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

Abstract

The present invention discloses a macrocyclic imidazo[1,2-b]pyridazine compound represented by formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, as well as a pharmaceutical composition of said 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 a disease or condition mediated by TRK or a TRK mutation. TIFF2025532532000353.tif38170

Description

[Technical Field]

[0001] This application claims priority to application number 202211090622.9, filed with the China Intellectual Property Office on September 7, 2022, entitled "Macrocyclic imidazo[1,2-b]pyridazine derivatives and their preparation methods and uses," the contents of which are incorporated herein by reference in their entirety.

[0002] The present application relates to the pharmaceutical field, in particular to macrocyclic imidazo[1,2-b]pyridazine derivatives and pharmaceutically acceptable salts thereof, their preparation methods and uses as TRK kinase inhibitors, and pharmaceutical compositions containing said derivatives. [Background technology]

[0003] Tropomyosin receptor kinase (TRK) proteins are a family of tyrosine receptor kinases composed of three members: TRKA, TRKB, and TRKC. These proteins are widely expressed in the nervous system and many non-neuronal tissue types. TRKA, TRKB, and TRKC are encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NRTK2, and NTRK3, respectively. The three isoforms share sequence and structural homology, consist of extracellular, transmembrane, and intracellular domains, and differ in their ligand- and tissue-specific expression. TRK receptors are activated by high-affinity binding of the extracellular domain to their homologous ligands, leading to receptor dimerization and subsequent autophosphorylation of tyrosine residues in the intracellular domain. Because most early studies of the role of TRK function focused on neurodevelopment, their homologous ligands were termed neurotrophic factors, namely nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3), and neurotrophic factor-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 key neurotrophic factor ligands, which bind to the receptor's extracellular domain. The specificity of neurotrophin ligand binding depends on the type of TRK receptor, and subsequent interaction induces receptor homodimerization, phosphorylation of tyrosine residues in the cytoplasmic domain, and activation of downstream signaling pathways known to be associated with growth and development. TRKA mediates signal transduction through the MAPK and RAS / ERK pathways to promote neuronal proliferation and differentiation; TRKB activates the RAS / ERK and PI3K signaling pathways, which are essential for neuronal survival; and TRKC activates the PI3K / AKT pathway to prevent apoptosis and enhance cell survival.

[0004] Fusions involving all three NTRK genes have been reported in multiple cancer types and are caused by intrachromosomal gene rearrangements or interchromosomal translocations. NTRK gene fusion events occur between NTRK1, NTRK2, or NTRK3 and various unrelated gene partners, representing major genomic alterations with oncogenic potential, compared to less common oncogenic mechanisms, including in-frame deletions and alternative splice variants of NTRK1. Oncogenic gene rearrangements involving NTRK genes typically result 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 the partner to form a new oncoprotein. Oncogenic fusion proteins are usually constitutively activated or overexpressed kinases, resulting in aberrant expression and activation of the resulting fusion oncoprotein, subsequently driving cancer cell and tumor development. For example, the incidence of NTRK1 and TPM3 fusion genes is approximately 0.04%, ranking first among various fusion genes, and is closely associated with breast cancer, cervical cancer, bile duct cancer, colorectal cancer, glioma, infantile fibrosarcoma, lung cancer, soft tissue sarcoma, thyroid cancer, uterine sarcoma, etc. For example, the incidence of NTRK3 and ETV6 fusion genes is approximately 0.09%, and is closely associated with acute lymphocytic 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, paranasal sinus adenocarcinoma, soft tissue sarcoma, Spitzoid melanoma, and thyroid cancer.

[0005] NTRK gene fusions in human cancer: Following the discovery of therapeutic kinase inhibitors in this area, 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 a variety of 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. Conversely, the prevalence of NTRK gene fusions is very high in several rare cancer types, including secretory breast cancer, mammary-like secretory carcinoma, infantile fibrosarcoma, and congenital mesenchymal kidney. NTRK fusions are rare oncogenic drivers that occur in a variety of childhood cancers. These include infantile fibrosarcoma and secretory breast cancer, where such fusions are nearly as characteristic as in a range of more common childhood cancers, where NTRK fusions occur at lower frequencies. In the past few years, two TRK inhibitors, larotrectinib and entrectinib, have demonstrated histological activity against cancers driven by NTRK fusions and received FDA approval.

[0006] Larotrectinib and entrectinib have demonstrated remarkable therapeutic efficacy in patients with cancers harboring TRK fusion genes. However, as with most kinase inhibitors, acquired resistance mediated by mutations in the kinase domain occurs. Based on a pooled analysis of early-stage studies, TRK acquired resistance mutations, such as solvent premutations, gatekeeper mutations, and DFG motif mutations, have led to a median response duration of 8.3 months to larotrectinib and 10.5 months to entrectinib in the NTRK fusion subgroup. Subsequent targeted sequencing at the time of initial response in patients with initial responses has revealed recurrent kinase domain mutations predicted to confer resistance in up to 90% of patients. Most reported mutations involve amino acid substitutions in the solvent front (NTRK1 p.G595R, NTRK2 p.G639R, NTRK3 p.G623R), gatekeeper residues (NTRK1 p.F589L, NTRK3 p.F617L), or activation loop X-aspartic acid-phenylalanine-glycine, or "xDFG" motif (NTRK1 p.G667C, NTRK2 p.G709C, NTRK3 p.G696A). The mutation sites are primarily located in TRKCG623R (homologous TRKAG595R) and TRKAG667C. Computational modeling and X-ray crystallography have revealed that most of these mutations cause steric clashes between the bulky side chains of the involved amino acids (e.g., arginine) and the hydroxypyrrolidine or difluorophenyl groups of first-generation TRK inhibitors. Some mutations are also predicted to increase the ATP affinity of the kinase domain. Some of the identified mutations are homologous to recurrent pre-solvent and gatekeeper resistance mutations reported in ALK- and ROS1-rearranged cancers, which occur frequently and negate the inhibitory effects of first-generation inhibitors.

[0007] To overcome acquired resistance, second-generation TRK inhibitors TPX-0005 and LOXO-195, which target wild-type and mutant TRK fusions, are currently in clinical development. TPX-0005 and LOXO-195 have demonstrated efficacy in both preclinical animal models and patient clinical studies. A potential drawback of TRK inhibitors TPX-0005 and LOXO-195 is their limited ability to cross the blood-brain barrier (BBB). Therefore, further research is needed to effectively target TRK fusion-associated tumors in the brain. For example, Chinese patent applications CN102264736A and CN104520300A disclose several newly developed TRK small molecule inhibitors. Therefore, the development of new TRK inhibitors that can effectively overcome drug resistance mutations may bring significant clinical benefits to patients. Summary of the Invention

[0008] According to a first aspect of the present invention, it is an object of the present invention to provide a macrocyclic imidazo[1,2-b]pyridazine compound as shown in formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof: Formula I: TIFF2025532532000002.tif37170 where, 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 is nitrogen; R 1 , R 2 , R 3are each independently selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, substituted or unsubstituted saturated or unsaturated C1-C6 alkyl group, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group, substituted or unsubstituted saturated or unsaturated C1-C6 alkoxy group, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy group, or R 1 and R 2 together with the N atom and C atom to which they are attached, 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 form, together with the C atom to which they are bonded, a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group, wherein the term "substituted" refers to the selective inclusion of 1 to 4 substituents selected from deuterium, a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, and a C3-C6 cycloalkoxy group; R 4 is selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C6 alkyl group, saturated or unsaturated C3 to C6 cycloalkyl group, saturated or unsaturated C1 to C6 alkoxy group, saturated or unsaturated C3 to C6 cycloalkoxy group, R 5 is selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C6 alkyl group, saturated or unsaturated C3-C6 cycloalkyl group, substituted or unsaturated C1-C6 alkoxy group, saturated or unsaturated C3-C6 cycloalkoxy group, or R 5 does not exist, L is -O-, -NH-, a substituted or unsubstituted branched or straight-chain C1-C6 alkylene group, a substituted or unsubstituted branched or straight-chain C1-C6 alkyleneoxy group, a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkylene group, a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyleneoxy group, a substituted or unsubstituted branched or straight-chain C1-C6 alkylenethio group, a substituted or unsubstituted saturated or unsaturated 3-6 membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 3-6 membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 3-6 membered thiacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 3-6 membered oxacycloalkyleneoxy group, a substituted or unsubstituted saturated or an 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 selectively containing 1 to 4 substituents selected from deuterium, halogen, cyano group, hydroxy group, carboxy group, carbonyl group, sulfonyl group, amino group, C1-C4 alkyl group, C1-C4 hydroxyalkyl group, C3-C6 cycloalkyl group, C1-C4 alkoxy group, C3-C6 cycloalkoxy group, 4- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S.

[0009] Preferably, R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, substituted or unsubstituted saturated or unsaturated C1-C4 alkyl group, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group, substituted or unsubstituted saturated or unsaturated C1-C4 alkoxy group, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy group, or R 1 and R 2together with the N atom and C atom to which they are attached, 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 form, together with the C atom to which they are bonded, a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl group, wherein the term "substituted" refers to the selective inclusion of 1 to 3 substituents selected from deuterium, a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, and a C3-C6 cycloalkoxy group; More preferably, R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, 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 N atom and C atom to which they are attached 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 atom to which they are bonded, form a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl group, where the term "substituted" refers to the selective inclusion of 1 to 3 substituents selected from deuterium, a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, a C1-C3 alkyl group, and a C5-C6 cycloalkyl group.

[0010] More preferably, R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, a substituted or unsubstituted saturated or unsaturated C1-C3 alkyl group, or R 1 and R 2together with the N atom and C atom to which they are attached 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 atom to which they are bonded, form a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl group, where the term "substituted" refers to the optional inclusion of one or two substituents selected from deuterium, a hydroxyl group, and a halogen.

[0011] Preferably, R 4 is selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C4 alkyl group, saturated or unsaturated C5 to C6 cycloalkyl group, saturated or unsaturated C1 to C4 alkoxy group, and saturated or unsaturated C5 to C6 cycloalkoxy group.

[0012] More preferably, R 4 is selected from hydrogen, deuterium, halogen, a cyano group, a hydroxy group, an amino group, a saturated or unsaturated C1 to C3 alkyl group, and a saturated or unsaturated C1 to C3 alkoxy group.

[0013] More preferably, R 4 is selected from hydrogen, deuterium, halogen, saturated or unsaturated C1 to C3 alkyl groups, and saturated or unsaturated C1 to C3 alkoxy groups.

[0014] More preferably, R 4 is selected from hydrogen, deuterium or a halogen.

[0015] Preferably, R 5 is selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C4 alkyl group, saturated or unsaturated C5-C6 cycloalkyl group, substituted or unsaturated C1-C4 alkoxy group, saturated or unsaturated C5-C6 cycloalkoxy group, or R 5 does not exist.

[0016] More preferably, R5 is selected from hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C3 alkyl group, substituted or unsaturated C1-C3 alkoxy group, or R 5 does not exist.

[0017] More preferably, R 5 is selected from hydrogen, deuterium, halogen, saturated or unsaturated C1-C3 alkyl group, substituted or unsaturated C1-C3 alkoxy group, or R 5 does not exist.

[0018] More preferably, R 5 is selected from hydrogen, deuterium, halogen, or R 5 does not exist.

[0019] Preferably, L is -O-, -NH-, a substituted or unsubstituted branched or straight chain C1-C4 alkylene group, a substituted or unsubstituted branched or straight chain C1-C4 alkyleneoxy group, a substituted or unsubstituted saturated or unsaturated C4-C6 cycloalkylene group, a substituted or unsubstituted saturated or unsaturated C4-C6 cycloalkyleneoxy group, a substituted or unsubstituted branched or straight chain C1-C4 alkylenethio group, a substituted or unsubstituted saturated or unsaturated 4-6 membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 4-6 membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated It is selected from an unsaturated 4- to 6-membered thiacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 4- to 6-membered oxacycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 4- to 6-membered azacycloalkyleneoxy group, and a substituted or unsubstituted saturated or unsaturated 4- to 6-membered thiacycloalkyleneoxy group, wherein the term "substituted" refers to the selective inclusion of 1 to 3 substituents selected from deuterium, halogen, cyano group, hydroxy group, carbonyl group, amino group, C1 to C4 alkyl group, C1 to C4 hydroxyalkyl group, and C3 to C6 cycloalkyl group.

[0020] More preferably, L is selected from -O-, -NH-, a substituted or unsubstituted branched or straight-chain C1-C3 alkylene group, a substituted or unsubstituted branched or straight-chain C1-C3 alkyleneoxy group, a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkylene group, a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 5-6-membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5-6-membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5-6-membered oxacycloalkyleneoxy group, and a substituted or unsubstituted saturated or unsaturated 5-6-membered azacycloalkyleneoxy group, wherein the term "substituted" refers to selectively containing 1 to 3 substituents selected from deuterium or halogen.

[0021] More preferably, L is selected from a substituted or unsubstituted branched or straight-chain C1-C3 alkylene group, a substituted or unsubstituted branched or straight-chain C1-C3 alkyleneoxy group, a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkylene group, a substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 5-6-membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5-6-membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5-6-membered oxacycloalkyleneoxy group, and a substituted or unsubstituted saturated or unsaturated 5-6-membered azacycloalkyleneoxy group, wherein the term "substituted" refers to selectively containing one or two substituents selected from deuterium or halogen.

[0022] More preferably, L is -CH2O-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH(CH3)O-, -CH(CH3)CH2O-, Selected from TIFF2025532532000003.tif14170.

[0023] Preferably, the compound represented by formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is represented by the following formula I-1, I-2, I-3, I-4, I-5 or I-6: TIFF2025532532000004.tif78170

[0024] Here, the substituent W 5 , R 1 , R 2 , R 3 , R 4 , R 5 , L are defined as in formula I above.

[0025] Preferably, the compound represented by formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is represented by the following formula I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1: TIFF2025532532000005.tif72170

[0026] Here, the substituent W 5 , R 1 , R 2 , R 3 , R 4 , R 5 is the same as in formula I above, L 1 and L 2 are each independently selected from a chemical bond, a substituted or unsubstituted branched or linear C1-C3 alkylene group, a substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkylene group, and a substituted or unsubstituted saturated or unsaturated 3- to 6-membered heterocycloalkyl group containing one or two heteroatoms selected from O or N, where the term "substituted" refers to selectively containing one or two substituents selected from deuterium or halogen; and L 1 and L 2 is not a chemical bond at the same time.

[0027] Preferably, L 1 and L 2 are each 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 oxiranylene group, an oxetanylidene group, a tetrahydrofuranylene group, a tetrahydropyranylene group, a tetrahydropyrrolylene group, a hexahydropyridylene group, a halogenated oxiranylene group, a halogenated oxetanylidene group, a halogenated tetrahydrofuranylene group, a halogenated tetrahydropyranylene group, a halogenated tetrahydropyrrolylene group, and a halogenated hexahydropyridylene group; and L 1 and L 2 is not a chemical bond at the same time.

[0028] 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 an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is selected from the following compounds: TIFF2025532532000006.tif216170TIFF2025532532000007.tif236170TIFF2025532532000008.tif207170 TIFF2025532532000009.tif228170TIFF2025532532000010.tif216170TIFF2025532532000011.tif109170

[0029] According to a 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 of the present invention or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

[0030] According to a third aspect of the present invention, another object of the present invention is to provide a use of a compound of the present invention represented by formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric 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, the medicament being used for treating or preventing a disease or condition mediated by TRK or a TRK mutation in a subject in need thereof.

[0031] Preferably, the disease or condition mediated by TRK or a TRK mutation is selected from one or more of cancer, neurodegenerative disease, inflammation, and pain.

[0032] More preferably, the disease or condition mediated by TRK or a TRK mutation is selected from postoperative 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 gland tumors, bile duct cancer, stromal tumors, brain tumors, and hematological malignancies.

[0033] According to a fourth aspect of the present invention, another object of the present invention is to provide a kit, said kit comprising the compound represented by formula I of the present invention or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or said pharmaceutical composition of the present invention, as well as a container and an instruction manual.

[0034] According to a fifth aspect of the present invention, it is another object of the present invention to provide a method for treating a TRK or TRK mutation-mediated disease or condition, said method comprising administering to a subject in need thereof an effective amount of a compound of formula I of the present invention or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or said pharmaceutical composition of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0035] 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 limitedly to their general meanings and dictionary meanings, but should be interpreted according to the meanings and concepts corresponding to the technical aspects of the present invention based on the principle that the inventor can appropriately define 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. Therefore, it should be understood that other equivalents or modifications can be made without departing from the spirit and scope of the present invention.

[0036] As used herein, terms such as "comprise," "include," "have," "contain," or any other similar term are open-ended transitional phrases intended to cover non-exclusive inclusion. For example, a composition or product containing multiple elements is not limited to only those elements listed herein and may include other elements not explicitly listed but traditionally inherent in the composition or product. Otherwise, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, the condition "A or B" is satisfied if A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), or both A and B are true (or present). Furthermore, as used herein, the terms "comprise," "include," "have," and "contain" should be interpreted as specifically disclosing and simultaneously covering closed or semi-closed conjunctions such as "consisting of" and "consisting essentially of."

[0037] Any characteristics or conditions defined herein in the form of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to include and specifically disclose all possible subranges and individual numerical values ​​within the range, particularly integer values. For example, a description of a range "1 to 8" is considered to specifically disclose all subranges, particularly subranges defined by all integer values, such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., and individual numerical values, such as 1, 2, 3, 4, 5, 6, 7, 8, etc., are considered to be within the specifically disclosed range. Unless otherwise specified, the above interpretation applies to all of the entire contents of the present invention, regardless of whether the range is broad or not.

[0038] When a number or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it is understood that all ranges consisting of the upper or preferred value of the range and the lower or preferred value of the range are specifically disclosed herein, whether or not those ranges are individually disclosed. Furthermore, when a range of numerical values ​​is referred to herein, unless otherwise stated, the range is intended to include its endpoints, and all integers and fractions within the range.

[0039] In this specification, numerical values ​​should be understood to have the accuracy of the number of significant digits as long as the object of the invention can be achieved. For example, the number 40.0 should be understood to cover the range of 39.50 to 40.49.

[0040] When a Markush group or any term is used herein to describe features or examples of the present invention, those skilled in the art will understand that any subgroup or any individual element of the elements in the Markush group or option list can also be used to describe the present invention. For example, when X is described as "selected from the group consisting of X1, X2, and X3," it means that the assertion that X is X1 and the assertion that X is X1 and / or X2 are fully explained. Furthermore, when a Markush group or any term is used to describe features or examples of the present invention, it will be understood by those skilled in the art that any combination of any subgroup or individual element of the elements in the Markush group or option list can also be used to describe the present invention. Accordingly, for example, when 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," it means that the assertion that X is X1, X2, or X3, and Y is Y1, Y2, or Y3 is fully explained.

[0041] Definitions of relevant terms used in this specification "Alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C1-8 In some embodiments, an alkyl group is a group having 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom (a "C alkyl group"). In some embodiments, the alkyl group has 1 to 6 carbon atoms (a "C 1-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, t-butyl, s-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl), and hexyl (C6) (e.g., n-hexyl). Further 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 (an "unsubstituted alkyl group") or substituted with one or more substituents (e.g., halogen, such as F) (a "substituted alkyl group"). In certain embodiments, an alkyl group is an unsubstituted C 1-8 In certain embodiments, the alkyl group is a substituted C 1-8 It is an alkyl group (eg, a substituted C1 alkyl group such as -CF3).

[0042] An "alkoxy group" refers to a monovalent -O-alkyl group, where the alkyl group portion has a specified number of carbon atoms. In the present disclosure, alkoxy groups typically contain 1 to 6 carbon atoms (a "C1-C6 alkoxy group") or 1 to 4 carbon atoms (a "C1-C4 alkoxy group"). For example, C1-C4 alkoxy groups include methoxy, ethoxy, isopropoxy, t-butyloxy, and the like. Unless otherwise specified, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy group") or substituted with one or more substituents (a "substituted alkoxy group"). In certain embodiments, an alkoxy group is an unsubstituted C1-C6 alkoxy group. In certain embodiments, an alkoxy group is a substituted C1-C6 alkoxy group.

[0043] A "cycloalkyl group" is a group having 3 to 8 ring carbon atoms ("C") in a non-aromatic ring system. 3-8 In some embodiments, a cycloalkyl group refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C cycloalkyl group"). In some embodiments, the cycloalkyl group has 5 to 8 ring carbon atoms ("C 5-8 cycloalkyl group). 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8Cycloalkyl groups include, but are not limited to, the C3-6 cycloalkyl groups described above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), and the like. Unless otherwise specified, each example of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted cycloalkyl group") or substituted with one or more substituents (a "substituted cycloalkyl group"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-8 In certain embodiments, the cycloalkyl group is a substituted C 3-8 It is a cycloalkyl group.

[0044] "Heterocycloalkyl group" refers to a 5- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spiro ring systems, e.g., bicyclic ring systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A "heterocyclic group" further includes ring systems in which a heterocycle, as defined above, is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or the heterocycle), or a heterocycle, as defined above, is fused to one or more aryl or heteroaryl groups (where 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 ring system. Unless otherwise specified, each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocycloalkyl group") or substituted with one or more substituents (a "substituted heterocycloalkyl group"). In certain embodiments, a heterocycloalkyl group is an unsubstituted 5- to 14-membered heterocycloalkyl group. In certain embodiments, a heterocycloalkyl group is a substituted 5- to 14-membered heterocycloalkyl group.

