CN119384422A - Pyridazine pyridone derivatives and uses thereof - Google Patents

Abstract

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

Description

Pyridazinopyridone derivatives and uses thereof Technical Field

The invention relates to the technical field of medicines, in particular to a pyridazinopyridone derivative serving as an SOS1 protein inhibitor and application thereof.

Background

SOS1 (son of sevenless homolog) protein is a regulatory protein widely expressed in cells, and plays an important role in regulating intracellular Ras or Rac1 signal transduction pathway as a class of guanine nucleotide exchange factor of Ras or Rac1 protein (Baltan as, F.C.; zarich, N.; rojas;)Santos, E.Biochim.Biophys.acta.Rev.cancer.2020,1874, 188445). The SOS1 protein plays a role in the Ras signal transduction pathway in promoting the release of GDP from Ras, binding GTP, and converting the Ras protein from an inactive state to an active state.

There are three genes of the RAS family known to date, KRAS, NRAS and HRAS. Mutations in RAS enzymes are closely related to tumorigenesis, with about 25% of all tumors detected (de CastroJ., belda-Iniesta C., transl Lung Cancer Res.2013,2 (2), 142-51), RAS mutation types are also different among different types of tumors. 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), ras proto-oncogene is the most common mutant 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), where v-Ki-Ras2Kirsten rat sarcoma viral oncogene (Kras) accounts for 90% of lung adenocarcinoma RAS mutations (Hunter, J.C.; et al, mol. Cancer Res.2015,13 (9), 1325-35).

SOS1 plays an important regulatory role in many signal transduction pathways within cells as a "cardiac pacemaker" of Kras. Studies have shown that inhibition of SOS1 activity has a potent inhibitory effect on cancer cell proliferation based on all major Kras gene mutations (Kessler, D.; gerlach, D.; kraut, N.; mcConnell, D.B.Curr.Opin.Chem.Biol.2021,62, 109-118). In addition, a clinical study in 62 ovarian cancer patients showed that RAS mutation and SOS1 mutation were significantly elevated in ovarian cancer tissue expression and that both prognosis were associated with patient PFS shortening, suggesting that RAS and SOS1 targeted therapy would be potentially valuable in ovarian cancer patients. At the same time, SOS1 gene mutations are also found in many other Cancer cells, such as embryonal rhabdomyosarcoma, seltoli cell testicular tumor, granulocytoma of the skin (Denayer et al, genes Chromosomes Cancer,2010,49 (3): 242-52), and lung adenocarcinoma (Cancer Genome ATIAS RESEARCH network, nature 2014,511 (7511), 543-50). In addition, SOS1 gene was found to be 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). During the development of chronic myeloid leukemia, BCR-ABL activates GRB2 by phosphorylation, recruiting SOS1, thereby continuously activating the Ras/MAPK signaling pathway, leading to malignant proliferation of hematopoietic stem cells. Thus, SOS1 protein is also a potential new target for chronic myeloid leukemia treatment. In addition to cancer, studies have shown that genetic SOS1 gene mutations are also closely associated with some pathogenic rashes such as Knonan syndrome (NS), cardiac skin syndrome (CFC) and type I hereditary gum fibromatosis (Pierre et al, biochem. Pharmacol.,2011,82 (9): 1049-56).

SOS1 inhibition was quite similar in mechanism to SHP2 inhibition (Nichols, R.J.; et al Nat Cell biol.2018,20 (9), 1064-1073), suggesting that SOS1 inhibition could also enhance the efficacy of KRAS ^G12C and MEK inhibitors. Preliminary data shows that there is a significant synergy between SOS1 and MEK inhibition in PDX models of multiple G12 and G13KRAS mutations (Hofmann, M.H.; et al; cancer discovery v.2020,10.1158/2159-8290. CD-20-0142.). In addition to inhibiting feedback activation of Kras ^wt, inhibition of SOS1 has the potential advantage of directly increasing the efficacy of Kras ^G12C inhibitors by increasing the number of mutant Kras ^G12C, since Kras ^G12C allosteric inhibitors can only bind to Kras ^GDP (Hillig, r.c., et al, proc NATL ACAD SCI U S a.2019,116 (7), 2551-2560). Although still to be further studied, inhibition of SOS1 has great potential for clinical use as a strategy for combination therapy.

At present, no medicine aiming at SOS1 targets is marketed on the global scale, and the compounds are in early clinical or preclinical research stages. Although there are a few pharmaceutical companies or research institutions that have studied SOS1 inhibitors and have been published in related patents, for example, boringer Johnsongahn discloses a class of benzyl amine substituted quinazoline derivatives as SOS1 inhibitors (US 20190358230A 1) and Bayer pharmacy discloses a class of 2-methyl-aza quinazoline compounds as SOS1 inhibitors (WO 2019201848A 1), the SOS1 inhibitors developed at the present stage still have very broad clinical application prospects, but the SOS1 inhibitors developed at the present stage still do not meet the clinical requirements.

Disclosure of Invention

The invention mainly solves the technical problem of providing a pyridazino-pyridone derivative which has a strong selective inhibition effect on SOS 1.

In order to solve the technical problems, the invention provides a compound shown in a formula I, or a tautomer, a stereoisomer, a solvate, a metabolite, an isotope label, pharmaceutically acceptable salt and a eutectic crystal thereof:

Wherein:

Ring a is selected from aryl, heteroaryl optionally substituted with a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, optionally further substituted with a substituent selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, alkyl, R ₁₂ is alkyl and optionally substituted with halogen;

r _a、R_b、R_c is independently selected from H, alkyl;

R ₁、R₃、R₄ is independently selected from H, halogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, alkylthio, -OH, -CN, -NR ₇R₈、-C(＝O)H、-C(＝O)NR₁₉R₂₀、-C(＝O)OR₂₁, said alkyl, alkoxy optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈、R₁₉、R₂₀、R₂₁ is independently selected from H, alkyl;

R ₂ is-X-R ₁₃, X is selected from alkylene, a single bond, R ₁₃ is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, wherein:

When R ₁₃ is alkyl, X is a single bond, said alkyl being optionally substituted with a substituent selected from-OH, alkoxy, halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁、-NR₂₂R₂₃, R ₉、R₁₀、R₁₁、R₂₂、R₂₃ being independently selected from H, alkyl;

When R ₁₃ is selected from aryl, heteroaryl, optionally substituted with a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, -NR ₁₄R₁₅, R ₁₄、R₁₅ is independently selected from H, alkyl;

When R ₁₃ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, optionally selected from halogen, alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH, alkoxy, -NR ₁₇R₁₈, wherein:

Y is alkylene, R ₁₆ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl;

or Y is selected from R ₁₆ is selected from alkyl, alkoxy, -NR ₁₇R₁₈, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl;

R ₁₇、R₁₈ is independently selected from H and alkyl.

Further, ring a is selected from aryl, heteroaryl optionally substituted with a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, -NR ₅R₆, optionally further substituted with a substituent selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, alkyl.

Further, ring A is selected from 6-12 membered aryl, 5-12 membered heteroaryl, said heteroaryl containing a heteroatom selected from N, O, S, the substituents of the foregoing groups being as defined above.

Preferably, ring A is selected from 6 membered aryl, 5 to 11 membered heteroaryl, said heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, the substituents of the foregoing groups being as defined above.

Preferably, ring a is selected from 6-membered aryl, 6-membered aryl-5-membered heteroaryl, said heteroaryl containing 1 heteroatom selected from N, O, S, the substituents of the foregoing groups being as defined previously.

Preferably, ring a is selected from phenyl, phenyl-thienyl, the substituents of which are as defined above.

Preferably, ring a is phenyl, the substituents of which are as defined previously.

Further, the substituent contained in the ring A is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN and-NR ₅R₆、-SF₅、-SO₂R₁₂, wherein the alkyl and alkoxy are optionally further substituted by a substituent selected from halogen, -NR ₅R₆, R ₅、R₆ is independently selected from H, C-C6 alkyl, R ₁₂ is C1-C6 alkyl and is optionally substituted by halogen.

Preferably, the substituents contained in ring A are selected from halogen, C1-C6 alkyl, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, the alkyl optionally being further substituted with substituents selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, C1-C6 alkyl, R ₁₂ is C1-C6 alkyl and optionally substituted with halogen.

Preferably, ring A contains said substituent selected from the group consisting of-F, methyl, -F substituted methyl, -NR ₅R₆ substituted methyl, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, wherein R ₅、R₆ is independently selected from H and methyl, and R ₁₂ is-F substituted methyl.

Preferably, ring A contains said substituent selected from -F、-CH₃、-CHF₂、-CF₃、-CH₂NHCH₃、-CN、-NH₂、-SF₅、-SO₂CHF₂.

Further, ring a contains said substituent selected from the group consisting of halogen, alkyl, -CN, said alkyl optionally further substituted with a substituent selected from the group consisting of halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from the group consisting of H, alkyl.

Preferably, the substituents contained in ring A are selected from halogen, C1-C6 alkyl, -CN, the alkyl optionally being further substituted with substituents selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, C1-C6 alkyl.

Preferably, the substituents contained in ring A are selected from the group consisting of-F, methyl, -F substituted methyl, -NR ₅R₆ substituted methyl, -CN, wherein R ₅、R₆ is independently selected from the group consisting of H, methyl.

Preferably, ring A contains said substituent selected from the group consisting of-F, -CH ₃、-CHF₂、-CF₃、-CH₂NHCH₃、-CN、-NH₂.

Further, ring a is selected from:

Preferably, ring a is selected from:

Further, R _a、R_b、R_c is independently selected from H, C-C6 alkyl.

Preferably, R _a、R_b、R_c is independently selected from H, methyl.

Preferably, R _a is methyl, R _b is H, and R _c is H.

Further, the structure of the compound is shown as a formula II:

wherein each group is as defined in any one of the preceding claims.

Further, R ₁、R₃、R₄ is independently selected from H, alkyl, alkoxy, -OH, -CN, -NR ₇R₈, said alkyl, alkoxy optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, alkyl.

Preferably, R ₁、R₃、R₄ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₇R₈, said alkyl, alkoxy optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, C1-C6 alkyl.

Preferably, R ₁、R₃、R₄ is independently selected from H, C C6 alkyl, C1C 6 alkoxy, -OH, -CN.

Preferably, R ₁、R₃、R₄ is independently selected from H, methyl, methoxy, -OH, -CN.

Preferably, R ₁ is selected from H, methyl, methoxy, -CN. Preferably, R ₃ is H. Preferably, R ₄ is selected from methyl, methoxy, -OH.

Further, R ₁、R₃、R₄ is independently selected from H, alkyl, alkoxy, -OH, -NR ₇R₈, said alkyl, alkoxy optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, alkyl.

Preferably, R ₁、R₃、R₄ is independently selected from H, alkyl.

Preferably, R ₁、R₃、R₄ is independently selected from H, C-C6 alkyl.

Preferably, R ₁、R₃、R₄ is independently selected from H, methyl.

Preferably, R ₁ is H. Preferably, R ₃ is H. Preferably, R ₄ is methyl.

Further, R ₁、R₃ is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -NR ₇R₈, wherein the alkyl and alkoxy are optionally substituted with substituents selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, C1-C6 alkyl.

Preferably, R ₁、R₃ is independently selected from H, C C6 alkyl, C1C 6 alkoxy, -CN.

Preferably, R ₁、R₃ is independently selected from H, methyl, methoxy, -CN.

Preferably, R ₁ is selected from H, methyl, methoxy, -CN. Preferably, R ₁ is selected from H, methyl, methoxy. Preferably, R ₃ is H.

Further, R ₄ 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 ₁₉R₂₀、-C(＝O)OR₂₁, said alkyl optionally being substituted with halogen, wherein R ₁₉、R₂₀、R₂₁ is independently selected from H, C1-C6 alkyl.

Preferably, R ₄ is selected from the group consisting of 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 ₁₉R₂₀、-C(＝O)OR₂₁, said alkyl optionally being substituted by halogen, wherein R ₁₉、R₂₀、R₂₁ is independently selected from the group consisting of H, C1-C6 alkyl.

Preferably, R ₄ is selected from C1-C6 alkyl, -OH.

Preferably, R ₄ is selected from methyl, ethyl, difluoromethyl, vinyl, cyclopropenyl, cyclopentenyl, methoxy, methylthio, -OH, -CN, -C (=o) H, -C (=o) NH ₂、-C(＝O)N(CH₃)₂、-C(＝O)OH、-C(＝O)OCH₃.

Further, R ₄ is halogen.

Preferably, R ₄ is chloro.

Further, when R ₁₃ is alkyl, X is a single bond, said alkyl is optionally substituted with a substituent selected from-OH, alkoxy, halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, and R ₉、R₁₀、R₁₁ is independently selected from H, alkyl.

Further, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by a substituent selected from-OH, C1-C6 alkoxy, halogen, -C (=O) NR ₉R₁₀、-C(＝O)OR₁₁、-NR₂₂R₂₃, and R ₉、R₁₀、R₁₁、R₂₂、R₂₃ is independently selected from H, C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with a substituent selected from-OH, halogen, -C (=O) NR ₉R₁₀、-NR₂₂R₂₃, R ₉、R₁₀、R₂₂、R₂₃ being independently selected from C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, said C1-C6 alkyl optionally being substituted with a substituent selected from-OH, -F, -C (=O) N (CH ₃)₂、-N(CH₃)₂).

Preferably, R ₂ is selected from the group consisting of-CH ₃,

Further, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by a substituent selected from-OH, C1-C6 alkoxy, halogen, -C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, and R ₉、R₁₀、R₁₁ is independently selected from H, C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with a substituent selected from-OH, halogen, -C (=O) NR ₉R₁₀, R ₉、R₁₀ being independently selected from C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, said C1-C6 alkyl optionally being substituted with a substituent selected from-OH, -F, -C (=O) N (CH ₃)₂).

Preferably, R ₂ is selected from the group consisting of-CH ₃,

Further, R ₂ is-X-R ₁₃, X is selected from C1-C3 alkylene, a single bond, R ₁₃ is selected from 6-12 membered aryl, 5-12 membered heteroaryl, the heteroaryl contains a heteroatom selected from N, O, S, the aryl, heteroaryl are optionally substituted with a substituent selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₁₄R₁₅, R ₁₄、R₁₅ is independently selected from H, C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is methylene, a single bond, R ₁₃ is phenyl, a 5-to 6-membered heteroaryl group containing 1-2 heteroatoms selected from N, O, S, said phenyl, heteroaryl group optionally being substituted with a substituent selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, NR ₁₄R₁₅, R ₁₄、R₁₅ being independently selected from H, C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is pyridinyl, pyrimidinyl, optionally substituted with C1-C6 alkoxy.

Preferably, R ₂ is selected from

Further, R ₂ is-X-R ₁₃, X is methylene, a single bond, R ₁₃ is phenyl, a 5-6 membered heteroaryl group, said heteroaryl group containing 1 heteroatom selected from N, O, S, said phenyl, heteroaryl group optionally substituted with a substituent selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₁₄R₁₅, R ₁₄、R₁₅ is independently selected from H, C1-C6 alkyl.

Preferably, R ₂ is-X-R ₁₃, X is a single bond, and R ₁₃ is pyridinyl, optionally substituted with C1-C6 alkoxy.

Preferably, R ₂ is

Further, R ₂ is-X-R 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, said heterocycloalkyl, heterocycloalkenyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl optionally being selected from halogen, C1-C6 alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH, C1-C6 alkoxy, -NR ₁₇R₁₈.

Preferably, R ₂ is-X-R ₁₃, X is selected from C1-C3 alkylene, a single bond, R ₁₃ is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being selected from halogen, C1-C6 alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH.

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from 3-10 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being selected from halogen, C1-C6 alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH.

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, adamantane, azetidine, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally substituted with halogen, C1-C6 alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH.

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from 3-to 6-membered cycloalkyl, 5-to 8-membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being selected from halogen, C1-C6-alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH.

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally substituted with halogen, C1-C6 alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH.

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from 3-6 membered cycloalkyl, said cycloalkyl optionally substituted with a substituent selected from halogen, C1-C6 alkyl, -Y-R ₁₆, said C1-C6 alkyl optionally further substituted with halogen.

