A triazole derivative, a process for its preparation and its use

Abstract

The application discloses a triazole compound shown in formula I or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, a preparation method thereof and a use as a TRK kinase inhibitor, and a pharmaceutical composition containing the derivative.

Description

Technical Field

[0001] This application belongs to the pharmaceutical field, and specifically relates to a triazole derivative and its pharmaceutically acceptable salt, a method for preparing the same and its use as a TRK kinase inhibitor, and a pharmaceutical composition comprising the derivative. Background Technology

[0002] Tropomyosin-related kinases (TRKs) are transmembrane receptor tyrosine kinases (RTKs). They contain a homologous hinge structure formed by multiple folded subunits, typically located between the N-terminal and C-terminal regions. This structure includes an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with kinase activity. When TRKs bind to ligands on the cell membrane surface, they self-phosphorylate specific tyrosine residues through dimerization, activating downstream signaling pathways (Ras / MAPK, PI3K / AKT, and PLCγ pathways). TRKs are a class of nerve growth factor receptors that regulate synaptic strength and plasticity in the mammalian nervous system. In this role, TRK family kinases regulate cell differentiation, proliferation, metabolism, apoptosis, and pain. The TRK family has three members: tropomyosin-associated kinase A (TRKA, encoded by the NTRK1 gene), tropomyosin-associated kinase B (TRKB, encoded by the NTRK2 gene), and tropomyosin-associated kinase CTRKC, encoded by the NTRK3 gene. All three are involved in the occurrence and development of malignant tumors. The main difference between the three subtypes of the TRK family lies in their ligands: TRKA binds to NGF, TRKB binds to brain-derived neurotrophic factor (BDNF), and TRKC specifically binds to neurotrophic factor (NT3).

[0003] Similar to the BCR-ABL gene fusion products that drive chronic myeloid leukemia (CML), NTRK rearrangements and fusion gene products have been observed in multiple tumor types. Unlike CML, the incidence of NTRK fusion genes in each specific tumor type is generally rare. This presents significant challenges for patient identification and adequate recruitment for clinical trials. For example, fusions of the NTRK2 gene have been found in 0.2% of lung adenocarcinomas; on the other hand, NTRK3 fusion genes have been found in almost all secretory breast cancers and mammary analogue secretory carcinomas (MASCs), an extremely rare salivary gland tumor (usually parotid gland tumors). In fact, the defining characteristic of MASCs compared to other salivary gland cancers is NTRK gene fusion; furthermore, NTRK fusions have been found in approximately 50% of diffuse pontine gliomas and non-brainstem glioblastomas in children. In major cancer subgroups, NTRK fusions occurred in 3.3% of lung cancer, 2.2% of colorectal cancer, 16.7% of thyroid cancer, 2.5% of glioblastoma, and 7.1% of pediatric gliomas in breast cancer. Finally, similar to receptor tyrosine kinase RET (which rearranges during transfection), NTRK fusions (especially ETV6-NTRK3) are common in papillary thyroid carcinoma induced after Chernobyl nuclear radiation. Therefore, targeting TRK oncogenes is an attractive therapeutic approach for treating a wide variety of, often rare, cancers.

[0004] The primary approach to targeting TRK oncogenes is through the use of small molecule kinase inhibitors. Since gene fusion products are observed to be major oncogenes, gene fusion of neurotrophic receptor tyrosine kinase (NTRK) leads to the loss of the extracellular domain of TRK, thereby triggering various tumors. The loss of the TRK extracellular domain renders antibody therapy targeting TRK ineffective, and other targeting strategies, such as antibody therapy, will also be ineffective because transmembrane tyrosine kinase fusions typically lack an extracellular domain. In this case, the fusion protein is only susceptible to inhibition by small molecules. Generally, small molecules are designed to target the adenosine triphosphate (ATP) binding site of TRK to block its catalytic activity. For example, some newly developed TRK small molecule inhibitors have been disclosed in Chinese patent applications CN102264736A and CN104520300A, making the development of TRK small molecule inhibitors highly significant. Summary of the Invention

[0005] According to one aspect of the invention, an object of the invention is to provide a compound of formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

[0006]

[0007] in:

[0008] W 1 W 2 W 3 W 4 W 5 W 6 W 7 Each is independently selected from carbon or nitrogen, and W 6 and W 7 It cannot be either carbon or nitrogen at the same time;

[0009] Ring A can be a benzene ring, a pyridine ring, or a heteroalkyl ring containing an N atom;

[0010] R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C6 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C6 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted saturated or unsaturated 4- to 14-membered heterocyclic alkyl containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 1 and R 2 Together with the N and C atoms attached to them, they form substituted or unsubstituted 4- to 14-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 14-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 2 and R 3 Together with the C atoms attached to them, they form substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl groups, substituted or unsubstituted 4- to 14-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein "substituted" means selectively containing 1 to 4 heteroatoms selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, -OC(=O)C 1-4 Alkyl groups, substituents of -OC (=O) C3-C6 cycloalkyl groups;

[0011] R 4Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C1-C6 alkoxy, and saturated or unsaturated C3-C6 cycloalkoxy.

[0012] R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, substituted or unsaturated C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkoxy, or R 5 It does not exist;

[0013] X 1 The group is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted saturated or unsaturated C1-C6 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C6 alkoxy, and substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, wherein "substituted" means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, sulfonyl, and amino.

[0014] L 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino, amide, substituted or unsubstituted saturated or unsaturated C1-C6 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C6 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, substituted or unsubstituted C6-C 14 The aryl group, substituted or unsubstituted saturated or unsaturated 4- to 14-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxyl, carboxyl, carbonyl, sulfonyl, C1-C4 alkylsulfonyl, amino, amide, -NR a R b C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, -C(=O)C 1-4 Alkyl group, -C(=O)NR a R b C 1-4 Alkyl sulfonyl, C6-C 14aryl, comprising 4- to 8-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein R a and R b Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, amino, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C3-C6 cycloalkoxy, and contains 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxyl, and amino in the form of C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C3-C6 cycloalkoxy groups.

[0015] Preferably, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C4 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C4 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 1 and R 2 Together with the N and C atoms attached to them, they form substituted or unsubstituted 4- to 10-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 2 and R 3 Together with the C atoms attached to them, they form substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl groups, substituted or unsubstituted 4- to 10-membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein “substituted” means selectively containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, and C3-C6 cycloalkoxy.

[0016] More preferably, R 1 R 2 R 3Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C3 alkoxy, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted saturated or unsaturated 4- to 6-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 7-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 1 and R 2 Together with the N and C atoms attached to them, they form substituted or unsubstituted 4- to 10-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 2 and R 3 Together with the C atoms attached to them, they form substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl groups, substituted or unsubstituted 4- to 7-membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein “substituted” means selectively containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, sulfonyl, amino, C1-C3 alkyl, C5-C6 cycloalkyl, C1-C3 alkoxy, and C5-C6 cycloalkoxy.

[0017] More preferably, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, and optionally R 1 and R 2 Together with the N and C atoms connecting them, they form substituted or unsubstituted 4- to 7-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, optionally R 2 and R 3 Together with the C atoms that connect them, they form substituted or unsubstituted C3-C5 cycloalkyl groups; wherein “substituted” means selectively containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, amino and C1-C3 alkyl groups.

[0018] More preferably, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, methyl, ethyl, and propyl; R may be selected from... 1 and R 2Together with the N and C atoms connecting them, they form hydroxyl-substituted 5- or 6-membered heterocyclic alkyl groups containing one or two heteroatoms selected from N and O; halogen-substituted 5- or 6-membered heterocyclic alkyl groups containing one or two heteroatoms selected from N and O; optionally R 2 and R 3 Together with the C atoms that connect them, they form cyclopropyl or cyclobutyl groups.

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

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

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

[0022] Preferably, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C4 alkyl, saturated or unsaturated C5-C6 cycloalkyl, substituted or unsaturated C1-C4 alkoxy, saturated or unsaturated C5-C6 cycloalkoxy, or R 5 It does not exist;

[0023] More preferably, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C1-C3 alkyl, substituted or unsaturated C1-C3 alkoxy, or R. 5 It does not exist;

[0024] More preferably, R 5 Selected from hydrogen, deuterium, halogen, saturated or unsaturated C1-C3 alkyl, substituted or unsaturated C1-C3 alkoxy, or R 5 It does not exist;

[0025] Preferably, X 1 The group is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C1-C4 alkyl, substituted or unsubstituted saturated or unsaturated C1-C4 alkoxy, wherein “substituted” means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, sulfonyl, and amino.

[0026] More preferably, X 1The group is selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C1-C3 alkoxy, wherein “substituted” means selectively containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, sulfonyl, and amino.

[0027] More preferably, X 1 Selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C1-C3 alkoxy, wherein “substituted” means selectively containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, hydroxyl, carbonyl, and amino.

[0028] Preferably, L 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino, amide, substituted or unsubstituted saturated or unsaturated C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C4 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, substituted or unsubstituted C6-C 10 The aryl group, substituted or unsubstituted saturated or unsaturated 4- to 10-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxyl, carboxyl, carbonyl, sulfonyl, C1-C4 alkylsulfonyl, amino, amide, -NR a R b C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, -C(=O)C 1-4 Alkyl group, -C(=O)NR a R b C 1-4 Alkyl sulfonyl, C6-C 10 aryl, comprising 4- to 8-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein R a and R b Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, amino, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, and contains 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxyl, and amino;

[0029] More preferably, L 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino, amide, substituted or unsubstituted saturated or unsaturated C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C1-C3 alkoxy, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkoxy, substituted or unsubstituted C6-C 10 The aryl group, substituted or unsubstituted saturated or unsaturated 4- to 6-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxyl, carboxyl, carbonyl, sulfonyl, C1-C4 alkylsulfonyl, amino, amide, -NR a R b C1-C3 alkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -C(=O)C 1-4 Alkyl group, -C(=O)NR a R b C 1-3 Alkylsulfonyl, phenyl, 4- to 6-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein R a and R b Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, amino, C1-C3 alkyl, and C1-C4 alkoxy.

[0030] More preferably, L 1 Selected from one of the following groups

[0031] -OH

[0032] Preferably, the compound represented by Formula I, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, is represented by the following Formula I-1, Formula I-2, or Formula I-3:

[0033]

[0034] Where the substituent W 5 W 6 W 7 R 1 R 2 R 3 R4 R 5 X 1 L 1 The definition is the same as in Equation 1 above.

[0035] Preferably, the compound represented by Formula I, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, is represented by the following formulas: I-1-a, I-1-b, I-2-a, I-2-b, I-3-a, or I-3-b.

[0036]

[0037] Where the substituent W 5 R 1 R 2 R 3 R 4 R 5 X 1 L 1 The definition is the same as in Equation 1 above.

[0038] Preferably, the compound or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or mixture of isomers, or pharmaceutically acceptable salt thereof, or its prodrug or its metabolite, represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-1-a, Formula I-1-b, Formula I-2-a, Formula I-2-b, Formula I-3-a or Formula I-3-b, is selected from the following compounds:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045] According to a second aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to the invention or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier thereof.

[0046] According to a third aspect of the invention, another object of the invention is to provide the use of the compound or isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a medicament as a TRK kinase inhibitor for the treatment or prevention of a disease or condition mediated by TRK or TRK mutation in a subject in need.

[0047] Preferably, the disease or condition mediated by TRK or TRK mutation is selected from one or more of cancer, neurodegenerative diseases, inflammation, and pain.

[0048] More preferably, the diseases or conditions mediated by TRK or TRK mutations are selected from surgical pain, inflammatory pain, neuropathic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, saliva-like tumors, bile duct cancer, stromal tumors, brain tumors, and hematologic malignancies.

[0049] According to a fourth aspect of the invention, another object of the invention is to provide a kit for a compound of formula I according to the invention or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to the invention, as well as a container and instructions for use.

[0050] According to a fifth aspect of the invention, another object of the invention is to provide a method for treating a disease or condition mediated by TRK or TRK mutations, the method comprising administering to a subject in need an effective amount of a compound of formula I according to the invention or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to the invention. Detailed Implementation

[0051] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0052] In this document, the terms “comprising,” “including,” “having,” “containing,” or any similar terms are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article containing a plural element is not limited to the elements listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated otherwise, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously encompassing closed or semi-closed transitional phrases such as “composed of” and “substantially composed of.”