[0045] An "aryl group" or "aromatic ring" or "aromatic ring group" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms (a "C aryl group," e.g., a phenyl group). In some embodiments, an aryl group has 10 ring carbon atoms (a "C 10 In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl group" includes an aryl group (e.g., an anthracenyl group). "Aryl group" further includes ring systems in which the aryl ring defined above is fused (the point of attachment is on the aromatic ring) to one or more cycloalkyl or heterocyclic groups, 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 specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl group") or substituted with one or more substituents (a "substituted aryl group"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is an aryl group.

[0046] A "heteroaryl group" is a 5- to 14-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 14-membered heteroaryl group"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl group"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl group"). In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 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 group") or substituted with one or more substituents (a "substituted heteroaryl group"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl group.

[0047] Structures such as "alkylene group," "alkyleneoxy group," "heterocycloalkylene group," "arylene group," "subaromatic ring," "subaromatic ring group," and "heteroarylene group" refer to a moiety that simultaneously bonds two or more other groups within a molecule and functions as an intermediate bonding group. For example, an alkylene group, like the alkyl group defined above, refers to a bonding group formed by simultaneously bonding two or more other groups, and its structural formula is -C n H 2n-, which are each linked to at least two different other groups via at least two separate bonds. For example, in certain embodiments, a methylene group represents -CH2-, in certain embodiments, an ethyleneoxy group represents -CH2CH2-O-, and in certain embodiments, a phenylene group represents Represents TIFF2025532532000012.tif14170.

[0048] "Halogen" or "halogenated" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

[0049] "Substituted" or "optionally substituted" refers to the replacement of an atom, e.g., a hydrogen atom, within a group. In certain embodiments, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are substituted (e.g., a "substituted" alkyl group, a "substituted" cycloalkyl group, a "substituted" heterocycloalkyl group, a "substituted" aryl group, or a "substituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of at least one hydrogen atom present on a group (e.g., a carbon atom or a nitrogen atom) with a permissible substituent, e.g., a substituent that forms a stable compound upon substitution; e.g., a compound that does not spontaneously change (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; and when multiple positions within a given structure are substituted, the substituents can be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, all substituents described herein that result in the formation of stable compounds. The present disclosure contemplates all such combinations to obtain stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents that satisfy the valence of the heteroatom as described herein and form a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

[0050] "Unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. A "partially unsaturated" ring system is intended to further include rings with multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Similarly, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains only single bonds.

[0051] As used herein, the term "pharmaceutically acceptable" means that those compounds, materials, compositions and / or dosage forms are, within the scope of sound medical judgment, suitable for contact with, and use by, the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0052] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents discovered in this invention and a relatively non-toxic acid or base. When a 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 a compound with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia, or magnesium salts or similar salts. When a 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 a compound with a sufficient amount of acid in a neat solution or in a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfuric acid, hydroiodic acid, phosphorous acid, and the like. Examples of organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, maloacetic acid, and the like. The salts of the various compounds of the present invention include salts of similar acids such as carboxylic 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, folic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, and stearic acid, and further include salts of amino acids (e.g., arginine) and organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0053] As used herein, the modifier "about" refers to variations that may occur in a value due, for example, to routine testing and procedures, inadvertent errors in such testing and procedures, differences in the manufacture, source, or purity of the components used in the invention, etc. As used herein, "about" a particular value further includes the particular value, for example, about 10% includes 10%. Whether modified by the term "about," the claims include equivalents to the recited number. In one embodiment, the term "about" refers to within 20% of the reported value.

[0054] As used herein, the term "treatment" refers to eliminating, alleviating, or ameliorating a disease or condition and / or its associated symptoms. Although not eliminating, treatment does not require complete elimination of the disease or condition, or its associated diseases, conditions, or symptoms. As used herein, the term "treatment," which can include "prophylactic treatment," refers to reducing the likelihood of recurrence of a disease or condition, or the likelihood of recurrence of a previously controlled disease or condition, in a subject who is not afflicted with, or who is afflicted with, or susceptible to, a disease or condition, or who is at risk of recurrence of a disease or condition. The term "treatment" and cognate terms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0055] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent to achieve the desired effect without toxicity. In the oral dosage forms of the present invention, an "effective amount" of an active agent in a composition refers to the dose necessary to achieve the desired effect when used in combination with another active agent in the composition. Determining an effective amount will vary from person to person, depending on the age and general condition of the recipient and the specific active agent, and the appropriate effective amount in each individual case can be determined by one of ordinary skill in the art through routine testing.

[0056] The macrocyclic triazole compound represented by formula I or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or isomeric mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, provided by the present invention, and pharmaceutical compositions containing the compound may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be present in a suitable solid or liquid carrier or diluent and in a suitable sterile device for injection or infusion.

[0057] Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. For example, the unit dose of the preparation contains 0.05 to 2000 mg of the macrocyclic triazole compound of formula I or a pharmaceutically acceptable salt thereof, preferably 0.1 mg to 1000 mg of the compound of formula I.

[0058] The compounds of Formula I and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via routes such as oral, nasal, cutaneous, pulmonary, or gastrointestinal routes. Oral administration is most preferred. The most preferred daily dose is 0.01 to 200 mg / kg body weight in a single dose or 0.01 to 100 mg / kg body weight in divided doses. Regardless of the method of administration, the optimal dose for an individual will vary depending on the specific treatment being administered. Typically, individuals start with a low dose and gradually increase the dose until they find the optimal dose for themselves. In the present invention, the term "effective amount" may refer to an amount effective at a dosage and duration necessary to achieve a desired effect. This effective amount may vary depending on factors such as the type of disease or symptoms of the disease being treated, the structure of the specific target organ to which it is administered, the physical size of the patient, or the severity of the disease or symptoms. Those skilled in the art can empirically determine the effective amount of a particular compound without undue experimentation.

[0059] A typical formulation is prepared by mixing a compound of Formula I of the present invention and 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 materials, gelatin, oils, solvents, water, and the like.

[0060] The specific carrier, diluent, or excipient used will vary depending on the intended use and purpose of the compound of the present invention. It is generally selected based on what those skilled in the art consider to be safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water, as well as other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like. The formulation may contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, flavorings, seasonings, or other known additives to prepare and use the drug in an acceptable form.

[0061] When the compound of formula I according to the present invention is used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, and are 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 by known methods, such as intravenous injection, rectal administration, vaginal administration, transdermal absorption, or other local or systemic administration.

[0062] These pharmaceutical compositions may contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, flavorings, seasonings, or other known additives to prepare and use the pharmaceutical compositions in an acceptable form.

[0063] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration can include capsules, tablets, powders, or granules. In solid dosage forms, 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 binders such as starch, lactose, sucrose, mannitol, silicic acid, etc., such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; humectants such as glycerol; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; adsorbents such as kaolin and bentonite; and lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium laurel sulfate. In the case of capsules and tablets, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose, high molecular weight polyethylene glycols, and the like.

[0064] 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 a pharmaceutical composition thereof, the liquid dosage forms 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, and the like, oils (e.g., cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, and the like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of dehydrated sorbitan, or mixtures of two or more of these substances.

[0065] In addition to these inert diluents, the composition can also include one or more of the following excipients: wetting agents, emulsifying agents, suspending agents, sweetening agents, and flavoring and perfuming agents.

[0066] In the case of a suspension, in addition to the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, the suspension may further contain carriers such as suspending agents, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of two or more of these substances.

[0067] The compound of formula I of the present invention or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, can be administered in other topical dosage forms such as creams, powders, sprays, and inhalants. The drug can be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent, or carrier, and any necessary preservatives, buffers, or propellants. Ophthalmic preparations, eye ointments, and powder solutions are also intended to be included within the scope of the present invention.

[0068] Additionally, the present disclosure further includes kits (e.g., pharmaceutical packages). The provided kits can include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispensing package or other suitable container). In some embodiments, the provided kits can optionally further include a second container containing a pharmaceutically acceptable 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 are combined to form a unit dosage form.

[0069] In certain embodiments, the kits described herein further comprise instructions for using the compound or pharmaceutical composition included in the kit. The kits described herein can further comprise information required by regulatory authorities (e.g., the U.S. Food and Drug Administration (FDA)). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions are used to treat a TRK mutation-mediated disease in a subject in need of treatment and / or to prevent a TRK mutation-mediated disease in a subject in need of prevention. The kits described herein can include one or more additional drug formulations as separate compositions.

[0070] The present invention will be described in more detail below in conjunction with specific examples, but the present invention is not limited to the following examples, and 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. Conditions not specified in the examples are standard conditions. Unless otherwise specified, all reagents and equipment used in the following examples are commercially available.

[0071] The compounds of formula I of the present application can be synthesized by various methods well known to those skilled in the art of organic synthesis. The following specific examples show some exemplary methods for synthesizing the compounds of formula I, and these methods are well known in the field of synthetic chemistry. Obviously, by referring to the exemplary schemes of this patent, those skilled in the art can easily design synthetic routes for other compounds of formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0072] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention. Unless otherwise specified, all reactants used in each example are commercially available products, and the instruments and devices used in the synthesis experiments and product analysis and detection are all conventional instruments and devices commonly used in organic synthesis.

[0073] In the following examples, the structures of exemplary compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0074] Liquid chromatography-mass spectrometry (LC-MS) measurements were performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC measurements were performed using an Agilent 1200DAD high-pressure liquid chromatograph. Thin-layer chromatography silica gel plates were Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally used Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier. Furthermore, unless otherwise specified, all reactions in the present invention were performed under continuous nuclear magnetic stirring in a dry nitrogen or argon atmosphere, the solvent was a dry solvent, and the reaction temperature unit was °C.

[0075] Furthermore, the meanings of the abbreviations used in the examples are as follows: NIS: N-iodosuccinimide, TMS: trimethylsilyl group, PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) 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'-bis(diphenylphosphine), RuPhos Pd G4: methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), DIAD: diisopropyl azodicarboxylate, TBSCl: t-butyldimethylsilyl chloride, Cs2CO3: cesium carbonate, Na2CO3: sodium carbonate; NaBH4: sodium borohydride, BBr3: boron tribromide, LAH: lithium aluminum hydride, NaOH: sodium hydroxide, BOC: t-butyloxy Dicarbonyl group, 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.

[0076] 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) Step A: 2-Bromo-4-t-butyldimethylsiloxymethylpyridine (2) TIFF2025532532000013.tif21170

[0077] 2-Bromo-4-pyridinemethanol (compound 1, 50 g, 265.93 mmol) and imidazole (23.53 g, 345.70 mmol) were added to dichloromethane (750 mL), and t-butyldimethylsilane chloride (52.11 g, 345.70 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours, and 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, the mixture was subjected to column chromatography to obtain 2-bromo-4-t-butyldimethylsiloxymethylpyridine (64.95 g, 81%).

[0078] LCMS: m / z (ESI), 302 [M+H] + .

[0079] Step B: 2-tributylstannyl-4-t-butyldimethylsiloxymethylpyridine (3) TIFF2025532532000014.tif22170

[0080] 2-Bromo-4-t-butyldimethylsiloxymethylpyridine (compound 2, 30 g, 99.25 mmol) was placed in tetrahydrofuran (750 mL), and butyllithium (2.5 M, 39.70 mmol) was added dropwise at -70°C. The mixture was stirred for 30 minutes, tributylstannyl chloride (38.77 g, 119.09 mmol) was added, and the mixture was stirred at -70°C for 2 hours. The mixture was 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, the mixture was subjected to column chromatography to obtain 2-tributylstannyl-4-t-butyldimethylsiloxymethylpyridine (52 g).

[0081] LCMS: m / z (ESI), 514.3 [M+H] + .

[0082] Step C: 3-(4-t-butyldimethylsiloxymethylpyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (5) TIFF2025532532000015.tif29170

[0083] 2-Tributylstannyl-4-t-butyldimethylsiloxymethylpyridine (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 sequentially. 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 combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was subjected to column chromatography to obtain 3-(4-t-butyldimethylsiloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (1.94 g, 5.3%).

[0084] 1 H NMR:(400MHz,DMSO-d6)δ 8.48(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).

[0085] Step D: 2-p-Methoxybenzyloxy-5-fluoroacetophenone (7) TIFF2025532532000016.tif24170

[0086] 2-Hydroxy-5-fluoroacetophenone (compound 6, 10 g, 64.88 mmol) was added to acetonitrile (200 mL), and p-methoxybenzyl chloride (12.19 g, 77.85 mmol) and cesium carbonate (63.41 g, 194.63 mmol) were added successively. The mixture was stirred at 90°C for 12 hours, and 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxy-5-fluoroacetophenone (14.1 g, 79%).

[0087] 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).

[0088] Step E: 2-p-Methoxybenzyloxy-5-fluoroacetophenone oxime (8) TIFF2025532532000017.tif26170

[0089] p-Methoxybenzyloxy-5-fluoro-2-acetophenone (compound 7, 14.1 g, 51.41 mmol) was added to ethanol (180 mL), and sodium acetate (12.65 g, 154.22 mmol) and hydroxylamine hydrochloride (4.29 g, 61.69 mmol) were added successively. The mixture was stirred at 70°C for 2 hours, and 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxy-5-fluoroacetophenone oxime (6.5 g, 44%).

[0090] 1H 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).

[0091] Step F: 2-p-Methoxybenzyloxy-5-fluorophenyl-1-ethylamine (9) TIFF2025532532000018.tif26170

[0092] 2-p-Methoxybenzyloxy-5-fluoroacetophenone oxime (compound 8, 6.50 g, 22.47 mmol) was dissolved in methanol (150 mL), and ammonium formate (14.7 g, 224.68 mmol) and zinc powder (14.69 g, 224.68 mmol) were added successively. The mixture was stirred at 40°C for 12 hours, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (2.8 g, 48.8%).

[0093] LCMS: m / z (ESI), 276.0 [M+H] + .

[0094] 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).

[0095] Step G: 3-(4-t-butyldimethylsiloxymethylpyridin-2-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (10) TIFF2025532532000019.tif34170

[0096] 3-(4-t-butyldimethylsiloxymethylpyridin-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) (15.34 mg, 0.027 mol), sodium t-butoxide (51.26 mg, Add Xantphos (15.43 mg, 0.027 mol) successively, stir at 100 °C for 16 hours, concentrate, and then separate by column chromatography to obtain 3-(4-t-butyldimethylsiloxymethylpyridin-2-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (24 mg, 15%).

[0097] LCMS: m / z (ESI), 614.5 [M+H] + .

[0098] 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).

[0099] Step H: 3-(4-hydroxymethylpyridin-2-yl)-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (11) TIFF2025532532000020.tif27170

[0100] 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 10, 24 mg, 0.039 mol) is placed in methanol (3 mL), hydrochloric acid methanol solution (4 M, 3 mL) is added, and the mixture is stirred at 25 ° C for 2 hours. Then, the mixture is neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate is concentrated and then separated by column chromatography to obtain 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (12 mg, 81%).

[0101] LCMS: m / z (ESI), 380 [M+H] + .

[0102] Stage 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) TIFF2025532532000021.tif32170

[0103] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (Compound 11, 34.37 mg, 0.091 mol) was placed in a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to prepare (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 (3.8 mg, 11.3%) was obtained.

[0104] LCMS: m / z (ESI), 362 [M+H] + .

[0105] 1 H 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).

[0106] 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) Step A: 2-p-Methoxybenzyloxy-3,5-difluoroacetophenone (12) TIFF2025532532000022.tif28170

[0107] 2-Hydroxy-3,5-difluoroacetophenone (10 g, 58.10 mmol) was added to DMF (200 mL), and p-methoxybenzyl chloride (10.01 g, 63.91 mmol) and potassium carbonate (24.09 g, 174.29 mmol) were added successively. 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxy-3,5-difluoroacetophenone (14.5 g, 85.4%).

[0108] 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).

[0109] Step B: 2-p-Methoxybenzyloxy-3,5-difluoroacetophenone oxime (13) TIFF2025532532000023.tif28170

[0110] p-Methoxybenzyloxy-3,5-difluoro-2-acetophenone (compound 12, 13.1 g, 44.82 mmol) was added to ethanol (180 mL), and sodium acetate (11.03 g, 134.46 mmol) and hydroxylamine hydrochloride (3.74 g, 53.78 mmol) were added successively. The mixture was stirred at 70 ° C for 2 hours, and 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxy-3,5-difluoroacetophenone oxime (6.25 g, 45.4%).

[0111] 1H 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).

[0112] Step C: 2-p-Methoxybenzyloxy-3,5-difluorophenyl-1-ethylamine (14) TIFF2025532532000024.tif29170

[0113] 2-p-Methoxybenzyloxy-3,5-difluoroacetophenone oxime (compound 13, 6.20 g, 20.18 mmol) was dissolved in methanol (150 mL), and ammonium formate (12.72 g, 201.76 mmol) and zinc powder (13.19 g, 201.76 mmol) were added sequentially. The mixture was stirred at 40°C for 12 hours, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 2-p-methoxybenzyloxy-3,5-difluorophenyl-1-ethylamine (2.6 g, 43.9%).

[0114] LCMS: m / z (ESI), 294.2 [M+H] + .

[0115] 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).

[0116] Step D: 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (15) TIFF2025532532000025.tif38170

[0117] 3-(4-t-butyldimethylsiloxymethylpyridin-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) (15.34 mg, 0.027 mol), sodium t-butoxide (51.26 mg, 0.53 mol) and Xantphos (15.43 mg, 0.027 mol) were added successively, and the mixture was stirred at 100 °C for 16 hours. After concentration, the mixture was separated by column chromatography to obtain 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (44 mg, 26%).

[0118] LCMS: m / z(ESI), 632.2 [M+H] + .

[0119] 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).

[0120] Step E: 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (16) TIFF2025532532000026.tif25170

[0121] 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 15, 44 mg, 0.069 mol) is placed in methanol (3 mL), hydrochloric acid methanol solution (4 M, 3 mL) is added, and the mixture is stirred at 25 ° C for 2 hours. Then, the mixture is neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate is concentrated and then separated by column chromatography to obtain 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (36 mg).

[0122] LCMS: m / z (ESI), 398 [M+H] + .

[0123] Stage 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) TIFF2025532532000027.tif35170

[0124] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(3,5-difluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 16, 36 mg, 0.091 mol) was placed in a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to prepare (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 (4.2 mg, 11.2%) was obtained.

[0125] LCMS: m / z (ESI), 380 [M+H] + .

[0126] 1 H 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).

[0127] 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) Step A: 2-p-Methoxybenzyloxyacetophenone (17) TIFF2025532532000028.tif22170

[0128] 2-Hydroxyacetophenone (10 g, 73.45 mmol) was added to acetonitrile (200 mL), and p-methoxybenzyl chloride (13.80 g, 88.14 mmol) and potassium carbonate (30.45 g, 220.35 mmol) were added successively. 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxyacetophenone (18 g, 95.6%).

[0129] 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).

[0130] Step B: 2-p-Methoxybenzyloxyacetophenone oxime (18) TIFF2025532532000029.tif27170

[0131] 2-p-Methoxybenzyloxyacetophenone (compound 17, 18 g, 70.23 mmol) was added to ethanol (180 mL), and sodium acetate (17.28 g, 210.69 mmol) and hydroxylamine hydrochloride (5.86 g, 84.28 mmol) were added successively. The mixture was stirred at 70°C for 2 hours, and 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxyacetophenone oxime (10 g, 50.4%).

[0132] 1H 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).

[0133] Step C: 2-p-Methoxybenzyloxyphenyl-1-ethylamine (19) TIFF2025532532000030.tif27170

[0134] 2-p-Methoxybenzyloxyacetophenone oxime (compound 18, 11.0 g, 40.54 mmol) was dissolved in methanol (150 mL), and ammonium formate (25.57 g, 405.44 mmol) and zinc powder (26.67 g, 407.94 mmol) were added sequentially. The mixture was stirred at 40°C for 12 hours, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 2-p-methoxybenzyloxy-phenyl-1-ethylamine (7.8 g, 74%).

[0135] LCMS: m / z (ESI), 258.2 [M+H] + .

[0136] 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).

[0137] Step D: 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (20) TIFF2025532532000031.tif39170

[0138] 3-(4-t-butyldimethylsiloxymethylpyridin-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) (215.89 mg, 0.38 mmol), sodium t-butoxide (487.00 mg, Add Xantphos (219.91 mg, 0.38 mmol) successively, stir at 100 °C for 16 hours, concentrate, and then separate by column chromatography to obtain 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (400 mg, 26.5%).

[0139] LCMS: m / z (ESI), 596.0 [M+H] + .

[0140] 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,2 H), 7.24-7.20(m,2 H), 7.09(d,J=7.8Hz,1H), 6.93(t,J=7.4Hz,1H), 6.84(d,J=9.6Hz,1H), 6.67(d,J=8.6Hz,2 H), 5.41(t,J=7.0Hz,1H), 5.13-5.04(m,2 H), 4.72-4.55(m,2 H), 3.65(s,3 H), 1.55(d,J=6.8Hz,3 H), 0.87(s,9 H), 0.04(d,J=7.8Hz,6 H).

[0141] Step E: 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (21) TIFF2025532532000032.tif29170

[0142] 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 20, 300 mg, 0.53 mol) was placed in methanol (3 mL), and hydrochloric acid methanol solution (4 M, 3 mL) was added. The mixture was stirred at 25 ° C for 2 hours, and then neutralized to pH = 7 with sodium bicarbonate. After filtration, the filtrate was concentrated and then separated by column chromatography to obtain 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (70 mg, 34%).

[0143] LCMS: m / z (ESI), 362 [M+H] + .

[0144] Step F: (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) TIFF2025532532000033.tif28170

[0145] 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 21, 25 mg, 0.066 mol) was added to a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90 ° C for 1.5 hours, filtered, and the filtrate was concentrated and separated to obtain (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (19.9 mg, 39.2%).

[0146] LCMS: m / z (ESI), 344 [M+H] + .

