Pyridazino ring derivative and pharmaceutical use thereof

Abstract

The present invention relates to a pyridazino ring derivative or a stereoisomer thereof, a pharmaceutical composition thereof, and a pharmaceutical use thereof.

Description

Pyridazinocyclic derivatives and their use in medicine TECHNICAL FIELD

[0001] The present invention relates to a pyridazinocyclic derivative or a stereoisomer thereof, a pharmaceutical composition thereof and use in medicine. BACKGROUND

[0002] Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a class of intracellular pattern recognition receptors (PRRs) located in the cytoplasm of mammalian cells, which play a very important role in innate immune response. NLRs are a group of cytoplasmic proteins with signal transduction function, which are widely involved in inflammatory response of the body. NLRs family includes NODs, NALPs (NLRPs), CIITA (NLRA) and IPAF (NLRC), among which NLRPs and NLRC subfamily are the main two types of NOD-like receptors (NLRs), NLRPs can be divided into NLRP1, NLRP3, NLRP6, NLRP7, NLRP12 and other inflammasome members. NLRP3 inflammasome is a multi-protein complex composed of NLRP3 protein itself, caspase 1 and apoptosis-associated speck-like protein containing CARD (ASC), which can recognize a variety of pathogenic microorganisms and stress-related endogenous signal molecules. The activation of classical NLRP3 inflammasome is stimulated by two signals, the first signal activates TLR4 (Toll like receptor 4) signaling pathway, promotes the nuclear translocation of nuclear transcription factor κB, and induces the production of IL-1β and IL-18 precursors. The second signal promotes the formation of NLRP3 / ASC / pro-caspase-1 complex, that is, ASC polymerizes with apoptosis-associated speck-like protein containing a CARD (ASC, Apoptosis-Associated Specklike Protein containing a CARD) when activated, and ASC interacts with cysteine protease caspase-1 to form a complex called inflammasome. The pro-caspase-1 is autocleaved into an activated form, (Wen, H., Miao, E. A. & Ting, J. P. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432-441 (2013)) activated caspase-1 cleaves pro-inflammatory cytokines IL-1β and IL-18 into active forms IL-1β and IL-18 and releases them into the extracellular, recruits inflammatory cells to aggregate and expands the inflammatory response.ASC speck proteins can also recruit and activate caspase-8, cleave pro-IL-1β and IL-18 to convert them to their mature forms and initiate pyroptosis. Non-canonical NLRP3 inflammasome activation is independent of TLR4 signaling pathway activation, it is initiated by direct recognition of intracellular LPS by caspase-11, which triggers NLRP3 inflammasome activation, promotes Gasdermin D activation and release to mediate cell death. (Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013-1022 (2014).).

[0003] Abnormal activation of NLRP3 inflammasome is closely related to the occurrence of many inflammatory diseases such as Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, Alzheimer's disease, Parkinson's disease, nonalcoholic fatty liver disease, atherosclerosis, asthma, nephropathy, enteritis, tumor, gout, neurodegenerative disease, diabetes and obesity. SUMMARY

[0004] The present application provides a pyridazino ring derivative, or all stereoisomers thereof, a pharmaceutical composition thereof.

[0005] One or more embodiments of the present application provide a pyridazino ring derivative represented by general formula (A), or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt or co-crystal thereof:

[0006] wherein:

[0007] R w , R x , R y and R z are each independently selected from C, CH, S, N or NH;

[0008] R a1 , R a2 are each independently selected from H, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl or C 1-6 haloalkyl;

[0009] R a3 is selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;

[0010] C is 8-12 membered heteroaryl;

[0011] L1is selected from the group consisting of a bond, -NR2-, -NR2-C 1-6 alkylene-;

[0012] R2is selected from the group consisting of H, C 1-6 alkyl or C 1-6 haloalkyl;

[0013] W is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 heterocycloalkyl or C 3-8 cycloalkyl, said W is optionally further substituted by one or more R3;

[0014] when R x is NH, W is C4cycloalkyl or 4 membered heterocycloalkyl, said W is optionally further substituted by one or more R3;

[0015] R3is selected from the group consisting of halogen, cyano, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl optionally further substituted by one or more halogen, cyano, hydroxy, carboxy substituents; 1-6 alkyl, C 1-6 haloalkyl, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl optionally further substituted by one or more halogen, cyano, hydroxy, carboxy substituents.

[0016] According to an embodiment of the present application, said R w is C, CH, N or NH, preferably said R w is C or CH.

[0017] According to an embodiment of the present application, said R x is C, CH, N, NH or S, preferably said R x is S.

[0018] According to an embodiment of the present application, said R y is C, CH, S or N, preferably said R y is N.

[0019] According to an embodiment of the present application, said R z is C, CH, S or N, preferably said R z is C or CH.

[0020] According to embodiments of the present application, said R a1 , R a2 are each independently selected from H, halogen, hydroxyl, C 1-4 alkyl or C 1-4 haloalkyl; preferably, said R a1 , R a2 are each independently selected from H or halogen.

[0021] According to embodiments of the present application, said R a3 is selected from H, halogen, cyano; preferably, said R a3 is selected from H, halogen.

[0022] According to embodiments of the present application, said C ring is selected from thienopyridazine, pyridopyridazine, imidazotriazine or benzopyridazine.

[0023] According to embodiments of the present application, said C ring is selected from

[0024] According to embodiments of the present application, said L1is selected from a bond, -NR2-, -NR2-C 1-4 alkylene-, R2being selected from H, C 1-4 alkyl or C 1-4 haloalkyl; preferably -NH- or -NH-C 1-3 alkylene-.

[0025] According to embodiments of the present application, said W is selected from C 1-4 alkyl, C 6-8 aryl, C 5-6 heteroaryl, C 5-6 heterocycloalkyl or C 4-6 cycloalkyl, said C 1-4 alkyl, C 6-8 aryl, C 5-6 heteroaryl, C 3-6 heterocycloalkyl or C 4-6 cycloalkyl being optionally further substituted with 1 or more R3.

[0026] According to embodiments of the present application, said W is selected from C 1-4 alkyl, phenyl, piperidinyl, cyclohexanyl, cyclopentanyl, cyclobutanyl, tetrahydrofuranyl or tetrahydropyranyl, said W being optionally further substituted with 1 or more R3.

[0027] when R x is NH, W is 4-membered cycloalkyl, said W being optionally further substituted with 1 or more R3.

[0028] when R xW is cyclobutyl, said W being optionally further substituted by one or more R3.

[0029] According to an embodiment of the application, said W is selected from

[0030] when R x is NH, W is

[0031] According to an embodiment of the application, said R3is selected from a substituent of halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl; said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl being optionally further substituted by one or more substituents of halogen, hydroxy.

[0032] According to an embodiment of the application, said R3is selected from a substituent of hydroxy, C 1-4 alkyl, C 1-4 alkoxy, tetrahydrofuranyl, said C 1-4 alkyl being optionally further substituted by one or more substituents of hydroxy.

[0033] According to an embodiment of the application, the pyridazino ring derivative of general formula (A) has the structure of general formula (I):

[0034] wherein:

[0035] R a1 , R a2 are each independently selected from H, halogen, cyano, hydroxy, carboxy, C 1-6 alkyl or C 1-6 haloalkyl;

[0036] R a3 is selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl.

[0037] C ring is selected from

[0038] Preferably, C ring is selected from

[0039] L1is selected from a bond, -NR2-, -NR2-C 1-6alkylene-;

[0040] R2is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0041] W is selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 heterocycloalkyl or C 3-8 cycloalkyl, said W being optionally further substituted by one or more R3;

[0042] R3is selected from halogen, cyano, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl; said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl being optionally further substituted by one or more halogen, cyano, hydroxy, carboxy substituents.

[0043] According to an embodiment of the present application, the pyridazino ring derivatives of general formula (A) have the structure of general formula (II):

[0044] wherein:

[0045] R a1 , R a2 are each independently selected from H or halogen;

[0046] R a3 is selected from H or halogen;

[0047] C ring is selected from

[0048] Preferably, C ring is selected from

[0049] W is selected from C 1-4 alkyl, C 6-8 aryl, C 5-6 heteroaryl, C 3-6 heterocycloalkyl or C 4-6 cycloalkyl; said W being optionally further substituted by one or more R3;

[0050] said R3is selected from halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4alkyl, C 3-6 heteroaryl, C 3-6 cycloalkyl, optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 heteroaryl, C 3-6 cycloalkyl, optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C

[0051] Preferably, W is selected from the group consisting of C 3-6 heteroaryl, C 3-6 heteroaryl, optionally further substituted by one or more substituents selected from the group consisting of C 1-4 alkyl.

[0052] According to an embodiment of the present application, the pyridazino ring derivatives of general formula (A) have the structure of general formula (Γ):

[0053] R a1 , R a2 are each independently selected from the group consisting of H, halogen, cyano, hydroxy, carboxyl, C 1-6 alkyl, or C 1-6 haloalkyl;

[0054] C ring is selected from the group consisting of

[0055] L1is selected from the group consisting of a bond, -NR2-, -NR2-C 1-6 alkylene-;

[0056] R2is selected from the group consisting of H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0057] W is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, said W being optionally further substituted by one or more R3;

[0058] R3is selected from the group consisting of halogen, cyano, hydroxy, carboxyl, C 1-6 alkyl, haloalkyl, C 1-6 alkyl, C 3-10 heteroaryl, C 3-10 heteroaryl, C 1-6 alkyl, haloalkyl, C 3-6 heteroaryl, C 3-6 cycloalkyl, optionally further substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, carboxyl.

[0059] According to embodiments of the present application, R a1 , R a2 each is independently selected from H or halo;

[0060] C ring is selected from

[0061] L1is selected from -NH- or -NH-C 1-4 alkylene-;

[0062] W is selected from C 1-4 alkyl, C 6-8 aryl, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl, said W is optionally further substituted with one or more R3;

[0063] R3is selected from hydroxy, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 heterocycloalkyl substituents; said C 1-4 alkyl is optionally further substituted with one or more hydroxy substituents.

[0064] According to embodiments of the present application, the pyridazino ring derivatives of general formula (A) have the structure of general formula (II):

[0065] R a1 , R a2 each is independently selected from H or halo;

[0066] C ring is selected from

[0067] W is selected from C 3-6 heterocycloalkyl, said C 3-6 heterocycloalkyl is optionally further substituted with one or more substituents selected from C 1-4 alkyl.

[0068] One or more embodiments of the present application provide pyridazino ring derivatives, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the following structures:

[0069] One or more embodiments of the present application provide pyridazino ring derivatives, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the following structures:

[0070] One or more embodiments of the present application provide a pharmaceutical composition comprising:

[0071] the above-mentioned compound or a tautomer, a stereoisomer, a solvate, a prodrug, a metabolite, a deuterated compound, a pharmaceutically acceptable salt or a co-crystal thereof;

[0072] one or more pharmaceutically acceptable carriers and / or excipients.

[0073] One or more embodiments of the present application provide a use of a pharmaceutical composition or the above-mentioned compound or a tautomer, a stereoisomer, a solvate, a prodrug, a metabolite, a deuterated compound, a pharmaceutically acceptable salt or a co-crystal thereof in the manufacture of an NLRP3 inhibitor or in the manufacture of a medicament for treating a disease associated with NLRP3.

[0074] One or more embodiments of the present application provide a use, wherein the NLRP3 inhibitor treats a disease or a disease associated with NLRP3, including an inflammatory disease, an autoimmune disease, a cardiovascular system disease, a cancer, a renal system disease, a gastrointestinal disease, a respiratory system disease, an endocrine system disease or a central nervous system disease.

[0075] One or more embodiments of the present application provide a use, wherein the disease includes cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer’s disease, atherosclerosis, gout or chronic kidney disease.

[0076] One or more embodiments of the present application provide a method of inhibiting NLRP3, comprising contacting a compound of general formula (I) of the present application or the above-mentioned specific structure or a stereoisomer, a solvate, a metabolite, a deuterated compound, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof of the present application or a composition of the present application with a subject in need thereof.

[0077] One or more embodiments of the present application provide a method of treating a disease associated with NLRP3, comprising administering a compound of general formula (I) of the present application or the above-mentioned specific structure or a stereoisomer, a solvate, a metabolite, a deuterated compound, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof of the present application or a composition of the present application to a subject in need thereof.

[0078] One or more embodiments of this application provide compounds of general formula (I) or the specific structures described above or their stereoisomers, solvates, metabolites, deuterated derivatives, pharmaceutically acceptable salts, cocrystals or prodrugs for the treatment of NLRP3-related diseases or as NLRP3 inhibitors.

[0079] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0080] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0081] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0082] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as that of "alkyl" as described above.

[0083] "Alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group containing from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group can be optionally further substituted with one or more substituents.

[0084] "Alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group containing from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptynyl-1-yl, heptynyl-3-yl, heptynyl-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group can be optionally further substituted with one or more substituents.

[0085] "Carbocyclyl" or "carbocyclic ring" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is defined identically to "aryl" above; when non-aromatic, it can be a monocyclic, bicyclic, or tricyclic ring system containing 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) members, 4 to 12 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12) members, or 10 to 15 (e.g., 10, 11, 12, 13, 14, 15) members, respectively, which can be fused or spiro, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclyl" or "carbocyclic" group is optionally further substituted with one or more substituents.

[0086] "Heterocyclyl" or "heterocycle" means a saturated or unsaturated aromatic or non-aromatic ring, which when aromatic is defined the same as "heteroaryl" above; and which when non-aromatic can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains one to four (e.g., one, two, three, four) heteroatoms selected from the group consisting of N, O, and S, preferably a 3- to 8-membered heterocyclyl. One to four (e.g., one, two, three, four) of the N, S in the ring of the "heterocyclyl" or "heterocycle" group are optionally oxidized at any available nitrogen or sulfur; the "heterocyclyl" or "heterocycle" group can be attached at any available carbon or heteroatom; the "heterocyclyl" or "heterocycle" group can be bridged or spiro. Non-limiting examples of "heterocyclyl" or "heterocycle" groups include epoxyl, propoxyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azacycloheptanyl, oxacycloheptanyl, thiacycloheptanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidyl, homopiperidyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolizinyl, quinolizinyl, N-pyridinylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantanyl, and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" group can be optionally further substituted with one or more substituents.

