Macrocyclic imidazo[1,2-b]pyridazine derivative, preparation method therefor, and use thereof

Abstract

Disclosed are a macrocyclic imidazo[1,2-b]pyridazine compound represented by formula (I) or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer, a tautomer thereof or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition of the derivative. The macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I or the pharmaceutical composition can be used as a TRK kinase inhibitor for treating or preventing diseases or symptoms mediated by TRK or TRK mutation.

Description

A macrocyclic imidazo[1,2-b]pyridazine derivative and its preparation method and use

[0001] This application claims the priority benefit of application number 202211090622.9 filed with the China Intellectual Property Office on September 7, 2022, entitled “A macrocyclic imidazo[1,2-b]pyridazine derivative, its preparation method and use”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present application belongs to the field of medicine, and specifically relates to a macrocyclic imidazo[1,2-b]pyridazine derivative and a pharmaceutically acceptable salt thereof, a preparation method thereof, and use thereof as a TRK kinase inhibitor, as well as a pharmaceutical composition containing the derivative. Background Art

[0003] Tropomyosin receptor kinase (TRK) proteins are a family of tyrosine receptor kinases consisting of three members, TRK A, TRK B, and TRK C, that are widely expressed in the nervous system and many non-neuronal tissue types. TRK A, TRK B, and TRK C are encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NRTK2, and NTRK3, respectively. These three isoforms share sequence and structural homology, consisting of extracellular, transmembrane, and intracellular domains, and differ in their ligand-specific and tissue-specific expression. TRK receptors are activated by high-affinity binding of the extracellular domain to their cognate ligands, leading to receptor dimerization and subsequent autophosphorylation of tyrosine residues in the intracellular domain. Since most early studies on TRK function focused on neurodevelopment, their cognate ligands are known as neurotrophins, namely nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4, also known as NT-5). During neuronal development, TRK proteins mediate neuronal survival and synaptic plasticity in the central and peripheral nervous systems. TRK receptors are physiologically activated through interaction with their primary neurotrophic factor ligands, which bind to the receptor's extracellular domain. The specificity of neurotrophin ligand binding is TRK receptor type-dependent. The subsequent interaction induces receptor homodimerization, phosphorylation of tyrosine residues on the cytoplasmic domain, and activation of downstream signaling pathways known to be involved in growth and development. TRKA mediates signaling through the MAPK and RAS / ERK pathways, promoting neuronal proliferation and differentiation. TRKB activates the RAS / ERK and PI3K signaling pathways, which are critical for neuronal survival. TRKC activates the PI3K / AKT pathway, thereby preventing apoptosis and increasing cell survival.

[0004] Fusions involving all three NTRK genes have been reported in multiple cancer types, arising from either intrachromosomal gene rearrangements or interchromosomal translocations. NTRK gene fusion events occur between NTRK1, 2, or 3 and various unrelated gene partners and represent major genomic alterations with oncogenic potential, compared to less common oncogenic mechanisms, which include in-frame deletions and alternative splice variants of NTRK1. Oncogenic rearrangements involving NTRK genes typically arise from the fusion of the 3′ region of an NTRK gene with the 5′ region of an unrelated gene. The resulting NTRK gene fusion retains the kinase domain of the TRK receptor, which is fused in frame with its partner to form a new oncoprotein. The oncogenic fusion protein is often a constitutively active or overexpressed kinase, and the resulting fusion oncoprotein is aberrantly expressed and activated, subsequently driving cancer cells and tumor development. For example, the frequency of NTRK1 and TPM3 fusion genes is approximately 0.04%, ranking first among various fusion genes, and is closely related to breast cancer, cervical cancer, bile duct cancer, colorectal cancer, glioma, infantile fibrosarcoma, lung cancer, soft tissue sarcoma, thyroid cancer, uterine sarcoma, etc. For another example, the frequency of NTRK3 and ETV6 fusion genes is approximately 0.09%, and is closely related to acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, colorectal cancer, congenital mesoblastic nephroma, gastrointestinal stromal tumor, glioma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, lung cancer, melanoma, neuroendocrine and secretory breast cancer, salivary gland secretory cancer, sinus adenocarcinoma, soft tissue sarcoma, spitzoid melanoma, and thyroid cancer.

[0005] NTRK gene fusions in human cancers: Following the discovery of therapeutically effective kinase inhibitors in this field, there has been renewed interest in NTRK gene fusions as oncogenes. Although NTRK gene fusions are rare (occurring in only approximately 1% of all malignancies), they have been identified in many different tumor types in both children and adults. In more common tumor types, such as lung cancer, sarcomas, thyroid cancer, and colorectal cancer, NTRK gene fusions occur at low frequencies. In contrast, the prevalence of NTRK gene fusions is high in several rare cancer types, including secretory breast cancer, breast-like secretory carcinoma, infantile fibrosarcoma, and congenital interstitial nephroblastoma. NTRK fusions are rare oncogenic drivers that occur in a range of pediatric cancers. These include infantile fibrosarcoma and secretory breast cancer, where such fusions are almost hallmarks, as well as a range of more common pediatric cancers, where NTRK fusions occur at lower frequencies. In the past few years, two TRK inhibitors, larotrectinib and entrectinib, have demonstrated histological activity against NTRK fusion-driven cancers and have received FDA approval.

[0006] Larotrectinib and entrectinib have demonstrated remarkable efficacy in patients with cancers harboring TRK fusions. However, as with most kinase inhibitors, acquired resistance mediated by mutations in the kinase domain has occurred. Acquired resistance mutations in TRKs, such as presolvant mutations, gatekeeper mutations, and DFG motif mutations, have been associated with a median duration of response of 8.3 months to larotrectinib and 10.5 months to entrectinib in the NTRK fusion subgroup, according to a pooled analysis of earlier trials. Subsequent targeted sequencing at the time of progression in patients with an initial response has shown that up to 90% of patients harbor secondary mutations in the kinase domain that are predicted to confer resistance. Most of the reported mutations involve amino acid substitutions in the solvent front (NTRK1p.G595R, NTRK2p.G639R, NTRK3p.G623R), gatekeeper residues (NTRK1p.F589L, NTRK3p.F617L), or activation loop X-aspartate-phenylalanine-glycine, "xDFG" motif (NTRK1p.G667C, NTRK2p.G709C, NTRK3p.G696A). The mutation sites are mainly TRKCG623R (homolog TRKAG595R) and TRKAG667C. Computational modeling and X-ray crystallography show that most of these mutations lead to steric conflicts between bulky side chains of participating amino acids (such as arginine) and the hydroxypyrrolidine or difluorophenyl groups of first-generation TRK inhibitors. Some of these mutations are also predicted to increase the ATP affinity of the kinase domain. Some of the identified mutations are homologous to recurrent pro-solvent and gatekeeper resistance mutations reported in ALK- and ROS1-rearranged cancers, which frequently arise and counteract the inhibitory effects of first-generation inhibitors.

[0007] In order to overcome acquired drug resistance, second-generation TRK inhibitors TPX-0005 and LOXO-195 targeting wild-type and mutant TRK fusions are currently in clinical development. TPX-0005 and LOXO-195 have been shown to be effective in preclinical animal models and patient clinical studies. A potential disadvantage of the TRK inhibitors TPX-0005 and LOXO-195 is their limited ability to penetrate the blood-brain barrier (BBB). For this reason, more research is needed to effectively target TRK fusion-related tumors in the brain. For example, some newly developed TRK small molecule inhibitors have been disclosed in Chinese patent applications CN102264736A, CN104520300A and other documents. Therefore, the development of new TRK inhibitors that can effectively overcome drug-resistant mutations can provide huge clinical benefits for patients.

[0008] Summary of the Invention

[0009] According to one aspect of the present invention, an object of the present invention is to provide a macrocyclic imidazo[1,2-b]pyridazine compound shown in Formula I or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

[0010] in:

[0011] W 1 、W 2 、W 3 、W 4 、W 5 are each independently selected from carbon or nitrogen, and W 1 、W 2 、W 3 、W 4 、W 5 At least one of them is nitrogen;

[0012] R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C6 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C6 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the carbon atoms to which they are attached, they form a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 to 4 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C3-C6 cycloalkoxy;

[0013] R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkoxy;

[0014] R 5is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, substituted or unsaturated C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkoxy, or R 5 does not exist;

[0015] L is selected from -O-, -NH-, substituted or unsubstituted branched or straight-chain C1-C6 alkylene, substituted or unsubstituted branched or straight-chain C1-C6 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyleneoxy, substituted or unsubstituted branched or straight-chain C1-C6 alkylenethio, substituted or unsubstituted saturated or unsaturated 3-6 membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered azacycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered thiacycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered thiacycloalkylene, substituted or unsubstituted saturated or unsaturated substituted or unsubstituted saturated or unsaturated 3 to 6 membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 3 to 6 membered azacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 3 to 6 membered thiacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxyl, carboxyl, carbonyl, sulfonyl, amino, C1~C4 alkyl, C1~C4 hydroxyalkyl, C3~C6 cycloalkyl, C1~C4 alkoxy, C3~C6 cycloalkyloxy, 4 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, and 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0016] Preferably, R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C4 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C4 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or R 2 and R 3Together with the carbon atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, and C3-C6 cycloalkoxy;

[0017] More preferably, R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the C atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C3 alkyl, C5-C6 cycloalkyl group.

[0018] More preferably, R 1 、R 2 、R 3 are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the C atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 or 2 atoms selected from deuterium, hydroxyl, and halogen.

[0019] Preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C4 alkyl, saturated or unsaturated C5-C6 cycloalkyl, saturated or unsaturated C1-C4 alkoxy, saturated or unsaturated C5-C6 cycloalkoxy.

[0020] More preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C1-C3 alkyl, saturated or unsaturated C1-C3 alkoxy.

[0021] More preferably, R 4 Selected from hydrogen, deuterium, halogen, saturated or unsaturated C1-C3 alkyl, saturated or unsaturated C1-C3 alkoxy.

[0022] More preferably, R 4 is selected from hydrogen, deuterium or halogen.

[0023] Preferably, R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C4 alkyl, saturated or unsaturated C5-C6 cycloalkyl, substituted or unsaturated C1-C4 alkoxy, saturated or unsaturated C5-C6 cycloalkoxy, or R 5 Does not exist.

[0024] More preferably, R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C3 alkyl, substituted or unsaturated C1-C3 alkoxy or R 5 Does not exist.

[0025] More preferably, R 5 is selected from hydrogen, deuterium, halogen, saturated or unsaturated C1-C3 alkyl, substituted or unsaturated C1-C3 alkoxy or R 5 Does not exist.

[0026] More preferably, R 5 Selected from hydrogen, deuterium, halogen, or R 5 Does not exist.

[0027] Preferably, L is selected from -O-, -NH-, substituted or unsubstituted branched or linear C1-C4 alkylene, substituted or unsubstituted branched or linear C1-C4 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C4-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C4-C6 cycloalkyleneoxy, substituted or unsubstituted branched or linear C1-C4 alkylenethio, substituted or unsubstituted saturated or unsaturated 4-6 membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 4-6 membered azacycloalkylene, Cycloalkyl, substituted or unsubstituted saturated or unsaturated 4 to 6-membered thiacycloalkylene, substituted or unsubstituted saturated or unsaturated 4 to 6-membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 4 to 6-membered azacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 4 to 6-membered thiacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium, halogen, cyano, hydroxyl, carbonyl, amino, C1~C4 alkyl, C1~C4 hydroxyalkyl, and C3~C6 cycloalkyl.

[0028] More preferably, L is selected from -O-, -NH-, substituted or unsubstituted branched or linear C1-C3 alkylene, substituted or unsubstituted branched or linear C1-C3 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium or halogen.

[0029] More preferably, L is selected from substituted or unsubstituted branched or straight-chain C1-C3 alkylene, substituted or unsubstituted branched or straight-chain C1-C3 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 or 2 substituents selected from deuterium or halogen.

[0030] More preferably, L is selected from -CH2O-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH(CH3)O-, -CH(CH3)CH2O-,

[0031] Preferably, the compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is represented by the following Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6:

[0032] Among them, the substituent W 5 、R 1 、R 2 、R 3 、R 4 、R 5 The definitions of L are the same as those in the above formula 1.

[0033] Preferably, the compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is represented by the following Formula I-1-1, Formula I-2-1, Formula I-3-1, Formula I-4-1, Formula I-5-1 or Formula I-6-1:

[0034] Among them, the substituent W 5 、R 1 、R 2 、R 3 、R 4 、R 5 The definition of is the same as that in the above formula 1;

[0035] L 1 and L 2 Various independently selected from chemical bonds, substituted or unsubstituted branched or linear C1-C3 alkylene, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O or N, wherein the "substituted" refers to optionally containing 1 or 2 substituents selected from deuterium or halogen, and L 1 and L 2 Not chemical bonds at the same time.

[0036] Preferably, L 1 and L 2 Each is independently selected from a chemical bond, a methylene group, an ethylene group, a propylene group, an isopropylene group, a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group, a halogenated methylene group, a halogenated ethylene group, a halogenated propylene group, a halogenated isopropylene group, a halogenated cyclopropylene group, a halogenated cyclobutylene group, a halogenated cyclopentylene group, a halogenated cyclohexylene group, an oxiranyl group, an oxacyclobutaneyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydropyrrolyl group, a hexahydropyridyl group, a halogenated oxiranyl group, a halogenated oxacyclobutaneyl group, a halogenated tetrahydrofuranyl group, a halogenated tetrahydropyranyl group, a halogenated tetrahydropyrrolyl group, a halogenated hexahydropyridyl group, and L 1 and L 2 Not chemical bonds at the same time.

[0037] Preferably, the compound represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-1-1, Formula I-2-1, Formula I-3-1, Formula I-4-1, Formula I-5-1 or Formula I-6-1, or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is selected from the following compounds:

[0038] According to the second aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by Formula I according to the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

[0039] According to the third aspect of the present invention, another object of the present invention is to provide a compound represented by formula I according to the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a drug as a TRK kinase inhibitor, wherein the drug is used to treat or prevent a disease or condition mediated by TRK or a TRK mutation in a subject in need thereof.

[0040] Preferably, the disease or condition mediated by TRK or TRK mutation is selected from one or more of cancer, neurodegenerative disease, inflammation, and pain.

[0041] More preferably, the disease or condition mediated by TRK or a TRK mutation is selected from surgical pain, inflammatory pain, neuropathic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, salivarius, bile duct cancer, stromal tumors, brain tumors and hematological malignancies.

[0042] According to the fourth aspect of the present invention, another object of the present invention is to provide a kit, which comprises a compound represented by formula I of the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention, as well as a container and instructions for use.

[0043] According to the fifth aspect of the present invention, another object of the present invention is to provide a method for treating diseases or conditions mediated by TRK or TRK mutations, the method comprising administering to a subject in need thereof an effective amount of a compound represented by formula I according to the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention. DETAILED DESCRIPTION

[0044] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended to limit the scope of the present invention. It should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0045] As used herein, the terms "comprise," "include," "have," "contain," or any similar terms are open-ended transitional phrases that are intended to encompass non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements not expressly listed but generally inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "comprise," "include," "have," and "contain" should be interpreted as specifically disclosing and encompassing closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of."

[0046] Throughout this document, all features or conditions defined as numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges, particularly integer values. For example, a description of a range "1 to 8" should be considered to specifically disclose all possible subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so forth, particularly those defined by all integer values, and should be considered to specifically disclose individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise indicated, the foregoing interpretation applies to all of the present disclosure, regardless of whether the ranges are comprehensive or not.

[0047] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0048] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0049] In this document, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," this fully describes the claim that X is X1 and the claim that X is X1 and / or X2. Furthermore, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," this fully describes the claim that X is X1, X2, or X3, and Y is Y1, Y2, or Y3.

[0050] Definitions of relevant terms in this article

[0051] “Alkyl” refers to a group of straight or branched saturated hydrocarbon radicals having 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-8 alkyl group (e.g., an unsubstituted C1 alkyl group, such as -CH3). In certain embodiments, the alkyl group is a substituted C1-8 alkyl group (e.g., a substituted C1 alkyl group, such as -CF3).

[0052] "Alkoxy" refers to a monovalent C-alkyl group, wherein the alkyl moiety has a specified number of carbon atoms. In the present disclosure, alkoxy groups typically contain 1 to 6 carbon atoms ("C1 to C6 alkoxy"), or 1 to 4 carbon atoms ("C1C4 alkoxy"). For example, C1C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise indicated, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy") with one or more substituents. In certain embodiments, alkoxy is an unsubstituted C1 to C6 alkoxy. In certain embodiments, alkoxy is a substituted C1 to C6 alkoxy.

[0053] "Cycloalkyl" refers to a group of non-aromatic cycloalkyl groups having 3 to 8 ring carbon atoms ("C3-8 cycloalkyl") and zero heteroatoms in a non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 8 ring carbon atoms ("C5-8 cycloalkyl"). Exemplary C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C3-8 cycloalkyl groups include, but are not limited to, the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), and the like. Unless otherwise specified, each instance of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C3-8 cycloalkyl group; in certain embodiments, a cycloalkyl group is a substituted C3-8 cycloalkyl group.

[0054] "Heterocycloalkyl" refers to a group of a 5 to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. A heterocyclic group may be a monocyclic ring ("monocyclic heterocyclic group") or a fused ring, bridged ring or spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclic radical"), and may be saturated or partially unsaturated. "Heterocyclic group" also includes a ring system in which a heterocycle as defined above is fused to one or more cycloalkyl groups (wherein the point of attachment is on the cycloalkyl group or the heterocycle), or a ring system in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocycle), and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise specified, each instance of a heterocycloalkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. In certain embodiments, heterocycloalkyl is an unsubstituted 5-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl is a substituted 5-14 membered heterocycloalkyl.

[0055] "Aryl" or "aromatic ring" or "aromatic ring group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C10 aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C14 aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups (wherein the point of attachment is on the aromatic ring), and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise indicated, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6-14 aryl group. In certain embodiments, an aryl group is a substituted C6-14 aryl group.

[0056] “Heteroaryl” is a 5-14 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0057] Structures such as "alkylene", "alkyleneoxy", "heterocycloalkylene", "arylene", "aromatic ring", "aromatic ring group", "heteroarylene" refer to parts of a molecule that simultaneously connect two or more other groups as intermediate linking groups. For example, an alkylene group refers to a connecting bond group formed by simultaneously connecting two or more other groups as in the above-defined alkyl group, and its structural formula can be represented by -CnH2n-, which is connected to at least two different other groups through at least two separate bonds. For example, in some embodiments, methylene represents -CH2-, in some embodiments, ethyleneoxy represents -CH2CH2-O-, and in some embodiments, phenylene represents

[0058] "Halogen" or "halo" refers to fluorine (F, -F), chlorine (Cl, -Cl), bromine (Br, -Br), or iodine (I, -I).

[0059] "Substituted" or "optionally substituted" refers to the atoms in the group, such as hydrogen atoms are replaced. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Typically, the term "substituted", whether or not there is the term "optionally" before, means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that forms a stable compound after replacement, such as a compound that does not spontaneously transform (e.g., by rearrangement, cyclization, elimination or other reactions). Unless otherwise indicated, a "substituted" group has a substituent on one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. It is contemplated that the term "substituted" includes replacing with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety. In certain embodiments, the substituents are carbon atom substituents. In certain embodiments, the substituents are nitrogen atom substituents. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituents are sulfur atom substituents.

[0060] "Unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. "Partially unsaturated" ring systems are also intended to encompass rings with multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Likewise, "saturated" refers to groups that do not contain double or triple bonds, i.e., contain all single bonds.

[0061] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0062] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by reacting a compound with a specific substituent discovered by the present invention with a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt (i.e., a pharmaceutically acceptable salt) can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts. The inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; the organic acid includes, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, Mandelic acid, malonic acid, propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, folinic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and the like; also including salts of amino acids (such as arginine, etc.) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into any base or acid addition salt. The parent form of the compound and its various salt forms differ in certain physical properties, such as solubility in polar solvents.

[0063] As used herein, the modifier term "about" refers to variations in values ​​that may occur, for example, through routine testing and processing; through inadvertent errors in such testing and processing; through differences in the manufacture, origin, or purity of the ingredients used in the present invention; and the like. As used herein, "about" a particular value also includes that particular value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalents of the recited quantities. In one embodiment, the term "about" refers to within 20% of the reported value.