[0053] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0054] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0055] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0056] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0057] definition

[0058] "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C"). 1–8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has one to six carbon atoms (“C6 alkyl”). 1-6 Alkyl group). C 1–6Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-8 Alkyl group (e.g., unsubstituted C1 alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C1 alkyl group. 1-8 Alkyl groups (e.g., substituted C1 alkyl groups, such as -CF3).

[0059] "Alkoxy" signifies a monovalent -O-alkyl group, wherein the alkyl moiety has a specified number of carbon atoms. In this disclosure, alkoxy groups typically contain 1-6 carbon atoms ("C1 to C6 alkoxy") or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise stated, each instance of an alkoxy group is optionally substituted independently, i.e., unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy"). In some embodiments, the alkoxy group is an unsubstituted C1 to C6 alkoxy. In some embodiments, the alkoxy group is a substituted C1 to C6 alkoxy.

[0060] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 8 ring carbon atoms ("C"). 3-8 The cycloalkyl group comprises a non-aromatic cycloalkyl group with 3 to 8 carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 8 cyclic carbon atoms (“C”). 5-8 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6Cycloalkyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Unless otherwise stated, each example of a cycloalkyl group is optionally independently substituted, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted by one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-8 Cycloalkyl; in some embodiments, the cycloalkyl group is a substituted C 3-8 Cycloalkyl.

[0061] "Heterocyclic alkyl" refers to a group having a 5- to 14-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided that the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. "Heterocyclic group" also includes ring systems in which the heterocycle as defined above is fused with one or more cycloalkyl groups (where the linkage is on the cycloalkyl group or heterocycle), or ring systems in which the heterocycle as defined above is fused with one or more aryl or heteroaryl groups (where the linkage is on the heterocycle), and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of a heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (“substituted heterocyclic alkyl”). In some embodiments, the heterocyclic alkyl is an unsubstituted 5-14 membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a substituted 5-14 membered heterocyclic alkyl.

[0062] "Aryl" or "aromatic ring" or "aromatic cyclic group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14"Aryl"; for example, anthracene. "Aryl" also includes cyclic systems in which the aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups (where the bonding point is on the aromatic ring), and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl group is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0063] A "heteroaryl" is a 5-14 cyclic aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 cyclic heteroaryl"). In some embodiments, a heteroaryl is a 5-8 cyclic aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 cyclic heteroaryl"). In some embodiments, a heteroaryl is a 5-6 cyclic aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 cyclic heteroaryl"). In some embodiments, a 5-6 cyclic heteroaryl has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 cyclic heteroaryl has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each instance of the heteroaryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0064] "Halogen" or "halogenated" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br), or iodine (iodine, -I).

[0065] "Substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, is substituted. In some embodiments, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocyclic alkyl, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted," regardless of whether the term "optionally" precedes it, means that at least one hydrogen atom present in the group (e.g., a carbon or nitrogen atom) is substituted by a permissible substituent, such that the substituent, upon substitution, forms a stable compound, for example, a compound that does not spontaneously transform (e.g., through rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a "substituted" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all such combinations to obtain stable compounds. For the purposes of this disclosure, the heteroatom of nitrogen may have a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent.

[0066] "Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. The term "partially unsaturated" ring systems also aims to encompass rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" means a group containing no double or triple bonds, i.e., entirely composed of single bonds.

[0067] The term “pharmaceutically acceptable” as used in this article refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0068] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and the organic acids include, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, etc. Acids such as mandelic acid, malonic acid, propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheponic acid, gluconic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, dihydroxynaphthyl acid, salicylic acid, succinic acid, folinic acid, edetate, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, etc.; also including salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain basic and acidic functional groups, thus they can be converted into any base or acid addition salt. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0069] As used herein, the modifier term "about" refers to possible numerical variations, for example, by routine testing and processing; by unintentional errors in such testing and processing; by differences in the manufacture, origin, or purity of the ingredients used in the invention; and so on. As used herein, "about" also includes a specific value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalents of the listed quantities. In one embodiment, the term "about" means within 20% of the reported value.

[0070] As used herein, the term “treatment” means the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treating a disease or condition does not require the complete elimination of its associated symptoms. As used herein, the term “treatment” and similar terms can include “preventive treatment,” which refers to reducing the likelihood of the recurrence of a disease or condition or the relapse of a previously controlled disease or condition in subjects who are not at risk or are at risk of developing or being at risk of developing or experiencing a disease or condition or its recurrence. The term “treatment” and its synonyms are considered in relation to the administration of a therapeutically effective amount of the compound described herein to a subject who requires such treatment.

[0071] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0072] The pharmaceutical compositions comprising the compound of Formula I or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug or its metabolite, and the pharmaceutical composition comprising the compound provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents and in suitable sterilizing devices for injection or infusion.

[0073] Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional pharmaceutical preparation methods. For example, the unit dose of the formulation contains 0.05-2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, preferably, the unit dose of the formulation contains 0.1 mg-1000 mg of a compound of formula I.

[0074] The compounds and pharmaceutical compositions of Formula I of this invention are for clinical use in mammals, including humans and animals, and can be administered via oral, nasal, skin, lung, or gastrointestinal routes. Oral administration is most preferred. The optimal daily dose is 0.01-200 mg / kg body weight, taken as a single dose, or 0.01-100 mg / kg body weight, divided into multiple doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Generally, a low dose is started, and the dose is gradually increased until the most suitable dose is found.

[0075] In this invention, the term "effective amount" can refer to the effective amount of dosage and duration required to achieve the desired effect. This effective amount may vary due to various factors, such as the type of disease or the severity of the disease at the time of treatment, the structure of the specific target organ to which the treatment is administered, the size of the patient, or the severity of the disease or symptoms. Those skilled in the art can determine the effective amount of a particular compound empirically without extensive experimentation.

[0076] A typical formulation is prepared by mixing the compound represented by Formula I of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, and water.

[0077] The specific carrier, diluent, or excipient used will depend on the manner and purpose of use of the compound according to the invention. Solvents are generally selected based on those deemed safe and effective by those skilled in the art to be administered 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 (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, or other known additives to manufacture or use the drug in an acceptable form.

[0078] When the compounds of formula (I) of the present invention are used in combination with at least one other drug, the two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of formula (I) of the present invention can be administered to the subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other local or systemic forms of administration.

[0079] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, or other known additives to make or use the pharmaceutical composition in an acceptable form.

[0080] The preferred route of administration for the pharmaceutical products of this invention is oral administration. Solid dosage forms for oral administration may include capsules, tablets, powders, or granules. In solid dosage forms, the compounds or pharmaceutical compositions of this invention are mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerin, etc.; disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, specific complex silicates, sodium carbonate, etc.; solution blocking agents such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using lactose and high molecular weight polyethylene glycol as excipients.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds of the present invention or their pharmaceutical compositions, the liquid dosage form may contain inert diluents 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-butanediol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerin; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitol; or mixtures of several of these substances.

[0082] In addition to these inert diluents, the composition may also include one or more excipients, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0083] In the case of suspensions, in addition to the compounds of formula I of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions containing them, they may further contain carriers such as suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitol ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, or mixtures of several of these substances.

[0084] The compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, may be administered in other topical dosage forms, including ointments, powders, sprays, and inhalers. The drug may be mixed under sterile conditions with pharmaceutically acceptable excipients, diluents, or carriers, and any desired preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be covered within the scope of the present invention.

[0085] Furthermore, this disclosure also covers kits (e.g., pharmaceutical packaging). The provided kits may contain the pharmaceutical compositions or compounds described herein and containers (e.g., vials, ampoules, bottles, syringes, and / or aliquots or other suitable containers). In some embodiments, the provided kits may optionally further include a second container containing pharmaceutical excipients for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein disposed in the first and second containers are combined to form a unit dose.

[0086] In some embodiments, the kit described herein further includes instructions for use of the compound or pharmaceutical composition contained within the kit. The kit described herein may also include information required by a regulatory agency (such as the U.S. Food and Drug Administration (FDA)). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions for use provide for the treatment of TRK mutation-mediated diseases in subjects who require it and / or the prevention of TRK mutation-mediated diseases in subjects who require it. The kit described herein may contain one or more additional pharmaceutical formulations as a separate composition.

[0087] The present invention will be further described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments. The embodiments are provided to better illustrate certain specific manifestations of the present invention and should not be construed as limiting the scope of the present invention in any way. Conditions not specified in the embodiments are conventional conditions. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0088] Compounds of Formula I of this application can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of Formula I, methods well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of Formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0089] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0090] In the following embodiments, the structures of the exemplary compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as an internal standard.

[0091] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph. Thin-layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the support. Unless otherwise specified, all reactions in this invention were carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature was expressed in degrees Celsius.

[0092] In addition, the abbreviations used in the examples have the following meanings: NIS: N-iodosuccinimide; TMS: trimethylsilyl; PdCl2(PPh3)2: bis(triphenylphosphine)palladium dichloride; CuI: cuprous iodide; KF: potassium fluoride; CuSO4: copper sulfate; VCNa: sodium ascorbate; Pd2(dba)3: tris(dibenzylacetone)palladium; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Cs2CO3: cesium carbonate; Na2CO3: sodium carbonate; NaBH4: sodium borohydride; BBr3: boron tribromide; LA H: Lithium aluminum hydride; NaOH: Sodium hydroxide; BOC: tert-Butoxycarbonyl; EA: Ethyl acetate; PE: Petroleum ether; MeOH: Methanol; EtOH: Ethanol; DIEA: N,N-Diisopropylethylamine; DMSO: Dimethyl sulfoxide; TEA: Triethylamine; DMAP: 4-Dimethylaminopyridine; Dioxane: Dioxane; DMF: N,N-Dimethylformamide; NMP: N-Methylpyrrolidone; THF: Tetrahydrofuran; DCM: Dichloromethane; TFA: Trifluoroacetic acid; TLC: Thin-layer chromatography; Structure: Structural formula.

[0093] Example 1: 2-(4-(6-((1-(2,5-difluorophenyl)ethyl)amino)imidazol[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-1)

[0094] Step A: 6-Chloro-3-iodoimidazole[1,2-b]pyridazine (2)

[0095]

[0096] 6-chloroimidazole[1,2-b]pyridazine (compound 1, 50 g, 0.33 mol) was placed in methanol (2 L), NIS (146.51 g, 0.65 mol) was added, and the mixture was stirred at 70 °C for 24 hours. The mixture was then extracted with water (2 L), filtered, and the filter cake was slurried with petroleum ether and ethyl acetate (10:1) to obtain brown solid compound 2 (60 g, yield: 66%).

[0097] LCMS(m / z): 280[M+H] + .

[0098] 1 H NMR (400MHz, CDCl3) δ = 7.89 (d, J = 9.4, 1H), 7.85 (s, 1H), 7.11 (d, J = 9.4, 1H).

[0099] Step B: 6-chloro-3-((trimethylsilyl)ethynyl)imidazol[1,2-b]pyridazine (3)

[0100]

[0101] 6-Chloro-3-iodoimidazole[1,2-b]pyridazine (compound 2, 50 g, 0.18 mol) was placed in tetrahydrofuran (750 mL), and ethynyltrimethylsilane (21.09 g, 0.21 mol), PdCl2(PPh3)2 (12.56 g, 0.02 mol), cuprous iodide (3.41 g, 0.02 mol), and triethylamine (90.51 g, 0.89 mol) were added sequentially. The mixture was stirred at 25 °C for 12 hours, then extracted with water (1.5 L), and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography yielded a gray solid compound 3 (25 g, yield: 56%).

[0102] LCMS(m / z): 250 [M+H] + .

[0103] Step C: N-(1-(2,5-difluorophenyl)ethyl)-3-ethynylimidazolium[1,2-b]pyridazine-6-methylamine (5)

[0104]

[0105] 6-Chloro-3-[2-(trimethylsilyl)ethynyl]imidazol[1,2-b]pyridazine (compound 3, 265 mg, 1.06 mmol) was placed in DMSO (6 mL), and 1-(2,5-difluorophenyl)ethylamine (compound 4, 200 mg, 1.27 mmol) and potassium fluoride (123.29 mg, 2.12 mmol) were added sequentially. The mixture was stirred at 100 °C for 16 hours, then extracted with water (100 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compound 5 (60 mg, yield: 19%) as a white solid.