[0147] 1 H NMR:(400MHz,MeOD-d4)δ 9.90(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,2) H), 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).

[0148] 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) Step A: 2-p-Methoxybenzyloxy-3-acetylpyridine (22) TIFF2025532532000034.tif22170

[0149] 2-Hydroxy-3-acetylpyridine (10 g, 72.99 mmol) was dissolved 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 successively. 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, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain 2-p-methoxybenzyloxy-3-acetylpyridine (6 g, 32%).

[0150] LCMS: m / z (ESI), 258.2 [M+H] + .

[0151] Step B: 2-p-Methoxybenzyloxypyridine-3-ethanone oxime (23) TIFF2025532532000035.tif29170

[0152] 2-p-Methoxybenzyloxy-3-acetylpyridine (compound 22, 6 g, 23.26 mmol) was added to ethanol (60 mL), and sodium acetate (5.76 g, 70.23 mmol) and hydroxylamine hydrochloride (1.96 g, 28.08 mmol) were added successively. The mixture was stirred at 70 ° C for 2 hours, and 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, the mixture was subjected to column chromatography to obtain 2-p-methoxybenzyloxypyridine-3-ethanone oxime (3 g, 47.4%).

[0153] LCMS: m / z (ESI), 273.2 [M+H] + .

[0154] Step C: 1-(2-p-Methoxybenzyloxypyridin-3-yl)-ethylamine (24) TIFF2025532532000036.tif28170

[0155] 2-p-Methoxybenzyloxypyridin-3-ethanone oxime (compound 23, 3.0 g, 11.03 mmol) was dissolved in methanol (50 mL), and ammonium formate (25.57 g, 405.44 mmol) and zinc powder (26.67 g, 407.94 mmol) were added sequentially. The mixture was stirred at 40°C for 12 hours, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 1-(2-p-methoxybenzyloxypyridin-3-yl)-ethylamine (2.1 g, 74%).

[0156] LCMS: m / z (ESI), 259.2 [M+H] + .

[0157] Step D: 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-pyridin-3-yl)ethyl)imidazole[1,2-b]pyridazin-6-amine (25) TIFF2025532532000037.tif41170

[0158] 3-(4-t-butyldimethylsiloxymethylpyridin-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), sodium t-butoxide (487.0 Add Xantphos (219.91 mg, 0.38 mmol) successively, stir at 100 °C for 16 hours, concentrate, and then separate by column chromatography to obtain 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-pyridin-3-yl)ethyl)imidazole[1,2-b]pyridazin-6-amine (300 mg, 20%).

[0159] LCMS: m / z (ESI), 597.0 [M+H] + .

[0160] Step E: 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxypyridin-3-yl)-ethyl)imidazole[1,2-b]pyridazin-6-amine (26) TIFF2025532532000038.tif26170

[0161] 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 25, 300 mg, 0.52 mol) is placed in methanol (3 mL), hydrochloric acid methanol solution (4 M, 3 mL) is added, and the mixture is stirred at 25 ° C for 2 hours. Then, the mixture is neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate is concentrated and then separated by column chromatography to obtain 3-(4-hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxypyridin-3-yl)-ethyl)imidazole[1,2-b]pyridazin-6-amine (50 mg, 24%).

[0162] LCMS: m / z (ESI), 363 [M+H] + .

[0163] Step F: (E)-6-Methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridine-cycloheptane (I-4) TIFF2025532532000039.tif32170

[0164] 3-(4-Hydroxymethyl)pyridin-2-yl-N-(1-(2-hydroxypyridin-3-yl)-ethyl)imidazole[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), thionyl chloride (215.57 mg, 1.81 mol) was added, and the mixture was stirred at 25°C for 30 minutes, followed by potassium carbonate. (500.84 mg, 3.62 mol) was added to neutralize to pH > 7, dichloromethane was removed by evaporation, the mixture was stirred at 90 °C for 1.5 hours, filtered, and the filtrate was concentrated and then separated to give (E)-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (14.9 mg, 30.2%).

[0165] LCMS: m / z (ESI), 345 [M+H] + .

[0166] 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) Step A: 2-Aminomethyl-4-fluorophenol (27) TIFF2025532532000040.tif26170

[0167] 5-Fluoro-2-hydroxybenzonitrile (2 g, 14.59 mmol) was placed in tetrahydrofuran (20 mL), and lithium aluminum tetrahydride (1.11 g, 29.17 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour, and then the reaction was quenched with sodium sulfate decahydrate, diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated and then subjected to column chromatography to obtain 2-aminomethyl-4-fluorophenol (2.3 g).

[0168] 1H NMR: (400MHz, CHLOROFORM-d) δ=6.74-6.48(m,2H), 6.29-6.11(m,1H), 3.57-3.46(m,2H).

[0169] Step B: 4-Fluoro-2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (28) TIFF2025532532000041.tif45170

[0170] 3-(4-t-butyldimethylsiloxymethylpyridin-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 t-butoxide (51.26 mg, 0.53 mol) were added sequentially. The mixture was stirred at 130°C for 1 hour, and the reaction mixture was filtered and then directly subjected to reverse phase separation to obtain 4-fluoro-2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (48 mg, 49%).

[0171] LCMS: m / z(ESI), 366.2 [M+H] + .

[0172] 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).

[0173] Stage 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) TIFF2025532532000042.tif32170

[0174] 4-Fluoro-2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (compound 28, 47 mg, 0.122 mol) was placed in a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to prepare (E)-5. 4 -fluoro-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-phenylcycloheptane (5.2 mg, 11.6%) was obtained.

[0175] LCMS: m / z (ESI), 348 [M+H] + 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).

[0176] 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) Step A: 2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (29) TIFF2025532532000043.tif30170

[0177] 3-(4-t-butyldimethylsiloxymethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (1 g, 2.13 mmol) was dissolved in DMSO (16 mL), and 2-aminomethylphenol (525.53 mg, 4.27 mmol) and sodium t-butoxide (51.26 mg, 0.53 mol) were added sequentially. The mixture was stirred at 130°C for 1 hour. The reaction mixture was filtered and then directly subjected to reverse-phase separation to obtain 2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (180 mg, 24%).

[0178] LCMS: m / z(ESI), 348.2 [M+H] + .

[0179] 1 H NMR(400MHz,DMSO-d6)δ 9.73-9.53(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,2) H), 7.09(t,J=7.4Hz,1H), 6.93-6.85(m,2 H), 6.78-6.70(m,1H), 5.39(d,J=6.9Hz,1H), 4.50(s,4 H).

[0180] Step B: (E)-4-Oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyridine-5(1,2)-benzocycloheptane (I-6) TIFF2025532532000044.tif30170

[0181] 2-(((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (compound 29, 50 mg, 0.137 mol) was added to a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90 ° C for 1.5 hours, filtered, and the filtrate was concentrated and separated 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%).

[0182] LCMS: m / z (ESI), 330 [M+H] + 1 H NMR:(400MHz,DMSO-d6)δ 9.74(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,2 H), 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).

[0183] 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) Step A: (5-(6-chloroimidazol[1,2-b]pyridazin-3-yl)pyridin-3-yl)methanol (30) TIFF2025532532000045.tif38170

[0184] 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), and potassium carbonate (11.28 g, 9.76 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL) and stirred at 100°C for 16 hours. The mixture was then diluted with water (1.5 L) and extracted three times with ethyl acetate (500 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was concentrated and subjected to column chromatography to give (5-(6-chloroimidazole[1,2-b]pyridazin-3-yl)pyridin-3-yl)methanol (150 mg, 17%).

[0185] LCMS: m / z (ESI), 261 [M+H] + .

[0186] Step B: 3-(5-((t-butyldimethylsilyloxy)methyl)-pyridin-3-yl)-6-chloroimidazole[1,2-b]pyridazine (31) TIFF2025532532000046.tif36170

[0187] (5-(6-chloroimidazole[1,2-b]pyridazin-3-yl)pyridin-3-yl)methanol (compound 30, 150 mg, 0.57 mmol) and imidazole (77.53 mg, 1.14 mmol) were added to dichloromethane (10 mL), and t-butyldimethylsilane chloride (128.25 mg, 0.85 mmol) was added at 0° C. and stirred at room temperature for 16 hours. The mixture was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 3-(5-((t-butyldimethylsilyloxy)methyl)-pyridin-3-yl)-6-chloroimidazole[1,2-b]pyridazine (70 mg, 32%).

[0188] LCMS: m / z (ESI), 375 [M+H] + .

[0189] Step C: 3-(5-t-butyldimethylsiloxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (32) TIFF2025532532000047.tif41170

[0190] 33-(5-((t-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 the resulting solution was treated with 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (73.43 mg, 0.187 mol), Pd(dba)2 (11.74 mg, 0.019 mol), sodium t-butoxide (35. Add Xantphos (10.03 mg, 0.019 mol) successively, stir at 100 °C for 16 hours, concentrate, and then separate by column chromatography to obtain 3-(5-t-butyldimethylsiloxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (12 mg, 10%).

[0191] LCMS: m / z (ESI), 614.2 [M+H] + .

[0192] Step D: 3-(5-hydroxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (33) TIFF2025532532000048.tif34170

[0193] 3-(4-t-butyldimethylsiloxymethyl)pyridin-2-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 32, 12 mg, 0.019 mol) is placed in methanol (3 mL), hydrochloric acid methanol solution (4 M, 3 mL) is added, and the mixture is stirred at 25 ° C for 2 hours. Then, the mixture is neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate is concentrated and then separated by column chromatography to obtain 3-(5-hydroxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (5 mg).

[0194] LCMS: m / z (ESI), 380 [M+H] + .

[0195] Stage 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) TIFF2025532532000049.tif30170

[0196] 3-(5-Hydroxymethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (Compound 33, 35.2 mg, 0.094 mol) was placed in a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to prepare (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 (7.6 mg, 22.6%) was obtained.

[0197] LCMS: m / z (ESI), 362 [M+H] + .

[0198] 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).

[0199] 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) Step A: 2-Bromo-4-hydroxyethylpyridine (34) TIFF2025532532000050.tif20170

[0200] 2-Bromopyridine-4-ethyl acetate (1 g, 4.35 mmol) in tetrahydrofuran (15 mL) and lithium aluminum tetrahydrofuran (142.03 mg, 6.52 mmol) were added, and the mixture was stirred at 25°C for 1 hour. Then, the mixture was 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, dried over anhydrous sodium sulfate, and concentrated to give 2-bromo-4-hydroxyethylpyridine (870 mg).

[0201] LCMS: m / z (ESI), 301 [M+H] + .

[0202] Step B: 2-Bromo-4-t-butyldimethylsilyloxyethylpyridine (35) TIFF2025532532000051.tif22170

[0203] 2-Bromo-4-hydroxyethylpyridine (compound 34, 2.57 g, 12.72 mmol) was placed in dichloromethane (30 mL), and t-butyldimethylsilyl chloride (3.83 g, 25.44 mmol) and imidazole (1.73 g, 25.44 mmol) were added successively at 0°C. The mixture was stirred at 25°C for 1 hour, and then directly concentrated and subjected to column chromatography to obtain colorless liquid 2-bromo-4-t-butyldimethylsilyloxyethylpyridine (4 g, 99%).

[0204] 1 H NMR:(400MHz,CHLOROFORM-d)δ 8.24-8.27(m,1H)7.38-7.39(m,1H)7.10-7.13(m,1H)3.83(t,J=6.19Hz,2 H)2.75-2.81(m,2 H)0.86(s,9 H), 0.02(s,6 H).

[0205] Step C: 2-tributylstannyl-4-t-butyldimethylsilyloxyethylpyridine (36) TIFF2025532532000052.tif23170

[0206] 2-Bromo-4-t-butyldimethylsilyloxyethylpyridine (compound 35, 4 g, 12.65 mmol) was placed in tetrahydrofuran (10 mL), and under nitrogen gas protection, n-butyllithium (2.5 M, 5.06 mL) was added at −78° C., followed by the addition of chlorotributyltin (6.17 g, 18.97 mmol). The mixture was stirred at −78° C. for 2 hours, and then quenched with saturated ammonium chloride solution (50 mL), potassium fluoride solution (50 mL) was added, and the mixture was stirred for 1 hour. The mixture was then extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated to obtain a yellow liquid, 2-tributylstannyl-4-t-butyldimethylsilyloxyethylpyridine (5 g, crude product).

[0207] Step D: 3-(4-t-butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (37) TIFF2025532532000053.tif29170

[0208] 3-Bromo-6-chloroimidazole[1,2-b]pyridazine (compound 36, 2.21 g, 9.50 mmol) and tetrakistriphenylphosphine palladium (1.10 g, 949.75 mmol) were placed in a toluene solution (10 mL), and 2-tributylstannyl-4-t-butyldimethylsilyloxyethylpyridine (compound 36, 5 g, 9.50 mmol) was added. The mixture was stirred at 80 °C for 12 hours under nitrogen gas protection, and then filtered. The filtrate was concentrated and separated by column chromatography to obtain a yellow solid, 3-(4-t-butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (270 mg, yield 7.31%).

[0209] 1 H NMR:(400MHz,CHLOROFORM-d)δ ppm 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,2 H)3.94(t,J=6.63Hz,2 H)2.95(t,J=6.57Hz,2 H)0.87(br,9 H), 0.00-0.02(m,6 H).

[0210] Step E: 4-Fluoro-2-(((3-(4-(hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (37-1) TIFF2025532532000054.tif28170

[0211] 3-(4-t-butyldimethylsilyloxyethylpyridin-2-yl-6-chloroimidazole[1,2-b]pyridazine (compound 37, 250 mg, 0.64 mmol) was dissolved 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 gas protection, and then directly concentrated and purified by reverse phase liquid chromatography to obtain a white solid 2-(((3-(4-(hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (100 mg, 43% yield).

[0212] LCMS: m / z (ESI), 362.1 [M+H] + .

[0213] 1 H NMR:(400MHz,METHANOL-d4)δ ppm 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)7.16-7.2 1(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,2 H)3.76(t,J=6.44Hz,2H)2.76(t,J=6.50Hz,2H).

[0214] Step F: (E)-6-Oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-8) TIFF2025532532000055.tif26170

[0215] 2-(((3-(4-(hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (compound 37-1, 30 mg, 0.083 mol) was placed in tetrahydrofuran (5 mL), triphenylphosphine (65.32 mg, 249.03 umol) and DIAD (50.36 mg, 249.03 umol) were added, and the mixture was stirred at 60 °C for 2 hours under nitrogen gas protection. Then, it was directly separated and purified by reverse-phase liquid chromatography to obtain (E)-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (10 mg, 34% yield).

[0216] LCMS: m / z (ESI), 344.0 [M+H] + .

[0217] 1 H NMR:(400MHz,METHANOL-d4)δ ppm 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,2 H)4.71(br s,2 H)4.34-4.38(m,2 H)3.27(t,J=4.88Hz,2 H).

[0218] 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) Step A: 3-(5-t-butyldimethylsiloxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (38) TIFF2025532532000056.tif39170

[0219] 3-(4-t-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 treated with sodium t-butoxide (2 M, 241.02 µL) and RuPhos Pd Add G4 (13.44 mg, 0.016 mmol) and stir at 100°C under nitrogen gas protection for 2 hours, then dilute with water (20 mL) and extract with ethyl acetate (20 mL) three times. The organic phases are combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture is separated by column chromatography to obtain a yellow solid 3-(5-t-butyldimethylsilyloxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (130 mg, 83%).

[0220] LCMS: m / z (ESI), 610.2 [M+H] + .

[0221] Step B: 3-(5-hydroxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (39) TIFF2025532532000057.tif37170

[0222] 3-(4-t-butyldimethylsiloxyethyl)pyridin-2-yl-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 38, 120 mg, 0.196 mmol) is placed in methanol (10 mL), hydrochloric acid methanol solution (4 M, 3 mL) is added, and the mixture is stirred at 25 ° C for 2 hours. Then, the mixture is neutralized with sodium bicarbonate to pH = 7, filtered, and the filtrate is concentrated and then separated by column chromatography to obtain 3-(5-hydroxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (35 mg, 23%).

[0223] LCMS: m / z (ESI), 376 [M+H] + .

[0224] 1 H NMR:(400MHz,METHANOL-d4)δ=8.43-8.39(m,2 H)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,2) H)5.46-5.39(m,1H)3.92-3.76(m,2 H)2.94(t,J=6.6Hz,2 H)1.59-1.56(m,3 H).

[0225] Step C: (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) TIFF2025532532000058.tif32170

[0226] 3-(5-Hydroxyethyl)pyridin-3-yl-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (compound 39, 30 mg, 0.079 mol) was placed in tetrahydrofuran (5 mL), triphenylphosphine (65.32 mg, 0.25 mmol) and DIAD (50.36 mg, 0.25 mmol) were added, and the mixture was stirred at 60 °C for 2 hours under nitrogen gas protection. Then, it was directly separated and purified by reverse-phase liquid chromatography to obtain (E)-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (6.74 mg, 18.4%).

[0227] LCMS: m / z (ESI), 358.0 [M+H] + .

[0228] 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)8.0 7-8.02(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,2) H)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)1.4 5 -1.41(m,3 H).

[0229] 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) Step A: 4-chloro-6-t-butyldimethylsilyloxymethylpyrimidine (40) TIFF2025532532000059.tif20170

[0230] Compound 40 was synthesized by using compound 6-chloro-4-hydroxymethylpyrimidine instead of compound 1 as the starting material and following the method for compound 2.

[0231] LCMS: m / z (ESI), 259 [M+H] + .

[0232] Step B: 4-Tributylstannyl-6-t-butyldimethylsilyloxymethylpyrimidine (41) TIFF2025532532000060.tif23170

[0233] Compound 41 was synthesized by using compound 40 instead of compound 2 as a starting material and following the procedure for compound 3.

[0234] LCMS: m / z (ESI), 515.0 [M+H] + .

[0235] Step C: 3-(6-t-butyldimethylsiloxymethylpyridin-4-yl)-6-chloroimidazole[1,2-b]pyridazine (42) TIFF2025532532000061.tif35170

[0236] Compound 42 was synthesized by using compound 41 instead of compound 3 as a raw material and following the method for compound 5.

[0237] LCMS: m / z (ESI), 376.0 [M+H] + .

[0238] Step D: 3-(6-t-butyldimethylsiloxymethylpyridin-4-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (43) TIFF2025532532000062.tif39170

[0239] Compound 42 was used as a starting material instead of compound 5, and compound 43 was synthesized according to the method for compound 20.

[0240] LCMS: m / z (ESI), 597.2 [M+H] + .

[0241] Step E: 3-(6-hydroxymethylpyrimidin-4-yl)-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (44) TIFF2025532532000063.tif26170

[0242] Compound 43 was used as a starting material instead of compound 10, and compound 44 was synthesized by the method for compound 11.

[0243] LCMS: m / z (ESI), 363 [M+H] + .

[0244] Step F: (E)-6-Methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(1,2)-benzocycloheptane (I-10) TIFF2025532532000064.tif29170

[0245] Compound 1-10 was synthesized by using compound 44 instead of compound 11 as the raw material and following the procedure for compound I-1.

[0246] LCMS: m / z (ESI), 345 [M+H] + .

[0247] 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) Step A: 4-chloro-6-hydroxyethylpyrimidine (45) TIFF2025532532000065.tif21170

[0248] Compound 45 was synthesized by using compound 44 instead of compound 33 as a starting material and following the method for compound 34.

[0249] LCMS: m / z (ESI), 159.2 [M+H] + .

[0250] Step B: 4-chloro-6-t-butyldimethylsilyloxyethylpyrimidine (46) TIFF2025532532000066.tif22170

[0251] Compound 46 was synthesized by using compound 45 instead of compound 34 as a starting material and following the method for compound 35.

[0252] LCMS: m / z (ESI), 273.0 [M+H] + .

[0253] Step C: 4-Tributylstannyl-6-t-butyldimethylsilyloxyethylpyrimidine (47) TIFF2025532532000067.tif25170

[0254] Compound 47 was synthesized by using compound 46 instead of compound 35 as a raw material and following the method for compound 36.

[0255] LCMS: m / z (ESI), 529.2 [M+H] + .

[0256] Step D: 3-(6-t-butyldimethylsilyloxyethylpyrimidin-4-yl-6-chloroimidazole[1,2-b]pyridazine (48) TIFF2025532532000068.tif33170

[0257] Compound 48 was synthesized by using compound 47 instead of compound 36 as a raw material and following the method for compound 37.

[0258] LCMS: m / z (ESI), 390.0 [M+H] + .

[0259] Step E: 3-(6-t-butyldimethylsiloxymethylpyrimidin-4-yl)-N-(1-(5-fluoro-2-(4-methoxybenzyloxy)-phenyl)ethyl)imidazole[1,2-b]pyridazin-6-amine (48-1) TIFF2025532532000069.tif33170

[0260] Compound 48-1 was synthesized by using compound 48 instead of compound 37 as the starting material and following the method for compound 38.

[0261] LCMS: m / z (ESI), 611.2 [M+H] + .

[0262] Step F: 2-(((3-(6-(hydroxyethylpyrimidin)-4-yl)imidazole[1,2-b]pyridazin-6-yl)-amino)-methyl)phenol (48-2) TIFF2025532532000070.tif27170

[0263] Compound 48-2 was synthesized by using compound 48-1 instead of compound 38 as a starting material and following the method for compound 39.

[0264] LCMS: m / z (ESI), 377.2 [M+H] + .

[0265] Step G: (E)-4-Methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-11) TIFF2025532532000071.tif29170

[0266] Compound I-11 was synthesized by using compound 48-2 instead of compound 39 as the starting material and following the procedure for compound I-9.

[0267] LCMS: m / z (ESI), 359 [M+H] + .