[0064] As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith. As used herein, the term "treatment" and the like may include "prophylactic treatment," which refers to reducing the likelihood of re-development of a disease or condition or recurrence of a previously controlled disease or condition in a subject who is not or is at risk of developing or susceptible to a disease or condition or recurrence of a disease or condition. The term "treating" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0065] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0066] The macrocyclic triazole compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, and the pharmaceutical composition containing the compound provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and can be present in a suitable solid or liquid carrier or diluent and in a suitable sterile device for injection or infusion.

[0067] The various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. For example, the unit dose of the formulation contains 0.05-2000 mg of the macrocyclic triazole compound of Formula I or a pharmaceutically acceptable salt thereof. Preferably, the unit dose of the formulation contains 0.1 mg-1000 mg of the compound of Formula I.

[0068] The compounds and pharmaceutical compositions represented by Formula I of the present invention can be used clinically in mammals, including humans and animals, and can be administered via the mouth, nose, skin, lungs, or gastrointestinal tract. Oral administration is most preferred. The optimal daily dose is 0.01-200 mg / kg body weight, taken as a single dose, or 0.01-100 mg / kg body weight, taken in divided doses. Regardless of the method of administration, the optimal individual dose will depend on the specific treatment. Typically, a low dose is started and the dose is gradually increased until the most suitable dose is found.

[0069] As used herein, the term "effective amount" refers to an amount effective at the dosage and for the time period required to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or condition being treated, the anatomy of the specific target organ being administered, the patient's size, or the severity of the disease or symptoms. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation.

[0070] A typical formulation is prepared by mixing a compound represented by Formula I of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like.

[0071] The specific carrier, diluent or excipient used will depend on the mode of use and purpose of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings or other known additives to enable the drug to be manufactured or used in an acceptable form.

[0072] When the compound of formula I of the present invention is used in combination with at least one other drug, the two or more drugs can be used separately or in combination, preferably administered in the form of a pharmaceutical composition. The compound of formula (I) or pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other topical or systemic administration form.

[0073] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0074] The medicament of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders, or granular formulations. In a solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; solution retardants such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, lactose and high molecular weight polyethylene glycols as excipients.

[0075] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of the present invention or its pharmaceutical composition, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances.

[0076] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0077] In the case of suspensions, in addition to the compound represented by Formula I of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, a carrier such as a suspending agent may be further contained, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

[0078] The compound represented by Formula I of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition comprising the same can be administered in other topical dosage forms, including creams, powders, sprays and inhalants. The drug can be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any desired preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be encompassed within the scope of the present invention.

[0079] In addition, the present disclosure also encompasses kits (e.g., pharmaceutical packaging). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a medicine bottle, an ampoule, a bottle, a syringe and / or a subpackage or other suitable container). In some embodiments, the kit provided may optionally further comprise a second container comprising a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein, disposed in the first container and the second container, is combined to form a unit dosage form.

[0080] In certain embodiments, the kits described herein further include instructions for use of the compound or pharmaceutical composition contained in the kit. The kits described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kits and instructions for use provide for treating TRK mutation-mediated diseases in subjects in need thereof and / or preventing TRK mutation-mediated diseases in subjects in need thereof. The kits described herein may include one or more additional pharmaceutical formulations as separate compositions.

[0081] The present invention will be further described in detail below with reference to specific examples. However, the present invention is not limited to the following examples. The examples are intended to better illustrate certain specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way. Conditions not specified in the examples are conventional conditions. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0082] The compounds of Formula I herein can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of Formula I, which are well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of Formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0083] The present invention is further illustrated below with reference to examples; however, these examples are not intended to limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples were obtained from commercial sources; and the instruments and equipment used in the synthesis experiments and product analysis and testing were conventional instruments and equipment commonly used in organic synthesis.

[0084] In the following examples, the structures of the exemplary compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer in deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0085] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph. Thin-layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254. Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as a support. Unless otherwise specified, all reactions in this invention were performed under continuous magnetic stirring in a dry nitrogen or argon atmosphere. Solvents were dry, and reaction temperatures were reported in degrees Celsius.

[0086] In addition, the abbreviations used in the examples have the following meanings: NIS: N-iodosuccinimide; TMS: trimethylsilyl; PdCl2(PPh3)2: bis(triphenylphosphine)palladium dichloride; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; CuI: cuprous iodide; KF: potassium fluoride; CuSO4: copper sulfate; VCNa: sodium ascorbate; Pd(dba)2: bis(dibenzylideneacetone)palladium; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; RuPhos Pd G4: methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); DIAD: diisopropyl azodicarboxylate; TBSCl: tert-butyldimethylchlorosilane; Cs2CO3: cesium carbonate; Na2CO3: sodium carbonate; NaBH4: sodium borohydride; BBr3: boron tribromide; LAH: lithium aluminum hydride; NaOH: sodium hydroxide; BOC: tert-butyloxycarbonyl; EA: Ethyl acetate; PE: petroleum ether; MeOH: methanol; EtOH: ethanol; DIEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; Dioxane: 1,4-dioxane; DMF: N,N-dimethylformamide; NMP: N-methylpyrrolidone; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; TLC: thin layer chromatography; Structure: structural formula.

[0087] Example 1: (E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-1)

[0088] Step A: 2-Bromo-4-tert-butyldimethylsilyloxymethylpyridine (2)

[0089] 2-Bromo-4-pyridinemethanol (compound 1, 50 g, 265.93 mmol) and imidazole (23.53 g, 345.70 mmol) were placed in dichloromethane (750 mL), and tert-butyldimethylsilyl chloride (52.11 g, 345.70 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours, then quenched with water (1.5 L), and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-bromo-4-tert-butyldimethylsilyloxymethylpyridine (64.95 g, 81%).

[0090] LCMS: m / z (ESI), 302 [M+H] + .

[0091] Step B: 2-tributyltin-4-tert-butyldimethylsilyloxymethylpyridine (3)

[0092] 2-Bromo-4-tert-butyldimethylsilyloxymethylpyridine (compound 2, 30 g, 99.25 mmol) was placed in tetrahydrofuran (750 mL), and butyl lithium (2.5 M, 39.70 mmol) was added dropwise at -70 ° C. and stirred for half an hour. Tributyltin chloride (38.77 g, 119.09 mmol) was then added and stirred at -70 ° C. for 2 hours, then quenched with saturated ammonium chloride (1.5 L), and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-tributyltin-4-tert-butyldimethylsilyloxymethylpyridine (52 g).

[0093] LCMS: m / z (ESI), 514.3 [M+H] + .

[0094] Step C: 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (5)

[0095] 2-tributyltin-4-tert-butyldimethylsilyloxymethylpyridine (50 g, 97.57 mmol) was placed in toluene (500 mL), and 3-bromo-6-chloroimidazole [1, 2-b] pyridazine (compound 4, 22.68 g, 97.57 mmol) and Pd (PPh3) 4 (11.28 g, 9.76 mmol) were added in sequence. The mixture was stirred at 100 ° C for 16 hours, then diluted with water (1.5 L) and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 3- (4-tert-butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole [1, 2-b] pyridazine (1.94 g, 5.3%).

[0096] 1 H NMR: (400MHz, DMSO-d6) δ8.48(d,J=5.0Hz,1H),8.35(d,J=17.6Hz,2H),8.21(d,J=9.5Hz,1H),7.34(d,J=9.5Hz,1H),7.13(br d,J=4.9Hz,1H),4.71(s,2H),0.80(s,9H),0.00(s,6H).

[0097] Step D: 2-p-methoxybenzyloxy-5-fluoroacetophenone (7)

[0098] 2-Hydroxy-5-fluoroacetophenone (compound 6, 10 g, 64.88 mmol) was placed in acetonitrile (200 mL), and p-methoxybenzyl chloride (12.19 g, 77.85 mmol) and cesium carbonate (63.41 g, 194.63 mmol) were added in sequence. The mixture was stirred at 90°C for 12 hours, then diluted with water (300 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-p-methoxybenzyloxy-5-fluoroacetophenone (14.1 g, 79%).

[0099] 1 H NMR: (400MHz, CHLOROFORM-d)δ=7.43-7.34(m,1H),7.29-7.21(m,2H),7.10-7.00(m,1H),6.94-6.78(m,3H),4.97(s,2H),3.74(s,3H),2.48(s,3H).

[0100] Step E: 2-p-methoxybenzyloxy-5-fluoroacetophenone oxime (8)

[0101] p-Methoxybenzyloxy-5-fluoro-2-acetophenone (compound 7, 14.1 g, 51.41 mmol) was placed in ethanol (180 mL), and sodium acetate (12.65 g, 154.22 mmol) and hydroxylamine hydrochloride (4.29 g, 61.69 mmol) were added in sequence. The mixture was stirred at 70°C for 2 hours, then diluted with water (600 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-p-methoxybenzyloxy-5-fluoroacetophenone oxime (6.5 g, 44%).

[0102] 1 H NMR: (400MHz, DMSO-d6) δ = 11.15 (s, 1H), 7.37 (d, J = 8.5Hz, 2H), 7.21-7.13 (m, 2H), 7.03 (dd ,J=2.4,8.9Hz,1H),6.98-6.91(m,2H),5.04(s,2H),3.81-3.72(m,3H),2.08-2.02(m,3H).

[0103] Step F: 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (9)

[0104] 2-p-Methoxybenzyloxy-5-fluoroacetophenone oxime (compound 8, 6.50 g, 22.47 mmol) was placed in methanol (150 mL), and ammonium formate (14.7 g, 224.68 mmol) and zinc powder (14.69 g, 224.68 mmol) were added in sequence. The mixture was stirred at 40°C for 12 hours, and then filtered and the filtrate was concentrated. Column chromatography was performed to obtain 2-p-Methoxybenzyloxy-5-fluorophenyl-1-ethylamine (2.8 g, 48.8%).

[0105] LCMS: m / z (ESI), 276.0 [M+H] + .

[0106] 1 H NMR: (400MHz, DMSO-d6)δ=7.38(br d,J=8.6Hz,2H),7.28(dd,J=3.1,10.0Hz,1H),7.06-7.00(m,1H),6.99-6.93( m,3H),5.05-4.96(m,2H),4.29-4.21(m,1H),3.76(s,3H),1.21-1.17(m,3H).

[0107] Step G: 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (10)

[0108] 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 5, 100 mg, 0.267 mmol) was placed in toluene (5 mL), and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (73.43 mg, 0.27 mol), Pd(dba)2 (15.34 mg, 0.027 mol), sodium tert-butoxide (51.26 mg, 0.53 mol) and Xantphos (15.43 mg, 0.027 mol) were added in sequence. The mixture was stirred at 100° C. for 16 hours. After concentration, 3-(4-tert-butyldimethylsilyloxymethylpyridin-2-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (24 mg, 15%) was obtained by column chromatography.

[0109] LCMS: m / z (ESI), 614.5 [M+H] + .

[0110] 1 H NMR: (400MHz, DMSO-d6)δ=8.59-8.54(m,1H),8.30(s,1H),8.03(s,1H),7.82(d, J=9.8Hz,1H),7.30-7.28(m,2H),7.28-7.26(m,2H),7.25-7.24(m,1H),7.20(br d,J=3.3Hz,2H),6.89-6.80(m,1H),6.68(d,J=8.6Hz,2H),5.41-5.34(m,1H),5 .10-5.03(m,2H),3.65(s,3H),3.17(s,3H),0.86(s,9H),0.03(d,J=7.1Hz,6H).

[0111] Step H: 3-(4-Hydroxymethylpyridin-2-yl)-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (11)

[0112] 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 10, 24 mg, 0.039 mol) was placed in methanol (3 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25° C. for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (12 mg, 81%).

[0113] LCMS: m / z (ESI), 380 [M+H] + .

[0114] Step I: (E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-1)

[0115] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 11, 34.37 mg, 0.091 mol) was placed in a mixed solution of dichloromethane and DMF (6 mL), thionyl chloride (215.57 mg, 1.81 mol) was added, and the mixture was stirred at 25°C for 0.5 hours, followed by the addition of potassium carbonate (500.84 mg, 3.62 mol), and the mixture was neutralized to pH>7. The dichloromethane was evaporated and stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to obtain (E)-5 4 -fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (3.8 mg, 11.3%).

[0116] LCMS: m / z (ESI), 362 [M+H] + .

[0117] 1H NMR: (400MHz, DMSO-d6) δ = 9.69 (s, 1H), 8.51 (d, J = 5.0Hz, 1H), 8.00 (s, 1H), 7.98-7.90 (m, 1H), 7.87 (d, J = 9.8Hz, 1H), 7.24 (d, J = 5.0Hz, 1H), 7.10-7.03(m,2H),6.89(d,J=9.8Hz,1H),6.80(br dd,J=3.2,7.9Hz,1H),5.75(d,J=15.4Hz,1H),5.47(d,J=16.0Hz,1H),5.35(br d,J=6.0Hz,1H),1.47(d,J=6.8Hz,3H).

[0118] Example 2: (E)-5 4 ,5 6 -Difluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-2)

[0119] Step A: 2-p-methoxybenzyloxy-3,5-difluoroacetophenone (12)

[0120] 2-Hydroxy-3,5-difluoroacetophenone (10 g, 58.10 mmol) was placed in DMF (200 mL), and p-methoxybenzyl chloride (10.01 g, 63.91 mmol) and potassium carbonate (24.09 g, 174.29 mmol) were added in sequence. The mixture was stirred at 60 ° C for 12 hours, then diluted with water (300 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-p-methoxybenzyloxy-3,5-difluoroacetophenone (14.5 g, 85.4%).

[0121] 1 H NMR: (400MHz, CHLOROFORM-d) δ = 7.33 (br d, J = 8.3Hz, 2H), 7.15 (br d, J = 1.1Hz, 1H), 7.05 (br s, 1H), 6.92 (br d,J=8.4Hz,2H),5.08(s,2H),3.84(s,3H),2.54(s,3H).

[0122] Step B: 2-p-methoxybenzyloxy-3,5-difluoroacetophenone oxime (13)

[0123] p-Methoxybenzyloxy-3,5-difluoro-2-acetophenone (compound 12, 13.1 g, 44.82 mmol) was placed in ethanol (180 mL), and sodium acetate (11.03 g, 134.46 mmol) and hydroxylamine hydrochloride (3.74 g, 53.78 mmol) were added in sequence. The mixture was stirred at 70°C for 2 hours, then diluted with water (600 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-p-methoxybenzyloxy-3,5-difluoroacetophenone oxime (6.25 g, 45.4%).

[0124] 1 H NMR: (400MHz, DMSO-d6) δ = 11.59-11.21 (m, 1H), 7.42-7.34 (m, 1H), 7.30 (br d, J = 8.0Hz, 2H), 7.03-6.97 (m, 1H), 6.93 (br d,J=8.1Hz,2H),4.91(s,2H),3.76(s,3H),2.07(s,3H).

[0125] Step C: 2-p-methoxybenzyloxy-3,5-difluorophenyl-1-ethylamine (14)

[0126] 2-p-Methoxybenzyloxy-3,5-difluoroacetophenone oxime (compound 13, 6.20 g, 20.18 mmol) was placed in methanol (150 mL), and ammonium formate (12.72 g, 201.76 mmol) and zinc powder (13.19 g, 201.76 mmol) were added in sequence. The mixture was stirred at 40°C for 12 hours, and then filtered and the filtrate was concentrated. Column chromatography gave 2-p-Methoxybenzyloxy-3,5-difluorophenyl-1-ethylamine (2.6 g, 43.9%).

[0127] LCMS: m / z (ESI), 294.2 [M+H] + .

[0128] 1 H NMR: (400MHz, DMSO-d6)δ=7.35(d,J=8.6Hz,2H),7.21-7.10(m,2H),6.95(d,J= 8.6Hz,2H),4.93(s,2H),4.28-4.18(m,1H),3.76(s,3H),1.11(d,J=6.6Hz,3H).

[0129] Step D: 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (15)

[0130] 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 5, 100 mg, 0.267 mmol) was placed in toluene (5 mL), and 2-p-methoxybenzyloxy-3,5-difluorophenyl-1-ethylamine (Compound 14, 78.23 mg, 0.27 mol), Pd(dba)2 (15.34 mg, 0.027 mol), tert-butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 5, 100 mg, 0.267 mmol) was added in sequence. Sodium butoxide (51.26 mg, 0.53 mol) and Xantphos (15.43 mg, 0.027 mol) were stirred at 100 ° C for 16 hours, concentrated and separated by column chromatography to give 3-(4-tert-butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (44 mg, 26%).

[0131] LCMS: m / z (ESI), 632.2 [M+H] + .

[0132] 1 H NMR: (400MHz, DMSO-d6) δ = 8.53 (d, J = 4.8Hz, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.79 (d, J = 9.6Hz, 1H), 7.44 (br d, J = 7.0Hz, 1H), 7.31 (br d,J=8.4Hz,1H),7.22-7.16(m,4H),7.09(br d,J=9.3Hz,1H),6.95-6.88(m,1H),6.77(d,J=9.9Hz,1H),5.29(br d,J=7.1Hz,1H),4.97-4.84(m,2H),4.70-4.53(m,2H),3.59(s,3H),1.40(br d,J=6.8Hz,3H),0.84(s,9H),0.00(s,6H).

[0133] Step E: 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (16)

[0134] 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 15, 44 mg, 0.069 mol) was placed in methanol (3 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25° C. for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (36 mg).

[0135] LCMS: m / z (ESI), 398 [M+H] + .

[0136] Step F: (E)-5 4 ,5 6 -Difluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-2)

[0137] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 16, 36 mg, 0.091 mol) was placed in a mixed solution (6 mL) of dichloromethane and DMF, thionyl chloride (215.57 mg, 1.81 mol) was added, and the mixture was stirred at 25°C for 0.5 hours, followed by the addition of potassium carbonate (500.84 mg, 3.62 mol), and the mixture was neutralized to pH>7. The dichloromethane was evaporated and stirred at 90°C for 1.5 hours. The mixture was filtered and the filtrate was concentrated to obtain (E)-5 4 , 5 6 -difluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (4.2 mg, 11.2%).

[0138] LCMS: m / z (ESI), 380 [M+H] + .

[0139] 1H NMR: (400MHz, DMSO-d6) δ = 9.34 (s, 1H), 8.63 (d, J = 5.0Hz, 2H), 8.54 (s, 1H), 8.11 (d, J = 9.9Hz, 1H), 7.45 ( d,J=4.9Hz,1H),7.35(d,J=9.9Hz,1H),6.98-6.85(m,2H),5.78-5.72(m,1H),5.62-5.54(m,1H),5.29(br d,J=6.7Hz,1H),1.46(d,J=6.8Hz,3H).

[0140] Example 3: (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-3)

[0141] Step A: 2-p-methoxybenzyloxyacetophenone (17)

[0142] 2-Hydroxyacetophenone (10 g, 73.45 mmol) was placed in acetonitrile (200 mL), and p-methoxybenzyl chloride (13.80 g, 88.14 mmol) and potassium carbonate (30.45 g, 220.35 mmol) were added in sequence. The mixture was stirred at 60°C for 12 hours, then diluted with water (300 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to give 2-p-methoxybenzyloxyacetophenone (18 g, 95.6%).

[0143] 1 H NMR: (400MHz, DMSO-d6) δ = 7.58 (dd, J = 1.8, 7.7Hz, 1H), 7.55-7.50 (m, 1H), 7.44 (d, J = 8.6Hz, 2H), 7 .27(d,J=8.3Hz,1H),7.04-7.00(m,1H),6.99-6.94(m,2H),5.15(s,2H),3.76(s,3H),2.48(s,3H).

[0144] Step B: 2-p-methoxybenzyloxyacetophenone oxime (18)

[0145] 2-p-Methoxybenzyloxyacetophenone (compound 17, 18 g, 70.23 mmol) was placed in ethanol (180 mL), and sodium acetate (17.28 g, 210.69 mmol) and hydroxylamine hydrochloride (5.86 g, 84.28 mmol) were added sequentially. The mixture was stirred at 70°C for 2 hours, then diluted with water (600 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-p-Methoxybenzyloxyacetophenone oxime (10 g, 50.4%).

[0146] 1 H NMR: (400MHz, DMSO-d6) δ = 10.96 (s, 1H), 7.38-7.31 (m, 3H), 7.21 (dd, J = 1.6, 7.4Hz, 1 H),7.14(d,J=8.3Hz,1H),6.97-6.93(m,3H),5.05(s,2H),3.76(s,3H),2.03(s,3H).