[0106] LCMS(m / z): 299[M+H] + .

[0107] Step D: 2-(4-(6-((1-(2,5-difluorophenyl)ethyl)amino)imidazol[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-1)

[0108]

[0109] N-[1-(2,5-difluorophenyl)ethyl]-3-ethynylimidazol[1,2-b]pyridazine-6-methylamine (compound 5, 50 mg, 0.17 mmol) was placed in tetrahydrofuran (1 mL) and water (1 mL), and 3-azido-1-propanol (compound 6, 14.59 mg, 0.17 mmol), copper sulfate (20.95 mg, 0.08 mmol), and sodium isoascorbate (66.41 mg, 0.33 mmol) were added sequentially. The mixture was stirred at 15 °C for 16 hours, and then the mixture was directly prepared by liquid chromatography to obtain a white solid compound I-1 (8.1 mg, yield: 15%).

[0110] LCMS(m / z): 386 [M+H] + .

[0111] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.82-7.78(m,2H),7.40-7.25(m,2H),7.20-7.11(m,1H),6.81(d,J=12. 0Hz,1H).5.27-5.24(m,1H),5.22-4.20(m,1H),4.53-4.44(m,2H),3.87-3.79(m,2H),1.51(d,J=7.2Hz,1H).

[0112] Example 2: 2-(4-(6-((1-(2-chloro-5-fluorophenyl)ethyl)amino)imidazol[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethane-1-ol (I-2)

[0113] Step A: 6-chloro-3-((trimethylsilyl)ethynyl)imidazol[1,2-b]pyridazine (7)

[0114]

[0115] 6-Chloro-3-iodoimidazole[1,2-b]pyridazine (compound 2, 20 g, 0.07 mol) was placed in tetrahydrofuran (400 mL), and ethynyltrimethylsilane (8.44 g, 0.08 mol), Pd(PPh3)2Cl2 (5.03 g, 0.007 mol), cuprous iodide (1.36 g, 0.07 mol), and triethylamine (36.23 g, 0.36 mol) were added sequentially. The mixture was stirred at 25 °C for 12 hours, then extracted with water (1 L), and extracted three times with ethyl acetate (300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid compound 7 (8.5 g, yield: 47%).

[0116] LCMS(m / z): 250 [M+H] + .

[0117] Step B: 6-Chloro-3-((trimethylsilyl)ethynyl)imidazol[1,2-b]pyridazine (8)

[0118]

[0119] 6-Chloro-3-[2-(trimethylsilyl)ethynyl]imidazol[1,2-b]pyridazine (compound 7, 8 g, 0.03 mol) was placed in a 1:1 mixture of tetrahydrofuran and methanol (80 mL), and potassium carbonate (8.85 g, 0.06 mol) was added in portions. The mixture was stirred at 15 °C for 1 hour under nitrogen protection, then extracted with water (40 mL) and extracted three times with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid compound 8 (6 g, yield: 85%).

[0120] LCMS(m / z): 178 [M+H] + .

[0121] 1H NMR (400MHz, CDCl3) δ = 8.37 (s, 1H), 7.55 (d, J = 7.5, 1.5Hz, 1H), 7.42 (dd, 7.2, 1.2Hz, 1H), 3.85 (s, 1H).

[0122] Step C: 2-(4-(6-chloroimidazole[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (9)

[0123]

[0124] 6-Chloro-3-ethynylimidazole[1,2-b]pyridazine (compound 8, 4 g, 0.02 mol) was placed in tetrahydrofuran (20 mL) and water (20 mL), and 2-azidoethanol (1.96 g, 0.02 mol), copper sulfate (2.81 g, 0.01 mol), and sodium isoascorbate (8.91 g, 0.05 mol) were added sequentially. The mixture was stirred at 15 °C for 16 hours. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), diluted with methyl tert-butyl ether (30 mL), and filtered to obtain a precipitated copper salt solid. This solid was dissolved in water, and the pH was adjusted to 4 with dilute hydrochloric acid, then adjusted to 8 with ammonia. The precipitate was filtered to obtain a white solid compound 9 (1 g, yield: 16%).

[0125] LCMS(m / z): 265[M+H] + .

[0126] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.35(d,J=9.6Hz,2H),7.46(d,J=9.6Hz,1H),5.12-5.10(m,1H),4.60-4.57(m,2H),3.86-3.83(m,2H).

[0127] Step D: 2-(4-(6-((1-(2-chloro-5-fluorophenyl)ethyl)amino)imidazolium[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-2)

[0128]

[0129] 2-(4-{6-chloroimidazole[1,2-b]pyridazin-3-yl}-1,2,3-triazol-1-yl)ethanol (compound 9, 60 mg, 0.23 mmol)) was placed in 1,4-dioxane (5 mL), followed by the addition of 1-(2-chloro-5-fluorophenyl)ethylamine (compound 10, 39.36 mg, 0.23 mmol), cesium carbonate (221.59 mg, 0.68 mmol), Pd2(dba)3 (20.76 mg, 0.02 mmol), and BINAP (12.4 mg, 0.02 mmol). The mixture was stirred at 100 °C for 12 hours under nitrogen protection, and then directly separated by liquid chromatography to obtain a white solid I-2 (4.5 mg, yield: 5%).

[0130] LCMS(m / z): 402[M+H] + .

[0131] 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.00-7.87(m,3H),7.60-7.57(m,1H),7.25-7.20(m,1H),7.20-7.15(m,1H),7 .86(d,J=8.0Hz,1H),5.25-5.21(m,1H),5.06(s,1H),4.55-4.47(m,1H),3.82-3.79(m,2H),1.51(d,J=5.6Hz,1H).

[0132] Example 3: 2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazol[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-3)

[0133] Step A: 1-(5-fluoro-2-methoxyphenyl)ethyl-1-methylamine (12)

[0134]

[0135] 1-(5-fluoro-2-methoxyphenyl)ethyl ketone (compound 11, 6 g, 0.04 mol) and ammonia (40 g, 0.29 mol) were placed in methanol (20 mL), sodium borohydride (5.4 g, 0.15 mol) was added, and the mixture was stirred at 15 °C for 12 hours. The mixture was then extracted with ammonium chloride aqueous solution (30 mL) and extracted 6 times with dichloromethane (20 mL). The organic phases were combined and dried with anhydrous sodium sulfate. The crude product was concentrated and slurried with methyl tert-butyl ether to give a yellow solid compound 12 (5.3 g, yield: 80%).

[0136] LCMS(m / z): 170 [M+H]+ .

[0137] Step B: 3-ethynyl-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)imidazolium[1,2-b]pyridazine-6-methylamine (13)

[0138]

[0139] 6-Chloro-3-[2-(trimethylsilyl)ethynyl]imidazol[1,2-b]pyridazine (compound 7, 1 g, 4.00 mmol) was placed in DMSO (10 mL), and 1-(5-fluoro-2-methoxyphenyl)ethylamine (compound 12, 1 g, 5.9 mmol) and cesium carbonate (3.91 g, 12 mmol) were added sequentially. The mixture was stirred at 100 °C for 16 hours, then diluted with water (10 mL), and extracted three times with dichloromethane (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give a white solid compound 13 (100 mg, yield: 9%).

[0140] LCMS(m / z): 311[M+H] + .

[0141] Step C: 2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazol[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-3)

[0142]

[0143] Compound I-3 was synthesized using compound 13 instead of compound 5 as the starting material, following the method for compound I-1 in Example 1.

[0144] LCMS(m / z): 398[M+H] + .

[0145] 1 H NMR(400MHz,DMSO-d6)δ8.30-8.25(m,1H),8.20-8.15(m,1H),8.14(s,1H),7.34(s,1H),7.20-7.00( m,2H),7.00-6.90(m,1H),5.33(s,1H),4.55-4.50(m,1H),4.00-3.95(m,5H),1.57(d,J=3.6Hz,1H).

[0146] Example 4: 4-Fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazol[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-4)

[0147] Step A: 2-(1-Aminoethyl)-4-fluorophenol (14)

[0148]

[0149] Compound 14 was synthesized using compound 1-(5-fluoro-2-hydroxyphenyl) ethyl ketone instead of compound 11 as the starting material, following the same method as compound 12.

[0150] LCMS(m / z): 156 [M+H] + .

[0151] 1 HNMR(DMSO-d6,400MHz)δ10.24(s,1H),8.48(br.s.,3H),7.31(dd,J=2.9,9.7Hz,1 H),7.05-6.99(m,1H),6.98-6.93(m,1H),4.59-4.45(m,1H),1.46(d,J=6.8Hz,3H).

[0152] Step B: 2-(1-((3-ethynylimidazol[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (15)

[0153]

[0154] Compound 15 was synthesized by using compound 14 instead of compound 12 as a raw material, following the same method as compound 13.

[0155] LCMS(m / z): 297[M+H] + .

[0156] Step C: Preparation of 4-fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazolium[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-4)

[0157]

[0158] Compound I-4 was synthesized by using compound 15 instead of compound 13 as the starting material, following the method for compound I-3.

[0159] LCMS(m / z): 384 [M+H] + .

[0160] 1 H NMR(400MHz, DMSO_d6)δ9.73(s,1H),8.19(s,1H),7.82-7.63(m,3H),6.87(d,J=4.8Hz,1H)6.83-6.81( m,2H),5.24(t,J=6.8Hz,1H),5.04(s,1H),4.49-4.48(m,2H),3.82-3.80(m,2H),1.38(d,J=6.8Hz,1H).

[0161] Example 5: 2-(4-(6-((1-(3,5-difluoro-2-methoxyphenyl)ethyl)amino)imidazo(1,2-b)pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-5)

[0162] Step A: 1-(3,5-difluoro-2-methoxyphenyl)ethyl-1-amine (16)

[0163]

[0164] The synthesis of compound 16 is based on the method described in reference WO2019063748.

[0165] LCMS(m / z): 188[M+H] + .

[0166] 1 H NMR(400MHz, DMSO_d6)δ8.32(s,1H),7.85(s,1H),7.81(d,J=9.6Hz,1H),7.70(d,J=7.2Hz,1H),7.20-7.14(m,1H),7.07-7.04(m,1H),6.80(d ,J=9.6Hz,1H),5.39-5.32(m,1H),5.08(t,J=5.6Hz,1H),4.56-4.42(m,2H),3.98(d,J=1.6Hz,2H),3.94-3.81(m,2H),1.51(d,J=6.8Hz,3H).

[0167] Step B: 2-(4-(6-((1-(3,5-difluoro-2-methoxyphenyl)ethyl)amino)imidazo(1,2-b)pyrazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-5)

[0168]

[0169] Compound I-5 was synthesized by using compound 16 instead of compound 10 as the starting material, following the same method as compound I-2.

[0170] LC-MS (m / z): 416 (M+H) +

[0171] 1 H NMR(400MHz, DMSO_d6)δ8.32(s,1H),7.85(s,1H),7.81(d,J=9.6Hz,1H),7.70(d,J=7.2Hz,1H),7.20-7.14(m,1H),7.07-7.04(m,1H),6.80(d ,J=9.6Hz,1H),5.39-5.32(m,1H),5.08(t,J=5.6Hz,1H),4.56-4.42(m,2H),3.98(d,J=1.6Hz,2H),3.94-3.81(m,2H),1.51(d,J=6.8Hz,3H).

[0172] Example 6: 2,4-Difluoro-6-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo(1,2-b)pyrazin-6-yl)amino)ethyl)phenol (I-6)

[0173]

[0174] At room temperature, a solution of boron tribromide (217.13 mg, 0.87 mmol) in dichloromethane (6 mL) was added dropwise to a solution of compound I-5 (120 mg, 0.29 mmol) in dichloromethane (2 mL). After the addition was complete, the reaction mixture was stirred at room temperature for about 16 hours. After the reaction was complete, an aqueous solution of saturated sodium bicarbonate was added to the reaction mixture, and the mixture was filtered. The filtrate was purified by preparative chromatography to give a white solid compound I-6 (11 mg, yield: 21.93%).

[0175] LCMS(m / z): 402(M+H) + .