[0268] Example 12: (E)-5 5 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-12) Step A: 2-Bromo-4-p-methoxybenzyloxymethylpyridine (50) TIFF2025532532000072.tif26170

[0269] 2-Bromo-4-fluoropyridine (compound 49, 10 g, 57.47 mmol) and p-methoxybenzyl alcohol (9.52 g, 68.96 mmol) were added to DMF (100 mL), evaporated sodium chloride (3.45 g, 86.21 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was then 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, the mixture was subjected to column chromatography to obtain 2-bromo-4-t-butyldimethylsiloxymethylpyridine (14.44 g, 85%).

[0270] LCMS: m / z (ESI), 294 [M+H] + .

[0271] Step B: 3-Tributylstannyl-6-chloroimidazole[1,2-b]pyridazine (51) TIFF2025532532000073.tif17170

[0272] 3-Chloro-6-chloroimidazole[1,2-b]pyridazine (compound 4, 10 g, 43.10 mmol) was placed in tetrahydrofuran (100 mL), and butyllithium (2.5 M, 17.24 mol) was added dropwise at -70°C. The mixture was stirred for 30 minutes, and chlorotributyltin (18.25 g, 43.10 mmol) was added. The mixture was stirred at -70°C for 2 hours, and 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, the mixture was subjected to column chromatography to obtain 3-tributylstannyl-6-chloroimidazole[1,2-b]pyridazine (2.1 g, 11%).

[0273] LCMS: m / z (ESI), 444.3 [M+H] + .

[0274] Step C: 3-(4-p-Methoxybenzyloxypyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (52) TIFF2025532532000074.tif33170

[0275] 3-Tributylstannyl-6-chloroimidazole[1,2-b]pyridazine (compound 51, 1 g, 2.25 mmol) was placed in toluene (50 mL), and 2-bromo-4-t-butyldimethylsiloxymethylpyridine (compound 50, 661.3 mg, 2.25 mmol) and Pd(PPh3)4 (58.5 mg, 0.225 mmol) were added sequentially. 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 combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was subjected to column chromatography to obtain 3-(4-p-methoxybenzyloxypyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (517 mg, 62%).

[0276] Step D: 3-Bromo-5-fluoropyridine-2-carboxylic acid methyl ester (54) TIFF2025532532000075.tif25170

[0277] 3-Bromo-5-fluoropyridine-2-carboxylic acid (compound 53, 10 g, 45.45 mmol) was added to methanol (200 mL), concentrated sulfuric acid (2 mL) was added, and the mixture was stirred at 80°C for 12 hours. The mixture was 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, the mixture was subjected to column chromatography to obtain 3-bromo-5-fluoropyridine-2-carboxylic acid methyl ester (6.3 g, 59%).

[0278] LCMS: m / z (ESI), 234.0 [M+H] + .

[0279] Step E: 3-(1-ethoxyvinyl)-5-fluoropyridine-2-carboxylic acid methyl ester (55) TIFF2025532532000076.tif31170

[0280] 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)tributylstannyl (6.94 g, 19.23 mmol) were added sequentially. 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, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain 3-(1-ethoxyvinyl)-5-fluoropyridine-2-carboxylic acid methyl ester (2.5 g, 86%).

[0281] LCMS: m / z (ESI), 226.0 [M+H] + .

[0282] Step F: (3-(1-ethoxyvinyl)-5-fluoropyridin-2-yl)-methanol (56) TIFF2025532532000077.tif27170

[0283] 3-(1-ethoxyvinyl)-5-fluoropyridine-2-carboxylic acid methyl ester (compound 55, 1.1 g, 4.89 mmol) was placed in tetrahydrofuran (50 mL), diisobutylaluminum hydride (9.77 mL, 9.77 mmol) was added, and the mixture was stirred at 0°C for 5 hours. The mixture was then quenched with water (600 mL), diluted, 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, the mixture was subjected to column chromatography to obtain (3-(1-ethoxyvinyl)-5-fluoropyridin-2-yl)-methanol (803 mg, 83%).

[0284] LCMS: m / z (ESI), 198.0 [M+H] + .

[0285] Step G: (3-acetyl-5-fluoropyridin-2-yl)-methanol (57) TIFF2025532532000078.tif22170

[0286] (3-(1-ethoxyvinyl)-5-fluoropyridin-2-yl)-methanol (compound 56, 803 mg, 4.07 mmol) was added to methanol (50 mL), and hydrochloric acid methanol solution (1 M, 10 mL) was added. The mixture was stirred at 25°C for 12 hours. Then, the mixture was diluted with saturated sodium bicarbonate solution (100 mL) to make it alkaline, and extracted with ethyl acetate (200 mL) three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was subjected to column chromatography to obtain (3-acetyl-5-fluoropyridin-2-yl)-methanol (650 mg, 94%).

[0287] LCMS: m / z (ESI), 170.0 [M+H] + .

[0288] Step H: 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone (58) TIFF2025532532000079.tif23170

[0289] (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 t-butyldimethylsilyl chloride (576 mg, 3.84 mmol) were added successively. The mixture was stirred at 25°C for 12 hours, and 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, the mixture was subjected to column chromatography to obtain 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone (343 mg, 32%).

[0290] LCMS: m / z (ESI), 284.0 [M+H] + .

[0291] Step I: 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone oxime (59) TIFF2025532532000080.tif26170

[0292] 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone (compound 58, 343 mg, 1.21 mmol) is placed in ethanol (20 mL), sodium acetate (198 mg, 2.42 mmol), hydroxylamine hydrochloride (168 mg, 2.42 mmol) are added successively, and the mixture is stirred at 70 ° C for 2 hours. Then, the mixture is diluted with water (60 mL) and extracted with ethyl acetate (20 mL) three times. The organic phases are combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture is subjected to column chromatography to obtain 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone oxime (309 mg, 85.6%).

[0293] LCMS: m / z (ESI), 299.0 [M+H] + .

[0294] Step J: 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethylamine (60) TIFF2025532532000081.tif25170

[0295] 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethanone oxime (compound 59, 309 mg, 1.07 mmol) in methanol (15 mL) was added ammonium formate (127 mg, 2.14 mmol) and zinc powder (139 mg, 2.14 mmol) successively, and the mixture was stirred at 40°C for 12 hours. The mixture was then filtered, and the filtrate was concentrated and subjected to column chromatography to give 1-((2-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethylamine (105 mg, 34.5%).

[0296] LCMS: m / z (ESI), 285.0 [M+H] + .

[0297] Step K: N-(1-(2-((t-butyldimethylsilyloxy)methyl)-5-fluoropyridin-3-yl)ethyl)-3-(4-(4-methoxybenzyloxypyridin)-2-yl)imidazole[1,2-b]pyridazin-6-amine (61) TIFF2025532532000082.tif38170

[0298] 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-t-butyldimethylsilyloxymethyl)-5-fluoropyridin-3-yl)-1-ethylamine (93.11 mg, 0.328 mol), Pd(dba)2 (15.34 mg, 0.027 mol), sodium t-butoxide (51.26 mg, 0.53 mol) and Xantphos (15.43 mg, 0.027 mol) were added successively, and the mixture was stirred at 100 °C for 16 hours. After concentration, the mixture was separated by column chromatography to give N-(1-(2-((t-butyldimethylsilyloxy)methyl)-5-fluoropyridin-3-yl)ethyl)-3-(4-(4-methoxybenzyloxypyridin)-2-yl)imidazole[1,2-b]pyridazin-6-amine (42 mg, 25%).

[0299] LCMS: m / z (ESI), 615.2 [M+H] + .

[0300] Step L: 2-(6-((1-(5-fluoro-2-(hydroxymethyl)pyridin-3-yl)-ethyl)-amino)imidazol[1,2-b]pyridazin-3-yl)pyridin-4-ol (62) TIFF2025532532000083.tif28170

[0301] N-(1-(2-((t-butyldimethylsilyloxy)methyl)-5-fluoropyridin-3-yl)ethyl)-3-(4-(4-methoxybenzyloxypyridin)-2-yl)imidazole[1,2-b]pyridazin-6-amine (compound 61, 42 mg, 0.068 mol) in methanol (3 mL), add hydrochloric acid methanol solution (4 M, 3 mL), stir at 25 ° C. for 2 hours, then neutralize with sodium bicarbonate to pH = 7, filter, and concentrate the filtrate, then separate by column chromatography to obtain 2-(6-((1-(5-fluoro-2-(hydroxymethyl)pyridin-3-yl)-ethyl)-amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-ol (22 mg, 85%).

[0302] LCMS: m / z (ESI), 381.2 [M+H] + .

[0303] Stage M:(E)-5 5 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-12) TIFF2025532532000084.tif28170

[0304] 2-(6-((1-(5-fluoro-2-(hydroxymethyl)pyridin-3-yl)-ethyl)-amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-ol (compound 62, 35.2 mg, 0.094 mol) was placed in a mixture 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 30 minutes. Potassium carbonate (500.84 mg, 3.62 mol) was then added to neutralize the mixture to pH > 7, and the dichloromethane was removed by evaporation. The mixture was stirred at 90°C for 1.5 hours, filtered, and the filtrate was concentrated to prepare (E)-5. 5 to obtain 1,3-fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (7.6 mg, 22.6%).

[0305] LCMS: m / z (ESI), 363 [M+H] + .

[0306] 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) Step A: Methyl 2-bromo-4-fluorobenzoate (63) TIFF2025532532000085.tif22170

[0307] Compound 63 is synthesized by using compound 62 instead of compound 53 as a raw material and following the method for compound 54.

[0308] LCMS: m / z (ESI), 233.0 [M+H] + .

[0309] Step B: Methyl 2-(1-ethoxyvinyl)-4-fluorobenzoate (64) TIFF2025532532000086.tif32170

[0310] Compound 64 was synthesized by using compound 63 instead of compound 54 and following the procedure for compound 55. LCMS: m / z (ESI), 225.0 [M+H] + .

[0311] Step C: 2-(1-ethoxyvinyl)-4-fluorobenzyl alcohol (65) TIFF2025532532000087.tif27170

[0312] Compound 65 was synthesized by using compound 64 instead of compound 55 and following the procedure for compound 56. LCMS: m / z (ESI), 197.0 [M+H] + .

[0313] Step D: 2-acetyl-4-fluorobenzyl alcohol (66) TIFF2025532532000088.tif22170

[0314] Compound 66 was synthesized by using compound 65 instead of compound 56 and following the procedure for compound 57. LCMS: m / z (ESI), 169.0 [M+H] + .

[0315] Step E: 2-t-butyldimethylsilyloxymethyl-5-fluoroacetophenone (67) TIFF2025532532000089.tif26170

[0316] Compound 67 was synthesized by using compound 66 instead of compound 57 and following the procedure for compound 58. LCMS: m / z (ESI), 283.0 [M+H] + .

[0317] Step F: 2-t-butyldimethylsilyloxymethyl-5-fluoroacetophenone oxime (68) TIFF2025532532000090.tif21170

[0318] Compound 68 was synthesized by using compound 67 instead of compound 58 and following the procedure for compound 59. LCMS: m / z (ESI), 298.0 [M+H] + .

[0319] Step G: 1-(2-t-butyldimethylsilyloxymethyl-5-fluorophenyl)-1-ethylamine (69) TIFF2025532532000091.tif24170

[0320] Using compound 68 instead of compound 59 as the raw material, compound 69 was synthesized according to the method for compound 60. LCMS: m / z (ESI), 284.0 [M+H] + .

[0321] Step H: N-(1-(2-t-butyldimethylsilyloxymethyl-5-fluorophenyl)ethyl)-3-(4-(4-methoxybenzyloxypyridin)-2-yl)imidazole[1,2-b]pyridazin-6-amine (70) TIFF2025532532000092.tif36170

[0322] Compound 70 was synthesized by using compound 69 instead of compound 60 and following the procedure for compound 61. LCMS: m / z (ESI), 614.2 [M+H] + .

[0323] Step I: 2-(6-((1-(5-fluoro-2-(hydroxymethyl)phenyl)-ethyl)-amino)imidazol[1,2-b]pyridazin-3-yl)pyridin-4-ol (70-1) TIFF2025532532000093.tif30170

[0324] Compound 70-1 was synthesized by using compound 70 instead of compound 61 as a raw material and following the method for compound 62.

[0325] LCMS: m / z (ESI), 380.2 [M+H] + .

[0326] Stage 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) TIFF2025532532000094.tif29170

[0327] Compound I-13 was synthesized by using compound 70-1 instead of compound 62 as the starting material and following the procedure for compound I-12.

[0328] LCMS: m / z (ESI), 362.2 [M+H] + .

[0329] Examples 14 and 15: (R)-(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-14) and (S)-(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-15) TIFF2025532532000095.tif29170

[0330] Compound I-1 is used as a starting material to prepare compounds I-14 and I-15 by chiral resolution.

[0331] LCMS: m / z (ESI), 362.2 [M+H] + (I-14), LCMS:m / z(ESI), 362.2[M+H] + (I-15).

[0332] Examples 16 and 17: (R)-(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-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) TIFF2025532532000096.tif31170

[0333] Compound I-2 is used as a starting material to prepare compounds I-16 and I-17 by chiral resolution.

[0334] LCMS: m / z (ESI), 380.2 [M+H] +(I-16), LCMS:m / z(ESI), 380.0[M+H] + (I-17).

[0335] Examples 18 and 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) and (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) TIFF2025532532000097.tif32170

[0336] Compound I-3 is used as a starting material to prepare compounds I-18 and I-19 by chiral resolution.

[0337] LCMS: m / z (ESI), 344.2 [M+H] + (I-18), LCMS:m / z(ESI), 344.2[M+H] + (I-19).

[0338] Examples 20 and 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) and (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) TIFF2025532532000098.tif32170

[0339] Compound I-4 is used as a starting material to prepare compounds I-20 and I-21 by chiral resolution.

[0340] LCMS: m / z (ESI), 345.2 [M+H] + (I-20), LCMS:m / z(ESI), 345.2[M+H] + (I-21).

[0341] Examples 22 and 23: (R)-(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-22) and (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) TIFF2025532532000099.tif28170

[0342] Compound I-7 is used as a starting material to prepare compounds I-22 and I-23 by chiral resolution.

[0343] LCMS: m / z (ESI), 362.2 [M+H] + (I-22), LCMS:m / z(ESI), 362.2[M+H] + (I-23).

[0344] Examples 24 and 25: (R)-(E)-5 5 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-24) and (S)-(E)-5 5 -Fluoro-6-methyl-3-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4),5(2,3)-bipyridylcycloheptane (I-25) TIFF2025532532000100.tif29170

[0345] Compound I-12 is used as a starting material to prepare compounds I-24 and I-25 by chiral resolution.

[0346] LCMS: m / z (ESI), 363.2 [M+H] +(I-24), LCMS:m / z(ESI), 363.2[M+H] + (I-25).

[0347] Examples 26 and 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) and (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) TIFF2025532532000101.tif34170

[0348] Compound I-10 is used as a starting material to prepare compounds I-26 and I-27 by chiral resolution.

[0349] LCMS: m / z (ESI), 363.2 [M+H] + (I-26), LCMS:m / z(ESI), 363.2[M+H] + (I-27).

[0350] Examples 28 and 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) and (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) TIFF2025532532000102.tif29170

[0351] Compound I-9 is used as a starting material to prepare compounds I-28 and I-29 by chiral resolution.

[0352] LCMS: m / z (ESI), 358.0 [M+H] + (I-28), LCMS:m / z(ESI), 358.0[M+H] +(I-29).

[0353] Examples 30 and 31: (R)-(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-30) and (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) TIFF2025532532000103.tif32170

[0354] Compound I-13 is used as a starting material to prepare compounds I-30 and I-31 by chiral resolution.

[0355] LCMS: m / z (ESI), 362.0 [M+H] + (I-30), LCMS:m / z(ESI), 362.0[M+H] + (I-31).

[0356] Examples 32 and 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) and (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) TIFF2025532532000104.tif26170

[0357] Compound I-11 is used as a starting material to prepare compounds I-32 and I-33 by chiral resolution.

[0358] LCMS: m / z (ESI), 359.0 [M+H] + (I-32), LCMS:m / z(ESI), 359.0[M+H] +(I-33).

[0359] Example 34: (4R,7R,E)-55-4,7-dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-3 4 ) Step A: (R)-1-(5-fluoro-2-methoxyphenyl)ethan-1-amine (71) TIFF2025532532000105.tif21170

[0360] The synthesis of compound 71 is carried out by referring to the method described in the literature, Journal of Medicinal Chemistry (1974), 17(7), 708-15.

[0361] LCMS: m / z (ESI), 170 [M+H] + .

[0362] Step B: (S)-1-(2-bromopyridin-4-yl)-2-propanol (73) TIFF2025532532000106.tif20170

[0363] The synthesis of compound 73 is prepared with reference to the method in the literature Tetrahedron Asymmetry, (2006), 17(2), 268-274.

[0364] LCMS: m / z (ESI), 216.2 [M+H] + .

[0365] Step C: (S)-2-Bromo-4-(2-t-butyldimethylsilyloxypropyl)pyridine (74) TIFF2025532532000107.tif20170

[0366] Compound 74 was synthesized by using compound 73 instead of compound 34 as a raw material and following the method for compound 35.

[0367] LCMS: m / z (ESI), 332.2 [M+H] + .

[0368] Step D: (S)-2-tributylstannyl-4-(2-t-butyldimethylsilyloxypropyl)pyridine (75) TIFF2025532532000108.tif22170

[0369] Compound 75 was synthesized by using compound 74 instead of compound 35 as a raw material and following the method for compound 36.

[0370] LCMS: m / z (ESI), 542.2 [M+H] + .

[0371] Step E: 3-(4-(2-t-butyldimethylsilyloxypropyl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (76) TIFF2025532532000109.tif34170

[0372] Compound 76 was synthesized by using compound 75 instead of compound 36 as a raw material and following the method for compound 37.

[0373] LCMS: m / z (ESI), 403.2 [M+H] + .

[0374] Step F: (S)-1-(2-(6-(((R)-1-(2-methoxy-5-fluorophenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (77) TIFF2025532532000110.tif33170

[0375] Compound 77 was synthesized by using compound 76 instead of compound 37 and compound 71 instead of compound 19 as raw materials, following the method for compound 38.

[0376] LCMS: m / z (ESI), 422.1 [M+H]+ .

[0377] Step G: (S)-1-(2-(6-(((R)-1-(2-hydroxy-5-fluorophenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (78) TIFF2025532532000111.tif32170

[0378] (S)-1-(2-(6-(((R)-1-(2-methoxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (compound 77, 74 mg, 0.183 mol) was placed in dichloromethane (5 mL), boron tribromide (1 M, 0.5 mL) was added, and the mixture was stirred at 25° C. for 2 hours. The mixture was then neutralized to pH=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and then separated by column chromatography to obtain (S)-1-(2-(6-(((R)-1-(2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine)2-propanol (25 mg, 35%).

[0379] LCMS: m / z (ESI), 408.1 [M+H] + .

[0380] Step H: (4R,7R,E)-55-4,7-dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-3 4 ) TIFF2025532532000112.tif30170

[0381] Compound I-34 was synthesized by using compound 78 instead of compound 39 as the raw material and following the method for compound I-9.

[0382] LCMS: m / z (ESI), 390 [M+H] + .

[0383] Example 35: (4R,7R,E)-55-4,7-dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-35) Step A: (S)-1-(6-chloropyrimidin-4-yl)-2-propanol (79) TIFF2025532532000113.tif21170

[0384] The synthesis of compound 79 is prepared with reference to the method in Tetrahedron Asymmetry, (2006), 17(2), 268-274.

[0385] LCMS: m / z (ESI), 173.2 [M+H] + .

[0386] Step B: (S)-6-chloro-4-(2-t-butyldimethylsilyloxypropyl)pyrimidine (80) TIFF2025532532000114.tif20170

[0387] Compound 80 was synthesized by using compound 79 instead of compound 73 as a raw material and following the method for compound 74.

[0388] LCMS: m / z (ESI), 287.0 [M+H] + .

[0389] Step C: (S)-6-tributylstannyl-4-(2-t-butyldimethylsilyloxypropyl)pyrimidine (81) TIFF2025532532000115.tif22170

[0390] Compound 81 is synthesized by using compound 80 instead of compound 74 as a raw material and following the method for compound 75.

[0391] LCMS: m / z (ESI), 543.2 [M+H] + .

[0392] Step D: 3-(6-(2-t-butyldimethylsilyloxypropyl)pyrimidin-4-yl)-6-chloroimidazole[1,2-b]pyridazine (82) TIFF2025532532000116.tif34170

[0393] Compound 82 is synthesized by using compound 81 instead of compound 75 as a raw material and following the method for compound 76.

[0394] LCMS: m / z (ESI), 404.2 [M+H] + .

[0395] Step E: (S)-1-(2-(6-(((R)-1-(2-methoxy-5-fluoro-phenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine) 2-propanol (82-1) TIFF2025532532000117.tif34170

[0396] Compound 82-1 was synthesized by using compound 82 instead of compound 76 as the starting material and following the method for compound 77.

[0397] LCMS: m / z (ESI), 423.1 [M+H] + .

[0398] Step F: (S)-1-(2-(6-(((R)-1-(2-hydroxy-5-fluorophenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyrimidine) 2-propanol (82-2) TIFF2025532532000118.tif28170

[0399] Compound 82-2 was synthesized by using compound 82-1 instead of compound 77 as the starting material and following the method for compound 78.

[0400] LCMS: m / z (ESI), 409.1 [M+H] + .

[0401] Step G: (4R,7R,E)-55-4,7-dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-35) TIFF2025532532000119.tif30170

[0402] Compound I-35 was synthesized by using compound 82-2 instead of compound 39 as the starting material and following the method for compound I-9.