[0147] Step C: 2-p-Methoxybenzyloxyphenyl-1-ethylamine (19)

[0148] 2-p-Methoxybenzyloxyacetophenone oxime (compound 18, 11.0 g, 40.54 mmol) was placed in methanol (150 mL), and ammonium formate (25.57 g, 405.44 mmol) and zinc powder (26.67 g, 407.94 mmol) were added in sequence. The mixture was stirred at 40°C for 12 hours, and then filtered and the filtrate was concentrated. Column chromatography gave 2-p-Methoxybenzyloxy-phenyl-1-ethylamine (7.8 g, 74%).

[0149] LCMS: m / z (ESI), 258.2 [M+H] + .

[0150] 1 H NMR: (400MHz, DMSO-d6)δ=7.48-7.34(m,3H),7.18-7.12(m,1H),7.03-6.88(m,4H),5.02(d, J=1.0Hz,2H),4.27(q,J=6.6Hz,1H),3.76(s,3H),1.80-1.59(m,2H),1.20(d,J=6.6Hz,3H).

[0151] Step D: 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (20)

[0152] 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 19, 1.9 g, 2.53 mmol) was placed in toluene (50 mL), and 2-p-methoxybenzyloxyphenyl-1-ethylamine (651.08 mg, 2.53 mmol), Pd(dba)2 (215.89 mg, 0.38 mmol), sodium tert-butoxide (487.00 mg, 5.07 mmol) and Xantphos (219.91 mg, 0.38 mmol) were added in sequence. The mixture was stirred at 100° C. for 16 hours. After concentration, 3-(4-tert-butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (400 mg, 26.5%) was obtained by column chromatography.

[0153] LCMS: m / z (ESI), 596.0 [M+H] + .

[0154] 1 H NMR: (400MHz, DMSO-d6) δ = 8.57 (d, J = 4.9Hz, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 9.6Hz, 1H), 7.42 (dd,J=1.3,7.4Hz,1H),7.32(d,J=7.3Hz,1H),7.27(d,J=8.6Hz,2H),7.24-7.20(m,2H),7.09(d,J=7.8H z,1H),6.93(t,J=7.4Hz,1H),6.84(d,J=9.6Hz,1H),6.67(d,J=8.6Hz,2H),5.41(t,J=7.0Hz,1H),5.13- 5.04(m,2H),4.72-4.55(m,2H),3.65(s,3H),1.55(d,J=6.8Hz,3H),0.87(s,9H),0.04(d,J=7.8Hz,6H).

[0155] Step E: 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (21)

[0156] 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 20, 300 mg, 0.53 mol) was placed in methanol (3 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25° C. for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (70 mg, 34%).

[0157] LCMS: m / z (ESI), 362 [M+H] + .

[0158] Step F: (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-3)

[0159] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 21, 25 mg, 0.066 mol) was placed in a mixed solution of dichloromethane and DMF (6 mL), and thionyl chloride (215.57 mg, 1.81 mol) was added. The mixture was stirred at 25°C for 0.5 hour, and then potassium carbonate (500.84 mg, 3.62 mol) was added. The mixture was neutralized to pH>7, and the dichloromethane was evaporated to remove the mixture. The mixture was stirred at 90°C for 1.5 hours and filtered. The filtrate was concentrated and then preparatively isolated to obtain (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (19.9 mg, 39.2%).

[0160] LCMS: m / z(ESI),344[M+H] + .

[0161] 1 H NMR: (400MHz, MeOD-d4) δ9.90(s,1H),8.59(d,J=5.3Hz,1H),8.34(s,1H),7.99(d,J=9.9Hz,1H),7.51(d,J =5.3Hz,1H),7.39-7.26(m,2H),6.99(d,J=3.4Hz,2H),6.79(td,J=4.1,8.0Hz,1H),5.82(d,J=15.9Hz,1H), 5.60-5.48(m,2H),1.58(d,J=6.9Hz,3H).

[0162] Example 4: (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-4)

[0163] Step A: 2-p-methoxybenzyloxy-3-acetylpyridine (22)

[0164] 2-Hydroxy-3-acetylpyridine (10 g, 72.99 mmol) was placed in acetonitrile (200 mL), and p-methoxybenzyl chloride (13.80 g, 88.14 mmol) and potassium carbonate (30.45 g, 220.35 mmol) were added in sequence. The mixture was stirred at 60°C for 12 hours, then diluted with water (300 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to give 2-p-methoxybenzyloxy-3-acetylpyridine (6 g, 32%).

[0165] LCMS: m / z (ESI), 258.2 [M+H] + .

[0166] Step B: 2-p-methoxybenzyloxypyridine-3-ethanone oxime (23)

[0167] 2-p-Methoxybenzyloxy-3-acetylpyridine (compound 22, 6 g, 23.26 mmol) was placed in ethanol (60 mL), and sodium acetate (5.76 g, 70.23 mmol) and hydroxylamine hydrochloride (1.96 g, 28.08 mmol) were added in sequence. The mixture was stirred at 70°C for 2 hours, then diluted with water (200 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-p-Methoxybenzyloxypyridine-3-ethanone oxime (3 g, 47.4%).

[0168] LCMS: m / z (ESI), 273.2 [M+H] + .

[0169] Step C: 1-(2-p-methoxybenzyloxypyridin-3-yl)-ethylamine (24)

[0170] 2-p-Methoxybenzyloxypyridine-3-ethanone oxime (compound 23, 3.0 g, 11.03 mmol) was placed in methanol (50 mL), and ammonium formate (25.57 g, 405.44 mmol) and zinc powder (26.67 g, 407.94 mmol) were added in sequence. The mixture was stirred at 40°C for 12 hours, and then filtered and the filtrate was concentrated. Column chromatography was performed to obtain 1-(2-p-Methoxybenzyloxypyridin-3-yl)-ethylamine (2.1 g, 74%).

[0171] LCMS: m / z (ESI), 259.2 [M+H] + .

[0172] Step D: 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-6-amine (25)

[0173] 3-(4-tert-butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 5, 1.9 g, 2.53 mmol) was placed in toluene (50 mL), and 1-(2-p-methoxybenzyloxypyridin-3-yl)-ethylamine (Compound 24, 651.08 mg, 2.53 mmol), Pd(dba)2 (215.89 mg, 0.38 mmol), tert-butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 5, 1.9 g, 2.53 mmol) were added in sequence. Sodium butoxide (487.00 mg, 5.07 mmol) and Xantphos (219.91 mg, 0.38 mmol) were stirred at 100 ° C for 16 hours, concentrated and separated by column chromatography to give 3-(4-tert-butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-6-amine (300 mg, 20%).

[0174] LCMS: m / z (ESI), 597.0 [M+H] + .

[0175] Step E: 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxypyridin-3-yl)-ethyl)imidazo[1,2-b]pyridazin-6-amine (26)

[0176] 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 25, 300 mg, 0.52 mol) was placed in methanol (3 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25° C. for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxypyridin-3-yl)-ethyl)imidazo[1,2-b]pyridazin-6-amine (50 mg, 24%).

[0177] LCMS: m / z(ESI),363[M+H] + .

[0178] Step F: (E)-6-Methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridine-cycloheptane (I-4)

[0179] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxypyridin-3-yl)-ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 26, 50 mg, 0.132 mol) was placed in a mixed solution of dichloromethane and DMF (6 mL), and thionyl chloride (215.57 mg, 1.81 mol) was added. The mixture was stirred at 25°C for 0.5 hour, and then potassium carbonate (500.84 mg, 3.62 mol) was added. The solution was neutralized to pH>7, and the dichloromethane was evaporated to remove the mixture. The mixture was stirred at 90°C for 1.5 hours and filtered. The filtrate was concentrated and preparatively isolated to obtain (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (14.9 mg, 30.2%).

[0180] LCMS: m / z (ESI), 345 [M+H] + .

[0181] Example 5: (E)-5 4 -Fluoro-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-5)

[0182] Step A: 2-aminomethyl-4-fluorophenol (27)

[0183] 5-Fluoro-2-hydroxybenzonitrile (2 g, 14.59 mmol) was placed in tetrahydrofuran (20 mL), lithium aluminum tetrahydride (1.11 g, 29.17 mmol) was added at 0°C, and stirred at 0°C for 1 hour. The reaction was then quenched with sodium sulfate decahydrate, diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated. Column chromatography gave 2-aminomethyl-4-fluorophenol (2.3 g).

[0184] 1 H NMR: (400MHz, CHLOROFORM-d) δ = 6.74-6.48 (m, 2H), 6.29-6.11 (m, 1H), 3.57-3.46 (m, 2H).

[0185] Step B: 4-Fluoro-2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (28)

[0186] 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 27, 100 mg, 0.267 mmol) was placed in DMSO (3 mL), and 2-aminomethyl-4-fluorophenol (188.23 mg, 1.33 mol) and sodium tert-butoxide (51.26 mg, 0.53 mol) were added in sequence. The mixture was stirred at 130°C for 1 hour. The reaction solution was filtered and directly separated by reverse phase preparative separation to obtain 4-fluoro-2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazine-6-yl)-amino)-methyl)phenol (48 mg, 49%).

[0187] LCMS: m / z (ESI), 366.2 [M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d6) δ = 8.59-8.49 (m, 2H), 8.19 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 9.8Hz, 1H), 7. 53-7.47(m,1H),7.25(d,J=4.5Hz,1H),7.12-7.06(m,1H),6.92-6.85(m,3H),4.54-4.44(m,4H).

[0189] Step C: (E)-5 4 -Fluoro-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-5)

[0190] 4-Fluoro-2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (Compound 28, 47 mg, 0.122 mol) was placed in a mixed solution of dichloromethane and DMF (6 mL), thionyl chloride (215.57 mg, 1.81 mol) was added, and the mixture was stirred at 25°C for 0.5 hours, followed by the addition of potassium carbonate (500.84 mg, 3.62 mol), and the mixture was neutralized to pH>7. The dichloromethane was evaporated and stirred at 90°C for 1.5 hours. The mixture was filtered and the filtrate was concentrated to obtain (E)-5 4 -fluoro-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (5.2 mg, 11.6%).

[0191] LCMS: m / z (ESI), 348 [M+H] +

[0192] 1 H NMR (400MHz, DMSO-d6) δ=9.69-9.62(m,1H),8.72-8.65(m,1H),8.61(d,J=5.3H z,1H),8.49(s,1H),8.07(d,J=9.8Hz,1H),7.43(d,J=4.3Hz,1H),7.32(d,J=9.9 Hz,1H),7.14(dd,J=4.5,9.4Hz,1H),7.06(dd,J=3.1,9.4Hz,1H),6.87-6.80(m, 1H),5.79(s,1H),5.51(d,J=15.8Hz,1H),5.07-4.98(m,1H),4.26-4.20(m,1H).

[0193] Example 6: (E)-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-6)

[0194] Step A: 2-(((3-(4-(Hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (29)

[0195] 3-(4-tert-Butyldimethylsilyloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (1 g, 2.13 mmol) was placed in DMSO (16 mL), and 2-aminomethylphenol (525.53 mg, 4.27 mmol) and sodium tert-butoxide (51.26 mg, 0.53 mol) were added in sequence. The mixture was stirred at 130°C for 1 hour. The reaction solution was filtered and directly subjected to reverse phase preparative separation to obtain 2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazine-6-yl)-amino)-methyl)phenol (180 mg, 24%).

[0196] LCMS: m / z (ESI), 348.2 [M+H] + .

[0197] 1 H NMR (400MHz, DMSO-d6) δ9.73-9.53(m,1H),8.60(s,1H),8.54(d,J=5.0Hz,1H),8.06(s,1H),7.80(d,J=9.8Hz,1H),7.39(t,J=5 .1Hz,1H),7.32-7.20(m,2H),7.09(t,J=7.4Hz,1H),6.93-6.85(m,2H),6.78-6.70(m,1H),5.39(d,J=6.9Hz,1H),4.50(s,4H).

[0198] Step B: (E)-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-benzocycloheptane (I-6)

[0199] 2-(((3-(4-(Hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (compound 29, 50 mg, 0.137 mol) was placed in a mixed solution of dichloromethane and DMF (6 mL), and thionyl chloride (215.57 mg, 1.81 mol) was added. The mixture was stirred at 25°C for 0.5 hour, and then potassium carbonate (500.84 mg, 3.62 mol) was added. The mixture was neutralized to pH>7, and the dichloromethane was evaporated to remove the mixture. The mixture was stirred at 90°C for 1.5 hours and filtered. The filtrate was concentrated and preparatively isolated to obtain (E)-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-benzocycloheptane (6.8 mg, 13.6%).

[0200] LCMS: m / z (ESI), 330 [M+H] +

[0201] 1 H NMR: (400MHz, DMSO-d6) δ9.74(s,1H),8.92-8.74(m,1H),8.60(d,J=5.0Hz,1H),8.55-8.47(m,1H),8.06(d,J=9.8Hz,1H),7.45(br d,J=3.6Hz,1H),7.38-7.27(m,2H),7.10(d,J=8.4Hz,1H),7.04-6.94(m,1H),6.84-6.75(m,1H),5.85 (d,J=15.9Hz,1H),5.49(d,J=15.9Hz,1H),5.05(dd,J=4.7,15.3Hz,1H),4.21(dd,J=5.8,15.4Hz,1H).

[0202] Example 7: (E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridine-5(1,2)-phenylcycloheptane (I-7)

[0203] Step A: (5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)methanol (30)

[0204] 5-Hydroxymethylpyridine-3-boronic acid (500 mg, 3.27 mmol), 3-bromo-6-chloroimidazole [1, 2-b] pyridazine (compound 2, 760 mg, 3.27 mmol), Pd (PPh3) 4 (381 mg, 0.33 mmol), potassium carbonate (11.28 g, 9.76 mmol) were placed in 1,4-dioxane (50 mL) and water (5 mL), stirred at 100 ° C for 16 hours, then diluted with water (1.5 L) and extracted 3 times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain (5- (6-chloroimidazole [1, 2-b] pyridazine-3-yl) pyridin-3-yl) methanol (150 mg, 17%).

[0205] LCMS: m / z (ESI), 261 [M+H] + .

[0206] Step B: 3-(5-((tert-Butyldimethylsilyloxy)methyl)-pyridin-3-yl)-6-chloroimidazo[1,2-b]pyridazine (31)

[0207] (5-(6-chloroimidazole[1,2-b]pyridazine-3-yl)pyridin-3-yl)methanol (compound 30, 150 mg, 0.57 mmol) and imidazole (77.53 mg, 1.14 mmol) were placed in dichloromethane (10 mL), and tert-butyldimethylsilyl chloride (128.25 mg, 0.85 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours, then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to give 3-(5-((tert-butyldimethylsilyloxy)methyl)-pyridin-3-yl)-6-chloroimidazole[1,2-b]pyridazine (70 mg, 32%).

[0208] LCMS: m / z (ESI), 375 [M+H] + .

[0209] Step C: 3-(5-tert-Butyldimethylsilyloxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (32)

[0210] 33-(5-((tert-butyldimethylsilyloxy)methyl)-pyridin-3-yl)-6-chloroimidazole[1,2-b]pyridazine (Compound 31, 70 mg, 0.187 mmol) was placed in toluene (5 mL), and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (73.43 mg, 0.187 mol), Pd(dba)2 (11.74 mg, 0.019 mol), Sodium tert-butoxide (35.93 mg, 0.37 mol) and Xantphos (10.03 mg, 0.019 mol) were stirred at 100 ° C for 16 hours, concentrated and separated by column chromatography to give 3-(5-tert-butyldimethylsilyloxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (12 mg, 10%).

[0211] LCMS: m / z (ESI), 614.2 [M+H] + .

[0212] Step D: 3-(5-Hydroxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (33)

[0213] 3-(4-tert-Butyldimethylsilyloxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 32, 12 mg, 0.019 mol) was placed in methanol (3 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25° C. for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give 3-(5-hydroxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (5 mg).

[0214] LCMS: m / z (ESI), 380 [M+H] + .

[0215] Step E: (E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridine-5(1,2)-benzocycloheptane (I-7)

[0216] 3-(5-Hydroxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 33, 35.2 mg, 0.094 mol) was placed in a mixed solution of dichloromethane and DMF (6 mL), thionyl chloride (215.57 mg, 1.81 mol) was added, and the mixture was stirred at 25°C for 0.5 hours, followed by the addition of potassium carbonate (500.84 mg, 3.62 mol), and the mixture was neutralized to pH>7. The dichloromethane was evaporated and stirred at 90°C for 1.5 hours. The mixture was filtered and the filtrate was concentrated to obtain (E)-5 4 -fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(3,5)-pyridine-5(1,2)-phenylcycloheptane (7.6 mg, 22.6%).

[0217] LCMS: m / z (ESI), 362 [M+H] + .

[0218] 1H NMR: (400MHz, DMSO-d6) δ = 9.69 (s, 1H), 8.51 (d, J = 5.0Hz, 1H), 8.00 (s, 1H), 7.98-7.90 (m, 1H), 7.87(d,J=9.8Hz,1H),7.24(d,J=5.0Hz,1H),7.10-7.03(m,2H),6.89(d,J=9.8Hz,1H),6.80(br dd,J=3.2,7.9Hz,1H),5.75(d,J=15.4Hz,1H),5.47(d,J=16.0Hz,1H),5.35(br d,J=6.0Hz,1H),1.47(d,J=6.8Hz,3H).

[0219] Example 8: 2-((((E)-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-8)

[0220] Step A: 2-Bromo-4-hydroxyethylpyridine (34)

[0221] 2-Bromopyridine-4-acetic acid ethyl ester (1 g, 4.35 mmol) was placed in tetrahydrofuran (15 mL), lithium aluminum tetrahydride (142.03 mg, 6.52 mmol) was added, and stirred at 25 ° C for 1 hour, then quenched with saturated ammonium chloride solution (20 mL), and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, 2-bromo-4-hydroxyethylpyridine (870 mg) was obtained.

[0222] LCMS: m / z (ESI), 301 [M+H] + .

[0223] Step B: 2-Bromo-4-tert-butyldimethylsilyloxyethylpyridine (35)

[0224] 2-Bromo-4-hydroxyethylpyridine (compound 34, 2.57 g, 12.72 mmol) was placed in dichloromethane (30 mL), and tert-butyldimethylsilyl chloride (3.83 g, 25.44 mmol) and imidazole (1.73 g, 25.44 mmol) were added in sequence at 0°C. The mixture was stirred at 25°C for 1 hour, and then directly concentrated and column chromatography was performed to obtain a colorless liquid 2-bromo-4-tert-butyldimethylsilyloxyethylpyridine (4 g, 99%).

[0225] 1H NMR: (400MHz, CHLOROFORM-d) δ8.24-8.27(m,1H)7.38-7.39(m,1H)7.10-7.13(m,1H)3.83(t,J=6.19Hz,2H)2.75-2.81(m,2H)0.86(s,9H),0.02(s,6H).

[0226] Step C: 2-tributyltin-4-tert-butyldimethylsilyloxyethylpyridine (36)

[0227] 2-Bromo-4-tert-butyldimethylsilyloxyethylpyridine (compound 35, 4 g, 12.65 mmol) was placed in tetrahydrofuran (10 mL), and n-butyllithium (2.5 M, 5.06 mL) was added at -78 ° C under nitrogen protection, followed by tributyltin chloride (6.17 g, 18.97 mmol). The mixture was stirred at -78 ° C for 2 hours, then quenched with saturated ammonium chloride solution (50 mL), and potassium fluoride solution (50 mL) was added and stirred for 1 hour. It was then extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a yellow liquid 2-tributyltin-4-tert-butyldimethylsilyloxyethylpyridine (5 g, crude product) was obtained.

[0228] Step D: 3-(4-tert-Butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (37)

[0229] 3-Bromo-6-chloroimidazole [1,2-b] pyridazine (compound 36, 2.21 g, 9.50 mmol) and tetrakistriphenylphosphine palladium (1.10 g, 949.75 umol) were placed in a toluene solution (10 mL), and 2-tributyltin-4-tert-butyldimethylsilyloxyethylpyridine (compound 36, 5 g, 9.50 mmol) was added. The mixture was stirred at 80 ° C. under nitrogen protection for 12 hours, and then filtered and the filtrate was concentrated and separated by column chromatography to obtain a yellow solid 3-(4-tert-butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole [1,2-b] pyridazine (270 mg, yield 7.31%).

[0230] 1H NMR: (400MHz, CHLOROFORM-d) δppm 8.59-8.62(m,1H)8.54-8.57(m,1H)8.39-8.42(m,1H)7.99-8.03(m,1H)7.12-7.18( m,2H)3.94(t,J=6.63Hz,2H)2.95(t,J=6.57Hz,2H)0.87(br,9H),0.00-0.02(m,6H).

