity of the SOS1 protein, can be used as an SOS1 protein inhibitor, is good in druggability, can be used for preparing medicines for treating diseases such as SOS1 protein mediated cancers and pathogenic rash, and has a wide application prospect.

Description

Pyridazinopyridone derivatives and uses thereof Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a class of pyridazine-pyridone derivatives used as SOS1 protein inhibitors and uses thereof. Background Art

[0002] SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells. As a guanine nucleotide exchange factor for Ras or Rac1 protein, it plays an important regulatory role in the intracellular Ras or Rac1 signal transduction pathway (Baltanás, FC; Zarich, N.; Rojas- JM; Santos, E. Biochim. Biophys. Acta. Rev. Cancer. 2020, 1874, 188445). The role of SOS1 protein in the Ras signal transduction pathway is to promote the release of GDP from Ras and bind to GTP, thereby converting the Ras protein from an inactive state to an active state.

[0003] There are three genes in the RAS family known to date: KRAS, NRAS, and HRAS. Mutations in RAS enzymes are closely associated with tumorigenesis, with mutations detected in approximately 25% of all tumors (de Castro J.; Belda-Iniesta C.; Transl Lung Cancer Res. 2013, 2(2), 142-51.), RAS mutation types vary in different tumor types. RAS mutations (KRAS, NRAS, HRAS) are present in 90% of pancreatic cancers, 45% of colon cancers, and 35% of lung cancers. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases (Jemal, B.; et al, CA Cancer J. Clin. 2011, 61(2), 69-90), and Ras proto-oncogene is the most commonly mutated gene in NSCLC (Prior, L. et al, Cancer Res. 2012, 72(10), 2457-2467; Li, L. et al, J Exp Clin Cancer Res. 2018, 37(1), 178), among which v-Ki-ras2Kirsten rat sarcoma viral oncogene (Kras) accounts for 90% of RAS mutations in lung adenocarcinoma (Hunter, JC; et al, Mol. Cancer Res. 2015, 13(9), 1325-35).

[0004] As the "pacemaker" of Kras, SOS1 plays an important regulatory role in many signal transduction pathways in cells. Studies have shown that inhibiting SOS1 activity has an effective inhibitory effect on the proliferation of cancer cells caused by all major Kras gene mutations (Kessler, D.; Gerlach, D.; Kraut, N., McConnell, DB Curr. Opin. Chem. Biol. 2021, 62, 109-118). In addition, a clinical study in 62 patients with ovarian cancer showed that RAS mutations and SOS1 mutations were significantly increased in ovarian cancer tissues, and were associated with a shortened PFS in patients with prognosis, suggesting that RAS and SOS1 targeted therapy has potential value in patients with ovarian cancer. At the same time, SOS1 gene mutations have also been found in many other cancer cells, such as embryonal rhabdomyosarcoma, Sertoli cell testicular tumors, cutaneous granulosa cell tumors (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3): 242-52) and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature 2014, 511(7511), 543-50). In addition, studies have found that the SOS1 gene is highly expressed in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49(4), 317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009, 35(4): 751-60). In the development and progression of chronic myeloid leukemia, BCR-ABL activates GRB2 by phosphorylation and recruits SOS1, thereby continuously activating the Ras / MAPK signaling pathway, leading to the malignant proliferation of hematopoietic stem cells. Therefore, SOS1 protein is also a potential new target for the treatment of chronic myeloid leukemia. In addition to cancer, studies have shown that hereditary SOS1 gene mutations are also closely related to some pathogenic rash diseases such as Noonan syndrome (NS), cardiofacial cutaneous syndrome (CFC) and hereditary gingival fibromatosis type I (Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56).

[0005] SOS1 inhibition is mechanistically similar to SHP2 inhibition (Nichols, RJ; et al. Nat Cell Biol. 2018, 20(9), 1064-1073), suggesting that SOS1 inhibition can also enhance KRAS G12CPreliminary data showed significant synergy between SOS1 and MEK inhibition in multiple PDX models with G12 and G13 KRAS mutations (Hofmann, MH; et al; Cancer Discov. 2020, 10.1158 / 2159-8290.CD-20-0142.). In addition to inhibiting Kras wt In addition to feedback activation of KRAS G12C Allosteric inhibitors can only bind to KRAS GDP Inhibition of SOS1 by increasing mutant KRAS G12C to directly increase the number of KRAS G12C The potential advantage of the efficacy of inhibitors (Hillig, RC, et al, Proc Natl Acad Sci US A. 2019, 116(7), 2551-2560). Although further research is needed, as a combination therapy strategy, inhibition of SOS1 has great potential for clinical application.

[0006] Currently, there are still no drugs targeting the SOS1 target on the market worldwide, and the compounds under development are all in the early clinical or preclinical research stage. Although a few pharmaceutical research companies or research institutions have conducted corresponding research on SOS1 inhibitors and have published relevant patents, such as Boehringer Ingelheim's disclosure of a class of benzylamine-substituted quinazoline derivatives as SOS1 inhibitors (US20190358230A1) and Bayer Pharmaceuticals' disclosure of a class of 2-methyl-azaquinazoline compounds as SOS1 inhibitors (WO2019201848A1), the SOS1 inhibitors currently developed are far from meeting clinical needs, and the development of new SOS1 inhibitors still has very broad clinical application prospects.

[0007] Summary of the Invention

[0008] The main technical problem solved by the present invention is to provide a class of pyridazine pyridone derivatives that have a potent and selective inhibitory effect on SOS1.

[0009] To solve the above technical problems, the present invention provides a compound represented by Formula I, or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, and cocrystals:

[0010] in:

[0011] Ring A is selected from aryl, heteroaryl, wherein the aryl, heteroaryl is optionally selected from halogen, alkyl, alkoxy, -OH, -CN, -NR5R6, -SF5, -SO2R 12The alkyl and alkoxy groups may be further substituted by substituents selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H, alkyl, R 12 is alkyl and is optionally substituted with halogen;

[0012] R a 、R b 、R c Independently selected from H, alkyl;

[0013] R1, R3, R4 are independently selected from H, halogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, alkylthio, -OH, -CN, -NR7R8, -C(=O)H, -C(=O)NR 19 R 20 、-C(=O)OR 21 The alkyl and alkoxy groups may be optionally substituted by a substituent selected from halogen, -NR7R8, wherein R7, R8, R 19 、R 20 、R 21 Independently selected from H, alkyl;

[0014] R2 is -XR 13 , X is selected from alkylene, a single bond, R 13 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein:

[0015] When R 13 When X is an alkyl group, it is a single bond, and the alkyl group can be optionally selected from -OH, alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 、-NR 22 R 23 Substituted by a substituent, R9, R 10 、R 11 、R 22 、R 23 Independently selected from H, alkyl;

[0016] When R 13 When selected from aryl, heteroaryl, optionally selected from halogen, alkyl, alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, alkyl;

[0017] When R 13 When selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, optionally selected from halogen, alkyl, -YR 16The alkyl group may be further substituted by a substituent selected from halogen, -OH, alkoxy, -NR 17 R 18 wherein:

[0018] Y is an alkylene group, R 16 is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl;

[0019] Alternatively, Y is selected from R 16 Selected from alkyl, alkoxy, -NR 17 R 18 , cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl;

[0020] R 17 、R 18 Independently selected from H, alkyl.

[0021] Furthermore, ring A is selected from aryl and heteroaryl, and the aryl and heteroaryl are optionally substituted by substituents selected from halogen, alkyl, alkoxy, -OH, -CN, and -NR5R6, and the alkyl and alkoxy are optionally further substituted by substituents selected from halogen and -NR5R6, wherein R5 and R6 are independently selected from H and alkyl.

[0022] Furthermore, ring A is selected from 6- to 12-membered aryl groups and 5- to 12-membered heteroaryl groups, wherein the heteroaryl group contains a heteroatom selected from N, O, and S, and the substituents of the above groups are as defined above.

[0023] Preferably, ring A is selected from a 6-membered aryl group and a 5- to 11-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S. The substituents of the above groups are as defined above.

[0024] Preferably, ring A is selected from 6-membered aryl, 6-membered aryl-5-membered heteroaryl, wherein the heteroaryl contains one heteroatom selected from N, O, and S, and the substituents of the above groups are as defined above.

[0025] Preferably, ring A is selected from phenyl and phenyl-thienyl, and the substituents of the above groups are as defined above.

[0026] Preferably, ring A is phenyl, and its substituents are as defined above.

[0027] Furthermore, the substituent contained in ring A is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR5R6, -SF5, -SO2R 12 The alkyl and alkoxy groups may be further substituted by a substituent selected from halogen and -NR5R6, wherein R5 and R6 are independently selected from H, C1-C6 alkyl, and R12 It is a C1-C6 alkyl group and is optionally substituted by halogen.

[0028] Preferably, the substituent contained in ring A is selected from halogen, C1-C6 alkyl, -CN, -NR5R6, -SF5, -SO2R 12 The alkyl group may be further substituted by a substituent selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H, C1-C6 alkyl, R 12 It is a C1-C6 alkyl group and is optionally substituted by halogen.

[0029] Preferably, the substituent contained in ring A is selected from -F, methyl, -F substituted methyl, -NR5R6 substituted methyl, -CN, -NR5R6, -SF5, -SO2R 12 , wherein R5 and R6 are independently selected from H, methyl, R 12 It is a methyl group substituted with -F.

[0030] Preferably, the substituent contained in ring A is selected from -F, -CH3, -CHF2, -CF3, -CH2NHCH3, -CN, -NH2, -SF5, -SO2CHF2.

[0031] Furthermore, the substituent contained in ring A is selected from halogen, alkyl, and -CN, and the alkyl is optionally further substituted by a substituent selected from halogen and -NR5R6, wherein R5 and R6 are independently selected from H and alkyl.

[0032] Preferably, the substituent contained in ring A is selected from halogen, C1-C6 alkyl, -CN, and the alkyl is optionally further substituted by a substituent selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H, C1-C6 alkyl.

[0033] Preferably, the substituent contained in ring A is selected from -F, methyl, methyl substituted by -F, methyl substituted by -NR5R6, and -CN, wherein R5 and R6 are independently selected from H and methyl.

[0034] Preferably, the substituent contained in ring A is selected from -F, -CH3, -CHF2, -CF3, -CH2NHCH3, -CN, and -NH2.

[0035] Further, Ring A is selected from:

[0036] Preferably, Ring A is selected from:

[0037] Furthermore, R a 、R b 、R cIndependently selected from H, C1-C6 alkyl.

[0038] Preferably, R a 、R b 、R c Independently selected from H, methyl.

[0039] Preferably, R a is methyl, R b H, R c For H.

[0040] Furthermore, the compound structure is shown in Formula II:

[0041] Wherein each group is as defined in any of the above technical solutions.

[0042] Furthermore, R1, R3, and R4 are independently selected from H, alkyl, alkoxy, -OH, -CN, and -NR7R8, and the alkyl and alkoxy groups are optionally substituted by substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and alkyl.

[0043] Preferably, R1, R3, and R4 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, and -NR7R8, and the alkyl and alkoxy groups are optionally substituted with substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and C1-C6 alkyl.

[0044] Preferably, R1, R3, and R4 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, and -CN.

[0045] Preferably, R1, R3, and R4 are independently selected from H, methyl, methoxy, -OH, and -CN.

[0046] Preferably, R1 is selected from H, methyl, methoxy, -CN. Preferably, R3 is H. Preferably, R4 is selected from methyl, methoxy, -OH.

[0047] Furthermore, R1, R3, and R4 are independently selected from H, alkyl, alkoxy, -OH, and -NR7R8, and the alkyl and alkoxy groups are optionally substituted by substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and alkyl.

[0048] Preferably, R1, R3, and R4 are independently selected from H and alkyl.

[0049] Preferably, R1, R3, and R4 are independently selected from H and C1-C6 alkyl.

[0050] Preferably, R1, R3, and R4 are independently selected from H and methyl.

[0051] Preferably, R1 is H. Preferably, R3 is H. Preferably, R4 is methyl.

[0052] Furthermore, R1 and R3 are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -NR7R8, and the alkyl and alkoxy groups are optionally substituted with substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and C1-C6 alkyl.

[0053] Preferably, R1 and R3 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, and -CN.

[0054] Preferably, R1 and R3 are independently selected from H, methyl, methoxy, and -CN.

[0055] Preferably, R1 is selected from H, methyl, methoxy, -CN. Preferably, R1 is selected from H, methyl, methoxy. Preferably, R3 is H.

[0056] Furthermore, R4 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -C(=O)H, -C(=O)NR 19 R 20 、-C(=O)OR 21 , the alkyl group is optionally substituted with halogen, wherein R 19 、R 20 、R 21 Independently selected from H, C1-C6 alkyl.

[0057] Preferably, R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, 3-5 membered cycloalkyl, 5 membered cycloalkenyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -C(=O)H, -C(=O)NR 19 R 20 、-C(=O)OR 21 , the alkyl group is optionally substituted with halogen, wherein R 19 、R 20 、R 21 Independently selected from H, C1-C6 alkyl.

[0058] Preferably, R4 is selected from C1-C6 alkyl, -OH.

[0059] Preferably, R4 is selected from methyl, ethyl, difluoromethyl, vinyl, cyclopropane, cyclopentenyl, methoxy, methylthio, -OH, -CN, -C(=O)H, -C(=O)NH2, -C(=O)N(CH3)2, -C(=O)OH, -C(=O)OCH3.

[0060] Furthermore, R4 is halogen.

[0061] Preferably, R4 is chlorine.

[0062] Furthermore, when R 13 When X is an alkyl group, it is a single bond, and the alkyl group can be optionally selected from -OH, alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 Substituted by a substituent, R9, R 10 、R 11 Independently selected from H, alkyl.

[0063] Further, R2 is -XR 13 , X is a single bond, R 13 C1~C6 alkyl, wherein the C1~C6 alkyl is optionally selected from -OH, C1~C6 alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 、-NR 22 R 23 Substituted by a substituent, R9, R 10 、R 11 、R 22 、R 23 Independently selected from H, C1-C6 alkyl.

[0064] Preferably, R2 is -XR 13 , X is a single bond, R 13 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally selected from -OH, halogen, -C(=O)NR9R 10 、-NR 22 R 23 Substituted by a substituent, R9, R 10 、R 22 、R 23 Independently selected from C1 to C6 alkyl.

[0065] Preferably, R2 is -XR 13 , X is a single bond, R 13 It is a C1-C6 alkyl group, which is optionally substituted by a substituent selected from -OH, -F, -C(=O)N(CH3)2, and -N(CH3)2.

[0066] Preferably, R2 is selected from -CH3,

[0067] Further, R2 is -XR 13 , X is a single bond, R 13 C1~C6 alkyl, wherein the C1~C6 alkyl is optionally selected from -OH, C1~C6 alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 Substituted by a substituent, R9, R 10 、R 11 Independently selected from H, C1-C6 alkyl.

[0068] Preferably, R2 is -XR 13 , X is a single bond, R 13 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally selected from -OH, halogen, -C(=O)NR9R 10 Substituted by a substituent, R9, R 10 Independently selected from C1 to C6 alkyl.

[0069] Preferably, R2 is -XR 13 , X is a single bond, R 13 It is a C1-C6 alkyl group, which is optionally substituted by a substituent selected from -OH, -F, and -C(=O)N(CH3)2.

[0070] Preferably, R2 is selected from -CH3,

[0071] Further, R2 is -XR 13 , X is selected from C1-C3 alkylene, a single bond, R 13 Selected from 6-12 membered aryl, 5-12 membered heteroaryl, the heteroaryl contains a heteroatom selected from N, O, S, and the aryl and heteroaryl are optionally selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, C1-C6 alkyl.

[0072] Preferably, R2 is -XR 13 , X is a methylene group, a single bond, R 13 is phenyl, 5-6 membered heteroaryl, the heteroaryl contains 1-2 heteroatoms selected from N, O, S, and the phenyl and heteroaryl are optionally selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR 14 R 15Substituents, R 14 、R 15 Independently selected from H, C1-C6 alkyl.

[0073] Preferably, R2 is -XR 13 , X is a single bond, R 13 is pyridyl or pyrimidinyl, and the pyridyl or pyrimidinyl is optionally substituted by a C1-C6 alkoxy group.

[0074] Preferably, R2 is selected from

[0075] Further, R2 is -XR 13 , X is a methylene group, a single bond, R 13 is phenyl, 5-6 membered heteroaryl, the heteroaryl contains one heteroatom selected from N, O, S, and the phenyl and heteroaryl are optionally selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, C1-C6 alkyl.

[0076] Preferably, R2 is -XR 13 , X is a single bond, R 13 is pyridyl, and the pyridyl is optionally substituted by a C1-C6 alkoxy group.

[0077] Preferably, R2 is

[0078] Further, R2 is -XR 13 , X is selected from C1-C3 alkylene, a single bond, R 13 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl groups contain heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further selected from halogen, -OH, C1-C6 alkoxy, -NR 17 R 18 substituted by a substituent.

[0079] Preferably, R2 is -XR 13 , X is selected from C1-C3 alkylene, a single bond, R 13is selected from 3 to 10 membered cycloalkyl, 3 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl contains a heteroatom selected from N, O, and S, and the cycloalkyl and heterocycloalkyl are optionally selected from halogen, C1 to C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by a substituent selected from halogen and -OH.

[0080] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from 3 to 10-membered cycloalkyl, 4 to 8-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O, and S, and the cycloalkyl and heterocycloalkyl are optionally selected from halogen, C1 to C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by a substituent selected from halogen and -OH.

[0081] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, adamantyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by a substituent selected from halogen and -OH.

[0082] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from 3-6 membered cycloalkyl, 5-8 membered heterocycloalkyl, the heterocycloalkyl contains 1-2 heteroatoms selected from N, O, S, the cycloalkyl, heterocycloalkyl can be selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by a substituent selected from halogen and -OH.

[0083] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by a substituent selected from halogen and -OH.

[0084] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from 3 to 6 membered cycloalkyl, wherein the cycloalkyl is optionally selected from halogen, C1 to C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by halogen.

[0085] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the above groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by halogen.

[0086] Furthermore, R 17 、R 18 Independently selected from H, C1-C6 alkyl.

[0087] Preferably, R 17 、R 18 Independently selected from H, methyl.

[0088] Preferably, R 17 、R 18 All are methyl.

[0089] Further, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 Selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, adamantyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from -F, methyl, substituted by a substituent, wherein the methyl group is optionally further substituted by a substituent selected from -F, -OH.

[0090] Preferably, R2 is selected from:

[0091] Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 Selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from -F, methyl, substituted by a substituent, wherein the methyl group is optionally further substituted by a substituent selected from -F, -OH.

[0092] Preferably, R2 is selected from:

[0093] Further, R2 is -XR 13 , X is a single bond, R 13 Selected from cyclopropane, cyclobutane, cyclopentane and cyclohexane, the above groups are optionally substituted by substituents selected from -F and methyl, wherein the methyl group is optionally further substituted by -F.

[0094] Preferably, R2 is selected from:

[0095] Furthermore, Y is a C1-C3 alkylene group, R 16 Selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl and heteroaryl contain a heteroatom selected from N, O and S.

[0096] Preferably, Y is C1-C3 alkylene, R 16 It is a 3- to 10-membered heterocycloalkyl group containing one heteroatom selected from N, O, and S.

[0097] Preferably, Y is methylene, R 16 is a 5-membered heterocycloalkyl group containing one heteroatom selected from N, O, and S.

[0098] Preferably, Y is methylene, R 16 It is a tetrahydropyrrolyl group.

[0099] Furthermore, R2 is

[0100] Furthermore, Y is selected from R 16 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 17 R 18, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, the heterocycloalkyl, heterocycloalkenyl and heteroaryl containing a heteroatom selected from N, O and S.

[0101] Preferably, Y is selected from R 16 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 17 R 18 , 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S.

[0102] Preferably, Y is selected from R 16 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 17 R 18 , 5- to 6-membered heterocycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1 to 2 heteroatoms selected from N and O.

[0103] Preferably, Y is selected from R 16 Selected from methyl, methoxy, -N(CH3)2, morpholinyl, phenyl, isoxazolyl.

[0104] Further, R2 is selected from

[0105] Preferably, R2 is selected from

[0106] Further, R2 is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl can be optionally selected from halogen, alkyl, halogen-substituted alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from alkyl, the alkyl group is optionally selected from halogen, -C (= O) NR9R 10 、-C(=O)OR 11 wherein R9, R 10 、R 11 Independently selected from H, alkyl.

[0107] Preferably, R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl groups contain heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups may be optionally selected from halogen, alkyl, halogen-substituted alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C6 alkyl, the C1 to C6 alkyl being optionally selected from halogen, -C(=O)NR9R 10 、-C(=O)OR 11 wherein R9, R 10 、R 11 Independently selected from H, alkyl.

[0108] Preferably, R2 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl groups contain heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups may be selected from halogen, alkyl, halogen-substituted alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C6 alkyl, the C1 to C6 alkyl being optionally selected from halogen, -C(=O)NR9R 10 、-C(=O)OR 11 wherein R9, R 10 、R 11 Independently selected from H, alkyl.

[0109] Preferably, R2 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, the heterocycloalkyl contains 1-2 heteroatoms selected from N, O, S, and the cycloalkyl and heterocycloalkyl can be optionally selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C6 alkyl, the C1 to C6 alkyl being optionally selected from halogen, -C(=O)NR9R 10 wherein R9, R 10 、R 11 Independently selected from C1 to C6 alkyl.

[0110] Preferably, R2 is selected from 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, the heterocycloalkyl contains one heteroatom selected from O, S, and the cycloalkyl, heterocycloalkyl can be optionally selected from halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C3 alkyl, the C1 to C3 alkyl being optionally selected from halogen, -C(=O)NR9R 10 wherein R9, R 10 、R 11 Independently selected from C1-C3 alkyl.

[0111] Preferably, R2 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the above groups are optionally selected from halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from methyl, ethyl, propyl, and the above groups are optionally selected from halogen, -C(=O)NR9R 10 wherein R9, R 10 、R 11 Independently selected from C1-C3 alkyl.

[0112] Preferably, R2 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the above groups are optionally selected from fluoro, methyl, trifluoromethyl, -C(=O)N(CH3)2, -C(=O)OCH3; or, R2 is selected from methyl, ethyl, propyl, and the above groups are optionally substituted by substituents selected from fluorine, -C(=O)N(CH3)2.

[0113] Preferably, R2 is selected from:

[0114] Preferably, The configuration is as follows:

[0115] Furthermore, the compound is selected from one of the following:

[0116] The present invention provides a pharmaceutical composition containing the compound, or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, and pharmaceutically acceptable excipients or auxiliary ingredients.

[0117] The present invention provides the use of the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition in the preparation of an SOS1 inhibitor.

[0118] The present invention provides use of the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition in the preparation of a medicament for treating a disease mediated by SOS1.

[0119] Furthermore, the disease is selected from: cancer, pathogenic rash disease.

[0120] Furthermore, the cancer is selected from the group consisting of non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, and breast cancer;

[0121] The pathogenic rash disease is selected from the group consisting of: Noonan syndrome, cardiofacial cutaneous syndrome, and hereditary gingival fibromatosis type I.

[0122] The present invention provides use of the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition in the preparation of a drug for treating a disease causing overexpression of SOS1 protein.

[0123] The present invention provides the use of the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition in the preparation of a drug for treating diseases caused by overexpression of SOS1 protein.

[0124] The present invention also provides a pharmaceutical composition comprising the compound, or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, and RAS inhibitors, which are administered simultaneously or separately.

[0125] Furthermore, the RAS inhibitor is a KRAS inhibitor.

[0126] Preferably, the RAS inhibitor is a KRAS G12C inhibitor.

[0127] Preferably, the RAS inhibitor is Adagrasib.

[0128] The present invention also provides use of the pharmaceutical composition in preparing drugs for treating cancer.

[0129] Furthermore, the cancer is selected from non-small cell lung cancer and pancreatic cancer.

[0130] The present invention provides a method for treating a disease mediated by SOS1, comprising the step of administering to a subject the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition.