[0403] LCMS: m / z (ESI), 391 [M+H] + .

[0404] Example 36: (4R,7R,E)-55-4,7-dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),5(3,2)-bipyridylcyclooctane (I-36) Step A: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine) 2-propanol (76-1) TIFF2025532532000120.tif32170

[0405] Compound 76-1 is synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 71 as a raw material and following the method for compound 77.

[0406] LCMS: m / z (ESI), 423.1 [M+H] + .

[0407] Step B: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)-4-pyridine) 2-propanol (76-2) TIFF2025532532000121.tif26170

[0408] Compound 76-2 was synthesized by using compound 76-1 instead of compound 77 as the starting material and following the method for compound 78.

[0409] LCMS: m / z (ESI), 409.1 [M+H] + .

[0410] Step C: (4R,7R,E)-55-4,7-dimethyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),5(3,2)-bipyridylcyclooctane (I-36) TIFF2025532532000122.tif26170

[0411] Compound I-36 was synthesized by using compound 76-2 instead of compound 39 as the starting material and following the method for compound I-9.

[0412] LCMS: m / z (ESI), 391 [M+H] + .

[0413] Example 37: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-37) Step A: (S)-1-(2-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-3) TIFF2025532532000123.tif32170

[0414] Compound 76-3 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 as a raw material and following the method for compound 77.

[0415] LCMS: m / z (ESI), 448.1 [M+H] + .

[0416] Step B: (S)-1-(2-(6-((R)-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-4) TIFF2025532532000124.tif30170

[0417] Compound 76-4 was synthesized by using 76-3 instead of compound 77 and following the procedure for compound 78.

[0418] LCMS: m / z (ESI), 434.1 [M+H] + .

[0419] Stage C: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-37) TIFF2025532532000125.tif29170

[0420] Compound I-37 was synthesized by using compound 76-4 instead of compound 39 as the starting material and following the method for compound I-9.

[0421] LCMS: m / z (ESI), 416 [M+H] + .

[0422] Example 38: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-38) Step A: (S)-1-(2-(6-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-5) TIFF2025532532000126.tif32170

[0423] Compound 76-5 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 as a raw material and following the method for compound 77.

[0424] LCMS: m / z (ESI), 449.1 [M+H] + .

[0425] Step B: (S)-1-(2-(6-((R)-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-6) TIFF2025532532000127.tif32170

[0426] Compound 76-6 was synthesized by using 76-5 instead of compound 77 and following the procedure for compound 78.

[0427] LCMS: m / z (ESI), 435.1 [M+H] + .

[0428] Stage C: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcyclooctane (I-38) TIFF2025532532000128.tif29170

[0429] Compound I-38 was synthesized by using compound 76-6 instead of compound 39 as the starting material and following the procedure for compound I-9.

[0430] LCMS: m / z (ESI), 417 [M+H] + .

[0431] Example 39: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-39) Step A: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-7) TIFF2025532532000129.tif35170

[0432] Compound 76-7 is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 as a raw material and following the method for compound 77.

[0433] LCMS: m / z (ESI), 466.1 [M+H] + .

[0434] Step B: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-8) TIFF2025532532000130.tif32170

[0435] Compound 76-8 was synthesized by using 76-7 instead of compound 77 and following the procedure for compound 78.

[0436] LCMS: m / z (ESI), 452.1 [M+H] + .

[0437] Stage C: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-3(1,2)-pyrrolidine-4(1,2)-phenylcyclooctane (I-39) TIFF2025532532000131.tif33170

[0438] Compound I-39 was synthesized by using compound 76-8 instead of compound 39 as the starting material and following the method for compound I-9.

[0439] LCMS: m / z (ESI), 434 [M+H] + .

[0440] Example 40: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcyclooctane (I-40) Step A: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-9) TIFF2025532532000132.tif34170

[0441] Compound 76-9 is synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 71 as a raw material and following the method for compound 77.

[0442] LCMS: m / z (ESI), 467.1 [M+H] + .

[0443] Step B: (S)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)-2-propanol (76-10) TIFF2025532532000133.tif33170

[0444] Compound 76-10 was synthesized by using compound 76-9 instead of compound 77 and following the procedure for compound 78.

[0445] LCMS: m / z (ESI), 453.1 [M+H] + .

[0446] Stage C: (3 2 R,3 4 S,6R,E)-3 4 ,4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4),4(3,2)-bipyridine-3(1,2)-pyrrolidinylcyclooctane (I-40) TIFF2025532532000134.tif35170

[0447] Compound I-40 was synthesized by using compound 76-10 instead of compound 39 and following the procedure for compound I-9.

[0448] LCMS: m / z (ESI), 435 [M+H] + .

[0449] Example 41: (33R,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) Step A: (S)-2-Bromo-4-(3-(t-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (83-1) TIFF2025532532000135.tif28170

[0450] Compound 83-1 is synthesized according to the method for compound 50, using compound (S)-3-((t-butyldimethylsilyl)oxy)pyrrolidine as the starting material instead of p-methoxybenzyl alcohol.

[0451] LCMS: m / z (ESI), 359.1 [M+H] + .

[0452] Step B: (S)-3-(4-(3-t-butyldimethylsilyloxypyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (83) TIFF2025532532000136.tif32170

[0453] Compound 83 was synthesized by using compound 83-1 instead of compound 50 as a raw material and following the method for compound 52.

[0454] LCMS: m / z (ESI), 430.1 [M+H] + .

[0455] Step C: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrole (83-2) TIFF2025532532000137.tif34170

[0456] Compound 83-2 was synthesized by using compound 83 instead of compound 76 and following the procedure for compound 77.

[0457] LCMS: m / z (ESI), 449.1 [M+H] + .

[0458] Step D: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrole (83-3) TIFF2025532532000138.tif35170

[0459] Compound 83-3 was synthesized by using 83-2 instead of compound 77 and following the procedure for compound 78.

[0460] LCMS: m / z (ESI), 435.1 [M+H] + .

[0461] Stage 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) TIFF2025532532000139.tif33170

[0462] Compound I-41 was synthesized by using compound 83-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0463] LCMS: m / z (ESI), 417 [M+H] + .

[0464] 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) Step A: (R)-2-Bromo-4-(3-(t-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (84-1) TIFF2025532532000140.tif28170

[0465] Compound 84-1 is synthesized according to the method for compound 50, using compound (R)-3-((t-butyldimethylsilyl)oxy)pyrrolidine as a starting material instead of p-methoxybenzyl alcohol.

[0466] LCMS: m / z (ESI), 359.1 [M+H] + .

[0467] Step B: (R)-3-(4-(3-t-butyldimethylsilyloxypyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (84) TIFF2025532532000141.tif30170

[0468] Compound 84 was synthesized by using compound 84-1 instead of compound 50 as a raw material and following the method for compound 52.

[0469] LCMS: m / z (ESI), 430.1 [M+H] + .

[0470] Step C: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrole (84-2) TIFF2025532532000142.tif33170

[0471] Compound 84-2 was synthesized by using compound 84 instead of compound 76 as the starting material and following the method for compound 77.

[0472] LCMS: m / z (ESI), 449.1 [M+H] + .

[0473] Step D: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-pyrrole (84-3) TIFF2025532532000143.tif33170

[0474] Compound 84-3 was synthesized by using 84-2 instead of compound 77 and following the procedure for compound 78.

[0475] LCMS: m / z (ESI), 435.1 [M+H] + .

[0476] Stage 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) TIFF2025532532000144.tif33170

[0477] Compound I-42 was synthesized by using compound 84-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0478] LCMS: m / z (ESI), 417 [M+H] + .

[0479] Example 43: (33R,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)-piperidine-5(1,2)-phenylcycloheptane (I-43) Step A: (S)-2-Bromo-4-(3-(t-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (87-1) TIFF2025532532000145.tif28170

[0480] Compound 87-1 is synthesized according to the method for compound 50, using compound (S)-3-((t-butyldimethylsilyl)oxy)piperidine as the raw material instead of p-methoxybenzyl alcohol.

[0481] LCMS: m / z (ESI), 371.1 [M+H] + .

[0482] Step B: (S)-3-(4-(3-(t-butyldimethylsilyloxy)piperidin-1-yl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (87) TIFF2025532532000146.tif32170

[0483] Compound 87 was synthesized by using compound 87-1 instead of compound 50 as a raw material and following the method for compound 52.

[0484] LCMS: m / z (ESI), 444.1 [M+H] + .

[0485] Step C: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (87-2) TIFF2025532532000147.tif36170

[0486] Compound 87-2 was synthesized by using compound 87 instead of compound 76 as the starting material and following the method for compound 77.

[0487] LCMS: m / z (ESI), 463.1 [M+H] + .

[0488] Step D: (S)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (87-3) TIFF2025532532000148.tif30170

[0489] Compound 87-3 was synthesized by using 87-2 instead of compound 77 and following the procedure for compound 78.

[0490] LCMS: m / z (ESI), 449.0 [M+H] + .

[0491] Stage E: (33R, 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)-piperidine-5(1,2)-phenylcycloheptane (I-43) TIFF2025532532000149.tif29170

[0492] Compound I-43 was synthesized by using compound 87-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0493] LCMS: m / z (ESI), 431 [M+H] + .

[0494] 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)-piperidine-5(1,2)-phenylcycloheptane (I-44) Step A: (R)-2-Bromo-4-(3-(t-butyldimethylsilyloxy)pyrrolidin-1-yl)pyridine (88-1) TIFF2025532532000150.tif30170

[0495] Compound 88-1 is synthesized according to the method for compound 50, using compound (R)-3-((t-butyldimethylsilyl)oxy)piperidine as the raw material instead of p-methoxybenzyl alcohol.

[0496] LCMS: m / z (ESI), 371.1 [M+H] + .

[0497] Step B: (R)-3-(4-(3-(t-butyldimethylsilyloxy)piperidin-1-yl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (88) TIFF2025532532000151.tif32170

[0498] Compound 88 was synthesized by using compound 88-1 instead of compound 50 as a raw material and following the method for compound 52.

[0499] LCMS: m / z (ESI), 444.1 [M+H] + .

[0500] Step C: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (88-2) TIFF2025532532000152.tif35170

[0501] Compound 88-2 was synthesized by using compound 88 instead of compound 76 and following the procedure for compound 77.

[0502] LCMS: m / z (ESI), 463.1 [M+H] + .

[0503] Step D: (R)-1-(2-(6-(((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-3-piperidinol (88-3) TIFF2025532532000153.tif31170

[0504] Compound 88-3 was synthesized by using 88-2 instead of compound 77 and following the procedure for compound 78.

[0505] LCMS: m / z (ESI), 449.1 [M+H] + .

[0506] Stage 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)-piperidine-5(1,2)-phenylcycloheptane (I-44) TIFF2025532532000154.tif29170

[0507] Compound I-44 was synthesized by using compound 88-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0508] LCMS: m / z (ESI), 431 [M+H] + .

[0509] Example 45: (8aR,11aR,16bR,E)-15-fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-etheno-4,8-(metheno)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-45) Step A: 2-Bromo-4-((1R,2S)-2-(t-butyldimethylsilyloxy)cyclopentyl)pyridine (103-1) TIFF2025532532000155.tif28170

[0510] The synthesis of compound 103-1 is prepared by referring to the method in the literature, Tetrahedron Asymmetry, 2004, 15, (3), 481-488.

[0511] LCMS: m / z (ESI), 358.1 [M+H] + .

[0512] Step B: 3-(4-((1R,2S)-2-((t-butyldimethylsilyl)oxy)cyclopentyl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (103) TIFF2025532532000156.tif30170

[0513] Compound 103 was synthesized by using compound 103-1 instead of compound 50 as a starting material and following the method for compound 52.

[0514] LCMS: m / z (ESI), 429.1 [M+H] + .

[0515] Step C: (1S,2R)-2-(2-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (103-2) TIFF2025532532000157.tif32170

[0516] Compound 103-2 was synthesized by using compound 103 instead of compound 76 as a starting material and following the method for compound 77.

[0517] LCMS: m / z (ESI), 474.1 [M+H] + .

[0518] Step D: (1S,2R)-(2-(6-((R)-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (103-3) TIFF2025532532000158.tif32170

[0519] Compound 103-3 was synthesized by using 103-2 instead of compound 77 as the starting material and following the procedure for compound 78.

[0520] LCMS: m / z (ESI), 460.1 [M+H] + .

[0521] Step E: (8aR,11aR,16bR,E)-15-fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-etheno-4,8-(metheno)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-4 5 ) TIFF2025532532000159.tif30170

[0522] Compound I-45 was synthesized by using compound 103-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0523] LCMS: m / z (ESI), 442 [M+H] + .

[0524] Example 46: (8aS,11aR,16bR,E)-15-fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-etheno-4,8-(metheno)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-46) Step A: 2-Bromo-4-((1S,2S)-2-(t-butyldimethylsilyloxy)cyclopentyl)pyridine (Compound 104-1) TIFF2025532532000160.tif29170

[0525] The synthesis of compound 104-1 is carried out with reference to the method described in Tetrahedron Asymmetry, 2004, 15, (3), 481-488.

[0526] LCMS: m / z (ESI), 358.1 [M+H] + .

[0527] Step B: 3-(4-((1S,2S)-2-((t-butyldimethylsilyl)oxy)cyclopentyl)pyridin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (104) TIFF2025532532000161.tif30170

[0528] Compound 104 was synthesized by using compound 104-1 instead of compound 50 as a starting material and following the method for compound 52.

[0529] LCMS: m / z (ESI), 429.1 [M+H] + .

[0530] Step C: (1S,2S)-2-(2-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (104-2) TIFF2025532532000162.tif32170

[0531] Compound 104-2 was synthesized by using compound 104 instead of compound 76 as a starting material and following the method for compound 77.

[0532] LCMS: m / z (ESI), 474.1 [M+H] + .

[0533] Step D: (1S,2S)-2-(2-(6-((R)-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl))-1-cyclopentanol (104-3) TIFF2025532532000163.tif32170

[0534] Compound 104-3 was synthesized by using 104-2 instead of compound 77 and following the procedure for compound 78.

[0535] LCMS: m / z (ESI), 460.1 [M+H] + .

[0536] Step E: (8aS,11aR,16bR,E)-15-fluoro-8a,10,11,11a,16b,17,18,19-octahydro-9H-1,21-etheno-4,8-(metheno)benzo[b]cyclopenta[o]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclohexadecane (I-46) TIFF2025532532000164.tif32170

[0537] Compound I-46 was synthesized by using compound 104-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0538] LCMS: m / z (ESI), 442 [M+H] + .

[0539] 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) Step A: 1-(5-fluoro-2-methoxy-phenyl)cyclopropylamine (111) TIFF2025532532000165.tif22170

[0540] The synthesis of compound 111 is prepared with reference to the method of literature CN112110938.

[0541] LCMS: m / z (ESI), 182.0 [M+H] + .

[0542] Step B: 3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-N-(1-(5-fluoro-2-((4-methoxybenzyl)oxy)phenyl)cyclopropyl)imidazole[1,2-b]pyridazin-6-amine (112) TIFF2025532532000166.tif40170

[0543] Compound 112 was synthesized by using compound 111 instead of compound 9 as a raw material and following the method for compound 10.

[0544] LCMS: m / z (ESI), 626.2 [M+H] + .

[0545] Step C: 4-Fluoro-2-(1-((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)amino)cyclopropyl)phenol (112-1) TIFF2025532532000167.tif28170

[0546] Compound 112-1 was synthesized by using compound 112 instead of compound 10 as a starting material and following the method for compound 11.

[0547] LCMS: m / z (ESI), 392 [M+H] + .

[0548] 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) TIFF2025532532000168.tif28170

[0549] Compound I-47 was synthesized by using compound 112-1 instead of compound 39 as the raw material and following the procedure for compound I-9.

[0550] LCMS: m / z (ESI), 374 [M+H] + .

[0551] 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) Step A: 2-(5-fluoro-2-methoxyphenyl)propyl-2-amine (113) TIFF2025532532000169.tif26170

[0552] The synthesis of compound 113 is prepared by referring to the method of document US2016221948.

[0553] LCMS: m / z (ESI), 184.0 [M+H] + .

[0554] Step B: 3-(4-(((t-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) TIFF2025532532000170.tif38170

[0555] Compound 114 was synthesized by using compound 113 instead of compound 9 as a raw material and following the method for compound 10.

[0556] LCMS: m / z (ESI), 628.2 [M+H] + .

[0557] Step C: 4-Fluoro-2-(1-((3-(4-(hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)amino)-2-propyl)phenol (114-1) TIFF2025532532000171.tif26170

[0558] Compound 114-1 was synthesized by using compound 114 instead of compound 10 as a starting material and following the method for compound 11.

[0559] LCMS: m / z (ESI), 394 [M+H] + .

[0560] Stage 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) TIFF2025532532000172.tif28170

[0561] Compound I-48 was synthesized by using compound 114-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0562] LCMS: m / z (ESI), 376 [M+H] + .

[0563] Example 49: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-49) Step A: (R)-3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (115) TIFF2025532532000173.tif32170

[0564] Compound 115 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 9 and following the method for compound 10.

[0565] LCMS: m / z (ESI), 420.1 [M+H] + .

[0566] Step B: (R)-4-Fluoro-2-(1-(3-(4-(2-hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (115-1) TIFF2025532532000174.tif28170

[0567] Compound 115-1 was synthesized by using compound 115 instead of compound 10 as the starting material and following the method for compound 11.

[0568] LCMS: m / z (ESI), 406.1 [M+H] + .

[0569] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-49) TIFF2025532532000175.tif26170

[0570] Using compound 115-1 of compound 39 as the raw material, compound I-49 was synthesized according to the method for compound I-9.

[0571] LCMS: m / z (ESI), 388 [M+H] + .

[0572] Example 50: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-50) Step A: (R)-3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (116) TIFF2025532532000176.tif30170

[0573] Compound 116 is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 9 and following the method for compound 10.

[0574] LCMS: m / z (ESI), 438.1 [M+H] + .

[0575] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(2-hydroxymethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (116-1) TIFF2025532532000177.tif33170

[0576] Compound 116-1 was synthesized by using compound 116 instead of compound 10 as the starting material and following the method for compound 11.

[0577] LCMS: m / z (ESI), 424.1 [M+H] + .

[0578] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-50) TIFF2025532532000178.tif33170

[0579] Compound I-50 was synthesized by using compound 116-1 instead of compound 39 as the raw material and following the method for compound I-9.

[0580] LCMS: m / z (ESI), 406 [M+H] + .

[0581] Example 51: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-51) Step A: (R)-(2-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)methanol (116-2) TIFF2025532532000179.tif35170

[0582] Compound 116-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 9 and following the method for compound 10.

[0583] LCMS: m / z (ESI), 421.1 [M+H] + .

[0584] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxymethyl)pyridin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (116-3) TIFF2025532532000180.tif30170

[0585] Compound 116-3 was synthesized by using 116-2 instead of compound 10 as the starting material and following the method for compound 11.

[0586] LCMS: m / z (ESI), 407.1 [M+H] + .

[0587] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-51) TIFF2025532532000181.tif30170

[0588] Compound I-51 was synthesized by using compound 116-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0589] LCMS: m / z (ESI), 389 [M+H] + .

[0590] Example 52: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-52) Step A: (2-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)methanol (116-4) TIFF2025532532000182.tif34170

[0591] Compound 116-4 is synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 9 and following the method for compound 10.

[0592] LCMS: m / z (ESI), 439.1 [M+H] + .

[0593] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyridin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (116-5) TIFF2025532532000183.tif34170

[0594] Compound 116-5 was synthesized by using 116-4 instead of compound 10 as the starting material and following the procedure for compound 11.

[0595] LCMS: m / z (ESI), 425.1 [M+H] + .

[0596] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-52) TIFF2025532532000184.tif32170

[0597] Compound I-52 was synthesized by using compound 116-5 instead of compound 39 as the starting material and following the method for compound I-9.

[0598] LCMS: m / z (ESI), 407 [M+H] + .

[0599] 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) Step A: (R)-3-(4-(hydroxyethyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (117) TIFF2025532532000185.tif35170

[0600] Compound 117 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 37 and following the method for compound 38.

[0601] LCMS: m / z (ESI), 434.1 [M+H] + .

[0602] Step B: (R)-4-Fluoro-2-(1-(3-(4-hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (117-1) TIFF2025532532000186.tif30170

[0603] Compound 117-1 was synthesized by using compound 117 instead of compound 10 as the starting material and following the method for compound 11.

[0604] LCMS: m / z (ESI), 420.1 [M+H] + .

[0605] Stage 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) TIFF2025532532000187.tif30170

[0606] Compound I-53 was synthesized by using compound 117-1 instead of compound 39 as the raw material and following the method for compound I-9.

[0607] LCMS: m / z (ESI), 402 [M+H] + .

[0608] 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) Step A: (R)-3-(4-(hydroxyethyl)pyridin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (118) TIFF2025532532000188.tif33170

[0609] Compound 118 is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 37 and following the method for compound 38.

[0610] LCMS: m / z (ESI), 452.1 [M+H] + .

[0611] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (118-1) TIFF2025532532000189.tif33170

[0612] Compound 118-1 was synthesized by using compound 118 instead of compound 10 as the starting material and following the method for compound 11.

[0613] LCMS: m / z (ESI), 438.1 [M+H] + .

[0614] Stage 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) TIFF2025532532000190.tif33170

[0615] Compound I-54 was synthesized by using compound 118-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0616] LCMS: m / z (ESI), 420 [M+H] + .

[0617] 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)-pyrrolealkylcycloheptane (I-55) Step A: (R)-(2-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)ethanol (118-2) TIFF2025532532000191.tif36170

[0618] Compound 118-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 38.