[0231] Step E: 4-Fluoro-2-(((3-(4-(hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (37-1)

[0232] 3-(4-tert-Butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (compound 37, 250 mg, 0.64 mmol) was placed in DMSO (5 mL), and 2-aminomethylphenol (158.31 mg, 1.29 mmol) and potassium fluoride (298.74 mg, 5.14 mmol) were added. The mixture was stirred at 130°C for 30 minutes under nitrogen protection, and then directly concentrated and subjected to reverse phase liquid chromatography to obtain a white solid 2-(((3-(4-(hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazine-6-yl)-amino)-methyl)phenol (100 mg, yield 43%).

[0233] LCMS: m / z (ESI), 362.1 [M+H] + .

[0234] 1 H NMR: (400MHz, METHANOL-d4) δppm 8.50-8.52(m,1H)8.43(d,J=5.00Hz,1H)8.06(s,1H)7.67-7.72(m,1H)7.26(d,J=7.50Hz,1H)7.16-7.21(m,1H)7.06-7.11(m,1H )6.87(d,J=9.76Hz,1H)6.83(d,J=8.00Hz,1H)6.77(t,J=7.50Hz,1H)4.63(s,2H)3.76(t,J=6.44Hz,2H)2.76(t,J=6.50Hz,2H).

[0235] Step F: (E)-6-Oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-8)

[0236] 2-(((3-(4-(Hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (compound 37-1, 30 mg, 0.083 mol) was placed in tetrahydrofuran (5 mL), and triphenylphosphine (65.32 mg, 249.03 umol) and DIAD (50.36 mg, 249.03 umol) were added. The mixture was stirred at 60° C. for 2 hours under nitrogen protection, and then directly separated by reverse phase liquid chromatography to obtain (E)-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (10 mg, yield 34%).

[0237] LCMS: m / z (ESI), 344.0 [M+H] + .

[0238] 1 H NMR: (400MHz, METHANOL-d4) δppm 9.42 (s, 1H) 8.76 (br s,1H)8.59-8.62(m,1H)8.46-8.50(m,1H)8.02(d,J=9.88Hz,1H)7.49-7.55(m,1H)7 .40-7.44(m,1H)7.28(d,J=9.88Hz,1H)7.15-7.22(m,1H)6.91-7.00(m,2H)4.71(br s,2H)4.34-4.38(m,2H)3.27(t,J=4.88Hz,2H).

[0239] Example 9: (E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-9)

[0240] Step A: 3-(5-tert-Butyldimethylsilyloxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (38)

[0241] 3-(4-tert-Butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (Compound 37, 500 mg, 1.28 mmol) and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (262.40 mg, 1.02 mmol) were placed in 2-methyl-2-butanol (20 mL), and sodium tert-butoxide (2 M, 241.02 uL) and RuPhos Pd G4 (13.44 mg, 0.016 mmol) was stirred at 100 ° C for 2 hours under nitrogen protection, then diluted with water (20 mL) and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was used to separate and obtain a yellow solid 3-(5-tert-butyldimethylsilyloxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazine-6-amine (130 mg, 83%).

[0242] LCMS: m / z (ESI), 610.2 [M+H] + .

[0243] Step B: 3-(5-Hydroxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (39)

[0244] 3-(4-tert-Butyldimethylsilyloxyethyl)pyridin-2-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (Compound 38, 120 mg, 0.196 mmol) was placed in methanol (10 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25° C. for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to obtain 3-(5-hydroxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (35 mg, 23%).

[0245] LCMS: m / z (ESI), 376 [M+H] + .

[0246] 1H NMR: (400MHz, METHANOL-d4)δ=8.43-8.39(m,2H)8.05-8.02(m,1H)7.69-7.65(m,1H)7.30-7.26(m,1H)7.21-7.18(m,1H)7.06- 7.01(m,1H)6.89(d,J=9.6Hz,1H)6.82-6.74(m,2H)5.46-5.39(m,1H)3.92-3.76(m,2H)2.94(t,J=6.6Hz,2H)1.59-1.56(m,3H).

[0247] Step C: (E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-9)

[0248] 3-(5-Hydroxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (compound 39, 30 mg, 0.079 mol) was placed in tetrahydrofuran (5 mL), and triphenylphosphine (65.32 mg, 0.25 mmol) and DIAD (50.36 mg, 0.25 mmol) were added. The mixture was stirred at 60° C. for 2 hours under nitrogen protection, and then directly separated by reverse phase liquid chromatography to obtain (E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (6.74 mg, 18.4%).

[0249] LCMS: m / z (ESI), 358.0 [M+H] + .

[0250] 1 H NMR: (400MHz, DMSO-d6)δ=9.32-9.28(m,1H)8.80-8.74(m,1H)8.64-8.60(m,1H)8.55-8.52(m,1H)8.07-8.02(m,1H)7.51-7.46(m,1H) 7.46-7.42(m,1H)7.28-7.24(m,1H)7.20-7.14(m,1H)7.01-6.92(m,2H)5.76-5.66(m,1H)4.53- 4.48(m,1H)4.22(t,J=9.2Hz,1H)3.30(d,J=4.4Hz,1H)3.21(d,J=4.8Hz,1H)1.45-1.41(m,3H).

[0251] Example 10: (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(1,2)-phenylcycloheptane (I-10)

[0252] Step A: 4-chloro-6-tert-butyldimethylsilyloxymethylpyrimidine (40)

[0253] Compound 40 was synthesized by using 6-chloro-4-hydroxymethylpyrimidine as raw material instead of compound 1 and referring to the method of compound 2.

[0254] LCMS: m / z (ESI), 259 [M+H] + .

[0255] Step B: 4-tributyltin-6-tert-butyldimethylsilyloxymethylpyrimidine (41)

[0256] Compound 41 was synthesized by using compound 40 instead of compound 2 as the starting material and referring to the method of compound 3.

[0257] LCMS: m / z (ESI), 515.0 [M+H] + .

[0258] Step C: 3-(6-tert-Butyldimethylsilyloxymethylpyridin-4-yl)-6-chloroimidazole[1,2-b]pyridazine (42)

[0259] Compound 42 was synthesized by using compound 41 instead of compound 3 as the raw material and referring to the method of compound 5.

[0260] LCMS: m / z (ESI), 376.0 [M+H] + .

[0261] Step D: 3-(6-tert-Butyldimethylsilyloxymethylpyridin-4-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (43)

[0262] Compound 43 was synthesized by using compound 42 instead of compound 5 as the starting material and referring to the method of compound 20.

[0263] LCMS: m / z (ESI), 597.2 [M+H] + .

[0264] Step E: 3-(6-Hydroxymethylpyrimidin-4-yl)-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (44)

[0265] Compound 44 was synthesized by using compound 43 instead of compound 10 as the starting material and referring to the method of compound 11.

[0266] LCMS: m / z(ESI),363[M+H] + .

[0267] Step F: (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(4,6)-pyrimidin-5(1,2)-benzocycloheptane (I-10)

[0268] Compound 1-10 was synthesized by using compound 44 instead of compound 11 as the raw material and referring to the method of compound 1-1.

[0269] LCMS: m / z (ESI), 345 [M+H] + .

[0270] Example 11: (E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-benzocyclooctane (I-11)

[0271] Step A: 4-Chloro-6-hydroxyethylpyrimidine (45)

[0272] Compound 45 was synthesized by using compound 44 instead of compound 33 as the starting material and referring to the method of compound 34.

[0273] LCMS: m / z (ESI), 159.2 [M+H] + .

[0274] Step B: 4-Chloro-6-tert-butyldimethylsilyloxyethylpyrimidine (46)

[0275] Compound 46 was synthesized by using compound 45 instead of compound 34 as the starting material and referring to the method of compound 35.

[0276] LCMS: m / z (ESI), 273.0 [M+H] + .

[0277] Step C: 4-tributyltin-6-tert-butyldimethylsilyloxyethylpyrimidine (47)

[0278] Compound 47 was synthesized by using compound 46 instead of compound 35 as the starting material and referring to the method of compound 36.

[0279] LCMS: m / z (ESI), 529.2 [M+H] + .

[0280] Step D: 3-(6-tert-Butyldimethylsilyloxyethylpyrimidin-4-yl-6-chloroimidazole[1,2-b]pyridazine (48)

[0281] Compound 48 was synthesized by using compound 47 instead of compound 36 as the starting material and referring to the method of compound 37.

[0282] LCMS: m / z (ESI), 390.0 [M+H] + .

[0283] Step E: 3-(6-tert-Butyldimethylsilyloxymethylpyrimidin-4-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (48-1)

[0284] Compound 48-1 was synthesized by using compound 48 instead of compound 37 as the raw material and referring to the method of compound 38.

[0285] LCMS: m / z (ESI), 611.2 [M+H] + .

[0286] Step F: 2-(((3-(6-(Hydroxyethylpyrimidin)-4-yl)imidazo[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (48-2)

[0287] Compound 48-2 was synthesized by using compound 48-1 instead of compound 38 as the starting material and referring to the method of compound 39.

[0288] LCMS: m / z (ESI), 377.2 [M+H] + .

[0289] Step G: (E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidin-5(1,2)-phenylcyclooctane (I-11)

[0290] Compound 1-11 was synthesized by using compound 48-2 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0291] LCMS: m / z (ESI), 359 [M+H] + .

[0292] Example 12: (E)-55 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-12)

[0293] Step A: 2-Bromo-4-p-methoxybenzyloxymethylpyridine (50)

[0294] 2-Bromo-4-fluoropyridine (compound 49, 10 g, 57.47 mmol) and p-methoxybenzyl alcohol (9.52 g, 68.96 mmol) were placed in DMF (100 mL), sodium hydride (3.45 g, 86.21 mmol) was added at 0°C, and stirred at room temperature for 16 hours. Then, the mixture was quenched with water (1 L) and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-bromo-4-tert-butyldimethylsilyloxymethylpyridine (14.44 g, 85%).

[0295] LCMS: m / z (ESI), 294 [M+H] + .

[0296] Step B: 3-tributyltin-6-chloroimidazole[1,2-b]pyridazine (51)

[0297] 3-Chloro-6-chloroimidazole [1, 2-b] pyridazine (compound 4, 10 g, 43.10 mmol) was placed in tetrahydrofuran (100 mL), and butyl lithium (2.5 M, 17.24 mol) was added dropwise at -70 ° C. and stirred for half an hour. Tributyltin chloride (18.25 g, 43.10 mmol) was then added and stirred at -70 ° C. for 2 hours, then quenched with saturated ammonium chloride (1.5 L), and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 3-tributyltin-6-chloroimidazole [1, 2-b] pyridazine (2.1 g, 11%).

[0298] LCMS: m / z (ESI), 444.3 [M+H] + .

[0299] Step C: 3-(4-p-methoxybenzyloxypyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (52)

[0300] 3-tributyltin-6-chloroimidazole [1, 2-b] pyridazine (compound 51, 1 g, 2.25 mmol) was placed in toluene (50 mL), and 2-bromo-4-tert-butyldimethylsilyloxymethylpyridine (compound 50, 661.3 mg, 2.25 mmol) and Pd (PPh3) 4 (58.5 mg, 0.225 mmol) were added in sequence. The mixture was stirred at 100 ° C for 16 hours, then diluted with water (1.5 L) and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 3- (4-p-methoxybenzyloxypyridin-2-yl) -6-chloroimidazole [1, 2-b] pyridazine (517 mg, 62%).

[0301] Step D: Methyl 3-bromo-5-fluoropyridine-2-carboxylate (54)

[0302] 3-Bromo-5-fluoropyridine-2-carboxylic acid (compound 53, 10 g, 45.45 mmol) was placed in methanol (200 mL), concentrated sulfuric acid (2 mL) was added, and the mixture was stirred at 80°C for 12 hours. Then, the mixture was diluted with water (300 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain methyl 3-bromo-5-fluoropyridine-2-carboxylate (6.3 g, 59%).

[0303] LCMS: m / z (ESI), 234.0 [M+H] + .

[0304] Step E: Methyl 3-(1-ethoxyvinyl)-5-fluoropyridine-2-carboxylate (55)

[0305] 3-Bromo-5-fluoropyridine-2-carboxylic acid methyl ester (compound 54, 3 g, 12.82 mmol) was placed in 1,4-dioxane (100 mL), and Pd(PPh3)4 (147.84 mg, 0.128 mmol) and (1-ethoxyvinyl)tributyltin (6.94 g, 19.23 mmol) were added in sequence. The mixture was stirred at 110°C for 16 hours, then diluted with water (600 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 3-(1-ethoxyvinyl)-5-fluoropyridine-2-carboxylic acid methyl ester (2.5 g, 86%).

[0306] LCMS: m / z (ESI), 226.0 [M+H] + .

[0307] Step F: (3-(1-ethoxyvinyl)-5-fluoropyridin-2-yl)-methanol (56)

[0308] Methyl 3-(1-ethoxyvinyl)-5-fluoropyridine-2-carboxylate (Compound 55, 1.1 g, 4.89 mmol) was placed in tetrahydrofuran (50 mL), and diisobutylaluminum hydride (9.77 mL, 9.77 mmol) was added. The mixture was stirred at 0°C for 5 hours, then quenched and diluted with water (600 mL), and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to give (3-(1-ethoxyvinyl)-5-fluoropyridin-2-yl)-methanol (803 mg, 83%).

[0309] LCMS: m / z (ESI), 198.0 [M+H] + .

[0310] Step G: (3-Acetyl-5-fluoropyridin-2-yl)-methanol (57)

[0311] (3-(1-Ethoxyvinyl)-5-fluoropyridin-2-yl)-methanol (Compound 56, 803 mg, 4.07 mmol) was placed in methanol (50 mL), and a methanolic hydrochloric acid solution (1 M, 10 mL) was added. The mixture was stirred at 25°C for 12 hours, then diluted with a saturated sodium bicarbonate solution (100 mL) for alkalization, and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain (3-acetyl-5-fluoropyridin-2-yl)-methanol (650 mg, 94%).

[0312] LCMS: m / z (ESI), 170.0 [M+H] + .

[0313] Step H: 1-((2-tert-Butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone (58)

[0314] (3-Acetyl-5-fluoropyridin-2-yl)-methanol (Compound 57, 650 mg, 3.84 mmol) was placed in dichloromethane (50 mL), and imidazole (537.6 mg, 7.68 mmol) and tert-butyldimethylsilyl chloride (576 mg, 3.84 mmol) were added in sequence. The mixture was stirred at 25°C for 12 hours, then diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 1-((2-tert-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone (343 mg, 32%).

[0315] LCMS: m / z (ESI), 284.0 [M+H] + .

[0316] Step I: 1-((2-tert-Butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone oxime (59)

[0317] 1-((2-tert-Butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone (Compound 58, 343 mg, 1.21 mmol) was placed in ethanol (20 mL), and sodium acetate (198 mg, 2.42 mmol) and hydroxylamine hydrochloride (168 mg, 2.42 mmol) were added in sequence. The mixture was stirred at 70°C for 2 hours, then diluted with water (60 mL) and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 1-((2-tert-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone oxime (309 mg, 85.6%).

[0318] LCMS: m / z (ESI), 299.0 [M+H] + .

[0319] Step J: 1-((2-tert-Butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanamine (60)

[0320] 1-((2-tert-Butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone oxime (Compound 59, 309 mg, 1.07 mmol) was placed in methanol (15 mL), and ammonium formate (127 mg, 2.14 mmol) and zinc powder (139 mg, 2.14 mmol) were added in sequence. The mixture was stirred at 40°C for 12 hours, and then filtered and the filtrate was concentrated. Column chromatography gave 1-((2-tert-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanamine (105 mg, 34.5%).

[0321] LCMS: m / z (ESI), 285.0 [M+H] + .

[0322] Step K: N-(1-(2-((tert-Butyldimethylsilyloxy)methyl)-5-fluoropyridin-3-yl)ethyl)-3-(4-(4-methoxybenzyloxypyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine (61)

[0323] 3-(4-p-methoxybenzyloxypyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (Compound 52, 100 mg, 0.272 mmol) was placed in toluene (5 mL), and 1-((2-tert-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanamine (93.11 mg, 0.328 mol), Pd(dba)2 (15.34 mg, 0.027 mol), tert-butyl Sodium alkoxide (51.26 mg, 0.53 mol) and Xantphos (15.43 mg, 0.027 mol) were stirred at 100° C. for 16 hours, concentrated, and separated by column chromatography to give N-(1-(2-((tert-butyldimethylsilyloxy)methyl)-5-fluoropyridin-3-yl)ethyl)-3-(4-(4-methoxybenzyloxypyridin)-2-yl)imidazo[1,2-b]pyridazin-6-amine (42 mg, 25%).

[0324] LCMS: m / z (ESI), 615.2 [M+H] + .

[0325] Step L: 2-(6-((1-(5-Fluoro-2-(hydroxymethyl)pyridin-3-yl)-ethyl)-amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-ol (62)

[0326] N-(1-(2-((tert-butyldimethylsilyloxy)methyl)-5-fluoropyridin-3-yl)ethyl)-3-(4-(4-methoxybenzyloxypyridin)-2-yl)imidazo[1,2-b]pyridazin-6-amine (Compound 61, 42 mg, 0.068 mol) was placed in methanol (3 mL), and a methanolic hydrochloric acid solution (4 M, 3 mL) was added. The mixture was stirred at 25°C for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give 2-(6-((1-(5-fluoro-2-(hydroxymethyl)pyridin-3-yl)-ethyl)-amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-ol (22 mg, 85%).

[0327] LCMS: m / z (ESI), 381.2 [M+H] + .

[0328] Step M: (E)-5 5 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-12)

[0329] 2-(6-((1-(5-fluoro-2-(hydroxymethyl)pyridin-3-yl)-ethyl)-amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-ol (Compound 62, 35.2 mg, 0.094 mol) was placed in a mixed solution (6 mL) of dichloromethane and DMF, thionyl chloride (215.57 mg, 1.81 mol) was added, and the mixture was stirred at 25°C for 0.5 hours, followed by the addition of potassium carbonate (500.84 mg, 3.62 mol), and the mixture was neutralized to pH>7. The dichloromethane was evaporated and stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to obtain (E)-5 5 -fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (7.6 mg, 22.6%).

[0330] LCMS: m / z(ESI),363[M+H] + .

[0331] Example 13: (E)-5 4 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-13)

[0332] Step A: Methyl 2-bromo-4-fluorobenzoate (63)

[0333] Compound 63 was synthesized by using compound 62 instead of compound 53 as the starting material and referring to the method of compound 54.

[0334] LCMS: m / z (ESI), 233.0 [M+H] + .

[0335] Step B: Methyl 2-(1-ethoxyvinyl)-4-fluorobenzoate (64)

[0336] Compound 64 was synthesized by using compound 63 instead of compound 54 as the starting material and referring to the method of compound 55.

[0337] LCMS: m / z (ESI), 225.0 [M+H] + .

[0338] Step C: 2-(1-ethoxyvinyl)-4-fluorobenzyl alcohol (65)

[0339] Compound 65 was synthesized by using compound 64 instead of compound 55 as the starting material and referring to the method for compound 56.

[0340] LCMS: m / z (ESI), 197.0 [M+H] + .

[0341] Step D: 2-Acetyl-4-fluorobenzyl alcohol (66)

[0342] Compound 66 was synthesized by using compound 65 instead of compound 56 as the starting material and referring to the method of compound 57.

[0343] LCMS: m / z (ESI), 169.0 [M+H] + .

[0344] Step E: 2-tert-Butyldimethylsilyloxymethyl-5-fluoroacetophenone (67)

[0345] Compound 67 was synthesized by using compound 66 instead of compound 57 as the starting material and referring to the method of compound 58.

[0346] LCMS: m / z (ESI), 283.0 [M+H] + .

[0347] Step F: 2-tert-Butyldimethylsilyloxymethyl-5-fluoroacetophenone oxime (68)

[0348] Compound 68 was synthesized by using compound 67 instead of compound 58 as the starting material and referring to the method for compound 59.

[0349] LCMS: m / z (ESI), 298.0 [M+H] + .

[0350] Step G: 1-(2-tert-Butyldimethylsilyloxymethyl-5-fluorophenyl)-1-ethylamine (69)

[0351] Compound 69 was synthesized by using compound 68 instead of compound 59 as the starting material and referring to the method for compound 60.

[0352] LCMS: m / z (ESI), 284.0 [M+H] + .

[0353] Step H: N-(1-(2-tert-Butyldimethylsilyloxymethyl-5-fluorophenyl)ethyl)-3-(4-(4-methoxybenzyloxypyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine (70)

[0354] Compound 70 was synthesized by using compound 69 instead of compound 60 as the starting material and referring to the method for compound 61.