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, optionally substituted with a substituent selected from halogen, C1-C6 alkyl, -Y-R ₁₆, optionally further substituted with halogen.

Further, R ₁₇、R₁₈ is independently selected from H, C-C6 alkyl.

Preferably, R ₁₇、R₁₈ is independently selected from H, methyl.

Preferably, R ₁₇、R₁₈ are both methyl.

Further, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, adamantane, azetidine, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally selected from-F, methyl,Wherein methyl is optionally further substituted with a substituent selected from-F, -OH.

Preferably, R ₂ is selected from:

Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally selected from-F, methyl, Wherein methyl is optionally further substituted with a substituent selected from-F, -OH.

Preferably, R ₂ is selected from:

Further, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, optionally substituted with a substituent selected from-F, methyl, wherein the methyl is optionally further substituted with-F.

Preferably, R ₂ is selected from:

Further, 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, and the heterocycloalkyl, heterocycloalkenyl, heteroaryl contain heteroatoms selected from N, O, S.

Preferably, Y is a C1-C3 alkylene group and R ₁₆ is a 3-to 10-membered heterocycloalkyl group containing 1 heteroatom selected from N, O, S.

Preferably, Y is methylene and R ₁₆ is a 5 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S.

Preferably, Y is methylene and R ₁₆ is tetrahydropyrrolyl.

Further, R ₂ is

Further, Y is selected fromR ₁₆ is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ₁₇R₁₈, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, said heterocycloalkyl, heterocycloalkenyl, heteroaryl containing a heteroatom selected from N, O, S.

Preferably Y is selected fromR ₁₆ is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ₁₇R₁₈, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl, heteroaryl contain 1-2 heteroatoms selected from N, O, S.

Preferably Y is selected fromR ₁₆ is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ₁₇R₁₈, 5-6 membered heterocycloalkyl, 6 membered aryl, 5-6 membered heteroaryl, said heterocycloalkyl, heteroaryl containing 1-2 heteroatoms selected from N, O.

Preferably Y is selected fromR ₁₆ is selected from methyl, methoxy, -N (CH ₃)₂, morpholinyl, phenyl, isoxazolyl).

Further, R ₂ is selected from

Preferably, R ₂ is selected from

Further, R ₂ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, optionally halogen-substituted alkyl, halogen-substituted alkyl,-C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from alkyl optionally substituted with a substituent selected from halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, wherein R ₉、R₁₀、R₁₁ is independently selected from H, alkyl.

Preferably, R ₂ is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, said heterocycloalkyl, heterocycloalkenyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl optionally substituted with an alkyl selected from halogen, alkyl, halogen, alkyl,-C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, -C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, wherein R ₉、R₁₀、R₁₁ is independently selected from H and alkyl.

Preferably, R ₂ is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl optionally substituted with an alkyl selected from halogen, alkyl, halogen, alkyl,-C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, -C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, wherein R ₉、R₁₀、R₁₁ is independently selected from H and alkyl.

Preferably, R ₂ is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being substituted by C1-C6 alkyl, halogen, C1-C6 alkyl,-C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, -C (=O) NR ₉R₁₀, wherein R ₉、R₁₀、R₁₁ is independently selected from C1-C6 alkyl.

Preferably, R ₂ is selected from 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl containing 1 heteroatom selected from O, S, said cycloalkyl, heterocycloalkyl optionally being substituted by C1-C3 alkyl selected from halogen, C1-C3 alkyl, halogen, C1-C3 alkyl,-C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by a substituent selected from halogen, -C (=O) NR ₉R₁₀, wherein R ₉、R₁₀、R₁₁ is independently selected from C1-C3 alkyl.

Preferably, R ₂ is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, the above groups are optionally halogen-, C1-C3 alkyl-, halogen-substituted C1-C3 alkyl,-C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from methyl, ethyl, propyl, optionally substituted with a substituent selected from halogen, -C (=O) NR ₉R₁₀, wherein R ₉、R₁₀、R₁₁ is independently selected from C1-C3 alkyl.

Preferably, R ₂ is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, optionally substituted with a member selected from the group consisting of fluorine, methyl, trifluoromethyl,-C (=o) N (CH ₃)₂、-C(＝O)OCH₃) substituted with a substituent or R ₂ is selected from methyl, ethyl, propyl, optionally substituted with a substituent selected from fluoro, -C (=o) N (CH ₃)₂).

Preferably, R ₂ is selected from:

Preferably, the method comprises the steps of, The following configuration is adopted:

further, the compound is selected from one of the following:

The invention provides a pharmaceutical composition which contains the compound, or a tautomer, a stereoisomer, a solvate, a metabolite, an isotope label, a pharmaceutically acceptable salt, a eutectic crystal, and pharmaceutically acceptable auxiliary materials or auxiliary components thereof.

The invention provides application of the compound, or tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt, eutectic or pharmaceutical composition thereof in preparation of SOS1 inhibitor.

The invention provides application of the compound, or tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt, eutectic or pharmaceutical composition thereof in preparing medicines for treating SOS 1-mediated diseases.

Further, the disease is selected from the group consisting of cancer, pathogenic rash.

Further, the cancer is selected from the group consisting of non-small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, stomach cancer, and breast cancer;

The pathogenic rash disease is selected from noonan syndrome, heart and face skin syndrome and type I hereditary gum fibromatosis.

The invention provides application of the compound, or tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt, eutectic or pharmaceutical composition thereof in preparing medicines for treating diseases causing over-expression of SOS1 protein.

The invention provides application of the compound, or tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt and eutectic crystal thereof, or application of the pharmaceutical composition in preparing medicines for treating diseases caused by over-expression of SOS1 protein.

The invention also provides pharmaceutical compositions comprising the compounds, or tautomers, stereoisomers, solvates, metabolites, isotopic labels, pharmaceutically acceptable salts, co-crystals, and RAS inhibitors, administered simultaneously or separately.

Further, the RAS inhibitor is a KRAS inhibitor.

Preferably, the RAS inhibitor is a KRAS G12C inhibitor.

Preferably, the RAS inhibitor is Adagrasib.

The invention also provides application of the pharmaceutical composition in preparing medicines for treating cancers.

Further, the cancer is selected from non-small cell lung cancer and pancreatic cancer.

The present invention provides a method of treating a disease mediated by SOS1 comprising the step of administering to a subject said compound, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal, or said pharmaceutical composition thereof.

The present invention provides a method of treating a disease causing overexpression of SOS1 protein comprising the step of administering said compound, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal, or said pharmaceutical composition thereof, to a subject.

The present invention provides a method of treating a disease caused by overexpression of SOS1 protein, comprising the step of administering said compound, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal, or said pharmaceutical composition thereof, to a subject.

In one embodiment, the amount of drug administered to the subject is an effective amount.

Definition of terms:

In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, the relative terms and laboratory procedures used herein are terms and conventional procedures that are widely used in the corresponding arts. Meanwhile, in order to better understand the present invention, definitions and explanations of related terms are provided below.

"Tautomer" as used herein refers to a functional isomer resulting from the movement of an atom in a molecule at two positions, particularly the presence of a mobile hydrogen atom in the molecule, e.g., ketoneAnd enol typeTautomers.

As used herein, "stereoisomers" refers to isomers produced by the same order of interconnection of atoms or groups of atoms in a molecule, but in different spatial arrangements, and include cis-trans isomers, optical isomers, conformational isomers. Stereoisomers according to the invention also include mixtures of two or more stereoisomers, such as mixtures of enantiomers and/or diastereomers in any ratio.

The term "isotopic label" as used herein means that one or more atoms in a molecule are replaced by atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to ²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³⁵S、¹⁸F、³⁶Cl、¹²³I and ¹²⁵ I, respectively. Certain isotopically-labeled compounds of the present invention are useful in drug and/or substrate tissue distribution studies, and the radioactive isotopes tritium, ³ H and carbon-14, ¹⁴ C, are particularly useful for this purpose because of their ease of incorporation and convenient detection means, e.g., the compounds of the present invention may be enriched in 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95% or 99% of the designated isotopes. In addition, substitution of the compounds of the invention with heavier isotopes such as deuterium, i.e., ² H, may afford certain therapeutic advantages.

The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. The acid base is a broad Lewis acid base. Suitable salts forming acids include inorganic acids, organic acids, acidic amino acids.

The term "solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention that is suitable for use as a drug. Solvents that form solvates include water, organic solvents.

In the present invention, "ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The "ring" in the present invention may be a single ring or multiple rings (including double rings), and may be a condensed ring, a spiro ring or a bridged ring.

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

In the present invention, "optionally substituted" means that it may be substituted with one or more (including two) specified substituents, or may be unsubstituted.

The term "cycloalkyl" refers to a saturated carbocyclic hydrocarbon group having a single ring or multiple rings. "3-10 membered cycloalkyl" refers to a saturated mono-or polycyclic hydrocarbon ring having 3-10 ring carbon atoms, examples include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, adamantane. For example, cyclopropane has the structural formulaThe structural formula of the cyclobutane isCyclopentane has the structural formulaBicyclo [1.1.1] pentanes of the formulaCyclohexane has the structural formula ofAdamantane has the structural formulaAs indicated otherwise, the cycloalkyl is optionally substituted with one or more suitable substituents.

The term "heterocycloalkyl" refers to a saturated cyclic group having a single ring or multiple rings, and 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 and the like, preferably N, O, S. "3-10 membered heterocycloalkyl" refers to a saturated monocyclic or polycyclic 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: as indicated otherwise, the heterocycloalkyl group is optionally substituted with one or more suitable substituents.

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 include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. As indicated otherwise, the cycloalkenyl group is optionally substituted with one or more suitable substituents.

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 and the like, preferably N, O, S. Examples of "3-10 membered heterocycloalkenyl" include, but are not limited to: As indicated otherwise, the heterocycloalkenyl is optionally substituted with one or more suitable substituents.

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

The term "heteroaryl" refers to a monocyclic or polycyclic aromatic radical having a conjugated pi-electron system, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The heteroatom is preferably N, O, S. Heteroaryl groups described herein include monocyclic heteroaryl groups (e.g., 5-membered ring thienyl, 5-membered ring isoxazolyl, 6-membered ring pyridyl), fused ring heteroaryl groups (having both a heteroaryl ring and a heteroaryl ring sharing a ring edge, or an aryl ring and a heteroaryl ring sharing a ring edge, e.g., 9-membered ring benzothienyl), and biaryl groups (forming heteroaryl-heteroaryl structures by single bond linkages, or aryl-heteroaryl structures, e.g., 11-membered ring phenyl-thienyl groups): ). As indicated otherwise, the heteroaryl group is optionally substituted with one or more suitable substituents.

The term "halogen" includes F, cl, br or I.

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group. "C1-C6 alkyl" refers to a straight 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 indicated otherwise, the alkyl group is optionally substituted with one or more suitable substituents.

The term "alkylene" refers to a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched chain aliphatic hydrocarbon group, i.e., one hydrogen in the alkyl group is substituted, and the definition of alkyl group is as described above. Examples of "C1-C3 alkylene" include, but are not limited to, methylene (-CH ₂ -), ethylene { including-CH ₂CH₂ -or-CH (CH ₃) - }, isopropylidene { including-CH (CH ₃)CH₂ -or-C (CH ₃)₂ - }, etc.).

The term "alkoxy" refers to an "alkyl" group as defined above attached through an oxygen atom, i.e., an "alkoxy" group may be defined as-OR, where 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 indicated otherwise, the alkoxy group is optionally substituted with one or more suitable substituents.

The term "alkylthio" refers to an "alkyl" group as defined above attached through a sulfur atom, i.e., an "alkylthio" group may be defined as-SR, wherein R is an alkyl group as defined above. As indicated otherwise, the alkylthio group is optionally substituted with one or more suitable substituents.

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 may exist as an E or Z isomer. The double bond may be located at any possible position of the hydrocarbon chain. Examples of "C2-C6 alkenyl" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. As indicated otherwise, the alkenyl group is optionally substituted with one or more suitable substituents.

The pharmaceutically acceptable auxiliary materials are the general names of all additional materials except the main drugs in the medicine, and the auxiliary materials have the following properties of (1) no toxic or side effect on human bodies, no side effect, stable chemical property, difficult influence of temperature, pH, preservation time and the like, (3) no incompatibility with the main drugs, no influence on the curative effect and quality inspection of the main drugs, and (4) no interaction with packaging materials. Adjuvants in the present invention include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, conditioning agents, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants, and the like. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

The term "subject" includes human or non-human animals. Exemplary human subjects include subjects (abbreviated patients) or normal individuals suffering from a disease such as those described herein. "non-human animals" include all vertebrates, such as non-mammals and mammals, such as non-human primates, domestic animals, and/or domesticated animals.

An "effective amount" as used herein refers to an amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disease being treated. The dosing regimen may be adjusted to provide the best desired response.

The invention has the beneficial effects that the invention provides a series of compounds with obvious inhibition effect on SOS1 protein, and provides a new scheme for treating diseases taking SOS1 as a treatment target, such as cancers, pathogenic rash and the like. Compared with the existing SOS1 inhibitor, the compound provided by the invention has obvious improvement in the aspects of activity, drug formation and the like, especially has better liver microsome stability and good drug property, can be used for preparing drugs for treating related diseases, and has wide application prospect.

Detailed Description

The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

As used herein and unless otherwise indicated, the terms "comprising," "including," "having," "containing," and their grammatical equivalents are generally understood to be open-ended and not to be limiting, e.g., not to exclude other, unrecited elements or steps.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The chemical shift (delta) of NMR is given in parts per million (ppm). NMR was performed using an AVANCE NEO 400MHz Bruker instrument with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) as the solvent and Tetramethylsilane (TMS) as the internal standard. The MS was determined using an ISQ-EC Thermo Fisher LC-MS instrument. Prep-HPLC is a GX-281Gilson chromatograph, and the separation method is (method 1) Sun FIRE PREP C, OBDTM, 5 μm, 30X 150mm Column,0.04%HCl aqueous solution/acetonitrile, (method 2) Sun FIRE PREP C, 18, OBDTM, 5 μm, 30X 150mm Column,0.06% aqueous formic acid/acetonitrile, (method 3) Xbridge Prep C18, OBDTM, 30X 150mm Column,10mM NH ₄HCO₃, aqueous solution/acetonitrile, and (method 4) SunFire Prep C18, OBDTM, 30X 150mm Column,0.02% aqueous trifluoroacetic acid/acetonitrile.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized according to methods known in the art.

The solvent used in the present invention is commercially available unless otherwise specified.

In the examples, the reaction temperature was 20 to 30℃at room temperature unless otherwise specified.

The chemical abbreviations referred to in the present invention have the following meanings:

DMF N, N-dimethylformamide

DMF-DMA N, N-dimethylformamide dimethyl acetal

DMSO-dimethyl sulfoxide

DIPEA N, N-diisopropylethylamine

HATU 2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate

NBS N-bromosuccinimide

THF tetrahydrofuran

Prep-HPLC (high Performance liquid chromatography) preparation type high performance liquid chromatograph

Example 1

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

Step a) preparation of dimethyl 2-formyl-3-oxoglutarate

Dimethyl 3-oxoglutarate (10.0 g, 57.426 mmol) and 1-methyltetrahydrofuran (100 mL) were added to the reaction flask, DMF-DMA (6.8 g,57.42 mmol) was added dropwise to the flask in an ice-water bath, and the reaction was stirred at room temperature for 2h. To the reaction mixture was added 4N diluted hydrochloric acid (30 mL), and the reaction was continued at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was extracted with methyl t-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 give dimethyl 2-formyl-3-oxoglutarate, which was used directly in the next reaction without further purification, yield 98.6%, ESI-MS (m/z): 203.2[ M+H ] ⁺.

Step b) preparation of 4-hydroxy-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

1-Methylcyclopropane-1-amine hydrochloride (4.7 g,43.925 mmol) and dimethyl 2-formyl-3-oxoglutarate (8.9 g,43.925 mmol) were dissolved in methanol (120 mL), sodium methoxide (5.2 g,96.635 mmol) was added to the solution while cooling with ice water, and the mixture was heated to 80℃for 6 hours. After the reaction, cooling the reaction solution to room temperature, concentrating under reduced pressure to remove most of the solvent, adding saturated ammonium chloride aqueous solution (100 mL) to quench the reaction, adjusting the pH of the reaction solution to be 2-3 by using 4N hydrochloric acid, precipitating a large amount of solid, filtering, washing a filter cake by using 1N dilute hydrochloric acid, collecting the filter cake, drying under reduced pressure, pulping the filter cake by using a mixed solvent of methyl tertiary butyl ether and petroleum ether (80 mL, v/v=4/1), filtering, drying the filter cake under reduced pressure to obtain 4-hydroxy-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-methyl formate, wherein the yield is 83.8%, and ESI-MS (m/z) is 224.2[ M+H ] ⁺.