[0619] LCMS: m / z (ESI), 435.1 [M+H] + .

[0620] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxyethyl)pyridin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118-3) TIFF2025532532000192.tif34170

[0621] Compound 118-3 was synthesized by using 118-2 instead of compound 10 as the starting material and following the procedure for compound 11.

[0622] LCMS: m / z (ESI), 421.1 [M+H] + .

[0623] Stage 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)-pyrrolealkylcycloheptane (I-55) TIFF2025532532000193.tif29170

[0624] Compound I-55 was synthesized by using compound 118-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0625] LCMS: m / z (ESI), 403 [M+H] + .

[0626] Example 56: (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),4(3,2)-bipyridine-3(1,2)-pyrrolealkylcycloheptane (I-56) Step A: (2-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridin-4-yl)ethanol (118-4) TIFF2025532532000194.tif35170

[0627] Compound 118-4 is synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 9 and following the method for compound 10.

[0628] LCMS: m / z (ESI), 453.1 [M+H] + .

[0629] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyridin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118-5) TIFF2025532532000195.tif39170

[0630] Compound 118-5 was synthesized by using 118-4 instead of compound 10 as the starting material and following the procedure for compound 11.

[0631] LCMS: m / z (ESI), 439.1 [M+H] + .

[0632] Stage 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),4(3,2)-bipyridine-3(1,2)-pyrrolealkylcycloheptane (I-56) TIFF2025532532000196.tif33170

[0633] Compound I-56 was synthesized using compound 118-5 instead of compound 39 and following the procedure for compound I-9.

[0634] LCMS: m / z (ESI), 421 [M+H] + .

[0635] Example 57: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-57) Step A: (R)-3-(6-(((t-butyldimethylsilyl)oxy)methyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (117A) TIFF2025532532000197.tif33170

[0636] Compound 117A is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 43.

[0637] LCMS: m / z (ESI), 535.1 [M+H] + .

[0638] Step B: (R)-4-Fluoro-2-(1-(3-(4-(6-hydroxymethyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (117A-1) TIFF2025532532000198.tif32170

[0639] Compound 117A-1 was synthesized by using 117A instead of compound 10 as a starting material and following the method for compound 11.

[0640] LCMS: m / z (ESI), 407.1 [M+H] + .

[0641] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-57) TIFF2025532532000199.tif29170

[0642] Compound I-57 was synthesized by using compound 117A-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0643] LCMS: m / z (ESI), 389 [M+H] + .

[0644] Example 58: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-58) Step A: (R)-3-(6-(((t-butyldimethylsilyl)oxy)methyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (118A) TIFF2025532532000200.tif36170

[0645] Compound 118A is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 43.

[0646] LCMS: m / z (ESI), 553.1 [M+H] + .

[0647] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(6-hydroxymethyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (118A-1) TIFF2025532532000201.tif36170

[0648] Compound 118A-1 was synthesized by using 118A instead of compound 10 as a starting material and following the method for compound 11.

[0649] LCMS: m / z (ESI), 425.1 [M+H] + .

[0650] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-58) TIFF2025532532000202.tif35170

[0651] Compound I-58 was synthesized by using compound 118A-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0652] LCMS: m / z (ESI), 407 [M+H] + .

[0653] Example 59: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-59) Step A: (R)-(6-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)methanol (118A-2) TIFF2025532532000203.tif35170

[0654] Compound 118A-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 43.

[0655] LCMS: m / z (ESI), 422.1 [M+H] + .

[0656] Step B: (R)-5-Fluoro-3-(1-(3-(6-(hydroxymethyl)pyrimidin-4-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118A-3) TIFF2025532532000204.tif30170

[0657] Compound 118A-3 was synthesized by using 118A-2 instead of compound 10 as a starting material and following the method for compound 11.

[0658] LCMS: m / z (ESI), 408.1 [M+H] + .

[0659] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-59) TIFF2025532532000205.tif32170

[0660] Compound I-59 was synthesized by using compound 118A-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0661] LCMS: m / z (ESI), 390 [M+H] + .

[0662] Example 60: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-60) Step A: (6-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)methanol (118A-4) TIFF2025532532000206.tif36170

[0663] Compound 118A-4 is synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and following the method for compound 43.

[0664] LCMS: m / z (ESI), 440.1 [M+H] + .

[0665] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(6-(hydroxymethyl)pyrimidin-4-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (118A-5) TIFF2025532532000207.tif36170

[0666] Compound 118A-5 was synthesized by using 118A-4 instead of compound 10 as the starting material and following the method for compound 11.

[0667] LCMS: m / z (ESI), 426.1 [M+H] + .

[0668] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[4,6,9,10,12]pentaazacyclopentadecane (I-60) TIFF2025532532000208.tif35170

[0669] Compound I-60 was synthesized by using compound 118A-5 instead of compound 39 as the raw material and following the method for compound I-9.

[0670] LCMS: m / z (ESI), 408 [M+H] + .

[0671] Example 61: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-61) Step A: 4-(((t-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (119) TIFF2025532532000209.tif22170

[0672] The synthesis of compound 119 is prepared by referring to the method of literature WO2016 / 196244.

[0673] LCMS: m / z (ESI), 259.0 [M+H] + .

[0674] Step B: 4-(((t-butyldimethylsilyl)oxy)methyl)-2-tributylstannylpyrimidine (120) TIFF2025532532000210.tif23170

[0675] Compound 120 was synthesized by using compound 119 instead of compound 2 as a raw material and following the method for compound 3.

[0676] LCMS: m / z (ESI), 515.0 [M+H] + .

[0677] Step C: 3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (121) TIFF2025532532000211.tif29170

[0678] Compound 121 was synthesized by using compound 120 instead of compound 3 as a raw material and following the method for compound 5.

[0679] LCMS: m / z (ESI), 376.0 [M+H] + .

[0680] Step D: (R)-3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (122) TIFF2025532532000212.tif33170

[0681] Compound 122 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 121 instead of compound 42, and following the method for compound 43.

[0682] LCMS: m / z (ESI), 535.1 [M+H] + .

[0683] Step E: (R)-4-Fluoro-2-(1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (122-1) TIFF2025532532000213.tif30170

[0684] Compound 122-1 was synthesized by using compound 122 instead of compound 10 as the starting material and following the method for compound 11.

[0685] LCMS: m / z (ESI), 407.1 [M+H] + .

[0686] Step F: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-61) TIFF2025532532000214.tif34170

[0687] Compound I-61 was synthesized by using compound 122-1 instead of compound 48-2 as the raw material and following the method for compound I-11.

[0688] LCMS: m / z (ESI), 389 [M+H] + .

[0689] Example 62: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-62) Step A: (R)-3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (123) TIFF2025532532000215.tif35170

[0690] Compound 123 is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, and compound 121 instead of compound 42, following the method for compound 43.

[0691] LCMS: m / z (ESI), 553.1 [M+H] + .

[0692] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (123-1) TIFF2025532532000216.tif34170

[0693] Compound 123-1 was synthesized by using compound 123 instead of compound 10 as the starting material and following the method for compound 11.

[0694] LCMS: m / z (ESI), 425.1 [M+H] + .

[0695] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)benzo[b]imidazo[1,5-h]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-62) TIFF2025532532000217.tif36170

[0696] Compound I-62 was synthesized by using compound 123-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0697] LCMS: m / z (ESI), 407 [M+H] + .

[0698] Example 63: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-63) Step A: (R)-(4-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-2-yl)methanol (123-2) TIFF2025532532000218.tif36170

[0699] Compound 123-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 121 instead of compound 42, and following the method for compound 43.

[0700] LCMS: m / z (ESI), 422.1 [M+H] + .

[0701] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (123-3) TIFF2025532532000219.tif32170

[0702] Compound 123-3 was synthesized by using 123-2 instead of compound 10 as the starting material and following the method for compound 11.

[0703] LCMS: m / z (ESI), 408.1 [M+H] + .

[0704] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-63) TIFF2025532532000220.tif32170

[0705] Compound I-63 was synthesized by using compound 123-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0706] LCMS: m / z (ESI), 390 [M+H] + .

[0707] Example 64: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-64) Step A: (4-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-2-yl)methanol (123-4) TIFF2025532532000221.tif36170

[0708] Use compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19, use compound 121 instead of compound 42, and synthesize compound 123-4 according to the method of compound 43.

[0709] LCMS: m / z (ESI), 440.1 [M+H] + .

[0710] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (123-5) TIFF2025532532000222.tif39170

[0711] Compound 123-5 was synthesized by using compound 123-4 instead of compound 10 as the starting material and following the procedure for compound 11.

[0712] LCMS: m / z (ESI), 426.1 [M+H] + .

[0713] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(azeno)imidazo[1,5-h]pyrido[2,3-b]pyrrolo[2,1-d][1]oxa[5,7,8,11]tetraazacyclopentadecane (I-64) TIFF2025532532000223.tif35170

[0714] Compound I-64 was synthesized by using compound 123-5 instead of compound 39 as the raw material and following the method for compound I-9.

[0715] LCMS: m / z (ESI), 408 [M+H] + .

[0716] Example 65: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-65) Step A: 4-Hydroxymethyl-6-chloropyridazine (124) TIFF2025532532000224.tif21170

[0717] Compound 124 is prepared by referring to the method in Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, #23.

[0718] LCMS: m / z (ESI), 145.0 [M+H] + .

[0719] Step B: 4-(((t-butyldimethylsilyl)oxy)methyl)-6-chloropyridazine (125) TIFF2025532532000225.tif23170

[0720] Compound 125 was synthesized by using compound 124 instead of compound 1 and following the method for compound 2.

[0721] LCMS: m / z (ESI), 259.0 [M+H] + .

[0722] Step C: 4-(((t-butyldimethylsilyl)oxy)methyl)-6-tributylstannylpyridazine (126) TIFF2025532532000226.tif21170

[0723] Compound 126 was synthesized by using compound 125 instead of compound 2 as a raw material and following the method for compound 3.

[0724] LCMS: m / z (ESI), 515.0 [M+H] + .

[0725] Step D: 3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyridazin-6-yl)-6-chloroimidazole[1,2-b]pyridazine (127) TIFF2025532532000227.tif28170

[0726] Compound 127 was synthesized by using compound 126 instead of compound 3 as a raw material and following the method for compound 5.

[0727] LCMS: m / z (ESI), 376.0 [M+H] + .

[0728] Step E: (R)-3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (128) TIFF2025532532000228.tif34170

[0729] Compound 128 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 127 instead of compound 42, and following the method for compound 43.

[0730] LCMS: m / z (ESI), 535.1 [M+H] + .

[0731] Step F: (R)-4-Fluoro-2-(1-(3-(4-(hydroxymethyl)pyridazin-6-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (128-1) TIFF2025532532000229.tif33170

[0732] Compound 128-1 was synthesized by using compound 128 instead of compound 10 and following the procedure for compound 11.

[0733] LCMS: m / z (ESI), 407.1 [M+H] + .

[0734] Step F: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-65) TIFF2025532532000230.tif28170

[0735] Compound I-65 was synthesized by using compound 128-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0736] LCMS: m / z (ESI), 389 [M+H] + Example 66: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-66) Step A: (R)-3-(4-(((t-butyldimethylsilyl)oxy)methyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (129) TIFF2025532532000231.tif34170

[0737] Use compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, use compound 127 instead of compound 42, and synthesize compound 129 according to the method for compound 43.

[0738] LCMS: m / z (ESI), 553.1 [M+H] + .

[0739] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyridazin-6-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (129-1) TIFF2025532532000232.tif35170

[0740] Compound 129-1 was synthesized by using compound 129 instead of compound 10 and following the procedure for compound 11.

[0741] LCMS: m / z (ESI), 425.1 [M+H] + .

[0742] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)benzo[b]imidazo[5,1-h]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-66) TIFF2025532532000233.tif38170

[0743] Compound I-66 was synthesized by using compound 129-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0744] LCMS: m / z (ESI), 407 [M+H] + .

[0745] Example 67: (14bR,E)-13-fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-67) Step A: (6-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)methanol (129-2) TIFF2025532532000234.tif36170

[0746] Compound 129-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 127 instead of compound 42, and following the method for compound 43.

[0747] LCMS: m / z (ESI), 422.1 [M+H] + .

[0748] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxymethyl)pyridazin-6-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (129-3) TIFF2025532532000235.tif32170

[0749] Compound 129-3 was synthesized by using 129-2 instead of compound 10 as the starting material and following the method for compound 11.

[0750] LCMS: m / z (ESI), 408.1 [M+H] + .

[0751] Step C: (14bR,E)-13-Fluoro-14b,15,16,17-tetrahydro-9H-1,19-etheno-4,8-(metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-67) TIFF2025532532000236.tif29170

[0752] Compound I-67 was synthesized by using compound 129-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0753] LCMS: m / z (ESI), 390 [M+H] + .

[0754] Example 68: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-68) Step A: (6-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)methanol (129-4) TIFF2025532532000237.tif35170

[0755] Use compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19, use compound 127 instead of compound 42, and synthesize compound 129-4 according to the method of compound 43.

[0756] LCMS: m / z (ESI), 440.1 [M+H] + .

[0757] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxymethyl)pyrimidin-6-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (129-5) TIFF2025532532000238.tif35170

[0758] Compound 129-5 was synthesized by using 129-4 instead of compound 10 as the starting material and following the procedure for compound 11.

[0759] LCMS: m / z (ESI), 426.1 [M+H] + .

[0760] Step C: (14bR,16S,E)-13,16-difluoro-14b,15,16,17-tetrahydro-9H-1,19-metheno)imidazo[5,1-h]pyrido[3,2-n]pyrrolo[1,2-l][1]oxa[5,6,9,10,12]pentaazacyclopentadecane (I-68) TIFF2025532532000239.tif36170

[0761] Compound I-68 was synthesized by using compound 129-5 instead of compound 39 as the starting material and following the method for compound I-9.

[0762] LCMS: m / z (ESI), 408 [M+H] + 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) Step A: (R)-3-(6-(hydroxyethyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (130) TIFF2025532532000240.tif36170

[0763] Compound 130 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 48-1.

[0764] LCMS: m / z (ESI), 435.1 [M+H] + .

[0765] Step B: (R)-4-Fluoro-2-(1-(3-(6-hydroxyethyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (130-1) TIFF2025532532000241.tif33170

[0766] Compound 130-1 was synthesized by using compound 130 instead of compound 10 and following the procedure for compound 11.

[0767] LCMS: m / z (ESI), 421.1 [M+H] + .

[0768] Stage 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) TIFF2025532532000242.tif32170

[0769] Compound I-69 was synthesized by using compound 130-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0770] LCMS: m / z (ESI), 403 [M+H] + .

[0771] 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) Step A: (R)-3-(6-(hydroxyethyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (131) TIFF2025532532000243.tif37170

[0772] Compound 131 is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 48-1.

[0773] LCMS: m / z (ESI), 453.1 [M+H] + .

[0774] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(6-(hydroxyethyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (131-1) TIFF2025532532000244.tif38170

[0775] Compound 131-1 was synthesized by using compound 131 instead of compound 10 as the starting material and following the method for compound 11.

[0776] LCMS: m / z (ESI), 439.1 [M+H] + .

[0777] Stage 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) TIFF2025532532000245.tif38170

[0778] Compound I-70 was synthesized by using compound 131-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0779] LCMS: m / z (ESI), 421 [M+H] + .

[0780] Example 71: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-71) Step A: (R)-(4-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-6-yl)ethanol (131-2) TIFF2025532532000246.tif27170

[0781] Compound 131-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19 and following the method for compound 48-1.

[0782] LCMS: m / z (ESI), 436.1 [M+H] + .

[0783] Step B: (R)-5-Fluoro-3-(1-(3-(6-(hydroxyethyl)pyrimidin-4-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (131-3) TIFF2025532532000247.tif34170

[0784] Compound 131-3 was synthesized by using compound 131-2 instead of compound 10 as the starting material and following the method for compound 11.

[0785] LCMS: m / z (ESI), 422.1 [M+H] + .

[0786] Stage C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-71) TIFF2025532532000248.tif32170

[0787] Compound I-71 was synthesized by using compound 131-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0788] LCMS: m / z (ESI), 404 [M+H] + .

[0789] Example 72: (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 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-72) Step A: (6-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-2-yl)ethanol (131-4) TIFF2025532532000249.tif36170

[0790] Compound 131-4 is synthesized by using compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19 and following the method for compound 48-1.

[0791] LCMS: m / z (ESI), 454.1 [M+H] + .

[0792] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(6-(hydroxyethyl)pyridin-4-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (131-5) TIFF2025532532000250.tif35170

[0793] Compound 131-5 was synthesized by using 131-4 instead of compound 10 as the starting material and following the method for compound 11.

[0794] LCMS: m / z (ESI), 440.1 [M+H] + .

[0795] Stage 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 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-72) TIFF2025532532000251.tif34170

[0796] Compound I-72 was synthesized by using compound 131-5 instead of compound 39 as the starting material and following the method for compound I-9.

[0797] LCMS: m / z (ESI), 422 [M+H] + .

[0798] Example 73: (4R,E)-55 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(3,2)-pyridylcyclooctane (I-73) Step A: (R)-2-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (48-2) TIFF2025532532000252.tif33170

[0799] Compound 48-2 is synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19 and following the method for compound 48-1.

[0800] LCMS: m / z (ESI), 410.1 [M+H] + .

[0801] Step B: (R)-5-Fluoro-3-(1-((3-(6-(hydroxyethyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (48-3) TIFF2025532532000253.tif30170

[0802] Compound 48-3 was synthesized by using 48-2 instead of compound 10 as the starting material and following the procedure for compound 11.

[0803] LCMS: m / z (ESI), 396.1 [M+H] + .

[0804] Stage C: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(3,2)-pyridylcyclooctane (I-73) TIFF2025532532000254.tif29170

[0805] Compound I-73 was synthesized by using compound 48-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0806] LCMS: m / z (ESI), 378 [M+H] + .

[0807] Example 74: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(3,2)-pyridylcyclooctane (I-74) Step A: (R)-2-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (48-4) TIFF2025532532000255.tif36170

[0808] Compound 48-4 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and following the method for compound 48-1.

[0809] LCMS: m / z (ESI), 395.1 [M+H] + .

[0810] Stage B: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-5(1,2)-phenylcyclooctane (I-74) TIFF2025532532000256.tif32170

[0811] Compound I-74 was synthesized by using compound 48-4 instead of compound 39 as the starting material and following the method for compound I-9.

[0812] LCMS: m / z (ESI), 377 [M+H] + .

[0813] Example 75: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(3,2)-pyridylcyclooctane (I-75) Step A: (R)-4-Fluoro-2-(1-((3-(4-(2-hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (37-2) TIFF2025532532000257.tif34170

[0814] Compound 37-2 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and following the method for compound 38.

[0815] LCMS: m / z (ESI), 394.1 [M+H] + .

[0816] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxyethyl)pyridin-2-yl)imidazol[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (37-3) TIFF2025532532000258.tif33170

[0817] Compound 37-3 was synthesized by using 37-2 instead of compound 10 as the starting material and following the procedure for compound 11.

[0818] LCMS: m / z (ESI), 380.1 [M+H] + .

[0819] Stage C: (4R,E)-5 5-Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(3,2)-pyridylcyclooctane (I-75) TIFF2025532532000259.tif32170

[0820] Compound I-75 was synthesized by using compound 37-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0821] LCMS: m / z (ESI), 362 [M+H] + .

[0822] Example 76: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-76) Step A: (R)-4-Fluoro-2-(1-((3-(4-(2-hydroxyethyl)pyridin-2-yl)imidazole[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (37-4) TIFF2025532532000260.tif38170

[0823] Compound 37-4 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and following the method for compound 38.

[0824] LCMS: m / z (ESI), 394.1 [M+H] + .

[0825] Stage B: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyridine-5(1,2)-phenylcyclooctane (I-76) TIFF2025532532000261.tif34170

[0826] Compound I-76 was synthesized using compound 37-4 instead of compound 39 and following the procedure for compound I-9.

[0827] LCMS: m / z (ESI), 377 [M+H] + Example 77: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(2,3)-pyridylcycloheptane (I-77) Step A: (R)-(2-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (42-2) TIFF2025532532000262.tif34170

[0828] Compound 42-2 is synthesized by using compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19 and following the method for compound 43.

[0829] LCMS: m / z (ESI), 396.1 [M+H] + .

[0830] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxymethyl)pyrimidin-6-yl)imidazole[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (42-3) TIFF2025532532000263.tif29170

[0831] Compound 42-3 was synthesized by using 42-2 instead of compound 10 as the starting material and following the procedure for compound 11.

[0832] LCMS: m / z (ESI), 382.1 [M+H] + .

[0833] Stage C: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(2,3)-pyridylcycloheptane (I-77) TIFF2025532532000264.tif27170

[0834] Compound I-77 was synthesized by using compound 42-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0835] LCMS: m / z (ESI), 364 [M+H] + .

[0836] Example 78: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(1,2)-phenylcycloheptane (I-78) Step A: (R)-(6-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (42-4) TIFF2025532532000265.tif35170

[0837] Compound 42-4 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19 and following the method for compound 43.

[0838] LCMS: m / z (ESI), 381.1 [M+H] + .

[0839] Stage B: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(4,6)-pyrimidine-5(1,2)-phenylcycloheptane (I-78) TIFF2025532532000266.tif29170

[0840] Compound I-78 was synthesized by using compound 42-4 instead of compound 39 as the starting material and following the procedure for compound I-9.

[0841] LCMS: m / z (ESI), 363 [M+H] + .

[0842] Example 79: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyrimidine-5(2,3)-pyridylcycloheptane (I-79) Step A: (R)-(2-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (121-2) TIFF2025532532000267.tif36170

[0843] Compound 121-2 is 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, following the method for compound 43.