[0087] "Cycloalkyl" refers to saturated cyclic hydrocarbon groups, which can be a 3 to 10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 membered) polycyclic ring system, with the ring carbon atoms preferably being 3 to 10 carbon atoms, and further preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When substituted, a cycloalkyl group can be optionally further substituted with one or more substituents.

[0088] "Heterocycloalkyl" refers to substituted or unsubstituted saturated non-aromatic ring groups, which can be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contain 1, 2, or 3 heteroatoms selected from N, O, or S, preferably 3 to 8 membered heterocycloalkyl groups. Optionally 1, 2, or 3 N, S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached at a heteroatom or carbon atom; "heterocycloalkyl" can be a bridged ring or spirocyclic. Non-limiting examples of "heterocycloalkyl" groups include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, and oxaspiro[3.3]heptanyl.

[0089] When "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocyclic", "heterocyclyl", "heterocyclic", "cycloalkyl", "heterocycloalkyl", or "heterocyclyl" as described above are substituted, they can be optionally further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, thiol, nitro, cyano, amino, C 1-6 alkylamino, =0, C 1-6 alkyl, C 1-6 alkoxy, C2 -6 alkenyl, C 2-6 alkynyl, -NR q4R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 ycloalkyl, C 3-8 ycloalkyl, C 6-10 ryl, C 5-10 aromatic heteroaryl, -C(=O)OC 6-10 ryl, -OC(=O)C 6-10 ryl, -OC(=O)C 5-10 aromatic heteroaryl, -C(=O)OC 5-10 aromatic heteroaryl, -OC(=O)C 3- 8ycloalkyl, -C(=O)OC 3-8 ycloalkyl, -OC(=O)C 3-8 ycloalkyl, -C(=O)OC 3-8 ycloalkyl, -NHC(=O)C 3-8 ycloalkyl, -NHC(=O)C 6-10 ryl, -NHC(=O)C 5-10 aromatic heteroaryl, -NHC(=O)C 3-8 ycloalkyl, -NHC(=O)C 3-8 ycloalkyl, -NHC(=O)C 2-6 lkenyl or -NHC(=O)C 2-6 kynyl, C 1-6 alkyl, C 1-6 lkoxyl, C 2-6 lkenyl, C 2-6 kynyl, C 3-8 ycloalkyl, C 3-8 ycloalkyl, C 6-10 ryl, C 5-10 aromatic heteroaryl, -NHC(=O)C 6-10 ryl, -NHC(=O)C 5-10 aromatic heteroaryl, -NHC(=O)C 3-8 ycloalkyl or -NHC(=O)C 3-8 ycloalkyl is optionally further substituted with one to three substituents selected from the group consisting of OH, F, CI, Br, I, C 1-6 alkyl, C 1-6 lkoxyl, -NR q4 R q5 or =O; R q1 is selected from the group consisting of C 1-6 alkyl, C 1-6 lkoxyl or C 6-10aryl; R q2 , R q3 is selected from H or C1-6alkyl; wherein R q4 , R q5 is selected from H, C 1-6 alkyl, -NH(C=NR q1 )NR q2 R q3 , -S(=O)2NR q 2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein said C 1-6 alkyl is optionally further substituted with one or more substituents selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 and R q5 , together with the N atom to which they are attached, form a 3- to 8-membered heterocyclic ring, which can contain one or more heteroatoms selected from N, O or S.

[0090] "Pharmaceutical composition" means a mixture of one or more compounds of the application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or active agents.

[0091] "Carrier" refers to a material, such as a liquid or solid, which does not itself induce the production of antibodies to it, and which does not have a significant stimulating effect on the subject.

[0092] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration to an individual. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose and its derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0093] "Prodrug" refers to a compound that can be converted into the biologically, pharmaceutically or pharmacologically active compound of the application after administration to a subject. Prodrugs of the application are prepared by modifying the amino or carboxyl groups of the compounds of the application in such a way that the modifications are cleaved in vivo when the prodrug is administered to a subject. Upon administration of a prodrug of the application to a subject, the prodrug is cleaved to form the free amino or carboxyl groups of the parent compound.

[0094] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0095] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0096] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0097] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0098] Example 1

[0099] (R)-4-(benzo[b]thiophene-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazine-7-amine (compound 1-1) and (R)-7-(benzo[b]thiophene-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazine-4-amine (compound 1-2)

[0100] (R)-4-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-7-amine and

[0101] (R)-7-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-4-amine

[0102] first step:

[0103] (R)-4-chloro-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-7-amine and(R)-7-chloro-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-4-amine

[0104] (R)-4-chloro-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-7-amine and(R)-7-chloro-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-4-amine

[0105] In 100 mL single necked flask, 1a (2.00 g, 9.75 mmol) was dissolved in 20 mL of DMSO with (R)-1-methylpiperidin-3-amine (1.13 g, 9.75 mmol) and DIPEA (1.89 g, 14.63 mmol) was added, reaction was carried out at 60 °C for 5 h. TLC monitoring reaction was completed, reaction was diluted with water and ethyl acetate, organic layer was dried and organic solvent was removed under reduced pressure, crude product was purified by column chromatography (TLC) (DCM: MeOH = 20:1) to get 1b-1 and 1b-2 mixture as white solid (420 mg, yield: 12.5 %), which was used directly for next step reaction.

[0106] LCMS m / z (ESI) = 383.1 [M+1].

[0107] Second step:

[0108] ((R)-4-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-7-amine and(R)-7-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-4-amine

[0109] ((R)-4-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-7-amine and(R)-7-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)thieno[2,3-d]pyridazin-4-amine

[0110] In a 50 mL flask, 1b-1 and 1b-2 (200 mg, 0.71 mmol) from the previous step, 2-(benzo[d]thiazol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (276 mg, 1.06 mmol), Pd(dppf)2Cl2(52 mg, 0.07 mmol), cesium carbonate (578 mg, 1.78 mmol) were dissolved in 1,4-dioxane solution (10 mL) and stirred at 100 °C for 4 h under nitrogen protection. The reaction was monitored by TLC, and the reaction was completed. The reaction was concentrated, and the crude product was purified by preparative HPLC (H2O:ACN = 5:1) and then by SFC chiral preparation to give compound 1-1 (10 mg, yield: 9.8%) as a white solid and compound 1-2 (10 mg, yield: 9.8%)

[0111] LCMS m / z (ESI) = 381.5 [M+1].

[0112] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.92 (d, 1H), 7.85 (d, 1H), 7.80 (dd, 1H), 7.31 (d, 1H), 7.12 (d, 1H), 7.55 (d, 1H), 7.41 (d, 1H), 4.35 (q, 1H), 3.15 - 3.04 (m, 1H), 2.74 - 2.66 (m, 1H), 2.18 (s, 3H), 2.04 - 1.80 (m, 4H), 1.61 (q, 1H), 1.45 (td, 1H).

[0113] Example 2

[0114] (R)-1-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazi n-4-amine(2-1)and

[0115] (R)-1-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazi n-4-amine(2-1)and

[0116] (R)-4-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]

[0117] pyridazin-1-amine(2-2)

[0118] first step:

[0119] (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazine-4-amine (2b-1) and (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazine-1-amine (2b-2)

[0120] (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and(R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0121] In a 100 mL single-necked flask, 2a (3.00 g, 15.0 mmol) and (R)-1-methylpiperidin-3-amine (1.8 g, 16.5 mmol) were dissolved in 30 mL DMSO, and DIPEA (2.90 g, 22.5 mmol) was added. The mixture was reacted at 60 °C for 5 h. After the reaction was completed by TLC, the reaction solution was extracted with water and ethyl acetate. The organic phase was dried and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to give a white solid mixture of 2b-2 and 2b-2 (1.60 g, yield: 45%), which was used directly in the next reaction without further separation.

[0122] LCMS m / z(ESI) = 378.1 [M+1].

[0123] Step Two:

[0124] (R)-1-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (compound 2-1) and (R)-4-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (compound 2-2)

[0125] (R)-1-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine(compound 2-1)and

[0126] (R)-4-(benzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]

[0127] pyridazin-1-amine (compound 2-2)

[0128] In a 50 mL three-necked flask, a mixture of 2b-1 and 2b-2 (100 mg, 0.36 mmol), 2-(benzothiophene-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (140 mg, 0.54 mmol), Pd(dppf)₂Cl₂ (27 mg, 0.04 mmol), and cesium carbonate (293 mg, 0.90 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was reacted at 100 °C for 4 h under nitrogen protection. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The crude product was purified by preparative HPLC (H₂O:ACN = 5:1) followed by chiral fractional ...

[0129] LCMS m / z(ESI) = 376.2 [M+1].

[0130] 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.30(d,2H),7.93(d,1H),7.87(d,1H),7.82(dd,1H),7.64(d,1H),7.55(d,1H),7.4 3(d,1H),4.41(q,1H),3.16–3.05(m,1H),2.73–2.65(m,1H),2.18(s,3H),2.05–1.80(m,4H),1.62(q,1H),1.48(td,1H).

[0131] Example 3

[0132] (R)-1-(3-fluorobenzo[b]thiophene-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 3)

[0133] (R)-1-(3-fluorobenzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0134] first step:

[0135] (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (3b)

[0136] (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0137] In a 100 mL single-necked flask, compound 3a (2 g, 10 mmol) was dissolved in dimethyl sulfoxide (25 mL). Under ice-water bath conditions, p-N,N-diisopropylethylamine (3.23 g, 25 mmol) and 1-methyl-(R)-3-aminopiperidine (1.71 g, 15 mmol) were added to the reaction system. After the addition was complete, the reaction system was heated to 100 °C and reacted for 6 h. After the reaction was monitored by LCMS, the mixture was extracted with ethyl acetate (150 × 3 mL) and water. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target crude product. SFC resolution yielded compound 3b (P2 peak, t = 1.636 min), a yellowish-white solid (905 mg, yield: 32%). LCMS m / z (ESI) = 278.86 [M+1].

[0138] Step Two:

[0139] R)-1-(3-fluorobenzo[b]thiophene-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (compound 3)

[0140] (R)-1-(3-fluorobenzo[b]thiophen-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0141] In a 100 mL round-bottom flask, 3b (253.35 mg, 0.91 mmol), cesium carbonate (741.24 mg, 2.28 mmol), 2-(3-fluorobenzo[b]thiophene-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (300 mg, 1.19 mmol), and DPPF palladium dichloride (66.53 mg, 0.09 mmol) were dissolved in 1,4-dioxane (15 mL) and refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS until completion. The 1,4-dioxane was removed under reduced pressure, and the residue was subjected to column chromatography (DCM:MeOH = 30:1) to give compound 3, a yellowish-white solid (55 mg, yield: 15%).

[0142] LC-MS m / z (ESI) = 395.52 [M+1].

[0143] 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.00 (d, 1H), 8.35 (d, 2H), 7.97 (d, 1H), 7.81 (dd, 1H), 7.61 (d, 1H), 7.46 (d, 1H), 4.43 (q, 1H), 3.11 - 3.03 (m, 1H), 2.74-2.66 (m, 1H), 2.09 - 1.86 (m, 4H), 1.61 (q, 1H), 1.47 (td, 1H).

[0144] 19 F NMR (377 MHz, DMSO-d6) δ -135.87.

[0145] Example 4

[0146] (1S,3R)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amin o)cyclohexan-1-ol

[0147] (1S,3R)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amin o)cyclohexan-1-ol

[0148] First step:

[0149] (1S,3R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0150] (1S,3R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0151] In a 100 mL single necked flask, compound 1a (439.67 mg, 2.19 mmol) was dissolved in N-methyl pyrrolidine (10 mL), under ice water bath, N,N-diisopropyl ethyl amine (706.28 mg, 5.48 mmol) and (1S,3R)-3-aminocyclohexanol (500 mg, 3.29 mmol) were added to the reaction mixture, after addition, the reaction mixture was warmed to 100 °C for 6 h. After monitoring the reaction completion by LCMS, the reaction mixture was extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the target crude product which was purified by column chromatography (DCM: MeOH = 30: 1) to get 4b as a yellow white solid (550 mg, yield: 90%). LCMS m / z (ESI) = 279.5 [M+1].

[0152] Second Step:

[0153] (1S,3R)-3-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol (Compound 4)

[0154] (1S,3R)-3-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0155] In a 100 mL round bottom flask, 4b (90 mg, 0.33 mmol), cesium carbonate (268.82 mg, 0.83 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98.03 mg, 0.39 mmol) and DPPF palladium dichloride (24.13 mg, 0.03 mmol) were dissolved in 1,4-dioxane (8 mL) under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. After monitoring the reaction completion by LCMS, 1,4-dioxane was removed under reduced pressure, compound 4 was obtained as a white solid (25 mg, yield: 19%) by reverse phase purification.

[0156] LC-MS m / z (ESI) = 395.2 [M+1].

[0157] 1H NMR (400 MHz, DMSO-d6) δ 9.81 (d, 1H), 8.91 (d, 1H), 8.3 (s, 1H), 7.95 (dd, 1H), 7.80 (d, 1H), 7.75 (dd, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 4.75 (d, 1H), 4.45 - 4.22 (m, 1H), 3.56 (tt, 1H), 2.38 - 2.26 (m, 1H), 2.04 (d, 1H), 1.88 (d, 1H), 1.82 - 1.74 (m, 1H), 1.36 (dq, 3H), 1.28 - 1.08 (m, 1H).