Step c) preparation of methyl 1- (1-methylcyclopropyl) -6-oxo-4- (trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate

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 to the ice-water bath and the reaction stirred for 2min under ice-water bath. The reaction was quenched with saturated aqueous ammonium chloride (50 mL), left to stand for separation, the aqueous phase was extracted with dichloromethane (100 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography over silica gel (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 91.2% yield, ESI-MS (m/z): 356.2[ m+h ] ⁺.

Step d) preparation of methyl 4-acetyl-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate

Methyl 1- (1-methylcyclopropyl) -6-oxo-4- (trifluoromethyl) sulfonyl) -1, 6-dihydropyridine-3-carboxylate (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 sequentially to the reaction flask, nitrogen was replaced three times, and the reaction was stirred at 100 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, 4N diluted hydrochloric acid was added to adjust the ph=2-3, stirring was continued at room temperature for 1 hour, saturated aqueous potassium fluoride (80 mL) was added to quench the reaction, ethyl acetate (100 mL) was added, stirring was continued for 30 minutes, filtration was continued, the cake was washed with ethyl acetate (50 mL), the filtrate was separated, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give methyl 4-acetyl-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate, yield 83.3%, ESI-MS (m/z): 250.2[ m+h ] ⁺.

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

4-Acetyl-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (5.0 g,20.059 mmol) and absolute ethanol (50 mL) were added to the reaction flask, hydrazine hydrate (5 mL, 80%) was added at room temperature, and the reaction stirred at 80℃for 1h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, ethyl acetate (30 mL) was added to the residue, slurried at room temperature for 1H, filtered, the cake was rinsed with ethyl acetate (30 mL), the cake was collected, dried under reduced pressure to give 4-hydroxy-1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one in 95.6% yield, and ESI-MS (m/z): 232.1[ M+H ] ⁺.

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

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 the reaction flask, and the mixture was warmed to reflux for 2H. The reaction solution was cooled to room temperature, quenched by pouring into a saturated aqueous sodium bicarbonate solution (200 mL), extracted with methylene chloride (200 mL. Times.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 give 4-bromo-1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one in 82.7% yield, ESI-MS (m/z): 294.0[ M+H ] ⁺.

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

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, 9.284 mmol), cesium fluoride (0.9 g,5.925 mmol) and DMSO (10 mL) were added to the reaction flask and warmed to 80℃for reaction for 3H. The reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (40 mL), extracted with dichloromethane (50 mL. Times.2), the combined organic phases were washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one, purified by Prep-HPLC (method 3), yield 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]⁺.

Example 2

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

Preparation method referring to example 1, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=5/95), followed by Pre _p -HPLC (method 3) to give (R) -1-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one in yield 14.3％;¹H 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]⁺.

Example 3

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

Preparation method referring to example 1, purification by Prep-HPLC (method 3) gives (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 yield 8.9％;¹H 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]⁺.

Example 4

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

Preparation method referring to example 1, purification by Prep-HPLC (method 3) gives (R) -4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H)) -one in yield 16.0％;¹H 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),6.46(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]⁺.

Example 5

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

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

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 the reaction flask and heated to 80℃for 3H. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (40 mL), extracted with dichloromethane (50 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=4/96) to give (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 ] ⁺.

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

(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, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methylamine (200 mg,0.372 mmol), pd (PPh ₃)₄ (120 mg,0.104 mmol), cesium carbonate (190 mg,1.504 mmol), 1, 4-dioxane (2 mL) and water (0.5 mL) were added to the reaction flask, the reaction mixture was cooled to room temperature at 100℃and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=15/85) and then by Prep-HPLC (method 3) to give (R) -1-methyl-4- ((1- (5- (2-methylamino) phenyl) 2-ethyl) thien-7-amino) pyrido [ 6- (0.5 mL) pyrido ] 6-7H ] pyridazin-7 (0.5 mL) ethyl) were obtained 3.0％;¹H 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]⁺.

Example 6

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

Step a) preparation of dimethyl 2-formyl-3-oxoglutarate

Dimethyl 3-oxoglutarate (5.0 g,28.711 mmol) and 1-methyltetrahydrofuran (100 mL) were added to the reaction flask, DMF-DMA (4.1 g,34.454 mmol) was added dropwise to the flask in an ice-water bath, and the reaction was stirred at room temperature for 2h. Hydrochloric acid (100 mL, 4N) was added to the reaction mixture, and the reaction was continued at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (100 mL. Times.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 give dimethyl 2-formyl-3-oxoglutarate in 99.9% yield, and ESI-MS (m/z): 203.2[ M+H ] ⁺.

Step b) preparation of 4-hydroxy-6-oxo-1- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydropyridine-3-carboxylic acid methyl ester

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

Step c) preparation of methyl 6-oxo-1- (tetrahydro-2H-pyran-4-yl) -4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate

4-Hydroxy-6-oxo-1- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydropyridine-3-carboxylic acid methyl ester (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 for 2min while maintaining an ice-water bath. The reaction was quenched with water (100 mL), the organic phases were separated by standing, the aqueous phase was extracted with dichloromethane (100 ml×2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3/1) to give methyl 6-oxo-1- (tetrahydro-2H-pyran-4-yl) -4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate in 89.1% yield; ESI-MS (m/z): 386.2[ m+h ] ⁺).

Preparation of 4-acetyl-6-oxo-1- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydropyridine-3-carboxylic acid methyl ester

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 (264 mg, 0.399 mmol) were added sequentially to the reaction flask, nitrogen was replaced three times, and 100℃stirring was maintained for 3H. The reaction mixture was cooled to room temperature, quenched with saturated aqueous potassium fluoride (30 mL), stirred at room temperature for 5min, filtered, the filter cake rinsed with ethyl acetate (30 mL. Times.2), the filtrate separated, the aqueous phase extracted with ethyl acetate (50 mL. Times.2), the combined organic phases washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, the residue dissolved with ethyl acetate (40 mL), diluted hydrochloric acid (40 mL, 1N) stirred at room temperature for 30min, saturated aqueous sodium bicarbonate solution was added, the reaction mixture was brought to neutral pH, the organic phase was separated, the aqueous phase extracted with ethyl acetate (50 mL. Times.2), the combined organic phases washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give methyl 4-acetyl-6-oxo-1- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydropyridine-3-carboxylate in 71.4%; ESI-280 m-35.m. ⁺.

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

Methyl 4-acetyl-6-oxo-1- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydropyridine-3-carboxylate (2.0 g,7.168 mmol) and absolute ethanol (40 mL) were added to the reaction flask, hydrazine hydrate (2 mL, 80%) was added at room temperature and the reaction stirred at 80℃for 1H. The reaction mixture was cooled to room temperature, filtered, the filter cake was rinsed with ethanol (5 mL. Times.2), and dried in vacuo to give 4-hydroxy-1-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one in 88.3% yield, ESI-MS (m/z): 262.2[ M+H ] ⁺.

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

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, phosphorus tribromoxide (2.2 g,7.655 mmol) was added at room temperature, nitrogen was replaced three times, and the temperature was raised to 80 ℃ and the reaction was stirred for 1 hour. After the completion of the reaction, the reaction mixture was cooled to 0℃and was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution, extracted with methylene chloride (20 mL. Times.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, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=15/1) to give 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 ] ⁺.

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

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) ethyl-1-amine hydrochloride (97 mg,0.432 mmol), cesium fluoride (197mg, 1.298 mmol), DIPEA (167 mg, 1.298 mmol) and DMF (4 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 80℃and the reaction was stirred for 1H. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (10 mL. Times.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, and the resulting crude product was purified by Prep-HPLC (method 3) to give (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 the yield 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),7.48(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]⁺.

Example 7

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

Preparation method referring to step g of example 6, purification by Prep-HPLC (method 3) gives (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 yield 19.3％;¹H 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),5.26-5.18(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]⁺.

Example 8

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

Preparation method referring to example 1, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=6/94), followed by Prep-HPLC (method 3) to give (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 yield 6.7％;¹H 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]⁺.

Example 9

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

Preparation method referring to example 8, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=6/94), followed by Prep-HPLC (method 3) to give (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 yield 5.3％;¹H NMR(400MHz,DMSO-d₆)δ9.01(s,1H),7.96(d,J＝6.4Hz,1H),7.72(d,J＝7.2Hz,1H),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]⁺.

Example 10

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

Preparation method referring to example 1, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=6/94), followed by Prep-HPLC (method 3) to give (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 yield 5.0％;¹H 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]⁺.

Example 11

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

Preparation method referring to example 1, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=4/96) followed by Prep-HPLC (method 3) to give (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 yield 7.3％;¹H 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]⁺.

Example 12

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

Step a) preparation of 1-cyclobutyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

Dimethyl 2-formyl-3-oxoglutarate (5.6 g,27.716 mmol), cyclobutylamine (2.4 g, 33.319 mmol), sodium methoxide (3.5 mg,60.975 mmol) and methanol (50 mL) were added to the reaction flask, and the temperature was raised to 80℃and the reaction was stirred for 2h. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with a saturated aqueous ammonium chloride solution (50 mL), adjusted to pH=3-4 with 4N hydrochloric acid, extracted with dichloromethane (20 mL. Times.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 give methyl 1-cyclobutyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate, which was used directly in the next step without purification in 82.2% yield, and ESI-MS (m/z): 224.1[ M+H ] ⁺.

Step b) preparation of methyl 1-cyclobutyl-6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate

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

Step c) preparation of methyl 4-acetyl-1-cyclobutyl-6-oxo-1, 6-dihydropyridine-3-carboxylate

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 (PPh ₃)Cl₂ (4816 mg,0.690 mmol), triethylamine (4.2 g, 42.09 mmol) and 1,4 dioxane (50 mL) were added to a reaction flask, nitrogen was replaced three times, the reaction was warmed to 100 ℃ and stirred for 5h, after the reaction was completed, the reaction solution was cooled to room temperature, quenched with 30% aqueous potassium fluoride (100 mL), filtered, the filtrate was extracted with ethyl acetate (20 mL. Times.3), the organic phase was combined, washed with saturated brine (20 mL. Times.3), the organic phase was concentrated under reduced pressure, the ethyl acetate (4M) solution of hydrogen chloride was adjusted to pH=2-3, the reaction flask was stirred for 30min, the reaction flask was concentrated under reduced pressure, and the residue was eluted with petroleum ethyl acetate (20 M=20M) and purified by chromatography (MS-6M 1, 4-dioxane/6-methyl ethyl acetate (250-6-methyl acetate/ethyl acetate) [ 250-1.43 z ] to obtain 1-diethyl carboxylate.

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

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

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

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, and the temperature was raised to 105℃under nitrogen protection, followed by stirring and reaction for 2H. The reaction solution was cooled to room temperature, quenched by slowly dropping a saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4/1) to give 4-bromo-6-cyclobutyl-1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in a yield of 51.5%, ESI-MS (m/z): 294.1[ m+h ] ⁺.

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

4-Bromo-6-cyclobutyl-1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one (300 mg, 1.020mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (460 mg,2.040 mmol), DIPEA (618 mg,5.100 mmol) and 1,4-dioxane (3 mL) were added to the reaction flask and reacted by microwave at 100℃for 2H. After the completion of the reaction, the reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL. Times.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, and the residue was purified by Prep-HPLC (method 3) to give (R) -6-cyclobutyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 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),2.34(s,3H),1.93-1.84(m,2H),1.58(d,J＝7.2Hz,3H);ESI-MS(m/z)：403.0[M+H]⁺.

Example 13

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

Preparation method referring to example 12, purification by Prep-HPLC (method 3) gives ((R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (1-methylcyclobutyl) pyrido [3,4-d ] pyridazin-7 (6H)) -one ;¹H 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＝7.2Hz,3H); in 6.7% yield, ESI-MS (m/z): 417.2[ M+H ] ⁺.

Example 14

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

Preparation method reference example 12, purification by Prep-HPLC (method 3) gives 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (tetrahydrofuran-3-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 24.7％;¹H 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]⁺.

Example 15

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

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

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 the reaction flask and the mixture was subjected to a microwave reaction at 100℃for 4H. After the completion of the reaction, the reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride (20 _m L), 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 concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=2/1) to give (R) -1-methyl-6- (1-methylcyclopropyl) -4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 54.6%; ESI-MS (m/z): 448.1[ m+h ] ⁺.

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

(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, 1.79mmol), methanol (4 mL) and saturated aqueous ammonium chloride solution (2 mL) were added to the reaction flask and reacted at 90℃for 30min. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) and methylene chloride (20 mL) were added and vigorously stirred for 5min, the filtrate was filtered, the organic phase was separated, the aqueous phase was extracted with methylene chloride (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to give (R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 29.1％;¹H 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]⁺.

Example 16

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

Preparation method referring to example 12, (R) -6-cyclopentyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one was purified by Prep-HPLC (method 3), yield 25.3％;¹H 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),5.67-5.59(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]⁺.

Example 17

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

Preparation method referring to example 12, purification by Prep-HPLC (method 4) gives (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 salt, yield 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]⁺.

Example 18

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

Preparation method referring to example 12, purification by Prep-HPLC (method 3) gives (R) -6- (bicyclo [1.1.1] pent-1-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in yield 19.7％;¹H 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]⁺.

Example 19

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

Preparation method referring to example 12, purification by Prep-HPLC (method 2) gives (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-isopropyl-1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one formate salt, yield 27.9％;¹H 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]⁺.

Example 20

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

Preparation method referring to example 12, purification by Prep-HPLC (method 2) gives (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1, 6-dimethylpyrido [3,4-d ] pyridazin-7 (6H) -one formate salt, yield 21.7％;¹H 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]⁺.

Example 21

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

Preparation method referring to example 12, purification by Prep-HPLC (method 3) gives (R) -6-cyclohexyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in yield 6.0％;¹H 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]⁺.

Example 22

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

Preparation method referring to example 12, purification by Prep-HPLC (method 3) gives (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (1- (trifluoromethyl) cyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 5.3％;¹H 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]⁺.

Example 23

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

Preparation method referring to example 12, purification by Prep-HPLC (method 3) gives (R) -6- (2, 2-difluoroethyl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one; yield 18.2％;¹H 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]⁺.

Example 24

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

Preparation method referring to example 12, purification by Prep-HPLC (method 3) gives (R) -6- (4, 4-difluorocyclohexyl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 23.7％;¹H NMR(400MHz,DMSO-d₆)δ9.02(s,1H),7.81(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＝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]⁺.

Example 25

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 salt

Preparation method referring to example 12, purification by Prep-HPLC (method 4) gives (R) -6- (3, 3-difluorocyclobutyl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one trifluoroacetate in yield 31.2％;¹H 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]⁺.

Example 26

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-dimethylpropanolamine

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

Preparation method referring to steps a-f of example 12, methyl 2- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) propanoate was obtained in 55.4% yield, ESI-MS (m/z): 435.4[ M+H ] ⁺.

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

Methyl 2- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) propionate (280 mg,0.645 mmol), aqueous lithium hydroxide solution (4M, 0.6 mL), methanol (2 mL) and THF (6 mL) were added to the reaction flask, and reacted at room temperature for 0.5H. The reaction solution was adjusted to ph=2-3 with 1N diluted hydrochloric acid, saturated brine (20 mL) was added, extracted with ethyl acetate (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and 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) propionic acid in 43.3% yield, ESI-MS (m/z): 421.4[ m+h ] ⁺.