[0355] LCMS: m / z (ESI), 614.2 [M+H] + .

[0356] Step I: 2-(6-((1-(5-fluoro-2-(hydroxymethyl)phenyl)-ethyl)-amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-ol (70-1)

[0357] Compound 70-1 was synthesized by using compound 70 instead of compound 61 as the starting material and referring to the method of compound 62.

[0358] LCMS: m / z (ESI), 380.2 [M+H] + .

[0359] Step J: (E)-5 4 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-13)

[0360] Compound 1-13 was synthesized by using compound 70-1 instead of compound 62 as the raw material and referring to the method of compound 1-12.

[0361] LCMS: m / z (ESI), 362.2 [M+H] + .

[0362] Examples 14, 15: (R)-(E)-5 4 -fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-14), (S)-(E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza

[0363] -1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-15),

[0364] Compounds I-14 and I-15 were prepared using compound I-1 as the starting material by chiral resolution.

[0365] LCMS: m / z (ESI), 362.2 [M+H] + (I-14),LCMS:m / z(ESI),362.2[M+H] + (I-15).

[0366] Examples 16, 17: (R)-(E)-5 4 ,5 6 -difluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-16), (S)-(E)-5 4 ,5 6 -Difluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-17)

[0367] Compounds I-16 and I-17 were prepared using compound I-2 as the starting material by chiral resolution.

[0368] LCMS: m / z (ESI), 380.2 [M+H] + (I-16),LCMS:m / z(ESI),380.0[M+H] + (I-17).

[0369] Examples 18, 19: (R)-(E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-18), (S)-(E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-19)

[0370] Compounds I-18 and I-19 were prepared using compound I-3 as the starting material by chiral resolution.

[0371] LCMS: m / z (ESI), 344.2 [M+H] + (I-18), LCMS:m / z(ESI),344.2[M+H] + (I-19).

[0372] Examples 20, 21: (R)-(E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-20), (S)-(E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-21)

[0373] Compounds I-20 and I-21 were prepared using compound I-4 as the starting material by chiral resolution.

[0374] LCMS: m / z (ESI), 345.2 [M+H] + (I-20),LCMS:m / z(ESI),345.2[M+H] + (I-21).

[0375] Examples 22, 23: (R)-(E)-5 4 -fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(3,5)-pyridine-5(1,2)-phenylcycloheptane (I-22), (S)-(E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridine-5(1,2)-phenylcycloheptane (I-23)

[0376] Compounds I-22 and I-23 were prepared using compound I-7 as the starting material by chiral resolution.

[0377] LCMS: m / z (ESI), 362.2 [M+H] + (I-22),LCMS:m / z(ESI),362.2[M+H] + (I-23).

[0378] Examples 24, 25: (R)-(E)-5 5 -fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-24), (S)-(E)-5 5 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-25)

[0379] Compounds I-24 and I-25 were prepared using compound I-12 as the starting material by chiral resolution.

[0380] LCMS: m / z (ESI), 363.2 [M+H] + (I-24),LCMS:m / z(ESI),363.2[M+H] + (I-25).

[0381] Examples 26, 27: (R)-(E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(1,2)-phenylcycloheptane (I-26), (S)-(E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(1,2)-phenylcycloheptane (I-27)

[0382] Compounds I-26 and I-27 were prepared using compound I-10 as the starting material by chiral resolution.

[0383] LCMS: m / z (ESI), 363.2 [M+H] + (I-26),LCMS:m / z(ESI),363.2[M+H] + (I-27).

[0384] Examples 28, 29: (R)-(E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-28), (S)-(E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-29)

[0385] Compounds I-28 and I-29 were prepared using compound I-9 as the starting material by chiral resolution.

[0386] LCMS: m / z (ESI), 358.0 [M+H] + (I-28),LCMS:m / z(ESI),358.0[M+H] + (I-29).

[0387] Examples 30, 31: (R)-(E)-5 4 -fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-30), (S)-(E)-5 4 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-31)

[0388] Compounds I-30 and I-31 were prepared using compound I-13 as the starting material by chiral resolution.

[0389] LCMS: m / z (ESI), 362.0 [M+H] + (I-30),LCMS:m / z(ESI),362.0[M+H] + (I-31).

[0390] Examples 32, 33: (R)-(E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-32), (S)-(E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-33)

[0391] Compounds I-32 and I-33 were prepared using compound I-11 as the starting material by chiral resolution.

[0392] LCMS: m / z (ESI), 359.0 [M+H] + (I-32),LCMS:m / z(ESI),359.0[M+H] + (I-33).

[0393] Example 34: (4R,7R,E)-5 5 -4,7-Dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-34)

[0394] Step A: (R)-1-(5-Fluoro-2-methoxyphenyl)ethan-1-amine (71)

[0395] The synthesis of compound 71 was carried out according to the method of Journal of Medicinal Chemistry (1974), 17(7), 708-15.

[0396] LCMS: m / z (ESI), 170 [M+H] + .

[0397] Step B: (S)-1-(2-bromopyridin-4-yl)-2-propanol (73)

[0398] The synthesis of compound 73 was prepared according to the method of Tetrahedron Asymmetry, (2006), 17(2), 268-274.

[0399] LCMS: m / z (ESI), 216.2 [M+H] + .

[0400] Step C: (S)-2-Bromo-4-(2-tert-butyldimethylsilyloxypropyl)pyridine (74)

[0401] Compound 74 was synthesized by using compound 73 instead of compound 34 as the starting material and referring to the method of compound 35.

[0402] LCMS: m / z (ESI), 332.2 [M+H] + .

[0403] Step D: (S)-2-tributylstannyl-4-(2-tert-butyldimethylsilyloxypropyl)pyridine (75)

[0404] Compound 75 was synthesized by using compound 74 instead of compound 35 as the starting material and referring to the method for compound 36.

[0405] LCMS: m / z (ESI), 542.2 [M+H] + .

[0406] Step E: 3-(4-(2-tert-Butyldimethylsilyloxypropyl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (76)

[0407] Compound 76 was synthesized by using compound 75 instead of compound 36 as the starting material and referring to the method of compound 37.

[0408] LCMS: m / z (ESI), 403.2 [M+H] + .

[0409] Step F: (S)-1-(2-(6-(((R)-1-(2-methoxy-5-fluorophenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (77)

[0410] Compound 77 was synthesized by referring to the method for compound 38 using compound 76 instead of compound 37 and compound 71 instead of compound 19 as raw materials.

[0411] LCMS: m / z (ESI), 422.1 [M+H] + .

[0412] Step G: (S)-1-(2-(6-(((R)-1-(2-hydroxy-5-fluorophenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (78)

[0413] (S)-1-(2-(6-(((R)-1-(2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (compound 77, 74 mg, 0.183 mol) was placed in dichloromethane (5 mL), and boron tribromide (1 M, 0.5 mL) was added. The mixture was stirred at 25°C for 2 hours, then neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate was concentrated and separated by column chromatography to give (S)-1-(2-(6-(((R)-1-(2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (25 mg, 35%).

[0414] LCMS: m / z (ESI), 408.1 [M+H] + .

[0415] Step H: (4R,7R,E)-5 5 -4,7-Dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-34)

[0416] Compound 1-34 was synthesized by using compound 78 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0417] LCMS: m / z (ESI), 390 [M+H] + .

[0418] Example 35: (4R,7R,E)-5 5 -4,7-Dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidin-5(1,2)-phenylcyclooctane (I-35)

[0419] Step A: (S)-1-(6-chloropyrimidin-4-yl)-2-propanol (79)

[0420] The synthesis of compound 79 was prepared according to the method of Tetrahedron Asymmetry, (2006), 17(2), 268-274.

[0421] LCMS: m / z (ESI), 173.2 [M+H] + .

[0422] Step B: (S)-6-chloro-4-(2-tert-butyldimethylsilyloxypropyl)pyrimidine (80)

[0423] Compound 80 was synthesized by using compound 79 instead of compound 73 as the starting material and referring to the method of compound 74.

[0424] LCMS: m / z (ESI), 287.0 [M+H] + .

[0425] Step C: (S)-6-tributyltin-4-(2-tert-butyldimethylsilyloxypropyl)pyrimidine (81)

[0426] Compound 81 was synthesized by using compound 80 instead of compound 74 as the starting material and referring to the method of compound 75.

[0427] LCMS: m / z (ESI), 543.2 [M+H] +.

[0428] Step D: 3-(6-(2-tert-Butyldimethylsilyloxypropyl)pyrimidin-4-yl)-6-chloroimidazo[1,2-b]pyridazine (82)

[0429] Compound 82 was synthesized by using compound 81 instead of compound 75 as the starting material and referring to the method of compound 76.

[0430] LCMS: m / z (ESI), 404.2 [M+H] + .

[0431] Step E: (S)-1-(2-(6-(((R)-1-(2-methoxy-5-fluoro-phenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (82-1)

[0432] Compound 82-1 was synthesized by using compound 82 instead of compound 76 as the starting material and referring to the method of compound 77.

[0433] LCMS: m / z (ESI), 423.1 [M+H] + .

[0434] Step F: (S)-1-(2-(6-(((R)-1-(2-hydroxy-5-fluorophenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyrimidinyl)propan-2-ol (82-2)

[0435] Compound 82-2 was synthesized by using compound 82-1 instead of compound 77 as the starting material and referring to the method of compound 78.

[0436] LCMS: m / z (ESI), 409.1 [M+H] + .

[0437] Step G: (4R, 7R, E)-5 5 -4,7-Dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidin-5(1,2)-phenylcyclooctane (I-35)

[0438] Compound 1-35 was synthesized by using compound 82-2 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0439] LCMS: m / z(ESI),391[M+H] + .

[0440] Example 36: (4R,7R,E)-5 5 -4,7-Dimethyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),5(3,2)-bipyridylcyclooctane (I-36)

[0441] Step A: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (76-1)

[0442] Compound 76-1 was synthesized by referring to the method of compound 77 using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 71 as the starting material.

[0443] LCMS: m / z (ESI), 423.1 [M+H] + .

[0444] Step B: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (76-2)

[0445] Compound 76-2 was synthesized by using compound 76-1 instead of compound 77 as the starting material and referring to the method of compound 78.

[0446] LCMS: m / z (ESI), 409.1 [M+H] + .

[0447] Step C: (4R,7R,E)-5 5 -4,7-Dimethyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),5(3,2)-bipyridylcyclooctane (I-36)

[0448] Compound 1-36 was synthesized by using compound 76-2 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0449] LCMS: m / z(ESI),391[M+H] + .

[0450] Example 37: (3 2 R,6R,E)-4 5-Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-37)

[0451] Step A: (S)-1-(2-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-3)

[0452] Compound 76-3 was synthesized by referring to the method of compound 77 using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 as the starting material.

[0453] LCMS: m / z (ESI), 448.1 [M+H] + .

[0454] Step B: (S)-1-(2-(6-((R)-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-4)

[0455] Compound 76-4 was synthesized by using 76-3 instead of compound 77 as the starting material and referring to the method of compound 78.

[0456] LCMS: m / z (ESI), 434.1 [M+H] + .

[0457] Step C: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-37)

[0458] Compound 1-37 was synthesized by using compound 76-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0459] LCMS: m / z (ESI), 416 [M+H] + .

[0460] Example 38: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-38)

[0461] Step A: (S)-1-(2-(6-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-5)

[0462] Compound 76-5 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 as the starting material and referring to the method of compound 77.

[0463] LCMS: m / z (ESI), 449.1 [M+H] + .

[0464] Step B: (S)-1-(2-(6-((R)-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-6)

[0465] Compound 76-6 was synthesized by using 76-5 instead of compound 77 as the starting material and referring to the method of compound 78.

[0466] LCMS: m / z (ESI), 435.1 [M+H] + .

[0467] Step C: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcyclooctane (I-38)

[0468] Compound 1-38 was synthesized by using compound 76-6 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0469] LCMS: m / z(ESI),417[M+H] + .

[0470] Example 39: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-39)

[0471] Step A: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-7)

[0472] Compound 76-7 was synthesized by using (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 as the starting material and referring to the method of compound 77.

[0473] LCMS: m / z (ESI), 466.1 [M+H] + .

[0474] Step B: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-8)

[0475] Compound 76-8 was synthesized by using 76-7 instead of compound 77 as the starting material and referring to the method of compound 78.

[0476] LCMS: m / z (ESI), 452.1 [M+H] + .

[0477] Step C: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-39)

[0478] Compound 1-39 was synthesized by using compound 76-8 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0479] LCMS: m / z(ESI),434[M+H] + .

[0480] Example 40: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcyclooctane (I-40)

[0481] Step A: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-9)

[0482] Compound 76-9 was synthesized by referring to the method of compound 77 using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 71 as the starting material.

[0483] LCMS: m / z (ESI), 467.1 [M+H] + .

[0484] Step B: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-10)

[0485] Compound 76-10 was synthesized by using compound 76-9 instead of compound 77 as the starting material and referring to the method of compound 78.

[0486] LCMS: m / z (ESI), 453.1 [M+H] + .

[0487] Step C: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcyclooctane (I-40)

[0488] Compound 1-40 was synthesized by using compound 76-10 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0489] LCMS: m / z(ESI),435[M+H] + .

[0490] Example 41: (3 3 R,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-pyrrolidine-5(1,2)-phenylcycloheptane (I-41)

[0491] Step A: (S)-2-Bromo-4-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (83-1)

[0492] Compound 83-1 was synthesized by following the method of compound 50 using compound (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine instead of p-methoxybenzyl alcohol as the starting material.

[0493] LCMS: m / z (ESI), 359.1 [M+H] + .

[0494] Step B: (S)-3-(4-(3-tert-Butyldimethylsilyloxypyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (83)

[0495] Compound 83 was synthesized using compound 83-1 instead of compound 50 as the starting material and referring to the method for compound 52.

[0496] LCMS: m / z (ESI), 430.1 [M+H] + .

[0497] Step C: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrolol (83-2)

[0498] Compound 83-2 was synthesized by using compound 83 instead of compound 76 as the starting material and referring to the method of compound 77.

[0499] LCMS: m / z (ESI), 449.1 [M+H] + .

[0500] Step D: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrolol (83-3)

[0501] Compound 83-3 was synthesized by using 83-2 instead of compound 77 as the starting material and referring to the method of compound 78.

[0502] LCMS: m / z (ESI), 435.1 [M+H] + .

[0503] Step E: (3 3 R,6R,E)-5 4-Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-pyrrolidine-5(1,2)-phenylcycloheptane (I-41)

[0504] Compound 1-41 was synthesized by using compound 83-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0505] LCMS: m / z(ESI),417[M+H] + .

[0506] Example 42: (3 3 S,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-pyrrolidine-5(1,2)-phenylcycloheptane (I-42)

[0507] Step A: (R)-2-Bromo-4-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (84-1)

[0508] Compound 84-1 was synthesized by following the method of Compound 50 using (R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine as the starting material instead of p-methoxybenzyl alcohol.

[0509] LCMS: m / z (ESI), 359.1 [M+H] + .

[0510] Step B: (R)-3-(4-(3-tert-Butyldimethylsilyloxypyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (84)

[0511] Compound 84 was synthesized using compound 84-1 instead of compound 50 as the starting material and referring to the method for compound 52.

[0512] LCMS: m / z (ESI), 430.1 [M+H] + .

[0513] Step C: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrolol (84-2)

[0514] Compound 84-2 was synthesized by using compound 84 instead of compound 76 as the starting material and referring to the method of compound 77.

[0515] LCMS: m / z (ESI), 449.1 [M+H] + .

[0516] Step D: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrolol (84-3)

[0517] Compound 84-3 was synthesized by using 84-2 instead of compound 77 as the starting material and referring to the method of compound 78.

[0518] LCMS: m / z (ESI), 435.1 [M+H] + .

[0519] Step E: (3 3 S,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-pyrrolidine-5(1,2)-phenylcycloheptane (I-42)

[0520] Compound 1-42 was synthesized by using compound 84-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0521] LCMS: m / z(ESI),417[M+H] + .

[0522] Example 43: (3 3 R,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-piperidin-5(1,2)-phenylcycloheptane (I-43)

[0523] Step A: (S)-2-Bromo-4-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (87-1)

[0524] Compound 87-1 was synthesized by referring to the method of compound 50 using compound (S)-3-((tert-butyldimethylsilyl)oxy)piperidine instead of p-methoxybenzyl alcohol as the starting material.

[0525] LCMS: m / z (ESI), 371.1 [M+H] + .

[0526] Step B: (S)-3-(4-(3-(tert-Butyldimethylsilyloxy)piperidin-1-yl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (87)

[0527] Compound 87 was synthesized using compound 87-1 instead of compound 50 as the starting material and referring to the method for compound 52.

[0528] LCMS: m / z (ESI), 444.1 [M+H] + .

[0529] Step C: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (87-2)

[0530] Compound 87-2 was synthesized by using compound 87 instead of compound 76 as the starting material and referring to the method of compound 77.

[0531] LCMS: m / z (ESI), 463.1 [M+H] + .

[0532] Step D: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (87-3)

[0533] Compound 87-3 was synthesized by using 87-2 instead of compound 77 as the starting material and referring to the method of compound 78.

[0534] LCMS: m / z (ESI), 449.0 [M+H] + .

[0535] Step E: (3 3 R,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-piperidin-5(1,2)-phenylcycloheptane (I-43)

[0536] Compound 1-43 was synthesized by using compound 87-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0537] LCMS: m / z(ESI),431[M+H] + .

[0538] Example 44: (3 3 S,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-piperidin-5(1,2)-phenylcycloheptane (I-44)

[0539] Step A: (R)-2-Bromo-4-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (88-1)

[0540] Compound 88-1 was synthesized by referring to the method of compound 50 using compound (R)-3-((tert-butyldimethylsilyl)oxy)piperidine instead of p-methoxybenzyl alcohol as the starting material.

[0541] LCMS: m / z (ESI), 371.1 [M+H] + .

[0542] Step B: (R)-3-(4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (88)

[0543] Compound 88 was synthesized using compound 88-1 instead of compound 50 as the starting material and referring to the method for compound 52.

[0544] LCMS: m / z (ESI), 444.1 [M+H] + .

[0545] Step C: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (88-2)

[0546] Compound 88-2 was synthesized by using compound 88 instead of compound 76 as the starting material and referring to the method of compound 77.

[0547] LCMS: m / z (ESI), 463.1 [M+H] + .

[0548] Step D: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (88-3)

[0549] Compound 88-3 was synthesized by using 88-2 instead of compound 77 as the starting material and referring to the method of compound 78.

[0550] LCMS: m / z (ESI), 449.1 [M+H] + .

[0551] Step E: (3 3 S,6R,E)-5 4 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)pyridine-3(1,3)-piperidin-5(1,2)-phenylcycloheptane (I-44)

[0552] Compound 1-44 was synthesized by using compound 88-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0553] LCMS: m / z(ESI),431[M+H] + .

[0554] Example 45: (8aR,11aR,16bR,E)-15-Fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-ethenylene-4,8-(ethenylene)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-45)

[0555] Step A: 2-Bromo-4-((1R,2S)-2-(tert-butyldimethylsilyloxy)cyclopentyl)pyridine (103-1)

[0556] The synthesis of compound 103-1 was prepared according to the method of Tetrahedron Asymmetry, 2004, 15, (3), 481-488.

[0557] LCMS: m / z (ESI), 358.1 [M+H] + .

[0558] Step B: 3-(4-((1R,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (103)

[0559] Compound 103 was synthesized using compound 103-1 instead of compound 50 as the starting material and following the method of compound 52.

[0560] LCMS: m / z (ESI), 429.1 [M+H] + .

[0561] Step C: (1S,2R)-2-(2-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (103-2)

[0562] Compound 103-2 was synthesized by using compound 103 instead of compound 76 as the starting material and referring to the method of compound 77.

[0563] LCMS: m / z (ESI), 474.1 [M+H] + .

[0564] Step D: (1S,2R)-(2-(6-((R)-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (103-3)

[0565] Compound 103-3 was synthesized by using 103-2 instead of compound 77 as the starting material and referring to the method of compound 78.

[0566] LCMS: m / z (ESI), 460.1 [M+H] + .

[0567] Step E: (8aR,11aR,16bR,E)-15-Fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-ethenylene-4,8-(methenylene)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-45)

[0568] Compound 1-45 was synthesized by using compound 103-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0569] LCMS: m / z(ESI),442[M+H] + .