[0131] The present invention provides a method for treating a disease resulting in overexpression of SOS1 protein, comprising the step of administering to a subject the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled form, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition.

[0132] The present invention provides a method for treating diseases caused by overexpression of SOS1 protein, comprising the step of administering to a subject the compound, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition.

[0133] In one embodiment, the amount of drug administered to a subject is an effective amount.

[0134] Definition of terms:

[0135] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0136] The term "tautomer" as used herein refers to a functional group isomer resulting from the movement of an atom in a molecule between two positions, especially when there is a mobile hydrogen atom in the molecule, such as keto- and enol form Tautomers.

[0137] As used herein, "stereoisomers" refer to isomers resulting from molecules in which the atoms or atomic groups have the same order of interconnection but different spatial arrangements, including cis-trans isomers, optical isomers, and conformational isomers. Stereoisomers herein also include mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers in any proportion.

[0138] As used herein, "isotopically labeled" refers to a molecule in which one or more atoms are replaced by atoms having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 35 S. 18 F. 36 Cl, 123 I and 125 I. Certain isotopically labeled compounds of the present invention may be used in drug and / or substrate tissue distribution studies. Radioactive isotopes such as tritium, 3 H and carbon-14 14 C is particularly useful for this purpose due to its ease of incorporation and convenient means of detection. For example, the compounds of the invention may be enriched with 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95% or 99% of a given isotope. In addition, the use of heavier isotopes such as deuterium, i.e. 2 H-substituted compounds of the invention may offer certain therapeutic advantages.

[0139] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention formed with an acid or base suitable for pharmaceutical use. The aforementioned acids and bases are broadly defined as Lewis acids and bases. Suitable acids for forming salts include inorganic acids, organic acids, and acidic amino acids.

[0140] The "solvate" of the present invention refers to an association compound suitable for use as a drug formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include water and organic solvents.

[0141] In the present invention, "ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., an aryl or cycloalkyl group), a heterocyclic ring (e.g., a heteroaryl or heterocycloalkyl group), an aromatic group (e.g., an aryl or heteroaryl group), and a non-aromatic group (e.g., a cycloalkyl or heterocycloalkyl group). The "ring" of the present invention can be a monocyclic ring or a polycyclic ring (including a bicyclic ring), and can be a fused ring, a spirocyclic ring, or a bridged ring.

[0142] In the present invention, "member" represents the number of ring atoms constituting the ring skeleton.

[0143] In the present invention, "optionally substituted..." means that the group may be substituted with one or more (including two) designated substituents, or may be unsubstituted.

[0144] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. "3-10 membered cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon ring with 3-10 ring carbon atoms, examples of which include but are not limited to cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, and adamantane. For example, the structural formula of cyclopropane is The structural formula of cyclobutane is The structural formula of cyclopentane is The structural formula of bicyclo[1.1.1]pentane is The structural formula of cyclohexane is The structural formula of adamantane is If otherwise indicated, the cycloalkyl group is optionally substituted with one or more suitable substituents.

[0145] The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic ring group, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. Heteroatoms include, but are not limited to, N, O, S, P, Si, etc., preferably N, O, and S. "3-10 membered heterocycloalkyl" refers to a saturated monocyclic or polycyclic ring group having 3-10 ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. Examples include, but are not limited to: If otherwise indicated, the heterocycloalkyl group is optionally substituted with one or more suitable substituents.

[0146] The term "cycloalkenyl" refers to a non-aromatic, monocyclic or polycyclic carbocyclic hydrocarbon group containing at least one carbon-carbon double bond (i.e., C=C). "3-10 membered cycloalkenyl" refers to an unsaturated, non-aromatic, monocyclic or polycyclic carbocyclic hydrocarbon group having 3-10 ring carbon atoms, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. As otherwise indicated, the cycloalkenyl group may be optionally substituted with one or more suitable substituents.

[0147] The term "heterocycloalkenyl" refers to a non-aromatic monocyclic or polycyclic group containing at least one double bond, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. Heteroatoms include, but are not limited to, N, O, S, P, Si, etc., preferably N, O, and S. Examples of "3-10 membered heterocycloalkenyl" include, but are not limited to: If otherwise indicated, the heterocycloalkenyl group is optionally substituted with one or more suitable substituents.

[0148] The term "aryl" refers to an all-carbon monocyclic or polycyclic aromatic group having a conjugated π electron system, including monocyclic aromatic groups (e.g., 6-membered phenyl), fused-ring aromatic groups (having aromatic rings and aromatic rings sharing a ring edge, such as 10-membered naphthyl), and biaryl groups (connected by a single bond to form an aryl-aryl structure, such as 12-membered biphenyl). As otherwise indicated, the aryl group is optionally substituted with one or more suitable substituents.

[0149] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group having a conjugated π-electron system, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The heteroatom is preferably N, O, or S. The heteroaryl groups described herein include monocyclic heteroaryl groups (e.g., 5-membered thienyl, 5-membered isoxazolyl, 6-membered pyridyl), fused-ring heteroaryl groups (having heteroaromatic rings and heteroaromatic rings sharing a ring edge, or aromatic rings and heteroaromatic rings sharing a ring edge, such as 9-membered benzothienyl), and bicyclic heteroaryl groups (forming a heteroaryl-heteroaryl structure or an aryl-heteroaryl structure connected by a single bond, such as 11-membered phenyl-thienyl): ). If otherwise indicated, the heteroaryl group is optionally substituted with one or more suitable substituents.

[0150] The term "halogen" includes F, Cl, Br or I.

[0151] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. "C1-C6 alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. As otherwise indicated, the alkyl group may be optionally substituted with one or more suitable substituents.

[0152] The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated straight-chain or branched aliphatic hydrocarbon group by removing two hydrogen atoms; that is, one hydrogen atom in an alkyl group is replaced, and the definition of alkyl is as described above. Examples of "C1-C3 alkylene" include, but are not limited to, methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and the like.

[0153] The term "alkoxy" refers to an "alkyl" group as defined above attached via an oxygen atom, i.e., an "alkoxy" group can be defined as -OR, wherein R is an alkyl group as defined above. Examples of "C1-C6 alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like. As otherwise indicated, the alkoxy group may be optionally substituted with one or more suitable substituents.

[0154] The term "alkylthio" refers to an "alkyl" group as defined above that is linked to an "alkyl" group through a sulfur atom, i.e., an "alkylthio" group can be defined as -SR, wherein R is an alkyl group as defined above. If otherwise indicated, the alkylthio group is optionally substituted with one or more suitable substituents.

[0155] The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing at least one carbon-carbon double bond (i.e., C=C). The double bond can exist as an E or Z isomer. The double bond can be located at any possible position of the hydrocarbon chain. Examples of "C2-C6 alkenyl" include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. As otherwise indicated, the alkenyl group may optionally be substituted with one or more suitable substituents.

[0156] The pharmaceutically acceptable excipients described in the present invention are a general term for all additional materials in a drug other than the main drug. Excipients should have the following properties: (1) no toxic effects on the human body and almost no side effects; (2) stable chemical properties and not easily affected by temperature, pH, storage time, etc.; (3) no incompatibility with the main drug and no impact on the efficacy and quality inspection of the main drug; (4) no interaction with the packaging material. Excipients in the present invention include but are not limited to fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc. There is no particular limitation on the mode of administration of the compound or pharmaceutical composition of the present invention. Representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0157] The term "subject" includes humans and non-human animals. Exemplary human subjects include subjects suffering from a disease (e.g., a disease described herein) (referred to as patients) or normal individuals. "Non-human animals" include all vertebrates, such as non-mammals and mammals, such as non-human primates, livestock, and / or domesticated animals.

[0158] As used herein, an "effective amount" refers to an amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disease being treated. Dosage regimens may be adjusted to provide the optimum desired response.

[0159] The present invention provides a series of compounds with significant inhibitory effects on the SOS1 protein, offering new treatment options for diseases targeting SOS1, such as cancer and pathogenic rashes. Compared to existing SOS1 inhibitors, the compounds of this invention exhibit significant improvements in activity and drugability, particularly improved liver microsomal stability and excellent drugability. They can be used to prepare drugs for treating related diseases and have broad application prospects. DETAILED DESCRIPTION

[0160] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0161] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0162] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE NEO 400 MHz Bruker instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an ISQ-EC Thermo Fisher LC-MS instrument. The Prep-HPLC was performed on a GX-281 Gilson chromatograph, and the separation methods were as follows: (Method 1) Sun Fire Prep C18 OBDTM 5 μm, 30×150 mm Column, 0.04% aqueous HCl / acetonitrile; (Method 2) Sun Fire Prep C18 OBDTM 5 μm, 30×150 mm Column, 0.06% aqueous formic acid / acetonitrile; (Method 3) Xbridge Prep C18 OBDTM 5 μm, 30×150 mm Column, 10 mM aqueous NH4HCO3 / acetonitrile; (Method 4) SunFire Prep C18 OBDTM 5 μm, 30×150 mm Column, 0.02% aqueous trifluoroacetic acid / acetonitrile.

[0163] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized according to methods known in the art.

[0164] Unless otherwise specified, the solvents used in the present invention are commercially available.

[0165] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0166] The chemical abbreviations used in the present invention have the following meanings:

[0167] DMF: N,N-dimethylformamide

[0168] DMF-DMA: N,N-dimethylformamide dimethyl acetal

[0169] DMSO: dimethyl sulfoxide

[0170] DIPEA: N,N-diisopropylethylamine

[0171] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0172] NBS: N-bromosuccinimide

[0173] THF: Tetrahydrofuran

[0174] Prep-HPLC: Preparative High Performance Liquid Chromatography

[0175] Example 1

[0176] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0177] Step a): Preparation of dimethyl 2-formyl-3-oxoglutarate

[0178] Dimethyl 3-oxoglutarate (10.0 g, 57.421 mmol) and 1-methyltetrahydrofuran (100 mL) were added to a reaction flask. DMF-DMA (6.8 g, 57.42 mmol) was added dropwise under an ice-water bath and the reaction was stirred at room temperature for 2 h. 4N dilute hydrochloric acid (30 mL) was added to the reaction solution and the reaction was continued at room temperature for 1 h. After the reaction was completed, the reaction solution was extracted with methyl tert-butyl ether (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain dimethyl 2-formyl-3-oxoglutarate, which was used directly in the next reaction without further purification in a yield of 98.6%; ESI-MS (m / z): 203.2 [M+H] + .

[0179] Step b): Preparation of methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0180] Dissolve 1-methylcyclopropane-1-amine hydrochloride (4.7 g, 43.925 mmol) and dimethyl 2-formyl-3-oxoglutarate (8.9 g, 43.925 mmol) in methanol (120 mL), add sodium methoxide (5.2 g, 96.635 mmol) under ice-water bath, and heat to 80°C for 6 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. A saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction. The reaction solution was adjusted to pH 2-3 with 4N hydrochloric acid to precipitate a large amount of solid. The solid was filtered and the filter cake was washed with 1N dilute hydrochloric acid. The filter cake was collected and dried under reduced pressure. The filter cake was slurried with a mixed solvent of methyl tert-butyl ether and petroleum ether (80 mL, v / v=4 / 1), filtered, and the filter cake was dried under reduced pressure to obtain methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 83.8%; ESI-MS (m / z): 224.2 [M+H] + .

[0181] Step c): Preparation of methyl 1-(1-methylcyclopropyl)-6-oxo-4-(trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate

[0182] Methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (6.4 g, 28.662 mmol), pyridine (4.5 g, 57.324 mmol) and 1,2-dichloroethane (60 mL) were added to the reaction flask, and trifluoromethanesulfonic anhydride (12.1 g, 42.993 mmol) was added under ice-water bath, and the reaction was stirred under ice-water bath for 2 min. The reaction was quenched by adding saturated aqueous ammonium chloride (50 mL). The mixture was allowed to stand and separate. The aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give methyl 1-(1-methylcyclopropyl)-6-oxo-4-(trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate in a yield of 91.2%; ESI-MS (m / z): 356.2 [M+H] + .

[0183] Step d): Preparation of methyl 4-acetyl-1-(1-methylcyclopropyl)-6-oxyl-1,6-dihydropyridine-3-carboxylate

[0184] 1-(1-methylcyclopropyl)-6-oxo-4-(trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (9.0 g, 25.352 mmol), 1,4-dioxane (60 mL), tributyl(1-ethoxyvinyl)tin (11.9 g, 32.958 mmol), triethylamine (3.3 g, 32.958 mmol) and bis(triphenylphosphine)palladium dichloride (356 mg, 0.507 mmol) were added to the reaction flask in sequence, the atmosphere was replaced with nitrogen three times, the temperature was raised to 100 ° C and the reaction was stirred overnight. After the reaction, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, 4N dilute hydrochloric acid was added to adjust the pH to 2-3, and stirring was continued at room temperature for 1 hour. Saturated potassium fluoride aqueous solution (80 mL) was added to quench the reaction, ethyl acetate (100 mL) was added, and stirring was continued for 30 minutes. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was separated, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 4-acetyl-1-(1-methylcyclopropyl)-6-oxy-1,6-dihydropyridine-3-carboxylate in a yield of 83.3%; ESI-MS (m / z): 250.2 [M+H] + .

[0185] Step e): Preparation of 4-hydroxy-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0186] Methyl 4-acetyl-1-(1-methylcyclopropyl)-6-oxyl-1,6-dihydropyridine-3-carboxylate (5.0 g, 20.059 mmol) and anhydrous ethanol (50 mL) were added to a reaction flask. Hydrazine hydrate (5 mL, 80%) was added at room temperature and stirred at 80°C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue and the mixture was stirred at room temperature for 1 h. The mixture was filtered and the filter cake was rinsed with ethyl acetate (30 mL). The filter cake was collected and dried under reduced pressure to obtain 4-hydroxy-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 95.6%. ESI-MS (m / z): 232.1 [M+H] + .

[0187] Step f): Preparation of 4-bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0188] 4-Hydroxy-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (950 mg, 4.108 mmol), phosphorus oxybromide (2.4 g, 8.720 mmol), and acetonitrile (100 mL) were added to a reaction flask and heated to reflux for 2 h. The reaction solution was cooled to room temperature and quenched with saturated sodium bicarbonate aqueous solution (200 mL). The mixture was extracted with dichloromethane (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in an 82.7% yield. ESI-MS (m / z): 294.0 [M+H] + .

[0189] Step g): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0190] 4-Bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (450 mg, 1.530 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (690 mg, 3.058 mmol), DIPEA (1.2 g, 9.285 mmol), cesium fluoride (0.9 g, 5.925 mmol) and DMSO (10 mL) were added to a reaction flask and the temperature was raised to 80 °C for 3 h. The reaction solution was cooled to room temperature, quenched by adding saturated aqueous ammonium chloride (40 mL), extracted with dichloromethane (50 mL × 2), and the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 8.1%; 1H NMR (400MHz, DMSO-d6) δ9.26(s,1H),7.74(d,J=6.8Hz,1H),7.61(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.39-7.09(m,2H),6. 48(s,1H),5.66-5.59(m,1H),2.32(s,3H),1.58-1.53(m,6H),1.20-1.14(m,2H),1.10-1.04(m,2H); ESI-MS(m / z): 403.0[M+H] + .

[0191] Example 2

[0192] Preparation of (R)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0193] Preparation method: Refer to Example 1. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 5 / 95), and then purified by Pre p -HPLC (Method 3) purification gave (R)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in 14.3% yield; 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),7.76(d,J=6.8Hz,1H),7.73(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),6.46( s,1H),5.64-5.54(m,1H),2.53(s,3H),2.32(s,3H),1.54(s,3H),1.51(d,J=7.2Hz,3H),1.20-1.04(m,4H); ESI-MS(m / z): 417.0[M+H] + .

[0194] Example 3

[0195] Preparation of (R)-2-methyl-3-(1-((1-methyl-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)benzonitrile

[0196] Preparation method: Refer to Example 1, and purify by Prep-HPLC (Method 3) to obtain (R)-2-methyl-3-(1-((1-methyl-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)benzonitrile in a yield of 8.9%; 1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),7.79-7.70(m,2H),7.62(d,J=6.8Hz,1H),7.34(t,J=7.6Hz,1H),6.46(s,1H),5.54- 5.45(m,1H),2.63(s,3H),2.32(s,3H),1.53(s,3H),1.50(d,J=7.2Hz,3H),1.19-1.04(m,4H); ESI-MS(m / z): 374.0[M+H] + .

[0197] Example 4

[0198] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H))-one

[0199] Preparation method: Refer to Example 1, and purify by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H))-one in a yield of 16.0%; 1 H NMR (400MHz, DMSO-d6) δ9.24 (s, 1H), 7.71 (d, J = 6.8Hz, 1H), 7.60 (d, J = 7.6Hz, 1H),7.38(d,J=7.6Hz,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=56.0Hz,1H),6.4 6(s,1H),5.64-5.58(m,1H),2.46(s,3H),2.32(s,3H),1.53(s,3H),1.49(d,J =6.8Hz,3H),1.16-1.12(m,2H),1.08-1.04(m,2H); ESI-MS(m / z):399.0[M+H] + .

[0200] Example 5

[0201] Preparation of (R)-1-methyl 4-((1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0202] Step a): Preparation of (R)-4-((1-(5-bromothien-2-yl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0203] 4-Bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (200 mg, 0.680 mmol), (R)-1-(5-bromothiophen-2-yl)ethane-1-amine hydrochloride (330 mg, 1.360 mmol), DIPEA (530 mg, 4.101 mmol), cesium fluoride (620 g, 4.082 mmol) and DMSO (2 mL) were added to a reaction flask and the temperature was raised to 80°C for 3 h. After the reaction, the reaction solution was cooled to room temperature and quenched by adding saturated aqueous ammonium chloride (40 mL). The mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 4 / 96) to obtain (R)-4-((1-(5-bromothiophen-2-yl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 42.1%; ESI-MS (m / z): 419.0 [M+H] + .

[0204] Step b): Preparation of (R)-1-methyl-4-((1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0205] (R)-4-((1-(5-bromothiophen-2-yl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (105 mg, 0.250 mmol), N-methyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (200 mg, 0.372 mmol), Pd(PPh3)4 (120 mg, 0.104 mmol), cesium carbonate (490 mg, 1.504 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) were added to a reaction flask and reacted at 100°C for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 15 / 85) and then purified by Prep-HPLC (Method 3) to obtain (R)-1-methyl-4-((1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 3.0%. 1 H NMR(400MHz, DMSO-d6)δ9.15(s,1H),7.77(d,J=8.0Hz,1H),7.49(d,J=7.2Hz,1H),7.37-7.22(m,4H),7.16-7.13(m,1H),7.09-7.06(m,1H),6.50( s,1H),5.87-5.77(m,1H),3.66(s,2H),2.39(s,3H),2.26(s,3H),1.68(d ,J=6.8Hz,3H),1.50(s,3H),1.16-0.98(m,4H); ESI-MS(m / z): 460.0[M+H] + .

[0206] Example 6

[0207] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0208] Step a): Preparation of dimethyl 2-formyl-3-oxoglutarate

[0209] Dimethyl 3-oxoglutarate (5.0 g, 28.711 mmol) and 1-methyltetrahydrofuran (100 mL) were added to a reaction flask. DMF-DMA (4.1 g, 34.454 mmol) was added dropwise under an ice-water bath and stirred at room temperature for 2 h. Hydrochloric acid (100 mL, 4 N) was added to the reaction solution and the reaction was continued at room temperature for 1 h. After the reaction, the reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain dimethyl 2-formyl-3-oxoglutarate in a yield of 99.9%; ESI-MS (m / z): 203.2 [M+H] + .

[0210] Step b): Preparation of methyl 4-hydroxy-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate

[0211] Dissolve tetrahydro-2H-pyran-4-amine (2.0 g, 19.773 mmol) and dimethyl 2-formyl-3-oxoglutarate (4.8 g, 23.727 mmol) in methanol (120 mL), add sodium methoxide (2.1 g, 39.545 mmol) under ice-water bath, and react at 80°C for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. The reaction was quenched by adding saturated aqueous ammonium chloride (100 mL). The reaction solution was adjusted to pH 1-2 with 4N hydrochloric acid and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain methyl 4-hydroxy-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate in a yield of 79.9%; ESI-MS (m / z): 254.2 [M+H] + .

[0212] Step c): Preparation of methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate

[0213] Methyl 4-hydroxy-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (3.0 g, 11.846 mmol), pyridine (1.9 g, 23.692 mmol) and 1,2-dichloroethane (60 mL) were added to the reaction flask, and trifluoromethanesulfonic anhydride (6.7 g, 23.692 mmol) was added dropwise under ice-water bath, and the reaction was stirred under ice-water bath for 2 min. Water (100 mL) was added to quench the reaction. The mixture was allowed to stand and the organic phase was separated. The aqueous phase was extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate in an 89.1% yield; ESI-MS (m / z): 386.2 [M+H] + .

[0214] Step d): Preparation of methyl 4-acetyl-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate

[0215] Methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (4.0 g, 10.381 mmol), 1,4-dioxane (80 mL), tributyl(1-ethoxyvinyl)tin (4.9 g, 13.496 mmol), triethylamine (3.1 g, 31.143 mmol) and bis(triphenylphosphine)palladium dichloride (364 mg, 0.519 mmol) were added sequentially into the reaction flask, the nitrogen was replaced three times, and the reaction was stirred at 100 °C for 3 h. The reaction solution was cooled to room temperature, saturated potassium fluoride aqueous solution (30 mL) was added to quench the reaction, stirred at room temperature for 5 min and then filtered, the filter cake was rinsed with ethyl acetate (30 mL × 2), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL), diluted hydrochloric acid (40 mL, 1N) was added and stirred at room temperature for 30 min, and then saturated sodium bicarbonate aqueous solution was added to the reaction mixture. The reaction mixture was adjusted to a neutral pH value, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 4-acetyl-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate in a yield of 71.4%; ESI-MS (m / z): 280.2 [M+H] + .

[0216] Step e): Preparation of 4-hydroxy-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0217] Methyl 4-acetyl-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (2.0 g, 7.168 mmol) and anhydrous ethanol (40 mL) were added to a reaction flask. Hydrazine hydrate (2 mL, 80%) was added at room temperature and stirred at 80°C for 1 h. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethanol (5 mL x 2) and dried under vacuum to obtain 4-hydroxy-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in an 88.3% yield; ESI-MS (m / z): 262.2 [M+H] + .

[0218] Step f): Preparation of 4-bromo-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0219] Acetonitrile (10 mL) and 4-hydroxy-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one (200 mg, 0.765 mmol) were added to the reaction flask, and phosphorus oxybromide (2.2 g, 7.655 mmol) was added at room temperature. The nitrogen was replaced three times, and the temperature was raised to 80°C and stirred for 1 hour. After the reaction, the reaction solution was cooled to 0°C and adjusted to a neutral pH by adding a saturated aqueous sodium bicarbonate solution. The solution was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain 4-bromo-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 28.2%; ESI-MS (m / z): 324.2 [M+H] + .

[0220] Step g): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0221] 4-Bromo-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one (70 mg, 0.216 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (97 mg, 0.432 mmol), cesium fluoride (197 mg, 1.296 mmol), DIPEA (167 mg, 1.296 mmol) and DMF (4 mL) were added to the reaction flask, replaced with nitrogen three times, and heated to 80°C with stirring for 1 h. After the reaction, the reaction solution was cooled to room temperature, water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 26.9%. 1H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 7.79 (d, J = 6.8Hz, 1H), 7.60 (t, J = 7.2Hz, 1H), 7.4 8(t,J=7.6Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=54.0Hz,1H),6.57(s,1H),5.67-5. 60(m,1H),5.27-5.18(m,1H),4.11-4.07(m,2H),3.56(t,J=11.6Hz,2H),2.34(s,3H), 2.19-2.09(m,2H),1.85-1.82(m,2H),1.57(d,J=6.8Hz,3H); ESI-MS(m / z): 433.0[M+H] + .