[0176] 1 H NMR(400MHz,DMSO_d6)δ8.31(s,1H),7.80(s,1H),7.68(d,J=9.6Hz,1H),6.89-6.84(m,1H),6.8 1-6.76(m,1H),5.44-5.39(m,1H),4.59-4.56(m,2H),4.06-3.98(m,2H),1.53(d,J=6.8Hz,3H).

[0177] Example 7: 2-[4-[6-[[1-(5-fluoro-2-methoxyphenyl)cyclopropane]amino]imidazo[1,2-b]piperazin-3-yl]triazol-1-yl]ethanol (I-7)

[0178] Step A: 1-(5-fluoro-2-methoxy-phenyl)cyclopropylamine (17)

[0179]

[0180] Compound 17 was prepared according to the method described in reference CN112110938.

[0181] LCMS(m / z): 182 [M+H] + .

[0182] 1 H NMR: (400MHz, DMSO-d6) δ = 6.86-6.95 (m, 2H), 6.76-6.81 (m, 1H), 3.89 (s, 3H), 0.93-1.00 (m, 2H), 0.78-0.84 (m, 2H).

[0183] Step B: 2-[4-[6-[[1-(5-fluoro-2-methoxy-phenyl)cyclopropyl]amino]imidazo[1,2-b]piperazin-3-yl]triazol-1-yl]ethanol (I-7)

[0184]

[0185] Compound I-7 was synthesized by using compound 17 instead of compound 10 as the starting material, following the method for compound I-2.

[0186] LCMS(m / z): 410[M+H] + .

[0187] 1 H NMR: (400MHz, MeOD-d4)δ=8.79(s,1H),7.91(s,1H),7.62-7.64(m,1H),7.36-7.39(m,1H), 6.89(m,1H),6.87(m,1H),4.69(m,2H),4.06(m,2H),3.90(s,3H),1.37(m,2H),1.25(m,2H).

[0188] Example 8: 4-Fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclopropyl)phenol (I-8)

[0189]

[0190] Compound I-8 was synthesized by using compound I-7 instead of compound I-5 as a raw material, following the method used for compound I-6.

[0191] LCMS(m / z): 396 [M+H] + .

[0192] Example 9: 2-(4-(6-((5-fluoro-2-methoxybenzyl)amino)imidazo[1,2-b]piperazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-9)

[0193] Step A: (5-Fluoro-2-methoxyphenyl)methaneamine (18)

[0194]

[0195] Compound 18 was prepared according to the method described in US2018127356.

[0196] LCMS(m / z): 156 [M+H] + .

[0197] 1 H NMR (400MHz, MeOD-d4)δ=7.15-7.11(2H,m),7.06-7.03(1H,m),4.06(2H,s),3.88(3H,s)

[0198] Step B: 2-(4-(6-((5-fluoro-2-methoxybenzyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-9)

[0199]

[0200] Compound I-9 was synthesized by using compound 18 instead of compound 10 as a starting material, following the method for compound I-2.

[0201] LCMS(m / z): 384 [M+H] + .

[0202] Example 10: 4-Fluoro-2-(((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazol[1,2-b]pyridazine-6-yl)amino)methyl)phenol (I-10)

[0203] Step A: Preparation of 2-(aminomethyl)-4-fluorophenol (20)

[0204]

[0205] 5-Fluoro-2-hydroxyphenethyl (compound 19, 2 g, 14.59 mmol) was placed in tetrahydrofuran (25 mL), and lithium aluminum hydride (1.11 g, 29.17 mmol) was added at 0 °C under nitrogen protection. The mixture was then stirred at 0 °C for 0.5 hours. After extraction, the mixture was diluted with methanol (20 mL) and filtered. The filtrate was concentrated and separated by reversed-phase liquid chromatography to obtain a yellow solid compound 20 (2.5 g, yield: 91.57%).

[0206] LCMS(m / z): 142 [M+H] + .

[0207] 1 H NMR: (400MHz, D2O) δ = 8.54-8.31 (m, 1H), 6.89 (d, J = 9.6Hz, 1H), 6.82 (dt, J = 2.9, 8.8Hz, 1H), 6.55 (dd, J = 5.3, 8.4Hz, 1H), 3.76 (s, 2H).

[0208] Step B: 4-Fluoro-2-(((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazol[1,2-b]pyridazine-6-yl)amino)methyl)phenol (I-10)

[0209]

[0210] Compound I-10 was synthesized by using compound 20 instead of compound 10 as a raw material, following the same method as compound I-2.

[0211] LCMS(m / z): 370 [M+H] + .

[0212] Example 11: 2-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-11)

[0213] Step A: 1-(5-fluoro-2-methoxypyridin-3-yl)ethyl-1-amine (21)

[0214]

[0215] Using the raw material, compound 21 was synthesized according to the method in reference WO2017004342.

[0216] LCMS(m / z): 171 [M+H] + .

[0217] Step B: 2-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-11)

[0218]

[0219] Compound I-11 was synthesized by using compound 21 instead of compound 10 as the starting material, following the method for compound I-2.

[0220] LCMS(m / z): 399[M+H] + .

[0221] Example 12: 5-Fluoro-3-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2-one (I-12)

[0222]

[0223] Compound I-12 was synthesized by using compound I-11 instead of compound I-5 as a raw material, following the method used for compound I-6.

[0224] LCMS(m / z): 385 [M+H] + .

[0225] Example 13: 2-(4-(6-((2-(5-fluoro-2-methoxyphenyl)propane-2-yl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-13)

[0226] Step A: 2-(5-fluoro-2-methoxyphenyl)propyl-2-amine (22)

[0227]

[0228] The synthesis of compound 22 is based on the method described in US2016221948.

[0229] LCMS(m / z): 184 [M+H] + .

[0230] 1 H NMR (400MHz, CDCl3) δ1.55(s,6H),6.99-7.12(m,2H),7.18-7.27(m,1H),7.41-7.46(m,1H)

[0231] Step B: 2-(4-(6-((2-(5-fluoro-2-methoxyphenyl)propane-2-yl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-13)

[0232]

[0233] Compound I-13 was synthesized by using compound 22 instead of compound 10 as a starting material, following the same method as compound I-2.

[0234] LCMS(m / z): 412[M+H] + .

[0235] Example 14: 4-Fluoro-2-(2-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)propane-2-yl)phenol (I-14)

[0236]

[0237] Compound I-14 was synthesized by using compound I-13 instead of compound I-5 as a raw material, following the method used for compound I-6.

[0238] LCMS(m / z): 398[M+H] + .

[0239] Example 15: 2-(4-(5-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-15)

[0240] Step A: 5-Chloro-3-((triethylsilyl)ethynyl)pyrazole[1,5-a]pyrimidine (24)

[0241]

[0242] Compound 24 was synthesized by using compound 23 instead of compound 2 as a raw material, following the same method as compound 3.

[0243] LCMS(m / z): 250 [M+H] + .

[0244] Step B: 3-ethynyl-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)pyrazole[1,5-a]pyrimidine-5-amine (25)

[0245]

[0246] Compound 25 was synthesized from compounds 12 and 24 (instead of compound 7) using the same method as compound 13.

[0247] LCMS(m / z): 311[M+H] + .

[0248] Step C: 2-(4-(5-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)pyrazol[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-15)

[0249]

[0250] Compound I-15 was synthesized using compound 25 instead of compound 5 as the starting material, following the method for compound I-1 in Example 1.

[0251] LCMS(m / z): 398[M+H] + .

[0252] Example 16: 4-Fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)pyrazol[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol (I-16)

[0253] Step A: 2-(1-((3-ethynylpyrazol[1,5-a]pyrimidin-5-yl)amino)ethyl)-4-fluorophenol (26)

[0254]

[0255] Compound 26 was synthesized using compounds 14 and 24 as raw materials, following the method used for compound 15.

[0256] LCMS(m / z): 297[M+H] + .

[0257] Step B: 4-Fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)pyrazol[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol (I-16)

[0258]

[0259] Compound I-16 was synthesized by using compound 26 instead of compound 15 as the starting material, following the method for compound I-4.

[0260] LCMS(m / z): 384 [M+H] + .

[0261] Example 17: (R)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-17)

[0262] Step A: (R)-1-(5-fluoro-2-methoxyphenyl)ethane-1-amine (27)

[0263]

[0264] Compound 27 was synthesized according to the method described in the Journal of Medicinal Chemistry (1974), 17(7), 708-15.

[0265] LCMS(m / z): 170 [M+H] + .

[0266] Step B: (R)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-17)

[0267]

[0268] Compound I-17 was synthesized by replacing compound 12 with compound 27, following the same method as compound I-3.

[0269] LCMS(m / z): 398[M+H] + .

[0270] Example 18: (S)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-18)

[0271] Step A: (S)-1-(5-fluoro-2-methoxyphenyl)ethane-1-amino (28)

[0272]

[0273] Compound 28 was synthesized according to the method described in the Journal of Medicinal Chemistry (1974), 17(7), 708-15.

[0274] LCMS(m / z): 170 [M+H] + .

[0275] Step B: (S)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-18)

[0276]

[0277] Compound I-18 was synthesized by replacing compound 12 with compound 28, following the same method as compound I-3.

[0278] LCMS(m / z): 398[M+H] + .

[0279] Example 19: (R)-4-fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-19)

[0280] Step A: (R)-2-(1-aminoethyl)-4-fluorophenol (29)

[0281]

[0282] Compound 29 was synthesized using the same method as compound 27.

[0283] LCMS(m / z): 156 [M+H] +

[0284] 1 H NMR(400MHz,DMSO-d6)δ10.24(s,IH),8.48(br.s.,3H),7.31(dd,7=2.9,9.7Hz,IH ),7.05-6.99(m,IH),6.98-6.93(m,IH),4.59-4.45(m,IH),1.46(d,7=6.8Hz,3H).

[0285] Step B: (R)-4-fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-19)

[0286]

[0287] Compound I-19 was synthesized by using compound 29 instead of compound 14 as the starting material, following the method for compound I-4.

[0288] LCMS(m / z): 384 [M+H] + .

[0289] Example 20: (S)-4-fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-20)

[0290] Step A: (S)-2-(1-aminoethyl)-4-fluorophenol (30)

[0291]

[0292] Compound 30 was synthesized using the same method as compound 28.

[0293] LCMS(m / z): 156 [M+H] + .

[0294] Step B: (S)-4-fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-20)

[0295]

[0296] Compound I-20 was synthesized by using compound 30 instead of compound 14 as a starting material, following the method for compound I-4.

[0297] LCMS(m / z): 384 [M+H] + .

[0298] Example 21: (R)-2-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-21)

[0299] Step A: (R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl-1-amine (31)

[0300]

[0301] Compound 31 was synthesized using the same method as compound 27.

[0302] LCMS(m / z): 171 [M+H] + .

[0303] Step B: (R)-2-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-21)

[0304]

[0305] Compound I-21 was synthesized by replacing compound 21 with compound 31, following the same method as compound I-11.

[0306] LCMS(m / z): 399[M+H] + .

[0307] Example 22: (S)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-22)

[0308] Step A: (S)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl-1-amine (32)

[0309]

[0310] Compound 32 was synthesized using the same method as compound 28.

[0311] LCMS(m / z): 171 [M+H] + .

[0312] Step B: (S)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl-1-ol (I-22)

[0313]

[0314] Compound I-22 was synthesized by using compound 32 instead of compound 21 as a raw material, following the method for compound I-11.

[0315] LCMS(m / z): 399[M+H] + .

[0316] Example 23: (R)-5-fluoro-3-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2-one (I-23)

[0317]

[0318] Compound I-23 was synthesized by using compound I-21 instead of compound I-5 as a raw material, following the method used for compound I-6.

[0319] LCMS(m / z): 385 [M+H] + .

[0320] Example 24: (S)-5-fluoro-3-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2-one (I-24)

[0321]

[0322] Compound I-24 was synthesized by using compound I-22 instead of compound I-5 as a raw material, following the same method as compound I-6.

[0323] LCMS(m / z): 385 [M+H] + .

[0324] Example 25: (R)-1-(4-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-25)

[0325] Step A: (R)-1-azidopropane-2-ol (33)

[0326]

[0327] Compound 33 was synthesized according to the method described in RSC Advances; vol. 6; nb. 91; (2016); p. 88859–88867.

[0328] Step B: (R)-1-(4-(6-(((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-25)

[0329]

[0330] Compound I-25 was synthesized by using compound 33 instead of compound 6 as a starting material, following the method for compound I-17.