[0158] 19 F NMR (377 MHz, DMSO-d6) δ -135.97.

[0159] Example 5

[0160] (3S,4R)-4-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0161] (3S,4R)-4-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0162] First step:

[0163] (3S,4R)-4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0164] (3S,4R)-4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0165] In a 100 mL single necked flask, compound 1a (2 g, 10 mmol) was dissolved in N-methyl pyrrolidine (25 mL), under ice water bath, N,N-diisopropyl ethylamine (3.23 g, 25 mmol) and (3S,4R)-4-amino-3-hydroxytetrahydropyran (2.3 g, 15 mmol) were added to the reaction system, after addition, the reaction system was warmed to 100 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was purified by column chromatography (DCM:MeOH = 30:1) to obtain compound 5b, yellow white solid (600 mg, yield: 21%, mixture). LCMS m / z (ESI) = 281.6 [M+1].

[0166] Second step:

[0167] ((3S,4R)-4-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4- yl)amino)tetrahydro-2H-pyran-3-ol (Compound 5)

[0168] (3S,4R)-4-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4- yl)amino)tetrahydro-2H-pyran-3-ol

[0169] In a 100 mL round bottom flask, 5b (64.72 mg, 0.23 mmol, mixture), cesium carbonate (187.35 mg, 0.58 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (70 mg, 0.28 mmol) and DPPF palladium dichloride (16.82 mg, 0.28 mmol) were dissolved in 1,4-dioxane (8 mL), under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. After the reaction was monitored to be completed by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 5 (P2 peak, t = 2.016 min) was obtained by SFC resolution, white solid (11.2 mg, yield: 12%).

[0170] LC-MS m / z (ESI) = 397.2 [M+1].

[0171] 1H NMR (400 MHz, DMSO-d6) δ 9.86 (d, 1H), 8.93 (d, 1H), 8.31 (d, 1H), 7.96 (dd, 1H), 7.88 (d, 1H), 7.76 (dd, 1H), 7.68 (dd, 1H), 7.62 (d, 1H), 5.25 (s, 1H), 4.55 - 4.34 (m, 1H), 3.91 (td, 2H), 3.74 (td, 1H), 3.51 - 3.39 (m, 1H), 3.14 (dd, 1H), 2.22 - 2.12 (m, 1H), 1.64 (qd, 1H).

[0172] 19 F NMR (377 MHz, DMSO-d6) δ -135.66.

[0173] Example 6

[0174] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0175] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0176] First step:

[0177] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0178] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0179] In a 100 mL single necked flask, compound 1a (1 g, 5 mmol) was dissolved in N-methyl pyrrolidine (10 mL), under ice water bath, N,N-diisopropyl ethylamine (1.61 g, 7.5 mmol) and (1R,2R)-2-aminocyclohexan-1-ol (1.14 g, 7.5 mmol) were added into the reaction system, after addition, the reaction system was warmed to 80 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, collected the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 6b (P2 peak, t = 2.016 min), yellow white solid (240 mg, yield: 17%). LCMS m / z (ESI) = 279.1 [M+1].

[0180] Second step:

[0181] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0182] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0183] In a 100 mL round bottom flask, 6b (60 mg, 0.22 mmol), cesium carbonate (179 mg, 0.55 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (60 mg, 0.22 mmol) and DPPF palladium dichloride (16 mg, 0.022 mmol) were dissolved in 1,4-dioxane: water = 4 mL: 0.5 mL, under nitrogen protection, refluxed at 100 °C for 8 h. After the reaction was monitored to be completed by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 6 was obtained by reverse phase column purification, yellow solid (20.7 mg, yield: 23.8%).

[0184] LC-MS m / z (ESI) = 395.2 [M+1].

[0185] 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.63 (s, 1H), 9.15 (d, 1H), 8.38 (d, 1H), 8.03 (d, 1H), 7.83 (d, 1H), 7.78 - 7.69 (m, 2H), 4.08 (m, 1H), 3.66 (td, 2H), 2.10 - 1.96 (m, 2H), 1.75 (d, 2H), 1.59 - 1.48 (m, 1H), 1.42 - 1.29 (m, 3H).

[0186] 19 F NMR (377 MHz, DMSO-d6) δ -135.75.

[0187] Example 7

[0188] 3-(((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)methyl)phenol (Compound 7)

[0189] 3-(((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)methyl)phenol

[0190] First Step:

[0191] 1-Chloro-N-(3-methoxybenzyl)pyrido[3,4-d]pyridazin-4-amine

[0192] 1-Chloro-N-(3-methoxybenzyl)pyrido[3,4-d]pyridazin-4-amine (7b)

[0193] In a 100 mL single neck flask, compound 1a (500 mg, 2.5 mmol) was dissolved in dimethyl sulfoxide (5 mL), N,N-diisopropylethylamine (645 mg, 5 mmol) and (3-methoxyphenyl)methanamine (360 mg, 2.63 mmol) were added to the reaction system under ice water bath, after adding, the reaction system was warmed to 50 °C for 5 h. After monitoring the end of the reaction by LCMS, it was extracted with ethyl acetate (50 x 3 mL) and water, the organic phase was collected, dried with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC (P2 peak, t = 2.141 min) to obtain 7b (yellow white solid, 280 mg, yield: 37%). LCMS m / z (ESI) = 301.0 [M+1].

[0194] Second Step:

[0195] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-(3-methoxybenzyl)pyrido[3,4-d]pyridazin-4-amine

[0196] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-(3-methoxybenzyl)pyrido[3,4-d]pyridazin-4-amine

[0197] In a 100 mL round bottom flask, 7b (60 mg, 0.2 mmol), cesium carbonate (163 mg, 0.5 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (56 mg, 0.2 mmol) and DPPF palladium dichloride (15 mg, 0.02 mmol) were dissolved in 1,4-dioxane: water = 3 mL: 0.5 mL, under nitrogen protection, reflux at 100 °C for 8 h. LCMS monitored the end of the reaction, 1,4-dioxane was removed under reduced pressure, and 7c was obtained as a yellow sticky solid (60 mg, yield: 72%) after purification by reverse phase column.

[0198] Third step:

[0199] 3-(((l-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)methyl)phenol

[0200] 3-(((l-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)methyl)phenol

[0201] In a 100 mL round bottom flask, 7c (60 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL), and after cooling to 0 °C, boron tribromide (1 M in THF, 0.4 mL) was added. The reaction was carried out at 0 °C for 5 h. LCMS monitored the end of the reaction, and after quenching with 2 mL of methanol, it was concentrated under reduced pressure. Compound 7 was obtained as a yellow solid (12.7 mg, yield: 22.7%) after purification by reverse phase column.

[0202] LCMS m / z (ESI) = 403.1 [M+1].

[0203] 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.40 (s, 2H), 9.03 (d, 1H), 8.34 (d, 1H), 7.98 (d, 1H), 7.80 - 7.72 (m, 2H), 7.65 (d, 1H), 7.16 (t, 1H), 6.93 - 6.85 (m, 2H), 6.67 (dd, 1H), 4.85 (d, 2H).

[0204] 19 F NMR (377 MHz, DMSO-d6) δ -135.44.

[0205] Example 8

[0206] (R)-2-(3-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4- yl)amino)piperidin-1-yl)ethan-1-ol (Compound 8)

[0207] (R)-2-(3-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4- yl)amino)piperidin-1-yl)ethan-1-ol

[0208] First step:

[0209] (R)-3-((1-Chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (8b)

[0210] tert-Butyl (R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate

[0211] In a 250 mL single neck flask, compound 1a (2 g, 10 mmol) was dissolved in dimethyl sulfoxide (50 mL), N,N-diisopropylethylamine (2.58 g, 20 mmol) and (R)-1-tert-butoxycarbonyl-3-aminopiperidine (2 g, 10 mmol) were added to the reaction system under ice water bath, after addition, the reaction system was warmed to 50 °C for 5 h. After the reaction was completed by LCMS monitoring, it was extracted with ethyl acetate (50 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC (P2 peak, t = 2.313 min) to obtain 8b (2 g, yield: 66.7%) as a light yellow white solid.

[0212] LCMS m / z (ESI) = 301.1 [M+1].

[0213] Second Step:

[0214] (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0215] (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0216] In a 100 mL single necked flask, compound 8b (500 mg, 1.38 mmol) was dissolved in ethyl acetate (5 mL), under ice water bath, ethyl acetate hydrochloride solution (7 mL, 13.8 mmol, 2M) was added slowly into the reaction system, after addition, the reaction system was warmed to room temperature for 1 h. After the reaction was monitored by LCMS, the filter cake was collected and dried to obtain the target product 8c (hydrochloride) (400 mg, yield: 97.1%). LCMS m / z (ESI) = 264.2 [M+1].

[0217] Third Step:

[0218] (R)-N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)-1-chloropyrido[3,4-d]pyridazin-4-amine

[0219] (R)-N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)-1-chloropyrido[3,4-d]pyridazin-4-amine

[0220] In a 250 mL single necked flask, compound 8c (210 mg, 0.69 mmol) was dissolved in acetonitrile (5 mL), under ice water bath, cesium carbonate (561 mg, 1.725 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (2 g, 10 mmol) were added into the reaction system, after addition, the reaction system was warmed to 70 °C for 5 h. After the reaction was monitored by LCMS, it was extracted with ethyl acetate (50 x 3 mL) and water, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was purified by silica gel column to obtain 8d (127 mg, yield: 43.7%). LCMS m / z (ESI) = 422.1 [M+1].

[0221] Fourth Step:

[0222] (R)-N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)-1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-amine

[0223] (R)-N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)-1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-amine

[0224] In a 100 mL single neck flask, 8d (127 mg, 0.3 mmol), cesium carbonate (245 mg, 0.75 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (84 mg, 0.3 mmol) and DPPF palladium dichloride (22 mg, 0.03 mmol) were dissolved in 1,4-dioxane: water = 3 mL: 0.5 mL, under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. LCMS showed that the reaction was complete, the reaction was added with appropriate amount of water, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (PE: EA = 1: 1) to give 8e (82 mg, yield: 50.9%). LCMS m / z (ESI) = 538.1 [M+1].

[0225] Fifth step:

[0226] (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 8)

[0227] (R)-2-(3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)ethan-1-ol

[0228] In a 100 mL single neck flask, 8e (80 mg, 0.15 mmol) was dissolved in tetrahydrofuran (5 mL), under an ice water bath, 3M aqueous hydrochloric acid (1 mL) was slowly added dropwise into the reaction system, after addition, the reaction system was elevated to room temperature for 1 h. LCMS monitoring showed that the reaction was completed, the solvent was removed under reduced pressure, the crude product was purified by reverse phase column (water: acetonitrile = 1: 1) to give the target product compound 8 (30 mg, yield: 47.3%).

[0229] LCMS m / z (ESI) = 424.2 [M+1].

[0230] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.02 (d, 1H), 8.74 (s, 1H), 8.34 (s, 1H), 7.99 (d, 1H), 7.84 - 7.73 (m, 2H), 7.66 (d, 1H), 4.84 (s, 1H), 3.81 (t, 2H), 3.74 (d, 1H), 3.67 - 3.44 (m, 2H), 3.27 (s, 2H), 3.18 - 2.93 (m, 2H), 2.26 - 2.14 (m, 1H), 2.06 - 1.92 (m, 2H), 1.79 (dd, 5.7 Hz, 1H).

[0231] 19 F NMR (377 MHz, DMSO-d6) δ -135.80, -74.51.

[0232] Example 9-p1 and 9-p2

[0233] 1-(3-fluorobenzo[b]thiophen-6-yl)-N-((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0234] 1-(3-fluorobenzo[b]thiophen-6-yl)-N-((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0235] First step:

[0236] 1-chloro-N-((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0237] 1-chloro-N-((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0238] In a 100 mL single necked flask, 6c (165 mg, 0.55 mmol) was dissolved in methanol (30 mL), dihydro-3(2H)-furanone (57 mg, 0.66 mmol) and sodium triacetoxyborohydride (175 mg, 0.825 mmol) were added, stirred at room temperature for 6 h. LCMS showed the reaction was complete, the reaction was directly concentrated, the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give product 9a (94 mg, yield: 51%, less polar) and 9b (91 mg, yield: 49%, more polar). LCMS m / z (ESI) = 334.8 [M+1].

[0239] Second step:

[0240] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 9-p1, Compound 9-p2)

[0241] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0242] In a 100 mL single necked flask, 9a (94 mg, 0.28 mmol), cesium carbonate (228 mg, 0.70 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.28 mmol) and DPPF palladium dichloride (21 mg, 0.028 mmol) were dissolved in 1,4-dioxane: water = 3 mL: 0.5 mL, under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. LCMS showed the reaction was complete, to the reaction liquid, added appropriate amount of water, added ethyl acetate extraction 3 times, combined organic phase, saturated brine washed once, anhydrous sodium sulfate drying, the organic solvent was removed under reduced pressure, the crude product was purified by reverse phase column (water: acetonitrile = 3:2) to give compound 9-p1 (3 mg, yield: 2.3%).

[0243] LCMS m / z (ESI) = 450.5 [M+1].

[0244] 1H NMR (400 MHz, DMSO-d6) δ 9.81 (d, 1H), 8.91 (d, 1H), 8.30 (d, 1H), 7.95 (d, 1H), 7.75 (dd, 1H), 7.68 (dd, 2H), 7.60 (d, 1H), 4.47 (dd, 1H), 3.85 - 3.70 (m, 2H), 3.62 (q, 1H), 3.52 (ddd, 1H), 3.24 (d, 1H), 3.10 - 2.94 (m, 2H), 2.90 - 2.65 (m, 1H), 2.14 - 1.91 (m, 4H), 1.84 - 1.71 (m, 2H), 1.66 - 1.44 (m, 2H).