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

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,0.67 mmol), dimethylamine hydrochloride (20 mg,0.250 mmol), HATU (95 mg,0.250 mmol), DIPEA (65 mg,0.501 mmol) and methylene chloride (6 mL) were successively added to a reaction flask, and the reaction was stirred at room temperature for 30min. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL. Times.3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by Prep-HPLC (method 3) to give 2- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) -N, N-dimethylpropionamide in the yield 13.7％;¹H 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,3H),1.72(d,J＝7.2Hz,3H),1.58(t,J＝6.8Hz,3H);ESI-MS(m/z)：448.0[M+H]⁺.

Example 27

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-methylphenylamine

Preparation method referring to example 26, purification by Prep-HPLC (method 3) gives (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 in 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]⁺.

Example 28

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

Step a) preparation of 1-cyclopropyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

Dimethyl 2-formyl-3-oxoglutarate (5.6 g,27.723 mmol), cyclopropylamine (1.7 g, 30.495mmol), sodium methoxide (1.5 mg,60.975 mmol) and methanol (50 mL) were added to the reaction flask, and the reaction was heated at 80℃with stirring for 2h. After the reaction, cooling to room temperature, adding saturated aqueous ammonium chloride (50 mL) to quench the reaction, adjusting the pH of the reaction solution to be 3-4 with 4N hydrochloric acid, extracting with dichloromethane (20 mL. Times.3), combining the organic phases, washing with saturated saline (50 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain methyl 1-cyclopropyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate, which is directly used in the next step without purification, yield 70.7%, ESI-MS (m/z) 210.1[ M+H ] ⁺.

Step b) preparation of methyl 1-cyclopropyl-6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate

Methyl 1-cyclopropyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (4.1 g, 19.611 mmol) was dissolved in dichloromethane (50 mL), pyridine (2.0 g,25.502 mmol) was added under ice-bath, then trifluoromethanesulfonic anhydride (7.2 g,25.502 mmol) was added dropwise, and after the addition was completed, the temperature was raised to room temperature and stirred for 20min. After the completion of the reaction, the reaction was quenched with water (50 mL), 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 concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give methyl 1-cyclopropyl-6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate in 54.5% yield and ESI-MS (m/z): 342.1[ m+h ] ⁺.

Step c) preparation of 4-acetyl-1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

Methyl 1-cyclopropyl-6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate (3.6 g,10.557 mmol), tributyl (1-ethoxyvinyl) tin (6.0 g,16.575 mmol), pd (PPh ₃)₂Cl₂ (4816 mg,0.690 mmol), triethylamine (4.2 g, 42.09 mmol) and 1, 4-dioxane (50 mL) were added to a reaction flask, nitrogen was replaced three times, the reaction was stirred at 100℃for 5h, the reaction solution was cooled to room temperature, 30% aqueous potassium fluoride (100 mL) was added to quench the reaction, filtration was carried out, the filtrate was extracted with ethyl acetate (20 mL. Times.3), the organic phase was combined, washed with saturated brine (20 mL. Times.3), the organic phase was concentrated under reduced pressure, the pH of the solution was adjusted to 2-3 with ethyl acetate (4M) of hydrogen chloride, the residue was stirred at room temperature for 30min, and purified by petroleum column chromatography (eluent: ethyl acetate: 2/ethyl acetate=2/6-ethoxymethyl acetate) [ 1-6-ethoxymethyl ethyl acetate ] [ 1.236-1-ethoxymethyl-6-carboxylate, 236-1-diethyl ether/6-ethoxymethyl formate (236M), and ESZ-1.84-1-diethyl ether was obtained.

Step d) preparation of 6-cyclopropyl-1-methylpyrido [3,4-d ] pyridazin-4, 7 (3H, 6H) -dione

Methyl 4-acetyl-1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (2.1 g,8.936 mmol), hydrazine hydrate (1.1 g,18.072mmol, 80%) and ethanol (20 mL) were added to the reaction flask and warmed to 90℃for 1h. After the reaction, the reaction solution was cooled to room temperature, filtered, and the cake was rinsed with ethanol (10 mL) and dried under vacuum to give 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 ] ⁺.

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

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 sequentially to a reaction flask, and the mixture was heated to reflux under nitrogen and stirred for 2h. After the completion of the reaction, the reaction was cooled to room temperature, quenched by slowly dropping a saturated aqueous sodium hydrogencarbonate solution (50 mL), extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1) to give 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 ] ⁺.

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

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 the reaction flask and reacted by microwave at 100℃for 2H. After the completion of the reaction, the reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL. Times.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, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 22.1％;¹H 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＝54.4Hz,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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 28 from the corresponding starting materials.

Example 30

Preparation of (R) -1-methyl-6- (1-methylcyclopropyl) -4- (1- (3- (pentafluoro-lambda ⁶ -sulfonyl) phenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one formate salt

4-Bromo-1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one (100 mg, 0.3417 mmol), (R) -1- (3- (pentafluoro-. Lambda. ⁶ -sulfonyl) phenyl) ethane-1-amine hydrochloride (125 mg,0.443 mmol), DIPEA (132 mg,1.023 mmol) and DMSO (8 mL) were added sequentially to a microwave reaction flask and reacted by microwaves at 105℃for 1.5H. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 2) to give (R) -1-methyl-6- (1-methylcyclopropyl) -4- (1- (3- (pentafluoro-lambda ⁶ -sulfonyl) phenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 25.7％;¹H 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]⁺.

Example 31

Preparation of (R) -4- ((1- (3- ((difluoromethyl) sulfophenyl) -2-methylphenyl) ethyl) amino) -1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one _{A kind of electronic device}

Step a) preparation of S- (3-bromo-2-methylphenyl) acetic acid mercaptoester

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), pd ₂(dba)₃ (1.8 g,2.021 mmol), toluene (65 mL) and acetonitrile (33 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 70℃and the reaction was stirred for 2h. After the reaction, cooling to room temperature, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to obtain S- (3-bromo-2-methylphenyl) thioglycolate, yield 93.2%, ESI-MS (m/z): 245.0[ M+H ] ⁺.

Step b) preparation of 3-bromo-2-methylphenylsulfiol

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

Step c) preparation of (3-bromo-2-methylphenyl) (difluoromethyl) sulfide

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

Step d) preparation of 1-bromo-3- ((difluoromethyl) sulfinyl) -2-methylbenzene

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

Step e) preparation of 1- (3- ((difluoromethyl) sulfinyl) -2-methylphenyl) ethan-1-one

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), diphenylphosphine palladium dichloride (222 mg,0.316 mmol) and 1, 4-dioxane (180 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 100℃and stirred for 16h. After the completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (80 mL) was added thereto, and the mixture was stirred at room temperature for 1h. Extraction with ethyl acetate (150 mL. Times.3), washing the combined organic phases with saturated brine (200 mL), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the residue by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) gave 1- (3- ((difluoromethyl) sulfinyl) -2-methylphenyl) ethan-1-one in 95.5% yield, ESI-MS (m/z): 233.0[ M+H ] ⁺.

Step f) preparation of 1- (3- ((difluoromethyl) sulfonyl) -2-methylbenzene) ethan-1-one

1- (3- ((Difluoromethyl) sulfinyl) -2-methylbenzene) ethan-1-one (1.2 g,4.952 mmol), acetonitrile (10 mL), water (10 mL) and chloroform (10 mL) were added to the reaction flask, sodium periodate (3.18 g,14.855 mmol) and ruthenium trichloride (103 mmol, 0.495mmol) were added under ice-bath, stirred at room temperature for 2h, diluted with water (100 mL), 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 concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give 1- (3- ((difluoromethyl) sulfonyl) -2-methylbenzene) ethan-1-one in 93.3% yield, ESI-MS (m/z): 249.0[ M+H ] ⁺.

Step g) (R, Z) -N- (1- (3- ((difluoromethyl) sulfonyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide

1- (3- ((Difluoromethyl) sulfonyl) -2-methylbenzene) ethan-1-one (1.1 g,4.431 mmol), (R) - (+) -tert-butylsulfinamide (698 mg,5.760 mmol), tetraethyltitanate (2.3 g,6.646mmol, 65%) and tetrahydrofuran (30 mL) were added to the reaction flask, warmed to 80℃and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) and ethyl acetate (100 mL) were added and stirred at room temperature for 5 minutes, the mixture was filtered, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give (R, Z) -N- (1- (3- ((difluoromethyl) sulfonyl) -2-methylphenyl) ethyl) -2-methylpropan-2-sulfinamide in 98.3% yield and ESI-MS (m/Z): 352.1[ M+H ] ⁺.

Step h) preparation of (S) -N- ((R)) -1- (3- ((difluoromethyl) sulfonyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfonamide

(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 the reaction flask, cooled to-78 ℃, sodium borohydride (275 mg,7.256 mmol) was slowly added, the addition was completed, stirring was continued for 1h at room temperature, saturated ammonium chloride aqueous solution (50 mL) was added to quench the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give (S) -N- ((R)) -1- (3- ((difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfonamide in 46.7% yield (ESI-MS (m/Z354.1M [ [ ⁺ ] ].

Step i) preparation of (R) -1- (3- ((difluoromethyl) sulfonyl) -2-methylphenyl) ethane-1-amine hydrochloride

(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, 1, 4-dioxane solution of hydrogen chloride (7 mL, 4N) was added, stirred at room temperature for 1h, 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 20min, filtered, and the filter cake was dried to give (R) -1- (3- ((difluoromethyl) sulfonyl) -2-methylphenyl) ethane-1-amine hydrochloride in 92.9% yield and ESI-MS (m/z): 250.1[ M+H ] ⁺.

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

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 (2919 mg,1.019 mmol), DIPEA (438 mg,3.390 mmol) and 1, 4-dioxane (8 mL) were added to a reaction flask, and the mixture was heated to 105℃in a microwave reactor and reacted with stirring for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- ((difluoromethyl) sulfonyl) -2-methylphenyl) ethyl) amino) -1-methyl-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 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]⁺.

Example 32

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

Step a) preparation of methyl 4-hydroxy-1- (1- (hydroxymethyl) cyclopropyl) methyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate

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) were added to the reaction flask, and the mixture was heated to 80℃and stirred for 2h. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (50 mL), adjusted to ph=3-4 with 4N hydrochloric acid, 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, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give methyl 4-hydroxy-1- (1- (hydroxymethyl) cyclopropyl) methyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate in 47.9% yield and ESI-MS (m/z): 254.2[ m+h ] ⁺.

Step b) preparation of methyl 4- (benzoyloxy) -1- (1- (benzoyloxy) cyclopropyl) methyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate

Methyl 4-hydroxy-1- (1- (hydroxymethyl) cyclopropyl) methyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (6.0 g, 23.015 mmol), dichloromethane (60 mL) and triethylamine (9.6 g,94.862 mmol) were added to the reaction flask, benzoyl chloride (10.0 g,71.145 mmol) was added dropwise, and the reaction was stirred at room temperature for 16h. The reaction was quenched with water (100 mL), extracted with dichloromethane (50 ml×3), the organic phases combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography on silica gel (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 88.7% yield and ESI-MS (m/z) 462.2[ m+h ] ⁺.

Step c) preparation of methyl 1- ((1- (benzoyloxy) methyl) cyclopropyl) methyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate

Methyl 4- (benzoyloxy) -1- (1- (benzoyloxy) cyclopropyl) methyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (9.7 g,21.041 mmol) and methanol (100 mL) were added to the reaction flask, potassium carbonate (5.8 g,42.082 mmol) was added under ice water bath, and the ice water bath stirred for 10min. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL), the reaction mixture was adjusted to ph=3-4 with 4N hydrochloric acid, extracted with dichloromethane (20 ml×3), the organic phases combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography on silica gel (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 81.2% yield and ESI-MS (m/z): 358.2[ m+h ] ⁺.

Step d) preparation of methyl 1- ((1- (benzoyloxy) methyl) cyclopropyl) methyl) -6-oxo-4- ((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate

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 under stirring for 20min under ice water bath. The reaction was quenched with water (60 mL), extracted with dichloromethane (30 ml×3), the organic phases combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=3/1) to give methyl 1- ((1- (benzoyloxy) methyl) cyclopropyl) -6-oxo-4- ((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate in 93.3% yield, ESI-MS (m/z): 490.1[ m+h ] ⁺.

Step e) preparation of methyl 4-acetyl-1- (1- (benzoyloxy) methyl) cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylate

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 (PPh ₃)₂Cl₂ (4818 mg,0.690 mmol), triethylamine (4.0 g, 40.3838 mmol) and 1, 4-dioxane (80 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 100℃and the reaction was stirred for 5h. After the reaction was completed, the reaction was cooled to room temperature, quenched with aqueous KF (80 mL), filtered, the filtrate was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, ethyl acetate (30 mL, 4N) solution of hydrogen chloride was added, stirred at room temperature for 30min, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give 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 ] ⁺.

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

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,24.282mmol, 80%) and ethanol (30 mL) were added to the reaction flask, heated to 90 ℃ and stirred for 1h. After the reaction, cooling to room temperature, filtering, leaching the filter cake with ethanol (10 mL), and vacuum drying to obtain methyl (1- ((1-methyl-4, 7-dioxo-3, 7-dihydropyrido [3,4-d ] pyridazin-6 (4H) -yl) methyl) cyclopropyl) benzoate, yield 81.2%, ESI-MS (m/z): 366.1[ M+H ] ⁺.

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

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 sequentially added to a reaction flask, and the temperature was raised to 105℃under nitrogen and the reaction was stirred for 2H. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL), 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 concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1) to give 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 ] ⁺.

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

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) ethyl-1-amine hydrochloride (336 mg,1.430 mmol), DIPEA (492 mg,3.812 mmol) and 1, 4-dioxane (10 mL) were added to the reaction flask and reacted by microwaves at 100℃for 2H. After the reaction was completed, cooled to room temperature, quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1) to give 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 58.7% yield, ESI-MS (m/z): 537.3[ m+h ] ⁺.

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

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 (300 mg,0.560 mmol), lithium hydroxide monohydrate (47 mg,1.120 mmol) and methanol (50 mL) were added to a reaction flask, and the reaction was stirred at room temperature for 1H. After the completion of the reaction, the reaction was quenched with water (20 mL), extracted with methylene chloride (20 mL. Times.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 give (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 in 98.7% yield, ESI-MS (m/z): 433.1[ M+H ] ⁺.

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

(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, thionyl chloride (630 mg,5.032 mmol) was added dropwise, and the reaction was stirred at room temperature after the addition for 1H. After the reaction was completed, the mixture was concentrated under reduced pressure to give (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 in the next step without purification, yield 97.1%, ESI-MS (m/z): 451.2[ M+H ] ⁺.

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

(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 mixture was heated to 80℃and reacted with stirring for 8H. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 2) to give (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 yield 17.5％;¹H 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]⁺.

Example 33

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

Preparation method referring to steps a-i of example 32, the crude product obtained was purified by Prep-HPLC (isolation procedure 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 salt in yield 18.4％;¹H 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]⁺.

Example 34

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

Preparation method referring to steps a-i of example 32, the crude product obtained was purified by Prep-HPLC (isolation procedure 3) to give 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (4-hydroxybut-2-yl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 26.7％;¹H 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]⁺.

Example 35

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

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

(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1- (hydroxymethyl) cyclopropyl) methyl) -1-methylpyridazo [3,4-d ] pyridazin-7 (6H) -one (200 mg,0.463 mmol), dess-martin oxidant (295 mg,0.695 mmol) and dichloromethane (10 mL) were added to the reaction flask, the reaction was stirred at room temperature for 5H, quenched with water (20 mL), extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and the residue purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (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%; ESz (431M: ⁺.35H).

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

(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 methylene chloride (10 mL) were added to a reaction flask, and diethylaminosulfur trifluoride (97 mg,0.604 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 18 hours. After the completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((1- (difluoromethyl) cyclopropyl) methyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 14.7％;¹H 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]⁺.

Example 36

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

Preparation method referring to steps a-i of example 32, the crude product obtained was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1- (hydroxymethyl) cyclopropyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 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]⁺.

Example 37

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

Preparation method reference example 35 and purification of the crude product obtained by Prep-HPLC (isolation method 3) gives (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1- (difluoromethyl) cyclopropyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in yield 15.7％;¹H 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]⁺.

Example 38

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

Preparation method reference example 28, purification of the crude product obtained by Prep-HPLC (isolation method 3) gives 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- ((tetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 21.8％;¹H 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]⁺.