[0222] Example 7

[0223] Preparation of (R)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0224] The preparation method was prepared by referring to step g of Example 6. Purification by Prep-HPLC (Method 3) gave (R)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 19.3%. 1 H NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 7.83 (d, J = 6.8Hz, 1H), 7.71 (t, J = 7.2Hz, 1H), 7. 54(t,J=8.0Hz,1H),7.36(t,J=7.6Hz,1H),6.56(s,1H),5.65-5.58(m,1H),5.26-5.1 8(m,1H),4.10-4.06(m,2H),3.55(t,J=11.6Hz,2H),2.54(s,3H),2.34(s,3H),2.20- 2.08(m,2H),1.82(d,J=12.0Hz,2H),1.52(d,J=7.2Hz,3H); ESI-MS(m / z): 447.0[M+H] + .

[0225] Example 8

[0226] Preparation of (R)-6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0227] Preparation method: With reference to Example 1, the crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 6 / 94), and then purified by Prep-HPLC (Method 3) to obtain (R)-6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 6.7%; 1 H NMR (400MHz, CD3OD-d6) δ9.13 (s, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.55-7.48 (m, 2H),7.32-7.25(m,1H),6.77(s,1H),5.75-5.65(m,1H),5.45-5.36(m,1H), 3.57-3.48(m,2H),3.26-3.18(m,2H),2.77-2.67(m,2H),2.58(s,3H),2.45 (s,3H),2.37-2.30(m,2H),1.61(d,J=6.8Hz,3H); ESI-MS(m / z): 495.0[M+H] + .

[0228] Example 9

[0229] Preparation of (R)-3-(1-((6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methyl-7-oxo-6,7-dihydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0230] Preparation method: With reference to Example 8, the crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 6 / 94), and then purified by Prep-HPLC (Method 3) to obtain (R)-3-(1-((6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methyl-7-oxo-6,7-dihydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-methylbenzonitrile in a yield of 5.3%; 1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.96(d,J=6.4Hz,1H),7.72(d,J=7.2Hz,1 H),7.63(d,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),6.59(s,1H),5.56-5.47(m,1H) ,5.35-5.26(m,1H),3.63-3.53(m,2H),3.28-3.22(m,2H),2.68-2.52(m,5H),2 .34(s,3H),2.25-2.18(m,2H),1.53(d,J=7.2Hz,3H); ESI-MS(m / z): 452.0[M+H] + .

[0231] Example 10

[0232] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0233] Preparation method: With reference to Example 1, the crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 6 / 94), and then purified by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 5.0%; 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),7.92(d,J=6.8Hz,1H),7.59(d,J=7.6Hz,1H) ,7.39(d,J=7.6Hz,1H),7.35-7.07(m,2H),6.59(s,1H),5.68-5.60(m,1H),5.35-5 .26(m,1H),3.63-3.52(m,2H),3.26-3.23(m,2H),2.68-2.54(m,2H),2.47(s,3H) ,2.34(s,3H),2.25-2.18(m,2H),1.52(d,J=7.2Hz,3H); ESI-MS(m / z): 477.0[M+H] + .

[0234] Example 11

[0235] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0236] Preparation method: With reference to Example 1, the crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 4 / 96), and then purified by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 7.3%; 1 H NMR (400MHz, DMSO-d6) δ9.05 (s, 1H), 7.95 (d, J = 6.4Hz, 1H), 7.60 (t, J = 7.2Hz, 1H),7.49(t,J=6.8Hz,1H),7.38-7.10(m,2H),6.62(s,1H),5.67-5.60(m,1H), 5.38-5.27(m,1H),3.65-3.53(m,2H),3.30-3.24(m,2H),2.65-2.53(m,2H),2. 35(s,3H),2.27-2.18(m,2H),1.59(d,J=7.2Hz,3H); ESI-MS(m / z): 481.0[M+H] + .

[0237] Example 12

[0238] Preparation of (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0239] Step a): Preparation of methyl 1-cyclobutyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate

[0240] Dimethyl 2-formyl-3-oxoglutarate (5.6 g, 27.716 mmol), cyclobutylamine (2.4 g, 33.259 mmol), sodium methoxide (3.5 mg, 60.975 mmol), and methanol (50 mL) were added to a reaction flask and stirred at 80°C for 2 h. After completion of the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (50 mL). The reaction mixture was adjusted to pH 3-4 with 4N hydrochloric acid and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 1-cyclobutyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate, which was used directly in the next step without purification in an 82.2% yield. ESI-MS (m / z): 224.1 [M+H] + .

[0241] Step b): Preparation of methyl 1-cyclobutyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate

[0242] Dissolve 1-cyclobutyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (5.1 g, 22.870 mmol) in dichloromethane (50 mL). Add pyridine (3.6 g, 45.740 mmol) under ice bath, and then add trifluoromethanesulfonic anhydride (9.7 g, 34.305 mmol) dropwise. After the addition is complete, warm to room temperature and stir for 20 min. The reaction was quenched by adding water (50 mL), and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give methyl 1-cyclobutyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate in a yield of 60.5%; ESI-MS (m / z): 356.1 [M+H] + .

[0243] Step c): Preparation of methyl 4-acetyl-1-cyclobutyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0244] 1-Cyclobutyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (4.9 g, 13.803 mmol), tributyl(1-ethoxyvinyl)stannane (6.0 g, 16.564 mmol), Pd(PPh3)Cl2 (486 mg, 0.690 mmol), triethylamine (4.2 g, 42.409 mmol) and 1,4-dioxane (50 mL) were added to the reaction flask, replaced with nitrogen three times, and heated to 100°C and stirred for 5 h. After the reaction, the reaction solution was cooled to room temperature, quenched by the addition of 30% potassium fluoride aqueous solution (100 mL), and filtered. The filtrate was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 3). The organic phase was concentrated under reduced pressure, and a solution of hydrogen chloride in ethyl acetate (4 M) was added to adjust the pH to 2-3. The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain methyl 4-acetyl-1-cyclobutyl-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 43.6%; ESI-MS (m / z): 250.1 [M+H] + .

[0245] Step d): Preparation of 6-cyclobutyl-4-hydroxy-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0246] Methyl 4-acetyl-1-cyclobutyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.5 g, 6.024 mmol), hydrazine hydrate (1.1 g, 18.072 mmol, 80%), and ethanol (20 mL) were added to a reaction flask and stirred at reflux for 1 hour. After the reaction, the reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with a small amount of ethanol and dried under vacuum to obtain 6-cyclobutyl-4-hydroxy-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 93.3%. ESI-MS (m / z): 232.1 [M+H] + .

[0247] Step e): Preparation of 4-bromo-6-cyclobutyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0248] 6-Cyclobutyl-4-hydroxy-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (500 g, 2.165 mmol), phosphorus oxybromide (1.2 g, 4.330 mmol), and acetonitrile (50 mL) were added sequentially to a reaction flask. The mixture was heated to 105°C and stirred for 2 h under nitrogen. The reaction solution was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (50 mL) dropwise. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 1) to obtain 4-bromo-6-cyclobutyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a 51.5% yield. ESI-MS (m / z): 294.1 [M+H] + .

[0249] Step f): Preparation of (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0250] 4-Bromo-6-cyclobutyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (300 mg, 1.020 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (460 mg, 2.040 mmol), DIPEA (658 mg, 5.100 mmol) and 1,4-dioxane (3 mL) were added to a reaction bottle and microwaved at 100°C for 2 h. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Method 3) to obtain (R)-6-cyclobutyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 23.5%. 1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.81(d,J=6.8Hz,1H),7.62(t,J=7.6Hz ,1H),7.48(t,J=7.2Hz,1H),7.27(t,J=7.2Hz,1H),7.27(t,J=52.0Hz,1H),6 .50(s,1H),5.69-5.62(m,1H),5.22-5.13(m,1H),2.45(t,J=7.6Hz,4H),2.3 4(s,3H),1.93-1.84(m,2H),1.58(d,J=7.2Hz,3H); ESI-MS(m / z): 403.0[M+H] + .

[0251] Example 13

[0252] Preparation of ((R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclobutyl)pyrido[3,4-d]pyridazin-7(6H))-one

[0253] Preparation method: Refer to Example 12, and purify by Prep-HPLC (Method 3) to obtain ((R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclobutyl)pyrido[3,4-d]pyridazin-7(6H))-one; 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.72(d,J=6.8Hz,1H),7.60(t,J=7.6Hz,1H),7.48(t,J=7.2Hz,1H),7.27(d,J=7.6Hz,1H)7.24(t,J =54.4Hz,1H),6.44(s,1H),5.62(p,J=6.8Hz,1H),2.62-2.54(m,2H),2.43(t,J=9.6Hz,2H),2.33(s,3H),1.99-1.90(m,1H),1.82-1.75(m 1H), 1.68 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H); yield 6.7%; ESI-MS (m / z): 417.2 [M+H] + .

[0254] Example 14

[0255] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0256] Preparation method: Refer to Example 12 and purify by Prep-HPLC (Method 3) to obtain 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 24.7%; 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=7.6Hz,1H),7.81(t,J=7.2Hz,1H),7.60(t,J=7.6Hz,1H),7 .48(t,J=7.2Hz,1H),7.26(t,J=7.6Hz,1H),7.26(t,J=56.0Hz,1H),6.57(s,1H),5.67-5.58( m,1H),5.56-5.48(m,1H),4.22-4.12(m,1H),4.03(d,J=5.6Hz,1H),4.01-3.87(m,1H),3.87- 3.80(m,1H),2.35(s,3H),2.34-2.14(m,2H),1.57(d,J=7.0Hz,3H); ESI-MS(m / z): 419.0[M+H] + .

[0257] Example 15

[0258] Preparation of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0259] Step a): Preparation of (R)-1-methyl-6-(1-methylcyclopropyl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0260] 4-Bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (200 mg, 0.680 mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride (280 mg, 1.035 mmol), DIPEA (440 mg, 3.404 mmol) and 1,4-dioxane (3 mL) were added to a reaction flask and microwave-dried for 4 h at 100 °C. After the reaction was completed, the mixture was cooled to room temperature and saturated aqueous ammonium chloride (20 mL) The reaction was quenched and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 2 / 1) to obtain (R)-1-methyl-6-(1-methylcyclopropyl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 54.6%; ESI-MS (m / z): 448.1 [M+H] + .

[0261] Step b): Preparation of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0262] (R)-1-methyl-6-(1-methylcyclopropyl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one (166 mg, 0.371 mmol), iron powder (100 mg, 1.790 mmol), methanol (4 mL) and saturated aqueous ammonium chloride solution (2 mL) were added to a reaction flask and reacted at 90 °C for 30 min. After the reaction, the reaction solution was cooled to room temperature, and water (20 mL) and dichloromethane (20 mL) were added and stirred vigorously for 5 min. The mixture was filtered, and the organic phase was separated from the filtrate. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 29.1%. 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.61(d,J=6.8Hz,1H),6.82(s,2H),6.68(s,1H),6.48(s,1H),5.49(s,2H),5 .38-5.30(m,1H),2.34(s,3H),1.55-1.46(m,6H),1.17-1.11(m,2H),1.10-1.03(m,2H); ESI-MS(m / z): 418.0[M+H] + .

[0263] Example 16

[0264] Preparation of (R)-6-cyclopentyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0265] Preparation method: Refer to Example 12, and purify by Prep-HPLC (Method 3) to obtain (R)-6-cyclopentyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 25.3%; 1 H NMR(400MHz, DMSO-d6)δ9.08(s,1H),7.72(d,J=6.8Hz,1H),7.60(t,J=7.2Hz,1H),7.48(t,J=6.8Hz,1H),7.37-7.17(m,2H),6.54(s,1H),5.67-5.5 9(m,1H),5.27-5.17(m,1H),2.34(s,3H),2.20-2.07(m,2H),2.01-1.89(m ,4H),1.77-1.67(m,2H),1.57(d,J=7.2Hz,3H); ESI-MS(m / z): 417.0[M+H] + .

[0266] Example 17

[0267] Preparation of methyl (1R,4,)-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)cyclohexane-1-carboxylate trifluoroacetate

[0268] Preparation method: With reference to Example 12, purification by Prep-HPLC (Method 4) gave (1R,4r)-4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)cyclohexane-1-carboxylic acid methyl ester trifluoroacetate in a yield of 17.6%; 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),9.75(s,1H),7.73(t,J=7.6Hz,1H),7.61( t,J=7.2Hz,1H),7.40-7.31(m,1H),7.25(t,J=56.0Hz,1H),6.92(s,1H),5.55-5. 48(m,1H),4.90-4.82(m,1H),3.63(s,3H),2.49-2.46(m,2H),2.45(s,3H),2.18- 1.88(m,6H),1.73(d,J=6.8Hz,3H),1.65-1.54(m,2H); ESI-MS(m / z): 489.0[M+H] + .

[0269] Example 18

[0270] Preparation of (R)-6-(bicyclo[1.1.11pentan-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0271] Preparation method: Refer to Example 12 and purify by Prep-HPLC (Method 3) to obtain (R)-6-(bicyclo[1.1.1]pentan-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 19.7%; 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),7.80(d,J=6.8Hz,1H),7.60(t,J=7.6Hz,1H),7.47(d,J=7.2Hz,1H),7.27(t,J=7.2Hz,1H),7.24(t, J=56.0Hz,1H),6.47(s,1H),5.68-5.61(m,1H),2.75(s,1H),2.46(s,6H),2.33(s,3H),1.57(d,J=7.2Hz,3H); ESI-MS(m / z): 415.0[M+H] + .

[0272] Example 19

[0273] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-isopropyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate

[0274] Preparation method: Refer to Example 12, and purify by Prep-HPLC (Method 2) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-isopropyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate in a yield of 27.9%; 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.13(s,1H),7.80(s,1H),7.63-7.59(m,1H),7.51-7.47(m,1H),7.38-7.11(m,2H),6.55( s,1H),5.66-5.59(m,1H),5.33-5.23(m,1H),2.35(s,3H),1.58(d,J=7.2Hz,3H),1.49-1.47(m,6H); ESI-MS(m / z): 391.2[M+H] + .

[0275] Example 20

[0276] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,6-dimethylpyrido[3,4-d]pyridazin-7(6H)-one formate

[0277] Preparation method: Refer to Example 12, and purify by Prep-HPLC (Method 2) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,6-dimethylpyrido[3,4-d]pyridazin-7(6H)-one formate in a yield of 21.7%; 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.14(s,1H),7.65-7.52(m,2H),7.48(t,J=7.2Hz,1H),7.26(t,J=7.6Hz,1H),7.26(t, J=52.0Hz,1H),6.53(s,1H),5.63-5.56(m,1H),3.69(s,3H),2.35(s,3H),1.54(d,J=7.2Hz,3H); ESI-MS(m / z): 363.0[M+H] + .

[0278] Example 21

[0279] Preparation of (R)-6-cyclohexyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0280] Preparation method: Refer to Example 12, and purify by Prep-HPLC (Method 3) to obtain (R)-6-cyclohexyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 6.0%; 1 H NMR(400MHz, DMSO-d6)δ9.06(s,1H),7.72(d,J=6.8Hz,1H),7.60(t,J=7.2Hz,1H),7.48(t,J=6.8Hz,1H),7.38-7.10(m,2H),6.56(s,1H),5.69 -6.59(t,J=6.8Hz,1H),4.96-4.85(m,1H),2.34(s,3H),1.99-1.72(m,8H),1.58(d,J=7.2Hz,3H),1.52-1.44(m,2H); ESI-MS(m / z): 431.0[M+H] + .

[0281] Example 22

[0282] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-(trifluoromethyl)cyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0283] Preparation method: Refer to Example 12 and purify by Prep-HPLC (Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-(trifluoromethyl)cyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 5.3%; 1 H NMR(400MHz,DMSO-d6)δ9.27(s,1H),7.84 (s,1H),7.58(t,J=7.2Hz,1H),7.49(t,J=6.8Hz,1H),7.37-7.10(m,2H),6.60(s,1H),5.61 -5.50(m,1H),2.33(s,3H),1.88-1.67(m,2H),1.60-1.49(m,5H); ESI-MS(m / z): 457.0[M+H] + .

[0284] Example 23

[0285] Preparation of (R)-6-(2,2-difluoroethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0286] The preparation method was similar to that of Example 12, and the product was purified by Prep-HPLC (Method 3) to give (R)-6-(2,2-difluoroethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in an 18.2% yield. 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.68(s,1H),7.59(t,J=7.2Hz,1H),7.49(t,J=7.2Hz,1H),7.28(t,J=7.6Hz,1H),7.23(t,J=54.4Hz,1H), 6.64(s,1H),6.46((t,J=55.2Hz,1H),5.62(p,J=6.8Hz,1H),4.65-4.48(m,2H),2.36(s,3H),1.55(d,J=7.2Hz,3H); ESI-MS(m / z): 413.1[M+H] + .

[0287] Example 24

[0288] Preparation of (R)-6-(4,4-difluorocyclohexyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0289] Preparation method: Refer to Example 12 and purify by Prep-HPLC (Method 3) to obtain (R)-6-(4,4-difluorocyclohexyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 23.7%; 1H NMR(400MHz, DMSO-d6)δ9.02(s,1H),7.81(d,J=6.8Hz,1H),7.59(t,J=7.6H z,1H),7.48(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=56.0Hz,1H), 6.60(s,1H),5.67-5.60(m,1H),5.16-5.04(m,1H),2.35(s,3H),2.29-2.16 (m,4H),2.07-1.93(m,4H),1.58(d,J=7.2Hz,3H); ESI-MS(m / z): 467.0[M+H] + .

[0290] Example 25

[0291] Preparation of (R)-6-(3,3-difluorocyclobutyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one trifluoroacetate

[0292] Preparation method: With reference to Example 12, purification by Prep-HPLC (Method 4) gave (R)-6-(3,3-difluorocyclobutyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one trifluoroacetate in a yield of 31.2%; 1 H NMR(400MHz,DMSO-d6)δ13.75(s,1H),9.51(s,1H),9.30(s,1H),7.71-7.60(m,2H),7.39-7.12(m,2H),6.91(s,1H),5 .58-5.51(m,1H),4.91-4.85(m,1H),3.36-3.17(m,4H),2.47(s,3H),1.70(d,J=6.4Hz,3H); ESI-MS(m / z): 439.2[M+H] + .

[0293] Example 26

[0294] 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazine-6(7H ) Preparation of -yl)-N, N-dimethylpropanolamine

[0295] Step af): methyl 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)propanoate

[0296] The preparation method was prepared by referring to steps af of Example 12 to obtain methyl 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)propanoate in a yield of 55.4%; ESI-MS (m / z): 435.4 [M+H] + .

[0297] Step g): Preparation of 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)propanoic acid

[0298] Methyl 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)propanoate (280 mg, 0.645 mmol), aqueous lithium hydroxide solution (4 M, 0.6 mL), methanol (2 mL) and THF (6 mL) were added to a reaction flask and reacted at room temperature for 0.5 h. The reaction solution was adjusted to pH 2-3 with 1N dilute hydrochloric acid, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by medium-pressure preparative chromatography (eluent: acetonitrile / water = 1 / 9) to give 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)propanoic acid in a yield of 43.3%; ESI-MS (m / z): 421.4 [M+H] + .

[0299] Step h): Preparation of 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)-N,N-dimethylpropionamide

[0300] 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)propanoic acid (70 mg, 0.167 mmol), dimethylamine hydrochloride (20 mg, 0.250 mmol), HATU (95 mg, 0.250 mmol), DIPEA (65 mg, 0.501 mmol) and dichloromethane (6 mL) were added sequentially to the reaction flask and stirred at room temperature for 30 min. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Method 3) to obtain 2-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)-N,N-dimethylpropanamide in a yield of 13.7%; 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.96-7.92(m,1H),7.62-7.56(m,1H) ,7.52-7.46(m,1H),7.32-7.26(m,1H),7.24(t,J=56.0Hz,1H),6.53(s,1H) ,6.09-6.01(m,1H),5.72-5.62(m,1H),3.20(s,3H),2.88(s,3H),2.35(s,3 H), 1.72 (d, J=7.2Hz, 3H), 1.58 (t, J=6.8Hz, 3H); ESI-MS (m / z): 448.0[M+H] + .

[0301] Example 27

[0302] Preparation of (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)-N,N-dimethylcyclopropane-1-methylphenolamine

[0303] Preparation method: With reference to Example 26, the product was purified by Prep-HPLC (Method 3) to give (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)-N,N-dimethylcyclopropane-1-carboxamide; yield 19.0%; 1H NMR (400MHz, DMSO-d6) δ9.28(s,1H),7.82(d,J=6.8Hz,1H),7.59(t,J=7.6Hz,1H),7.48(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J= 54.4Hz,1H),6.53(s,1H),5.62(p,J=6.8Hz,1H),2.84(s,6H),2.34(s,3H),1.79-1.68(m,2H),1.63-1.50(m,5H); ESI-MS(m / z): 460.2[M+H] + .

[0304] Example 28

[0305] (R)-6-Cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazine - Preparation of 7(6H)-ketone

[0306] Step a): Preparation of methyl 1-cyclopropyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate

[0307] Dimethyl 2-formyl-3-oxoglutarate (5.6 g, 27.723 mmol), cyclopropylamine (1.7 g, 30.495 mmol), sodium methoxide (1.5 mg, 60.975 mmol), and methanol (50 mL) were added to a reaction flask and stirred at 80°C for 2 h. After completion of the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (50 mL). The reaction mixture was adjusted to pH 3-4 with 4N hydrochloric acid and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 1-cyclopropyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate, which was used directly in the next step without purification in a yield of 70.7%. ESI-MS (m / z): 210.1 [M+H] + .

[0308] Step b): Preparation of methyl 1-cyclopropyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate

[0309] Methyl 1-cyclopropyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (4.1 g, 19.617 mmol) was dissolved in dichloromethane (50 mL). Pyridine (2.0 g, 25.502 mmol) was added under ice bath, followed by dropwise addition of trifluoromethanesulfonic anhydride (7.2 g, 25.502 mmol). After completion of the addition, the mixture was heated to room temperature and stirred for 20 min. After the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 1-cyclopropyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate in a yield of 54.5%; ESI-MS (m / z): 342.1 [M+H] + .

[0310] Step c): Preparation of methyl 4-acetyl-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0311] 1-Cyclopropyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (3.6 g, 10.557 mmol), tributyl(1-ethoxyvinyl)tin (6.0 g, 16.575 mmol), Pd(PPh3)2Cl2 (486 mg, 0.690 mmol), triethylamine (4.2 g, 42.409 mmol) and 1,4-dioxane (50 mL) were added to the reaction flask, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 100 ° C. and stirred for 5 h. The reaction solution was cooled to room temperature and 30% fluorine was added. The reaction was quenched with aqueous potassium chloride (100 mL), filtered, and the filtrate was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 3). The organic phase was concentrated under reduced pressure, and a solution of hydrogen chloride in ethyl acetate (4 M) was added to adjust the pH to 2-3. The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give methyl 4-acetyl-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 84.0%; ESI-MS (m / z): 236.1 [M+H] + .

[0312] Step d): Preparation of 6-cyclopropyl-1-methylpyrido[3,4-d]pyridazine-4,7(3H,6H)-dione

[0313] Methyl 4-acetyl-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.1 g, 8.936 mmol), hydrazine hydrate (1.1 g, 18.072 mmol, 80%), and ethanol (20 mL) were added to a reaction flask and heated to 90°C for 1 h. After the reaction, the reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethanol (10 mL) and dried under vacuum to obtain 6-cyclopropyl-1-methylpyrido[3,4-d]pyridazine-4,7(3H,6H)-dione in a yield of 57.9%; ESI-MS (m / z): 218.2 [M+H] + .

[0314] Step e): Preparation of 4-bromo-6-cyclopropyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0315] 6-Cyclopropyl-1-methylpyrido[3,4-d]pyridazine-4,7(3H,6H)-dione (300 mg, 1.382 mmol), phosphorus oxybromide (770 mg, 2.764 mmol) and acetonitrile (30 mL) were added to the reaction flask in sequence, and the temperature was raised to reflux under nitrogen protection and stirred for 2 h. After the reaction, the mixture was cooled to room temperature and quenched by slowly adding saturated aqueous sodium bicarbonate solution (50 mL) dropwise. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 1) to obtain 4-bromo-6-cyclopropyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 42.6%; ESI-MS (m / z): 280.1 [M+H] + .