[0245] 19 F NMR (377 MHz, DMSO-d6) δ -135.84.

[0246] By the same coupling conditions, using 9b as the substrate, the target product compound 9-p2 (8 mg, yield: 6.3%) was synthesized.

[0247] LCMS m / z (ESI) = 450.5 [M+1].

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (d, 1H), 8.91 (d, 1H), 8.30 (s, 1H), 7.95 (d, 1H), 7.75 (dd, 1H), 7.67 (t, 2H), 7.60 (d, 1H), 4.47 (s, 1H), 3.77 (tdd, 2H), 3.62 (q, 1H), 3.53 (t, 1H), 3.28 - 3.18 (m, 1H), 3.12 - 2.63 (m, 3H), 2.17 - 1.91 (m, 4H), 1.78 (dt, 2H), 1.67 - 1.44 (m, 2H).

[0249] 19 F NMR (377 MHz, DMSO-d6) δ -135.85.

[0250] Example 10

[0251] (S)-3-((1-(3-Fluorobenzo[b]thiophene-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol (Compound 10)

[0252] (S)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0253] First step:

[0254] (S)-1-chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)pyrido[3,4-d]pyridazin-4-amine

[0255] (S)-1-chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)pyrido[3,4-d]pyridazin-4-amine

[0256] In a 100 mL single neck flask, compound 1a (600 mg, 3 mmol) was dissolved in dimethyl sulfoxide (10 mL), N,N-diisopropylethylamine (774 mg, 6 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (412.6 mg, 3.15 mmol) were added to the reaction system under ice water bath, after addition, the reaction system was warmed to 50 °C for 5 h. After the reaction was monitored by LCMS, it was extracted with ethyl acetate (50 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 10b (P2 peak, t = 2.132 min), light yellow white solid (144 mg, yield: 16.3%). LCMS m / z (ESI) = 295.2 [M+1].

[0257] Second step:

[0258] (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-amine

[0259] (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-amine

[0260] In a 100 mL single neck flask, 10b (140 mg, 0.476 mmol), cesium carbonate (388 mg, 1.19 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (132 mg, 0.476 mmol) and DPPF palladium dichloride (35 mg, 0.0476 mmol) were dissolved in 1,4-dioxane: water = 6 mL: 1 mL, under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. LCMS showed that the reaction was complete, the reaction was added with appropriate amount of water, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, the crude product was purified by silica gel column (PE: EA = 2:3) to give 10c (118 mg, yield: 60.5%). LCMS m / z (ESI) = 411.1 [M+1].

[0261] Third step:

[0262] (S)-3-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol (Compound 10)

[0263] (S)-3-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0264] In a 100 mL single neck flask, 10c (118 mg, 0.287 mmol) was dissolved in dichloromethane (5 mL), 3M aqueous hydrochloric acid (1 mL) was slowly added dropwise to the reaction system under ice water bath, after addition, the reaction system was elevated to room temperature for 1 h. After the reaction was monitored by LCMS, the solvent was removed under reduced pressure, and the crude product was purified by reverse phase column (water: acetonitrile = 1:1) to give the target product compound 10 (35 mg, yield: 33%).

[0265] LCMS m / z (ESI) = 371.2 [M+1].

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (d, 1H), 8.92 (d, 1H), 8.31 (d, 1H), 8.17 (t, 1H), 7.95 (dd, 1H), 7.76 (dd, 1H), 7.68 (dd, 1H), 7.61 (d, 1H), 5.11 (d, 1H), 4.79 (t, 1H), 3.92 (q, 1H), 3.81 (dt, 1H), 3.58 (dt, 1H), 3.45 (t, 2H).

[0267] 19 F NMR (377 MHz, DMSO-d6) δ -135.83.

[0268] Example 11

[0269] (1s,3s)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0270] (1s,3s)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0271] First step:

[0272] (1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0273] (1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0274] In a 100 mL single neck flask, compound 1a (1.00 g, 5.00 mmol) was dissolved in N-methyl pyrrolidone (15 mL), under ice water bath, N,N-diisopropyl ethylamine (1.61 g, 12.5 mmol) and cis-3-amino-1-methylcyclobutanol hydrochloride (1.03 g, 7.5 mmol) were added into the reaction system, after addition, the reaction system was warmed to 100 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 11b, yellow white solid (300 mg, yield: 21%). LCMS m / z (ESI) = 265.6 [M+1].

[0275] Second step:

[0276] (1s,3s)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0277] (1s,3s)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0278] In a 100 mL round bottom flask, 11b (80 mg, 0.31 mmol, mixture), cesium carbonate (244.37 mg, 0.75 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (126.35 mg, 0.45 mmol) and DPPF palladium dichloride (21.93 mg, 0.03 mmol) were dissolved in 1,4-dioxane (8 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 11 was purified by silica gel column chromatography and obtained as a white solid (30 mg, yield: 26%).

[0279] LC-MS m / z (ESI) = 381.2 [M+1].

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.91 (d, 1H), 8.30 (s, 1H), 8.16 (d, 1H), 7.95 (d, 1H), 7.75 (dd, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 5.08 (s, 1H), 4.38 - 4.22 (m, 1H), 2.53 (dt, 2H), 2.21 (td, 2H), 1.35 (s, 3H).

[0281] 19 F NMR (377 MHz, DMSO-d6) δ -135.84.

[0282] Example 12

[0283] ((1s,3s)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclobutyl)methanol

[0284] ((1s,3s)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclobutyl)methanol

[0285] First step:

[0286] ((1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutyl)methanol

[0287] ((1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutyl)methanol

[0288] In a 100 mL single neck flask, compound 1a (760.56 mg, 3.81 mmol) was dissolved in N-methyl pyrrolidine (15 mL), under ice water bath, N,N-diisopropyl ethylamine (1.23 g, 12.5 mmol) and (cis-3-aminocyclobutyl)methanol (500 mg, 7.5 mmol) were added into the reaction system, after addition, the reaction system was warmed to 100 °C for 6 h. After the reaction was completed by LCMS monitoring, it was extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 12b, yellow white solid (220 mg, yield: 21%). LCMS m / z (ESI) = 265.6 [M+1].

[0289] Second step:

[0290] ((1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutyl)methanol

[0291] ((1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutyl)methanol

[0292] In a 100 mL round bottom flask, 12b (80 mg, 0.31 mmol), cesium carbonate (244.37 mg, 0.75 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101.09 mg, 0.37 mmol) and DPPF palladium dichloride (21.93 mg, 0.03 mmol) were dissolved in 1,4-dioxane (8 mL), under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. After the reaction was completed by LCMS monitoring, 1,4-dioxane was removed under reduced pressure, and compound 12 was purified by silica gel column chromatography to obtain a white solid (30 mg, yield: 26%).

[0293] LC-MS m / z (ESI) = 381.3 [M+1].

[0294] 1 H NMR (400 MHz, DMSO-d6) δ 9.83 - 9.81 (m, 1H), 8.89 (d, 1H), 8.29 (d, 1H), 8.11 (d, 1H), 7.93 (d, 1H), 7.74 (dd, 1H), 7.65 (dd, 1H), 7.60 (d, 1H), 4.69 - 4.61 (m, 1H), 4.58 (q, 1H), 3.45 (t, 2H), 2.50 - 2.42 (m, 2H), 2.20 (dddd, 1H), 1.90 (qd, 2H).

[0295] 19 F NMR (377 MHz, DMSO-d6) δ -135.82.

[0296] Example 13

[0297] (3S,4R)-4-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol

[0298] (3S,4R)-4-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol

[0299] First step:

[0300] (3S,4R)-4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol

[0301] (3S,4R)-4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol

[0302] In a 100 mL single necked flask, compound 1a (745 mg, 3.73 mmol) was dissolved in N-methyl pyrrolidine (10 mL), under ice water bath, N,N-diisopropyl ethylamine (1.21 g, 9.33 mmol) and (3S,4R)-4-aminotetrahydrofuranol (500 mg, 4.85 mmol) were added into the reaction system, after addition, the reaction system was warmed to 100 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, collected the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 13b, yellow white solid (300 mg, yield: 30%). LCMS m / z (ESI) = 267.6 [M+1].

[0303] Second step:

[0304] (3S,4R)-4-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol (Compound 13)

[0305] (3S,4R)-4-((1-(3-Fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol

[0306] In a 100 mL round bottom flask, 13b (80 mg, 0.31 mmol), cesium carbonate (244.37 mg, 0.75 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.36 mmol) and DPPF palladium dichloride (21.93 mg, 0.03 mmol) were dissolved in 1,4-dioxane (8 mL), under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. After the reaction was monitored to be completed by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 13 was purified by silica gel column chromatography to obtain a yellow white solid (40 mg, yield: 33%).

[0307] LC-MS m / z (ESI) = 383.2 [M+1].

[0308] 1H NMR (400 MHz, DMSO-d6) δ 9.91 - 9.87 (m, 1H), 8.94 (d, 1H), 8.33 (d, 1H), 8.00 (d, 1H), 7.96 (d, 1H), 7.77 (dd, 1H), 7.70 (dd, 1H), 7.62 (d, 1H), 5.43 (d, 1H), 4.61 (tt, 1H), 4.45 (tt, 1H), 4.20 (dd, 1H), 4.03 (dd, 1H), 3.86 (dd, 1H), 3.63 (dd, 1H).

[0309] 19 F NMR (377 MHz, DMSO-d6) δ -135.83.

[0310] Example 14

[0311] 1 -(3-fluorobenzo[ b]thiophen-6-yl)-N-(( 1 R,2S)-2-methoxycyclobutyl)pyrido [3,4- d]pyridazin-4-amine

[0312] 1 -(3-fluorobenzo[ b]thiophen-6-yl)-N-(( 1 R,2S)-2-methoxycyclobutyl)pyrido [3,4- d]pyridazin-4-amine

[0313] First step:

[0314] 1 -(3-fluorobenzo[ b]thiophen-6-yl)-N-(( 1 R,2S)-2-methoxycyclobutyl)pyrido [3,4- d]pyridazin-4-amine

[0315] 1 -(3-fluorobenzo[ b]thiophen-6-yl)-N-(( 1 R,2S)-2-methoxycyclobutyl)pyrido [3,4- d]pyridazin-4-amine

[0316] In a 100 mL single necked flask, compound 1a (868 mg, 3.93 mmol) was dissolved in N-methyl pyrrolidine (10 mL), under ice water bath, N,N-diisopropyl ethylamine (3.2 g, 9.83 mmol) and (1R,2R)-2-methoxycyclobutane hydrochloride (700 mg, 5.11 mmol) were added into the reaction system, after addition, the reaction system was warmed to 100 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 14b, yellow white solid (300 mg, yield: 29%). LCMS m / z (ESI) = 265.2 [M+1].

[0317] Second step:

[0318] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((1R,2R)-2-methoxycyclobutyl)pyrido[3,4- d]pyridazin-4-amine (Compound 14)

[0319] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((1R,2R)-2-methoxycyclobutyl)pyrido[3,4- d]pyridazin-4-amine (Compound 14)

[0320] In a 100 mL round bottom flask, 14b (80 mg, 0.31 mmol), cesium carbonate (252.51 mg, 0.78 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (101.09 mg, 0.37 mmol) and DPPF palladium dichloride (22.67 mg, 0.03 mmol) were dissolved in 1,4-dioxane (8 mL), under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. After the reaction was monitored to be completed by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 14 was purified by silica gel column chromatography to obtain a yellow white solid (30 mg, yield: 25%).

[0321] LC-MS m / z (ESI) = 381.2 [M+1].

[0322] 1H NMR (400 MHz, DMSO-d6) δ 9.83 (d, 1H), 8.93 (d, 1H), 8.31 (d, 1H), 8.28 (d, 1H), 7.96 (dd, 1H), 7.76 (dd, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 4.77 (p, 1H), 4.07 (q, 1H), 3.66 - 3.53 (m, 1H), 3.26 (s, 3H), 2.23 (d, 1H), 2.13 (d, 1H), 1.64 - 1.51 (m, 2H).

[0323] 19 F NMR (377 MHz, DMSO-d6) δ -135.84.

[0324] Example 15

[0325] (1R,3S)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-2,2-dimethylcyclobutan-1-ol

[0326] (1R,3S)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-2,2-dimethylcyclobutan-1-ol

[0327] First step:

[0328] (1R,3S)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-2,2-dimethylcyclobutan-1-ol

[0329] (1R,3S)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-2,2-dimethylcyclobutan-1-ol

[0330] In a 100 mL single necked flask, compound 1a (364.24 mg, 1.37 mmol) was dissolved in N-methyl pyrrolidine (10 mL), under ice water bath, N,N-diisopropyl ethylamine (441.83 mg, 3.43 mmol) and trans-3-amino-2,2-dimethyl-cyclobutanol hydrochloride (250 mg, 1.66 mmol) were added into the reaction system, after addition, the reaction system was warmed to 100 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, collected the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was separated by SFC to obtain 15b, yellow white solid (80 mg, yield: 21%). LCMS m / z (ESI) = 279.1 [M+1].

[0331] Second step:

[0332] (1R,3S)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-2,2-dimethylcyclobutan-1-ol

[0333] (1R,3S)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-2,2-dimethylcyclobutan-1-ol

[0334] In a 100 mL round bottom flask, 15b (80 mg, 0.29 mmol), cesium carbonate (233.78 mg, 0.72 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101.09 mg, 0.37 mmol) and DPPF palladium dichloride (22.67 mg, 0.03 mmol) were dissolved in 1,4-dioxane (8 mL), under nitrogen protection, the reaction was refluxed at 100 °C for 8 h. After the reaction was monitored to be completed by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 15 was purified by silica gel column chromatography to obtain a yellow white solid (25 mg, yield: 22%).

[0335] LC-MS m / z (ESI) = 395.2 [M+1].