[0331] LCMS(m / z): 412[M+H] + .

[0332] Example 26: 4-Fluoro-2-((R)-1-((3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-26)

[0333]

[0334] Compound I-26 was synthesized by using compound 33 instead of compound 6 as a starting material, following the method for compound I-19.

[0335] LCMS(m / z): 398[M+H] + .

[0336] Example 27: (R)-1-(4-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-27)

[0337]

[0338] Compound I-27 was synthesized by using compound 33 instead of compound 6 as a starting material, following the method for compound I-21.

[0339] LCMS(m / z): 413[M+H] + .

[0340] Example 28: 5-Fluoro-3-((R)-1-((3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyridin-2-one (I-28)

[0341]

[0342] Compound I-28 was synthesized by using compound 33 instead of compound 6 as a starting material, following the method for compound I-23.

[0343] LCMS(m / z): 399[M+H] + .

[0344] Example 29: 2-(4-(5-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethane-1-ol (I-29)

[0345] Step A: 5-Bromo-3-iodopyrazolo[1,5-a]pyridine (34)

[0346]

[0347] Compound 34 was synthesized from compound 5-bromopyrazolo[1,5-a]pyridine, following the method described in Journal of Medicinal Chemistry; vol.61; nb.10; (2018); p.4386–4396.

[0348] LCMS(m / z): 279 [M+H] + .

[0349] Step B: 2-(4-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethane-1-ol (35)

[0350]

[0351] Compound 35 was synthesized by replacing compound 2 with compound 34, following the same method as compound 9.

[0352] LCMS(m / z): 308[M+H] + .

[0353] Step C: 2-(4-(5-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethane-1-ol (I-29)

[0354]

[0355] Compound I-29 was synthesized by using compound 35 instead of compound 9 as a starting material and compound 12 instead of compound 10 as a starting material, following the same method as compound I-2.

[0356] LCMS(m / z): 397 [M+H] + .

[0357] 1H NMR(400MHz,DMSO_d6)δ9.69(s,1H),8.21(s,1H),8.32(d,J=7.2Hz,1H),8 .03(d,J=8.0Hz,2H),7.01-6.89(m,1H),6.85-6.70(m,3H),6.62(d,J=2.0H z,1H),6.46(dd,J=7.6Hz,2.4Hz,1H),5.07-5.05(m,1H),4.88-4.84(m,1H) ,4.46-4.40(m,2H),4.25(s,3H),3.82-3.79(m,2H),1.43(d,J=6.8Hz,1H).

[0358] Example 30: 4-Fluoro-2-(1-((3-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-5-yl)amino)ethyl)phenol (I-30)

[0359]

[0360] Compound I-30 was synthesized by using compound 35 instead of compound 9 as a starting material and compound 14 instead of compound 10 as a starting material, following the same method as compound I-2.

[0361] LCMS(m / z): 383[M+H] + .

[0362] 1 H NMR(400MHz, DMSO_d6)δ9.69(s,1H),8.21(s,1H),8.32(d,J=7.2Hz,1H),8.03(d,J=8.0Hz,2H),7.01-6.89(m,1H),6.85-6.70(m,3H),6.62(d,J =2.0Hz,1H),6.46(dd,J=7.6Hz,2.4Hz,1H),5.07-5.05(m,1H),4.88-4.84(m,1H),4.46-4.40(m,2H),3.82-3.79(m,2H),1.43(d,J=6.8Hz,1H).

[0363] Example 31: (R)-1-(4-(6-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-31)

[0364]

[0365] Compound I-31 was synthesized by replacing compound 27 with compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine, following the same method as compound I-25.

[0366] LCMS(m / z): 438[M+H] + .

[0367] Example 32: 4-Fluoro-2-((R)-1-(3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-32)

[0368]

[0369] Compound I-32 was synthesized by using compound I-31 instead of compound I-5 as a raw material, following the same method as compound I-6.

[0370] LCMS(m / z): 424[M+H] +

[0371] Example 33: (3S,5R)-5-(5-fluoro-2-methoxyphenyl)-1-(3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-ol (I-33)

[0372]

[0373] Compound I-33 was synthesized by replacing compound 27 with compound (3S,5S)-5-(5-fluoro-2-methoxyphenyl)pyrrolidine-3-ol, following the same method as compound I-25.

[0374] LCMS(m / z): 454 [M+H] + .

[0375] Example 34: (R)-1-(4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-34)

[0376]

[0377] Compound I-34 was synthesized by replacing compound 27 with compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine, following the same method as compound I-25.

[0378] LCMS(m / z): 456 [M+H] + .

[0379] Example 35: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-35)

[0380]

[0381] Compound I-35 was synthesized by using compound I-34 instead of compound I-5 as a raw material, following the method used for compound I-6.

[0382] LCMS(m / z): 442[M+H] + .

[0383] Example 36: (R)-1-(4-(6-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-36)

[0384]

[0385] Compound I-36 was synthesized by replacing compound 27 with compound (R)-5-fluoro-2-methoxy-3-(pyrrolidine-2-yl)pyridine, following the same method as compound I-25.

[0386] LCMS(m / z): 439[M+H] + .

[0387] Example 37: 5-Fluoro-3-((R)-1-(3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)pyridin-2(1H)-one (I-37)

[0388]

[0389] Compound I-37 was synthesized by using compound I-36 instead of compound I-5 as a raw material, following the same method as compound I-6.

[0390] LCMS(m / z): 425 [M+H] + .

[0391] Example 38: (R)-1-(4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)propane-2-ol (I-38)

[0392]

[0393] Compound I-38 was synthesized by replacing compound 27 with compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidine-2-yl)-2-methoxypyridine, following the same method as compound I-25.

[0394] LCMS(m / z): 457[M+H] + .

[0395] Example 39: 5-Fluoro-3-((2R,4S)-4-Fluoro-1-(3-(1-((R)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)pyridin-2(1H)-one (I-39)

[0396]

[0397] Compound I-39 was synthesized by using compound I-38 instead of compound I-5 as a raw material, following the method used for compound I-6.

[0398] LCMS(m / z): 443[M+H] + .

[0399] Example 40: (R)-4-fluoro-2-(1-((3-(1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-40)

[0400] Step A: 1-Azide-2-fluoroethane (36)

[0401]

[0402] A solution of pyridine (8 mL) in 1.0 g (15.6 mmol) of 2-fluoroethanol was cooled to 0 °C, and a solution of pyridine (10 mL) in 5.95 g (31.2 mmol) of p-toluenesulfonyl chloride was added dropwise. The reaction mixture was stirred at 0 °C for approximately 3 hours. After the reaction was complete, the reaction mixture was poured into an ice-water mixture, and a precipitate formed. The precipitate was filtered, washed with an aqueous solution of saturated sodium carbonate, and dried to obtain 2-fluoroethyl-4-methylbenzenesulfonic acid. 2-fluoroethyl-4-methylbenzenesulfonic acid was dissolved in 15 mL of dry DMF. Sodium azide (1.1 g, 16.9 mmol) was added to the solution in portions. The mixture was stirred at room temperature for 48 hours. The resulting solid was filtered to give 1-azido-2-fluoroethane (579 mg).

[0403] 1 H NMR: (400MHz, CDCl3) δ = 3,51 (dt, J = 4.6Hz, 2H), 4.60 (dm, J = 4.6Hz, 2H).

[0404] Step B: (R)-4-fluoro-2-(1-((3-(1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-40)

[0405]

[0406] Compound I-40 was synthesized by replacing compound 6 with compound 36, following the same method as compound I-19.

[0407] LCMS(m / z): 386 [M+H] + .

[0408] Example 41: 4-Fluoro-2-((R)-1-(3-(1-((R)-2-fluoropropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-41)

[0409] Step A: (R)-1-azido-2-fluoropropane (37)

[0410]

[0411] Compound 37 was synthesized using compound (R)-2-fluoropropane-1-ol instead of 2-fluoroethanol, following the same method as compound 36.

[0412] Step B: 4-Fluoro-2-((R)-1-(3-(1-((R)-2-fluoropropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-41)

[0413]

[0414] Compound I-40 was synthesized by using compound 37 instead of compound 33 as the starting material, following the method for compound I-32.

[0415] LCMS(m / z): 426 [M+H] + .

[0416] Example 42: (R)-2-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)acetic acid (I-42)

[0417]

[0418] Compound I-42 was synthesized by replacing the starting material at position 6 of compound I-42 with commercially available azidoacetic acid, following the method used for compound I-27.

[0419] LCMS(m / z): 413[M+H] + .

[0420] Example 43: (R)-3-(1-(2-aminoethyl)-1H-1,2,3-triazol-4-yl)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)imidazo[1,2-b]pyridazine-6-amine (I-43)

[0421] Step A: (R)-(2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)tert-butyl formate

[0422]

[0423] Compound 38 was synthesized by replacing the starting material at position 6 of the compound with commercially available N-Boc-2-azidoethylamine, following the method used for compound I-17.

[0424] LCMS(m / z): 497[M+H] + .

[0425] Step B: (R)-3-(1-(2-aminoethyl)-1H-1,2,3-triazol-4-yl)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)imidazo[1,2-b]pyridazine-6-amine (I-43)

[0426]

[0427] Compound 38 (20 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for about 1 hour. After the reaction was completed, saturated sodium carbonate aqueous solution was added to the reaction system to adjust the pH to about 8-9. The mixture was extracted three times with 5 mL of dichloromethane, and the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain compound I-43.

[0428] LCMS(m / z): 397 [M+H] + .

[0429] Example 44: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(2-(methylamino)ethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-44)

[0430] Step A: 2-Azide-N-methylethane-1-amine (39)

[0431]

[0432] N-methylamino-1-ethylbromobromobromide (2.5 g, 12.5 mmol) and sodium azide (1.5 g, 23 mmol) were dissolved in water (25 mL). The mixture was heated at 75 °C for 15 hours. The reaction mixture was cooled in an ice bath, and sodium hydroxide (4 g) was added. The aqueous phase was separated, and the organic phase was removed. The aqueous phase was extracted twice with diethyl ether, and the organic layers were bound together. The product was dried over magnesium sulfate and concentrated to give 1.3 g.

[0433] 1 H NMR: (400MHz, CDCl3) δ = 7.26 (s, 2H), 3.41 (m, 2H), 2.74 (tt, J = 5.7Hz, 2H), 2.43 (s, 3H).

[0434] LCMS(m / z): 101[M+H] + .

[0435] Step B: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(2-(methylamino)ethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-44)

[0436]

[0437] Compound I-44 was synthesized by using compound 39 instead of compound 33 as the starting material, following the method for compound I-35.

[0438] LCMS(m / z): 441[M+H] + .

[0439] Example 45: (R)-2-(1-((3-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-45)

[0440] Step A: 2-Azide-N,N-dimethylethane-1-amine (40)

[0441]

[0442] 2-Chloro-N,N-dimethylethylamine hydrochloride (720 mg, 5.0 mmol) was dissolved in deionized water (20 mL). Sodium azide (975 mg, 15.0 mmol) was added to the mixture. The mixture was stirred at 80 °C for 24 hours. The mixture was cooled. 1 M sodium hydroxide solution was added to adjust the pH of the mixture to 10. The mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound 40.

[0443] 1 H NMR: (400MHz, CDCl3) δ = 3.41 (t, J = 6.2Hz, 2H), 2.56 (t, J = 6.2Hz, 2H), 2.32 (s, 6H).

[0444] LCMS(m / z): 115 [M+H] + .

[0445] Step B: (R)-2-(1-((3-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-45)

[0446]

[0447] Compound I-45 was synthesized by using compound 40 instead of compound 6 as a starting material, following the method for compound I-19.

[0448] LCMS(m / z): 411[M+H] + .

[0449] Example 46: (R)-2-(4-(6-((1-(5-fluoro-2-methoxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)acetamide (I-46)

[0450] Step A: 2-Azideacetamide (41)

[0451]

[0452] A mixed solution of 2-chloroacetamide (1 g), sodium iodide (1.65 g; 11 mmol), and sodium azide (1.65 g; 2.2 mmol) in water (100 mL) was heated to 80 °C overnight. After the reaction was complete, the mixture was cooled to room temperature and the product was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with a small amount of saturated sodium solution. The organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the product.