[0316] Step f): Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0317] 4-Bromo-6-cyclopropyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (165 mg, 0.589 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine hydrochloride (172 mg, 0.766 mmol), DIPEA (228 mg, 1.767 mmol) and 1,4-dioxane (3 mL) were added to a reaction bottle and microwaved at 100°C for 2 h. After the reaction, the mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 22.1%. 1 H NMR (400MHz, DMSO-d6) δ9.02(s,1H),7.73(d,J=6.8Hz,1H),7.60(t,J=7.6Hz,1H),7.48(t,J=7.2Hz,1H),7.26(t,J=7.6Hz,1H),7.23(t,J=54.4 Hz,1H),6.51(s,1H),5.63(p,J=7.2Hz,1H),3.66-3.60(m,1H),2.33(s, 3H), 1.55 (d, J=7.2Hz, 3H), 1.21-1.08 (m, 4H); ESI-MS (m / z): 389.2[M+H] + .

[0318] With reference to the preparation method of Example 28, the compounds in the following examples were prepared using corresponding raw materials.

[0319] Example 30

[0320] (R)-1-methyl-6-(1-methylcyclopropyl)-4-(1-(3-(pentafluoro-λ 6 Preparation of 1-(2-(4-thiazolyl)-1,2-dimethylthiazolyl)-1,4-d-pyridazin-7(6H)-one formate

[0321] 4-Bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.341 mmol), (R)-1-(3-(pentafluoro-λ 6-sulfonyl)phenyl)ethane-1-amine hydrochloride (125 mg, 0.443 mmol), DIPEA (132 mg, 1.023 mmol) and DMSO (8 mL) were added to a microwave reaction bottle in sequence and microwave reaction was carried out at 105°C for 1.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 2) to obtain (R)-1-methyl-6-(1-methylcyclopropyl)-4-(1-(3-(pentafluoro-λ)-1-yl ... 6 -sulfonyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one, yield 25.7%; 1 H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.15(s,1H),7.90(s,1H),7.75-7.68(m,3H),7.55(t,J=8.0Hz,1H),6.48(s,1H),5.50-5 .43(m,1H),2.33(s,3H),1.57(d,J=7.2Hz,3H),1.54(s,3H),1.17-1.12(m,2H),1.10-1.06(m,2H); ESI-MS(m / z): 461.0[M+H] + .

[0322] Example 31

[0323] (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one 的 preparation

[0324] Step a): Preparation of S-(3-bromo-2-methylphenyl)acetic acid thioester

[0325] 2-Bromo-6-iodotoluene (10.0 g, 33.681 mmol), potassium thioacetate (4.6 g, 40.417 mmol), Xant-phos (2.3 g, 4.042 mmol), Pd2(dba)3 (1.8 g, 2.021 mmol), toluene (65 mL), and acetonitrile (33 mL) were added to a reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was raised to 70°C with stirring for 2 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain S-(3-bromo-2-methylphenyl)acetic acid thioester in a yield of 93.2%; ESI-MS (m / z): 245.0 [M+H] + .

[0326] Step b): Preparation of 3-bromo-2-methylthiophenol

[0327] S-(3-Bromo-2-methylphenyl)acetic acid thioester (7.6 g, 31.101 mmol) and methanol (80 mL) were added to a reaction flask, followed by potassium hydroxide (2.6 g, 46.512 mmol). The mixture was stirred at room temperature for 30 min, diluted with water (150 mL), and adjusted to pH 2-3 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-bromo-2-methylthiophenol; yield: 95.8%; ESI-MS (m / z): 203.0 [M+H] + .

[0328] Step c): Preparation of (3-bromo-2-methylphenyl)(difluoromethyl)sulfide

[0329] Sodium difluorobromoacetate (9.7 g, 49.483 mmol), potassium carbonate (9.1 g, 65.998 mmol), and acetonitrile (70 mL) were added to a reaction flask, followed by 3-bromo-2-methylthiophenol (6.7 g, 32.999 mmol). The mixture was heated to 100°C and stirred for 1 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain (3-bromo-2-methylphenyl)(difluoromethyl)sulfide in a yield of 73.0%; ESI-MS (m / z): 252.9 [M+H] + .

[0330] Step d): Preparation of 1-bromo-3-((difluoromethyl)sulfinyl)-2-methylbenzene

[0331] (3-Bromo-2-methylphenyl)(difluoromethyl)sulfide (5.0 g, 19.755 mmol) and dichloromethane (60 mL) were added to a reaction flask. m-Chloroperbenzoic acid (10.2 g, 59.265 mmol) was added portionwise under an ice-water bath. The mixture was warmed to room temperature and stirred overnight. After completion of the reaction, saturated aqueous sodium bicarbonate solution (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 1-bromo-3-((difluoromethyl)sulfinyl)-2-methylbenzene in a 33.8% yield. ESI-MS (m / z): 268.9 [M+H] + .

[0332] Step e): Preparation of 1-(3-((difluoromethyl)sulfinyl)-2-methylphenyl)ethan-1-one

[0333] 1-Bromo-3-((difluoromethyl)sulfinyl)-2-methylbenzene (1.7 g, 6.317 mmol), tributyl(1-ethoxyethylene)tin (3.0 g, 8.213 mmol), triethylamine (1.3 g, 12.634 mmol), bis(triphenylphosphine palladium dichloride) (222 mg, 0.316 mmol), and 1,4-dioxane (180 mL) were added to a reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C and stirred for 16 h. After the reaction, the reaction solution was cooled to room temperature, 2N hydrochloric acid (80 mL) was added, and the mixture was stirred at room temperature for 1 h. The mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 1-(3-((difluoromethyl)sulfinyl)-2-methylphenyl)ethan-1-one in a yield of 95.5%; ESI-MS (m / z): 233.0 [M+H] + .

[0334] Step f): Preparation of 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-one

[0335] 1-(3-((difluoromethyl)sulfinyl)-2-methylphenyl)ethane-1-one (1.2 g, 4.952 mmol), acetonitrile (10 mL), water (10 mL) and chloroform (10 mL) were added to a reaction flask. Sodium periodate (3.18 g, 14.855 mmol) and ruthenium trichloride (103 mmol, 0.495 mmol) were added under ice bath. The mixture was stirred at room temperature for 2 h. Water (100 mL) was added. The mixture was diluted and extracted with dichloromethane (80 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-one in a yield of 93.3%; ESI-MS (m / z): 249.0 [M+H] + .

[0336] Step g): Preparation of (R,Z)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide

[0337] 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-one (1.1 g, 4.431 mmol), (R)-(+)-tert-butylsulfenamide (698 mg, 5.760 mmol), tetraethyl titanate (2.3 g, 6.646 mmol, 65%) and tetrahydrofuran (30 mL) were added to the reaction flask, heated to 80°C and stirred overnight. After the reaction, the mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added and stirred at room temperature for 5 min. The mixture was filtered and the filtrate was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain (R,Z)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide in a yield of 98.3%; ESI-MS (m / z): 352.1 [M+H] + .

[0338] Step h): Preparation of (S)-N-((R))-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonamide

[0339] (R,Z)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.7 g, 4.837 mmol), tetrahydrofuran (30 ml) and water (0.5 mL) were added to a reaction flask, cooled to -78 ° C, and sodium borohydride (275 mg, 7.256 mmol) was slowly added. After the addition was completed, the mixture was warmed to room temperature and stirred for 1 h. Saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction and the mixture was washed with acetic acid. The mixture was extracted with ethyl ester (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain (S)-N-((R))-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonamide in a yield of 46.7%; ESI-MS (m / z): 354.1 [M+H] + .

[0340] Step i): Preparation of (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-amine hydrochloride

[0341] (S)-N-((R))-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonamide (798 mg, 2.258 mmol) and 1,4-dioxane (15 mL) were added to a reaction flask, and a solution of hydrogen chloride in 1,4-dioxane (7 mL, 4N) was added. The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was added to a mixed solvent of ethyl acetate and petroleum ether (20 mL, V / V = 1:10), stirred at room temperature for 20 min, filtered, and the filter cake was dried to obtain (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-amine hydrochloride in a yield of 92.9%; ESI-MS (m / z): 250.1 [M+H] + .

[0342] Step j): Preparation of (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0343] 4-Bromo-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (200 mg, 0.678 mmol), (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-amine hydrochloride (291 mg, 1.019 mmol), DIPEA (438 mg, 3.390 mmol) and 1,4-dioxane (8 mL) were added to a reaction bottle, heated to 105 ° C in a microwave reactor, and stirred for 3 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to obtain (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one with a yield of 28.0%; 1H NMR (400MHz, DMSO-d6) δ9.24(s,1H),7.95(d,J=7.6Hz,1H),7.88(d,J=6.8Hz,1H),7.81(d,J=6.4Hz,1H),7.53(t,J=8.0Hz,1H),7.33(t,J= 52.0Hz,1H),6.47(s,1H),5.61(p,J=6.8Hz,1H),2.77(s,3H),2.32(s,3H),1.55-1.50(m,6H),1.20-1.06(m,4H); ESI-MS(m / z): 463.1[M+H] + .

[0344] Example 32

[0345] Preparation of (R)-4-(1-(3-(difluoromethyl)-2-fluorophenylethyl)amino)-1-methyl-6-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)pyrido[3,4-d]pyridazin-7(6H)-one formate

[0346] Step a): Preparation of methyl 4-hydroxy-1-(1-(hydroxymethyl)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0347] Add dimethyl 2-formyl-3-oxoglutarate (10.0 g, 49.505 mmol), (1-(aminomethyl)cyclopropyl)methanol (6.0 g, 59.406 mmol), sodium methoxide (5.9 g, 108.911 mmol) and methanol (100 mL) into the reaction flask, heat to 80°C and stir to react for 2 h. After completion of the reaction, the mixture was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The reaction solution was adjusted to pH 3-4 with 4N hydrochloric acid and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 4-hydroxy-1-(1-(hydroxymethyl)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 47.9%; ESI-MS (m / z): 254.2 [M+H] + .

[0348] Step b): Preparation of methyl 4-(benzoyloxy)-1-(1-(benzoyloxy)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0349] Add 4-hydroxy-1-(1-(hydroxymethyl)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (6.0 g, 23.715 mmol), dichloromethane (60 mL) and triethylamine (9.6 g, 94.862 mmol) to the reaction flask, and add benzoyl chloride (10.0 g, 71.145 mmol) dropwise. After the addition is complete, stir the reaction at room temperature for 16 h. The reaction was quenched by adding water (100 mL), and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give methyl 4-(benzoyloxy)-1-(1-(benzoyloxy)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in an 88.7% yield; ESI-MS (m / z): 462.2 [M+H] + .

[0350] Step c): Preparation of methyl 1-((1-(benzoyloxy)methyl)cyclopropyl)methyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate

[0351] Add 4-(benzoyloxy)-1-(1-(benzoyloxy)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (9.7 g, 21.041 mmol) and methanol (100 mL) to the reaction flask, add potassium carbonate (5.8 g, 42.082 mmol) under ice-water bath, and stir in ice-water bath for 10 min. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL). The reaction solution was adjusted to pH 3-4 with 4N hydrochloric acid and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl 1-((1-(benzoyloxy)methyl)cyclopropyl)methyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate in an 81.2% yield; ESI-MS (m / z): 358.2 [M+H] + .

[0352] Step d): Preparation of methyl 1-((1-(benzoyloxy)methyl)cyclopropyl)methyl)-6-oxo-4-((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate

[0353] Methyl 1-((1-(benzoyloxy)methyl)cyclopropyl)methyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (6.1 g, 17.087 mmol) and dichloromethane (60 mL) were added to the reaction flask, pyridine (2.7 g, 34.174 mmol) was added under ice-water bath, and trifluoromethanesulfonic anhydride (7.2 g, 25.631 mmol) was added dropwise, and the reaction was continued with stirring under ice-water bath for 20 min. The reaction was quenched by adding water (60 mL), and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give methyl 1-((1-(benzoyloxy)methyl)cyclopropyl)methyl)-6-oxo-4-((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate in a yield of 93.3%; ESI-MS (m / z): 490.1 [M+H] + .

[0354] Step e): Preparation of methyl 4-acetyl-1-(1-(benzoyloxy)methyl)cyclopropyl)methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0355] 1-((1-(benzoyloxy)methyl)cyclopropyl)methyl)-6-oxo-4-((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (7.8 g, 16.155 mmol), tributyl(1-ethoxyvinyl)tin (6.3 g, 14.650 mmol), Pd(PPh3)2Cl2 (486 mg, 0.690 mmol), triethylamine (4.0 g, 40.388 mmol) and 1,4-dioxane (80 mL) were added to the reaction flask, replaced with nitrogen three times, and heated to 100°C and stirred for 5 h. After the reaction, the mixture was cooled to room temperature, and aqueous KF solution (80 mL) was added to quench the reaction. The mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated under reduced pressure. A solution of hydrogen chloride in ethyl acetate (30 mL, 4N) was added, and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 4-acetyl-1-(1-(benzoyloxy)methyl)cyclopropyl)methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 50.5%; ESI-MS (m / z): 384.2 [M+H] + .

[0356] Step f): Preparation of methyl (1-((1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)methyl)cyclopropyl)benzoate

[0357] Methyl 4-acetyl-1-(1-(benzoyloxy)methyl)cyclopropyl)methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3.1 g, 8.094 mmol), hydrazine hydrate (917 mg, 24.282 mmol, 80%), and ethanol (30 mL) were added to a reaction flask and stirred at 90°C for 1 h. After the reaction, the mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethanol (10 mL) and dried under vacuum to obtain methyl (1-((1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)methyl)cyclopropyl)benzoate in an 81.2% yield; ESI-MS (m / z): 366.1 [M+H] + .

[0358] Step g): Preparation of methyl (1-(4-bromo-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropyl)benzoate

[0359] Methyl (1-((1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)methyl)cyclopropyl)benzoate (500 mg, 1.370 mmol), phosphorus oxybromide (777 mg, 2.740 mmol) and acetonitrile (50 mL) were added sequentially to the reaction flask, and the temperature was raised to 105 ° C. under nitrogen protection, and the reaction was stirred for 2 h. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 1) to obtain methyl (1-(4-bromo-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropyl)benzoate in a yield of 68.2%; ESI-MS (m / z): 428.1 [M+H] + .

[0360] Step h): Preparation of methyl (R)-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropyl)benzoate

[0361] Methyl (1-(4-bromo-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropyl)benzoate (408 mg, 0.953 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (336 mg, 1.430 mmol), DIPEA (492 mg, 3.812 mmol) and 1,4-dioxane (10 mL) were added to a reaction bottle and microwaved at 100°C for 2 h. After completion of the reaction, the mixture was cooled to room temperature, quenched by the addition of saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 1) to obtain methyl (R)-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropyl)benzoate in a yield of 58.7%; ESI-MS (m / z): 537.3 [M+H] + .

[0362] Step i): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0363] (R)-methyl(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropyl)benzoate (300 mg, 0.560 mmol), lithium hydroxide monohydrate (47 mg, 1.120 mmol) and methanol (50 mL) were added to the reaction flask and the reaction was stirred at room temperature for 1 h. After the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one, which was used directly in the next step without purification with a yield of 98.7%; ESI-MS (m / z): 433.1 [M+H] + .

[0364] Step j): Preparation of (R)-6-((1-(chloromethyl)cyclopropyl)methyl)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0365] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (230 mg, 0.532 mmol) and chloroform (50 mL) were added to a reaction flask, and thionyl chloride (630 mg, 5.032 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain (R)-6-((1-(chloromethyl)cyclopropyl)methyl)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one, which was used directly in the next step without purification in a yield of 97.1%. ESI-MS (m / z): 451.2 [M+H] + .

[0366] Step k): Preparation of (R)-4-(1-(3-(difluoromethyl)-2-fluorophenylethyl)amino)-1-methyl-6-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)pyrido[3,4-d]pyridazin-7(6H)-one formate

[0367] (R)-6-((1-(chloromethyl)cyclopropyl)methyl)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (252 mg, 0.559 mmol), pyrrolidine (252 mg, 1.112 mmol), DIPEA (216 mg, 1.677 mmol) and acetonitrile (10 mL) were added to a reaction flask, and the temperature was raised to 80°C and stirred for 8 h. After the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 2) to obtain (R)-4-(1-(3-(difluoromethyl)-2-fluorophenylethyl)amino)-1-methyl-6-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)pyrido[3,4-d]pyridazin-7(6H)-one formate in a yield of 17.5%. 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.16 (s, 1H), 7.60 (t, J = 7.6Hz, 1H), 7.54 -7.45(m,2H),7.26(t,J=7.6Hz,1H),7.23(t,J=56.0Hz,1H),6.47(s,1H),5.63 -5.57(m,1H),4.18(s,2H),2.42-2.38(m,4H),2.34(s,3H),2.24(s,2H),1.59 -1.51(m,7H),0.87-0.77(m,2H),0.40-0.33(m,2H); ESI-MS(m / z): 486.0[M+H] + .

[0368] Example 33

[0369] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-hydroxyethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate

[0370] The preparation method was prepared by referring to steps ai of Example 32. The crude product was purified by Prep-HPLC (Separation Method 2) to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-hydroxyethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate in an 18.4% yield.1 H NMR (400MHz, DMSO-d6) δ13.7(1H),9.28(s,1H),8.14(1H),7.84(s,1H),7.60(t,J=7. 6Hz,1H),7.50(t,J=7.2Hz,1H),7.28(t,J=7.6Hz,1H),7.24(d,J=54.4Hz,1H),6.57( s,1H),5.61(q,J=7.2Hz,1H),5.06(t,J=5.6Hz,1H),4.25-4.20(1H),4.16-4.10(1H) ,3.75(q,J=5.4Hz,2H),2.36(s,3H),1.56(d,J=7.2Hz,3H); ESI-MS(m / z): 393.1[M+H] + .

[0371] Example 34

[0372] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(4-hydroxybutan-2-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0373] The preparation method was prepared by referring to steps ai of Example 32. The crude product was purified by Prep-HPLC (Separation Method 3) to give 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(4-hydroxybutan-2-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 26.7%. 1 H NMR (400MHz, DMSO-d6) δ9.12(s,1H),7.70(d,J=6.8Hz,1H),7.59(t,J=7.2Hz,1H),7. 48(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=56.0Hz,1H),6.53(s,1H),5.66 -5.59(m,1H),5.33-5.25(m,1H),4.57(s,1H),3.44-3.39(m,2H),2.34(s,3H),2.06- 2.00(m,2H),1.57(d,J=7.2Hz,3H),1.47(d,J=6.8Hz,3H)); ESI-MS(m / z): 421.0[M+H] + .

[0374] Example 35

[0375] Preparation of (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1-(difluoromethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0376] Step a): Preparation of (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropane-1-carbaldehyde

[0377] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (200 mg, 0.463 mmol), Dess-Martin periodinane (295 mg, 0.695 mmol) and dichloromethane (10 mL) were added to the reaction flask and stirred at room temperature for 5 h. The reaction was quenched by adding water (20 mL) and extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropane-1-carbaldehyde in a yield of 65.7%; ESI-MS (m / z): 431.0 [M+H] + .

[0378] Step b): Preparation of (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1-(difluoromethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0379] (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)methyl)cyclopropane-1-carbaldehyde (130 mg, 0.302 mmol) and dichloromethane (10 mL) were added to a reaction flask, and diethylaminosulfur trifluoride (97 mg, 0.604 mmol) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 18 h. After the reaction, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((1-(difluoromethyl)cyclopropyl)methyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 14.7%. 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 7.70-7.59 (m, 1H), 7.56 (d, J = 7.6Hz, 1H), 7 .48(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.23(t,J=52.0Hz,1H),6.57(s,1H), 5.96(t,J=56.0Hz,1H),5.66-5.59(m,1H),4.43-4.25(m,2H),2.35(s,3H),1.56( d,J=7.2Hz,3H),1.01-0.98(m,2H),0.88-0.84(m,2H); ESI-MS(m / z): 453.0[M+H] + .

[0380] Example 36

[0381] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0382] The preparation method was prepared by referring to steps ai of Example 32. The crude product was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 23.7%. 1H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 7.84 (d, J = 6.8Hz, 1H), 7.58 (t, J = 7.6Hz, 1H),7.48(t,J=7.2Hz,1H),7.26(t,J=7.6Hz,1H),7.24(t,J=56.0Hz,1H),6.48 (s,1H),5.67-5.61(m,1H),5.03(t,J=5.8Hz,1H),3.70(s,1H),3.58(s,1H),2. 33(s,3H),1.56(d,J=7.2Hz,3H),1.24-1.10(m,4H); ESI-MS(m / z): 419.0[M+H] + .

[0383] Example 37

[0384] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0385] Preparation method: With reference to Example 35, the crude product was purified by Prep-HPLC (Separation Method 3) to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 15.7%; 1 H NMR (400MHz, DMSO-d6) δ9.20(s,1H),7.86(s,1H),7.58(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=56.0Hz, 1H),6.58(s,1H),6.34(t,J=56.0Hz,1H),5.66-5.59(m,1H),2.34(s,3H),1.59-1.52(m,5H),1.50-1.38(m,2H); ESI-MS(m / z): 439.0[M+H] + .

[0386] Example 38

[0387] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0388] Preparation method: With reference to Example 28, the crude product was purified by Prep-HPLC (Separation Method 3) to give 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 21.8%; 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),7.62-7.56(m,2H),7.50-7.47(m,1H), 7.37-7.10(m,2H),6.56(s,1H),5.65-5.59(m,1H),4.20-4.06(m,2H),3.88- 3.83(m,1H),3.69-3.56(m,3H),2.88-2.78(m,1H),2.35(s,3H),2.01-1.91 (m,1H),1.73-1.64(m,1H),1.56(d,J=7.2Hz,3H); ESI-MS(m / z): 433.2[M+H] + .

[0389] Example 39

[0390] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0391] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (150 mg, 0.359 mmol) and dichloromethane (10 mL) were added to a reaction flask, and diethylaminosulfur trifluoride (97 mg, 0.604 mmol) was added dropwise under ice-water bath, and the reaction was stirred under ice bath for 20 min. The mixture was warmed to room temperature, and saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 13.2%. 1H NMR (400MHz, DMSO-d6) δ9.24(s,1H),7.90(s,1H),7.59(t,J=7.6Hz,1H),7.49(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=56.0Hz, 1H),6.57(s,1H),5.65-5.58(m,1H),4.78-4.52(m,2H),2.34(s,3H),1.57(d,J=7.2Hz,3H),1.37-1.32(m,4H); ESI-MS(m / z): 421.0[M+H] + .

[0392] Example 40

[0393] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride

[0394] Step a): Preparation of (R)-8-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0395] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (2.5 g, 6.213 mmol) and dichloromethane (20 mL) were added to a reaction flask at room temperature, and liquid bromine (2.0 g, 12.426 mmol) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 3 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium thiosulfate (20 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain (R)-8-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one; yield: 43.5%; ESI-MS (m / z): 481.1 [M+H] + .

[0396] Step b): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride

[0397] (R)-8-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (190 mg, 0.392 mmol) and methanol (5 mL) were added to a reaction flask at room temperature, and sodium methoxide (32 mg, 0.588 mmol) was slowly added. The mixture was reacted at room temperature for 30 min, and saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction. The mixture was stirred for 2 hours with ethyl acetate. The product was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 1) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride in a yield of 47.4%; 1 H NMR (400MHz, DMSO-d6) δ13.46(s,1H),9.60(s,1H),7.59-7.76(m,2H),7.11-7.38(m,3H),5.49-5.53(m,1H)3. 99(s,3H),2.61(s,3H),1.70-1.72(d,J=8.0Hz,3H),1.56(s,3H),1.09-1.26(m,4H); ESI-MS(m / z): 433.1[M+H] + .