[0570] Example 46: ((8aS,11aR,16bR,E)-15-Fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-ethenylene-4,8-(methenylene)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-46)

[0571] Step A: 2-Bromo-4-((1S,2S)-2-(tert-butyldimethylsilyloxy)cyclopentyl)pyridine (104-1)

[0572] The synthesis of compound 104-1 was prepared according to the method of Tetrahedron Asymmetry, 2004, 15, (3), 481-488.

[0573] LCMS: m / z (ESI), 358.1 [M+H] + .

[0574] Step B: 3-(4-((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (104)

[0575] Compound 104 was synthesized using compound 104-1 instead of compound 50 as the starting material and referring to the method for compound 52.

[0576] LCMS: m / z (ESI), 429.1 [M+H] + .

[0577] Step C: (1S,2S)-2-(2-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (104-2)

[0578] Compound 104-2 was synthesized by using compound 104 instead of compound 76 as the starting material and referring to the method of compound 77.

[0579] LCMS: m / z (ESI), 474.1 [M+H] + .

[0580] Step D: (1S,2S)-2-(2-(6-((R)-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (104-3)

[0581] Compound 104-3 was synthesized by using 104-2 instead of compound 77 as the starting material and referring to the method of compound 78.

[0582] LCMS: m / z (ESI), 460.1 [M+H] + .

[0583] Step E: (8aS,11aR,16bR,E)-15-Fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-ethenylene-4,8-(methenylene)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-46)

[0584] Compound 1-46 was synthesized by using compound 104-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0585] LCMS: m / z(ESI),442[M+H] + .

[0586] Example 47: (E)-4'-Fluorospiro[cyclopropane-1,6'-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane] (I-47)

[0587] Step A: 1-(5-Fluoro-2-methoxy-phenyl)cyclopropylamine (111)

[0588] The synthesis of compound 111 was prepared according to the method of CN112110938.

[0589] LCMS: m / z (ESI), 182.0 [M+H] + .

[0590] Step B: 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-N-(1-(5-fluoro-2-((4-methoxybenzyl)oxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-amine (112)

[0591] Compound 112 was synthesized by using compound 111 instead of compound 9 as the starting material and referring to the method of compound 10.

[0592] LCMS: m / z (ESI), 626.2 [M+H] + .

[0593] Step C: 4-Fluoro-2-(1-((3-(4-(hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclopropyl)phenol (112-1)

[0594] Compound 112-1 was synthesized by using compound 112 instead of compound 10 as the starting material and referring to the method of compound 11.

[0595] LCMS: m / z (ESI), 392 [M+H] + .

[0596] Step D: (E)-4'-Fluorospiro[cyclopropane-1,6'-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane] (I-47)

[0597] Compound I-47 was synthesized by using compound 112-1 instead of compound 39 as the raw material and referring to the method of compound I-9.

[0598] LCMS: m / z (ESI), 374 [M+H] + .

[0599] Example 48: (E)-5 4 -Fluoro-6,6-dimethyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-48)

[0600] Step A: 2-(5-Fluoro-2-methoxyphenyl)propyl-2-amine (113)

[0601] The synthesis of compound 113 was prepared according to the method of document US2016221948.

[0602] LCMS: m / z (ESI), 184.0 [M+H] + .

[0603] Step B: 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-N-(2-(5-fluoro-2-((4-methoxybenzyl)oxy)phenyl)-2-propyl)imidazo[1,2-b]pyridazin-6-amine (114)

[0604] Compound 114 was synthesized by using compound 113 instead of compound 9 as the starting material and referring to the method of compound 10.

[0605] LCMS: m / z (ESI), 628.2 [M+H] + .

[0606] Step C: 4-Fluoro-2-(1-((3-(4-(hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)-2-propyl)phenol (114-1)

[0607] Compound 114-1 was synthesized by using compound 114 instead of compound 10 as the starting material and referring to the method of compound 11.

[0608] LCMS: m / z(ESI),394[M+H] + .

[0609] Step D: (E)-5 4 -Fluoro-6,6-dimethyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (I-48)

[0610] Compound 1-48 was synthesized by using compound 114-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0611] LCMS: m / z (ESI), 376 [M+H] + .

[0612] Example 49: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-49)

[0613] Step A: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (115)

[0614] Compound 115 was synthesized by following the method of Compound 10, using (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of Compound 9.

[0615] LCMS: m / z (ESI), 420.1 [M+H] + .

[0616] Step B: (R)-4-Fluoro-2-(1-(3-(4-(2-hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (115-1)

[0617] Compound 115-1 was synthesized by using 115 instead of compound 10 as the starting material and referring to the method of compound 11.

[0618] LCMS: m / z (ESI), 406.1 [M+H] + .

[0619] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-49)

[0620] Compound 1-49 was synthesized by using compound 115-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0621] LCMS: m / z (ESI), 388 [M+H] + .

[0622] Example 50: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-50)

[0623] Step A: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (116)

[0624] Compound 116 was synthesized by following the method of compound 10, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 9.

[0625] LCMS: m / z (ESI), 438.1 [M+H] + .

[0626] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(2-hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (116-1)

[0627] Compound 116-1 was synthesized by using 116 instead of compound 10 as the starting material and referring to the method of compound 11.

[0628] LCMS: m / z (ESI), 424.1 [M+H] + .

[0629] Step C: (14bR,16S,E)-13,16-Difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-50)

[0630] Compound 1-50 was synthesized by using compound 116-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0631] LCMS: m / z (ESI), 406 [M+H] + .

[0632] Example 51: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-51)

[0633] Step A: (R)-(2-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)methanol (116-2)

[0634] Compound 116-2 was synthesized by following the method of compound 10, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 9.

[0635] LCMS: m / z (ESI), 421.1 [M+H] + .

[0636] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (116-3)

[0637] Compound 116-3 was synthesized by using 116-2 instead of compound 10 as the starting material and referring to the method of compound 11.

[0638] LCMS: m / z (ESI), 407.1 [M+H] + .

[0639] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-51)

[0640] Compound 1-51 was synthesized by using compound 116-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0641] LCMS: m / z (ESI), 389 [M+H] + .

[0642] Example 52: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-52)

[0643] Step A: (2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)methanol (116-4)

[0644] Compound 116-4 was synthesized by following the method of compound 10, using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 9.

[0645] LCMS: m / z (ESI), 439.1 [M+H] + .

[0646] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (116-5)

[0647] Compound 116-5 was synthesized using 116-4 instead of compound 10 as the starting material and following the method of compound 11.

[0648] LCMS: m / z (ESI), 425.1 [M+H] + .

[0649] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-52)

[0650] Compound 1-52 was synthesized by using compound 116-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0651] LCMS: m / z(ESI),407[M+H] + .

[0652] Example 53: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-53)

[0653] Step A: (R)-3-(4-(Hydroxyethyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (117)

[0654] Compound 117 was synthesized by following the method of Compound 38, using (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of Compound 37.

[0655] LCMS: m / z (ESI), 434.1 [M+H] + .

[0656] Step B: (R)-4-Fluoro-2-(1-(3-(4-hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (117-1)

[0657] Compound 117-1 was synthesized by using 117 instead of compound 10 as the starting material and referring to the method of compound 11.

[0658] LCMS: m / z (ESI), 420.1 [M+H] + .

[0659] Step C: (3 2 R,E)-4 5-Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-53)

[0660] Compound 1-53 was synthesized by using compound 117-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0661] LCMS: m / z(ESI),402[M+H] + .

[0662] Example 54: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-54)

[0663] Step A: (R)-3-(4-(Hydroxyethyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (118)

[0664] Compound 118 was synthesized by following the method of compound 38, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 37.

[0665] LCMS: m / z (ESI), 452.1 [M+H] + .

[0666] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (118-1)

[0667] Compound 118-1 was synthesized by using 118 instead of compound 10 as the starting material and referring to the method of compound 11.

[0668] LCMS: m / z (ESI), 438.1 [M+H] + .

[0669] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5-Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-54)

[0670] Compound 1-54 was synthesized by using compound 118-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0671] LCMS: m / z (ESI), 420 [M+H] + .

[0672] Example 55: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcycloheptane (I-55)

[0673] Step A: (R)-(2-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)ethanol (118-2)

[0674] Compound 118-2 was synthesized by following the method of compound 38, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19.

[0675] LCMS: m / z (ESI), 435.1 [M+H] + .

[0676] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118-3)

[0677] Compound 118-3 was synthesized by using 118-2 instead of compound 10 as the starting material and referring to the method of compound 11.

[0678] LCMS: m / z (ESI), 421.1 [M+H] + .

[0679] Step C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcycloheptane (I-55)

[0680] Compound 1-55 was synthesized by using compound 118-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0681] LCMS: m / z(ESI),403[M+H] + .

[0682] Example 56: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcycloheptane (I-56)

[0683] Step A: (2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)ethanol (118-4)

[0684] Compound 118-4 was synthesized by following the method of compound 10, using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 9.

[0685] LCMS: m / z (ESI), 453.1 [M+H] + .

[0686] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118-5)

[0687] Compound 118-5 was synthesized by using 118-4 instead of compound 10 as the starting material and referring to the method of compound 11.

[0688] LCMS: m / z (ESI), 439.1 [M+H] + .

[0689] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcycloheptane (I-56)

[0690] Compound 1-56 was synthesized by using compound 118-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0691] LCMS: m / z(ESI),421[M+H] + .

[0692] Example 57: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-57)

[0693] Step A: (R)-3-(6-(((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (117A)

[0694] Compound 117A was synthesized by following the method of compound 43, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19.

[0695] LCMS: m / z (ESI), 535.1 [M+H] + .

[0696] Step B: (R)-4-Fluoro-2-(1-(3-(4-(6-hydroxymethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (117A-1)

[0697] Compound 117A-1 was synthesized using 117A instead of compound 10 as the starting material and following the method for compound 11.

[0698] LCMS: m / z (ESI), 407.1 [M+H] + .

[0699] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-57)

[0700] Compound I-57 was synthesized by using compound 117A-1 instead of compound 39 as the raw material and referring to the method of compound I-9.

[0701] LCMS: m / z (ESI), 389 [M+H] + .

[0702] Example 58: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-58)

[0703] Step A: (R)-3-(6-(((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (118A)

[0704] Compound 118A was synthesized by following the method of compound 43, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19.

[0705] LCMS: m / z (ESI), 553.1 [M+H] + .

[0706] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(6-hydroxymethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (118A-1)

[0707] Compound 118A-1 was synthesized using 118A instead of compound 10 as the starting material and following the method for compound 11.

[0708] LCMS: m / z (ESI), 425.1 [M+H] + .

[0709] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-58)

[0710] Compound 1-58 was synthesized by using compound 118A-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0711] LCMS: m / z(ESI),407[M+H]+ .

[0712] Example 59: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-59)

[0713] Step A: (R)-(6-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)methanol (118A-2)

[0714] Compound 118A-2 was synthesized by following the method of compound 43, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19.

[0715] LCMS: m / z (ESI), 422.1 [M+H] + .

[0716] Step B: (R)-5-Fluoro-3-(1-(3-(6-(hydroxymethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118A-3)

[0717] Compound 118A-3 was synthesized using 118A-2 instead of compound 10 as the starting material and following the method of compound 11.

[0718] LCMS: m / z (ESI), 408.1 [M+H] + .

[0719] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-59)

[0720] Compound 1-59 was synthesized using compound 118A-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0721] LCMS: m / z (ESI), 390 [M+H] + .

[0722] Example 60: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-60)

[0723] Step A: (6-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)methanol (118A-4)

[0724] Compound 118A-4 was synthesized by following the method of compound 43, using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19.

[0725] LCMS: m / z (ESI), 440.1 [M+H] + .

[0726] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(6-(hydroxymethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118A-5)

[0727] Compound 118A-5 was synthesized using 118A-4 instead of compound 10 as the starting material and following the method of compound 11.

[0728] LCMS: m / z (ESI), 426.1 [M+H] + .

[0729] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-60)

[0730] Compound 1-60 was synthesized by using compound 118A-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0731] LCMS: m / z(ESI),408[M+H] + .

[0732] Example 61: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-61)

[0733] Step A: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (119)

[0734] The synthesis of compound 119 was prepared according to the method of document WO2016 / 196244.

[0735] LCMS: m / z (ESI), 259.0 [M+H] + .

[0736] Step B: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-tributyltinpyrimidine (120)

[0737] Compound 120 was synthesized by using compound 119 instead of compound 2 as the starting material and referring to the method of compound 3.

[0738] LCMS: m / z (ESI), 515.0 [M+H] + .

[0739] Step C: 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (121)

[0740] Compound 121 was synthesized by using compound 120 instead of compound 3 as the starting material and referring to the method of compound 5.

[0741] LCMS: m / z (ESI), 376.0 [M+H] + .

[0742] Step D: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (122)

[0743] Compound 122 was synthesized by referring to the method for compound 43, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 121 instead of compound 42.

[0744] LCMS: m / z (ESI), 535.1 [M+H]+ .

[0745] Step E: (R)-4-Fluoro-2-(1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (122-1)

[0746] Compound 122-1 was synthesized by using 122 instead of compound 10 as the starting material and referring to the method of compound 11.

[0747] LCMS: m / z (ESI), 407.1 [M+H] + .

[0748] Step F: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-61)

[0749] Compound 1-61 was synthesized by using compound 122-1 instead of compound 48-2 as the raw material and referring to the method of compound 1-11.

[0750] LCMS: m / z (ESI), 389 [M+H] + .

[0751] Example 62: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-62)

[0752] Step A: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (123)

[0753] Compound 123 was synthesized by following the method of Compound 43, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of Compound 19 and Compound 121 instead of Compound 42.

[0754] LCMS: m / z (ESI), 553.1 [M+H] + .

[0755] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (123-1)

[0756] Compound 123-1 was synthesized by using 123 instead of compound 10 as the starting material and referring to the method of compound 11.

[0757] LCMS: m / z (ESI), 425.1 [M+H] + .

[0758] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-62)

[0759] Compound 1-62 was synthesized by using compound 123-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0760] LCMS: m / z(ESI),407[M+H] + .

[0761] Example 63: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-63)

[0762] Step A: (R)-(4-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-yl)methanol (123-2)

[0763] Compound 123-2 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 121 instead of compound 42, and referring to the method of compound 43.

[0764] LCMS: m / z (ESI), 422.1 [M+H] + .

[0765] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (123-3)

[0766] Compound 123-3 was synthesized by using 123-2 instead of compound 10 as the starting material and referring to the method of compound 11.

[0767] LCMS: m / z (ESI), 408.1 [M+H] + .

[0768] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-63)

[0769] Compound 1-63 was synthesized by using compound 123-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0770] LCMS: m / z (ESI), 390 [M+H] + .

[0771] Example 64: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-64)

[0772] Step A: (4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-yl)methanol (123-4)

[0773] Compound 123-4 was synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and compound 121 instead of compound 42, following the method of compound 43.

[0774] LCMS: m / z (ESI), 440.1 [M+H] + .

[0775] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (123-5)

[0776] Compound 123-5 was synthesized by using 123-4 instead of compound 10 as the starting material and referring to the method of compound 11.

[0777] LCMS: m / z (ESI), 426.1 [M+H] + .

[0778] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-vinylidene-4,8-(oxazolidinyl)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-64)

[0779] Compound 1-64 was synthesized by using compound 123-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0780] LCMS: m / z(ESI),408[M+H] + .

[0781] Example 65: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-65)

[0782] Step A: 4-Hydroxymethyl-6-chloropyridazine (124)

[0783] The synthesis of compound 124 was prepared according to the method of Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, #23.

[0784] LCMS: m / z (ESI), 145.0 [M+H] + .

[0785] Step B: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloropyridazine (125)

[0786] Compound 125 was synthesized by using compound 124 instead of compound 1 as the starting material and referring to the method of compound 2.

[0787] LCMS: m / z (ESI), 259.0 [M+H] + .

[0788] Step C: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-6-tributyltinpyridazine (126)

[0789] Compound 126 was synthesized by using compound 125 instead of compound 2 as the starting material and referring to the method of compound 3.

[0790] LCMS: m / z (ESI), 515.0 [M+H] + .

[0791] Step D: 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridazin-6-yl)-6-chloroimidazo[1,2-b]pyridazine (127)

[0792] Compound 127 was synthesized by using compound 126 instead of compound 3 as the starting material and referring to the method of compound 5.

[0793] LCMS: m / z (ESI), 376.0 [M+H] + .

[0794] Step E: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (128)

[0795] Compound 128 was synthesized by referring to the method for compound 43, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 127 instead of compound 42.

[0796] LCMS: m / z (ESI), 535.1 [M+H] + .

[0797] Step F: (R)-4-Fluoro-2-(1-(3-(4-(hydroxymethyl)pyridazin-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (128-1)

[0798] Compound 128-1 was synthesized by using 128 instead of compound 10 as the starting material and referring to the method of compound 11.

[0799] LCMS: m / z (ESI), 407.1 [M+H] + .

[0800] Step F: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-65)

[0801] Compound 1-65 was synthesized by using compound 128-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0802] LCMS: m / z (ESI), 389 [M+H] +

[0803] Example 66: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-66)

[0804] Step A: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (129)

[0805] Compound 129 was synthesized by referring to the method for compound 43, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 127 instead of compound 42.

[0806] LCMS: m / z (ESI), 553.1 [M+H] + .

[0807] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyridazin-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (129-1)

[0808] Compound 129-1 was synthesized by using 129 instead of compound 10 as the starting material and referring to the method of compound 11.

[0809] LCMS: m / z (ESI), 425.1 [M+H] + .

[0810] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(methenylene)benzo[b]imidazo[5,1-h]pyrrolo[1,2-1][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-66)

[0811] Compound 1-66 was synthesized by using compound 129-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0812] LCMS: m / z(ESI),407[M+H] + .

[0813] Example 67: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-67)

[0814] Step A: (6-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)methanol (129-2)

[0815] Compound 129-2 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 127 instead of compound 42, and referring to the method of compound 43.

[0816] LCMS: m / z (ESI), 422.1 [M+H] + .

[0817] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxymethyl)pyridazin-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (129-3)

[0818] Compound 129-3 was synthesized using 129-2 instead of compound 10 as the starting material and following the method of compound 11.

[0819] LCMS: m / z (ESI), 408.1 [M+H] + .

[0820] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-ethenylene-4,8-(ethenylene)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-67)

[0821] Compound 1-67 was synthesized by using compound 129-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0822] LCMS: m / z (ESI), 390 [M+H] + .

[0823] Example 68: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-methoxy-imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-68)

[0824] Step A: (6-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)methanol (129-4)

[0825] Compound 129-4 was synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and compound 127 instead of compound 42, and referring to the method of compound 43.

[0826] LCMS: m / z (ESI), 440.1 [M+H] + .

[0827] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyrimidin-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (129-5)

[0828] Compound 129-5 was synthesized using 129-4 instead of compound 10 as the starting material and following the method of compound 11.

[0829] LCMS: m / z (ESI), 426.1 [M+H] + .

[0830] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-methanoyl)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-68)

[0831] Compound 1-68 was synthesized by using compound 129-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0832] LCMS: m / z(ESI),408[M+H] +

[0833] Example 69: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-69)

[0834] Step A: (R)-3-(6-(hydroxyethyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (130)

[0835] Compound 130 was synthesized by following the method of compound 48-1, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19.

[0836] LCMS: m / z (ESI), 435.1 [M+H] + .

[0837] Step B: (R)-4-Fluoro-2-(1-(3-(6-hydroxyethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (130-1)

[0838] Compound 130-1 was synthesized by using 130 instead of compound 10 as the starting material and referring to the method of compound 11.

[0839] LCMS: m / z (ESI), 421.1 [M+H] + .

[0840] Step C: (3 2 R,E)-4 5-Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-69)

[0841] Compound 1-69 was synthesized by using compound 130-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0842] LCMS: m / z(ESI),403[M+H] + .

[0843] Example 70: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-70)

[0844] Step A: (R)-3-(6-(hydroxyethyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (131)

[0845] Compound 131 was synthesized by following the method of compound 48-1, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19.

[0846] LCMS: m / z (ESI), 453.1 [M+H] + .

[0847] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(6-(hydroxyethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (131-1)

[0848] Compound 131-1 was synthesized by using 131 instead of compound 10 as the starting material and referring to the method of compound 11.

[0849] LCMS: m / z (ESI), 439.1 [M+H] + .

[0850] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5-Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-70)

[0851] Compound 1-70 was synthesized by using compound 131-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0852] LCMS: m / z(ESI),421[M+H] + .