[0844] LCMS: m / z (ESI), 396.1 [M+H] + .

[0845] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxymethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (121-3) TIFF2025532532000268.tif33170

[0846] Compound 121-3 was synthesized by using compound 121-2 instead of compound 10 as the starting material and following the method for compound 11.

[0847] LCMS: m / z (ESI), 382.1 [M+H] + .

[0848] Stage C: (6R,E)-5 5 -Fluoro-6-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyrimidine-5(2,3)-pyridylcycloheptane (I-79) TIFF2025532532000269.tif28170

[0849] Compound I-79 was synthesized by using compound 121-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0850] LCMS: m / z (ESI), 364 [M+H] + .

[0851] Example 80: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyrimidine-5(1,2)-phenylcycloheptane (I-80) Step A: (R)-(2-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methanol (121-4) TIFF2025532532000270.tif34170

[0852] Compound 121-4 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19, compound 121 instead of compound 42, and the method for compound 43.

[0853] LCMS: m / z (ESI), 381.1 [M+H]+ .

[0854] Stage B: (6R,E)-5 4 -Fluoro-5-methyl-4-oxa-7-aza-1(3,6)-imidazole[1,2-b]pyridazine-2(2,4)-pyrimidine-5(1,2)-phenylcycloheptane (I-80) TIFF2025532532000271.tif32170

[0855] Compound I-80 was synthesized by using compound 121-4 instead of compound 39 as the raw material and following the method for compound I-9.

[0856] LCMS: m / z (ESI), 363 [M+H] + .

[0857] 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) Step A: (R)-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-methanol (127-2) TIFF2025532532000272.tif34170

[0858] Compound 127-2 is 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, according to the method of compound 43.

[0859] LCMS: m / z (ESI), 396.1 [M+H] + .

[0860] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxymethyl)pyridazin-6-yl)imidazole[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (127-3) TIFF2025532532000273.tif35170

[0861] Compound 127-3 was synthesized by using 127-2 instead of compound 10 as the starting material and following the procedure for compound 11.

[0862] LCMS: m / z (ESI), 382.1 [M+H] + .

[0863] Stage 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) TIFF2025532532000274.tif32170

[0864] Compound I-81 was synthesized by using compound 127-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0865] LCMS: m / z (ESI), 364 [M+H] + .

[0866] 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) Step A: (R)-(6-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-methanol (127-4) TIFF2025532532000275.tif36170

[0867] Compound 127-4 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19, compound 127 instead of compound 42, and the method for compound 43.

[0868] LCMS: m / z (ESI), 381.1 [M+H] + .

[0869] Stage 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) TIFF2025532532000276.tif29170

[0870] Compound I-82 was synthesized by using compound 127-4 instead of compound 39 as the starting material and following the method for compound I-9.

[0871] LCMS: m / z (ESI), 363 [M+H] + .

[0872] Example 83: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-5(3,2)-pyridylcyclooctane (I-83) Step A: (R)-2-(2-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (137-2) TIFF2025532532000277.tif34170

[0873] Compound 137-2 is 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, following the method for compound 43.

[0874] LCMS: m / z (ESI), 410.1 [M+H] + .

[0875] Step B: (R)-5-Fluoro-3-(1-((3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (137-3) TIFF2025532532000278.tif33170

[0876] Compound 137-3 was synthesized by using 137-2 instead of compound 10 as the starting material and following the method for compound 11.

[0877] LCMS: m / z (ESI), 396.1 [M+H] + .

[0878] Stage C: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-5(3,2)-pyridylcyclooctane (I-83) TIFF2025532532000279.tif32170

[0879] Compound I-83 was synthesized by using compound 137-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0880] LCMS: m / z (ESI), 378 [M+H] + .

[0881] Example 84: (4R,E)-5 5-Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-5(3,2)-pyridylcyclooctane (I-74) Step A: (R)-2-(2-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethanol (137-4) TIFF2025532532000280.tif35170

[0882] Compound 137-4 is synthesized by using compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19, compound 137 instead of compound 42, and the method for compound 43.

[0883] LCMS: m / z (ESI), 395.1 [M+H] + .

[0884] Stage 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) TIFF2025532532000281.tif30170

[0885] Compound I-84 was synthesized by using compound 137-4 instead of compound 39 as the starting material and following the method for compound I-9.

[0886] LCMS: m / z (ESI), 377 [M+H] + .

[0887] 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) Step A: (R)-3-(4-(hydroxyethyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (138) TIFF2025532532000282.tif36170

[0888] Compound 138 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 137 instead of compound 48, and referring to the method of compound 48-1.

[0889] LCMS: m / z (ESI), 435.1 [M+H] + .

[0890] Step B: (R)-4-Fluoro-2-(1-(3-(4-hydroxyethyl)pyrimidin-2-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (138-1) TIFF2025532532000283.tif33170

[0891] Compound 138-1 was synthesized by using compound 138 instead of compound 10 as the starting material and following the method for compound 11.

[0892] LCMS: m / z (ESI), 421.1 [M+H] + .

[0893] Stage 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) TIFF2025532532000284.tif30170

[0894] Compound I-85 was synthesized by using compound 138-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0895] LCMS: m / z (ESI), 403 [M+H] + .

[0896] Example 86: (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)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-86) Step A: (R)-3-(4-(hydroxyethyl)pyrimidin-2-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (139) TIFF2025532532000285.tif33170

[0897] Use compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, use compound 137 instead of compound 48, and synthesize compound 139 according to the method of compound 48-1.

[0898] LCMS: m / z (ESI), 453.1 [M+H] + .

[0899] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (139-1) TIFF2025532532000286.tif33170

[0900] Compound 139-1 was synthesized by using compound 139 instead of compound 10 as the starting material and following the method for compound 11.

[0901] LCMS: m / z (ESI), 439.1 [M+H] + .

[0902] Stage 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)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-86) TIFF2025532532000287.tif33170

[0903] Compound I-86 was synthesized by using compound 139-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0904] LCMS: m / z (ESI), 421 [M+H] + .

[0905] Example 87: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-87) Step A: (R)-(4-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-6-yl)ethanol (139-2) TIFF2025532532000288.tif35170

[0906] Compound 139-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 137 instead of compound 48, and the method for compound 48-1 is used.

[0907] LCMS: m / z (ESI), 436.1 [M+H] + .

[0908] Step B: (R)-5-Fluoro-3-(1-(3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (139-3) TIFF2025532532000289.tif32170

[0909] Compound 139-3 was synthesized by using 139-2 instead of compound 10 as the starting material and following the method for compound 11.

[0910] LCMS: m / z (ESI), 422.1 [M+H] + .

[0911] Stage C: (3 2 R,E)-4 5 -Fluoro-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-87) TIFF2025532532000290.tif32170

[0912] Compound I-87 was synthesized by using compound 139-3 instead of compound 39 and following the procedure for compound I-9.

[0913] LCMS: m / z (ESI), 404 [M+H] + .

[0914] Example 88: (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)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-88) Step A: (2-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)ethanol (139-4) TIFF2025532532000291.tif33170

[0915] Use compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19, use compound 137 instead of compound 48, and synthesize compound 139-4 according to the method of compound 48-1.

[0916] LCMS: m / z (ESI), 454.1 [M+H] + .

[0917] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (139-5) TIFF2025532532000292.tif33170

[0918] Compound 139-5 was synthesized by using 139-4 instead of compound 10 and following the procedure for compound 11.

[0919] LCMS: m / z (ESI), 440.1 [M+H] + .

[0920] Stage 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)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-88) TIFF2025532532000293.tif34170

[0921] Compound I-88 was synthesized by using compound 139-5 instead of compound 39 and following the procedure for compound I-9.

[0922] LCMS: m / z (ESI), 422 [M+H] + .

[0923] Example 89: (4R,E)-5 5 -Fluoro-4-methyl-6-oxa-3-aza-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-5(3,2)-pyridylcyclooctane (I-89) Step A: (R)-2-(6-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-ethanol (143-2) TIFF2025532532000294.tif34170

[0924] Use compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)-1-ethylamine instead of compound 19, use compound 143 instead of compound 48, and synthesize compound 143-2 according to the method of compound 48-1.

[0925] LCMS: m / z (ESI), 410.1 [M+H] + .

[0926] Step B: (R)-5-Fluoro-3-(1-((3-(5-(hydroxyethyl)pyrimidin-3-yl)imidazol[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2(1H)-one (143-3) TIFF2025532532000295.tif29170

[0927] Compound 143-3 was synthesized by using 143-2 instead of compound 10 as the starting material and following the method for compound 11.

[0928] LCMS: m / z (ESI), 396.1 [M+H] + .

[0929] Stage 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) TIFF2025532532000296.tif29170

[0930] Compound I-89 was synthesized by using compound 143-3 instead of compound 39 as the raw material and following the method for compound I-9.

[0931] LCMS: m / z (ESI), 378 [M+H] + .

[0932] 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) Step A: (R)-2-(6-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)-1-ethanol (143-4) TIFF2025532532000297.tif35170

[0933] Use compound (R)-1-(5-fluoro-2-hydroxyphenyl)-1-ethylamine instead of compound 19, use compound 143 instead of compound 48, and synthesize compound 143-4 according to the method of compound 48-1.

[0934] LCMS: m / z (ESI), 395.1 [M+H] + .

[0935] Stage 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) TIFF2025532532000298.tif27170

[0936] Compound I-90 was synthesized by using compound 143-4 instead of compound 39 as the starting material and following the procedure for compound I-9.

[0937] LCMS: m / z (ESI), 377 [M+H] + .

[0938] 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) Step A: (R)-3-(4-(((t-butyldimethylsilyl)oxy)ethyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (144) TIFF2025532532000299.tif33170

[0939] Compound 144 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 143 instead of compound 48, and the method for compound 48-1 is used.

[0940] LCMS: m / z (ESI), 435.1 [M+H] + .

[0941] Step B: (R)-4-Fluoro-2-(1-(3-(4-(hydroxyethyl)pyridazin-6-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (144-1) TIFF2025532532000300.tif30170

[0942] Compound 144-1 was synthesized by using compound 144 instead of compound 10 as the starting material and following the method for compound 11.

[0943] LCMS: m / z (ESI), 421.1 [M+H] + .

[0944] Stage 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) TIFF2025532532000301.tif32170

[0945] Compound I-91 was synthesized by using compound 144-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0946] LCMS: m / z (ESI), 403 [M+H] + .

[0947] 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) Step A: (R)-3-(4-(((t-butyldimethylsilyl)oxy)ethyl)pyridazin-6-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (145) TIFF2025532532000302.tif35170

[0948] Use compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, use compound 143 instead of compound 48, and synthesize compound 145 according to the method of compound 48-1.

[0949] LCMS: m / z (ESI), 439.1 [M+H] + .

[0950] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(4-(hydroxyethyl)pyridazin-6-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (145-1) TIFF2025532532000303.tif35170

[0951] Compound 145-1 was synthesized by using compound 145 instead of compound 10 and following the procedure for compound 11.

[0952] LCMS: m / z (ESI), 439.1 [M+H] + .

[0953] Stage 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) TIFF2025532532000304.tif35170

[0954] Compound I-92 was synthesized by using compound 145-1 instead of compound 39 as the starting material and following the method for compound I-9.

[0955] LCMS: m / z (ESI), 421 [M+H] + .

[0956] Example 93: (32 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)-pyrrolealkylcycloheptane (I-93) Step A: (R)-(6-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyridazin-4-yl)ethanol (145-2) TIFF2025532532000305.tif35170

[0957] Compound 145-2 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 143 instead of compound 48, and the method for compound 48-1 is used.

[0958] LCMS: m / z (ESI), 436.1 [M+H] + .

[0959] Step B: (R)-5-Fluoro-3-(1-(3-(5-(hydroxyethyl)pyrimidin-3-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (145-3) TIFF2025532532000306.tif32170

[0960] Compound 145-3 was synthesized by using 145-2 instead of compound 10 as the starting material and following the method for compound 11.

[0961] LCMS: m / z (ESI), 422.1 [M+H] + .

[0962] Stage 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)-pyrrolealkylcycloheptane (I-93) TIFF2025532532000307.tif32170

[0963] Compound I-93 was synthesized by using compound 145-3 instead of compound 39 as the starting material and following the method for compound I-9.

[0964] LCMS: m / z (ESI), 404 [M+H] + .

[0965] 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)-pyrrole alkylcycloheptane (I-94) Step A: (2-(6-((2R,4S)-4-fluoro-2-(5fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)ethanol (145-4) TIFF2025532532000308.tif33170

[0966] Use compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19, use compound 143 instead of compound 48, and synthesize compound 145-4 according to the method of compound 48-1.

[0967] LCMS: m / z (ESI), 454.1 [M+H] + .

[0968] Step B: 5-Fluoro-3-((2R,4S)-4-fluoro-1-(3-(5-(hydroxyethyl)pyridazin-3-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (145-5) TIFF2025532532000309.tif35170

[0969] Compound 145-5 was synthesized by using 145-4 instead of compound 10 as the starting material and following the method for compound 11.

[0970] LCMS: m / z (ESI), 440.1 [M+H] + .

[0971] Stage 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)-pyrrole alkylcycloheptane (I-94) TIFF2025532532000310.tif33170

[0972] Compound I-94 was synthesized by using compound 145-5 instead of compound 39 as the starting material and following the method for compound I-9.

[0973] LCMS: m / z (ESI), 422 [M+H] + .

[0974] Example 95: (3 2 R,6S,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-95) Step A: (R)-1-(2-chloropyrimidin-4-yl)-2-propanol (147) TIFF2025532532000311.tif24170

[0975] Compound 147 is synthesized by using compound 2-chloro-4-iodopyrimidine instead of compound 78 as a raw material and following the method for compound 79.

[0976] LCMS: m / z (ESI), 173.0 [M+H] + .

[0977] Step B: (R)-4-(2-((t-butyldimethylsilyl)oxy)propyl)-2-chloropyrimidine (148) TIFF2025532532000312.tif20170

[0978] Compound 148 was synthesized by using compound 147 instead of compound 1 and following the procedure for compound 2.

[0979] LCMS: m / z (ESI), 287.0 [M+H] + .

[0980] Step C: (R)-4-(2-((t-butyldimethylsilyl)oxy)propyl)-2-tributylstannylpyrimidine (149) TIFF2025532532000313.tif22170

[0981] Compound 149 was synthesized by using compound 148 instead of compound 2 as a raw material and following the method for compound 3.

[0982] LCMS: m / z (ESI), 543.0 [M+H] + .

[0983] Step D: (R)-3-(4-(2-((t-butyldimethylsilyl)oxy)propyl)pyrimidin-2-yl)-6-chloroimidazole[1,2-b]pyridazine (150) TIFF2025532532000314.tif26170

[0984] Compound 150 was synthesized by using compound 149 instead of compound 3 as a raw material and following the method for compound 5.

[0985] LCMS: m / z (ESI), 404.0 [M+H] + .

[0986] Step E: (R)-1-(2-(6-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)ethyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-propanol (151) TIFF2025532532000315.tif37170

[0987] Compound 151 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 19, compound 150 instead of compound 48, and the method for compound 48-1 is used.

[0988] LCMS: m / z (ESI), 436.1 [M+H] + .

[0989] Step F: (R)-5-Fluoro-3-(1-(3-(4-((R)-hydroxypropyl))pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (152) TIFF2025532532000316.tif33170

[0990] Compound 152 was synthesized by using compound 151 instead of compound 10 as a raw material and following the method for compound 11.

[0991] LCMS: m / z (ESI), 436.1 [M+H] + .

[0992] Stage G: (3 2 R,6S,E)-4 5-Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine-4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-95) TIFF2025532532000317.tif30170

[0993] Compound I-95 was synthesized by using compound 152 instead of compound 39 as the raw material and following the method for compound I-9.

[0994] LCMS: m / z (ESI), 418 [M+H] + .

[0995] Example 96: (3 2 R,3 4 S,6S,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-96) Step A: (R)-1-(2-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-propanol (153) TIFF2025532532000318.tif35170

[0996] Use compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine instead of compound 19, use compound 150 instead of compound 48, and synthesize compound 153 according to the method of compound 48-1.

[0997] LCMS: m / z (ESI), 454.1 [M+H] + .

[0998] Step B: 5-fluoro-3-((2R,4S)-4-fluoro-1-(3-(4-((R)-hydroxypropyl)pyrimidin-2-yl)imidazol[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)pyridin-2(1H)-one (154) TIFF2025532532000319.tif35170

[0999] Compound 154 was synthesized by using 153 instead of compound 10 as a raw material and following the method for compound 11.

[1000] LCMS: m / z (ESI), 454.1 [M+H] + .

[1001] Stage C: (3 2 R,3 4 S,6S,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(2,4)-pyrimidine 4(3,2)-pyridine-3(1,2)-pyrrole alkylcycloheptane (I-96) TIFF2025532532000320.tif35170

[1002] Compound I-96 was synthesized using compound 154 instead of compound 39 and following the procedure for compound I-9.

[1003] LCMS: m / z (ESI), 436 [M+H] + .

[1004] Example 97: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-97) Step A: (R)-3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (155) TIFF2025532532000321.tif34170

[1005] Compound 155 is synthesized by using compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 and following the method for compound 82-1.

[1006] LCMS: m / z (ESI), 449.1 [M+H] + .

[1007] Step B: (R)-4-Fluoro-2-(1-(3-(6-(S)-2-hydroxypropyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (156) TIFF2025532532000322.tif32170

[1008] Compound 156 was synthesized by using compound 155 instead of compound 77 and following the procedure for compound 78.

[1009] LCMS: m / z (ESI), 434.1 [M+H] + .

[1010] Stage C: (3 2 R,6R,E)-4 5 -Fluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-97) TIFF2025532532000323.tif32170

[1011] Compound I-97 was synthesized by using compound 156 instead of compound 39 as the raw material and following the method for compound I-9.

[1012] LCMS: m / z (ESI), 417 [M+H] + .

[1013] Example 98: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (I-98) Step A: (R)-3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)-6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)imidazole[1,2-b]pyridazine (157) TIFF2025532532000324.tif35170

[1014] Compound 157 is synthesized by using compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine instead of compound 71 and following the method for compound 82-1.

[1015] LCMS: m / z (ESI), 467.1 [M+H] + .

[1016] Step B: 4-Fluoro-2-((2R,4S)-4-fluoro-1-(3-(6-((S)-2-hydroxypropyl)pyrimidin-4-yl)imidazole[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)phenol (158) TIFF2025532532000325.tif33170

[1017] Compound 158 was synthesized by using 157 instead of compound 77 as the raw material and following the method for compound 78.

[1018] LCMS: m / z (ESI), 453.1 [M+H] + .

[1019] Stage C: (3 2 R,3 4S,6R,E)-3 4 ,4 5 -Difluoro-6-methyl-5-oxa-2(3,6)-imidazole[1,2-b]pyridazine-1(4,6)-pyrimidine-3(1,2)-pyrrolidine-4(1,2)-phenylcycloheptane (I-98) TIFF2025532532000326.tif34170

[1020] Compound I-98 was synthesized by using compound 158 instead of compound 39 as the raw material and following the method for compound I-9.

[1021] LCMS: m / z (ESI), 435 [M+H] + .

[1022] Example 99: Biological Evaluation Test 1: Inhibitory activity of compounds against TRKA and TRKA(F589L) kinases Experimental method: Compounds were prepared by dissolving each of the compounds of Examples 1 to 98 in 100% DMSO to prepare a 10 mM stock solution, which was then frozen and stored at -20°C.

[1023] The chemical structure of the compound Loxo-195 is as follows, and it is commercially available. Specifically, it can be prepared by referring to WO2010 / 48314.

[1024] TIFF2025532532000327.tif32170 The chemical structure of compound TPX-0005 is as follows, and it is commercially available. Specifically, it can be prepared by referring to WO2017004342.

[1025] TIFF2025532532000328.tif33170 Kinase reaction step: Prepare 1x kinase buffer and prepare a compound concentration gradient. The test concentrations of the compounds of test examples 1 to 96 and compound Loxo-101 are 1000nM. They are diluted in 100% DMSO solution at 100 times the final concentration in a 384-well plate. The compounds are diluted 3 times with Precision to form 10 concentrations (1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.4, 0.16, 0.15 and 0.05nM). Using the Echo550 dispenser, 250nL of compound at 100x the final concentration was transferred to the target plate, OptiPlate-384F. A kinase solution at 2.5x the final concentration was prepared with 1x kinase buffer. 10μL of 2.5x the final concentration of kinase solution was added to the compound wells and positive control wells, and 10μL of 1x kinase buffer was added to the negative control wells. The reaction plate was centrifuged at 1000rpm for 30 seconds, shaken to mix evenly, and then incubated at room temperature for 10 minutes. A mixed solution of ATP and kinase substrate 22 at 5 / 3x the final concentration was prepared with 1x kinase buffer. 15μL of the mixed solution of ATP and substrate at 5 / 3x the final concentration was added to start the reaction. The 384-well plate was centrifuged at 1000rpm for 30 seconds, shaken to mix evenly, and then incubated at room temperature for the corresponding time. 30μL of stop detection solution was added to stop the kinase reaction. The plate was centrifuged at 1000rpm for 30 seconds, shaken to mix evenly, and then incubated at room temperature for the corresponding time. Read the conversion rate with Reader.