[0398] Example 41

[0399] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride

[0400] At room temperature, (R)-8-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (230 mg, 0.483 mmol), 1,4-dioxane (4 mL), water (1 mL), methylboric acid (58 mg, 0.967 mmol), Pd(dppf)Cl2 (72 mg, 0.096 mmol) and potassium carbonate (200 mg, 1.449 mmol) were added to a microwave tube, purged with nitrogen for 1 min, and microwaved at 100°C for 1.5 h. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 1) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride in a yield of 20.0%. 1 H NMR (400MHz, DMSO-d6) δ13.45(s,1H),9.81(s,1H),7.59-7.79(m,2H),7.11-7.38(m,3H),5.51-5.55(m,1H),2. 71(s,3H),2.50(s,3H),1.71-1.73(d,J=8.0Hz,3H),1.56(s,3H),1.08-1.27(m,4H); ESI-MS(m / z): 417.2[M+H] + .

[0401] Example 42

[0402] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-8-carbonitrile

[0403] (R)-8-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (160 mg, 0.332 mmol), DMF (5 mL), zinc cyanide (59 mg, 0.659 mmol) and tetrakis(triphenylphosphine)palladium (7.7 mg, 6.661 mmol) were added to the reaction flask at room temperature. The atmosphere was replaced with nitrogen three times and the temperature was raised to 100°C for 1 h. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-8-carbonitrile in a yield of 17.7%. 1 H NMR(400MHz,DMSO-d6)δ9.89(s,1H),7.55-7.73(m,2H),7.11-7.38(m,3H),5.57-5.62(m,1H),2. 74(s,3H),1.66-1.68(d,J=8.0Hz,3H),1.59(s,3H),1.10-1.32(m,4H); ESI-MS(m / z): 428.1[M+H] + .

[0404] Example 43

[0405] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methoxy-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0406] Step a): Preparation of methyl 4-cyano-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0407] Methyl 1-(1-methylcyclopropyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (4.3 g, 12.113 mmol), zinc cyanide (2.2 g, 24.226 mmol), tetrakistriphenylphosphine palladium (280 mg, 0.242 mmol) and DMF (20 mL) were added to the reaction flask at room temperature. The atmosphere was replaced with nitrogen three times and the temperature was raised to 80 °C for 1 h. After the reaction, the mixture was cooled and filtered. The filtrate was poured into water (30 mL) and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 4-cyano-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 78.2%; ESI-MS (m / z): 233.1 [M+H] + .

[0408] Step b): Preparation of dimethyl 1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3,4-dicarboxylate

[0409] Methyl 4-cyano-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.1 g, 9.052 mmol) and 6N hydrochloric acid (10 mL) were added to a reaction flask at room temperature. The temperature was raised to reflux for 5 h, and methanol (40 mL) was added. The reaction was continued at reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, and the mixture was diluted with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain dimethyl 1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3,4-dicarboxylate, which was used directly in the next reaction without purification in a yield of 75.1%. ESI-MS (m / z): 266.0 [M+H] + .

[0410] Step c): Preparation of 6-(1-methylcyclopropyl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione

[0411] Dimethyl 1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3,4-dicarboxylate (1.6 g, 6.038 mmol) and hydrazine hydrate (10 mL, 80%) were added to a reaction flask at room temperature, heated to 100°C and reacted overnight. The reaction solution was cooled to room temperature, acetonitrile (100 mL) was added, and stirred at room temperature for 10 min. The mixture was filtered, and the filter cake was rinsed with acetonitrile (10 mL) and dried in vacuo to obtain 6-(1-methylcyclopropyl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione in a yield of 68.3%; ESI-MS (m / z): 234.0 [M+H] + .

[0412] Step d): Preparation of 1,4-dibromo-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0413] 6-(1-Methylcyclopropyl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (780 mg, 3.348 mmol), tribromophosphine oxide (1.9 g, 6.696 mmol) and acetonitrile (70 mL) were added to the reaction flask at room temperature, and the temperature was raised to 105 °C for 3 h. After the reaction, the mixture was cooled to room temperature and slowly poured into a saturated aqueous sodium bicarbonate solution (200 mL). The mixture was stirred thoroughly and extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain 1,4-dibromo-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 47%; ESI-MS (m / z): 358.0 [M+H] + .

[0414] Step e): Preparation of (R)-1-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0415] 1,4-Dibromo-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (205 mg, 0.571 mmol), DIPEA (369 mg, 2.855 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (142 mg, 0.628 mmol) and 1,4-dioxane (5 mL) were added to a microwave reaction bottle and heated to 40 ℃ for 2 h. The reaction mixture was reacted at 105°C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain (R)-1-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 56.0%; ESI-MS (m / z): 423.1 [M+H] + .

[0416] Step f): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methoxy-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0417] (R)-1-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (65 mg, 0.154 mmol), sodium methoxide (13 mg, 0.231 mmol) and methanol were added to the reaction flask, heated to 80 °C and stirred for 2 h. After the reaction, the mixture was cooled to room temperature, diluted with dichloromethane (30 ml), poured into a saturated aqueous ammonium chloride solution (50 mL), and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methoxy-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 35.0%. 1 H NMR(400MHz, DMSO-d6)δ9.21(s,1H),7.61(t,J=7.6Hz,1H),7.47(d,J=7.2Hz,2H),7.38-7.11(m,2H),6.48( s,1H),5.50(p,J=6.4Hz,1H),3.83(s,3H),1.55-1.52(m,6H),1.18-1.06(m,4H); ESI-MS(m / z): 419.2[M+H] + .

[0418] Example 44

[0419] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-hydroxy-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0420] (R)-1-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (65 mg, 0.154 mmol) and acetic acid (3 mL) were added to a reaction flask, heated to 100°C, and stirred for 30 minutes. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-hydroxy-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 33.0%. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.98(s,1H),7.61(t,J=7.6Hz,1H),7.48(t,J=7.2Hz,1H),7.29(t,J=7.6Hz,1H),7.22(t,J=54 .4Hz,1H),6.99(d,J=6.8Hz,1H),6.80(s,1H),5.17(p,J=6.8Hz,1H),1.56-1.47(m,6H),1.20-1.03(m,4H); ESI-MS(m / z): 405.2[M+H] + .

[0421] Example 45

[0422] Preparation of (R)-3-(1-((6-cyclopropyl-1-methyl-7-oxo-6,7-dihydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0423] 4-Bromo-6-cyclopropyl-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.357 mmol), DIPEA (231 mg, 1.786 mmol), (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride (105 mg, 0.535 mmol), and 1,4-dioxane (5 mL) were added to a reaction flask and stirred at 105°C in a microwave reactor for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-3-(1-((6-cyclopropyl-1-methyl-7-oxo-6,7-dihydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-methylbenzonitrile in a yield of 31.7%. 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),7.78(s,1H),7.72(d,J=7.6,1H),7.63(d,J=7.6,1H),7.34(t,J=7.6Hz,1H),6.50(s,1H),5.50 (p,J=6.8Hz,1H),3.64-3.58(m,1H),2.62(s,3H),2.33(s,3H),1.50(d,J=7.2Hz,3H),1.18-1.06(m,4H); ESI-MS(m / z): 360.2[M+H] + .

[0424] Example 46

[0425] Preparation of (R)-6-cyclopropyl-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0426] Preparation method: Refer to Example 45. The crude product was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 10.3%; 1H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 7.78-7.70 (m, 2H), 7.53 (d, J = 8.0Hz, 1H), 7.34 (t, J = 7.6Hz, 1H), 6.49 (s, 1H), 5.67-5. 56(m,1H),3.67-3.57(m,1H),2.53(s,3H),2.33(s,3H),1.50(d,J=6.8Hz,3H),1.20-1.06(m,4H); ESI-MS(m / z): 403.0[M+H] + .

[0427] Example 47

[0428] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one

[0429] Step a): Preparation of methyl 4-acetyl-5-bromo-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0430] Methyl 4-acetyl-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3.4 g, 14.468 mmol), NBS (3.1 g, 17.362 mmol), and acetic acid (30 mL) were added to a reaction flask and stirred at room temperature for 24 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and quenched with saturated aqueous sodium bicarbonate (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 4-acetyl-5-bromo-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate in an 86.1% yield. ESI-MS (m / z): 314.0 [M+H] + .

[0431] Step b): Preparation of methyl 4-acetyl-1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0432] Methyl 4-acetyl-5-bromo-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.5 g, 7.962 mmol), methylboric acid (704 mg, 11.943 mmol), K2CO3 (2.2 g, 15.924 mmol), Pd(PPh3)4 (460 mg, 0.398 mmol), 1,4-dioxane (30 mL) and water (6 mL) were added to the reaction flask in sequence, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 100°C for 16 h. After the reaction, the mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 4-acetyl-1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 33.0%; ESI-MS (m / z): 250.1 [M+H] + .

[0433] Step c): Preparation of 6-cyclopropyl-1,8-dimethylpyrido[3,4-d]pyridazine-4,7(3H,6H)-dione

[0434] Methyl 4-acetyl-1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (650 mg, 2.610 mmol), hydrazine hydrate (0.5 mL, 80%), and ethanol (10 mL) were added to a reaction flask and stirred at 90°C for 1 h. After the reaction, the reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethanol (2 mL) and dried under vacuum to obtain 6-cyclopropyl-1,8-dimethylpyrido[3,4-d]pyridazine-4,7(3H,6H)-dione in a yield of 92.3%; ESI-MS (m / z): 232.1 [M+H] + .

[0435] Step d): Preparation of 4-bromo-6-cyclopropyl-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one

[0436] 6-Cyclopropyl-1,8-dimethylpyrido[3,4-d]pyridazine-4,7(3H,6H)-dione (300 mg, 1.299 mmol), phosphorus oxybromide (743 mg, 2.597 mmol) and acetonitrile (50 mL) were added to the reaction flask in sequence, and the temperature was raised to reflux under nitrogen protection and stirred for 2 h. After the reaction, the reaction solution was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 1) to obtain 4-bromo-6-cyclopropyl-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 49.7%; ESI-MS (m / z): 294.1 [M+H] + .

[0437] Step e): Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one

[0438] 4-Bromo-6-cyclopropyl-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one (110 mg, 0.374 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (132 mg, 0.561 mmol), DIPEA (241 mg, 1.870 mmol) and 1,4-dioxane (3 mL) were added to a reaction bottle and microwaved at 100°C for 1 h. The reaction was quenched by adding saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 23.5%. 1H NMR(400MHz, DMSO-d6)δ8.80(s,1H),7.63(d,J=6.8Hz,1H),7.57(t,J=7.6H z,1H),7.47(t,J=7.2Hz,1H),7.25(t,J=7.6Hz,1H),7.24(t,J=54.0Hz,1H), 5.64-5.57(m,1H),3.66-3.61(m,1H),2.61(s,3H),2.46(s,3H),1.55(d,J= 7.2Hz,3H),1.16-1.13(m,2H),1.11-1.08(m,2H); ESI-MS(m / z): 403.0[M+H] + .

[0439] Example 48

[0440] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one

[0441] Preparation method: Refer to step e of Example 47. The crude product was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1,8-dimethylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 13.5%; 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),7.65-7.55(m,2H),7.36(t,J=7.6Hz,1H),7.26(t,J=7.6Hz,1H),7.21(t,J=56.0Hz,1H),5.6 3-5.56(m,1H),3.65-3.59(m,1H),2.61(s,3H),2.45(s,6H),1.48(d,J=6.8Hz,3H),1.17-1.05(m,4H); ESI-MS(m / z): 399.0[M+H] + .

[0442] Example 49

[0443] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0444] Step ad): Preparation of tert-butyl 4-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)piperidine-1-carboxylate

[0445] The preparation method refers to steps ad of Example 28.

[0446] Step e): Preparation of tert-butyl 4-(1-methyl-7-oxo-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-6(7H)-yl)piperidine-1-carboxylate

[0447] tert-Butyl 4-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)piperidine-1-carboxylate (2.0 g, 5.549 mmol), 1H-1,2,4-triazole (3.1 g, 44.394 mmol), acetonitrile (60 mL) and triethylamine (9.0 g, 88.788 mmol) were added to the reaction flask, and a solution of phosphorus oxychloride (1.7 g, 11.098 mmol) in acetonitrile (20 mL) was added dropwise to the reaction solution, and the reaction was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure to remove most of the solvent. Water (100 mL) was added and the mixture was slurried at room temperature for 20 min. The mixture was filtered, and the filter cake was rinsed with water (10 mL × 2) and dried under vacuum to obtain tert-butyl 4-(1-methyl-7-oxo-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-6(7H)-yl)piperidine-1-carboxylate in a yield of 90.1%; ESI-MS (m / z): 412.2 [M+H] + .

[0448] Step f): Preparation of tert-butyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidine-1-carboxylate

[0449] Tert-butyl 4-(1-methyl-7-oxo-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-6(7H)-yl)piperidine-1-carboxylate (2.2 g, 5.347 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (1.7 g, 7.485 mmol) and 1,4-dioxane (20 mL) were added to a microwave tube and microwave reaction was maintained at 110 °C for 4 h. After completion of the reaction, the reaction solution was transferred to a round-bottom flask and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain tert-butyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidine-1-carboxylate in a yield of 88.6%; ESI-MS (m / z): 518.2 [M+H] + .

[0450] Step g): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0451] (R)-tert-Butyl 4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxopyrido[3,4-d]pyridazine-6(7H)-yl)piperidine-1-carboxylate (100 mg, 0.193 mmol) and tetrahydrofuran (2 mL) were added to the reaction flask, and a 1,4-dioxane solution of hydrogen chloride (4 M, 2 mL) was added dropwise to the reaction solution at room temperature, and the reaction was maintained at room temperature for 0.5 h. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (4 mL), triethylamine (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 41.8%. 1H NMR (400MHz, DMSO-d6) δ9.16(s,1H),7.86(d,J=6.8Hz,1H),7.58(t,J=7.2Hz,1H),7.48(t ,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H),6.55(s,1H),5.66-5.51(m,1 H),5.03-4.95(m,1H),3.16-3.13(m,2H),2.70-2.64(m,2H),2.44-2.40(m,1H),2.34(s,3 H),2.03-1.93(m,2H),1.83-1.75(m,2H),1.57(d,J=6.8Hz,3H); ESI-MS(m / z): 432.0[M+H] + .

[0452] With reference to the preparation method of Example 49, the compounds in the following examples were prepared using corresponding starting materials.

[0453] Example 51

[0454] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0455] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (100 mg, 0.214 mmol), dichloromethane (2 mL) and triethylamine (86 mg, 0.855 mmol) were added to the reaction flask, and a solution of morpholine-4-carbonyl chloride (320 mg, 2.137 mmol) in dichloromethane (3 mL) was slowly added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 21.2%. 1H NMR (400MHz, DMSO-d6) δ9.05(s,1H),7.85(d,J=6.4Hz,1H),7.59(t,J=7.2Hz,1H),7.48(t,J=7 .2Hz,1H),7.26(t,J=7.6Hz,1H),7.24(t,J=54.0Hz,1H),6.59(s,1H),5.66-5.59(m,1H),5.11 -5.03(m,1H),3.89(d,J=12.8Hz,2H),3.60(t,J=4.8Hz,4H),3.17(t,J=4.8Hz,4H),3.02(d,J= 12.4Hz, 2H), 2.34 (s, 3H), 2.02-1.88 (m, 4H), 1.57 (d, J = 6.8Hz, 3H); ESI-MS (m / z): 545.0[M+H] + .

[0456] Example 52

[0457] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0458] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (100 mg, 0.214 mmol), dichloromethane (2 mL), and triethylamine (86 mg, 0.855 mmol) were added to a reaction flask. A solution of iodomethane (33 mg, 0.235 mmol) in dichloromethane (2 mL) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 26.5%. 1H NMR (400MHz, DMSO-d6) δ9.18(s,1H),7.81(d,J=6.8Hz,1H),7.58(t,J=7.6Hz,1H),7. 48(t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H),6.56(s,1H),5.65 -5.58(m,1H),4.97-4.90(m,1H),2.98(d,J=8.8Hz,2H),2.34(s,3H),2.26(s,3H),2. 19-2.06(m,4H),1.83-1.80(m,2H),1.56(d,J=6.8Hz,3H); ESI-MS(m / z): 446.0[M+H] + .

[0459] Example 53

[0460] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(isoxazole-4-carbonyl)piperidin-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0461] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (100 mg, 0.214 mmol), isoxazole-4-carboxylic acid (48 mg, 0.428 mmol), HATU (163 mg, 0.428 mmol), dichloromethane (2 mL) and triethylamine (86 mg, 0.855 mmol) were added to the reaction flask and the reaction was stirred at room temperature for 2 h. After the reaction, the product was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(isoxazole-4-carbonyl)piperidin-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 38.8%. 1H NMR (400MHz, DMSO-d6) δ9.44(s,1H),9.06(s,1H),8.91(s,1H),7.72(s,1H),7.58(t,J=7.6Hz, 1H),7.48(t,J=7.2Hz,1H),7.26(t,J=7.6Hz,1H),7.23(t,J=54.4Hz,1H),6.60(s,1H),5.66-5 .60(m,1H),5.28-5.21(m,1H),4.81-4.74(m,1H),4.21-4.12(m,1H),3.51-3.42(m,1H),3.04- 3.96(m,1H),2.35(s,3H),2.07-1.91(m,4H),1.56(d,J=6.8Hz,3H); ESI-MS(m / z):527.0[M+H] + .

[0462] Example 54

[0463] Preparation of (R)-6-(1-acetylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyridone[3,4-d]pyridazin-7(6H)-one

[0464] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (100 mg, 0.214 mmol), acetyl chloride (18 mg, 0.235 mmol), dichloromethane (2 mL), and triethylamine (86 mg, 0.855 mmol) were added to a reaction flask and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-(1-acetylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 22.7%. 1H NMR (400MHz, DMSO-d6) δ9.05(s,1H),7.73(t,J=7.6Hz,1H),7.58(t,J=7.6Hz,1H),7.48(t,J=7. 2Hz,1H),7.27(t,J=7.2Hz,1H),7.24(t,J=54.4Hz,1H),6.59(s,1H),5.66-5.59(m,1H),5.22-5 .14(m,1H),4.67(t,J=13.2Hz,1H),4.07(t,J=13.6Hz,1H),3.30-3.24(m,1H),2.76-2.67(m,1H ),2.35(s,3H),2.09(s,3H),1.97-1.88(m,4H),1.57(d,J=6.8Hz,3H); ESI-MS(m / z): 474.0[M+H] + .

[0465] Example 55

[0466] Preparation of (R)-6-(1-benzoylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0467] Preparation method: Refer to Example 54. The crude product was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-(1-benzoylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 41.2%. 1 H NMR(400MHz, DMSO-d6)δ9.06(s,1H),7.43(t,J=6.8Hz,1H),7.61(t,J=7.2Hz,1H),7.50- 7.46(m,6H),7.27(t,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H),6.59(s,1H),5.67-5.60(m,1H ),5.24-5.16(m,1H),4.87-4.73(m,1H),3.91-3.76(m,1H),3.44-3.33(m,1H),3.10-2.97 (m,1H),2.35(s,3H),2.18-1.87(m,4H),1.59(d,J=7.2Hz,3H); ESI-MS(m / z):536.0[M+H] + .

[0468] Example 56

[0469] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(quinuclidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0470] The preparation method was prepared by referring to steps af of Example 49. The crude product was purified by Prep-HPLC (Separation Method 3) to give 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(quinuclidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 10.4%; 1 H NMR(400MHz,DMSO-d6)δ9.03-8.91(m,1H),8.01-7.87(m,1H),7.62-7.53(m,1H),7.52-7 .45(m,1H),7.37-7.12(m,2H),6.61-6.57(m,1H),5.74-5.60(m,1H),5.07-4.90(m,1H),3 .50-3.36(m,1H),3.19-3.07(m,1H),2.86-2.65(m,4H),2.38-2.34(m,3H),2.15-2.03(m ,1H),1.82-1.69(m,2H),1.61-1.55(m,3H),1.49-1.35(m,2H); ESI-MS(m / z): 458.0[M+H] + .

[0471] Referring to the preparation method of Example 56, the compounds in the following examples were prepared with corresponding starting materials.

[0472] Example 60

[0473] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxypyridin-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0474] The preparation method was prepared by referring to steps af of Example 49. The crude product was purified by Prep-HPLC (Separation Method 3) to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxypyridin-4-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 25.5%; 1H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.40(d,J=5.6Hz,1H),7.65(d,J=6.8Hz,1H),7.59(t,J=7.8Hz,1H),7.48(t,J=7.2Hz,1H),7.30-7.24(m,2H) ,7.23(t,J=56.0Hz,1H),7.18(s,1H),6.66(s,1H),5.66-5.99(m,1H),3. 96(s,3H),2.38(s,3H),1.51(d,J=7.2Hz,3H); ESI-MS(m / z): 456.0[M+H] + .

[0475] Example 61

[0476] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-morpholino[3,4-d]pyridazin-7(6H)-one

[0477] Preparation method: Refer to steps af of Example 49. The crude product was purified by Prep-HPLC (Separation Method 3) to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-morpholino[3,4-d]pyridazin-7(6H)-one in a yield of 33.1%. 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),7.82(d,J=6.8Hz,1H),7.61(t,J=7.2Hz,1H),7.48(t,J=6.8Hz,1H),7.26(t,J=7.6Hz,1H),7.24 (t,J=54.4Hz,1H),6.59(s,1H),5.65-5.58(m,1H),3.79-3.49(m,8H),2.34(s,3H),1.54(d,J=7.2Hz,3H); ESI-MS(m / z): 434.0[M+H] + .

[0478] Example 62

[0479] Preparation of (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-N, anthocyanin-3-oxopropionamide

[0480] Step a): Preparation of (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-3-oxopropanoic acid methyl ester

[0481] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (100 mg, 0.214 mmol), 3-methoxy-3-oxopropanoic acid (51 mg, 0.428 mmol), HATU (163 mg, 0.428 mmol), dichloromethane (5 mL) and triethylamine (86 mg, 0.855 mmol) were added to the reaction flask and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-3-oxopropanoic acid methyl ester in a yield of 81.2%; ESI-MS (m / z): 532.2 [M+H] + .

[0482] Step b): Preparation of (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-3-oxopropanoic acid

[0483] (R)-methyl 3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-3-oxopropanoate (92 mg, 0.174 mmol), lithium hydroxide monohydrate (35 mg, 0.871 mmol), methanol (1 mL) and water (1 mL) were added to the reaction flask and stirred at room temperature for 1 h. The reaction solution was adjusted to pH 2-3 with dilute hydrochloric acid (1N), extracted with dichloromethane (10 mL×3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-3-oxopropanoic acid in a yield of 97.2%; ESI-MS (m / z): 518.2 [M+H]+.

[0484] Step c): Preparation of (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-N,N-dimethyl-3-oxopropionamide

[0485] (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-3-oxopropanoic acid (88 mg, 0.169 mmol), dimethylamine hydrochloride (28 mg, 0.338 mmol), HATU (129 mg, 0.338 mmol), dichloromethane (5 mL) and triethylamine (51 mg, 0.507 mmol) were added to the reaction flask and the reaction was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to obtain (R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperidin-1-yl)-N,N-dimethyl-3-oxopropanamide in a yield of 33.1%; 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),7.83(d,J=6.4Hz,1H),7.59(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.27( t,J=8.0Hz,1H),7.24(t,J=54.0Hz,1H),6.59(s,1H),5.66-5.59(m,1H),5.22-5.12(m,1H),4.67(d,J=13.2Hz, 1H),4.02(d,J=13.6Hz,1H),3.72(d,J=16.0Hz,1H),3.53(d,J=16.0Hz,1H),3.26-3.19(m,1H),2.96(s,3H),2. 84(s,3H),2.81-2.73(m,1H),2.35(s,3H),2.07-1.85(m,4H),1.57(d,J=6.8Hz,3H); ESI-MS(m / z): 545.0[M+H] + .