[0853] Example 71: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-71)

[0854] Step A: (R)-(4-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-6-yl)ethanol (131-2)

[0855] Compound 131-2 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and referring to the method of compound 48-1.

[0856] LCMS: m / z (ESI), 436.1 [M+H] + .

[0857] Step B: (R)-5-Fluoro-3-(1-(3-(6-(hydroxyethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (131-3)

[0858] Compound 131-3 was synthesized using 131-2 instead of compound 10 as the starting material and referring to the method of compound 11.

[0859] LCMS: m / z (ESI), 422.1 [M+H] + .

[0860] Step C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-71)

[0861] Compound I-71 was synthesized by using compound 131-3 instead of compound 39 as the raw material and referring to the method of compound I-9.

[0862] LCMS: m / z(ESI),404[M+H] + .

[0863] Example 72: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-72)

[0864] Step A: (6-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-yl)ethanol (131-4)

[0865] Compound 131-4 was synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19, following the method of compound 48-1.

[0866] LCMS: m / z (ESI), 454.1 [M+H] + .

[0867] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(6-(hydroxyethyl)pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (131-5)

[0868] Compound 131-5 was synthesized using 131-4 instead of compound 10 as the starting material and referring to the method of compound 11.

[0869] LCMS: m / z (ESI), 440.1 [M+H] + .

[0870] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-72)

[0871] Compound 1-72 was synthesized by using compound 131-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0872] LCMS: m / z(ESI),422[M+H] + .

[0873] Example 73: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidin-5(3,2)-pyridylcyclooctane (I-73)

[0874] Step A: (R)-2-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (48-2)

[0875] Compound 48-2 was synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethanamine instead of compound 19 according to the method of compound 48-1.

[0876] LCMS: m / z (ESI), 410.1 [M+H] + .

[0877] Step B: (R)-5-Fluoro-3-(1-((3-(6-(hydroxyethyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (48-3)

[0878] Compound 48-3 was synthesized by using 48-2 instead of compound 10 as the raw material and referring to the method of compound 11.

[0879] LCMS: m / z (ESI), 396.1 [M+H] + .

[0880] Step C: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidin-5(3,2)-pyridylcyclooctane (I-73)

[0881] Compound 1-73 was synthesized by using compound 48-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0882] LCMS: m / z (ESI), 378 [M+H] + .

[0883] Example 74: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidin-5(3,2)-pyridylcyclooctane (I-74)

[0884] Step A: (R)-2-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (48-4)

[0885] Compound 48-4 was synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 according to the method of compound 48-1.

[0886] LCMS: m / z (ESI), 395.1 [M+H] + .

[0887] Step B: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-74)

[0888] Compound 1-74 was synthesized by using compound 48-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0889] LCMS: m / z(ESI),377[M+H] + .

[0890] Example 75: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(3,2)-pyridylcyclooctane (I-75)

[0891] Step A: (R)-4-Fluoro-2-(1-((3-(4-(2-hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (37-2)

[0892] Compound 37-2 was synthesized by following the method of compound 38, using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19.

[0893] LCMS: m / z (ESI), 394.1 [M+H]+ .

[0894] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (37-3)

[0895] Compound 37-3 was synthesized by using 37-2 instead of compound 10 as the raw material and referring to the method of compound 11.

[0896] LCMS: m / z (ESI), 380.1 [M+H] + .

[0897] Step C: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(3,2)-pyridylcyclooctane (I-75)

[0898] Compound 1-75 was synthesized by using compound 37-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0899] LCMS: m / z (ESI), 362 [M+H] + .

[0900] Example 76: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-76)

[0901] Step A: (R)-4-Fluoro-2-(1-((3-(4-(2-hydroxyethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (37-4)

[0902] Compound 37-4 was synthesized by following the method of compound 38, using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19.

[0903] LCMS: m / z (ESI), 394.1 [M+H] + .

[0904] Step B: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-76)

[0905] Compound 1-76 was synthesized by using compound 37-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0906] LCMS: m / z(ESI),377[M+H] +

[0907] Example 77: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidin-5(2,3)-pyridylcycloheptane (I-77)

[0908] Step A: (R)-(2-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (42-2)

[0909] Compound 42-2 was synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19, following the method of compound 43.

[0910] LCMS: m / z (ESI), 396.1 [M+H] + .

[0911] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxymethyl)pyrimidin-6-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (42-3)

[0912] Compound 42-3 was synthesized by using 42-2 instead of compound 10 as the raw material and referring to the method of compound 11.

[0913] LCMS: m / z (ESI), 382.1 [M+H] + .

[0914] Step C: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidin-5(2,3)-pyridylcycloheptane (I-77)

[0915] Compound 1-77 was synthesized by using compound 42-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0916] LCMS: m / z (ESI), 364 [M+H] + .

[0917] Example 78: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidin-5(1,2)-phenylcycloheptane (I-78)

[0918] Step A: (R)-(6-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (42-4)

[0919] Compound 42-4 was synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and referring to the method of compound 43.

[0920] LCMS: m / z (ESI), 381.1 [M+H] + .

[0921] Step B: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidin-5(1,2)-phenylcycloheptane (I-78)

[0922] Compound 1-78 was synthesized by using compound 42-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0923] LCMS: m / z(ESI),363[M+H] + .

[0924] Example 79: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyrimidin-5(2,3)-pyridylcycloheptane (I-79)

[0925] Step A: (R)-(2-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (121-2)

[0926] Compound 121-2 was synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19 and compound 121 instead of compound 42, and referring to the method of compound 43.

[0927] LCMS: m / z (ESI), 396.1 [M+H] + .

[0928] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (121-3)

[0929] Compound 121-3 was synthesized using 121-2 instead of compound 10 as the starting material and following the method of compound 11.

[0930] LCMS: m / z (ESI), 382.1 [M+H] + .

[0931] Step C: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazo[1,2-b]pyridazine-2(2,4)-pyrimidin-5(2,3)-pyridylcycloheptane (I-79)

[0932] Compound 1-79 was synthesized by using compound 121-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0933] LCMS: m / z (ESI), 364 [M+H] + .

[0934] Example 80: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyrimidin-5(1,2)-phenylcycloheptane (I-80)

[0935] Step A: (R)-(2-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (121-4)

[0936] Compound 121-4 was synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and compound 121 instead of compound 42, referring to the method of compound 43.

[0937] LCMS: m / z (ESI), 381.1 [M+H] + .

[0938] Step B: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyrimidin-5(1,2)-phenylcycloheptane (I-80)

[0939] Compound 1-80 was synthesized by using compound 121-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0940] LCMS: m / z(ESI),363[M+H] + .

[0941] Example 81: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridazine-5(2,3)-pyridylcycloheptane (I-81)

[0942] Step A: (R)-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-methanol (127-2)

[0943] Compound 127-2 was synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19 and compound 127 instead of compound 42, and referring to the method of compound 43.

[0944] LCMS: m / z (ESI), 396.1 [M+H] + .

[0945] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxymethyl)pyridazin-6-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (127-3)

[0946] Compound 127-3 was synthesized using 127-2 instead of compound 10 as the starting material and following the method of compound 11.

[0947] LCMS: m / z (ESI), 382.1 [M+H] + .

[0948] Step C: (6R,E)-5 5-Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridazine-5(2,3)-pyridylcycloheptane (I-81)

[0949] Compound I-81 was synthesized by using compound 127-3 instead of compound 39 as the raw material and referring to the method of compound I-9.

[0950] LCMS: m / z (ESI), 364 [M+H] + .

[0951] Example 82: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridazine-5(1,2)-phenylcycloheptane (I-82)

[0952] Step A: (R)-(6-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-methanol (127-4)

[0953] Compound 127-4 was synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and compound 127 instead of compound 42, referring to the method of compound 43.

[0954] LCMS: m / z (ESI), 381.1 [M+H] + .

[0955] Step B: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(3,5)-pyridazine-5(1,2)-phenylcycloheptane (I-82)

[0956] Compound 1-82 was synthesized by using compound 127-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0957] LCMS: m / z(ESI),363[M+H] + .

[0958] Example 83: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidin-5(3,2)-pyridylcyclooctane (I-83)

[0959] Step A: (R)-2-(2-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (137-2)

[0960] Compound 137-2 was synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19 and compound 137 instead of compound 42, and referring to the method of compound 43.

[0961] LCMS: m / z (ESI), 410.1 [M+H] + .

[0962] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (137-3)

[0963] Compound 137-3 was synthesized using 137-2 instead of compound 10 as the starting material and following the method of compound 11.

[0964] LCMS: m / z (ESI), 396.1 [M+H] + .

[0965] Step C: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidin-5(3,2)-pyridylcyclooctane (I-83)

[0966] Compound 1-83 was synthesized by using compound 137-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0967] LCMS: m / z (ESI), 378 [M+H] + .

[0968] Example 84: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidin-5(3,2)-pyridylcyclooctane (I-74)

[0969] Step A: Example 129: (R)-2-(2-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (137-4)

[0970] Compound 137-4 was synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and compound 137 instead of compound 42, referring to the method of compound 43.

[0971] LCMS: m / z (ESI), 395.1 [M+H] + .

[0972] Step B: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-5(1,2)-phenylcyclooctane (I-84)

[0973] Compound 1-84 was synthesized by using compound 137-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0974] LCMS: m / z(ESI),377[M+H] + .

[0975] Example 85: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-85)

[0976] Step A: (R)-3-(4-(Hydroxyethyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (138)

[0977] Compound 138 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 137 instead of compound 48, and referring to the method of compound 48-1.

[0978] LCMS: m / z (ESI), 435.1 [M+H] + .

[0979] Step B: (R)-4-Fluoro-2-(1-(3-(4-hydroxyethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (138-1)

[0980] Compound 138-1 was synthesized by using 138 instead of compound 10 as the starting material and referring to the method of compound 11.

[0981] LCMS: m / z (ESI), 421.1 [M+H] + .

[0982] Step C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-85)

[0983] Compound 1-85 was synthesized by using compound 138-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0984] LCMS: m / z(ESI),403[M+H] + .

[0985] Example 86: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-86)

[0986] Step A: (R)-3-(4-(Hydroxyethyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (139)

[0987] Compound 139 was synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 137 instead of compound 48, and referring to the method of compound 48-1.

[0988] LCMS: m / z (ESI), 453.1 [M+H] + .

[0989] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (139-1)

[0990] Compound 139-1 was synthesized by using 139 instead of compound 10 as the starting material and referring to the method of compound 11.

[0991] LCMS: m / z (ESI), 439.1 [M+H] +.

[0992] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-86)

[0993] Compound 1-86 was synthesized by using compound 139-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[0994] LCMS: m / z(ESI),421[M+H] + .

[0995] Example 87: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-87)

[0996] Step A: (R)-(4-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-6-yl)ethanol (139-2)

[0997] Compound 139-2 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 137 instead of compound 48, referring to the method of compound 48-1.

[0998] LCMS: m / z (ESI), 436.1 [M+H] + .

[0999] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (139-3)

[1000] Compound 139-3 was synthesized using 139-2 instead of compound 10 as the starting material and following the method of compound 11.

[1001] LCMS: m / z (ESI), 422.1 [M+H] + .

[1002] Step C: (3 2R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-87)

[1003] Compound 1-87 was synthesized by using compound 139-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1004] LCMS: m / z(ESI),404[M+H] + .

[1005] Example 88: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-88)

[1006] Step A: (2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)ethanol (139-4)

[1007] Compound 139-4 was synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and compound 137 instead of compound 48, referring to the method of compound 48-1.

[1008] LCMS: m / z (ESI), 454.1 [M+H] + .

[1009] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (139-5)

[1010] Compound 139-5 was synthesized using 139-4 instead of compound 10 as the starting material and following the method of compound 11.

[1011] LCMS: m / z (ESI), 440.1 [M+H] + .

[1012] Step C: (3 2 R,3 4S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-88)

[1013] Compound 1-88 was synthesized by using compound 139-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1014] LCMS: m / z(ESI),422[M+H] + .

[1015] Example 89: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidin-5(3,2)-pyridylcyclooctane (I-89)

[1016] Step A: (R)-2-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-ethanol (143-2)

[1017] Compound 143-2 was synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19 and compound 143 instead of compound 48, and referring to the method of compound 48-1.

[1018] LCMS: m / z (ESI), 410.1 [M+H] + .

[1019] Step B: (R)-5-Fluoro-3-(1-((3-(5-(hydroxyethyl)pyrimidin-3-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (143-3)

[1020] Compound 143-3 was synthesized using 143-2 instead of compound 10 as the starting material and following the method of compound 11.

[1021] LCMS: m / z (ESI), 396.1 [M+H] + .

[1022] Step C: (4R,E)-5 5-Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-5(3,2)-pyridylcyclooctane (I-89)

[1023] Compound 1-89 was synthesized by using compound 143-3 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1024] LCMS: m / z (ESI), 378 [M+H] + .

[1025] Example 90: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-5(3,2)-pyridylcyclooctane (I-90)

[1026] Step A: Example 129: (R)-2-(6-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-ethanol (143-4)

[1027] Compound 143-4 was synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and compound 143 instead of compound 48, following the method of compound 48-1.

[1028] LCMS: m / z (ESI), 395.1 [M+H] + .

[1029] Step B: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-5(1,2)-phenylcyclooctane (I-90)

[1030] Compound 1-90 was synthesized by using compound 143-4 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1031] LCMS: m / z(ESI),377[M+H] + .

[1032] Example 91: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-91)

[1033] Step A: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)ethyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (144)

[1034] Compound 144 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 143 instead of compound 48, and referring to the method of compound 48-1.

[1035] LCMS: m / z (ESI), 435.1 [M+H] + .

[1036] Step B: (R)-4-Fluoro-2-(1-(3-(4-(hydroxyethyl)pyridazin-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (144-1)

[1037] Compound 144-1 was synthesized by using 144 instead of compound 10 as the starting material and referring to the method of compound 11.

[1038] LCMS: m / z (ESI), 421.1 [M+H] + .

[1039] Step C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-91)

[1040] Compound 1-91 was synthesized by using compound 144-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1041] LCMS: m / z(ESI),403[M+H] + .

[1042] Example 92: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-92)

[1043] Step A: (R)-3-(4-(((tert-Butyldimethylsilyl)oxy)ethyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (145)

[1044] Compound 145 was synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 143 instead of compound 48, and referring to the method of compound 48-1.

[1045] LCMS: m / z (ESI), 439.1 [M+H] + .

[1046] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyridazin-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (145-1)

[1047] Compound 145-1 was synthesized by using 145 instead of compound 10 as the starting material and referring to the method of compound 11.

[1048] LCMS: m / z (ESI), 439.1 [M+H] + .

[1049] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-92)

[1050] Compound 1-92 was synthesized by using compound 145-1 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1051] LCMS: m / z(ESI),421[M+H] + .

[1052] Example 93: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-93)

[1053] Step A: (R)-(6-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridazin-4-yl)ethanol (145-2)

[1054] Compound 145-2 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 143 instead of compound 48, and referring to the method of compound 48-1.

[1055] LCMS: m / z (ESI), 436.1 [M+H] + .

[1056] Step B: (R)-5-Fluoro-3-(1-(3-(5-(hydroxyethyl)pyrimidin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (145-3)

[1057] Compound 145-3 was synthesized using 145-2 instead of compound 10 as the starting material and following the method of compound 11.

[1058] LCMS: m / z (ESI), 422.1 [M+H] + .

[1059] Step C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-93)

[1060] Compound I-93 was synthesized by using compound 145-3 instead of compound 39 as the raw material and referring to the method of compound I-9.

[1061] LCMS: m / z(ESI),404[M+H] + .

[1062] Example 94: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-94)

[1063] Step A: (2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)ethanol (145-4)

[1064] Compound 145-4 was synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and compound 143 instead of compound 48, following the method of compound 48-1.

[1065] LCMS: m / z (ESI), 454.1 [M+H] + .

[1066] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(5-(hydroxyethyl)pyridazin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (145-5)

[1067] Compound 145-5 was synthesized using 145-4 instead of compound 10 as the starting material and following the method of compound 11.

[1068] LCMS: m / z (ESI), 440.1 [M+H] + .

[1069] Step C: (3 2 R,3 4 S,E)-3 4 ,4 5 -Difluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(3,5)-pyridazine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-94)

[1070] Compound 1-94 was synthesized by using compound 145-5 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1071] LCMS: m / z(ESI),422[M+H] + .

[1072] Example 95: (3 2 R,6S,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-95)

[1073] Step A: (R)-1-(2-chloropyrimidin-4-yl)-2-propanol (147)

[1074] Compound 147 was synthesized by following the method of Compound 79 using 2-chloro-4-iodopyrimidine as the starting material instead of Compound 78.

[1075] LCMS: m / z (ESI), 173.0 [M+H] + .

[1076] Step B: (R)-4-(2-((tert-Butyldimethylsilyl)oxy)propyl)-2-chloropyrimidine (148)

[1077] Compound 148 was synthesized by using compound 147 instead of compound 1 as the starting material and referring to the method of compound 2.

[1078] LCMS: m / z (ESI), 287.0 [M+H] + .

[1079] Step C: (R)-4-(2-((tert-butyldimethylsilyl)oxy)propyl)-2-tributyltinpyrimidine (149)

[1080] Compound 149 was synthesized by using compound 148 instead of compound 2 as the starting material and referring to the method for compound 3.

[1081] LCMS: m / z (ESI), 543.0 [M+H] + .

[1082] Step D: (R)-3-(4-(2-((tert-butyldimethylsilyl)oxy)propyl)pyrimidin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (150)

[1083] Compound 150 was synthesized by using compound 149 instead of compound 3 as the starting material and referring to the method of compound 5.

[1084] LCMS: m / z (ESI), 404.0 [M+H] + .

[1085] Step E: (R)-1-(2-(6-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)ethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-propanol (151)

[1086] Compound 151 was synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and compound 150 instead of compound 48, following the method of compound 48-1.

[1087] LCMS: m / z (ESI), 436.1 [M+H] + .

[1088] Step F: (R)-5-Fluoro-3-(1-(3-(4-((R)-hydroxypropyl))pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (152)

[1089] Compound 152 was synthesized by using 151 instead of compound 10 as the starting material and referring to the method for compound 11.

[1090] LCMS: m / z (ESI), 436.1 [M+H] + .

[1091] Step G: (3 2 R,6S,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-95)

[1092] Compound 1-95 was synthesized by using compound 152 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1093] LCMS: m / z(ESI),418[M+H] + .

[1094] Example 96: (3 2 R,3 4 S,6S,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-96)

[1095] Step A: (R)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-propanol (153)

[1096] Compound 153 was synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and compound 150 instead of compound 48, and referring to the method of compound 48-1.

[1097] LCMS: m / z (ESI), 454.1 [M+H] + .

[1098] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-((R)-hydroxypropyl)pyrimidin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (154)

[1099] Compound 154 was synthesized by using 153 instead of compound 10 as the starting material and referring to the method for compound 11.

[1100] LCMS: m / z (ESI), 454.1 [M+H] + .

[1101] Step C: (3 2 R,3 4 S,6S,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrolidinylcycloheptane (I-96)

[1102] Compound 1-96 was synthesized by using compound 154 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1103] LCMS: m / z(ESI),436[M+H] + .

[1104] Example 97: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-97)

[1105] Step A: (R)-3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (155)

[1106] Compound 155 was synthesized by following the method of compound 82-1, using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71.

[1107] LCMS: m / z (ESI), 449.1 [M+H] + .

[1108] Step B: (R)-4-Fluoro-2-(1-(3-(6-(S)-2-hydroxypropyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (156)

[1109] Compound 156 was synthesized by using 155 instead of compound 77 as the starting material and referring to the method of compound 78.

[1110] LCMS: m / z (ESI), 434.1 [M+H] + .

[1111] Step C: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-97)

[1112] Compound 1-97 was synthesized by using compound 156 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1113] LCMS: m / z(ESI),417[M+H] + .

[1114] Example 98: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (I-98)

[1115] Step A: (R)-3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (157)

[1116] Compound 157 was synthesized by following the method of compound 82-1, using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71.

[1117] LCMS: m / z (ESI), 467.1 [M+H]+ .

[1118] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (158)

[1119] Compound 158 was synthesized by using 157 instead of compound 77 as the starting material and referring to the method of compound 78.

[1120] LCMS: m / z (ESI), 453.1 [M+H] + .

[1121] Step C: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazo[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-98)

[1122] Compound 1-98 was synthesized by using compound 158 instead of compound 39 as the raw material and referring to the method of compound 1-9.