[0336] 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.97 (d, 1H), 8.34 (d, 1H), 7.97 (d, 1H), 7.77 (dd, 1H), 7.72 (d, 1H), 7.63 (d, 1H), 4.18 (dt, 1H), 3.68 (t, 1H), 2.62 - 2.53 (m, 1H), 2.22 (q, 1H), 2.00 (q, 1H), 1.28 (s, 3H), 0.93 (s, 3H).

[0337] 19 F NMR (377 MHz, DMSO-d6) δ -135.83.

[0338] Example 16

[0339] (3S,4R)-4-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0340] (3S,4R)-4-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0341] First step:

[0342] 6-bromo-2,3-difluorobenzo[b]thiophene

[0343] 6-bromo-2,3-difluorobenzo[b]thiophene

[0344] In a 500 mL three-necked flask, compound 16a (6-bromobenzothiophene, 10 g, 46.95 mmol) was dissolved in tetrahydrofuran (120 mL), after pre-cooling for 10 min at -78 °C, diisopropylaminolithium (28.17 mL, 56.34 mmol) was slowly dropped into the reaction solution, after 1 h, N-fluorobenzenesulfonimide (17.75 g, 56.34 mmol) was added to the reaction system, after addition, the reaction system was slowly warmed to room temperature for 2 h. After monitoring the end of the reaction by LCMS, it was extracted with ethyl acetate (150 x 3 mL) and saturated ammonium chloride, the organic phase was collected, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the target product compound 16b was obtained by silica gel column chromatography, white solid (1.1 g, yield: 15%). LCMS m / z (ESI) = 248.9 [M+1].

[0345] Second Step:

[0346] 2-(2,3-difluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0347] 2-(2,3-difluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0348] In a 100 mL round bottom flask, compound 16b (1.1 g, 4.44 mmol), cesium carbonate (3.6 g, 11.1 mmol), bis(pinacolato)diboron (1.68 g, 6.66 mmol) and DPPF palladium dichloride (324.57 mg, 0.45 mmol) were dissolved in 1,4-dioxane (30 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 16c was purified by silica gel column chromatography to obtain a white solid (800 mg, yield: 78%).

[0349] LC-MS m / z (ESI) = 296.1 [M+1].

[0350] Third Step:

[0351] (3S,4R)-4-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0352] (3S,4R)-4-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0353] In a 100 mL round bottom flask, compound 16c (126.84 mg, 0.43 mmol), cesium carbonate (293.24 mg, 0.9 mmol), compound 5b (100 mg, 0.36 mmol) and DPPF palladium dichloride (26.32 mg, 0.04 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 16 was purified by silica gel column chromatography to obtain a white solid (40 mg, yield: 27%).

[0354] LC-MS m / z (ESI) = 415.1 [M+1].

[0355] 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.93 (d, 1H), 8.32 (d, 1H), 7.94 (d, 1H), 7.86 (d, 1H), 7.80 (dd, 1H), 7.68 (dd, 1H), 5.19 (d, 1H), 4.55 - 4.36 (m, 1H), 3.91 (td, 2H), 3.74 (tt, 1H), 3.52 - 3.39 (m, 1H), 3.14 (t, 1H), 2.16 (dd, 1H), 1.64 (qd, 1H).

[0356] 19 F NMR (377 MHz, DMSO-d6) δ -147.79, -154.51.

[0357] Example 17

[0358] (1s,3s)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0359] (1s,3s)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0360] First step:

[0361] (1s,3s)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0362] (1s,3s)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0363] In a 100 mL round bottom flask, 16c (134.25 mg, 0.45 mmol), cesium carbonate (309.53 mg, 0.95 mmol), 11b (100 mg, 0.38 mmol) and DPPF palladium dichloride (27.78 mg, 0.04 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 17 was purified by silica gel column chromatography and obtained as a white solid (40 mg, yield: 26%).

[0364] LC-MS m / z (ESI) = 399.1 [M+1].

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 9.84 (d, 1H), 8.92 (d, 1H), 8.32 (d, 1H), 8.17 (d, 1H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.67 (dd, 1H), 5.06 (s, 1H), 4.30 (h, 1H), 2.21 (dd, 2H), 1.35 (s, 3H).

[0366] 19 F NMR (377 MHz, DMSO-d6) δ -147.81, -154.52.

[0367] Example 18

[0368] (S)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0369] (S)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0370] First step:

[0371] (S)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0372] (S)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0373] In a 100 mL round bottom flask, 16c (120 mg, 0.41 mmol), cesium carbonate (276.95 mg, 0.85 mmol), 10b (98.94 mg, 0.34 mmol) and DPPF palladium dichloride (24.85 mg, 0.03 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the reaction was completed. The 1,4-dioxane was removed under reduced pressure and the compound 18a was purified by silica gel column chromatography as a yellow solid (30 mg, yield: 17%).

[0374] LC-MS m / z (ESI) = 428.2 [M+1].

[0375] Second step:

[0376] (S)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol (Compound 18)

[0377] (S)-3-((1-(2,3-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)propane-1,2-diol

[0378] In a 100 mL single neck flask, compound 18a (70 mg, 0.16 mmol) was dissolved in tetrahydrofuran (5 mL) and 3M aqueous hydrochloric acid (1 mL) was slowly added dropwise to the reaction system under an ice water bath. After the addition was completed, the reaction system was allowed to react at room temperature for 1 h. After the reaction was completed, the solvent was removed under reduced pressure and the crude product was purified by reverse phase column (water: acetonitrile = 1:1) to obtain the target product compound 18 (30 mg, yield: 48%).

[0379] LCMS m / z (ESI) = 389.2 [M+1].

[0380] 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.02 (d, 1H), 8.36 (s, 1H), 8.16 (dt, 2H), 8.00 (d, 1H), 7.94 (d, 1H), 7.78 (dd, 1H), 3.96 (t, 1H), 3.85 - 3.69 (m, 2H), 3.63 - 3.51 (m, 3H).

[0381] 19 F NMR (377 MHz, DMSO-d6) δ -146.24, -154.37.

[0382] Example 19

[0383] (1s,3s)-3-((1-(3-fluoro-1H-indol-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0384] (1s,3s)-3-((1-(3-fluoro-1H-indol-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0385] First Step:

[0386] 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0387] 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0388] In a 250 mL round bottom flask, compound 19a (6-bromo-3-fluoro-1H-indole, 4 g, 18.69 mmol), cesium carbonate (15.22 g, 46.73 mmol), bis(pinacolato)diboron (7.1 g, 28.03 mmol) and DPPF palladium dichloride (1.37 g, 1.87 mmol) were dissolved in 1,4-dioxane (70 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 19b was purified by silica gel column chromatography and obtained as a white solid (2 g, yield: 40%).

[0389] LC-MS m / z (ESI) = 262.2 [M+1].

[0390] Second Step:

[0391] (1s,3s)-3-((1-(3-fluoro-1H-indol-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol

[0392] (1s,3s)-3-((1-(3-fluoro-1H-indol-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol

[0393] In a 250 mL round bottom flask, 19b (118.64 mg, 0.46 mmol), cesium carbonate (309.53 mg, 0.95 mmol), 11b (100 mg, 0.38 mmol) and DPPF palladium dichloride (27.78 mg, 0.04 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 19 was obtained as a light yellow solid (30 mg, yield: 28%) after purification by silica gel column chromatography.

[0394] LC-MS m / z (ESI) = 364.2 [M+1].

[0395] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (d, 1H), 9.82 (s, 1H), 8.90 (d, 1H), 8.10 (d, 1H), 7.69 (d, 1H), 7.68 - 7.61 (m, 2H), 7.45 (t, 1H), 7.31 (dd, 1H), 5.12 (s, 1H), 4.29 (q, 1H), 2.20 (td, 2H), 1.34 (s, 3H).

[0396] 19 F NMR (377 MHz, DMSO-d6) δ -176.15.

[0397] Example 20

[0398] (1s,3s)-3-((1-(3-fluoro-1H-indol-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol

[0399] (1s,3s)-3-((1-(3-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0400] First step:

[0401] 6-bromo-3-chlorobenzo[b]thiophene

[0402] 6-bromo-3-chlorobenzo[b]thiophene

[0403] In a 100 mL round bottom flask, compound 20a (6-bromo-3-chloro-benzo[b]thiophene-2-carboxylic acid, 1 g, 3.43 mmol), cuprous iodide (326.63 mg, 1.72 mmol), triethylamine (173.72 mg, 1.72 mmol) were dissolved in dimethyl sulfoxide (20 mL) and reacted at 120 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and ended. The organic phase was collected by extraction with ethyl acetate and water, and purified by silica gel column chromatography to obtain compound 20b as a white solid (600 mg, yield: 71%).

[0404] LC-MS m / z (ESI) = 246.9 [M+1].

[0405] Second step:

[0406] 2-(3-chlorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0407] 2-(3-chlorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0408] In a 250 mL round bottom flask, 20b (600 mg, 2.44 mmol), cesium carbonate (1.99 g, 6.1 mmol), bis(pinacolato)diboron (929.27 mg, 3.66 mmol) and DPPF palladium dichloride (178.6 mg, 0.24 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 100 °C under reflux for 8 h under nitrogen protection. The reaction was monitored by LCMS and ended. The 1,4-dioxane was removed under reduced pressure and the compound 20c was purified by silica gel column chromatography to obtain a white solid (400 mg, yield: 56%).

[0409] LC-MS m / z (ESI) = 295.2 [M+1].

[0410] Third Step:

[0411] ((1s,3s)-3-((1-(3-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol (Compound 20)

[0412] (1s,3s)-3-((1-(3-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0413] In a 250 mL round bottom flask, 20c (150 mg, 0.51 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 11b (103.61 mg, 0.39 mmol) and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 20 was purified by silica gel column chromatography as a light yellow solid (40 mg, yield: 28%).

[0414] LC-MS m / z (ESI) = 397.5 [M+1].

[0415] 1 H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.91 (d, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 8.04 (s, 1H), 7.97 (d, 1H), 7.81 (dd, 1H), 7.68 (d, 1H), 5.11 (s, 1H), 4.30 (q, 1H), 2.67 (dd, 1H), 2.21 (dd, 2H), 1.35 (s, 3H).

[0416] Example 21

[0417] (3R,4R)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol

[0418] (3R,4R)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol

[0419] First step:

[0420] (3R,4R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol

[0421] (3R,4R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol

[0422] In a 250 mL single necked flask, compound 1a (400 mg, 2.00 mmol) was dissolved in DMSO (15 mL), under ice water bath, N,N-diisopropyl ethylamine (516 mg, 4.00 mmol) and (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (250 mg, 2.10 mmol) were added into the reaction system, after addition, the reaction system was warmed to 50 °C for 5 h. After the reaction was monitored to be completed by LCMS, it was extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (DCM:MeOH = 95:5) to obtain the target product 21b (250 mg, yield: 44.6%). LCMS m / z (ESI) = 281.1 [M+1].

[0423] Second step:

[0424] (3R,4R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol

[0425] (3R,4R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol

[0426] In a 100 mL round bottom flask, 21b (125 mg, 0.47 mmol), cesium carbonate (363 mg, 1.12 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (125 mg, 0.47 mmol) and DPPF palladium dichloride (32.6 mg, 0.047 mmol) were dissolved in 1,4-dioxane (8 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. Compound 21 was obtained as a white solid (10 mg, yield: 5.6%) by SFC resolution.

[0427] LC-MS m / z (ESI) = 397.1 [M+1].

[0428] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (d, 1H), 8.93 (d, 1H), 8.32 (d, 1H), 7.97 (d, 1H), 7.79 - 7.71 (m, 2H), 7.69 (dd, 1H), 7.62 (d, 1H), 5.11 (d, 1H), 4.42 - 4.30 (m, 1H), 4.10 (m, 1H), 3.89 (m, 2H), 3.45 (m, 1H), 3.17 (m, 1H), 2.05 - 1.94 (m, 2H).

[0429] 19 F NMR (377 MHz, DMSO-d6) δ -135.84.

[0430] Example 22

[0431] (3S,4R)-4-((1-(2-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0432] (3S,4R)-4-((1-(2-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0433] First step:

[0434] (3S,4R)-4-((1-chloropyrido[3,4-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-3-ol (Compound 22b)

[0435] (3S,4R)-4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0436] In a 250 mL single neck flask, compound 1a (200 mg, 1.00 mmol) was dissolved in DMSO (15 mL), N,N-diisopropylethylamine (258 mg, 2.00 mmol) and (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (125 mg, 1.05 mmol) were added to the reaction under ice water bath, after addition, the reaction was warmed to 50 °C for 5 h. LCMS monitored the reaction was completed, extracted with ethyl acetate (150 x 3 mL) and water, collected the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude product, purified by column chromatography (DCM:MeOH = 95:5) to get the target product 22b (120 mg, yield: 44%). LCMS m / z (ESI) = 281.1 [M+1].

[0437] Second step:

[0438] (3S,4R)-4-((1-(2-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol (Compound 22)

[0439] (3S,4R)-4-((1-(2-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0440] In a 100 mL round bottom flask, 22b (125 mg, 0.47 mmol), cesium carbonate (363 mg, 1.12 mmol), 2-(2-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (125 mg, 0.47 mmol) and DPPF palladium dichloride (32.6 mg, 0.047 mmol) were dissolved in 1,4-dioxane (15 mL) under nitrogen protection, refluxed at 100 °C for 8 h. LCMS monitored the reaction was completed, removed 1,4-dioxane under reduced pressure, compound 22 was obtained by SFC resolution, white solid (20 mg, yield: 11.2%).

[0441] LC-MS m / z (ESI) = 397.1 [M+1].