[1026] Data Analysis: Calculation formula: %Inhibition = (conversion %_max - conversion %_sample) ÷ (conversion %_max - conversion %_min) × 100 where conversion %_sample is the conversion rate reading of the sample, conversion %_min is the average value of the negative control wells, representing the conversion rate reading of wells without enzyme activity, and conversion %_max is the average ratio of the positive control wells, representing the conversion rate reading of wells without compound inhibition. The dose-effect curve was fitted using the logarithm of concentration on the X-axis and the percentage of inhibition on the Y-axis, and the log(inhibitor) vs. slope of the response variable in the analytical software GraphPad Prism 5, thereby obtaining the IC50 value of each compound on enzyme activity. The calculation formula is as follows:

[1027] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) Here, X represents the concentration of the test compound, Y represents the inhibition rate of the test compound at the concentration of X, Top refers to the maximum response, Bottom refers to the baseline response, and Hill Slope refers to the slope of the curve, i.e., the slope rate.

[1028] IC of each compound on enzyme activity 50 The values ​​are shown in Tables 1 and 2 below.

[1029] Table 1. Kinase TRKA WT IC of various compounds in vitro inhibition experiments against 50 Test result (nM) TIFF2025532532000329.tif249170TIFF2025532532000330.tif98170

[1030] Experimental results show that most of the compounds of the present application have very strong inhibitory potency in in vitro inhibition experiments of kinase TRKAWT.

[1031] Table 2. Kinase TRKA F589L IC of various compounds in vitro inhibition experiments against 50 Test result (nM) TIFF2025532532000331.tif249170TIFF2025532532000332.tif98170

[1032] ---- indicates not detected or found Experimental results show that most of the compounds in this application inhibit the kinase TRKA F589L In vitro inhibition experiments have shown that it has stronger inhibitory activity than LOXO-195.

[1033] Experiment 2: Inhibitory effects of compounds on the growth of Ba / F3-TPM3-NTRK1-G667C cells TIFF2025532532000333.tif234170

[1034] Preparation of compound solutions: In a biological safety cabinet, the compounds of Examples 1 to 96 and compound Loxo-101 were each dissolved in 100% DMSO to prepare 10 mM stock solutions, which were then frozen and stored at -20°C. The compound stock solutions were then gradient diluted with DMSO. A clean, sterile V-bottom 96-well microplate was placed in a biological safety cabinet. 4 μL of DMSO was added to well B2, and 10 μL of DMSO was added to wells B3 to B11. 6 μL of 10 mM compound stock solution was then added to well B2 and mixed thoroughly by pipetting up and down 10 times. In this case, the compound concentration in well B2 was 6 mM, 100% DMSO. 5 μL of the solution was removed from well B2 and transferred to well B3, and mixed thoroughly by pipetting up and down 10 times. The dilutions were sequentially made until B10 was reached. DMSO alone, without the test compound, was added to well B11.

[1035] Prepare a 6X compound solution (6-fold dilution, X represents the dilution factor) (initial final concentration is 10 μM). Place a clean and sterile V-bottom 96-well microplate in a biological safety cabinet, add 99 μL of cell culture medium to each well of B2-G11, and use a 12-channel pipette to add 1 μL of the compound solution prepared in the previous compound solution preparation step to the corresponding well. Mix the solution in each well evenly by pipetting it up and down 10 times with the pipette. In this case, the highest compound concentration is 60 μM. Compound-treated cells: remove the seeded cell culture plate from the incubator, take 20 μL of compound solution from each well and add it to the corresponding cell culture well, use the lowest possible pipetting speed when adding the sample to avoid sticking to the wall and contacting the bottom of the culture plate, gently shake the cell culture plate to mix the compound solution evenly, then return the cell culture plate to the incubator and continue culturing for 72 hours; In this case, the maximum treatment concentration of the compound was 10 μM. After treating the cells for 72 hours, the Cell TiterGlo (CTG) test was performed. First, the cell culture plate was removed from the CO2 incubator and placed at room temperature for 30 minutes to allow the temperature to uniformly distribute throughout the culture plate. The Cell TiterGlo reagent, prepared according to the manufacturer's instructions, was removed and placed at room temperature to dissolve. 60 μL of Cell TiterGlo reagent was then added to each well containing cells. The plate was then incubated at room temperature in the dark on a horizontal shaker at 225 rpm for 1 hour. The plate was then read using a Tecan Spark microplate reader by chemiluminescence according to the manufacturer's instructions to determine the IC values ​​of some of the compounds for various cell lines. 50 The values ​​are shown in Table 3 below.

[1036] Table 3: IC of in vitro inhibition experiments of various compounds against cells Ba / F3-TPM3-NTRK1-G667C 50 Test result (nM) TIFF2025532532000334.tif246170TIFF2025532532000335.tif251170TIFF2025532532000336.tif72170

[1037] ---- indicates not detected or found Experimental results show that most of the compounds disclosed herein have stronger inhibitory abilities than compound Loxo-195 in in vitro inhibition experiments of Ba / F3-TPM3-NTRK1-G667C cells. In in vitro inhibition experiments of Ba / F3-TPM3-NTRK1-G667C cells, the inhibitory abilities of 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 are stronger than those of compound TPX-0005.

[1038] Table 4: IC of in vitro inhibition experiments of various compounds against cells Ba / F3-TPM3-NTRK1-G595R 50 Test result (nM) TIFF2025532532000337.tif172170

[1039] The experimental results show that in the in vitro inhibition experiment of cells Ba / F3-TPM3-NTRK1-G595R, the inhibitory ability of 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 of the present application is stronger than that of compounds Loxo-195 and TPX-0005.

[1040] Table 5: IC of in vitro inhibition experiments of various compounds against cells Ba / F3-TPM3-NTRK1-WT 50 Test result (nM) TIFF2025532532000338.tif164170

[1041] The experimental results show that in the in vitro inhibition experiment of cells Ba / F3-TPM3-NTRK1-WT, the inhibitory ability of 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 of the present application is stronger than that of compounds Loxo-195 and TPX-0005.

[1042] Experiment 3: Evaluation of the pharmacodynamics of compounds in a NOD-SCID mouse Ba / F3-TPM3-NTRK1-WT subcutaneous tumor model 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 harvested, the total number of cells required was calculated, and then resuspended in an appropriate volume of PBS mixture (PBS:Matrigel = 1:1 (v / v)). The cell suspension concentration was 5 x 10 6 / 0.1 mL and used for subcutaneous inoculation into the right flank of NOD-SCID mice.

[1043] Methods: On day 0 (Day 0), all animals were subcutaneously inoculated with 0.1 mL (5 × 10 Ba / F3-TPM3-NTRK1-WT cells) of a cell suspension (PBS:Matrigel = 1:1, V / V) into the right back. Tumors grew to a mean volume of 178.3 mm. 3 When the tumors reached the tumor size, they were divided into groups and administered medication. The mean tumor volume of the enrolled animals was 178.3 mm. 3 The experiment was divided into two groups: Group 1 (vehicle) and Group 2 (10 mg / kg I-52). Each group consisted of six animals, for a total of two groups. All groups were orally administered twice daily for a total of 29 days.

[1044] Tumor volume inhibition rate TGI TV (%): TGI% = (1-△T / △C) × 100% where △C is the control group C t-C0 tumor volume, where C0 is the mean tumor volume of the control group at the time of grouping, and C t is the mean tumor volume in the control group after treatment, and ΔT is the mean tumor volume in the treatment group T t - T0 tumor volume, where T0 is the mean tumor volume of the treatment group at the time of grouping, and T t is the mean tumor volume of the treatment group after treatment.

[1045] Tumor inhibition rate (TGI TV Pharmacodynamic activity is evaluated based on the body weight change and mortality of the animals, and tolerance is evaluated based on the body weight change and mortality of the animals.

[1046] Table 6. Drug efficacy analysis of tumor volume on day 29 in the Ba / F3-TMP3-NTRK1-WT subcutaneously transplanted tumor model. TIFF2025532532000339.tif97170

[1047] Table 7. Raw records of the mean tumor volume of experimental animals during the experimental period (unit: mm 3 ) TIFF2025532532000340.tif126170

[1048] Compared with the tumor volume of the vehicle group (Group 1), the average tumor volume of Group 2 was significantly different. At the end of the experiment, the tumors of each group were collected and weighed. It was found that the tumors of all mice in Group 2 had disappeared, and the tumor regression rate reached 100%.

[1049] The results showed that the test compound I-52 had significant pharmacodynamic activity in inhibiting the growth of subcutaneously transplanted BA / F3-TPM3-NTRK1-WT tumors in mice. At a dose of 10 mg / kg, the tumor regression rate reached 100% and was well tolerated. There was no significant change in the body weight of the mice, and no significant clinical abnormalities were observed.

[1050] Experiment 4: Evaluation of the pharmacodynamics of the compound in a NOD-SCID mouse Ba / F3-TPM3-NTRK1-G667C subcutaneous tumor model Cell culture: Ba / F3-TPM3-NTRK1-G667C cells were cultured in RPMI 1640 medium containing 10% FBS. Ba / F3-TPM3-NTRK1-G667C cells in the logarithmic growth phase were harvested, the total number of cells required was calculated, and then resuspended in an appropriate volume of PBS (PBS:Matrigel = 1:1 (v / v)) to a cell suspension concentration of 5 x 10. 6 / 0.1 mL and used for subcutaneous inoculation into the right flank of NOD-SCID mice.

[1051] Methods: On day 0 (Day 0), all animals received 0.1 mL (5 × 10 6 A cell suspension of Ba / F3-TPM3-NTRK1-G667C cells (PBS:Matrigel = 1:1, V / V) was inoculated subcutaneously. Tumors grew to an average volume of 197.2 mm. 3 When the tumors reached the tumor size, they were divided into groups and administered medication. The mean tumor volume of the enrolled animals was 197.2 mm. 3 The experiment was divided into two groups: Group 1 (vehicle) and Group 2 (10 mg / kg I-52). Each group consisted of six animals, for a total of two groups. All groups were orally administered twice daily for a total of 29 days.

[1052] Tumor volume inhibition rate TGI TV (%): TGI% = (1-△T / △C) × 100% where △C is the control group C t -C0 tumor volume, where C0 is the mean tumor volume of the control group at the time of grouping, and C t is the mean tumor volume in the control group after treatment, and ΔT is the mean tumor volume in the treatment group T t - T0 tumor volume, where T0 is the mean tumor volume of the treatment group at the time of grouping, and T t is the mean tumor volume of the treatment group after treatment.

[1053] Tumor inhibition rate (TGI TV Pharmacodynamic activity is evaluated based on the body weight change and mortality of the animals, and tolerance is evaluated based on the body weight change and mortality of the animals.

[1054] Table 8. Drug efficacy analysis of tumor volume on day 29 in the Ba / F3-TMP3-NTRK1-G667C subcutaneously transplanted tumor model by group TIFF2025532532000341.tif72170

[1055] Table 9. Raw records of average body weights of experimental animals during the experiment (unit: g) TIFF2025532532000342.tif96170

[1056] Compared with the tumor volume of the vehicle group (Group-1), the mean tumor volume of Group-2 was significantly different. At the end of the experiment, the tumors of each group were collected and weighed, and the mean tumor weights of each group were compared, which was consistent with the results of the mean tumor volume analysis.

[1057] The results showed that the test compound I-52 had significant pharmacodynamic activity in inhibiting the growth of subcutaneously transplanted BA / F3-TPM3-NTRK1-G667C tumors in mice. At a dose of 10 mg / kg, the tumor growth inhibition rate reached 84%. The compound was well tolerated, with no significant changes in the body weight of the mice and no significant clinical abnormalities.

[1058] The above description is merely a specific embodiment of the present invention, and the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily think of modifications or substitutions within the technical scope disclosed in the present invention, which should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be based on the protection standard of the claims.

Claims

1. A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, where: 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 is nitrogen; R １ , R ２ , R ３ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, an amino group, a substituted or unsubstituted saturated or unsaturated C １ ~C ６ alkyl group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ cycloalkoxy groups, or R １ and R ２ together with the N atom and the C atom to which they are attached 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 C atoms to which they are attached, form a substituted or unsubstituted saturated or unsaturated C ３ ~C ６ Forms a cycloalkyl group, wherein the "substituted" means a group selected from the group consisting of deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C １ ~C ４ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ４ Alkoxy group, C ３ ~C ６ optionally containing 1 to 4 substituents selected from cycloalkoxy groups; R ４ is hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C １ ~C ６ Alkyl group, saturated or unsaturated C ３ ~C ６ Cycloalkyl group, saturated or unsaturated C １ ~C ６ Alkoxy group, saturated or unsaturated C ３ ~C ６ cycloalkoxy groups, R ５ is hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C １ ~C ６ Alkyl group, saturated or unsaturated C ３ ~C ６ Cycloalkyl groups, substituted or unsaturated C １ ~C ６ Alkoxy group, saturated or unsaturated C ３ ~C ６ cycloalkoxy groups, or R ５ does not exist, L is -O-, -NH-, substituted or unsubstituted branched or linear C １ ~C ６ Alkylene group, substituted or unsubstituted branched or linear C １ ~C ６ Alkyleneoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ Cycloalkylene group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ Cycloalkyleneoxy group, substituted or unsubstituted branched or linear C １ ~C ６ and a substituted or unsubstituted saturated or unsaturated 3- to 6-membered thiacycloalkylene group; a substituted or unsubstituted saturated or unsaturated 3- to 6-membered oxacycloalkylene group; a substituted or unsubstituted saturated or unsaturated 3- to 6-membered azacycloalkylene group; a substituted or unsubstituted saturated or unsaturated 3- to 6-membered thiacycloalkylene group; a substituted or unsubstituted saturated or unsaturated 3- to 6-membered oxacycloalkyleneoxy group; a substituted or unsubstituted saturated or unsaturated 3- to 6-membered azacycloalkyleneoxy group; a substituted or unsubstituted saturated or unsaturated 3- to 6-membered thiacycloalkyleneoxy group, wherein the "substituted" group is selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, carbonyl, sulfonyl, amino, C １ ~C ４ Alkyl group, C １ ~C ４ Hydroxyalkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ４ Alkoxy group, C ３ ~C ６ the macrocyclic imidazo[1,2-b]pyridazine compound, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the macrocyclic imidazo[1,2-b]pyridazine compound, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is characterized in that the macrocyclic imidazo[1,2-b]pyridazine compound, or an isotope-labeled compound ...

2. Preferably, R １ , R ２ , R ３ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, an amino group, a substituted or unsubstituted saturated or unsaturated C １ ~C ４ alkyl group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated C １ ~C ４ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ cycloalkoxy groups, or R １ and R ２ together with the N atom and C atom to which they are attached 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 C atoms to which they are attached, form a substituted or unsubstituted saturated or unsaturated C ３ ~C ６ Forms a cycloalkyl group, wherein the "substituted" means a group selected from the group consisting of deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ３ Alkoxy group, C ３ ~C ６ optionally containing 1 to 3 substituents selected from cycloalkoxy groups; More preferably, R １ , R ２ , R ３ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, an amino group, a substituted or unsubstituted saturated or unsaturated C １ ~C ３ alkyl group, substituted or unsubstituted saturated or unsaturated C ５ ~C ６ cycloalkyl groups, or R １ and R ２ together with the N atom and C atom to which they are attached 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 attached, form a substituted or unsubstituted saturated or unsaturated C ５ ~C ６ Forms a cycloalkyl group, wherein the "substituted" means a group selected from the group consisting of deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C １ ~C ３ Alkyl group, C ５ ~C ６ optionally containing 1 to 3 substituents selected from cycloalkyl groups; More preferably, R １ , R ２ , R ３ are each independently hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C １ ~C ３ alkyl groups, or R １ and R ２ together with the N atom and C atom to which they are attached 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 attached, form a substituted or unsubstituted saturated or unsaturated C ５ ~C ６ forming a cycloalkyl group, wherein the term "substituted" refers to selectively containing one or two selected from deuterium, a hydroxyl group, and a halogen; Preferably, R ４ is hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C １ ~C ４ Alkyl group, saturated or unsaturated C ５ ~C ６ Cycloalkyl group, saturated or unsaturated C １ ~C ４ Alkoxy group, saturated or unsaturated C ５ ~C ６ cycloalkoxy groups, More preferably, R ４ is hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C １ ~C ３ Alkyl group, saturated or unsaturated C １ ~C ３ alkoxy groups, More preferably, R ４ is hydrogen, deuterium, halogen, saturated or unsaturated C １ ~C ３ Alkyl group, saturated or unsaturated C １ ~C ３ alkoxy groups, More preferably, R ４ is selected from hydrogen, deuterium or a halogen; Preferably, R ５ is hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C １ ~C ４ Alkyl group, saturated or unsaturated C ５ ~C ６ Cycloalkyl groups, substituted or unsaturated C １ ~C ４ Alkoxy group, saturated or unsaturated C ５ ~C ６ cycloalkoxy groups, or R ５ does not exist, More preferably, R ５ is hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C １ ~C ３ Alkyl group, substituted or unsaturated C １ ~C ３ alkoxy groups, or R ５ does not exist, More preferably, R ５ is hydrogen, deuterium, halogen, saturated or unsaturated C １ ~C ３ Alkyl group, substituted or unsaturated C １ ~C ３ alkoxy groups, or R ５ does not exist, More preferably, R ５ is selected from hydrogen, deuterium, halogen, or R ５ is characterized by the absence A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

3. L is -O-, -NH-, substituted or unsubstituted branched or linear C １ ~C ４ Alkylene group, substituted or unsubstituted branched or linear C １ ~C ４ Alkyleneoxy group, substituted or unsubstituted saturated or unsaturated C ４ ~C ６ Cycloalkylene group, substituted or unsubstituted saturated or unsaturated C ４ ~C ６ Cycloalkyleneoxy group, substituted or unsubstituted branched or linear C １ ~C ４ and a substituted or unsubstituted saturated or unsaturated 4- to 6-membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 4- to 6-membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 4- to 6-membered thiacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 4- to 6-membered oxacycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 4- to 6-membered azacycloalkyleneoxy group, and a substituted or unsubstituted saturated or unsaturated 4- to 6-membered thiacycloalkyleneoxy group, wherein the "substituted" group is selected from the group consisting of deuterium, halogen, cyano, hydroxy, carbonyl, amino, C １ ~C ４ Alkyl group, C １ ~C ４ Hydroxyalkyl group, C ３ ~C ６ optionally containing 1 to 3 substituents selected from cycloalkyl groups; More preferably, L is —O—, —NH—, substituted or unsubstituted branched or linear C １ ~C ３ Alkylene group, substituted or unsubstituted branched or linear C １ ~C ３ Alkyleneoxy group, substituted or unsubstituted saturated or unsaturated C ５ ~C ６ Cycloalkylene group, substituted or unsubstituted saturated or unsaturated C ５ ~C ６ a cycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkyleneoxy group, or a substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkyleneoxy group, wherein the term "substituted" refers to the optional inclusion of 1 to 3 substituents selected from deuterium or halogen; More preferably, L is a substituted or unsubstituted branched or linear C １ ~C ３ Alkylene group, substituted or unsubstituted branched or linear C １ ~C ３ Alkyleneoxy group, substituted or unsubstituted saturated or unsaturated C ５ ~C ６ Cycloalkylene group, substituted or unsubstituted saturated or unsaturated C ５ ~C ６ a cycloalkyleneoxy group, a substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkylene group, a substituted or unsubstituted saturated or unsaturated 5- to 6-membered oxacycloalkyleneoxy group, or a substituted or unsubstituted saturated or unsaturated 5- to 6-membered azacycloalkyleneoxy group, wherein the term "substituted" refers to the optional inclusion of one or two substituents selected from deuterium or halogen; More preferably, L is —CH ２ O-, -CH ２ CH ２ O-, -CH ２ CH ２ CH ２ O-, -CH ２ CH(CH3)O-, -CH(CH3)CH ２ O-, characterized in that it is selected from A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

4. The compound represented by formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is represented by the following formula I-1, I-2, I-3, I-4, I-5 or I-6: Here, the substituent W ５ , R １ , R ２ , R ３ , R ４ , R ５ , L are defined as in claim 1. A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

5. The compound represented by formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is represented by the following formula I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1, Here, the substituent W ５ , R １ , R ２ , R ３ , R ４ , R ５ The definitions of are the same as in claim 1, L １ and L ２ are each independently a chemical bond, a substituted or unsubstituted branched or linear C １ ~C ３ Alkylene group, substituted or unsubstituted saturated or unsaturated C ３ ~C ６ a cycloalkylene group, a substituted or unsubstituted saturated or unsaturated 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from O or N, wherein the term "substituted" refers to the optional inclusion of 1 or 2 substituents selected from deuterium or halogen; and L １ and L ２ is not a chemical bond at the same time, Preferably, L １ and L ２ are each 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 oxiranylene group, an oxetanylidene group, a tetrahydrofuranylene group, a tetrahydropyranylene group, a tetrahydropyrrolylene group, a hexahydropyridylene group, a halogenated oxiranylene group, a halogenated oxetanylidene group, a halogenated tetrahydrofuranylene group, a halogenated tetrahydropyranylene group, a halogenated tetrahydropyrrolylene group, and a halogenated hexahydropyridylene group; and L １ and L ２ is characterized by not being a chemical bond at the same time A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

6. characterized in that the compound is selected from the group consisting of A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I according to any one of claims 1 to 5, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

7. 1. A pharmaceutical composition comprising: The pharmaceutical composition comprises a therapeutically effective amount of the compound according to any one of claims 1 to 6 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound of formula I according to any one of claims 1 to 6 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric 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, comprising: The medicament is used to treat or prevent 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 a 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 the group consisting of postoperative 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 gland tumor, bile duct cancer, stromal tumor, brain tumor, and malignant hematological disease.

9. A kit comprising: The kit comprises a compound represented by 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 isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition of the present invention, as well as a container and an instruction manual.

10. 1. A method of treating a TRK or TRK mutation mediated disease or condition, comprising:

10. A method for treating a TRK or TRK mutation-mediated disease or condition, 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 isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to claim 7.

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