[1123] LCMS: m / z(ESI),435[M+H] + .

[1124] Example 99: Biological Evaluation

[1125] Experiment 1: Inhibition of TRKA and TRKA(F589L) kinase activity by compounds

[1126] Experimental method: Compound preparation: The compounds of Examples 1-98 were respectively dissolved in 100% DMSO to prepare 10 mM stock solutions, which were frozen at -20°C.

[1127] The chemical structure of the compound Loxo-195 is as follows. It is commercially available and can be prepared according to WO2010 / 48314.

[1128] The chemical structure of compound TPX-0005 is as follows. It is commercially available and can be prepared according to WO2017004342.

[1129] Kinase reaction process: Prepare 1× Kinase buffer; Preparation of compound concentration gradient: The test concentration of the compounds of Test Examples 1-96 and compound Loxo-101 was 1000 nM, which was diluted to 100 times the final concentration of 100% DMSO solution in a 384-well plate. The compound was diluted 3-fold with Presision to form 10 concentrations (1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.4, 0.16, 0.15, and 0.05 nM). Use an Echo550 dispenser to transfer 250 nL of compound at 100x final concentration to the destination plate, OptiPlate-384F. Prepare a kinase solution at 2.5x final concentration with 1× Kinase buffer. Add 10 μL of 2.5x final concentration kinase solution to the compound wells and positive control wells, and 10 μL of 1× Kinase buffer to the negative control wells. Centrifuge at 1000 rpm for 30 seconds, vortex the reaction plate to mix, and incubate at room temperature for 10 minutes. Prepare a mixture of ATP and Kinase substrate 22 at 5 / 3 final concentration with 1× Kinase buffer. Initiate the reaction by adding 15 μL of a 5 / 3 final concentration mixture of ATP and substrate. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for the appropriate time. Stop the kinase reaction by adding 30 μL of stop assay solution, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a Caliper EZ Reader.

[1130] Data analysis: Calculation formula:

[1131] %Inhibition=(Conversion%_max-conversion%_sample)÷(Conversion%_max-c onversion%_min)x 100

[1132] Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min is the mean of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; Conversion%_max is the mean of the ratio of the positive control wells, representing the conversion rate reading of the wells without compound inhibition. The concentration-effect curve was fitted using the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis. The log(inhibitor) vs. response-variable slope analysis software GraphPad Prism 5 was used to fit the concentration-effect curve to obtain the IC value of each compound on the enzyme activity. 50 The calculation formula is:

[1133] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[1134] Where X represents the concentration of the test compound, Y represents the inhibition rate of the test compound at concentration X, Top refers to the maximum response, Bottom refers to the baseline response, and Hill Slope refers to the slope of the curve.

[1135] IC values ​​of each compound on enzyme activity 50 The values ​​are shown in Tables 1 and 2 below.

[1136] Table 1. Effects of different compounds on the kinase TRKA WT In vitro inhibition assay IC 50 Test results (nM)

[1137] The experimental results show that the vast majority of compounds in this application are active in the kinase TRKA WT The inhibitory abilities in the in vitro inhibition experiments were very strong.

[1138] Table 2. Effects of different compounds on TRKA kinase F589L In vitro inhibition assay IC 50 Test results (nM)

[1139] ----Indicates not detected or not found

[1140] The experimental results show that the vast majority of compounds in this application are active in the kinase TRKA F589L The inhibitory ability in the in vitro inhibition experiment was stronger than that of LOXO-195.

[1141] Experiment 2: Inhibitory effect of compounds on the growth of Ba / F3-TPM3-NTRK1-G667C cells

[1142] Reagents:

[1143] Cell lines:

[1144] Compound solution preparation: In a biosafety cabinet, the compounds of Examples 1-96 and compound Loxo-101 were pre-dissolved in 100% DMSO to prepare 10 mM stock solutions and stored frozen at -20°C. The compound stock solutions were serially diluted with DMSO: a clean, sterile, V-bottomed 96-well microplate was placed in a biosafety cabinet. First, 4 μL of DMSO was added to well B2, and 10 μL of DMSO was added to wells B3-B11. Then, 6 μL of the 10 mM compound stock solution was added to well B2 and mixed by pipetting up and down 10 times. At this point, the compound concentration in well B2 was 6 mM, 100% DMSO. 5 μL of the solution from well B2 was transferred to well B3 and mixed by pipetting up and down 10 times. The solution was then diluted sequentially until the dilution reached B10. Well B11 was diluted with only DMSO, without the test compound.

[1145] To prepare a 6X compound solution (6-fold dilution, where X represents the dilution factor) (starting at a concentration of 10 μM), place a clean, sterile, V-bottomed 96-well microplate in a biosafety cabinet. Add 99 μL of cell culture medium to each well of plates B2-G11. Using a 12-channel pipette, add 1 μL of the compound solution prepared in the previous step to the corresponding well. Pipette the solution up and down 10 times to mix. The maximum compound concentration at this point is 60 μM.

[1146] Treat cells with compounds: Remove the inoculated cell culture plate from the incubator; pipette 20 μL of compound solution from each well into the corresponding cell culture well at the lowest pipetting speed, allowing the cells to adhere to the wall and avoid contact with the bottom of the culture plate; gently shake the cell culture plate to mix the compound solution, then return the cell culture plate to the incubator and continue culturing for 72 hours.

[1147] At this time, the maximum treatment concentration of the compound is 10μM. After the cells were treated for 72 hours, the Cell TiterGlo (CTG) assay was performed. First, the cell culture plate was removed from the CO2 incubator and placed at room temperature for 30 minutes to ensure uniform temperature throughout the culture plate; the Cell TiterGlo reagent prepared in advance according to the instructions was taken out and placed at room temperature to melt; then 60μL of Cell TiterGlo reagent was added to each well containing cells, and the plate was placed on a horizontal shaker at room temperature in the dark, at 225rpm, and incubated for 1 hour; then, the plate was read using the Tecan Spark microplate reader according to the chemiluminescence method according to the method in the instructions, and the IC values ​​of some compounds for different cell lines were measured. 50 As shown in Table 3 below:

[1148] Table 3: In vitro inhibition IC values ​​of different compounds on Ba / F3-TPM3-NTRK1-G667C cells50 Test results (nM)

[1149] ----Indicates not detected or not found

[1150] The experimental results show that most of the compounds in this application have stronger inhibitory abilities than compound Loxo-195 in the in vitro inhibition assay of Ba / F3-TPM3-NTRK1-G667C cells. Compounds I-2, I-39, I-40, I-50, I-52, I-54, I-56, I-58, I-60, I-62, I-64, I-66, I-68, I-70, I-72, I-86, I-88, I-92, I-94, I-96, and I-98 have stronger inhibitory abilities than compound TPX-0005 in the in vitro inhibition assay of Ba / F3-TPM3-NTRK1-G667C cells.

[1151] Table 4: In vitro inhibition IC values ​​of different compounds on Ba / F3-TPM3-NTRK1-G595R cells 50 Test results (nM)

[1152] The experimental results show that the compounds I-39, I-40, I-50, I-52, I-54, I-56, I-58, I-60, I-62, I-64, I-66, I-68, I-70, I-72, I-86, I-88, I-92, I-94, I-96, and I-98 in the present application have stronger inhibitory abilities in the in vitro inhibition experiment of Ba / F3-TPM3-NTRK1-G595R cells than the compounds Loxo-195 and TPX-0005.

[1153] Table 5: In vitro inhibition IC values ​​of different compounds on Ba / F3-TPM3-NTRK1-WT cells 50 Test results (nM)

[1154] The experimental results show that the compounds I-39, I-40, I-50, I-52, I-54, I-56, I-58, I-60, I-62, I-64, I-66, I-68, I-70, I-72, I-86, I-88, I-92, I-94, I-96, and I-98 in the present application have stronger inhibitory abilities in the in vitro inhibition experiment of Ba / F3-TPM3-NTRK1-WT cells than the compounds Loxo-195 and TPX-0005.

[1155] Experiment 3: Pharmacodynamic evaluation of the compound in the NOD-SCID mouse Ba / F3-TPM3-NTRK1-WT subcutaneous transplant tumor model

[1156] Cell culture: Ba / F3-TPM3-NTRK1-WT cells were cultured in RPMI 1640 medium containing 10% FBS. Ba / F3-TPM3-NTRK1-WT cells in the logarithmic growth phase were collected, the total number of cells required was calculated, and then resuspended in an appropriate volume of PBS mixture (PBS:Matrigel = 1:1 (v / v)) at a cell suspension concentration of 5x10 6 / 0.1mL, used for subcutaneous inoculation on the right side of NOD-SCID mice.

[1157] Methods: On day 0, all animals were subcutaneously inoculated with 0.1 mL of a cell suspension (PBS:Matrigel = 1:1, V / V) (5 × 106 Ba / F3-TPM3-NTRK1-WT cells) on the right side of the back. 3 At the beginning of group drug administration, the average tumor volume of the animals in the group was 178.3 mm 3 The experiment was divided into two groups: Group 1 (Vehicle) and Group 2 (10 mg / kg, I-52). Six animals were included in each group, for a total of two groups. All groups received oral administration via gavage, with a dosing frequency of BID for a total of 29 days.

[1158] Tumor volume inhibition rate TGI TV (%): TGI% = (1-ΔT / ΔC) × 100%; where ΔC is the tumor volume of the control group, C t -C0, C0 is the average tumor volume of the control group when grouped, C t is the average tumor volume of the control group after treatment, and ΔT is the tumor volume T of the treatment group t -T0, the average tumor volume of the control group at T0, T t is the average tumor volume of the control group after treatment.

[1159] According to the tumor inhibition rate (TGI TV ) were used to evaluate the pharmacodynamic activity, and the tolerance was evaluated based on the changes in animal body weight and mortality.

[1160] Table 6 Pharmacological analysis of tumor volume on day 29 in the Ba / F3-TMP3-NTRK1-WT subcutaneous transplant tumor model

[1161] Table 7 Original record of average tumor volume of experimental animals during the experiment (unit: mm 3 )

[1162] Compared to the tumor volume in the Vehicle (Group-1) group, the average tumor volume in Group-2 was significantly different. At the end of the experiment, tumors from each group were collected and weighed, and it was found that all mice in Group-2 had no tumors, achieving a tumor regression rate of 100%.

[1163] The results showed that the test compound I-52 had significant pharmacodynamic activity in inhibiting the proliferation of BA / F3-TPM3-NTRK1-WT subcutaneous transplanted tumors in mice. At a dose of 10 mg / kg, the tumor regression rate reached 100%, and it was well tolerated. There was no significant change in the weight of the mice, and no significant clinical abnormalities were observed.

[1164] Experiment 4: Pharmacodynamic evaluation of the compound in the NOD-SCID mouse Ba / F3-TPM3-NTRK1-G667C subcutaneous transplant tumor model

[1165] Cell culture: Ba / F3-TPM3-NTRK1-G667C cells were cultured in RPMI1640 medium containing 10% FBS. Ba / F3-TPM3-NTRK1-G667C cells in the logarithmic growth phase were collected, the total number of cells required was calculated, and then resuspended in an appropriate volume of PBS mixture (PBS:Matrigel = 1:1 (v / v)) at a cell suspension concentration of 5x10 6 / 0.1mL, used for subcutaneous inoculation on the right side of NOD-SCID mice.

[1166] Methods: On Day 0, all animals were subcutaneously inoculated with 0.1 mL of a cell suspension (5×106 Ba / F3-TPM3-NTRK1-G667C cells) in PBS:Matrigel (1:1, v / v) on the right side of their back. Once tumors grew to an average volume of 197.2 mm3, group dosing began. The average tumor volume of the enrolled animals was 197.2 mm3. The experiment was divided into two groups: Group 1 (Vehicle) and Group 2 (10 mg / kg, I-52). Each group consisted of 6 animals, for a total of 2 groups. All groups were administered orally by gavage twice daily for a total of 29 days.

[1167] Tumor volume inhibition rate TGI TV (%): TGI% = (1-ΔT / ΔC) × 100%; where ΔC is the tumor volume of the control group, C t -C0, C0 is the average tumor volume of the control group when grouped, C t is the average tumor volume of the control group after treatment, and ΔT is the tumor volume T of the treatment group t -T0, the average tumor volume of the control group at T0, Tt is the average tumor volume of the control group after treatment.

[1168] According to the tumor inhibition rate (TGI TV ) were used to evaluate the pharmacodynamic activity, and the tolerance was evaluated based on the changes in animal body weight and mortality.

[1169] Table 8 Pharmacodynamic analysis of tumor volume on day 29 in the Ba / F3-TMP3-NTRK1-G667C subcutaneous transplant tumor model

[1170] Table 9 Original record of average body weight of experimental animals during the experiment (unit: g)

[1171] Compared with the tumor volume of the Vehicle (Group-1) group, the average tumor volume of Group-2 was significantly different. Tumors were collected and weighed in each group at the end of the experiment. The comparison of the mean tumor weights of each group was consistent with the analysis results of the mean tumor volume.

[1172] The results showed that the test compound I-52 had significant pharmacodynamic activity in inhibiting the proliferation of BA / F3-TPM3-NTRK1-G667C subcutaneous transplanted tumors in mice. At a dose of 10 mg / kg, the tumor growth inhibition rate reached 84%, and it was well tolerated. There was no significant change in the weight of the mice, and no significant clinical abnormalities were observed.

[1173] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A macrocyclic imidazo[1,2-b]pyridazine compound of formula I or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in: W 1 、W 2 、W 3 、W 4 、W 5 are each independently selected from carbon or nitrogen, and W 1 、W 2 、W 3 、W 4 、W 5 At least one of them is nitrogen; R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C6 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C6 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the carbon atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 to 4 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C3-C6 cycloalkoxy; R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkoxy; R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, substituted or unsaturated C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkoxy, or R 5 does not exist; L is selected from -O-, -NH-, substituted or unsubstituted branched or straight-chain C1-C6 alkylene, substituted or unsubstituted branched or straight-chain C1-C6 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyleneoxy, substituted or unsubstituted branched or straight-chain C1-C6 alkylenethio, substituted or unsubstituted saturated or unsaturated 3-6 membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered azacycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered thiacycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered thiacycloalkylene, substituted or unsubstituted saturated or unsaturated a 3- to 6-membered oxacycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 3- to 6-membered azacycloalkyleneoxy group, or a substituted or unsubstituted saturated or unsaturated 3- to 6-membered thiacycloalkyleneoxy group, wherein the "substituted" refers to a substituent optionally containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxyl, carboxyl, carbonyl, sulfonyl, amino, C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyloxy, a 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, and a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S.

2. The macrocyclic imidazo[1,2-b]pyridazine compound of formula I according to claim 1, or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, characterized in that: Preferably, R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C4 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C4 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the carbon atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, and C3-C6 cycloalkoxy; More preferably, R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the carbon atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C3 alkyl, and C5-C6 cycloalkyl; More preferably, R 1 、R 2 、R 3 are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, or R 1 and R 2 Together with the nitrogen and carbon atoms to which they are attached, they form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, or R 2 and R 3 Together with the C atoms to which they are connected, they form a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl group; wherein the "substituted" refers to optionally containing 1 or 2 groups selected from deuterium, hydroxyl, and halogen; Preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C1-C4 alkyl, saturated or unsaturated C5-C6 cycloalkyl, saturated or unsaturated C1-C4 alkoxy, saturated or unsaturated C5-C6 cycloalkoxy; More preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C1-C3 alkyl, saturated or unsaturated C1-C3 alkoxy; More preferably, R 4 Selected from hydrogen, deuterium, halogen, saturated or unsaturated C1-C3 alkyl, saturated or unsaturated C1-C3 alkoxy; More preferably, R 4 selected from hydrogen, deuterium or halogen; Preferably, R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C4 alkyl, saturated or unsaturated C5-C6 cycloalkyl, substituted or unsaturated C1-C4 alkoxy, saturated or unsaturated C5-C6 cycloalkoxy, or R 5 does not exist; More preferably, R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C3 alkyl, substituted or unsaturated C1-C3 alkoxy or R 5 does not exist; More preferably, R 5 is selected from hydrogen, deuterium, halogen, saturated or unsaturated C1-C3 alkyl, substituted or unsaturated C1-C3 alkoxy or R 5 does not exist; More preferably, R 5 Selected from hydrogen, deuterium, halogen, or R 5 Does not exist.

3. The macrocyclic imidazo[1,2-b]pyridazine compound of formula I according to claim 1, or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, characterized in that: L is selected from -O-, -NH-, substituted or unsubstituted branched or linear C1-C4 alkylene, substituted or unsubstituted branched or linear C1-C4 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C4-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C4-C6 cycloalkyleneoxy, substituted or unsubstituted branched or linear C1-C4 alkylenethio, substituted or unsubstituted saturated or unsaturated 4- to 6-membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 4- to 6-membered azacycloalkylene substituted or unsubstituted saturated or unsaturated 4- to 6-membered thiacycloalkylene, substituted or unsubstituted saturated or unsaturated 4- to 6-membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 4- to 6-membered azacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 4- to 6-membered thiacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium, halogen, cyano, hydroxyl, carbonyl, amino, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C3-C6 cycloalkyl; More preferably, L is selected from -O-, -NH-, substituted or unsubstituted branched or linear C1-C3 alkylene, substituted or unsubstituted branched or linear C1-C3 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 to 3 substituents selected from deuterium or halogen; More preferably, L is selected from substituted or unsubstituted branched or straight-chain C1-C3 alkylene, substituted or unsubstituted branched or straight-chain C1-C3 alkyleneoxy, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkylene, substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkyleneoxy, substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkyleneoxy, wherein the "substituted" refers to optionally containing 1 or 2 substituents selected from deuterium or halogen; More preferably, L is selected from -CH2O-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH(CH3)O-, -CH(CH3)CH2O-, 4. The macrocyclic imidazo[1,2-b]pyridazine compound of formula I according to claim 1, or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, characterized in that: The compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is represented by the following Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6: Among them, the substituent W 5 、R 1 、R 2 、R 3 、R 4 、R 5 , and L are defined the same as in claim 1.

5. The macrocyclic imidazo[1,2-b]pyridazine compound of formula I according to claim 1, or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, characterized in that: The compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is represented by the following Formula I-1-1, Formula I-2-1, Formula I-3-1, Formula I-4-1, Formula I-5-1 or Formula I-6-1: Among them, the substituent W 5 、R 1 、R 2 、R 3 、R 4 、R 5 The definition is the same as in claim 11; L 1 and L 2 Various independently selected from chemical bonds, substituted or unsubstituted branched or linear C1-C3 alkylene, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkylene, substituted or unsubstituted saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O or N, wherein the "substituted" refers to optionally containing 1 or 2 substituents selected from deuterium or halogen, and L 1 and L 2 Not all chemical bonds; Preferably, L 1 and L 2 Each is independently selected from a chemical bond, a methylene group, an ethylene group, a propylene group, an isopropylene group, a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group, a halogenated methylene group, a halogenated ethylene group, a halogenated propylene group, a halogenated isopropylene group, a halogenated cyclopropylene group, a halogenated cyclobutylene group, a halogenated cyclopentylene group, a halogenated cyclohexylene group, an oxiranyl group, an oxacyclobutaneyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydropyrrolyl group, a hexahydropyridyl group, a halogenated oxiranyl group, a halogenated oxacyclobutaneyl group, a halogenated tetrahydrofuranyl group, a halogenated tetrahydropyranyl group, a halogenated tetrahydropyrrolyl group, a halogenated hexahydropyridyl group, and L 1 and L 2 Not chemical bonds at the same time.

6. The macrocyclic imidazo[1,2-b]pyridazine compound of formula I according to any one of claims 1 to 5, or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, characterized in that: It is selected from the following compounds:

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6 or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, and a pharmaceutically acceptable carrier.

8. Use of a compound of formula I according to any one of claims 1 to 6, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a medicament as a TRK kinase inhibitor for treating or preventing a disease or condition mediated by TRK or a TRK mutation in a subject in need thereof; Preferably, the disease or condition mediated by TRK or TRK mutation is selected from one or more of cancer, neurodegenerative disease, inflammation, and pain; More preferably, the disease or condition mediated by TRK or a TRK mutation is selected from surgical pain, inflammatory pain, neuropathic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, salivary tumors, bile duct cancer, stromal tumors, brain tumors and hematological malignancies.

9. A kit comprising the compound of formula I according to any one of claims 1 to 6, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention, as well as a container and instructions for use.

10. A method for treating a disease or condition mediated by TRK or a TRK mutation, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I according to any one of claims 1 to 6 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 7.