Example 39

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

(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 methylene chloride (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 20min. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL. Times.3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1- (fluoromethyl) cyclopropyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 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]⁺.

Example 40

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

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

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

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

(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, 0.399mmol) and methanol (5 mL) were added to a reaction flask at room temperature, sodium methoxide (32 mg,0.588 mmol) was slowly added, the reaction was carried out at room temperature for 30min, quenched with saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 1) to give (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 the yield 47.4％;¹H 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]⁺.

Example 41

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

(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, 0.4813 mmol), 1, 4-dioxane (4 mL), water (1 mL), methylboronic acid (58 mg,0.967 mmol), pd (dppf) Cl ₂ (72 mg,0.096 mmol) and potassium carbonate (200 mg,1.449 mmol) were added to a microwave tube at room temperature, and the mixture was subjected to a 100℃microwave reaction with a nitrogen purge of 1min for 1.5H. After the completion of the reaction, it was cooled to room temperature, quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 1) to give (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 the yield 20.0％;¹H 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]⁺.

Example 42

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

(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, nitrogen was replaced three times, and the mixture was warmed to 100℃for 1H. After completion of the reaction, cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (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, yield 17.7％;¹H 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]⁺.

Example 43

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

Step a) preparation of 4-cyano-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

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), palladium tetraphenyl phosphine (280 mg,0.242 mmol) and DMF (20 mL) were added to the reaction flask at room temperature, nitrogen was replaced three times, and the temperature was raised to 80℃for 1h. After the reaction was completed, the filtrate was cooled and filtered, poured into water (30 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 ml×3)), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give methyl 4-cyano-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate in 78.2% yield, ESI-MS (m/z): 233.1[ m+h ] ⁺.

Step b) preparation of 1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3, 4-dicarboxylic acid dimethyl ester

4-Cyano-1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (2.1 g,9.052 mmol) and 6N hydrochloric acid (10 mL) were added to the reaction flask at room temperature, warmed to reflux for 5h, methanol (40 mL) was added, and reflux was continued overnight. After the reaction was completed, cooled to room temperature, the organic solvent was removed under reduced pressure, diluted with water (30 mL), extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated aqueous sodium hydrogencarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give dimethyl 1- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridine-3, 4-dicarboxylate, which was used directly in the next reaction without purification, yield 75.1%, ESI-MS (m/z): 266.0[ M+H ] ⁺.

Step c) preparation of 6- (1-methylcyclopropyl) -2, 3-dihydropyrido [3,4-d ] pyridazin-1, 4,7 (6H) -trione

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, the reaction was warmed to 100℃overnight, the reaction mixture was cooled to room temperature, acetonitrile (100 mL) was added, stirred at room temperature for 10min, filtered, the filter cake was rinsed with acetonitrile (10 mL) and dried in vacuo to give 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 ] ⁺.

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

6- (1-Methylcyclopropyl) -2, 3-dihydropyrido [3,4-d ] pyridazin-1, 4,7 (6H) -trione (780 mg,3.348 mmol), phosphine oxide tribromide (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℃for 3H. After the completion of the reaction, cooled to room temperature, slowly poured into a saturated aqueous sodium bicarbonate solution (200 mL), stirred well, extracted with methylene chloride (100 mL. Times.2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/2) to give 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 ] ⁺.

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

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 flask, the reaction was allowed to react at 105℃for 1H in a microwave reactor, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/2) to give (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 ] ⁺).

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

(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, and the mixture was heated to 80℃and stirred for 2 hours. After the completion of the reaction, cooled to room temperature, diluted with dichloromethane (30 mL), poured into a saturated aqueous ammonium chloride solution (50 mL), extracted with dichloromethane (30 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methoxy-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 35.0％;¹H 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]⁺.

Example 44

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

(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, and the mixture was heated to 100℃and stirred for 30min. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-hydroxy-6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one in the following yield 33.0％;¹H 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]⁺.

Example 45

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

4-Bromo-6-cyclopropyl-1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one (100 mg, 0.317 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 the mixture was heated to 105℃in a microwave reactor and stirred for 1H. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -3- (1- ((6-cyclopropyl-1-methyl-7-oxo-6, 7-dihydropyrido [3,4-d ] pyridazin-4-yl) amino) ethyl) -2-methylbenzonitrile in yield 31.7％;¹H 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]⁺.

Example 46

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

Preparation method referring to example 45, the crude product obtained was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-1-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one in yield 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]⁺.

Example 47

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

Step a) preparation of 4-acetyl-5-bromo-1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

Methyl 4-acetyl-1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (3.4 g, 14.4638 mmol), NBS (3.1 g,17.362 mmol) and acetic acid (30 mL) were added to the reaction flask and reacted at room temperature under stirring for 24h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, quenched with saturated aqueous sodium hydrogencarbonate (50 mL), extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=3/1) to give methyl 4-acetyl-5-bromo-1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylate in 86.1% yield, ESI-MS (m/z): 314.0[ M+H ] ⁺.

Step b) preparation of 4-acetyl-1-cyclopropyl-5-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

Methyl 4-acetyl-5-bromo-1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (2.5 g, 7.9622 mmol), methyl boronic acid (704mg,11.943mmol)、K₂CO₃(2.2g,15.924mmol)、Pd(PPh₃)₄(460mg,0.398mmol)、1,4- dioxane (30 mL) and water (6 mL) were added sequentially to the reaction flask, nitrogen was replaced three times and the reaction was stirred at 100 ℃ for 16h. After the completion of the reaction, the reaction was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give methyl 4-acetyl-1-cyclopropyl-5-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylate in 33.0% yield and ESI-MS (m/z): 250.1[ m+h ] ⁺.

Step c) preparation of 6-cyclopropyl-1, 8-dimethylpyrido [3,4-d ] pyridazin-4, 7 (3H, 6H) -dione

4-Acetyl-1-cyclopropyl-5-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (650 mg,2.610 mmol), hydrazine hydrate (0.5 mL, 80%) and ethanol (10 mL) were added to the reaction flask, and the temperature was raised to 90℃and the reaction was stirred for 1h. After the reaction, the reaction solution was cooled to room temperature, filtered, and the cake was rinsed with ethanol (2 mL) and dried under vacuum to give 6-cyclopropyl-1, 8-dimethylpyrido [3,4-d ] pyridazine-4, 7 (3H, 6H) -dione in 92.3% yield, ESI-MS (m/z): 232.1[ M+H ] ⁺.

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

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 successively added to the reaction flask, and the mixture was heated to reflux under nitrogen and stirred for 2 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (50 mL), extracted with methylene chloride (50 mL. Times.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, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4/1) to give 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 ] ⁺.

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

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, 0.560 mmol), DIPEA (241 mg,1.870 mmol) and 1,4-dioxane (3 mL) were added to the reaction flask and the reaction was subjected to 100℃microwave reaction for 1H. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1, 8-dimethylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 23.5％;¹H NMR(400MHz,DMSO-d₆)δ8.80(s,1H),7.63(d,J＝6.8Hz,1H),7.57(t,J＝7.6Hz,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]⁺.

Example 48

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

Preparation method referring to example 47 step e, the crude product obtained was purified by Prep-HPLC (isolation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -1, 8-dimethylpyrido [3,4-d ] pyridazin-7 (6H) -one in yield 13.5％;¹H 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),5.63-5.56(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]⁺.

Example 49

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

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

The preparation method is referred to in steps a-d of example 28.

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

A solution of 4- (1-methyl-4, 7-dioxo-3, 7-dihydropyrido [3,4-d ] pyridazin-6 (4H) -yl) piperidine-1-carboxylic acid tert-butyl ester (2.0 g,5.549 mmol), 1H-1,2, 4-triazole (3.1 g, 44.399 mmol), acetonitrile (60 mL) and triethylamine (9.0 g,88.788 mmol) in acetonitrile (20 mL) was added dropwise to the reaction mixture, and the reaction was stirred at room temperature overnight. After the reaction, the solvent was mostly removed by vacuum concentration, and water (100 mL) was added and slurried at room temperature for 20min, filtered, and the filter cake was rinsed with water (10 mL. Times.2) and dried under vacuum to give 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 90.1% yield and ESI-MS (m/z): 412.2[ M+H ] ⁺.

Step f) preparation of (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) piperidine-1-carboxylic acid tert-butyl ester

4- (1-Methyl-7-oxo-4- (1H-1, 2, 4-triazol-1-yl) pyrido [3,4-d ] pyridazin-6 (7H) -yl) piperidine-1-carboxylic acid tert-butyl ester (2.2 g,5.347 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (1.7 g, 7.481mmol) and 1,4-dioxane (20 mL) were added to a microwave tube and the microwave reaction was maintained at 110℃for 4H. After the reaction was completed, the reaction mixture was transferred to a round bottom flask and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1) to give 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 88.6% yield, ESI-MS (m/z): 518.2[ m+h ] ⁺.

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

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) piperidine-1-carboxylic acid tert-butyl ester (100 mg,0.193 mmol) and tetrahydrofuran (2 mL) were added to the reaction flask, and a1, 4-dioxane solution (4M, 2 mL) of hydrogen chloride was added dropwise to the reaction solution at room temperature, and the reaction was maintained at room temperature for 0.5H. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (4 mL), triethylamine (1 mL) was added, and concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (piperidin-4-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 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,1H),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,3H),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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 49 starting from the corresponding starting materials.

Example 51

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

(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), methylene chloride (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 methylene chloride (3 mL) was slowly added dropwise thereto, and the reaction was stirred at room temperature for 1H. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (1- (morpholin-4-carbonyl) piperidin-4-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 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]⁺.

Example 52

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

(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), methylene chloride (2 mL) and triethylamine (86 mg,0.855 mmol) were added to the reaction flask, a solution of methyl iodide (33 mg,0.235 mmol) in methylene chloride (2 mL) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1H. After the reaction was completed, the residue was purified by Prep-HPLC (separation method 3) to give (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 yield 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]⁺.

Example 53

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

(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 stirred at room temperature for 2H. After the reaction was completed, the residue was purified by Prep-HPLC (separation method 3) to give (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 the yield 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]⁺.

Example 54

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

(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 the reaction flask and the reaction was stirred at room temperature for 1H. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6- (1-acetylpiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrrolidone [3,4-d ] pyridazin-7 (6H) -one, yield 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]⁺.

Example 55

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

Preparation method referring to example 54, the crude product obtained was purified by Prep-HPLC (isolation method 3) to give (R) -6- (1-benzoylpiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in yield 41.2％;¹H 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]⁺.

Example 56

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

Preparation method referring to steps a-f of example 49, the crude product obtained 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 the yield 10.4％;¹H 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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 56 from the corresponding starting materials.

Example 60

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

Preparation method referring to steps a-f of example 49, the crude product obtained 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 the yield 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]⁺.

Example 61

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

Preparation method referring to steps a-f of example 49, the crude product obtained 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 the yield 33.1％;¹H 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]⁺.

Example 62

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, tussah-dimethyl-3-oxopropanamide

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

(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 stirred at room temperature for 2H. After the reaction was completed, the residue was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to give methyl (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-oxopropionate, yield 81.2%; ESI-MS (m/z): 532.2[ m+h ] ⁺.

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

Methyl (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-oxopropanoate (92 mg,0.174 mmol), lithium hydroxide monohydrate (35 mg,0.871 mmol), methanol (1 mL) and water (1 mL) were added to a reaction flask, and the reaction was stirred at room temperature for 1H. The reaction solution was adjusted to ph=2 to 3 with dilute hydrochloric acid (1N), 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 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-oxopropionic acid in 97.2% yield, ESI-MS (m/z): 518.2[ m+h ] +.

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-oxopropanamide

(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 2H. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) 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) -N, N-dimethyl-3-oxopropanamide in yield 33.1％;¹H 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]⁺.

Example 63

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

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 methylene chloride (3 mL) were added to a reaction flask, acetyl chloride (21 mg,0.264 mmol) was added dropwise at room temperature, and the reaction stirred at room temperature for 30min after the addition. After the completion of the reaction, water (30 mL) was added to the reaction mixture to dilute it, dichloromethane (20 mL. Times.3) was used to extract it, 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, and the residue was purified by Prep-HPLC (separation method 3) to give 6- (1-acetylpyrrolidin-3-yl) -4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyridazo [3,4-d ] pyridazin-7 (6H) -one in the yield 12.3％;¹H 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,1H),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),5.56-5.42(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]⁺.

Example 64

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

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 methylene chloride (4 mL) were added to a reaction flask, methyl iodide (63 mg,0.441 mmol) was added dropwise to the reaction solution at room temperature, and the reaction was stirred at room temperature for 1H. Water (30 mL) was added to the reaction mixture to dilute it, dichloromethane (20 mL. Times.3) was used to extract it, 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, and the residue was purified by Prep-HPLC (separation method 3) to give 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (1-methylpyrrolidin-3-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 10.0％;¹H 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]⁺.

Example 65

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

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, 0.390 mmol), HATU (151 mg, 0.390 mmol), triethylamine (80 mg,0.793 mmol) and methylene chloride (5 mL) were added to the reaction flask and the reaction was stirred at room temperature for 30min. The reaction mixture was diluted with water (40 mL), extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1- (isoxazol-4-carbonyl) pyrrolidin-3-yl) -1-methylpyridazin-7 (6H) -one, yield 11.8％;¹H 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),7.61(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]⁺.

Example 66

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

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 methylene chloride (3 mL) were added to the reaction flask, and morpholine-4-carbonyl chloride (79 mg,0.264 mmol) was added dropwise to the reaction solution at room temperature, followed by stirring at room temperature for 30min. Water (30 mL) was added to the reaction solution, extracted with methylene chloride (20 mL. Times.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, and the residue was purified by Prep-HPLC (separation method 3) to give 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (1- (morpholin-4-carbonyl) pyrrolidin-3-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 15.2％;¹H 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]⁺.

Example 67

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

Step a) preparation of tert-butyl 4- (4-hydroxy-5- (methoxycarbonyl) -2-oxopyridin-1 (2H) -yl) piperazine-1-carboxylate.

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 sequentially to the reaction flask, sodium methoxide (2.2 g,0.040 mol) was slowly added under stirring at room temperature, and the mixture was heated to 80℃under nitrogen protection for reaction for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 2M hydrochloric acid was added to adjust the ph=4-5, and concentrated under reduced pressure, methylene chloride (25 mL) and methanol (25 mL) were added to the residue, stirred at room temperature for 20min, filtered, and the cake was rinsed with methanol (10 mL), and the filtrate was concentrated under reduced pressure to give 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 ] ⁺.

Step b) preparation of tert-butyl 4- (5- (methoxycarbonyl) -2-oxo-4- (((trifluoromethyl) sulfonyl) oxy) pyridin-1 (2H) -yl) piperazine-1-carboxylate.

Tert-butyl 4- (4-hydroxy-5- (methoxycarbonyl) -2-oxopyridin-1 (2H) -yl) piperazine-1-carboxylate (4.0 g, 0.0111 mol) was dissolved in 1, 2-dichloroethane (100 mL), pyridine (1.8 g,0.023 mol) was added under ice-water bath, trifluoromethanesulfonic anhydride (6.4 g,0.023 mol) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 5min. After the completion of the reaction, the reaction was quenched with water (50 mL), extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give tert-butyl 4- (5- (methoxycarbonyl) -2-oxo-4- (((trifluoromethyl) sulfonyl) oxy) pyridin-1 (2H) -yl) piperazine-1-carboxylate in 45.5% yield, ESI-MS (m/z): 486.1[ M+H ] ⁺.

Step c) preparation of tert-butyl 4- (4-acetyl-5- (methoxycarbonyl) -2-oxopyridin-1 (2H) -yl) piperazine-1-carboxylate.

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), bis triphenylphosphine palladium dichloride (289 mg,0.412 mmol) and 1, 4-dioxane (50 mL) were added sequentially to the reaction flask, nitrogen was replaced 3 times, and the temperature was raised to 100℃for 2H. After the completion of the reaction, the mixture was cooled to room temperature, ethyl acetate (50 mL) and a 20% aqueous potassium fluoride solution (50 mL) were added, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with ethyl acetate (30 mL. Times.3), the filtrate was allowed to stand for delamination, the organic phase was collected, washed with a 20% aqueous potassium fluoride solution (40 mL) and saturated brine (40 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (30 mL), and an aqueous ethyl acetate solution of hydrogen chloride (10 mL, 4M) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate (50 mL. Times.2) and saturated brine (30 mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=7/3) to give 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 ] ⁺.