[0453] 1 H NMR: (400MHz, DMSO-d6) δ = 3.69 (s, 2H), 7.13 (s, 1H), 7.39 (s, 1H).

[0454] LCMS(m / z): 101[M+H] + .

[0455]

[0456] Compound I-46 was synthesized by using compound 41 instead of compound 6 as a starting material, following the method for compound I-17.

[0457] LCMS(m / z): 411[M+H] + .

[0458] Example 47: (R)-N-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-3-(1-(2-(methanesulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-amine (I-47)

[0459]

[0460] Compound I-47 was synthesized by replacing compound 6 with commercially available 1-azido-2-methanesulfonylethane, following the same method as compound I-21.

[0461] LCMS(m / z): 461[M+H] + .

[0462] Example 48: (R)-2-(1-((3-(1-(2-(1H-imidazo[1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-48)

[0463] Step A: 5-(2-azidoethyl)-1H-imidazolium (42)

[0464]

[0465] Compound 42 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0466] LCMS(m / z): 138 [M+H] + .

[0467] Step B: (R)-2-(1-((3-(1-(2-(1H-imidazo[1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-48)

[0468]

[0469] LCMS(m / z): 434[M+H] + .

[0470] Example 49: (R)-2-(1-((3-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-49)

[0471] Step A: Azide cyclopropane (43)

[0472]

[0473] Compound 43 was synthesized according to the method described in Chemical Biology and Drug Design (2016); pp. 398-403.

[0474] LCMS(m / z): 84[M+H]+ .

[0475] Step B: (R)-2-(1-((3-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-49)

[0476]

[0477] Compound I-49 was synthesized by using compound 43 instead of compound 6 as a starting material, following the method for compound I-19.

[0478] LCMS(m / z): 380 [M+H] + .

[0479] Example 50: (R)-1-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)cyclopropane-1-ol (I-50)

[0480] Step A: 1-Azidecyclopropane-1-ol (44)

[0481]

[0482] Compound 44 was synthesized according to the method described in Recueil des Travaux Chimiques des Pays-Bas, 1974, vol. 93, p. 287-289.

[0483] LCMS(m / z): 100[M+H] + .

[0484] Step B: (R)-1-(4-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)cyclopropane-1-ol (I-50)

[0485]

[0486] Compound I-50 was synthesized by replacing the 6-position precursor with compound 44, following the method used for compound I-21.

[0487] LCMS(m / z): 411[M+H] + .

[0488] Example 51: (R)-4-fluoro-2-(1-((3-(1-(((1-hydroxycyclopropyl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-51)

[0489] Step A: 1-(azidomethylene)cyclopropane-1-ol (45)

[0490]

[0491] Compound 45 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0492] LCMS(m / z): 114 [M+H] + .

[0493] Step B: (R)-4-fluoro-2-(1-((3-(1-(((1-hydroxycyclopropyl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-51)

[0494]

[0495] Compound I-51 was synthesized by using compound 45 instead of compound 6 as a starting material, following the method for compound I-19.

[0496] LCMS(m / z): 410[M+H] + .

[0497] Example 52: (R)-4-fluoro-2-(1-((3-(1-(1-(hydroxymethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-52)

[0498] Step A: (1-Azidecyclopropyl)methanol (46)

[0499]

[0500] Compound 46 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0501] LCMS(m / z): 114 [M+H] + .

[0502] Step B: (R)-4-fluoro-2-(1-((3-(1-(1-(hydroxymethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-52)

[0503]

[0504] Compound I-52 was synthesized by using compound 46 instead of compound 6 as the starting material, following the method for compound I-19.

[0505] LCMS(m / z): 410[M+H] + .

[0506] Example 53: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(2-hydroxycyclopropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-53)

[0507] Step A: 2-Azidecyclopropane-1-ol (47)

[0508]

[0509] Compound 47 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0510] LCMS(m / z): 100[M+H] + .

[0511] Step B: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(2-hydroxycyclopropyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-53)

[0512]

[0513] Compound I-53 was synthesized by using compound 47 instead of compound 33 as a raw material, following the method for compound I-35.

[0514] LCMS(m / z): 440 [M+H] + .

[0515] Example 54: (R)-2-(1-((3-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-54)

[0516] Step A: Azide cyclobutane (48)

[0517]

[0518] Compound 48 was synthesized according to the method described in Synthesis, 1971, pp. 325-326.

[0519] LCMS(m / z): 98[M+H] + .

[0520] Step B: (R)-2-(1-((3-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-54)

[0521]

[0522] Compound I-54 was synthesized by using compound 48 instead of compound 6 as a starting material, following the method for compound I-19.

[0523] LCMS(m / z): 394 [M+H] + .

[0524] Example 55: (R)-4-fluoro-2-(1-((3-(1-(oxecyclobutane-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-55)

[0525] Step A: 3-Azide-oxyhexacyclic butane (49)

[0526]

[0527] Compound 49 was synthesized according to the method described in the Journal of Organic Chemistry (1983), 48(18), 2953-2956.

[0528] LCMS(m / z): 98[M+H] + .

[0529] Step B: (R)-4-fluoro-2-(1-((3-(1-(oxecyclobutane-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-55)

[0530]

[0531] Compound I-55 was synthesized by using compound 49 instead of compound 6 as a starting material, following the method for compound I-19.

[0532] LCMS(m / z): 396 [M+H] + .

[0533] Example 56: (R)-3-(1-(azacyclobutane-3-yl)-1H-1,2,3-triazol-4-yl)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)imidazo[1,2-b]pyridazine-6-amine (I-56)

[0534] Step A: 3-Azide-heterocyclic butane (50)

[0535]

[0536] Compound 50 was synthesized according to the method described in the Journal of Organic Chemistry (1983), 48(18), 2953-2956.

[0537] LCMS(m / z): 99[M+H] + .

[0538] Step B: (R)-3-(1-(azacyclobutane-3-yl)-1H-1,2,3-triazol-4-yl)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine (I-56)

[0539]

[0540] Compound I-56 was synthesized by using compound 50 instead of compound 6 as a starting material, following the method for compound I-17.

[0541] LCMS(m / z): 409[M+H] + .

[0542] Example 57: (R)-4-fluoro-2-(1-((3-(1-(3-hydroxycyclobutyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-57)

[0543] Step A: 3-Azidecyclobutane-1-ol (51)

[0544]

[0545] Compound 51 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0546] LCMS(m / z): 114 [M+H] + .

[0547] Step B: (R)-4-fluoro-2-(1-((3-(1-(3-hydroxycyclobutyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-57)

[0548]

[0549] Compound I-57 was synthesized by using compound 51 instead of compound 6 as a starting material, following the method for compound I-19.

[0550] LCMS(m / z): 410[M+H] + .

[0551] Example 58: 4-(4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidone-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)azacyclobutane-2-one (I-58)

[0552] Step A: 4-Azide-butane-2-one (52)

[0553]

[0554] Compound 52 was synthesized according to the method described in Science of Synthesis (2005), 21, 325-386.

[0555] LCMS(m / z): 113[M+H] + .

[0556] Step B: 4-(4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidone-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)azacyclobutane-2-one (I-58)

[0557]

[0558] Compound I-58 was synthesized by using compound 52 instead of compound 33 as a starting material, following the method for compound I-35.

[0559] LCMS(m / z): 453 [M+H] + .

[0560] Example 59: 4-Fluoro-2-((R)-1-((3-(1-((1R,2R)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-59)

[0561] Step A: (1R,2R)-2-azidocyclopentane-1-ol (53)

[0562]

[0563] Compound 53 was synthesized according to the method described in Synthesis (2002), (15), 2254-2258.

[0564] 1 H NMR: (400MHz, CDCl3) δ4.10(m,1H),3.72(m,1H),2.10(m,2H),1.72-1.60(m,4H).

[0565] LCMS(m / z): 128 [M+H] + .

[0566] Step B: 4-Fluoro-2-((R)-1-((3-(1-((1R,2R)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-59)

[0567]

[0568] I-59 was synthesized by using compound 53 instead of compound 6 as the starting material, following the method for compound I-19.

[0569] LCMS(m / z): 424[M+H] + .

[0570] Example 60: 4-Fluoro-2-((R)-1-((3-(1-((1R,2S)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-60)

[0571] Step A: (1R,2S)-2-azidocyclopentane-1-ol (54)

[0572]

[0573] Compound 54 was synthesized according to the method described in Science of Synthesis (2007), 29, 193-249.

[0574] LCMS(m / z): 128 [M+H] + .

[0575] Step B: 4-Fluoro-2-((R)-1-((3-(1-((1R,2S)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-60)

[0576]

[0577] Compound I-60 was synthesized by using compound 54 instead of compound 6 as a starting material, following the method for compound I-19.

[0578] LCMS(m / z): 424[M+H] + .

[0579] Example 61: (3S,4S)-4-(4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-3-hydroxy(I-61)

[0580] Step A: (3S,4S)-4-azidopyrrolidine-3-ol (55)

[0581]

[0582] Compound 55 was synthesized according to the method described in Organic Letters; vol. 10; nb. 8; (2008); p. 1617-1619.

[0583] 1 H NMR: (400MHz, DMSO-d6) δ: 4.06 (m, 2H), 3.24 (m, J = 12.3, 5.6Hz, 1H), 3.09 (dd, J =12.0,5.0Hz,1H),2.92(dd,J=12.3,2.6Hz,1H),2.82(dd,J=12.0,2.6Hz,1H).

[0584] LCMS(m / z): 129 [M+H] + .

[0585] Step B: (3S,4S)-4-(4-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-3-hydroxy(I-61)

[0586]

[0587] Compound I-61 was synthesized by using compound 55 instead of compound 33 as a raw material, following the method for compound I-34.

[0588] LCMS(m / z): 483[M+H] + .

[0589] Example 62: 4-Fluoro-2-((R)-1-((3-(1-((1R,3S)-3-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-62)

[0590] Step A: (1S,3R)-3-azidocyclopentane-1-ol (56)

[0591]

[0592] Compound 56 was synthesized according to the method described in reference WO2011086053.

[0593] 1 H NMR: (400MHz, CDCl3) δ: 4.25-4.30 (m, 1H), 3.95-3.80 (m, 6H).

[0594] LCMS(m / z): 128 [M+H] + .

[0595] Step B: 4-Fluoro-2-((R)-1-((3-(1-((1R,3S)-3-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-62)

[0596]

[0597] Compound I-62 was synthesized by replacing the 6-position precursor with compound 56, following the method used for compound I-19.

[0598] LCMS(m / z): 424[M+H] + .

[0599] Example 63: 4-Fluoro-2-((R)-1-((3-(1-((1R,3R)-3-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-63)

[0600] Step A: (1R,3R)-3-azidocyclopentane-1-ol (57)

[0601]

[0602] Compound 57 was synthesized according to the method described in reference WO2011086053.

[0603] 1 H NMR: (400MHz, CDCl3) δ: 4.27-4.35 (m, 1H), 3.90-3.65 (m, 6H).

[0604] LCMS(m / z): 128 [M+H] + .

[0605] Step B: 4-Fluoro-2-((R)-1-((3-(1-((1R,3R)-3-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-63)

[0606]

[0607] Compound I-63 was synthesized by using compound 57 instead of compound 6 as a starting material, following the method for compound I-19.

[0608] LCMS(m / z): 424[M+H] + .

[0609] Example 64: 4-Fluoro-2-((R)-1-((3-(1-((S)-tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-64)

[0610] Step A: (S)-3-azidotetrahydrofuran (58)

[0611]

[0612] Compound 58 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0613] LCMS(m / z): 114 [M+H] + .

[0614] Step B: 4-Fluoro-2-((R)-1-((3-(1-((S)-tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-64)

[0615]

[0616] Compound I-64 was synthesized by using compound 58 instead of compound 6 as a starting material, following the method for compound I-19.

[0617] LCMS(m / z): 410[M+H] + .

[0618] Example 65: N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-3-(1-((R)-tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-amine (I-65)

[0619] Step A: (R)-3-azidotetrahydrofuran (59)

[0620]

[0621] Compound 59 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0622] LCMS(m / z): 114 [M+H] + .

[0623] Step B: N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-3-(1-((R)-tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-amine (I-65)

[0624]

[0625] Compound I-65 was synthesized by using compound 59 instead of compound 6 as a starting material, following the method for compound I-21.