[0442] 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.92 (d, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.73 - 7.63 (m, 2H), 7.22 (d, 1H), 5.20 (s, 1H), 4.51 - 4.36 (m, 1H), 3.90 (m, 2H), 3.74 (m, 1H), 3.14 (t, 1H), 2.20 - 2.12 (m, 1H), 1.63 (m, 1H).

[0443] 19 F NMR (377 MHz, DMSO-d6) δ -124.46.

[0444] Example 23

[0445] (3S,4R)-4-((1-(2-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0446] (3S,4R)-4-((1-(2-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0447] First step:

[0448] (3S,4R)-4-((1-(2-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0449] (3S,4R)-4-((1-(2-chlorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0450] In a 50 mL round bottom flask, 22b (78.5 mg, 0.28 mmol), cesium carbonate (208 mg, 0.64 mmol), 2-(2-chlorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 0.26 mmol) and DPPF palladium dichloride (18.6 mg, 0.026 mmol) were dissolved in 1,4-dioxane (15 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. Compound 23 was obtained by SFC separation as a white solid (18 mg, yield: 15.6%).

[0451] LC-MS m / z (ESI) = 413.1 [M+1].

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.92 (d, 1H), 8.29 - 8.22 (m, 1H), 7.95 (d, 1H), 7.84 (d, 1H), 7.72 - 7.67 (m, 2H), 7.65 (s, 1H), 5.21 (d, 1H), 4.43 (s, 1H), 3.91 (m, 2H), 3.74 (m, 1H), 3.51 - 3.39 (m, 1H), 3.14 (t, 1H), 2.22 - 2.12 (m, 1H), 1.71 - 1.57 (m, 1H).

[0453] Example 24

[0454] (1S,3S)-3-((1-(benzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol (Compound 24)

[0455] (1s,3s)-3-((1-(benzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0456] First step:

[0457] (1S,3S)-3-((1-(benzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol (Compound 24)

[0458] (1s,3s)-3-((1-(benzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0459] In a 50 mL round bottom flask, 11b (101.5 mg, 0.38 mmol), cesium carbonate (310 mg, 0.95 mmol), 2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.38 mmol) and DPPF palladium dichloride (28 mg, 0.038 mmol) were dissolved in 1,4-dioxane (15 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. Compound 24 was obtained by SFC separation as a white solid (62 mg, yield: 45.1%).

[0460] LC-MS m / z (ESI) = 363.1 [M+1].

[0461] 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.89 (d, 1H), 8.21 - 8.07 (m, 3H), 7.87 (d, 1H), 7.68 (d, 1H), 7.63 (dd, 1H), 7.57 (d, 1H), 5.08 (s, 1H), 4.30 (q, 1H), 2.53 (d, H), 2.21 (m, 2H), 1.35 (s, 3H).

[0462] Example 25

[0463] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 25)

[0464] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine

[0465] First step:

[0466] 1-Chloro-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 25b)

[0467] 1-chloro-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine

[0468] In a 100 mL round-bottom flask, 1a (400 mg, 2 mmol) was dissolved in DMSO (4 mL), N,N-diisopropylethylamine (516 mg, 4.00 mmol), (3S,4R)-3-methoxytetrahydro-2H-pyran-4-amine (275 mg, 2.1 mmol) were added slowly, and the reaction was carried out at 50 °C for 8 h. The reaction was monitored by LCMS, and when the reaction was completed, the reaction liquid was added with an appropriate amount of water, extracted with EA 5 times until the aqueous phase was free of product, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 5:1) to obtain 25b, a yellow solid (240 mg, yield: 42%).

[0469] LC-MS m / z (ESI) = 295.1 [M+1].

[0470] 1 H NMR (400 MHz, DMSO-d6) δ 9.88 - 9.65 (m, 1H), 9.08 (d, 1H), 7.97 (d, 1H), 7.88 (dd, 1H), 4.52 - 4.36 (m, 1H), 4.13 (dd, 1H), 3.87 (dt, 1H), 3.47 (dtd, 2H), 3.35 (s, 3H), 3.14 (dd, 1H), 2.11 (ddt, 1H), 1.61 (dtd, 1H). Second step:

[0471] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 25)

[0472] 1-(3-Fluorobenzo[b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine (Compound 25)

[0473] In a 100 mL round bottom flask, 25b (80 mg, 0.27 mmol), cesium carbonate (220 mg, 0.68 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (91 mg, 0.33 mmol) and DPPF palladium dichloride (20 mg, 0.03 mmol) were dissolved in 1,4-dioxane: water = 5 mL: 0.5 mL, under nitrogen protection, 100 °C reflux reaction for 8 h. LCMS monitored the end of the reaction, 1,4-dioxane was removed under reduced pressure, and compound 25 was obtained as a light yellow solid (11 mg, yield: 9.9%) after reverse phase column purification.

[0474] LCMS m / z (ESI) = 411.2 [M+1].

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (d, 1H), 8.94 (d, 1H), 8.32 (d, 1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.77 (dd, 1H), 7.70 (dd, 1H), 7.62 (d, 1H), 4.62 (d, 1H), 4.16 (dd, 1H), 3.90 (d, 1H), 3.55 (td, 1H), 3.20 - 3.13 (m, 1H), 2.17 (dd, 1H), 1.98 (d, 1H), 1.71 - 1.61 (m, 1H), 1.24 (d, 3H).

[0476] 19 F NMR (377 MHz, DMSO-d6) δ -135.85.

[0477] Example 26

[0478] 1-(2,3-difluorobenzo[b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine

[0479] 1-(2,3-difluorobenzo[b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine

[0480] First step:

[0481] 1 -(2,3-difluorobenzo[ b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4- yl)pyrido[3,4-d]pyridazin-4-amine

[0482] 1 -(2,3-difluorobenzo[ b]thiophen-6-yl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4- yl)pyrido[3,4-d]pyridazin-4-amine

[0483] In a 100 mL round bottom flask, 25b (80 mg, 0.27 mmol), cesium carbonate (220 mg, 0.68 mmol), (2,3-difluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91 mg, 0.33 mmol) and DPPF palladium dichloride (20 mg, 0.03 mmol) were dissolved in 1,4-dioxane: water = 5 mL: 0.5 mL, under nitrogen protection, refluxed at 100 °C for 8 h. LCMS monitored the end of the reaction, 1,4-dioxane was removed under reduced pressure, after purification by reverse phase column, compound 26 was obtained as a light yellow solid (8.5 mg, yield: 7.4%).

[0484] LCMS m / z (ESI) = 428.1 [M+1].

[0485] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1 H), 8.92 (d, 1 H), 8.03 (d, 1 H), 7.85 (d, 1 H), 7.78 (d, 1 H), 7.70 (dd, 1 H), 7.43 (dd, 1 H), 5.76 (s, 1 H), 5.32 (t, 1 H), 4.61 (s, 2 H), 4.16 (dd, 1 H), 3.90 (d, 1 H), 2.17 (d, 1 H), 2.01 - 1.97 (m, 1 H), 1.23 (s, 3 H).

[0486] 19 F NMR (377 MHz, DMSO-d6) δ -119.86, -119.87, -134.21, -134.23.

[0487] (1 R,2R)-2-((1 -(3-fluorobenzo[ b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1 -ol (Compound 27)

[0488] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0489] First step:

[0490] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0491] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0492] In a 100 mL round-bottom flask, 1a (400 mg, 2 mmol) was dissolved in DMSO (4 mL), N,N-diisopropyl ethylamine (516 mg, 4 mmol), (1R,2R)-2-aminocyclopentan-1-ol (212 mg, 2.1 mmol) were added slowly, and the reaction was carried out at 50 °C for 5 h. The reaction was monitored by LCMS, and when the reaction was completed, the reaction solution was added with an appropriate amount of water, extracted with EA 5 times, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) and then sent for chiral resolution to obtain 27b (P2), yellow solid (300 mg, yield: 57%).

[0493] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (d, 1H), 9.05 (d, 1H), 7.85 (dd, 2H), 4.96 (d, 1H), 4.34 - 4.26 (m, 1H), 4.18 - 4.08 (m, 1H), 2.20 (dtd, 1H), 1.93 (ddt, 1H), 1.80 - 1.64 (m, 2H), 1.63 - 1.44 (m, 2H).

[0494] LC-MS m / z (ESI) = 265.1 [M+1].

[0495] Second step:

[0496] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0497] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0498] In a 100 mL round bottom flask, 27b (80 mg, 0.30 mmol), cesium carbonate (244 mg, 0.75 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (83 mg, 0.30 mmol) and DPPF palladium dichloride (22 mg, 0.03 mmol) were dissolved in 1,4-dioxane: water = 3 mL: 0.3 mL, under nitrogen protection, 100 °C reflux reaction for 8 h. LCMS monitored the end of the reaction, 1,4-dioxane was removed under reduced pressure, and compound 27 was obtained as a light yellow solid (30 mg, yield: 26.3%) after purification by reverse phase column.

[0499] LCMS m / z (ESI) = 381.1 [M+1].

[0500] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (d, 1H), 8.93 (d, 1H), 8.32 (d, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.77 (dd, 1H), 7.69 (dd, 1H), 7.62 (d, 1H), 5.15 (d, 1H), 4.41 (p, 1H), 4.19 (p, 1H), 3.94 (s, 1H), 2.25 (dq, 1H), 2.01 - 1.94 (m, 1H), 1.79 - 1.72 (m, 2H), 1.57 (ddd, 1H).

[0501] 19 F NMR (377 MHz, DMSO-d6) δ -135.85.

[0502] Example 28

[0503] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0504] (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclobutan-1-ol (1R,2R)-2-((1-(3-fluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0505] First Step:

[0506] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutan-1-ol

[0507] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutan-1-ol

[0508] In a 100 mL round-bottom flask, 1a (400 mg, 2 mmol) was dissolved in DMSO (4 mL), N,N-diisopropyl ethylamine (516 mg, 4 mmol), (1R,2R)-2-aminocyclobutan-1-ol (258 mg, 2.1 mmol) were added slowly, and the reaction was carried out at 50 °C for 7 h. LCMS was used to monitor the end of the reaction. The reaction solution was added with an appropriate amount of water, and extracted with EA for 5 times. The crude product was purified by silica gel column chromatography (PE:EA = 3:1), and then sent for chiral resolution to obtain 28b (P2), yellow solid (300 mg, yield: 60%).

[0509] 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (d, 1H), 9.06 (d, 1H), 8.33 (d, 1H), 7.86 (dd, 1H), 5.37 (d, 1H), 4.48 (p, 1H), 4.17 (p, 1H), 2.19 - 2.01 (m, 2H), 1.55 (tt, 1H), 1.38 (tt, 1H).

[0510] LC-MS m / z (ESI) = 251.1 [M+1].

[0511] Second Step:

[0512] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutan-1-ol

[0513] (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclobutan-1-ol

[0514] In a 100 mL round-bottom flask, 28b (60 mg, 0.24 mmol), cesium carbonate (195 mg, 0.6 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (80 mg, 0.29 mmol) and DPPF palladium dichloride (18 mg, 0.02 mmol) were dissolved in 1,4-dioxane:water = 3 mL:0.3 mL, under nitrogen protection, 100 °C reflux reaction for 8 h. LCMS monitored the end of the reaction, 1,4-dioxane was removed under reduced pressure, and compound 28 was obtained after reverse phase column purification, white solid (30 mg, yield: 34.1%).

[0515] 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.93 (d, 1H), 8.41 - 8.18 (m, 2H), 7.96 (d, 1H), 7.76 (dd, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 5.44 (d, 1H), 4.60 (p, 1H), 4.20 (q, 1H), 2.23 - 2.05 (m, 2H), 1.64 - 1.38 (m, 2H).

[0516] 19 F NMR (377 MHz, DMSO-d6) δ -135.85.

[0517] LCMS m / z (ESI) = 367.1 [M+1].

[0518] Example 29

[0519] (1s,3s)-3-((1-(3,7-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0520] (1s,3s)-3-((1-(3,7-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0521] First step:

[0522] (1s,3s)-3-((1-(3,7-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0523] (1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0524] In a 100 mL round-bottom flask, 1a (400 mg, 2 mmol) was dissolved in DMSO (5 mL), N, N-diisopropyl ethylamine (516 mg, 4 mmol), (1S,3S)-3-amino-1-methylcyclobutan-1-ol (212 mg, 2.1 mmol) were added slowly, and the reaction was carried out at 50 °C for 7 h. The reaction was monitored by LCMS, and when the reaction was completed, the reaction solution was added with an appropriate amount of water, extracted with EA for 5 times, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain 29b, yellow solid (200 mg, yield: 37.8%).

[0525] LC-MS m / z (ESI) = 265.2 [M+1].

[0526] Second step:

[0527] (1s,3s)-3-((1-(3,7-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0528] (1s,3s)-3-((1-(3,7-difluorobenzo[b]thiophen-6-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0529] In a 100 mL round-bottom flask, 29b (60 mg, 0.23 mmol), cesium carbonate (187 mg, 0.58 mmol), 2-(3,7-difluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (80 mg, 0.27 mmol), and DPPF palladium dichloride (17 mg, 0.02 mmol) were dissolved in 1,4-dioxane: water = 3 mL: 0.3 mL, and the reaction was carried out at 100 °C under nitrogen protection for 8 h. The reaction was monitored by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 29 was obtained as a white solid (3 mg, yield: 3.2%) after purification by reverse phase column.

[0530] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.92 (d, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.69 (dd, 1H), 7.53 (s, 1H), 7.43 (q, 1H), 5.11 (s, 1H), 4.32 - 4.26 (m, 1H), 2.44 (s, 2H), 2.28 - 2.20 (m, 2H), 1.35 (s, 3H).

[0531] 19 F NMR (377 MHz, DMSO-d6) δ -134.18, -119.76.

[0532] LCMS m / z (ESI) = 399.1 [M+1].