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.

4- (4-Acetyl-5- (methoxycarbonyl) -2-oxopyridin-1 (2H) -yl) piperazine-1-carboxylic acid tert-butyl ester (1.0 g,2.636 mmol) and ethanol (20 mL) were added to the reaction flask, hydrazine hydrate (660 mg,10.543mmol, 80%) was added with stirring at room temperature and the temperature was raised to 90℃under nitrogen for 1H. After the reaction, cooling to room temperature, adding methyl tert-butyl ether (20 mL), stirring at room temperature for 10min, filtering, decompressing and drying a filter cake to obtain 4- (1-methyl-4, 7-dioxo-3, 7-dihydropyrida [3,4-d ] pyridazin-6 (4H) -yl) piperazine-1-tert-butyl formate, wherein the yield is 81.9%, and ESI-MS (m/z): 362.2[ M+H ] ⁺.

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.

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 successively added to a reaction flask, the mixture was replaced with nitrogen 3 times, and a solution of triethylamine (3.5 g,34.528 mmol) and phosphorus oxychloride (827 mg, 5.3995 mmol) in acetonitrile (3 mL) was added thereto, and the mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. After the reaction was completed, the reaction was quenched by slowly adding water (20 mL), extracted with dichloromethane (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=97/3) to give 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 39.3% yield, ESI-MS (m/z): 413.2[ m+h ] ⁺.

Preparation of (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) piperazine-1-carboxylic acid tert-butyl ester.

4- (1-Methyl-7-oxo-4- (1H-1, 2, 4-triazol-1-yl) pyrido [3,4-d ] pyridazin-6 (7H) -yl) piperazine-1-carboxylic acid tert-butyl ester (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 sequentially added to a microwave reaction flask, and the mixture was placed in a microwave reactor to be heated to 115℃for reaction for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19:1) to give 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 79.7% yield, ESI-MS (m/z): 533.2[ m+h ] ⁺.

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.

A solution of (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.188 mmol) and ethyl acetate (5 mL, 2M) of hydrogen chloride was added to the reaction flask, and the mixture was stirred at room temperature for 1H. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (piperazin-1-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 17.8％;¹H 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]⁺.

Example 68

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 salt

(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, acetyl chloride (22 mg,0.277 mmol) was slowly added under an ice-water bath, and the reaction was stirred at room temperature under nitrogen for 10min. After the completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (10 mL), extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 2) to give (R) -6- (4-acetylpiperazin-1-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -ketonic acid salt in yield 30.1％;¹H 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,1H),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]⁺.

Example 69

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 salt

(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, morpholine-4-carbonyl chloride (42 mg,0.277 mmol) was added under stirring at room temperature, and the reaction was stirred at room temperature under nitrogen for 10min. After the completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (10 mL), extracted with dichloromethane (20 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 2) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (4- (morpholin-4-carbonyl) piperazin-1-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one formate in yield 29.5％;¹H 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]⁺.

Example 70

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

Preparation method referring to steps a-f of example 67, purification by Prep-HPLC (isolation method 3) afforded (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-6- (pyrimidin-5-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one in yield 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]⁺.

Example 71

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

Step a-e) preparation of 6- (adamantan-1-yl) -1-methyl-4- (1H-1, 2, 4-triazol-1-yl) pyrido [3,4-d ] pyridazin-7 (6H) -one

Preparation method referring to steps a-e of example 67, 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 ] ⁺ is obtained.

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

6- (Adamantan-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, 1.284 mmol) and 1, 4-dioxane (6 mL) were added to a microwave reaction flask, and the mixture was heated to 110℃in a microwave apparatus for reaction for 5 hours. After the reaction was completed, the residue was purified by Prep-HPLC (separation method 3) to give (R) -6- (adamantan-1-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 4.9％;¹H 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]⁺.

Example 72

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 salt

Step a) preparation of methyl 4-hydroxy-1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate.

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 the reaction flask, sodium methoxide (2.2 g,0.040 mol) was slowly added under stirring at room temperature, and the mixture was heated to 80℃under nitrogen protection for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, adjusted to ph=4-5 with concentrated hydrochloric acid, concentrated under reduced pressure, methylene chloride (50 mL) was added to the residue, stirred at room temperature for 20min, filtered, the cake was rinsed with methylene chloride (10 mL), and the filtrate was concentrated under reduced pressure to give methyl 4-hydroxy-1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate in 78.2% yield, ESI-MS (m/z): 214.1[ m+h ] ⁺.

Step b) preparation of methyl 4- (benzoyloxy) -1- (2- (benzoyloxy) ethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate.

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

Step c) preparation of methyl 1- (2- (benzoyloxy) ethyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate.

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 the reaction flask, and potassium carbonate (4.0 g,0.029 mol) was added under an ice-water bath and reacted at 0℃under nitrogen for 2h. After the completion of the reaction, the reaction mixture was quenched with 2M diluted hydrochloric acid (30 mL), extracted with dichloromethane (80 mL. Times.3), and the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 1- (2- (benzoyloxy) ethyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate in 73.0% yield, ESI-MS (M/z): 318.1[ M+H ] ⁺.

Step d) preparation of methyl 1- (2- (benzoyloxy) ethyl) -6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate.

Methyl 1- (2- (benzoyloxy) ethyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (4.4 g,0.014 mol) was dissolved in 1, 2-dichloroethane (100 mL), pyridine (2.2 g,0.028 mol) was added dropwise slowly to the solution under ice water, trifluoromethanesulfonic anhydride (7.8 g,0.028 mol) was added, the reaction was stirred at room temperature for 5min, water (50 mL) was added to quench the reaction, extracted with dichloromethane (50 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to give 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: 0. ⁺ H).

Step e) preparation of methyl 4-acetyl-1- (2- (benzoyloxy) ethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate.

Methyl 1- (2- (benzoyloxy) ethyl) -6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate (4.0 g,8.902 mmol), tributyl (1-ethoxyvinyl) tin (3.8 g,10.682 mmol), triethylamine (2.7 g,0.027 mol), bis-triphenylphosphine palladium dichloride (312 mg,0.445 mmol) and 1, 4-dioxane (80 mL) were added to a reaction flask, and after 3 times of nitrogen substitution, the temperature was raised to 100 ℃ for 2h of reaction. After the completion of the reaction, the mixture was cooled to room temperature, ethyl acetate (50 mL) and a 20% aqueous potassium fluoride solution (50 mL) were added, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with ethyl acetate (30 mL. Times.3), the filtrate was allowed to stand for delamination, the organic phase was collected, washed with a 20% aqueous potassium fluoride solution (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, dissolved in ethyl acetate (30 mL) was added to the residue, and an aqueous ethyl acetate solution of hydrogen chloride (15 mL, 4M) was added with stirring at room temperature, and reacted at room temperature for 1 hour. 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 give methyl 4-acetyl-1- (2- (benzoyloxy) ethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate in 62.5% yield, and ESI-MS (m/z): 344.1[ M+H ] ⁺.

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

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 the reaction flask, hydrazine hydrate (1.1 g,0.022mol, 80%) was added at room temperature, and the mixture was allowed to react at 90℃under nitrogen for 10min. After the reaction, cooling to room temperature, adding methyl tert-butyl ether (40 mL), stirring at room temperature for 10min, filtering, eluting with methyl tert-butyl ether (10 mL×2), and vacuum drying the filter cake to obtain ethyl 2- (1-methyl-4, 7-dioxo-3, 7-dihydropyridazo [3,4-d ] pyridazin-6 (4H) -yl) benzoate, yield 83.9%, and ESI-MS (m/z): 326.1[ M+H ] ⁺.

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

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 a reaction flask, and the mixture was heated to 105℃under nitrogen protection for 1H. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (40 mL), extracted with dichloromethane (40 mL. Times.3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography over silica gel (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 55.9% yield, ESI-MS (m/z): 388.0[ M+H ] ⁺.

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

Ethyl 2- (4-bromo-1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) benzoate (1.0 g, 2.319 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (706 mg,3.131 mmol), N-diisopropylethylamine (1.0 g,7.827 mmol) and 1,4-dioxane (15 mL) were added to a microwave reactor, and the mixture was allowed to react for 3 hours at 100℃in the microwave reactor. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1) to give ethyl (R) -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 ] ⁺.

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.

Ethyl (R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methyl-7-oxopyrido [3,4-d ] pyridazin-6 (7H) -yl) benzoate (830 mg, 1.6752 mmol), methanol (10 mL) and tetrahydrofuran (10 mL) were added to a reaction flask, an aqueous lithium hydroxide solution (2.5 mL, 3M) was added with stirring at room temperature, and the reaction was stirred at room temperature for 20min. After the reaction was completed, the mixture was adjusted to ph=3-4 with 1M diluted hydrochloric acid, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (2-hydroxyethyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in 88.1% yield and ESI-MS (M/z): 393.1[ m+h ] ⁺.

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.

(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (2-hydroxyethyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one (570 mg, 1.4573 mmol) and methylene chloride (15 mL) were sequentially added to a reaction flask, thionyl chloride (691 mg,5.811 mmol) was added under stirring at room temperature, and the reaction was stirred under nitrogen at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution (30 mL) and methylene chloride (30 mL) were added to the residue, stirred at room temperature for 5min, the layers were left standing, the organic phase was collected, the aqueous phase was extracted with methylene chloride (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=97:3) to give (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 ] ⁺.

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 salt.

(R) -6- (2-chloroethyl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one (100 mg,0.245 mmol), N-diisopropylethylamine (315 mg, 2.433 mmol) and tetrahydrofuran (5 mL) were added to a glass constant volume reaction flask, and a solution of dimethylamine in tetrahydrofuran (1.3 mL, 2M) was added under stirring at room temperature, and the mixture was warmed to 80℃and stirred overnight. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 2) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (2- (dimethylamino) ethyl) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one formate salt, yield 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,1H),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]⁺.

Example 73

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

Preparation method referring to example 68, the crude product obtained was purified by Prep-HPLC (isolation method 3) to give (R) -6- (1-acetylazetidin-3-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one in yield 12.4％;¹H 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＝6.4Hz,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]⁺.

Example 74

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 salt

Preparation method referring to example 67, (R) -6- (azetidin-3-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methylpyrido [3,4-d ] pyridazin-7 (6H) -one trifluoroacetate was obtained by purification by Prep-HPLC (separation method 4); yield 21.7％;¹H 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]⁺.

Example 75

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

(R) -1-chloro-6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one (250 mg, 0.313 mmol), potassium vinyltrifluoroborate (164 mg,1.226 mmol), cesium carbonate (390 mg,1.226 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (45 mg,0.061 mmol), 1, 4-dioxane (10 mL) and water (2 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 80℃and the mixture was stirred for 2 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (20 mL), extracted with dichloromethane (20 mL. Times.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, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-vinylpyridazo [3,4-d ] pyridazin-7 (6H) -one in the yield 17.5％;¹H 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]⁺.

Example 76

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

(R) -1-chloro-6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one (250 mg, 0.803 mmol), 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (238 mg,1.226 mmol), cesium carbonate (390 mg,1.226 mmol), 1' -diphenylphosphino ferrocene palladium dichloride (45 mg,0.061 mmol), 1, 4-dioxane (10 mL) and water (2 mL) were sequentially added to a reaction flask, nitrogen was replaced three times, and the temperature was raised to 80℃to stir the reaction for 2H. The reaction mixture was cooled to room temperature, quenched with aqueous saturated ammonium chloride (20 mL), extracted with dichloromethane (20 mL. Times.3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (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 the yield 28.5％;¹H 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,1H),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]⁺.

Example 77

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

Preparation method referring to example 76, the residue was purified by Prep-HPLC (isolation method 3) to give (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 yield 5.8％;¹H 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]⁺.

Example 78

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

(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' -bis-diphenylphosphino ferrocene palladium dichloride (17 mg,0.024 mmol), toluene (3 mL) and water (1 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the mixture was warmed to 100℃and stirred for 3H. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then saturated aqueous ammonium chloride (20 mL) was added thereto to quench the reaction, followed by extraction with methylene chloride (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 2) to give (R) -1-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1-methylcyclopropyl) pyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 18.5％;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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 78 from the corresponding starting materials.

Example 80

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

(R) -1-chloro-6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one (65 mg,0.248 mmol), sodium methoxide (40 mg, 0.284 mmol) and methanol were added to a reaction flask, and the mixture was heated to 80℃and stirred for 2 hours. After the completion of the reaction, cooled to room temperature, diluted with dichloromethane (30 mL), poured into a saturated aqueous ammonium chloride solution (50 mL) and quenched, extracted with dichloromethane (30 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1-methoxypyrido [3,4-d ] pyridazin-7 (6H) -one in the yield 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),6.51(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]⁺.

Example 81

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

(R) -1-chloro-6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one (100 mg, 0.248 mmol), sodium methyl mercaptan (25.8 mg, 0.365 mmol) and methanol (4 mL) were added to the reaction flask and reacted at room temperature for 4H. Quenched with saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -1- (methylthio) pyrido [3,4-d ] pyridazin-7 (6H) -one in yield 27.6％;¹H 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]⁺.

Example 82

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

(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' -bis-diphenylphosphino ferrocene palladium dichloride (76 mg,0.104 mmol) and DMF (5 mL) were added to the reaction flask, nitrogen was replaced three times, and the mixture was heated to 100℃with stirring for 3H. The reaction mixture was cooled to room temperature, quenched with water (50 mL), extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give ((R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (1-methylcyclopropyl) -7-oxo-6, 7-dihydropyrido [3,4-d ] pyridazine-1-carbonitrile, yield 38.5％;¹H 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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 82 from the corresponding starting materials.

Example 84

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

(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 a reaction flask, purged with nitrogen 3 times, and heated to reflux for 30min. After the completion of the reaction, the reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-6, 7-dihydropyrido [3,4-d ] pyridazine-1-carbaldehyde in the yield 19.2％;¹H 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]⁺.

Example 85

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

(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 methylene chloride (5 mL) were added to a reaction flask, and diethylaminosulfur trifluoride (84 mg,0.522 mmol) was added dropwise under an ice-water bath and the reaction was maintained at 0℃for 30min under nitrogen. After the completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-1- (difluoromethyl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 11.2％;¹H 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,1H),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]⁺.

Example 86

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

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

6-Cyclopropyl-2, 3-dihydropyrido [3,4-d ] pyridazin-1, 4,7 (6H) -trione (8.8 g,68.493 mmol) and acetonitrile (500 mL) were added to the reaction flask, DIPEA (26.5 g,205.479 mmol) and phosphorus oxychloride (31.5 g,205.479 mmol) were added with stirring at room temperature, and the temperature was raised to 100℃under nitrogen to react for 3H. After the reaction was completed, it was cooled to room temperature, the reaction solution was slowly poured into a mixture of ice cubes and sodium bicarbonate to quench, dichloromethane was extracted (100 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=49/1) to give 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 ] ⁺.

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

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 flask, and the mixture was heated to 120℃in a microwave apparatus for 2 hours. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -1-chloro-6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyrido [3,4-d ] pyridazin-7 (6H) -one, yield 26.6％;¹H 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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 86 starting from the corresponding starting materials.

Example 88

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 methyl ester

(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-diphenylphosphino ferrocene palladium dichloride (18 mg,0.024 mmol) were added to the reaction flask and the reaction was continued by bubbling carbon monoxide gas under stirring at room temperature for 2 hours. After the reaction was completed, the residue was purified by Prep-HPLC (separation method 3) to give (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 yield 34.1％;¹H 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,1H),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]⁺.

Example 89

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

(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 (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 reacted at room temperature for 1h. After the reaction was completed, the residue was purified by Prep-HPLC (separation method 3) to give (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 the yield 44.5％;¹H 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]⁺.

Example 90

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

(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), t-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 this order under stirring at room temperature, and the reaction was stirred at room temperature under nitrogen for 1h. After the completion of the reaction, saturated brine (10 mL) was added, extracted with dichloromethane (20 mL. Times.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, and the residue was purified by Prep-HPLC (separation method 2) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-6, 7-dihydropyrido [3,4-d ] pyridazine-1-carboxylic acid in the yield 10.5％;¹H 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]⁺.