[0486] Example 63

[0487] Preparation of 6-(1-acetylpyrrolidin-3-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0488] 4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(pyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (120 mg, 0.264 mmol), triethylamine (80 mg, 0.793 mmol) and dichloromethane (3 mL) were added to a reaction flask, and acetyl chloride (21 mg, 0.264 mmol) was added dropwise at room temperature. After the addition was completed, the reaction was stirred at room temperature for 30 min. After the reaction, water (30 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to obtain 6-(1-acetylpyrrolidin-3-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 12.3%. 1 H NMR (400MHz, DMSO-d6) δ9.13-9.06(m,1H),7.72(s,1H),7.61(t,J=7.6Hz,1H),7.49(t,J=7.2Hz,1 H),7.27(t,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H),6.60(d,J=7.6Hz,1H),5.62(q,J=6.8Hz,1H),5.5 6-5.42(m,1H),4.07-3.91(m,1H),3.87-3.76(m,1H),3.67-3.57(m,1H),3.52-3.39(m,1H),2.48- 2.40(m,2H),2.35(s,3H),1.99(d,J=13.2Hz,3H),1.57(d,J=7.2Hz,3H); ESI-MS(m / z): 460.2[M+H] + .

[0489] Example 64

[0490] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylpyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0491] 4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(pyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (200 mg, 0.441 mmol), triethylamine (133 mg, 1.322 mmol) and dichloromethane (4 mL) were added to the reaction flask. Iodomethane (63 mg, 0.441 mmol) was added dropwise to the reaction solution at room temperature, and the reaction was stirred at room temperature for 1 h. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-methylpyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 10.0%; 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 7.72 (d, J = 6.8Hz, 1H), 7.60 (d, J = 5.2Hz, 1H), 7.48 (t, J = 7.2Hz, 1H),7.28(d,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H),6.53(s,1H),5.65-5.59(m,1H),5.49-5.38(m,1H ),3.09-3.02(m,1H),2.90-2.83(m,1H),2.78-2.72(m,1H),2.47-2.41(m,1H),2.36(d,J=6.8Hz,3H) ,2.34(s,3H),2.35-2.14(m,1H),2.12-2.04(m,1H),1.57(d,J=7.2Hz,3H); ESI-MS(m / z): 432.2[M+H] + .

[0492] Example 65

[0493] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(isoxazole-4-carbonyl)pyrrolidin-3-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0494] 4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(pyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (120 mg, 0.264 mmol), 4-isoxazolecarboxylic acid (45 mg, 0.396 mmol), HATU (151 mg, 0.396 mmol), triethylamine (80 mg, 0.793 mmol) and dichloromethane (5 mL) were added to the reaction flask and stirred at room temperature for 30 min. The reaction solution was diluted with water (40 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(isoxazole-4-carbonyl)pyrrolidin-3-yl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one; the yield was 11.8%; 1 H NMR(400MHz,DMSO-d6)δ9.55-9.46(m,1H),9.22-9.10(m,1H),8.99-8.89(m,1H),7.73(s,1H),7.6 1(t,J=7.2Hz,1H),7.49(t,J=7.2Hz,1H),7.27(t,J=7.2Hz,1H),7.23(t,J=54.4Hz,1H),6.62(s,1H ),5.73-5.51(m,2H),4.27-4.09(m,1H),4.07-3.94(m,1H),3.93-3.81(m,1H),3.78-3.60(m,1H),2 .63-2.53(m,1H),2.47-2.40(m,1H),2.36(s,3H),1.57(d,J=7.2Hz,3H); ESI-MS(m / z): 513.2[M+H] + .

[0495] Example 66

[0496] Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0497] 4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(pyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one hydrochloride (120 mg, 0.264 mmol), triethylamine (80 mg, 0.793 mmol) and dichloromethane (3 mL) were added to a reaction flask. Morpholine-4-carbonyl chloride (79 mg, 0.264 mmol) was added dropwise to the reaction solution at room temperature, and the reaction was stirred at room temperature for 30 min. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 15.2%. 1 H NMR(400MHz, DMSO-d6)δ9.05(d,J=9.2Hz,1H),7.76(s,1H),7.59(t,J=7.6Hz,1H),7. 50(t,J=7.2Hz,1H),7.26(t,J=7.2Hz,1H),7.26(t,J=54.4Hz,1H),6.60(s,1H),5.65 -5.54(m,1H),5.47-5.38(m,1H),3.85-3.79(m,1H),3.623.53(m,8H),3.23-3.16(m, 4H), 2.35 (s, 3H), 2.34-2.30 (s, 1H), 1.57 (t, J = 6.0Hz, 3H); ESI-MS (m / z): 531.2[M+H] + .

[0498] Example 67

[0499] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0500] Step a): Preparation of tert-butyl 4-(4-hydroxy-5-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)piperazine-1-carboxylate.

[0501] Dimethyl 2-formyl-3-oxoglutarate (5.5 g, 0.027 mol), tert-butyl 4-aminopiperazine-1-carboxylate (6.0 g, 0.030 mol) and methanol (150 mL) were added to the reaction flask in sequence. Sodium methoxide (2.2 g, 0.040 mol) was slowly added under stirring at room temperature. The temperature was raised to 80°C under nitrogen protection and the reaction was carried out for 1.5 h. After the reaction, the reaction solution was cooled to room temperature, 2M hydrochloric acid was added to adjust the pH to 4-5, and the mixture was concentrated under reduced pressure. Dichloromethane (25 mL) and methanol (25 mL) were added to the residue, and the mixture was stirred at room temperature for 20 min. The mixture was filtered, and the filter cake was rinsed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4-hydroxy-5-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)piperazine-1-carboxylate in a yield of 41.9%; ESI-MS (m / z): 354.2 [M+H] + .

[0502] Step b): Preparation of tert-butyl 4-(5-(methoxycarbonyl)-2-oxo-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-1(2H)-yl)piperazine-1-carboxylate.

[0503] Dissolve tert-butyl 4-(4-hydroxy-5-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)piperazine-1-carboxylate (4.0 g, 0.011 mol) in 1,2-dichloroethane (100 mL). Add pyridine (1.8 g, 0.023 mol) under ice-water bath, and slowly add trifluoromethanesulfonic anhydride (6.4 g, 0.023 mol) dropwise. After completion of the addition, warm to room temperature and stir for 5 min. After the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl 4-(5-(methoxycarbonyl)-2-oxo-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-1(2H)-yl)piperazine-1-carboxylate in a yield of 45.5%; ESI-MS (m / z): 486.1 [M+H] + .

[0504] Step c): Preparation of tert-butyl 4-(4-acetyl-5-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)piperazine-1-carboxylate.

[0505] Tert-butyl 4-(5-(methoxycarbonyl)-2-oxo-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-1(2H)-yl)piperazine-1-carboxylate (2.5 g, 5.150 mmol), tributyl(1-ethoxyvinyl)tin (2.2 g, 6.180 mmol), triethylamine (1.6 g, 0.015 mol), bistriphenylphosphine palladium dichloride (289 mg, 0.412 mmol) and 1,4-dioxane (50 mL) were added sequentially into the reaction flask, the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for reaction for 2 h. After the reaction is completed, cool to room temperature, add ethyl acetate (50 mL) and 20% potassium fluoride aqueous solution (50 mL), stir at room temperature for 10 min, filter, rinse the filter cake with ethyl acetate (30 mL×3), let the filtrate stand for stratification, collect the organic phase, wash with 20% potassium fluoride aqueous solution (40 mL) and saturated brine (40 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), and a solution of hydrogen chloride in ethyl acetate (10 mL, 4 M) was added. The reaction was stirred at room temperature for 1 h. The reaction solution was washed sequentially with saturated aqueous sodium bicarbonate (50 mL×2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3) to obtain tert-butyl 4-(4-acetyl-5-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)piperazine-1-carboxylate in a yield of 51.2%; ESI-MS (m / z): 380.2 [M+H] + .

[0506] Step d): Preparation of tert-butyl 4-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)piperazine-1-carboxylate.

[0507] tert-Butyl 4-(4-acetyl-5-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)piperazine-1-carboxylate (1.0 g, 2.636 mmol) and ethanol (20 mL) were added to a reaction flask. Hydrazine hydrate (660 mg, 10.543 mmol, 80%) was added with stirring at room temperature. The reaction was heated to 90°C under nitrogen for 1 h. After the reaction was completed, the mixture was cooled to room temperature and methyl tert-butyl ether (20 mL) was added. The mixture was stirred at room temperature for 10 min, filtered, and the filter cake was dried under reduced pressure to obtain tert-butyl 4-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)piperazine-1-carboxylate in an 81.9% yield. ESI-MS (m / z): 362.2 [M+H] + .

[0508] Step e): Preparation of tert-butyl 4-(1-methyl-7-oxo-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-6(7H)-yl)piperazine-1-carboxylate.

[0509] Tert-butyl 4-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)piperazine-1-carboxylate (780 mg, 2.158 mmol), 1,2,4-triazole (1.2 g, 17.264 mmol) and acetonitrile (30 mL) were added to the reaction flask in sequence, and the atmosphere was replaced with nitrogen three times. A solution of triethylamine (3.5 g, 34.528 mmol) and phosphorus oxychloride (827 mg, 5.395 mmol) in acetonitrile (3 mL) was added, and the reaction was stirred at room temperature under nitrogen for 3 h. After the reaction, water (20 mL) was slowly added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97 / 3) to obtain tert-butyl 4-(1-methyl-7-oxo-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-6(7H)-yl)piperazine-1-carboxylate in a yield of 39.3%; ESI-MS (m / z): 413.2 [M+H] + .

[0510] Step f): Preparation of (R)-tert-butyl 4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperazine-1-carboxylate.

[0511] Tert-butyl 4-(1-methyl-7-oxo-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-6(7H)-yl)piperazine-1-carboxylate (350 mg, 0.848 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (249 mg, 1.102 mmol) and 1,4-dioxane (10 mL) were added sequentially into a microwave reaction bottle, placed in a microwave reactor and heated to 115 °C for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19:1) to obtain tert-butyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperazine-1-carboxylate in a yield of 79.7%; ESI-MS (m / z): 533.2 [M+H] + .

[0512] Step g): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one.

[0513] (R)-tert-Butyl 4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)piperazine-1-carboxylate (100 mg, 0.188 mmol) and a 2M solution of hydrogen chloride in ethyl acetate (5 mL) were added to a reaction flask and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 17.8%. 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 7.80 (d, J = 6.8Hz, 1H), 7.63-7.59(m,1H),7.50-7.46(m,1H),7.37-7.10(m,2H),6.57(s,1H),5.65-5.58(m,1H),3.28(s,2H),3.18 -3.15(m,1H),2.88(s,3H),2.79-2.66(m,2H),2.34(s,4H),1.54(d,J=6.8Hz,3H); ESI-MS(m / z): 433.2[M+H] + .

[0514] Example 68

[0515] Preparation of (R)-6-(4-acetylpiperazin-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate

[0516] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.231 mmol), triethylamine (117 mg, 1.156 mmol) and dichloromethane (5 mL) were added to the reaction flask, and acetyl chloride (22 mg, 0.277 mmol) was slowly added under ice-water bath, and the reaction was stirred at room temperature under nitrogen protection for 10 min. After the reaction, the reaction was quenched with saturated aqueous ammonium chloride (10 mL), extracted with dichloromethane (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 2) to obtain (R)-6-(4-acetylpiperazin-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate in a yield of 30.1%. 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.13(s,1H),7.90(s,1H),7.64-7.60(m,1H),7.51-7.48(m,1H),7.38-7.11(m,2H),6.62(s,1 H),5.64-5.57(m,1H),3.55-3.46(m,2H),3.33(s,6H),2.35(s,3H),2.08(s,3H),1.55(d,J=7.2Hz,3H); ESI-MS(m / z): 475.2[M+H] + .

[0517] Example 69

[0518] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(4-(morpholine-4-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one formate

[0519] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.231 mmol), triethylamine (117 mg, 1.156 mmol) and dichloromethane (5 mL) were added to a reaction flask, and morpholine-4-carbonyl chloride (42 mg, 0.277 mmol) was added with stirring at room temperature. The reaction was stirred at room temperature for 10 min under nitrogen protection. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 2) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(4-(morpholine-4-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one formate in a yield of 29.5%; 1 H NMR(400MHz,DMSO-d6)δ13.77(s,1H),9.48(s,1H),9.08(s,2H),7.68-7.64( m,1H),7.55-7.52(m,1H),7.38-7.11(m,2H),6.72(s,1H),5.62-5.55(m,1H) ,3.77(t,J=4.8Hz,4H),3.59(t,J=4.8Hz,4H),3.19(t,J=4.8Hz,4H),3.08(t ,J=4.8Hz,4H),2.38(s,3H),1.59(d,J=6.8Hz,3H); ESI-MS(m / z): 546.2[M+H] + .

[0520] Example 70

[0521] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(pyrimidin-5-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0522] Preparation method: Refer to steps af of Example 67, and purify by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-6-(pyrimidin-5-yl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 15.5%; 1H NMR (400MHz, DMSO-d6) δ9.38(s,1H),9.31(s,1H),9.18(s,2H),7.64-7.56(m,2H),7.49(t,J=7.2Hz,1H),7.27(t,J=7.2Hz, 1H),7.24(t,J=56.0Hz,1H),6.73(s,1H),5.67-5.60(m,1H),2.40(s,3H),1.52(d,J=7.2Hz,3H); ESI-MS(m / z): 427.0[M+H] + .

[0523] Example 71

[0524] Preparation of (R)-6-(adamantan-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0525] Step ae): Preparation of 6-(adamantan-1-yl)-1-methyl-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one

[0526] Preparation method: Refer to steps ae of Example 67 to obtain 6-(adamantan-1-yl)-1-methyl-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one, ESI-MS (m / z): 363.2 [M+H] + .

[0527] Step f): Preparation of (R)-6-(adamantan-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0528] 6-(Adamantane-1-yl)-1-methyl-4-(1H-1,2,4-triazol-1-yl)pyrido[3,4-d]pyridazin-7(6H)-one (309 mg, 0.853 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (290 mg, 1.285 mmol), and 1,4-dioxane (6 mL) were added to a microwave reaction vial and heated to 110°C in a microwave oven for 5 hours. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-(adamantan-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a 4.9% yield.1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),7.83(s,1H),7.63(t,J=7.2Hz,1H),7.51-7.47(m,1H),7.38-7.11(m,2H),6.46(s,1H ),5.67-5.60(m,1H),3.32(s,3H),2.42-2.20(m,9H),1.80-1.71(m,6H),1.57(d,J=7.3Hz,3H); ESI-MS(m / z): 483.0[M+H] + .

[0529] Example 72

[0530] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-(dimethylamino)ethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate

[0531] Step a): Preparation of methyl 4-hydroxy-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate.

[0532] Dimethyl 2-formyl-3-oxoglutarate (5.5 g, 0.027 mol), 2-aminoethanol (1.8 g, 0.030 mol), and methanol (120 mL) were added sequentially to a reaction flask. Sodium methoxide (2.2 g, 0.040 mol) was slowly added with stirring at room temperature. The reaction was heated to 80°C under nitrogen for 2 h. After completion of the reaction, the mixture was cooled to room temperature, adjusted to pH 4-5 with concentrated hydrochloric acid, and concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue, stirred at room temperature for 20 min, and filtered. The filter cake was rinsed with dichloromethane (10 mL), and the filtrate was concentrated under reduced pressure to obtain methyl 4-hydroxy-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 78.2%. ESI-MS (m / z): 214.1 [M+H] + .

[0533] Step b): Preparation of methyl 4-(benzoyloxy)-1-(2-(benzoyloxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate.

[0534] Methyl 4-hydroxy-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (4.5 g, 0.021 mol), triethylamine (10.6 g, 0.105 mol) and dichloromethane (100 mL) were added to the reaction flask, and benzoyl chloride (8.8 g, 0.063 mol) was added under stirring at room temperature. The reaction was stirred at room temperature under nitrogen protection for 10 min. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution (30 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 4-(benzoyloxy)-1-(2-(benzoyloxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 92.6%; ESI-MS (m / z): 422.1 [M+H] + .

[0535] Step c): Preparation of methyl 1-(2-(benzoyloxy)ethyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate.

[0536] Methyl 4-(benzoyloxy)-1-(2-(benzoyloxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (8.2 g, 0.019 mol) and methanol (200 mL) were added to a reaction flask. Potassium carbonate (4.0 g, 0.029 mol) was added under an ice-water bath, and the mixture was allowed to react at 0°C for 2 h under nitrogen. After completion of the reaction, the mixture was quenched with 2M dilute hydrochloric acid (30 mL) and extracted with dichloromethane (80 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 1-(2-(benzoyloxy)ethyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 73.0%. ESI-MS (m / z): 318.1 [M+H] + .

[0537] Step d): Preparation of methyl 1-(2-(benzoyloxy)ethyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate.

[0538] Dissolve methyl 1-(2-(benzoyloxy)ethyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (4.4 g, 0.014 mol) in 1,2-dichloroethane (100 mL). Add pyridine (2.2 g, 0.028 mol) under ice-water bath, and slowly add trifluoromethanesulfonic anhydride (7.8 g, 0.028 mol) dropwise. After addition, heat to room temperature and stir for 5 min. Add water (50 mL) to quench the reaction, and extract with dichloromethane. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain methyl 1-(2-(benzoyloxy)ethyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate in a yield of 63.6%; ESI-MS (m / z): 450.0 [M+H] + .

[0539] Step e): Preparation of methyl 4-acetyl-1-(2-(benzoyloxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate.

[0540] 1-(2-(Benzoyloxy)ethyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (4.0 g, 8.902 mmol), tributyl(1-ethoxyvinyl)tin (3.8 g, 10.682 mmol), triethylamine (2.7 g, 0.027 mol), bistriphenylphosphine palladium dichloride (312 mg, 0.445 mmol) and 1,4-dioxane (80 mL) were added to the reaction flask, replaced with nitrogen three times, and then heated to 100 ° C for reaction for 2 h. After the reaction, the mixture was cooled to room temperature, and ethyl acetate (50 mL) and a 20% aqueous potassium fluoride solution (50 mL) were added. The mixture was stirred at room temperature for 10 min and filtered. The filter cake was rinsed with ethyl acetate (30 mL x 3). The filtrate was allowed to stand for separation, and the organic phase was collected and washed with a 20% aqueous potassium fluoride solution (40 mL) and saturated brine (40 mL). It was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue and dissolved. A 4 M solution of hydrogen chloride in ethyl acetate (15 mL) was added with stirring at room temperature and the mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 4-acetyl-1-(2-(benzoyloxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate in a yield of 62.5%; ESI-MS (m / z): 344.1 [M+H] + .

[0541] Step f): Preparation of ethyl 2-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)benzoate

[0542] Methyl 4-acetyl-1-(2-(benzoyloxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.9 g, 5.564 mmol) and ethanol (40 mL) were added to a reaction flask. Hydrazine hydrate (1.1 g, 0.022 mol, 80%) was added at room temperature and the mixture was heated to 90°C for 10 min under nitrogen. After the reaction, the mixture was cooled to room temperature and methyl tert-butyl ether (40 mL) was added. The mixture was stirred at room temperature for 10 min, filtered, and rinsed with methyl tert-butyl ether (10 mL x 2). The filter cake was dried under vacuum to obtain ethyl 2-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)benzoate in an 83.9% yield. ESI-MS (m / z): 326.1 [M+H] + .

[0543] Step g): Preparation of ethyl 2-(4-bromo-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)benzoate.

[0544] Ethyl 2-(1-methyl-4,7-dioxo-3,7-dihydropyrido[3,4-d]pyridazin-6(4H)-yl)benzoate (1.5 g, 4.668 mmol), phosphorus oxybromide (2.7 g, 9.336 mmol) and acetonitrile (40 mL) were added to the reaction flask, and the temperature was raised to 105 ° C under nitrogen protection for 1 h. The reaction solution was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution (40 mL), and extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 7) to give ethyl 2-(4-bromo-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)benzoate in a yield of 55.9%; ESI-MS (m / z): 388.0 [M+H] + .

[0545] Step h): Preparation of (R)-ethyl 2-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)benzoate.

[0546] Ethyl 2-(4-bromo-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)benzoate (1.0 g, 2.609 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (706 mg, 3.131 mmol), N,N-diisopropylethylamine (1.0 g, 7.827 mmol) and 1,4-dioxane (15 mL) were added to a microwave reaction bottle, placed in a microwave reactor and heated to 100°C for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19 / 1) to give (R)-ethyl 2-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)benzoate in a yield of 64.8%; ESI-MS (m / z): 497.2 [M+H] + .

[0547] Step i): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-hydroxyethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one.

[0548] (R)-ethyl 2-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-7-oxopyrido[3,4-d]pyridazin-6(7H)-yl)benzoate (830 mg, 1.672 mmol), methanol (10 mL) and tetrahydrofuran (10 mL) were added to a reaction flask, and an aqueous lithium hydroxide solution (2.5 mL, 3 M) was added with stirring at room temperature, and the reaction was stirred at room temperature for 20 min. After the reaction, the pH was adjusted to 3-4 with 1 M dilute hydrochloric acid, and the product was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19 / 1) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-hydroxyethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in an 88.1% yield; ESI-MS (m / z): 393.1 [M+H] + .

[0549] Step j): Preparation of (R)-6-(2-chloroethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one.

[0550] (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-hydroxyethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (570 mg, 1.453 mmol) and dichloromethane (15 mL) were added to the reaction flask in sequence, and dichlorothionyl (691 mg, 5.811 mmol) was added with stirring at room temperature. The reaction was stirred at room temperature for 4 h under nitrogen protection. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (30 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. After standing for stratification, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97:3) to obtain (R)-6-(2-chloroethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 37.2%; ESI-MS (m / z): 411.1 [M+H] + .

[0551] Step k): Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-(dimethylamino)ethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate.

[0552] (R)-6-(2-chloroethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.243 mmol), N,N-diisopropylethylamine (315 mg, 2.434 mmol) and tetrahydrofuran (5 mL) were added to a glass constant volume reaction bottle. Dimethylamine tetrahydrofuran solution (1.3 mL, 2 M) was added with stirring at room temperature, and the temperature was raised to 80°C and stirred for reaction overnight. After the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 2) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2-(dimethylamino)ethyl)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one formate in a yield of 13.5%. 1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.13(s,1H),7.65-7.61(m,2H),7.51-7.47(m,1H),7.37-7.10(m,2H),6.55(s,1H),5.65-5.60(m,1 H),4.35-4.22(m,2H),3.31(s,3H),2.95-2.80(m,2H),2.43-2.41(m,3H),2.35(s,3H),1.56(d,J=6.8Hz,3H); ESI-MS(m / z): 420.2[M+H] + .

[0553] Example 73

[0554] Preparation of (R)-6-(1-acetazetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one

[0555] Preparation method: Refer to Example 68, and the resulting crude product is purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-(1-acetazetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one; Yield: 12.4%; 1 H NMR(400MHz, DMSO-d6)δ9.11(d,J=7.6Hz,1H),7.85-7.78(m,1H),7.61(t,J=7.6Hz,1H),7.49 (t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H),6.57(s,1H),5.65(p,J=6.4H z,1H),5.39-5.29(m,1H),4.62(t,J=8.8Hz,1H),4.55-4.49(m,1H),4.43-4.39(m,1H),4.32( t,J=10.0Hz,1H),2.36(s,3H),1.83(s,3H),1.57(d,J=7.2Hz,3H); ESI-MS(m / z): 446.2[M+H] + .

[0556] Example 74

[0557] Preparation of (R)-6-(azetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one trifluoroacetate

[0558] Preparation method: Refer to Example 67, and purify by Prep-HPLC (Separation Method 4) to obtain (R)-6-(azetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one trifluoroacetate; yield 21.7%; 1 H NMR (400MHz, DMSO-d6) δ13.88(s,1H),9.33(s,1H),9.10(s,2H),7.59-7.68(m,2H),7.39-7.32(m,1H),7.24(t,J=54.0Hz,1H),6.93(s,1H),5. 58(p,J=6.8Hz,1H),5.29(p,J=8.0Hz,1H),4.62-4.52(m,2H),4.42-4.33(m,2H),2.47(s,3H),1.67(d,J=6.7Hz,3H); ESI-MS(m / z): 404.2[M+H] + .