[0533] Example 30

[0534] ((1s,3s)-3-((1-(3-Fluorobenzo[b]thiophen-6-yl)imidazo[1,5-d][1,2,4]triazin-4- yl)amino)-1-methylcyclobutan-1-ol (Compound 30)

[0535] (1r,3r)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)imidazo[1,5-d][1,2,4]triazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0536] First Step:

[0537] 6-(3-Fluorobenzo[b]thiophen-6-yl)-3-(methylthio)-1,2,4-triazine (Compound 30b)

[0538] 6-(3-Fluorobenzo[b]thiophen-6-yl)-3-(methylthio)-1,2,4-triazine

[0539] In a 100 mL round bottom flask, 30a (290 mg, 1.41 mmol), cesium carbonate (1.15 g, 3.53 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (470 mg, 1.69 mmol) and DPPF palladium dichloride (103.07 mg, 0.14 mmol) were dissolved in 1,4-dioxane (15 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give 30b as a yellow-white solid (270 mg, yield: 60%).

[0540] LCMS m / z (ESI) = 278.1 [M+1].

[0541] Second step:

[0542] 6-(3-Fluorobenzo[b]thiophen-6-yl)-3-(methylthio)-1,2,4-triazine (Compound 30c)

[0543] 1-(3-Fluorobenzo[b]thiophen-6-yl)-4-(methylthio)imidazo[1,5-d][1,2,4]triazine

[0544] In a 100 mL single-neck flask, compound 30b (270 mg, 0.97 mmol) was dissolved in 1,2-dichloroethane (10 mL) and p-toluenesulfonylmethyl isocyanide (228.36 mg, 1.17 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (176.93 mg, 1.17 mmol) were added to the reaction system under nitrogen protection. After addition, the reaction was carried out at room temperature for 6 h. After the reaction was completed by LCMS monitoring, the target crude product was obtained by concentration under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 30:1) to give compound 30c as a yellow-white solid (200 mg, yield: 70%).

[0545] LCMS m / z (ESI) = 317.2 [M+1].

[0546] Third step:

[0547] ((1r,3r)-3-((1-(3-Fluorobenzo[b]thiophen-6-yl)imidazo[1,5-d][1,2,4]triazin-4-yl)amino)-1- methylcyclobutan-1-ol (Compound 30)

[0548] (1r,3r)-3-((1-(3-fluorobenzo[b]thiophen-6-yl)imidazo[1,5-d][1,2,4]triazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0549] In a 100 mL single necked flask, compound 30c (100 mg, 0.32 mmol) was dissolved in N,N-dimethylacetamide (5 mL), N,N-diisopropylethylamine (412.8 mg, 3.2 mmol) and cis-3-amino-1-methylcyclobutan-1-ol hydrochloride (76.12 mg, 2.5 mmol) were added to the reaction system under ice water bath, after addition, the reaction system was warmed to 140 °C for 6 h. After the reaction was monitored to be completed by LCMS, extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was purified by silica gel column chromatography (DCM:MeOH = 30:1) to obtain compound 30, yellow white solid (40 mg, yield: 40%).

[0550] LCMS m / z (ESI) = 370.5 [M+1].

[0551] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 8.00 (s, 1H), 7.89 (d, 1H), 7.58 (d, 1H), 5.15 (s, 1H), 4.26 - 4.07 (m, 1H), 2.25 - 2.14 (m, 2H), 1.33 (s, 3H).

[0552] 19 F NMR (377 MHz, DMSO-d6) δ -135.88.

[0553] Implementation column 31

[0554] (3S,4R)-4-((1-(3-fluorobenzo[b]thiophen-6-yl)imidazo[1,5-d][1,2,4]triazin-4-yl)amino)tetrahydro-2H-pyran-3-ol (Compound 31)

[0555] (3S,4R)-4-((1-(3-fluorobenzo[b]thiophen-6-yl)imidazo[1,5-d][1,2,4]triazin-4-yl)amino)tetrahydro-2H-pyran-3-ol

[0556] First Step:

[0557] In a 100 mL single necked flask, compound 30c (100 mg, 0.32 mmol) was dissolved in N,N-dimethylacetamide (5 mL), under ice water bath, N,N-diisopropyl ethylamine (412.8 mg, 3.2 mmol) and (1S,3R)-3-aminocyclohexanol (76.12 mg, 2.5 mmol) were added into the reaction system, after addition, the reaction system was warmed to 140 °C for 6 h. After the reaction was completed by LCMS monitoring, extracted with ethyl acetate (150 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, which was purified by silica gel column chromatography (DCM:MeOH = 30:1) to obtain compound 31, yellow white solid (25 mg, yield: 21%).

[0558] LCMS m / z (ESI) = 386.6 [M+1].

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.61 (s, 1H), 8.10 (dd, 1H), 8.04 (s, 1H), 7.92 (t, 2H), 7.82 - 7.74 (m, 1H), 7.59 (d, 1H), 5.24 (d, 1H), 4.28 (dq, 1H), 3.91 (ddd, 3H), 3.69 (dq, 2H), 3.21 - 3.07 (m, 1H), 2.18 - 2.05 (m, 1H), 1.67 (qd, 1H).

[0560] 19 F NMR (377 MHz, DMSO-d6) δ -135.87.

[0561] Example 32

[0562] (3S,4R)-4-((4-(benzo[d]isothiazol-6-yl)phthalazin-1-yl)methyl)amino)tetrahydro-2H-pyran-3-ol (Compound 32)

[0563] (3S,4R)-4-(((4-(benzo[d]isothiazol-6-yl)phthalazin-1-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0564] First Step:

[0565] (3S,4R)-4-(((4-chlorophthalazin-1-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0566] (3S,4R)-4-(((4-chlorophthalazin-1-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0567] In a 100 mL round-bottom flask, 32a (2.00 g, 10 mmol) was dissolved in NMP (20 mL), N,N-diisopropylethylamine (2.58 g, 20 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (1.61 g, 10.5 mmol) were added slowly, and the reaction was carried out at 110 °C for 7 h. The reaction was monitored by LCMS, and when the reaction was completed, the reaction solution was added with an appropriate amount of water, extracted with EA for 5 times, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain 32b, yellow solid (1.2 g, yield: 40.9%).

[0568] LC-MS m / z (ESI) = 280.2 [M+1].

[0569] Second step:

[0570] (3S,4R)-4-(((4-chlorophthalazin-1-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0571] (3S,4R)-4-(((4-chlorophthalazin-1-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0572] In a 100 mL round-bottom flask, 32b (107 mg, 0.38 mmol), cesium carbonate (310 mg, 0.95 mmol), 6-(3,3,4,4-tetramethylcyclopentyl)benzo[d]isothiazole (100 mg, 0.38 mmol), and DPPF palladium dichloride (28 mg, 0.04 mmol) were dissolved in 1,4-dioxane:water = 4 mL:0.4 mL, and the reaction was carried out at 100 °C under nitrogen protection for 8 h. The reaction was monitored by LCMS, 1,4-dioxane was removed under reduced pressure, and compound 32 was obtained by reverse phase column purification, white solid (30 mg, yield: 20.1%).

[0573] LCMS m / z (ESI) = 379.1 [M+1].

[0574] 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.49 (d, 2H), 8.36 (d, 1H), 7.95 (t, 1H), 7.90 - 7.79 (m, 2H), 7.75 (d, 1H), 7.39 (d, 1H), 5.27 (s, 1H), 4.38 (d, 1H), 3.90 (td, 2H), 3.73 (s, 1H), 3.23 - 3.06 (m, 2H), 1.63 (d, 1H).

[0575] Example 33

[0576] (3S,4R)-4-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)tetrahydro-2H-pyran-3-ol

[0577] (3S,4R)-4-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)tetrahydro-2H-pyran-3-ol

[0578] First step:

[0579] (3S,4R)-4-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)tetrahydro-2H-pyran-3-ol

[0580] (3S,4R)-4-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)tetrahydro-2H-pyran-3-ol

[0581] In a 100 mL round-bottom flask, 32b (94 mg, 0.36 mmol), cesium carbonate (245 mg, 0.75 mmol), 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (800 mg, 0.38 mmol) and DPPF palladium dichloride (22 mg, 0.03 mmol) were dissolved in 1,4-dioxane: water = 4 mL: 0.4 mL, under nitrogen protection, 100 °C reflux reaction for 8 h. LCMS monitored the end of the reaction, 1,4-dioxane was removed under reduced pressure, and compound 33 was obtained after reverse phase column purification, white solid (10 mg, yield: 7.3%).

[0582] LCMS m / z (ESI) = 379.1 [M+1].

[0583] 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, 1H), 8.77 (d, 1H), 8.50 (d, 1H), 8.26 (d, 1H), 7.96 (ddd, 1H), 7.92 - 7.84 (m, 2H), 7.68 (d, 1H), 7.41 (d, 1H), 5.27 (s, 1H), 4.38 (dt, 1H), 3.91 (td, 2H), 3.74 (td, 1H), 3.48 - 3.41 (m, 1H), 3.14 (t, 1H), 2.23 - 2.13 (m, 1H), 1.64 (qd, 1H).

[0584] Example 34

[0585] (S)-3-((4-(3-Fluorobenzo[b]thiophen-6-yl)phthalazin-1-yl)amino)propane-1,2-diol (Compound 34)

[0586] (S)-3-((4-(3-Fluorobenzo[b]thiophen-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0587] First Step:

[0588] (S)-4-Chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)phthalazin-1-amine (34b)

[0589] (S)-4-Chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)phthalazin-1-amine

[0590] In a 100 mL single neck flask, compound 32a (300 mg, 1.5 mmol) was dissolved in dimethyl sulfoxide (10 mL), N,N-diisopropylethylamine (387 mg, 3 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (206 mg, 1.57 mmol) were added to the reaction mixture under ice water bath, after addition, the reaction mixture was warmed to 50 °C for 5 h. After the reaction was completed by LCMS monitoring, extracted with ethyl acetate (50 x 3 mL) and water, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the target crude product, purified by reverse phase to obtain 34b as a white solid (70 mg, yield: 16%). LCMS m / z (ESI) = 294.1 [M+1].

[0591] Second Step:

[0592] (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(3-fluorobenzo[b]thiophen-6-yl)phthalazin-1-amine

[0593] (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(3-fluorobenzo[b]thiophen-6-yl)phthalazin-1-amine

[0594] In a 100 mL single-necked flask, 34b (106 mg, 0.36 mmol), cesium carbonate (293 mg, 0.9 mmol), 2-(3-fluorobenzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.36 mmol) and DPPF palladium dichloride (26 mg, 0.036 mmol) were dissolved in 1,4-dioxane: water = 6 mL: 1 mL, and the reaction was refluxed at 100 °C under nitrogen protection for 8 h. LCMS showed that the reaction was complete, and the reaction was added with an appropriate amount of water, and extracted with ethyl acetate for 3 times, and the organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column (PE: EA = 2:3) to obtain 34c (100 mg, yield: 67.7%).

[0595] LCMS m / z (ESI) = 410.1 [M+1].

[0596] Third step:

[0597] (S)-3-((4-(3-fluorobenzo[b]thiophen-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0598] (S)-3-((4-(3-fluorobenzo[b]thiophen-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0599] In a 100 mL single-necked flask, 34c (50 mg, 0.122 mmol) was dissolved in dichloromethane (5 mL), and 3M aqueous hydrochloric acid (1 mL) was slowly added dropwise to the reaction system under an ice water bath. After the addition was completed, the reaction system was allowed to react at room temperature for 1 h. After the reaction was monitored by LCMS, the solvent was removed under reduced pressure, and the crude product was purified by a reverse phase column (water: acetonitrile = 1:1) to obtain the target product compound 34 (20 mg, yield: 44.3%).

[0600] LCMS m / z (ESI) = 370.2 [M+1].

[0601] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 8.28 (d, 1H), 7.94 (dd, 2H), 7.90 - 7.80 (m, 2H), 7.72 (dd, 2H), 7.61 (d, 1H), 5.31 (s, 1H), 4.87 (s, 1H), 3.88 (dt, 1H), 3.77 (dt, 1H), 3.57 (dt, 1H), 3.43 (d, 2H).

[0602] Example 35

[0603] (S)-3-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0604] (S)-3-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0605] First step:

[0606] (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-amine

[0607] (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-amine

[0608] In a 100 mL single neck flask, 34b (141 mg, 0.48 mmol), cesium carbonate (330 mg, 1.0 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (104 mg, 0.4 mmol) and DPPF palladium dichloride (30 mg, 0.04 mmol) were dissolved in 1,4-dioxane: water = 6 mL: 1 mL, under nitrogen protection, 100 °C reflux reaction for 8 h. LCMS showed that the reaction was complete, the reaction solution was added with appropriate amount of water, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, the crude product was purified by silica gel column to give 35c (35 mg, yield: 18.5%).

[0609] LCMS m / z (ESI) = 393.1 [M+1].

[0610] Second Step:

[0611] (S)-3-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0612] (S)-3-((4-(thieno[3,2-b]pyridin-6-yl)phthalazin-1-yl)amino)propane-1,2-diol

[0613] In a 100 mL single necked flask, compound 35c (35 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), 3M aqueous hydrochloric acid (1 mL) was added slowly dropwise into the reaction system under ice water bath, after addition, the reaction system was elevated to room temperature for 1 h. After the reaction was monitored by LCMS, the solvent was removed under reduced pressure, and the crude product was purified by reverse phase column (water: acetonitrile = 1:1) to obtain the target product compound 35 (13 mg, yield: 41.3%).

[0614] LCMS m / z (ESI) = 353.1 [M+1].

[0615] 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (d, 1H), 9.23 (d, 1H), 9.13 (s, 1H), 9.04 (s, 1H), 8.54 (d, 1H), 8.15 (t, 2H), 8.01 (d, 1H), 7.82 (d, 1H), 4.05 - 3.72 (m, 4H), 3.51 (d, 2H).