Example 91

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 methyl ester

(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, 2.87mmol) and dichloromethane (5 mL) were added to the reaction flask and reacted at room temperature for 2h. After the completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (40 mL), extracted with methylene chloride (30 mL. Times.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, and the residue was purified by Prep-HPLC (separation method 3) to give methyl (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-6, 7-dihydropyrido [3,4-d ] pyridazine-1-carboxylate in the yield 18.5％;¹H 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＝54.4Hz,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]⁺.

Example 92

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

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 methanolic ammonia (6 ml,7 m) were added to a constant volume reaction flask and stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (separation method 3) to give (R) -6-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-6, 7-dihydropyrido [3,4-d ] pyridazine-1-carboxamide in yield 22.8％;¹H 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]⁺.

Example 93

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

(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, 0.399 mmol), HATU (136 mg, 0.319 mmol), triethylamine (73 mg, 0.719 mmol), a solution of dimethylamine in tetrahydrofuran (358. Mu.L, 2M) and methylene chloride (8 mL) were added to a reaction flask and reacted at room temperature for 2h. After the completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (40 mL), extracted with methylene chloride (30 mL. Times.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, and the residue was purified by Prep-HPLC (separation method 3) to give (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 in the yield 31.0％;¹H 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]⁺.

The compounds of the following examples were prepared according to the preparation method of example 93 starting from the corresponding starting materials.

Biological Activity test

Test example 1 SOS1 inhibitory Activity assay

The effect of SOS1 inhibitors on the interaction between SOS1 and KRAS proteins was examined by Homogeneous Time Resolved Fluorescence (HTRF) to assess the level of inhibition of SOS1 proteins. The protein and the detection reagent are KRAS-G12D/SOS1 BINDING ASSAY KIT (Cisbio), firstly 2mM of the test compound mother liquor is diluted 20 times (100 mu M) by a reagent, and then 5 times of concentration gradient dilution is sequentially carried out by the reagent (5% DMSO) to obtain 8 concentrations of the test compound working solution. In 384 well plates, 4. Mu.L of tag2-KRAS ^G12D protein (containing 50. Mu.M GTP), 2. Mu.L of test compound, 4. Mu.L of tag1-SOS1 protein were added to each well in sequence, and the wells were double-plated and incubated at room temperature for 15min. Each well was sequentially added with 5. Mu.L of Anti-tag1-Tb ³⁺ working solution and Anti-tag2-XL665 working solution, and incubated at 4℃for 3h. The 384-well plate was placed on a multifunctional microplate reader to read the values, the excitation light wavelength was set to 337nm, and the read values at 620nm and 665nm were recorded. The data results are presented as the Ratio of 665nm signal values to 620nm signal values per well, i.e., ratio = 10 ⁴ x 665nm signal values/620 nm signal values. The inhibition Ratio is calculated by Ratio value%inhibition = [ (Ratio _{Negative of} -Ratio _{Compounds of formula (I)} )/(Ratio _{Negative of} -Ratio_Blank) ]. Times.100

Note that negative is the no inhibitor group and Blank is the no enzyme group.

IC ₅₀ was calculated by GRAPHPAD PRISM software via inhibition. 2 duplicate wells were measured per compound. The compounds of the present invention have an IC ₅₀ value of 3.7-308.0 nM for inhibiting SOS1 activity, and some of the test data for the compounds of the examples are shown in Table 1:

TABLE 1

From the data, the compound has obvious inhibition effect on SOS1 in vitro, can be used as an SOS1 inhibitor, and has wide application prospect in the fields of diseases such as cancers, pathogenic rash and the like mediated by SOS1 protein.

Test example 2 measurement of metabolic stability of liver microsomes

Metabolic stability affects the clearance, half-life and oral bioavailability of a compound in the body, and is one of the most important ADME patent properties of a compound. Liver microsomal stability assays are a common method of studying metabolic stability. The invention adopts rat liver microsome assay to examine the metabolic stability of the compound.

Test method

A. Preparing a solution:

Compound stock solution preparation test compound and testosterone were prepared in 1mM stock solution with DMSO and stored in 4 ℃ refrigerator.

The compound working solution is prepared by taking 1mM of compound stock solution respectively, and then diluting to 100 mu M by acetonitrile-water (v: v=1:1).

NADPH working solution preparation an appropriate amount of NADPH was weighed and prepared with 16mM MgCl ₂ to give a 4.0mM NADPH working solution.

The working solution of the rat liver microsome is prepared by taking a proper amount of the rat liver microsome and diluting the rat liver microsome into the working solution of the liver microsome of 1mg/ml by PBS.

B. sample incubation:

48 mu L of PBS,100 mu L of rat liver microsome working solution and 2 mu L of test compound working solution are sequentially added into an incubation system, uniformly mixed, and 50 mu L of NADPH is added after 5min of pre-incubation at 37 ℃ to start the reaction. After incubation for a corresponding time point, adding a proper amount of glacial acetonitrile containing an internal standard to terminate the reaction, vortex uniformly mixing, centrifuging to obtain supernatant, and detecting the metabolic residual quantity of the compound by sample injection LC-MS/MS.

C. and (3) data processing:

Data processing was performed on T _1/2 and CL _(liver) using Excel et al software according to the following formula.

Default f _u (free fraction in blood) is equal to 1.

The test results of the compound of the invention on the stability of rat liver microsomes are shown in Table 2, wherein T _1/2 is 9.8-129 min, CL _(liver) is 14.3-45.4 ml/min/kg:

TABLE 2

As can be seen from the data in Table 2, some of the compounds of the examples of the present invention have better metabolic stability and have good pharmaceutical properties than compound MRTX 0902. MRTX0902 is a compound disclosed in WO2021127429 (examples 12-10), which has been reported to have SOS1 inhibitory activity.

Test example 3 plasma stability test

In addition to the hepatic metabolic stability of the compounds, the plasma stability of the compounds is also an important contributor to the development of new drugs. Good plasma stability is an important guarantee with good pharmacokinetics and pharmacodynamics. The invention incubates the compound in the example with rat, mouse, monkey, dog and human plasma at 37 ℃ respectively, and the stability of the compound in 5 kinds of plasma is evaluated by measuring the sample concentration at different incubation time points and calculating corresponding residual percentage.

Test method

A. Solution preparation

Working solution of intermediate concentration of compound test compound and enalapril maleate 10mM stock solution were diluted with DMSO to 1mM and stored in a 4℃refrigerator.

The compound working solution is prepared by respectively taking a proper amount of working solution with the intermediate concentration of 1mM, and then diluting to 50 mu M by acetonitrile-water (v: v=1:1).

Blank plasma preparation, namely, respectively taking a proper amount of frozen plasma of blank rats, mice, monkeys, dogs and humans, and thawing at 37 ℃.

B. sample incubation:

The reaction was terminated by adding 5. Mu.L of compound working solution to 245. Mu.L of blank rat plasma, mixing well, incubating at 37℃and taking 50. Mu.L of plasma sample from the incubation system after reaching the corresponding time point, and adding 450. Mu.L of glacial acetonitrile (containing internal standard). Vortex mixing, centrifuging and collecting supernatant.

C. Data processing, using LC-MS/MS detection of compound at each time point of internal standard normalized peak area ratio, 0 time point of compound residual amount as 100%, using excel to calculate compound at each time point of the residual amount.

Experimental results show that the compounds of the invention act with 5 species of plasma of rats, mice, monkeys, dogs and humans for 2 hours at37 ℃, the residual amounts are about 100%, and obvious changes do not occur, so that the compounds have good plasma stability and good patent medicine properties. For example, table 3 below lists plasma stability test data for 2 exemplary compounds of the invention:

TABLE 3 Table 3

Test example 4 determination of liver drug metabolizing enzyme inhibitory Activity

The main site of drug metabolism is the liver, and the main component of the mixed-function oxidase system present in the liver is the CYP450 enzyme, which causes the interaction of most drugs clinically, and thus leads to an increased incidence of adverse drug reactions. CYP450 is a large family of supergenes consisting of many isoenzymes, with CYP3A4 as the primary metabolizing enzyme involved in the metabolism of nearly half of the drugs in the clinic. Likewise, CYP2C9 and CYP2C19 are also important metabolic enzymes, and are involved in various drug metabolism clinically. Therefore, the inhibition activity of the compound on CYP450 enzyme can be tested in early stage, so that the risk of drug-drug interaction can be judged, and the medication safety is improved.

In the present invention, human liver microsomes are used as a source of CYP3A4 enzyme, and specific probe substrates (CYP 3A4 is two substrates of midazolam and testosterone, respectively represented by CYP3A4-M and CYP3A 4-T) of each CYP isozyme are incubated with a series of concentrations of test compounds in the presence of cofactor NADPH, respectively. The amount of metabolite production of the probe substrate in the incubation system was measured using LC-MS/MS, the IC ₅₀ values of the test compounds for each CYP450 enzyme subtype were calculated, and their inhibition of each CYP450 enzyme subtype was evaluated. In the experiment, 49 mu L of PBS,50 mu L of probe substrate and 50 mu L of human liver microsome working solution are sequentially added into an incubation system, then 1 mu L of test compound working solution with various concentrations are added, the mixture is uniformly mixed, and 50 mu L of NADPH is added after 5min of pre-incubation at 37 ℃ to start the reaction. After incubation for a corresponding time, adding a proper amount of glacial acetonitrile containing an internal standard to terminate the reaction, vortex uniformly mixing, centrifuging to obtain supernatant, and detecting the generation amount of metabolites of the probe substrate by sample injection LC-MS/MS. The percentage of enzyme activity remaining for the metabolites at the different test compound concentrations was calculated using the 0 concentration point enzyme activity (characterized by metabolite production) as 100%. IC ₅₀ was calculated by the GRAPHPAD PRISM software by residual enzyme activity.

Experimental results show that the inhibition activity of the compound of the invention on CYP2C9, CYP2C19 and CYP3A4-M, CYP A4-T is obviously weaker than that of the reference compound MRTX0902, which is beneficial to reducing the risk of drug-drug interaction. For example, table 4 below lists test data for 3 exemplary compounds of the invention and reference compound MRTX 0902:

TABLE 4 Table 4

Test example 5 in vivo efficacy study 1

The anti-tumor activity of the compound is evaluated by adopting a human pancreatic cancer MIA PaCa-2 cell subcutaneous xenograft tumor model.

Experimental procedures Balb/c-nu nude mice, females, 6-8 weeks, and body weight of about 18-22 g. Each mouse was inoculated subcutaneously with 0.1mL (5X 10 ⁶) MIA PaCa-2 cells (matrigel added, volume ratio 1:1) on the right shoulder blade. Administration was started when the average tumor volume reached 127mm ³. The test compounds were orally administered by gavage daily (administration volume 10 mL/kg) for 21 consecutive days, and the administration doses and administration frequency are shown in table 5. Tumor volumes were measured twice a week and the volumes were measured in mm ³ and 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 tumor-inhibiting effect of the compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate. Calculation of TGI (%) = [1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/(average tumor volume at the end of administration of vehicle control group-average tumor volume at the start of administration of vehicle control group) ]100%. Calculation of body weight change (%) = (mean body weight of animals at the end of administration of a certain treatment group-mean body weight of animals at the beginning of administration of the treatment group)/mean body weight of animals at the beginning of administration of the treatment group x 100%.

Experimental results show that the compound of the invention has stronger tumor inhibition activity on a tumor model of subcutaneous xenograft of human pancreatic cancer MIA PaCa-2 cells, the tumor volume after administration is obviously smaller than that of a reference compound MRTX0902 experimental group, and the tumor growth inhibition rate TGI (%) is obviously improved. For example, table 5 below lists experimental data for 2 exemplary compounds of the invention and reference compound MRTX0902 at 25mg/kg of administered dose:

TABLE 5

Test example 6 in vivo efficacy study 11

The anti-tumor activity of the compound is evaluated by adopting a human non-small cell lung cancer NCI-H358 cell subcutaneous xenograft tumor model.

Experimental procedures Balb/c-nu nude mice, females, 6-8 weeks, and body weight of about 18-22 g. Each mouse was inoculated subcutaneously with 0.1mL (5X 10 ⁶) NCI-H358 cells (matrigel added, volume ratio 1:1) on the right shoulder blade. Administration was started when the average tumor volume reached about 170mm ³. The test compounds were orally administered by gavage daily (administration volume 10 mL/kg) for 21 consecutive days, and the administration doses and administration frequency are shown in table 6. Tumor volumes were measured twice a week and the volumes were measured in mm ³ and 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 tumor-inhibiting effect of the compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate. Calculation of TGI (%) = [1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/(average tumor volume at the end of administration of vehicle control group-average tumor volume at the start of administration of vehicle control group) ]100%. Calculation of body weight change (%) = (mean body weight of animals at the end of administration of a certain treatment group-mean body weight of animals at the beginning of administration of the treatment group)/mean body weight of animals at the beginning of administration of the treatment group x 100%.

Experimental results show that the compound of the invention has stronger tumor inhibiting activity on a human non-small cell lung cancer NCI-H358 cell subcutaneous xenograft tumor model, the tumor volume after administration is obviously smaller than that of a reference compound MRTX0902 experimental group, and the tumor growth inhibition rate TGI (%) is obviously improved. For example, table 6 below lists experimental data for 1 exemplary compound of the invention at 25mg/kg, 50mg/kg of administered dose, and reference compound MRTX0902 at 25mg/kg of administered dose, respectively:

TABLE 6

From the data, the compound has obvious inhibition effect on SOS1 in vitro, can be used as SOS1 inhibitor, has better anti-tumor effect in animals, and has wide application prospect in the fields of diseases such as cancers, pathogenic rash and the like mediated by SOS1 protein. In addition, compared with MRTX0902, the compound has better metabolism stability and plasma stability of liver microsomes, weaker inhibition effect on liver drug metabolizing enzyme, obviously improved in vivo anti-tumor activity and good pharmaceutical property and clinical application prospect.

Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (38)

1. A compound of formula I, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

   Wherein:

   Ring a is selected from aryl, heteroaryl optionally substituted with a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, optionally further substituted with a substituent selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, alkyl, R ₁₂ is alkyl and optionally substituted with halogen;

   r _a、R_b、R_c is independently selected from H, alkyl;

   R ₁、R₃、R₄ is independently selected from H, halogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, alkylthio, -OH, -CN, -NR ₇R₈、-C(＝O)H、-C(＝O)NR₁₉R₂₀、-C(＝O)OR₂₁, said alkyl, alkoxy optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈、R₁₉、R₂₀、R₂₁ is independently selected from H, alkyl;

   R ₂ is-X-R ₁₃, X is selected from alkylene, a single bond, R ₁₃ is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, wherein:

   When R ₁₃ is alkyl, X is a single bond, said alkyl being optionally substituted with a substituent selected from-OH, alkoxy, halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁、-NR₂₂R₂₃, R ₉、R₁₀、R₁₁、R₂₂、R₂₃ being independently selected from H, alkyl;

   When R ₁₃ is selected from aryl, heteroaryl, optionally substituted with a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, -NR ₁₄R₁₅, R ₁₄、R₁₅ is independently selected from H, alkyl;

   When R ₁₃ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, optionally selected from halogen, alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH, alkoxy, -NR ₁₇R₁₈, wherein:

   Y is alkylene, R ₁₆ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl;

   or Y is selected from R ₁₆ is selected from alkyl, alkoxy, -NR ₁₇R₁₈, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl;

   R ₁₇、R₁₈ is independently selected from H and alkyl.
2. The compound of claim 1, wherein ring a is selected from aryl, heteroaryl optionally substituted with a substituent selected from halogen, alkyl, alkoxy, -OH, -CN, -NR ₅R₆, optionally further substituted with a substituent selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, alkyl.
3. A compound according to claim 1 or2, wherein ring a is selected from 6-12 membered aryl, 5-12 membered heteroaryl, said heteroaryl containing a heteroatom selected from N, O, S, the substituents of which are as defined in claim 1 or 2;

   Preferably, ring a is selected from 6 membered aryl, 5-11 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from N, O, S, the substituents of said groups being as defined in claim 1 or 2;

   Preferably, ring a is selected from 6-membered aryl, 6-membered aryl-5-membered heteroaryl, said heteroaryl containing 1 heteroatom selected from N, O, S, the substituents of which are as defined in claim 1 or 2;

   preferably, ring a is selected from phenyl, phenyl-thienyl, the substituents of which are as defined in claim 1 or 2;

   Preferably, ring a is phenyl, the substituents of which are as defined in claim 1 or 2.
4. A compound according to claim 1 or 3, wherein ring a contains substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, said alkyl, alkoxy optionally being further substituted by substituents selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, C-C6 alkyl, R ₁₂ is C1-C6 alkyl and optionally substituted by halogen;

   Preferably, the substituents contained in ring A are selected from halogen, C1-C6 alkyl, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, the alkyl optionally being further substituted with substituents selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, C1-C6 alkyl, R ₁₂ is C1-C6 alkyl and is optionally substituted with halogen;

   Preferably, the substituents contained in ring a are selected from-F, methyl, -F substituted methyl, -NR ₅R₆ substituted methyl, -CN, -NR ₅R₆、-SF₅、-SO₂R₁₂, wherein R ₅、R₆ is independently selected from H, methyl, R ₁₂ is-F substituted methyl;

   Preferably, ring A contains said substituent selected from -F、-CH₃、-CHF₂、-CF₃、-CH₂NHCH₃、-CN、-NH₂、-SF₅、-SO₂CHF₂.
5. A compound according to any one of claims 1 to 3 wherein ring a contains substituents selected from halogen, alkyl, -CN, said alkyl optionally being further substituted with substituents selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, alkyl;

   Preferably, the substituent is selected from halogen, C1-C6 alkyl, -CN, the alkyl optionally being further substituted with a substituent selected from halogen, -NR ₅R₆, wherein R ₅、R₆ is independently selected from H, C1-C6 alkyl;

   Preferably, the substituents are selected from-F, methyl, -F substituted methyl, -NR ₅R₆ substituted methyl, -CN, wherein R ₅、R₆ is independently selected from H, methyl;

   Preferably, the substituents are selected from the group consisting of-F, -CH ₃、-CHF₂、-CF₃、-CH₂NHCH₃、-CN、-NH₂.
6. The compound of claim 1, wherein ring a is selected from the group consisting of:

   Preferably, ring a is selected from:
7. The compound of any one of claims 1-6, wherein R _a、R_b、R_c is independently selected from H, C1-C6 alkyl;

   Preferably, R _a、R_b、R_c is independently selected from H, methyl;

   Preferably, R _a is methyl, R _b is H, and R _c is H.
8. The compound of claim 7, wherein the structure is as shown in formula II:

   Wherein each group is as defined in any one of claims 1 to 6.
9. A compound according to any one of claims 1 to 8, wherein R ₁、R₃、R₄ is independently selected from H, alkyl, alkoxy, -OH, -CN, -NR ₇R₈, said alkyl, alkoxy being optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, alkyl, preferably R ₁、R₃、R₄ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₇R₈, said alkyl, alkoxy being optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, C-C6 alkyl, preferably R ₁、R₃、R₄ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, preferably R ₁、R₃、R₄ is independently selected from H, methyl, methoxy, -OH, -CN, preferably R ₁ is selected from H, methyl, methoxy, -CN, preferably R ₃ is H, preferably R ₄ is selected from methyl, methoxy, -OH.
10. A compound according to any one of claims 1 to 8, wherein R ₁、R₃、R₄ is independently selected from H, alkyl, alkoxy, -OH, -NR ₇R₈, optionally substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, alkyl, preferably R ₁、R₃、R₄ is independently selected from H, alkyl, preferably R ₁、R₃、R₄ is independently selected from H, C1-C6 alkyl, preferably R ₁、R₃、R₄ is independently selected from H, methyl, preferably R ₁ is H, preferably R ₃ is H, preferably R ₄ is methyl.
11. A compound according to any one of claims 1 to 8, wherein R ₁、R₃ is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -OH, -CN, -NR ₇R₈, said alkyl, alkoxy optionally being substituted with a substituent selected from halogen, -NR ₇R₈, wherein R ₇、R₈ is independently selected from H, C1-C6 alkyl, preferably R ₁、R₃ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, -CN, preferably R ₁、R₃ is independently selected from H, methyl, methoxy, -CN, preferably R ₁ is selected from H, methyl, methoxy, -CN, preferably R ₁ is selected from H, methyl, methoxy, preferably R ₃ is H.
12. A compound according to any one of claims 1 to 8, wherein R ₄ is selected from H, C-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 ₁₉R₂₀、-C(＝O)OR₂₁, optionally substituted by halogen, wherein R ₁₉、R₂₀、R₂₁ is independently selected from H, C1-C6 alkyl;

    preferably, R ₄ 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 ₁₉R₂₀、-C(＝O)OR₂₁, said alkyl optionally substituted with halogen, wherein R ₁₉、R₂₀、R₂₁ is independently selected from H, C1-C6 alkyl;

    preferably, R ₄ is selected from C1-C6 alkyl, -OH;

    Preferably, R ₄ is selected from methyl, ethyl, difluoromethyl, vinyl, cyclopropenyl, cyclopentenyl, methoxy, methylthio, -OH, -CN, -C (=o) H, -C (=o) NH ₂、-C(＝O)N(CH₃)₂、-C(＝O)OH、-C(＝O)OCH₃.
13. The compound according to any one of claims 1 to 8, wherein R ₄ is halogen, preferably R ₄ is chlorine.
14. The compound of any one of claims 1-13, wherein when R ₁₃ is alkyl, X is a single bond, said alkyl is optionally substituted with a substituent selected from-OH, alkoxy, halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, and R ₉、R₁₀、R₁₁ is independently selected from H, alkyl.
15. The compound of any one of claims 1 to 13, wherein R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl optionally substituted with a substituent selected from-OH, C1-C6 alkoxy, halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁、-NR₂₂R₂₃, and R ₉、R₁₀、R₁₁、R₂₂、R₂₃ is independently selected from H, C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by a substituent selected from-OH, halogen, -C (=O) NR ₉R₁₀、-NR₂₂R₂₃, and R ₉、R₁₀、R₂₂、R₂₃ is independently selected from C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, said C1-C6 alkyl optionally substituted with a substituent selected from-OH, -F, -C (=O) N (CH ₃)₂、-N(CH₃)₂;

    preferably, R ₂ is selected from the group consisting of-CH ₃,
16. The compound of any one of claims 1 to 13, wherein R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl optionally substituted with a substituent selected from-OH, C1-C6 alkoxy, halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, and R ₉、R₁₀、R₁₁ is independently selected from H, C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by a substituent selected from-OH, halogen, -C (=O) NR ₉R₁₀, and R ₉、R₁₀ is independently selected from C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is C1-C6 alkyl, said C1-C6 alkyl optionally substituted with a substituent selected from-OH, -F, -C (=O) N (CH ₃)₂;

    preferably, R ₂ is selected from the group consisting of-CH ₃,
17. A compound according to any one of claims 1 to 13 wherein R ₂ is-X-R ₁₃, X is selected from C1-C3 alkylene, a single bond, R ₁₃ is selected from 6-12 membered aryl, 5-12 membered heteroaryl containing a heteroatom selected from N, O, S, said aryl, heteroaryl optionally being substituted with a substituent selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₁₄R₁₅, R ₁₄、R₁₅ is independently selected from H, C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is methylene, a single bond, R ₁₃ is phenyl, a 5-to 6-membered heteroaryl group containing 1-2 heteroatoms selected from N, O, S, said phenyl, heteroaryl group optionally being substituted with a substituent selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, NR ₁₄R₁₅, R ₁₄、R₁₅ being independently selected from H, C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is pyridyl, pyrimidinyl, the pyridyl, pyrimidinyl optionally substituted with C1-C6 alkoxy;

    Preferably, R ₂ is selected from
18. A compound according to any one of claims 1 to 13 wherein R ₂ is-X-R ₁₃, X is methylene, a single bond, R ₁₃ is phenyl, a 5-to 6-membered heteroaryl group containing 1 heteroatom selected from N, O, S, said phenyl, heteroaryl group optionally being substituted by a substituent selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -CN, -NR ₁₄R₁₅, R ₁₄、R₁₅ being independently selected from H, C1-C6 alkyl;

    Preferably, R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is pyridinyl, optionally substituted with C1-C6 alkoxy;

    Preferably, R ₂ is
19. A compound according to any one of claims 1 to13 wherein R ₂ is-X-R 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, said heterocycloalkyl, heterocycloalkenyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl optionally being selected from halogen, C1-C6 alkyl,-Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH, C1-C6 alkoxy, -NR ₁₇R₁₈;

    Preferably, R ₂ is-X-R ₁₃, X is selected from C1-C3 alkylene, a single bond, R ₁₃ is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being selected from halogen, C1-C6 alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH;

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from 3-10 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being selected from halogen, C1-C6 alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH;

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, adamantane, azetidine, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally substituted with halogen, C1-C6 alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH;

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from 3-to 6-membered cycloalkyl, 5-to 8-membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being selected from halogen, C1-C6-alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH;

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally substituted with halogen, C1-C6 alkyl, -Y-R ₁₆, optionally further substituted with a substituent selected from halogen, -OH;

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from 3-6 membered cycloalkyl, said cycloalkyl is optionally substituted with a substituent selected from halogen, C1-C6 alkyl, -Y-R ₁₆, said C1-C6 alkyl is optionally further substituted with halogen;

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, optionally substituted with a substituent selected from halogen, C1-C6 alkyl, -Y-R ₁₆, optionally further substituted with halogen.
20. The compound of any one of claims 1 to 13, 19, wherein R ₁₇、R₁₈ is independently selected from H, C1 to C6 alkyl, preferably R ₁₇、R₁₈ is independently selected from H, methyl, preferably R ₁₇、R₁₈ is both methyl.
21. The compound of claim 19, wherein R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, adamantane, azetidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydropyran, piperidinyl, piperazinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally selected from-F, methyl,Wherein methyl is optionally further substituted with a substituent selected from-F, -OH;

    Preferably, R ₂ is selected from:

    Preferably, R ₂ is-X-R ₁₃, X is selected from methylene, a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, piperidinyl, 1, 4-ethylenepiperidinyl, morpholinyl, optionally selected from-F, methyl, Wherein methyl is optionally further substituted with a substituent selected from-F, -OH;

    Preferably, R ₂ is selected from:
22. A compound according to claim 19 or 21, wherein R ₂ is-X-R ₁₃, X is a single bond, R ₁₃ is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, optionally substituted with a substituent selected from-F, methyl, optionally further substituted with-F;

    Preferably, R ₂ is selected from:
23. The compound according to any one of claims 1 to 13, 19, wherein 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, said heterocycloalkyl, heterocycloalkenyl, heteroaryl containing a heteroatom selected from N, O, S;

    Preferably, Y is C1-C3 alkylene, R ₁₆ is 3-10 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S;

    Preferably, Y is methylene and R ₁₆ is a 5 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S;

    preferably, Y is methylene and R ₁₆ is tetrahydropyrrolyl.
24. The compound of claim 23, wherein R ₂ is
25. The compound according to any one of claims 1 to 13, 19, 20, wherein Y is selected fromR ₁₆ is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ₁₇R₁₈, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, said heterocycloalkyl, heterocycloalkenyl, heteroaryl containing a heteroatom selected from N, O, S;

    Preferably Y is selected from R ₁₆ is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ₁₇R₁₈, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the heterocycloalkyl, heteroaryl contain 1-2 heteroatoms selected from N, O, S;

    Preferably Y is selected from R ₁₆ is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ₁₇R₁₈, 5-6 membered heterocycloalkyl, 6 membered aryl, 5-6 membered heteroaryl, wherein the heterocycloalkyl, heteroaryl contains 1-2 heteroatoms selected from N, O;

    Preferably Y is selected from R ₁₆ is selected from methyl, methoxy, -N (CH ₃)₂, morpholinyl, phenyl, isoxazolyl).
26. The compound of claim 25, wherein R ₂ is selected from the group consisting of

    Preferably, R ₂ is selected from
27. The compound of any one of claims 1 to 13, wherein R ₂ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, optionally halogen-substituted alkyl, halogen-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,-C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from alkyl optionally substituted with a substituent selected from halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, wherein R ₉、R₁₀、R₁₁ is independently selected from H, alkyl;

    Preferably, R ₂ is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, said heterocycloalkyl, heterocycloalkenyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl optionally substituted with an alkyl selected from halogen, alkyl, halogen, alkyl, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C6 alkyl, said C1-C6 alkyl optionally substituted with a substituent selected from halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, wherein R ₉、R₁₀、R₁₁ is independently selected from H, alkyl;

    Preferably, R ₂ is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl containing a heteroatom selected from N, O, S, said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl optionally substituted with an alkyl selected from halogen, alkyl, halogen, alkyl, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C6 alkyl, said C1-C6 alkyl optionally substituted with a substituent selected from halogen, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, wherein R ₉、R₁₀、R₁₁ is independently selected from H, alkyl;

    Preferably, R ₂ is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl optionally being substituted by C1-C6 alkyl, halogen, C1-C6 alkyl, -C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, -C (=O) NR ₉R₁₀, wherein R ₉、R₁₀、R₁₁ is independently selected from C1-C6 alkyl;

    Preferably, R ₂ is selected from 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl containing 1 heteroatom selected from O, S, said cycloalkyl, heterocycloalkyl optionally being substituted by C1-C3 alkyl selected from halogen, C1-C3 alkyl, halogen, C1-C3 alkyl, -C (=O) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by a substituent selected from halogen, -C (=O) NR ₉R₁₀, wherein R ₉、R₁₀、R₁₁ is independently selected from C1-C3 alkyl;

    Preferably, R ₂ is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, the above groups are optionally halogen-, C1-C3 alkyl-, halogen-substituted C1-C3 alkyl, -C (=o) NR ₉R₁₀、-C(＝O)OR₁₁, or R ₂ is selected from methyl, ethyl, propyl, optionally substituted with a substituent selected from halogen, -C (=o) NR ₉R₁₀, wherein R ₉、R₁₀、R₁₁ is independently selected from C1-C3 alkyl;

    Preferably, R ₂ is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, bicyclo [1.1.1] pentane, cyclohexane, tetrahydrofuran, tetrahydropyranyl, tetrahydrothiopyranyl, optionally substituted with a member selected from the group consisting of fluorine, methyl, trifluoromethyl, -C (=o) N (substituted with a substituent of CH ₃)₂、-C(＝O)OCH₃; or R ₂ is selected from methyl, ethyl, propyl, optionally substituted with a substituent selected from fluoro, -C (=o) N (CH ₃)₂);

    Preferably, R ₂ is selected from: -CH₃、 Preferably, the method comprises the steps of, The following configuration is adopted:
28. The compound of any one of claims 1 to 27, selected from one of:
29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof, and pharmaceutically acceptable adjuvant or auxiliary ingredient.
30. Use of a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof, or a pharmaceutical composition according to claim 29, for the preparation of an SOS1 inhibitor.
31. Use of a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof, or a pharmaceutical composition according to claim 29, for the manufacture of a medicament for the treatment of a SOS1 mediated disease.
32. The use according to claim 31, wherein the disease is selected from the group consisting of cancer, pathogenic rash;

    Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, stomach cancer, and breast cancer;

    The pathogenic rash disease is selected from noonan syndrome, heart and face skin syndrome and type I hereditary gum fibromatosis.
33. Use of a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof, or a pharmaceutical composition according to claim 29, for the manufacture of a medicament for the treatment of a disease causing overexpression of SOS1 protein.
34. The use of a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof, or a pharmaceutical composition according to claim 29, for the manufacture of a medicament for the treatment of a disease caused by overexpression of SOS1 protein.
35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal, and RAS inhibitor, administered simultaneously or separately.
36. The pharmaceutical composition according to claim 35, wherein 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 a pharmaceutical composition according to claim 35 or 36 for the manufacture of a medicament for the treatment of cancer.
38. A method of treating a SOS1 mediated disease comprising the step of administering to a subject a compound of any one of claims 1-28, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal, or a pharmaceutical composition of any one of claims 29, 35 or 36.