[0559] Example 75

[0560] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-vinylpyrido[3,4-d]pyridazin-7(6H)-one

[0561] (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one (250 mg, 0.613 mmol), potassium ethylene trifluoroborate (164 mg, 1.226 mmol), cesium carbonate (398 mg, 1.226 mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (45 mg, 0.061 mmol), 1,4-dioxane (10 mL) and water (2 mL) were added sequentially into the reaction flask, the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and the reaction was stirred for 2 h. After the reaction, the reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-vinylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 17.5%. 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),8.00(d,J=6.8Hz,1H),7.62(t,J=7.6Hz,1H),7.49(t,J=7.2Hz,1H),7.27(t,J= 7.2Hz,1H),7.25(t,J=52.0Hz,1H),7.13-7.09(m,1H),6.74(s,1H),6.09-6.04(m,1H),5.75-5.68(m,1H),5.38-5.55 (m,1H),3.67-3.61(m,1H),1.58(d,J=7.2Hz,3H),1.18-1.12(m,4H); ESI-MS(m / z): 401.0[M+H] + .

[0562] Example 76

[0563] Preparation of (R)-1-(cyclopent-1-en-1-yl)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0564] (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one (250 mg, 0.613 mmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (238 mg, 1.226 mmol), cesium carbonate (398 mg, 1.226 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (45 mg, 0.061 mmol), 1,4-dioxane (10 mL) and water (2 mL) were added sequentially to the reaction flask, the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and the reaction was stirred for 2 h. The reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-1-(cyclopent-1-en-1-yl)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 28.5%. 1 H NMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 7.92 (d, J = 6.8Hz, 1H), 7.62 (t, J = 7.6Hz, 1H), 7.49 (t,J=7.2Hz,1H),7.27(t,J=7.6Hz,1H),7.24(t,J=52.0Hz,1H),6.68(s,1H),6.16(s,1 H),5.73-5.66(m,1H),3.67-3.61(m,1H),2.68(d,J=7.8Hz,2H),2.56(d,J=7.8Hz,2H), 1.92-1.85(m,2H),1.57(d,J=7.2Hz,3H),1.20-1.10(m,4H); ESI-MS(m / z): 441.0[M+H] + .

[0565] Example 77

[0566] Preparation of (R)-1-(cyclopent-1-en-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0567] Preparation method: Refer to Example 76, and the residue is purified by Prep-HPLC (Separation Method 3) to obtain (R)-1-(cyclopent-1-en-1-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 5.8%; 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),7.93(d,J=6.8Hz,1H),7.63(t,J=7.6Hz,1H),7.49(t,J=6.8Hz,1H),7.38-7.11(m,2H),6.65(s,1H),6.15(s, 1H),5.72-5.63(m,1H),2.72-2.64(m,2H),2.59-2.52(m,2H),1.92-1.85 (m,2H),1.60-1.54(m,6H),1.21-1.07(m,4H); ESI-MS(m / z): 455.0[M+H] + .

[0568] Example 78

[0569] Preparation of (R)-1-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one

[0570] (R)-1-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.237 mmol), cyclopropylboronic acid (41 mg, 0.474 mmol), cesium carbonate (154 mg, 0.474 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (17 mg, 0.024 mmol), toluene (3 mL), and water (1 mL) were added sequentially to a reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C with stirring for 3 h. After completion of the reaction, the reaction solution was cooled to room temperature, quenched by the addition of saturated aqueous ammonium chloride (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 2) to obtain (R)-1-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one in an 18.5% yield. 1H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 7.74 (d, J = 6.8Hz, 1H), 7.62 (t, J = 7.6Hz, 1H),7.48(t,J=7.6Hz,1H),7.26(t,J=7.6Hz,1H),7.24(t,J=52.0Hz,1H),6.79 (s,1H),5.62-5.99(m,1H),2.21-2.24(m,1H),1.55(s,3H),1.54(s,3H),1.22 -1.14(m,2H),1.11-1.03(m,2H),0.86-0.77(s,4H); ESI-MS(m / z): 429.0[M+H] + .

[0571] Referring to the preparation method of Example 78, the compounds in the following examples were prepared with corresponding starting materials.

[0572] Example 80

[0573] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methoxypyrido[3,4-d]pyridazin-7(6H)-one

[0574] (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one (65 mg, 0.245 mmol), sodium methoxide (40 mg, 0.734 mmol) and methanol were added to the reaction flask, and the temperature was raised to 80°C and stirred for 2 h. After the reaction, the mixture was cooled to room temperature, diluted with dichloromethane (30 mL), and quenched by pouring into saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methoxypyrido[3,4-d]pyridazin-7(6H)-one in a yield of 32.3%. 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),7.60(t,J=7.6Hz,1H),7.48(t,J=6.8Hz,2H),7.27(d,J=7.6Hz,1H),7.24(s,J=53.6Hz,1H),6.5 1(s,1H),5.52(p,J=7.2Hz,1H),3.84(s,3H),3.65-3.59(m,1H),1.54(d,J=6.9Hz,3H),1.19-1.10(m,4H); ESI-MS(m / z): 405.2[M+H] + .

[0575] Example 81

[0576] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-(methylthio)pyrido[3,4-d]pyridazin-7(6H)-one

[0577] (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.245 mmol), sodium thiomethoxide (25.8 mg, 0.368 mmol), and methanol (4 mL) were added to a reaction flask and reacted at room temperature for 4 h. Saturated aqueous ammonium chloride (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-(methylthio)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 27.6%. 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 7.78-7.76 (d, J = 8.0Hz, 1H), 7.65- 7.60(m,1H),7.51-7.48(m,1H),7.38-7.11(m,2H),6.38(s,1H),5.64-5.57(m,1H),3.65-3.59 (m,1H),2.46(s,3H),1.57-1.55(d,J=8.0Hz,3H),1.17-1.10(m,4H); ESI-MS(m / z): 421.0[M+H] + .

[0578] Example 82

[0579] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carbonitrile

[0580] (R)-1-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)pyrido[3,4-d]pyridazin-7(6H)-one (440 mg, 1.043 mmol), zinc cyanide (73 mg, 0.626 mmol), tris(dibenzylideneacetone)dipalladium (95 mg, 0.104 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (76 mg, 0.104 mmol) and DMF (5 mL) were added to the reaction flask, the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and the reaction was stirred for 3 h. The reaction solution was cooled to room temperature, quenched with water (50 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain ((R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carbonitrile in a yield of 38.5%. 1 H NMR (400MHz, DMSO-d6) δ9.52(s,1H),8.91(d,J=6.8Hz,1H),7.67(t,J=7.6Hz,1H),7.53(t,J=7.2Hz,1H),7.31(t,J=7.6Hz,1H),7.25(t,J=56. 0Hz,1H),6.28(s,1H),5.87-5.80(m,1H),1.63(d,J=7.2Hz,3H),1.55(s,3H),1.24-1.14(m,2H),1.14-1.06(m,2H); ESI-MS(m / z): 414.0[M+H] + .

[0581] Referring to the preparation method of Example 82, the compounds in the following examples were prepared with corresponding starting materials.

[0582] Example 84

[0583] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carbaldehyde

[0584] (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methylpyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.257 mmol), selenium dioxide (86 mg, 0.772 mmol) and 1,4-dioxane (5 mL) were added to the reaction flask, replaced with nitrogen three times, and heated to reflux for 30 min. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carbaldehyde in a yield of 19.2%. 1 H NMR(400MHz, DMSO-d6)δ9.83(s,1H),9.22(s,1H),8.96(d,J=6.8Hz,1H),7.70-7.66(m,1H),7.55-7.51(m,1H),7.47(s,1H), 7.39-7.12(m,2H),5.99-5.92(m,1H),3.68-3.62(m,1H),1.65(d,J=7.2Hz,3H),1.20-1.10(m,4H); ESI-MS(m / z): 403.1[M+H] + .

[0585] Example 85

[0586] Preparation of (R)-6-cyclopropyl-1-(difluoromethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0587] (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carbaldehyde (100 mg, 0.248 mmol) and dichloromethane (5 mL) were added to a reaction flask, and diethylaminosulfur trifluoride (84 mg, 0.522 mmol) was added dropwise under an ice-water bath. The reaction was maintained at 0°C under nitrogen protection for 30 min. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-1-(difluoromethyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 11.2%; 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.51(s,1H),7.67-7.63(m,1H),7.53-7.50(m,1H),7.38-7.11(m,2H),7.05-6.78(m,1 H),6.56(s,1H),5.79-5.72(m,1H),3.67-3.61(m,1H),1.60(d,J=7.2Hz,3H),1.21-1.13(m,4H); ESI-MS(m / z): 425.1[M+H] + .

[0588] Example 86

[0589] Preparation of (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0590] Step a): Preparation of 1,4-dichloro-6-cyclopropylpyrido[3,4-d]pyridazin-7(6H)-one

[0591] 6-Cyclopropyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (8.8 g, 68.493 mmol) and acetonitrile (500 mL) were added to a reaction flask. DIPEA (26.5 g, 205.479 mmol) and phosphorus oxychloride (31.5 g, 205.479 mmol) were added under stirring at room temperature. The temperature was raised to 100 ° C under nitrogen protection and the reaction was carried out for 3 h. After the reaction, the mixture was cooled to room temperature and slowly poured into a mixture of ice and sodium bicarbonate to quench the mixture. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 49 / 1) to obtain 1,4-dichloro-6-cyclopropylpyrido[3,4-d]pyridazin-7(6H)-one in a yield of 5.6%; ESI-MS (m / z): 256.0 [M+H] + .

[0592] Step b): Preparation of (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one

[0593] 1,4-Dichloro-6-cyclopropylpyrido[3,4-d]pyridazin-7(6H)-one (500 mg, 1.953 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (439 mg, 1.953 mmol), and 1,4-dioxane (10 mL) were added to a microwave reaction vial and heated to 120°C in a microwave oven for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-1-chloro-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one in a yield of 26.6%. 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.14(d,J=6.8Hz,1H),7.63(t,J=7.6Hz,1H),7.50(t,J=7.2Hz,1H),7.28(t,J=7.6Hz,1H),7.24(t ,J=56.0Hz,1H),6.51(s,1H),5.66-5.59(m,1H),3.66-3.60(m,1H),1.58(d,J=7.2Hz,3H),1.20-1.09(m,4H); ESI-MS(m / z): 409.0[M+H] + .

[0594] Referring to the preparation method of Example 86, the compounds in the following examples were prepared with corresponding starting materials.

[0595] Example 88

[0596] Preparation of methyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylate

[0597] (R)-1-chloro-6-(1-methylcyclopropyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7(6H)-one (100 mg, 0.236 mmol), triethylamine (96 mg, 0.946 mmol), methanol (3 mL) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (18 mg, 0.024 mmol) were added to a reaction flask, and carbon monoxide gas was continuously bubbled into the reaction mixture with stirring at room temperature for 2 h. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid methyl ester in a yield of 34.1%. 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.95(d,J=6.8Hz,1H),7.65(t,J=7.6Hz,1H),7.51(t,J=8.2Hz,1H),7.29(t,J=7.6Hz,1H),7.25(t,J=54.4Hz,1 H),7.12(s,1H),5.84-5.78(m,1H),3.81(s,3H),1.62(d,J=6.8Hz,3H),1. 55(s,3H),1.23-1.15(m,2H),1.12-1.06(m,2H); ESI-MS(m / z): 447.0[M+H] + .

[0598] Example 89

[0599] Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid

[0600] Methyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylate (100 mg, 0.224 mmol), lithium hydroxide (27 mg, 1.120 mmol), methanol (2 mL), and water (2 mL) were added to a reaction flask and allowed to react at room temperature for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Isolation Method 3) to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid in a yield of 44.5%. 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),9.41(s,1H),8.59(s,1H),7.66(t,J=7.6Hz,1H),7.51(t,J=7.2Hz,1H),7.31(s,1H),7.29(t,J=7 .6Hz,1H),7.24(t,J=54.4Hz,1H),5.83-5.76(m,1H),1.62(d,J=6.8Hz,3H),1.56(s,3H),1.23-1.08(m,4H); ESI-MS(m / z): 433.0[M+H] + .

[0601] Example 90

[0602] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid

[0603] (R)-6-Cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carbaldehyde (100 mg, 0.248 mmol), tetrahydrofuran (4 mL), tert-butanol (2 mL) and water (2 mL) were added to a reaction flask. Sodium chlorite (112 mg, 1.240 mmol) and potassium dihydrogen phosphate (169 mg, 1.240 mmol) were added in sequence with stirring at room temperature, and the reaction was stirred at room temperature for 1 h under nitrogen protection. After the reaction, saturated brine (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 2) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid in a yield of 10.5%; 1 H NMR(400MHz,DMSO-d6)δ12.83(s,1H),9.17(s,1H),8.61(d,J=6.8Hz,1H),7.67-7.63 (m,1H),7.53-7.49(m,1H),7.38-7.11(m,3H),5.85-5.78(m,1H),3.68-3.62(m,1H), 1.62(d,J=7.2Hz,3H),1.21-1.13(m,4H); ESI-MS(m / z): 419.1[M+H] + .

[0604] Example 91

[0605] Preparation of methyl (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylate

[0606] (R)-6-Cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid (120 mg, 0.287 mmol), HATU (164 mg, 0.431 mmol), triethylamine (58 mg, 0.574 mmol), methanol (92 mg, 2.870 mmol) and dichloromethane (5 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction, saturated aqueous ammonium chloride solution (40 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid methyl ester; the yield was 18.5%; 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.60(d,J=6.8Hz,1H),7.64(t,J=7.6Hz,1H),7.51(t,J=7.2Hz,1H),7.29(t,J=7.6Hz,1H),7.24(t,J=54.4 Hz,1H),7.15(s,1H),5.81(p,J=7.2Hz,1H),3.81(s,3H),3.70-3.59(m, 1H), 1.61 (d, J=7.2Hz, 3H), 1.21-1.08 (m, 4H); ESI-MS (m / z): 433.1[M+H] + .

[0607] Example 92

[0608] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-cresolamine

[0609] Methyl (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylate (150 mg, 0.347 mmol) and a methanolic ammonia solution (6 mL, 7 M) were added to a constant volume reaction flask and stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxamide; the yield was 22.8%. 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.40(d,J=6.8Hz,1H),8.00(s,1H),7.68-7.60(m,2H),7.50(t,J=7.2Hz,1H),7.31-7.25(m,2H), 7.24(s,J=54.4Hz,1H),5.77(p,J=7.2Hz,1H),3.68-3.61(m,1H),1.60(d,J=7.2Hz,3H),1.19-1.10(m,4H); ESI-MS(m / z): 418.2[M+H] + .

[0610] Example 93

[0611] Preparation of (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N, anthocyanin-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxamide

[0612] (R)-6-Cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxylic acid (100 mg, 0.239 mmol), HATU (136 mg, 0.359 mmol), triethylamine (73 mg, 0.717 mmol), a tetrahydrofuran solution of dimethylamine (358 μL, 2 M) and dichloromethane (8 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction, saturated aqueous ammonium chloride solution (40 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (R)-6-cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N-dimethyl-7-oxo-6,7-dihydropyrido[3,4-d]pyridazine-1-carboxamide; the yield was 31.0%; 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.15(d,J=6.8Hz,1H),7.65(t,J=7.6Hz,1H),7.50(t,J=7.2Hz,1H),7.29(t,J=7.6Hz,1H),7.24(t,J=54.4Hz,1H) ,6.22(s,1H),5.74(p,J=7.2Hz,1H),3.68-3.60(m,1H),3.01(s,3H),2.81( s,3H),1.59(d,J=7.0Hz,3H),1.21-1.09(m,4H); ESI-MS(m / z):446.2[M+H] + .

[0613] Referring to the preparation method of Example 93, the compounds in the following examples were prepared using corresponding starting materials.

[0614] Biological activity test

[0615] Test Example 1: SOS1 inhibitory activity assay

[0616] The effect of SOS1 inhibitors on the interaction between SOS1 and KRAS proteins was detected by homogeneous time-resolved fluorescence technology (HTRF), thereby evaluating the inhibitory level of SOS1 protein. The protein and detection reagent used were KRAS-G12D / SOS1 BINDING ASSAY KIT (Cisbio). First, the 2mM test compound stock solution was diluted 20 times (100μM) with Diluent reagent, and then the concentration was gradually diluted 5 times with Diluent reagent (5% DMSO) to obtain a total of 8 concentrations of the test compound working solution. In a 384-well plate, 4μL tag2-KRAS was added to each well in turn. G12D Protein (containing 50 μM GTP), 2 μL test compound, 4 μL tag1-SOS1 protein, duplicate wells, incubate at room temperature for 15 minutes. Anti-tag1-Tb 3+ 5 μL each of the working solution and Anti-tag2-XL665 working solution were incubated at 4°C for 3 h. The 384-well plate was placed on a multifunctional microplate reader and read. The excitation wavelength was set to 337 nm, and the readings at 620 nm and 665 nm were recorded. The data were presented as the ratio of the 665 nm signal value to the 620 nm signal value for each well, i.e., Ratio = 10 4 ×665nm signal value / 620nm signal value. The inhibition rate is calculated by the Ratio value: % inhibition rate = [(Ratio 阴性 -Ratio 化合物 ) / (Ratio 阴性 -Ratio Blank )]×100

[0617] Note: Negative refers to the group without inhibitor; Blank refers to the group without enzyme.

[0618] IC 50 The inhibition rate was calculated by GraphPad Prism software. Two replicate wells were tested for each compound. IC 50 The value is 3.7~308.0nM. The test data of some example compounds are shown in Table 1:

[0619] Table 1

[0620] From the above data, it can be seen that the compound of the present invention has a significant inhibitory effect on SOS1 in vitro, can be used as an SOS1 inhibitor, and has broad application prospects in the fields of cancer, pathogenic rash and other diseases mediated by SOS1 protein.

[0621] Test Example 2: Determination of metabolic stability of liver microsomes

[0622] Metabolic stability influences a compound's clearance rate, half-life, and oral bioavailability, and is one of its most important ADME (Adverse Reactions, Metabolism, and Metabolism) properties. Liver microsomal stability assays are a common method for studying metabolic stability. This study employed rat liver microsomal assays to investigate the metabolic stability of compounds.

[0623] Test methods

[0624] a. Solution preparation:

[0625] Preparation of compound stock solution: Take appropriate amount of test compound and testosterone, prepare into 1 mM stock solution with DMSO, and store in a refrigerator at 4°C.

[0626] Preparation of compound working solution: Take 1 mM compound stock solution respectively, and then dilute it to 100 μM with acetonitrile-water (v:v=1:1).

[0627] Preparation of NADPH working solution: Weigh an appropriate amount of NADPH and use 16mM MgCl2 to prepare a 4.0mM NADPH working solution.

[0628] Preparation of rat liver microsome working solution: Take an appropriate amount of rat liver microsomes and dilute them with PBS to make 1 mg / ml liver microsome working solution.

[0629] b. Sample incubation:

[0630] To the incubation system, 48 μL of PBS, 100 μL of rat liver microsome working solution, and 2 μL of the test compound working solution were added sequentially and mixed thoroughly. After preincubation at 37°C for 5 minutes, 50 μL of NADPH was added to initiate the reaction. After incubation for the appropriate time point, the reaction was terminated by adding an appropriate amount of glacial acetonitrile containing an internal standard. The mixture was vortexed and centrifuged, and the supernatant was collected and injected into LC-MS / MS to determine the residual amount of the compound metabolites.

[0631] c. Data processing:

[0632] Use Excel and other software to analyze T 1 / 2 and CL (liver) The data were processed according to the following formula.

[0633] Default f u (free fraction in blood) is equal to 1.

[0634] Testing the T of the compounds of the present invention 1 / 2 9.8~129min, CL (liver)The stability test results of the compounds in some examples on rat liver microsomes are shown in Table 2:

[0635] Table 2

[0636] As can be seen from the data in Table 2, some of the compounds of the present invention have better metabolic stability and excellent drug properties compared to the compound MRTX0902. MRTX0902 is a compound disclosed in WO2021127429 (Examples 12-10) and has been reported to have SOS1 inhibitory activity.

[0637] Test Example 3: Plasma stability test

[0638] In addition to the compound's hepatic metabolic stability, its plasma stability is also an important factor influencing new drug development. Good plasma stability is an important guarantee for good pharmacokinetics and pharmacodynamics. The compounds in the examples were incubated with rat, mouse, monkey, dog, and human plasma at 37°C. The stability of the compounds in the plasma of the five species was evaluated by measuring the sample concentrations at different incubation time points and calculating the corresponding residual percentages.

[0639] Test methods

[0640] a. Solution preparation

[0641] Compound intermediate concentration working solution: Take appropriate amount of test compound and 10 mM stock solution of enalapril maleate, dilute to 1 mM with DMSO, and store in a refrigerator at 4°C.

[0642] Preparation of compound working solution: Take an appropriate amount of 1 mM intermediate concentration working solution of each compound, and then dilute it to 50 μM with acetonitrile-water (v:v=1:1).

[0643] Preparation of blank plasma: Take appropriate amounts of blank frozen plasma from rats, mice, monkeys, dogs, and humans and thaw them at 37°C.

[0644] b. Sample incubation:

[0645] Add 5 μL of compound working solution to 245 μL of blank rat plasma and mix thoroughly. Incubate at 37°C. At the appropriate time point, remove 50 μL of plasma sample from the incubation system and terminate the reaction by adding 450 μL of glacial acetonitrile (containing internal standard). Vortex to mix thoroughly and centrifuge to obtain the supernatant.

[0646] c. Data processing: LC-MS / MS was used to detect the peak area ratio of the compound after internal standard normalization at each time point. The remaining amount of the compound at time 0 was set as 100%, and Excel was used to calculate the remaining amount of the compound at each time point.

[0647] Experimental results show that after the compounds of the present invention were exposed to plasma from five species (rat, mouse, monkey, dog, and human) at 37°C for 2 hours, the residual amount remained approximately 100%, with no significant change. This indicates that these compounds have excellent plasma stability and possess excellent drug-like properties. For example, Table 3 below lists the plasma stability test data for two exemplary compounds of the present invention:

[0648] Table 3

[0649] Test Example 4: Determination of liver drug metabolizing enzyme inhibitory activity

[0650] The liver is the primary site of drug metabolism, and the primary component of the mixed-function oxidase system present in the liver is the CYP450 enzyme. This enzyme system causes the majority of clinical drug interactions, leading to an increased incidence of adverse drug reactions. CYP450 is a large supergene family composed of numerous isoenzymes, of which CYP3A4, as the primary metabolizing enzyme, is involved in the metabolism of nearly half of all drugs used clinically. Similarly, CYP2C9 and CYP2C19 are also important metabolizing enzymes, clinically involved in the metabolism of a wide range of drugs. Therefore, early testing of compounds for their inhibitory activity against CYP450 enzymes can assess the risk of drug-drug interactions and improve medication safety.

[0651] In the present invention, human liver microsomes were used as the CYP3A4 enzyme source, and specific probe substrates for each CYP isoform (CYP3A4 uses two substrates, midazolam and testosterone, represented by CYP3A4-M and CYP3A4-T, respectively) were incubated with a series of concentrations of the test compound in the presence of the cofactor NADPH. LC-MS / MS was used to measure the amount of metabolites of the probe substrate in the incubation system, and the IC values ​​of the test compound for each CYP450 enzyme isoform were calculated. 50The inhibitory effect on each CYP450 enzyme subtype was evaluated by measuring the IC value. During the experiment, 49 μL PBS, 50 μL probe substrate, and 50 μL human liver microsome working solution were added to the incubation system in sequence, and then 1 μL of each concentration of the test compound working solution was added and mixed evenly; after pre-incubation at 37°C for 5 minutes, 50 μL NADPH was added to start the reaction. After incubation for the corresponding time, an appropriate amount of glacial acetonitrile containing the internal standard was added to terminate the reaction, vortexed to mix, centrifuged to obtain the supernatant, and injected into LC-MS / MS to detect the amount of metabolites produced by the probe substrate. The enzyme activity at the 0 concentration point (characterized by the amount of metabolite produced) was taken as 100%, and the percentage of residual enzyme activity of the metabolite at different test compound concentrations was calculated. IC 50 The residual enzyme activity was calculated using Graphpad Prism software.