[0626] LCMS(m / z): 425 [M+H] + .

[0627] Example 66: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(pyrrolidine-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-66)

[0628] Step A: 3-Azidepyrrolidine (60)

[0629]

[0630] Compound 60 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0631] LCMS(m / z): 113[M+H] + .

[0632] Step B: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(pyrrolidine-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-66)

[0633]

[0634] Compound I-66 was synthesized by using compound 60 instead of compound 33 as a raw material, following the method for compound I-26.

[0635] LCMS(m / z): 453 [M+H] + .

[0636] Example 67: 4-Fluoro-2-((R)-1-((3-(1-((1R,2R)-2-hydroxycyclohexane)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-67)

[0637] Step A: (1R,2R)-2-azidocyclohexane-1-ol (61)

[0638]

[0639] Compound 61 was synthesized according to the method described in RSC Advances; vol. 5; nb. 112; (2015); p. 92387-92393.

[0640] 1H NMR: (400MHz, CDCl3)δ: 3.34(m,1H),3.14(m,1H),2.87(s,1H),1.99(m,2H),1.69(m,2H),1.31-1.18(m,4H)

[0641] LCMS(m / z): 142 [M+H] + .

[0642] Step B: 4-Fluoro-2-((R)-1-((3-(1-((1R,2R)-2-hydroxycyclohexane)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-67)

[0643]

[0644] Compound I-67 was synthesized by using compound 61 instead of compound 6 as the starting material, following the method for compound I-19.

[0645] LCMS(m / z): 438[M+H] + .

[0646] Example 68: (1R,4r)-4-(4-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)cyclohexane-1-hydroxy(I-68)

[0647] Step A: (1r,4r)-4-azidocyclohexane-1-ol (62)

[0648]

[0649] Compound 62 was synthesized according to the method described in the literature Advanced Synthesis and Catalysis; vol. 354; nb. 8; (2012); p. 1417-1421.

[0650] 1 H NMR: (500MHz, CDCl3) δ: 3.68 (tt, J = 9.4, 3.6Hz, 1H), 3.39–3.32 (m, 1H), 2.04–1.96 (m, 4H), 1.61 (s, 1H), 1.48–1.31 (m, 4H).

[0651] LCMS(m / z): 142 [M+H] + .

[0652] Step B: (1R,4r)-4-(4-(6-(((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)cyclohexane-1-hydroxy(I-68)

[0653]

[0654] Compound I-68 was synthesized by using compound 62 instead of compound 6 as the starting material, following the method for compound I-21.

[0655] LCMS(m / z): 453 [M+H] + .

[0656] Example 69: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-69)

[0657] Step A: (5-azidotetrahydro-2H-pyran-2-yl)methanol (63)

[0658]

[0659] Compound 63 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0660] LCMS(m / z): 158 [M+H] + .

[0661] Step B: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-69)

[0662]

[0663] Compound I-69 was synthesized by using compound 63 instead of compound 33 as a raw material, following the method for compound I-35.

[0664] LCMS(m / z): 498[M+H] + .

[0665] Example 70: 4-Fluoro-2-((R)-1-((3-(1-((1R,3R)-3-hydroxycyclohexane)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-70)

[0666] Step A: (1R,3R)-3-azidocyclohexane-1-ol (64)

[0667]

[0668] Compound 64 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0669] LCMS(m / z): 142 [M+H] + .

[0670] Step B: 4-Fluoro-2-((R)-1-((3-(1-((1R,3R)-3-hydroxycyclohexane)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)phenol (I-70)

[0671]

[0672] Compound I-70 was synthesized by replacing the 6-position precursor with compound 64, following the method used for compound I-19.

[0673] LCMS(m / z): 438[M+H] + .

[0674] Example 71: 3-(1-((1R,2R)-2-aminocyclohexane)-1H-1,2,3-triazol-4-yl)-N-((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)imidazo[1,2-b]pyridazine-6-amine (I-71)

[0675] Step A: (1R,2R)-2-azidocyclohexane-1-amine (65)

[0676]

[0677] Compound 65 was synthesized according to the method described in Materials Today Communications (2020), 22, 100747.

[0678] 1H NMR: (400MHz, CDCl3)δ:2.99-2.93(m,1H),2.55-2.49(m,1H),2.08-2.04(m,1H),1.92-1 .87(m,1H),1.82-1.78(m,1H),1.73-1.69(m,1H),1.41-1.22(m,3H),1.19-1.09(m,1H).

[0679] LCMS(m / z): 141 [M+H] + .

[0680] Step B: 3-(1-((1R,2R)-2-aminocyclohexane)-1H-1,2,3-triazol-4-yl)-N-((R)-1-(5-fluoro-2-methoxyphenyl)ethyl)imidazo[1,2-b]pyridazine-6-amine (I-71)

[0681]

[0682] Compound I-71 was synthesized by using compound 65 instead of compound 6 as the starting material, following the method for compound I-17.

[0683] LCMS(m / z): 451 [M+H] + .

[0684] Example 72: (R)-4-fluoro-2-(1-((3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-72)

[0685] Step A: 4-Azidetetrahydro-2H-pyran (66)

[0686]

[0687] Compound 66 was synthesized according to the method in reference WO2011 / 41399.

[0688] 1 H NMR: (400MHz, CDCl3)δ:1.60-1.70(m,2H),1.88-1.92(m,2H),3.44-3.50(m,2H),3.56-3.63(m,1H),3.92-3.97(m,2H)

[0689] LCMS(m / z): 128 [M+H] + .

[0690]

[0691] Compound I-72 was synthesized by replacing the starting material at position 6 with compound 66, following the method used for compound I-19.

[0692] LCMS(m / z): 424[M+H] + .

[0693] Example 73: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-((R)-piperidin-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-73)

[0694] Step A: (R)-3-azidopiperidine (67)

[0695]

[0696] Compound 67 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0697] LCMS(m / z): 127 [M+H] + .

[0698] Step B: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(1-((R)-piperidin-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-73)

[0699]

[0700] Compound I-73 was synthesized by using compound 67 instead of compound 33 as a raw material, following the method for compound I-35.

[0701] LCMS(m / z): 467[M+H] + .

[0702] Example 74: (R)-4-fluoro-2-(1-((3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-74)

[0703] Step A: 4-Azidopididine (68)

[0704]

[0705] Compound 68 was synthesized according to the method described in the European Journal of Medicinal Chemistry, 2018, vol. 145, pp. 191-205.

[0706] 1 H NMR (300MHz, CDCl3) δ6.30 (s, 1H), 3.84 (app.tt, dddd, J = 6.7, 6.7, 3.4, 3.4Hz, 1H), 3.27 (ddd,J=12.8,9.1,3.6Hz,2H),3.15–3.03(m,2H),2.22–2.08(m,2H),1.99–1.82(m,2H). 13 C NMR (151MHz, CDCl3) δ54.3, 40.6, 27.4.

[0707] LCMS(m / z): 127 [M+H] + .

[0708] Step B: (R)-4-fluoro-2-(1-((3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-74)

[0709]

[0710] Compound I-74 was synthesized by using compound 68 instead of compound 6 as the starting material, following the method for compound I-19.

[0711] LCMS(m / z): 423[M+H] + .

[0712] Example 75: 4-Fluoro-2-((R)-1-(3-(1-((S)-tetrahydro-2H-pyran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-75)

[0713] Step A: (S)-3-azidotetrahydro-2H-pyran (69)

[0714]

[0715] Compound 69 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0716] LCMS(m / z): 128 [M+H] + .

[0717] Step B: 4-Fluoro-2-((R)-1-(3-(1-((S)-tetrahydro-2H-pyran-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-75)

[0718]

[0719] Compound I-75 was synthesized by using compound 69 instead of compound 33 as a starting material, following the method for compound I-32.

[0720] LCMS(m / z): 450 [M+H] + .

[0721] Example 76: (R)-2-(1-((3-(1-(3-aminophenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-76)

[0722] Step A: 3-Azide aniline (70)

[0723]

[0724] Compound 70 was synthesized according to the method described in the literature Organic & Biomolecular Chemistry (2016), 14(24), 5761-5767.

[0725] 1 H NMR (300MHz, CDCl3) δ7.13(t,J=7.9Hz,1H),7.48-7.46(m,1H),7.46-7.44(m,1H),6.32(t,J=2.1Hz,1H),3.70(s,2H); 13 C NMR (100MHz, CDCl3)147.7,140.8,130.3,111.6,108.8,105.2.

[0726] LCMS(m / z): 135 [M+H] + .

[0727] Step B: (R)-2-(1-((3-(1-(3-aminophenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-76)

[0728]

[0729] Compound I-76 was synthesized by using compound 70 instead of compound 6 as a raw material, following the method for compound I-19.

[0730] LCMS(m / z): 431[M+H] + .

[0731] Example 77: (R)-2-(1-((3-(1-(2-aminopyridin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-77)

[0732] Step A: 3-Azidepyridine-2-amine (71)

[0733]

[0734] Compound 71 was synthesized according to the method described in Tetrahedron Letters (2015), 56(47), 6606-6609.

[0735] 1 H NMR (300MHz, DMSO-d6) δ6.15 (s, 2H), 6.18 (d, J = 1.9Hz, 1H), 6.29 (dd, J = 5.5Hz, J = 2.0Hz, 1H), 7.91 (d, J = 5.5Hz, 1H); 13 C NMR (100MHz, DMSO-d6)96.51,103.12,148.44,149.59,161.12.

[0736] LCMS(m / z): 136 [M+H] + .

[0737] Step B: (R)-2-(1-((3-(1-(2-aminopyridin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-77)

[0738]

[0739] Compound I-77 was synthesized by using compound 71 instead of compound 6 as the starting material, following the method for compound I-19.

[0740] LCMS(m / z): 432[M+H] + .

[0741] Example 78: (R)-2-(1-((3-(1-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-78)

[0742] Step A: 5-Azidepyridine-2-amine (72)

[0743]

[0744] Compound 72 was synthesized according to the method described in Letters in Drug Design & Discovery (2011), 8(5), 401-405.

[0745] LCMS(m / z): 136 [M+H] + .

[0746] Step B: (R)-2-(1-((3-(1-(6-aminopyridin-3-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-yl)amino)ethyl)-4-fluorophenol

[0747]

[0748] Compound I-78 was synthesized by using compound 72 instead of compound 6 as a starting material, following the method for compound I-19.

[0749] LCMS(m / z): 432[M+H] + .

[0750] Example 79: (R)-2-(1-((3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-79)

[0751] Step A: 4-Azide aniline (73)

[0752]

[0753] Compound 73 was synthesized according to the method described in the literature Organic & Biomolecular Chemistry (2016), 14(24), 5761-5767.

[0754] 1 H NMR (400MHz, DMSO-d6) δ6.84 (d, 2H, J = 10.7Hz), 6.67 (d, 2H, J = 10.9Hz), 3.65 (s, 2H); 13C NMR(100MHz,DMSO-d6)143.7,130.0,119.9,116.2.

[0755] LCMS(m / z): 135 [M+H] + .

[0756] Step B: (R)-2-(1-((3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)-4-fluorophenol (I-79)

[0757]

[0758] Compound I-79 was synthesized by using compound 73 instead of compound 6 as a starting material, following the method for compound I-19.

[0759] LCMS(m / z): 431[M+H] + .

[0760] Example 80: (R)-4-fluoro-2-(1-((3-(1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-80)

[0761] Step A: 4-Azide-benzylamine (74)

[0762]

[0763] Compound 74 was synthesized according to the method described in reference WO2021 / 5222.

[0764] LCMS(m / z): 149 [M+H] + .

[0765] Step B: (R)-4-fluoro-2-(1-((3-(1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-80)

[0766]

[0767] Compound I-80 was synthesized by using compound 74 instead of compound 6 as the starting material, following the method for compound I-19.

[0768] LCMS(m / z): 445[M+H] + .

[0769] Example 81: (R)-5-(4-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)pyridine-3-hydroxy (I-81)

[0770] Step A: 5-Azidepyridine-3-ol (75)

[0771]

[0772] Compound 75 was synthesized according to the method described in reference WO2009143507.

[0773] LCMS(m / z): 137 [M+H] + .

[0774] Step B: (R)-5-(4-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)pyridine-3-hydroxy(I-81)

[0775]

[0776] Compound I-81 was synthesized by using compound 75 instead of compound 6 as a starting material, following the method for compound I-19.