[0616] Example 36

[0617] (1s,3s)-3-((1-(benzo[c]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0618] (1s,3s)-3-((1-(benzo[c]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0619] First Step:

[0620] 2-(benzo[c]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0621] 2-(benzo[c]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0622] In a 250 mL round bottom flask, 36a (500 mg, 2.35 mmol), cesium carbonate (1.92 g, 5.88 mmol), bis(pinacolato)diboron (890.47 mg, 3.52 mmol) and DPPF palladium dichloride (171.79 mg, 0.24 mmol) were dissolved in 1,4-dioxane (20 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 36b was purified by silica gel column chromatography as a white solid (300 mg, yield: 70%).

[0623] LC-MS m / z (ESI) = 261.2 [M+1].

[0624] Second Step:

[0625] (1s,3s)-3-((1-(benzo[c]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0626] (1s,3s)-3-((1-(benzo[c]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0627] In a 250 mL round bottom flask, 36b (128 mg, 0.51 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 11b (100 mg, 0.38 mmol) and DPPF palladium dichloride (27.78 mg, 0.04 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. The compound 36 was purified by silica gel column chromatography as a light yellow solid (20 mg, yield: 28%).

[0628] LC-MS m / z (ESI) = 363.2 [M+1].

[0629] 1HNMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.89 (d, 1H), 8.21 - 8.06 (m, 3H), 7.86 (d, 1H), 7.72 - 7.51 (m, 3H), 5.08 (s, 1H), 4.38 - 4.23 (m, 1H), 2.22 (t, 2H), 1.35 (s, 3H).

[0630] Example 37

[0631] (1s,3s)-3-((1-(2-fluorobenzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0632] (1s,3s)-3-((1-(2-fluorobenzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0633] First step:

[0634] 5-bromo-2-fluorobenzo[b]thiophene

[0635] 5-bromo-2-fluorobenzo[b]thiophene

[0636] In a 500 mL three-necked flask, compound 37a (5-bromobenzothiophene, 2 g, 9.39 mmol) was dissolved in tetrahydrofuran (60 mL), after pre-cooling for 10 min at -78 °C, diisopropylaminolithium (10.33 mL, 20.66 mmol) was slowly dropped into the reaction solution, after 1 h, N-fluorobenzenesulfonimide (4.5 g, 14.07 mmol) was added to the reaction system, after addition, the reaction system was slowly warmed to room temperature for 2 h. After the reaction was completed by LCMS monitoring, it was extracted with ethyl acetate (150 x 3 mL) and saturated ammonium chloride, the organic phase was collected, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the target product compound 37b was obtained by silica gel column chromatography, white solid (160 mg, yield: 15%). LCMS m / z (ESI) = 230.9 [M+1].

[0637] Second step:

[0638] 2-(2-fluorobenzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37c)

[0639] 2-(2-fluorobenzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0640] In a 100 mL round bottom flask, compound 37b (160 mg, 0.69 mmol), cesium carbonate (562.04 mg, 1.73 mmol), bis(pinacolato)diboron (228.63 mg, 0.9 mmol) and DPPF palladium dichloride (50.44 mg, 0.7 mmol) were dissolved in 1,4-dioxane (10 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. Compound 16c was obtained as a white solid (800 mg, yield: 78%) after purification by silica gel column chromatography.

[0641] LC-MS m / z (ESI) = 152.1 [M+1].

[0642] Third step:

[0643] (1s,3s)-3-((1-(2-fluorobenzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol (Compound 37)

[0644] (1s,3s)-3-((1-(2-fluorobenzo[b]thiophen-5-yl)pyrido[3,4-d]pyridazin-4-yl)amino)-1- methylcyclobutan-1-ol (Compound 37)

[0645] In a 100 mL round bottom flask, compound 37c (100 mg, 0.36 mmol), potassium acetate (88.2 mg, 0.9 mmol), compound 11b (94.96 mg, 0.36 mmol) and Pd(triphenylphosphine)4 (41.6 mg, 0.04 mmol) were dissolved in 1,4-dioxane (12 mL) and the reaction was refluxed at 100 °C for 8 h under nitrogen protection. The reaction was monitored by LCMS and the 1,4-dioxane was removed under reduced pressure. Compound 37 was obtained as a white solid (30 mg, yield: 27%) after purification by silica gel column chromatography.

[0646] LC-MS m / z (ESI) = 381.2 [M+1].

[0647] 1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.90(d,1H),8.12(d,1H),8.08(d,1H),7.99(s,1H),7.66 (d,1H),7.61(dd,1H),7.21(d,1H),5.08(s,1H),4.37–4.22(m,1H),2.21(td,2H),1.34(s,3H).

[0648] 19 F NMR(377MHz,DMSO-d6)δ-124.97.

[0649] Biological test cases

[0650] 1. THP-1 cell culture

[0651] Human mononuclear cell line THP-1 ( TIB-202TM was cultured in RPMI-1640 medium containing 10% FBS, 1mM pyruvate, 0.05mM β-mercaptoethanol and 1% antibiotics at 37°C and 5% CO2.

[0652] 2. Detection of pyroptosis in THP-1 cells

[0653] Cell counting was performed, and 50,000 THP-1 cells were seeded per well in 96-well plates. Induction was initiated at 37°C with 5% CO2 for 48 hours using 20 nM PMA. The medium was discarded, and 100 μL of serum-free RPMI-1640 medium containing 1 μg / mL LPS was added. 5 μL of the compound or solvent control was added, starting with the highest dose of 10 μM and serially diluted 3-fold to establish 10 different concentrations. Incubation was continued at 37°C with 5% CO2 for 3 hours. After incubation, the cells were centrifuged at 300g for 5 minutes, the medium was discarded, and pyroptosis analysis was performed. 1. Follow the detailed instructions for the Inflammasome Assay Kit. Calculate the IC50 using GraphPad Prism 7.0 software. The results are shown in Table 1.

[0654] Table 1. Results of pyroptosis assay for compound THP-1

[0655] Note: A≤30nM, 30nM<B≤300nM, 300nM<C≤1000nM, D>1uM.

[0656] The results showed that the compound of the present invention can effectively inhibit pyroptosis in the human mononuclear cell line THP-1.

[0657] 3. IL-1β Release Analysis in Human PBMCs

[0658] Take 5 mL of human venous whole blood from a healthy donor and place it in a Li-heparin tube. Isolate PBMCs and incubate with 10 ng / mL LPS in culture medium at 37℃ with 5% CO2 concentration for 3 hours. Plate cells in a 96-well plate at 50 μL per well. Add 25 μL of compound or solvent control to each well, starting from the highest dose of 10 μM, with a 3-fold gradient dilution, a total of 8 gradient concentrations, and incubate for 0.5 hours. Add 25 μL of ATP with a final concentration of 5 mM to each well and incubate for 1 hour. After incubation, centrifuge at 1500 rpm for 20 minutes, collect the supernatant, and detect the expression of IL-1β by ELISA (BD, Human IL-1β ELISA Set II, Cat# 557953). Calculate IC 50 .

[0659] The results show that the compound of the present application can significantly down-regulate the release of IL-1β.

[0660] 4. Human PBMC TNFα release analysis

[0661] Take 5 mL of human venous whole blood from a healthy donor and place it in a Li-heparin tube. Isolate PBMCs and plate cells in a 96-well plate at 50 μL per well. Add 25 μL of compound or solvent control to each well, starting from the highest dose of 10 μM, with a 5-fold gradient dilution, a total of 9 gradient concentrations, and incubate at 37℃ with 5% CO2 concentration for 24 hours. Add 25 μL of LPS with a final concentration of 100 ng / mL to each well. Add 25 μL of ATP with a final concentration of 5 mM to each well and incubate for 1.5 hours. After incubation, centrifuge at 1500 rpm for 20 minutes, collect the supernatant, and detect the expression of TNFα by ELISA (BD, Human TNFα ELISA Set II, Cat# 555212). Calculate IC 50 .

[0662] The results show that the compound of the present application has no down-regulation effect on the expression of TNFα produced by LPS-induced PBMCs.

[0663] The present application is described in detail in the specification of the specific embodiments, and those skilled in the art should recognize that the above embodiments are exemplary and cannot be understood as limiting the present application. For those skilled in the art, without departing from the principles of the present application, through several improvements and modifications of the present application, the technical solutions obtained by the improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A pyridazine ring derivative of general formula (A), or its tautomers, stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals: wherein: R w , R x , R y and R z are each independently selected from C, CH, S, N or NH; R a1 , R a2 are each independently selected from H, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl or C 1-6 haloalkyl; R a3 selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; C ring is 8-12 membered heteroaryl; L1is selected from a bond, -NR2-, -NR2-C 1-6 alkylene-; R2is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; W is selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 heterocycloalkyl, or C 3-8 cycloalkyl, said W being optionally further substituted by one or more R3; When R x When W is NH, W is a C4 cycloalkyl or a 4-membered heterocycloalkyl, and W is optionally further substituted with one or more R3s; R3is selected from halo, cyano, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, cyano, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, cyano, hydroxy, carboxy, C 2. The pyridazino ring derivative of claim 1, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein: R w is C, CH, N or NH; R x is C, CH, N, NH or S; R y is C, CH, S or N; R z is C, CH, S or N; R a1 , R a2 each independently is selected from H, halogen, hydroxyl, C 1-4 alkyl or C 1-4 haloalkyl; R a3 selected from H, halogen, cyano; C ring is selected from thienopyridazine, pyridopyridazine, imidazotriazine, or benzopyridazine; L1is selected from a bond, -NR2-, -NR2-C 1-4 alkylene-; R2is selected from H, C 1-4 alkyl or C 1-4 haloalkyl; W is selected from C 1-4 alkyl, C 6-8 aryl, C 5-6 heteroaryl, C 3-6 heterocycloalkyl or C 4-6 cycloalkyl, said W being optionally further substituted by one or more R3; When R x When W is NH, W is a C4 cycloalkyl group, and W is optionally further substituted with one or more R3 groups; R3is selected from halo, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, hydroxy, C 3. The pyridazino ring derivative of claim 1, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein: R w is C, CH, N or NH; R x is C, CH, N, NH or S; R y is C, CH, S or N; R z is C, CH, S or N; R a1 , R a2 are each independently selected from H or halogen; R a3 selected from H or halogen; C ring is selected from L1is selected from -NH-, -NH-C 1-3 alkylene-; W is selected from C 1-4 alkyl, phenyl, piperidinyl, cyclohexanyl, cyclopentanyl, cyclobutanyl, tetrahydrofuranyl, or tetrahydropyranyl, said W being optionally further substituted by one or more R3; When R x When W is NH, W is cyclobutane, and W may optionally be further substituted with one or more R3 molecules; R3is selected from the group consisting of hydroxy, C 1-4 alkyl, C 1-4 alkoxy, tetrahydrofuranyl, substituted with 1 or more substituents selected from the group consisting of hydroxy, C 1-4 alkyl, optionally further substituted with 1 or more substituents selected from the group consisting of hydroxy, C 4. The pyridazino ring derivative according to claim 1, or a tautomer, a stereoisomer, a solvate, a prodrug, a metabolite, a deuteride, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that, The pyridazino ring derivatives represented by General Formula (A) have a structure represented by General Formula (I): R a1 , R a2 are each independently selected from the group consisting of H, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl or C 1-6 haloalkyl; R a3 selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; C ring is selected from L1is selected from a bond, -NR2-, -NR2-C 1-6 alkylene-; R2is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; W is selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 heterocycloalkyl or C 3-8 cycloalkyl, said W being optionally further substituted by one or more R3; R3is selected from halo, cyano, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, cyano, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 heterocycloalkyl or C 3-10 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, cyano, hydroxy, carboxy, C 5. The pyridazino ring derivative of claim 4, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein: R a1 , R a2 are each independently selected from H or halogen; C ring is selected from L1is selected from -NH- or -NH-C 1-4 alkylene-; W is selected from C 1-4 alkyl, C 6-8 aryl, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl, said W is optionally further substituted by one or more R3; R3 is selected from hydroxyl group, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Heterocyclic alkyl substituents; the C 1-4 The alkyl group may optionally be further substituted with one or more hydroxyl groups.

6. The pyridazino ring derivative according to claim 1, or a tautomer, a stereoisomer, a solvate, a prodrug, a metabolite, a deuteride, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that, The pyridazino ring derivatives of the general formula (A) have the structure of the general formula (II): R a1 , R a2 are each independently selected from H or halogen; R a3 selected from H or halogen; C ring is selected from W is selected from C 1-4 alkyl, C 6-8 aryl, C 5-6 heteroaryl, C 3-6 heterocycloalkyl or C 4-6 cycloalkyl; said W is optionally further substituted with 1 or more R3; R3is selected from halo, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 heterocycloalkyl or C 3-6 cycloalkyl optionally further substituted by 1 or more substituents selected from halo, hydroxy, C 7. The pyridazino ring derivative of claim 1, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the following structures:

8. The pyridazino ring derivative according to any one of claims 1 to 3, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the following structures:

9. A pharmaceutical composition comprising: the compound of any one of claims 1-8, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof; one or more pharmaceutically acceptable carriers and / or excipients.

10. Use of the pharmaceutical composition of claim 9 or the compound of any one of claims 1-8, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof, in the manufacture of an NLRP3 inhibitor or in the manufacture of a medicament for treating a disease associated with NLRP3.

11. The use according to claim 10, the diseases treated by the NLRP3 inhibitor or the diseases associated with NLRP3 include: an inflammatory disease, an autoimmune disease, a cardiovascular system disease, a cancer, a renal system disease, a gastrointestinal tract disease, a respiratory system disease, an endocrine system disease, or a central nervous system disease.

12. The use according to claim 11, said disease comprising: cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.

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