[0652] The experimental results show that the inhibitory activity of the compounds of the present invention against CYP2C9, CYP2C19, CYP3A4-M, and CYP3A4-T is significantly weaker than that of the reference compound MRTX0902, which helps reduce the risk of drug-drug interactions. For example, Table 4 below lists the test data for three exemplary compounds of the present invention and the reference compound MRTX0902:

[0653] Table 4

[0654] Test Example 5: In vivo efficacy study 1

[0655] Objective: This study used a human pancreatic cancer MIA PaCa-2 cell subcutaneous xenograft tumor model to evaluate the anti-tumor activity of the compound.

[0656] Experimental procedures: Female Balb / c-nu nude mice, 6-8 weeks old, weighing approximately 18-22 g were selected. Each mouse was inoculated subcutaneously with 0.1 mL (5 × 10 6 When the average tumor volume reached 127 mm 3 The test compound was administered orally by gavage daily (dosage volume 10 mL / kg) for 21 consecutive days. The dosage and frequency of administration are shown in Table 5. Tumor volume was measured twice a week and the volume was expressed in mm. 3 Measurement, calculated by the following formula: V = 0.5a × b 2, where a and b are the long and short diameters of the tumor, respectively. The anti-tumor efficacy of a compound is evaluated using TGI (%), which reflects the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of dosing in the vehicle control group - average tumor volume at the start of dosing in the vehicle control group)] × 100%. Calculation of body weight change (%): Body weight change (%) = (average weight of animals in a given treatment group at the end of dosing - average weight of animals in that treatment group at the start of dosing) / average weight of animals in that treatment group at the start of dosing × 100%.

[0657] Experimental results showed that the compounds of the present invention exhibited strong tumor inhibition activity in a subcutaneous xenograft tumor model of human pancreatic cancer MIA PaCa-2 cells. Tumor volumes were significantly smaller after administration than in the experimental group treated with the reference compound MRTX0902, and the tumor growth inhibition rate (TGI) (%) was significantly improved. For example, Table 5 below lists experimental data for two exemplary compounds of the present invention and the reference compound MRTX0902 at a dose of 25 mg / kg:

[0658] Table 5

[0659] Test Example 6: In vivo efficacy study 11

[0660] Objective: This study used the human non-small cell lung cancer NCI-H358 cell subcutaneous xenograft tumor model to evaluate the anti-tumor activity of the compound.

[0661] Experimental procedures: Female Balb / c-nu nude mice, 6-8 weeks old, weighing approximately 18-22 g were selected. Each mouse was inoculated subcutaneously with 0.1 mL (5 × 10 6 When the average tumor volume reached approximately 170 mm 3 The test compound was administered orally by gavage daily (dosage volume 10 mL / kg) for 21 consecutive days. The dosage and frequency of administration are shown in Table 6. Tumor volume was measured twice a week and the volume was expressed in mm. 3 Measurement, calculated by the following formula: V = 0.5a × b 2, where a and b are the long and short diameters of the tumor, respectively. The anti-tumor efficacy of a compound is evaluated using TGI (%), which reflects the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of dosing in the vehicle control group - average tumor volume at the start of dosing in the vehicle control group)] × 100%. Calculation of body weight change (%): Body weight change (%) = (average weight of animals in a given treatment group at the end of dosing - average weight of animals in that treatment group at the start of dosing) / average weight of animals in that treatment group at the start of dosing × 100%.

[0662] Experimental results showed that the compounds of the present invention exhibited strong tumor inhibition activity in a subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells. Tumor volumes after administration were significantly smaller than those in the experimental group treated with the reference compound MRTX0902, and the tumor growth inhibition rate (TGI) (%) was significantly improved. For example, Table 6 below lists experimental data for an exemplary compound of the present invention at doses of 25 mg / kg and 50 mg / kg, respectively, and for the reference compound MRTX0902 at a dose of 25 mg / kg:

[0663] Table 6

[0664] The above data demonstrate that the compounds of this invention exhibit significant inhibitory effects on SOS1 in vitro, can be used as SOS1 inhibitors, and exhibit excellent anti-tumor effects in animals. These compounds have broad application prospects in the treatment of SOS1-mediated diseases, such as cancer and pathogenic eczema. Furthermore, compared to MRTX0902, these compounds exhibit improved metabolic stability in liver microsomes and plasma, less inhibitory effects on liver drug-metabolizing enzymes, and significantly enhanced anti-tumor activity in vivo, demonstrating promising drug-like properties and promising clinical application prospects.

[0665] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A compound of formula I, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof: in: Ring A is selected from aryl, heteroaryl, wherein the aryl, heteroaryl is optionally selected from halogen, alkyl, alkoxy, -OH, -CN, -NR5R6, -SF5, -SO2R 12 The alkyl and alkoxy groups may be further substituted by substituents selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H, alkyl, R 12 is alkyl and is optionally substituted with halogen; R a 、R b 、R c Independently selected from H, alkyl; R1, R3, R4 are independently selected from H, halogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, alkylthio, -OH, -CN, -NR7R8, -C(=O)H, -C(=O)NR 19 R 20 、-C(=O)OR 21 The alkyl and alkoxy groups may be optionally substituted by a substituent selected from halogen, -NR7R8, wherein R7, R8, R 19 、R 20 、R 21 Independently selected from H, alkyl; R2 is -XR 13 , X is selected from alkylene, a single bond, R 13 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein: When R 13 When X is an alkyl group, it is a single bond, and the alkyl group can be optionally selected from -OH, alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 、-NR 22 R 23 Substituted by a substituent, R9, R 10 、R 11 、R 22 、R 23 Independently selected from H, alkyl; When R 13 When selected from aryl, heteroaryl, optionally selected from halogen, alkyl, alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, alkyl; When R 13 When selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, optionally selected from halogen, alkyl, -YR 16 The alkyl group may be further substituted by a substituent selected from halogen, -OH, alkoxy, -NR 17 R 18 wherein: Y is an alkylene group, R 16 is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; Alternatively, Y is selected from R 16 Selected from alkyl, alkoxy, -NR 17 R 18 , cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl; R 17 、R 18 Independently selected from H, alkyl.

2. The compound according to claim 1, characterized in that Ring A is selected from aryl and heteroaryl, and the aryl and heteroaryl are optionally substituted by a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, and -NR5R6, and the alkyl and alkoxy are optionally further substituted by a substituent selected from halogen and -NR5R6, wherein R5 and R6 are independently selected from H and alkyl.

3. The compound according to claim 1 or 2, characterized in that Ring A is selected from 6- to 12-membered aryl groups and 5- to 12-membered heteroaryl groups, wherein the heteroaryl group contains a heteroatom selected from N, O, and S, and the substituents of the above groups are as defined in claim 1 or 2; Preferably, ring A is selected from a 6-membered aryl group and a 5- to 11-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S, and the substituents of the above groups are as defined in claim 1 or 2; Preferably, ring A is selected from 6-membered aryl, 6-membered aryl-5-membered heteroaryl, wherein the heteroaryl contains 1 heteroatom selected from N, O, and S, and the substituents of the above groups are as defined in claim 1 or 2; Preferably, ring A is selected from phenyl, phenyl-thienyl, and the substituents of the above groups are as defined in claim 1 or 2; Preferably, ring A is phenyl, and its substituents are as defined in claim 1 or 2.

4. The compound according to claim 1 or 3, characterized in that The substituent contained in ring A is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR5R6, -SF5, -SO2R 12 The alkyl and alkoxy groups may be further substituted by a substituent selected from halogen and -NR5R6, wherein R5 and R6 are independently selected from H, C1-C6 alkyl, and R 12 is a C1-C6 alkyl group and is optionally substituted by halogen; Preferably, the substituent contained in ring A is selected from halogen, C1-C6 alkyl, -CN, -NR5R6, -SF5, -SO2R 12 The alkyl group may be further substituted by a substituent selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H, C1-C6 alkyl, R 12 is a C1-C6 alkyl group and is optionally substituted by halogen; Preferably, the substituent contained in ring A is selected from -F, methyl, -F substituted methyl, -NR5R6 substituted methyl, -CN, -NR5R6, -SF5, -SO2R 12 , wherein R5 and R6 are independently selected from H, methyl, R 12 is a methyl group substituted with -F; Preferably, the substituent contained in ring A is selected from -F, -CH3, -CHF2, -CF3, -CH2NHCH3, -CN, -NH2, -SF5, -SO2CHF2.

5. The compound according to any one of claims 1 to 3, characterized in that The substituent contained in ring A is selected from halogen, alkyl, -CN, and the alkyl group is optionally further substituted by a substituent selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H and alkyl; Preferably, the substituent is selected from halogen, C1-C6 alkyl, -CN, and the alkyl is optionally further substituted by a substituent selected from halogen, -NR5R6, wherein R5 and R6 are independently selected from H, C1-C6 alkyl; Preferably, the substituent is selected from -F, methyl, -F substituted methyl, -NR5R6 substituted methyl, -CN, wherein R5 and R6 are independently selected from H and methyl; Preferably, the substituent is selected from -F, -CH3, -CHF2, -CF3, -CH2NHCH3, -CN, -NH2.

6. The compound according to claim 1, characterized in that Ring A is selected from: Preferably, Ring A is selected from:

7. The compound according to any one of claims 1 to 6, characterized in that R a 、R b 、R c Independently selected from H, C1-C6 alkyl; Preferably, R a 、R b 、R c independently selected from H, methyl; Preferably, R a is methyl, R b H, R c For H.

8. The compound according to claim 7, characterized in that The structure is shown in Formula II: wherein each group is as defined in any one of claims 1 to 6.

9. The compound according to any one of claims 1 to 8, characterized in that R1, R3, and R4 are independently selected from H, alkyl, alkoxy, -OH, -CN, and -NR7R8, and the alkyl and alkoxy groups are optionally substituted with substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and alkyl; preferably, R1, R3, and R4 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, and -NR7R8, and the alkyl and alkoxy groups are optionally substituted with substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and C1-C6 alkyl; preferably, R1, R3, and R4 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, and -CN; preferably, R1, R3, and R4 are independently selected from H, methyl, methoxy, -OH, and -CN; preferably, R1 is selected from H, methyl, methoxy, and -CN; preferably, R3 is H; preferably, R4 is selected from methyl, methoxy, and -OH.

10. The compound according to any one of claims 1 to 8, characterized in that R1, R3, and R4 are independently selected from H, alkyl, alkoxy, -OH, and -NR7R8, and the alkyl and alkoxy groups are optionally substituted by substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H and alkyl; preferably, R1, R3, and R4 are independently selected from H and alkyl; preferably, R1, R3, and R4 are independently selected from H and C1~C6 alkyl; preferably, R1, R3, and R4 are independently selected from H and methyl; preferably, R1 is H; preferably, R3 is H; preferably, R4 is methyl.

11. The compound according to any one of claims 1 to 8, characterized in that R1 and R3 are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -NR7R8, and the alkyl and alkoxy groups are optionally substituted by substituents selected from halogen and -NR7R8, wherein R7 and R8 are independently selected from H, C1-C6 alkyl; preferably, R1 and R3 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -CN; preferably, R1 and R3 are independently selected from H, methyl, methoxy, -CN; preferably, R1 is selected from H, methyl, methoxy, -CN; preferably, R1 is selected from H, methyl, methoxy, -CN; preferably, R1 is selected from H, methyl, methoxy; preferably, R3 is H.

12. The compound according to any one of claims 1 to 8, characterized in that R4 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -C(=O)H, -C(=O)NR 19 R 20 、-C(=O)OR 21 , the alkyl group is optionally substituted with halogen, wherein R 19 、R 20 、R 21 Independently selected from H, C1-C6 alkyl; Preferably, R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, 3-5 membered cycloalkyl, 5 membered cycloalkenyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -C(=O)H, -C(=O)NR 19 R 20 、-C(=O)OR 21 , the alkyl group is optionally substituted with halogen, wherein R 19 、R 20 、R 21 Independently selected from H, C1-C6 alkyl; Preferably, R4 is selected from C1-C6 alkyl, -OH; Preferably, R4 is selected from methyl, ethyl, difluoromethyl, vinyl, cyclopropane, cyclopentenyl, methoxy, methylthio, -OH, -CN, -C(=O)H, -C(=O)NH2, -C(=O)N(CH3)2, -C(=O)OH, -C(=O)OCH3.

13. The compound according to any one of claims 1 to 8, characterized in that R4 is halogen; preferably, R4 is chlorine.

14. The compound according to any one of claims 1 to 13, characterized in that When R 13 When X is an alkyl group, it is a single bond, and the alkyl group can be optionally selected from -OH, alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 Substituted by a substituent, R9, R 10 、R 11 Independently selected from H, alkyl.

15. The compound according to any one of claims 1 to 13, characterized in that R2 is -XR 13 , X is a single bond, R 13 C1~C6 alkyl, wherein the C1~C6 alkyl is optionally selected from -OH, C1~C6 alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 、-NR 22 R 23 Substituted by a substituent, R9, R 10 、R 11 、R 22 、R 23 Independently selected from H, C1-C6 alkyl; Preferably, R2 is -XR 13 , X is a single bond, R 13 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally selected from -OH, halogen, -C(=O)NR9R 10 、-NR 22 R 23 Substituted by a substituent, R9, R 10 、R 22 、R 23 Independently selected from C1 to C6 alkyl; Preferably, R2 is -XR 13 , X is a single bond, R 13 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by a substituent selected from -OH, -F, -C(=O)N(CH3)2, or -N(CH3)2; Preferably, R2 is selected from -CH3, 16. The compound according to any one of claims 1 to 13, characterized in that R2 is -XR 13 , X is a single bond, R 13 C1~C6 alkyl, wherein the C1~C6 alkyl is optionally selected from -OH, C1~C6 alkoxy, halogen, -C(=O)NR9R 10 、-C(=O)OR 11 Substituted by a substituent, R9, R 10 、R 11 Independently selected from H, C1-C6 alkyl; Preferably, R2 is -XR 13 , X is a single bond, R 13 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally selected from -OH, halogen, -C(=O)NR9R 10 Substituted by a substituent, R9, R 10 Independently selected from C1 to C6 alkyl; Preferably, R2 is -XR 13 , X is a single bond, R 13 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by a substituent selected from -OH, -F, or -C(=O)N(CH3)2; Preferably, R2 is selected from -CH3, 17. The compound according to any one of claims 1 to 13, characterized in that R2 is -XR 13 , X is selected from C1-C3 alkylene, a single bond, R 13 Selected from 6-12 membered aryl, 5-12 membered heteroaryl, the heteroaryl contains a heteroatom selected from N, O, S, and the aryl and heteroaryl are optionally selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, C1-C6 alkyl; Preferably, R2 is -XR 13 , X is a methylene group, a single bond, R 13 is phenyl, 5-6 membered heteroaryl, the heteroaryl contains 1-2 heteroatoms selected from N, O, S, and the phenyl and heteroaryl are optionally selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, C1-C6 alkyl; Preferably, R2 is -XR 13 , X is a single bond, R 13 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by a C1-C6 alkoxy group; Preferably, R2 is selected from 18. The compound according to any one of claims 1 to 13, characterized in that R2 is -XR 13 , X is a methylene group, a single bond, R 13 is phenyl, 5-6 membered heteroaryl, the heteroaryl contains one heteroatom selected from N, O, S, and the phenyl and heteroaryl are optionally selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR 14 R 15 Substituents, R 14 、R 15 Independently selected from H, C1-C6 alkyl; Preferably, R2 is -XR 13 , X is a single bond, R 13 is pyridyl, which is optionally substituted by a C1-C6 alkoxy group; Preferably, R2 is 19. The compound according to any one of claims 1 to 13, characterized in that R2 is -XR 13 , X is selected from C1-C3 alkylene, a single bond, R 13 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl groups contain heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further selected from halogen, -OH, C1-C6 alkoxy, -NR 17 R 18 substituted by a substituent; Preferably, R2 is -XR 13 , X is selected from C1-C3 alkylene, a single bond, R 13 is selected from 3 to 10 membered cycloalkyl, 3 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl contains a heteroatom selected from N, O, and S, and the cycloalkyl and heterocycloalkyl are optionally selected from halogen, C1 to C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted with a substituent selected from halogen, -OH; Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from 3 to 10-membered cycloalkyl, 4 to 8-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O, and S, and the cycloalkyl and heterocycloalkyl are optionally selected from halogen, C1 to C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted with a substituent selected from halogen, -OH; Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, adamantyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted with a substituent selected from halogen, -OH; Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from 3-6 membered cycloalkyl, 5-8 membered heterocycloalkyl, the heterocycloalkyl contains 1-2 heteroatoms selected from N, O, S, the cycloalkyl, heterocycloalkyl can be selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted with a substituent selected from halogen, -OH; Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted with a substituent selected from halogen, -OH; Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from 3 to 6 membered cycloalkyl, wherein the cycloalkyl is optionally selected from halogen, C1 to C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted with a halogen; Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the above groups are optionally selected from halogen, C1-C6 alkyl, -YR 16 The C1-C6 alkyl group may be further substituted by halogen.

20. The compound according to any one of claims 1 to 13 and 19, characterized in that R 17 、R 18 Independently selected from H, C1-C6 alkyl; preferably, R 17 、R 18 Independently selected from H, methyl; preferably, R 17 、R 18 All are methyl.

21. The compound according to claim 19, characterized in that R2 is -XR 13 , X is selected from methylene, a single bond, R 13 Selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, adamantyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from -F, methyl, substituted by a substituent, wherein the methyl group is optionally further substituted by a substituent selected from -F, -OH; Preferably, R2 is selected from: Preferably, R2 is -XR 13 , X is selected from methylene, a single bond, R 13 Selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1,4-ethylenepiperidinyl, morpholinyl, the above groups are optionally selected from -F, methyl, substituted by a substituent, wherein the methyl group is optionally further substituted by a substituent selected from -F, -OH; Preferably, R2 is selected from:

22. The compound according to claim 19 or 21, characterized in that R2 is -XR 13 , X is a single bond, R 13 is selected from cyclopropane, cyclobutane, cyclopentane and cyclohexane, wherein the above groups are optionally substituted by a substituent selected from -F and methyl, wherein the methyl group is optionally further substituted by -F; Preferably, R2 is selected from:

23. The compound according to any one of claims 1 to 13 and 19, characterized in that Y is C1-C3 alkylene, R 16 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl contain a heteroatom selected from N, O, and S; Preferably, Y is C1-C3 alkylene, R 16 is a 3- to 10-membered heterocycloalkyl group containing one heteroatom selected from N, O, and S; Preferably, Y is methylene, R 16 is a 5-membered heterocycloalkyl group containing one heteroatom selected from N, O, and S; Preferably, Y is methylene, R 16 It is a tetrahydropyrrolyl group.

24. The compound according to claim 23, characterized in that R2 is 25. The compound according to any one of claims 1 to 13, 19, and 20, characterized in that Y is selected from R 16 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 17 R 18 , 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl and heteroaryl groups contain a heteroatom selected from N, O and S; Preferably, Y is selected from R 16 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 17 R 18 , 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N, O, and S; Preferably, Y is selected from R 16 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 17 R 18 , 5-6 membered heterocycloalkyl, 6 membered aryl, 5-6 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-2 heteroatoms selected from N and O; Preferably, Y is selected from R 16 Selected from methyl, methoxy, -N(CH3)2, morpholinyl, phenyl, isoxazolyl.

26. The compound according to claim 25, characterized in that R2 is selected from Preferably, R2 is selected from 27. The compound according to any one of claims 1 to 13, characterized in that R2 is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl can be optionally selected from halogen, alkyl, halogen substituted alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from alkyl, the alkyl group is optionally selected from halogen, -C (= O) NR9R 10 、-C(=O)OR 11 substituted by a substituent; Among them, R9, R 10 、R 11 Independently selected from H, alkyl; Preferably, R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl groups contain heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups may be optionally selected from halogen, alkyl, halogen-substituted alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C6 alkyl, the C1 to C6 alkyl being optionally selected from halogen, -C(=O)NR9R 10 、-C(=O)OR 11 wherein R9, R 10 、R 11 Independently selected from H, alkyl; Preferably, R2 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl groups contain heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups may be selected from halogen, alkyl, halogen-substituted alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C6 alkyl, the C1 to C6 alkyl being optionally selected from halogen, -C(=O)NR9R 10 、-C(=O)OR 11 wherein R9, R 10 、R 11 Independently selected from H, alkyl; Preferably, R2 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, the heterocycloalkyl contains 1-2 heteroatoms selected from N, O, S, and the cycloalkyl and heterocycloalkyl can be optionally selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C6 alkyl, the C1 to C6 alkyl being optionally selected from halogen, -C(=O)NR9R 10 wherein R9, R 10 、R 11 Independently selected from C1 to C6 alkyl; Preferably, R2 is selected from 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, the heterocycloalkyl contains one heteroatom selected from O, S, and the cycloalkyl, heterocycloalkyl can be optionally selected from halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from C1 to C3 alkyl, the C1 to C3 alkyl being optionally selected from halogen, -C(=O)NR9R 10 wherein R9, R 10 、R 11 Independently selected from C1 to C3 alkyl; Preferably, R2 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the above groups are optionally selected from halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, -C(=O)NR9R 10 、-C(=O)OR 11 or, R2 is selected from methyl, ethyl, propyl, and the above groups are optionally selected from halogen, -C(=O)NR9R 10 wherein R9, R 10 、R 11 Independently selected from C1 to C3 alkyl; Preferably, R2 is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo[1.1.1]pentane, cyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the above groups are optionally selected from fluoro, methyl, trifluoromethyl, -C(=O)N(CH3)2, -C(=O)OCH3; or, R2 is selected from methyl, ethyl, propyl, and the above groups are optionally substituted by substituents selected from fluorine, -C(=O)N(CH3)2; Preferably, R2 is selected from: -CH3、 Preferably, The configuration is as follows:

28. The compound according to any one of claims 1 to 27, characterized in that Select one of the following:

29. A pharmaceutical composition, characterized in that A composition comprising the compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal thereof, and a pharmaceutically acceptable excipient or auxiliary component.

30. Use of the compound according to any one of claims 1 to 28, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or the pharmaceutical composition according to claim 29 in the preparation of an SOS1 inhibitor.

31. Use of the compound of any one of claims 1 to 28, or its tautomer, stereoisomer, solvate, metabolite, isotopically labeled, pharmaceutically acceptable salt, cocrystal, or the pharmaceutical composition of claim 29 in the preparation of a medicament for treating a disease mediated by SOS1.

32. The use according to claim 31, characterized in that The disease is selected from the group consisting of: cancer, pathogenic rash disease; Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, and breast cancer; The pathogenic rash disease is selected from the group consisting of: Noonan syndrome, cardiofacial cutaneous syndrome, and hereditary gingival fibromatosis type I.

33. Use of the compound of any one of claims 1 to 28, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or the pharmaceutical composition of claim 29 in the preparation of a medicament for treating a disease causing overexpression of SOS1 protein.

34. Use of the compound of any one of claims 1 to 28, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, or the pharmaceutical composition of claim 29 in the preparation of a medicament for treating a disease caused by overexpression of SOS1 protein.

35. A pharmaceutical composition, characterized in that A method comprising administering the compound according to any one of claims 1 to 28 simultaneously or separately, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, and RAS inhibitor thereof.

36. The pharmaceutical composition according to claim 35, characterized in that The RAS inhibitor is a KRAS inhibitor; preferably, the RAS inhibitor is a KRAS G12C inhibitor; preferably, the RAS inhibitor is Adagrasib.

37. Use of the pharmaceutical composition according to claim 35 or 36 in the preparation of a medicament for treating cancer.

38. A method for treating a disease mediated by SOS1, characterized in that The method comprises administering to a subject a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal thereof, or a pharmaceutical composition according to any one of claims 29, 35 or 36.