[0777] LCMS(m / z): 433[M+H] + .

[0778] Example 82: 6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine (I-82)

[0779] Step A: 1-Azide-4-methoxybenzene (76)

[0780]

[0781] Compound 76 was synthesized according to the method described in reference WO2009143507.

[0782] LCMS(m / z): 150 [M+H] + .

[0783] Step B: 6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine (I-82)

[0784]

[0785] Compound I-82 was synthesized by using compound 76 instead of compound 33 as a raw material, following the method for compound I-34.

[0786] LCMS(m / z): 504 [M+H] + .

[0787] Example 83: (R)-4-fluoro-2-(1-((3-(1-(3-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-83)

[0788] Step A: 3-Azidephenol (77)

[0789]

[0790] Compound 77 was synthesized according to the method described in Synlett (2005), (14), 2209-2213.

[0791] 1 H NMR (400MHz, DMSO-d6): δ = 9.74 (s, 1H), 7.19 (t, J = 8.01Hz, 1H), 6.60 (ddd, J = 8.01 ,2.29,0.76Hz,1H),6.54(ddd,J=8.01,2.29,0.76Hz,1H),6.48(t,J=2.29Hz,1H). 13 C NMR (100MHz, DMSO): δ = 158.7, 140.2, 130.7, 112.4, 109.6, 105.7.

[0792] LCMS(m / z): 136 [M+H] + .

[0793] Step B: (R)-4-fluoro-2-(1-((3-(1-(3-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-83)

[0794]

[0795] Compound I-83 was synthesized by using compound 77 instead of compound 6 as a starting material, following the method for compound I-19.

[0796] LCMS(m / z): 432[M+H] + .

[0797] Example 84: (R)-4-fluoro-2-(1-((3-(1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-84)

[0798] Step A: 2-Azidephenol (78)

[0799]

[0800] Compound 78 was synthesized according to the method described in the European Journal of Medicinal Chemistry; vol. 210; (2021); 112988.

[0801] 1 H NMR (300MHz, DMSO-d6): δ = 7.09-7.07 (m, 1H); 7.06-7.03 (m, 1H); 6.94 (td, J = 7.7, J = 1.5, 2H); 6.93-6.91 (m, 1H). 13 C NMR (100MHz, DMSO-d6): δ = 147.2, 125.9, 121.2, 118.3.

[0802] LCMS(m / z): 136 [M+H] + .

[0803] Step B: (R)-4-fluoro-2-(1-((3-(1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-84)

[0804]

[0805] Compound I-84 was synthesized by using compound 78 instead of compound 6 as a starting material, following the method for compound I-19.

[0806] LCMS(m / z): 432[M+H] + .

[0807] Example 85: (R)-2-(4-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)acetonitrile (I-85)

[0808] Step A: 2-Azide Acetonitrile (79)

[0809]

[0810] Compound 79 was synthesized according to the method described in ChemPhysChem (2020), 21(11), 1126-1133.

[0811] Step B: (R)-2-(4-(6-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)acetonitrile (I-85)

[0812]

[0813] Compound I-85 was synthesized by using compound 79 instead of compound 6 as a starting material, following the method for compound I-19.

[0814] LCMS(m / z): 379 [M+H] + .

[0815] Example 86: (R)-4-fluoro-2-(1-((3-(1-(((5-methylfuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-86)

[0816] Step A: 2-(azidomethyl)-5-methylfuran (80)

[0817]

[0818] Compound 80 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0819] LCMS(m / z): 138 [M+H] + .

[0820] Step B: (R)-4-fluoro-2-(1-((3-(1-(((5-methylfuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-86)

[0821]

[0822] Compound I-86 was synthesized by using compound 80 instead of compound 6 as a raw material, following the method for compound I-19.

[0823] LCMS(m / z): 434[M+H] + .

[0824] Example 87: 2-((2R,4S)-1-(3-(1-((1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-4-fluoropyrrolidine-2-yl)-4-fluorophenol (I-87)

[0825] Step A: 4-(azidomethyl)-1H-pyrazole (81)

[0826]

[0827] Compound 81 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0828] LCMS(m / z): 124 [M+H] + .

[0829] Step B: 2-((2R,4S)-1-(3-(1-((1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-4-fluoropyrrolidine-2-yl)-4-fluorophenol (I-87)

[0830]

[0831] Compound I-87 was synthesized by using compound 81 instead of compound 33 as a raw material, following the method for compound I-35.

[0832] LCMS(m / z): 464[M+H] + .

[0833] Example 88: (R)-4-fluoro-2-(1-((3-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-88)

[0834] Step A: 4-(azidomethyl)-1-methyl-1H-pyrazole (82)

[0835]

[0836] Compound 82 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0837] LCMS(m / z): 138 [M+H] + .

[0838] Step B: (R)-4-fluoro-2-(1-((3-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-88)

[0839]

[0840] Compound I-88 was synthesized by using compound 82 instead of compound 6 as a starting material, following the method for compound I-19.

[0841] LCMS(m / z): 434[M+H] + .

[0842] Example 89: (R)-4-fluoro-2-(1-((3-(1-((1-(methyl-d3)-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-89)

[0843] Step A: 4-(azidomethyl)-1-methyl-d3-1H-pyrazole (83)

[0844]

[0845] Compound 83 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0846] LCMS(m / z): 141 [M+H] + .

[0847] Step B: (R)-4-fluoro-2-(1-((3-(1-((1-(methyl-d3)-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-89)

[0848]

[0849] Compound I-89 was synthesized by using compound 83 instead of compound 6 as the starting material, following the method for compound I-19.

[0850] LCMS(m / z): 437[M+H] + .

[0851] Example 90: (R)-N-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-3-(1-((5-methylthiophen-3-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-amine (I-90)

[0852] Step A: 4-(azidomethyl)-2-methylthiophene (84)

[0853]

[0854] Compound 84 was synthesized according to the method described in Nature (London, United Kingdom) (2019), 574(7776), 86-89.

[0855] LCMS(m / z): 154 [M+H] + .

[0856] Step B: (R)-N-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-3-(1-((5-methylthiophen-3-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-6-amine (I-90)

[0857]

[0858] Compound I-90 was synthesized by using compound 84 instead of compound 6 as a raw material, following the method for compound I-21.

[0859] LCMS(m / z): 465[M+H] + .

[0860] Example 91: (R)-4-fluoro-2-(1-((3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-91)

[0861] Step A: 2-(1-(6-clomizo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)methyl acetate (85)

[0862]

[0863] Compound 85 was synthesized from commercially available compounds 3-amino-6-chloroimidazolo[1,2-B]pyridazine and methyl 4,4-dimethoxyacetoacetate, following the method described in Synlett, 2020, 31, 175–178.

[0864] LCMS(m / z): 293[M+H]+ .

[0865] Step B: 2-(1-(6-chloroimidazolo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)ethane-1-ol (86)

[0866]

[0867] 2-(1-(6-chloroimidazolo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)methyl acetate (compound 85, 293 mg, 1 mmol) was placed in tetrahydrofuran (5 mL), and lithium aluminum hydride (47.4 mg, 2.14 mmol) was added. The mixture was stirred at 25 °C for 1 hour, then extracted with saturated ammonium chloride solution (5 mL) and extracted twice with ethyl acetate (5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-bromo-4-hydroxyethylpyridine (150 mg).

[0868] LCMS(m / z): 265[M+H] + .

[0869] Step C: (R)-4-fluoro-2-(1-((3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol (I-91)

[0870]

[0871] Compound I-91 was synthesized by using compound 86 instead of compound 9 as a starting material and compound 29 instead of compound 10 as a starting material, following the same method as compound I-2.

[0872] LCMS(m / z): 384 [M+H] + .

[0873] Example 91: (R)-4-fluoro-2-(1-(3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-92)

[0874] Step A: (R)-2-(1-(6-(2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)ethane-1-ol (87)

[0875]

[0876] Compound 87 was synthesized by replacing compound 9 with compound 86 and replacing compound 10 with compound (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine, following the same method as compound I-2.

[0877] LCMS(m / z): 424[M+H] + .

[0878] Step B: (R)-4-fluoro-2-(1-(3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-92)

[0879]

[0880] Compound I-92 was synthesized by using compound 87 instead of compound I-5 as a raw material, following the method for compound I-6.

[0881] LCMS(m / z): 410[M+H] +

[0882] Example 93: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-93)

[0883] Step A: 2-(1-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)ethane-1-ol (88)

[0884]

[0885] Compound 88 was synthesized by replacing compound 9 with compound 86 and replacing compound 10 with compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine, following the same method as compound I-2.

[0886] LCMS(m / z): 442[M+H] + .

[0887] Step B: 4-Fluoro-2-((2R,4S)-4-Fluoro-1-(3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-yl)phenol (I-93)

[0888]

[0889] Compound I-93 was synthesized by using compound 88 instead of compound I-5 as a raw material, following the method for compound I-6.

[0890] LCMS(m / z): 428[M+H] +

[0891] Example 94: (R)-2-(1-(6-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)ethane-1-ol (I-94)

[0892]

[0893] Compound I-94 was synthesized by using compound 86 instead of compound 9 as a starting material and compound 31 instead of compound 10 as a starting material, following the same method as compound I-2.

[0894] LCMS(m / z): 399[M+H] + .

[0895] Example 95: (R)-2-(1-(6-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)ethane-1-ol (I-95)

[0896]

[0897] Compound I-95 was synthesized by using compound 86 instead of compound 9 as a starting material, and by using compound (R)-5-fluoro-2-methoxy-3-(pyrrolidine-2-yl)pyridine instead of compound 10 as a starting material, following the same method as compound I-2.

[0898] LCMS(m / z): 425 [M+H] + .

[0899] Example 96: 2-(1-(6-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-4-yl)ethane-1-ol (I-96)

[0900]

[0901] Compound I-96 was synthesized by replacing compound 9 with compound 86 and replacing compound 10 with compound 5-fluoro-3-((2R,4S)-4-fluoropyrrolidine-2-yl)-2-methoxypyridine, following the same method as compound I-2.

[0902] LCMS(m / z): 443[M+H] + .

[0903] Example 97: Biological Evaluation

[0904] Experiment 1: Inhibition of TRKA, TRKA(F589L), TRKA(G595R / G667C), TRKC, and TRKC(G696A) kinases by the compounds

[0905] Experimental methods: Compound preparation: The compounds in Examples 1-96 and compound Loxo-101 were pre-dissolved in 100% DMSO to prepare 10 mM stock solutions, which were then frozen at -20°C.

[0906] The chemical structure of compound Loxo-101 is shown below. It is commercially available and can be prepared according to WO2010 / 48314.

[0907]

[0908] Kinase reaction procedure: Prepare 1×Kinase buffer; Preparation of compound concentration gradient: The compounds of test examples 1-96 and compound Loxo-101 were tested at a concentration of 1000 nM and diluted 100 times to a final concentration of 100% DMSO solution in a 384-well plate. The compounds were then diluted 3 times with Presision to form 10 concentrations (1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.4, 0.16, 0.15 and 0.05 nM). Transfer 250 nL of the compound at a final concentration of 100 to the target plate OptiPlate-384F using an Echo550 dispenser; prepare a kinase solution at a final concentration of 2.5 using 1×Kinase buffer; add 10 μL of the kinase solution at a final concentration of 2.5 to the compound wells and the positive control wells, and add 10 μL of 1×Kinase buffer to the negative control wells; centrifuge at 1000 rpm for 30 seconds, vortex the plate to mix, and incubate at room temperature for 10 minutes; prepare a mixture of ATP and Kinase substrate 22 at a final concentration of 5 / 3 using 1×Kinase buffer; add 15 μL of the mixture to start the reaction; centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for the appropriate time; add 30 μL of stop assay solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix; read the conversion rate using a CaliperEZ Reader.

[0909] Data Analysis: Calculation Formula:

[0910] %Inhibition=(Conversion%_max-conversion%_sample)÷(Conversion%_max-conversion%_min)x 100

[0911] Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min is the mean value of the negative control wells, representing the conversion rate reading of wells without enzyme activity; Conversion%_max is the mean value of the positive control wells, representing the conversion rate reading of wells without compound inhibition. A dose-response curve was fitted, with the log value of concentration as the X-axis and the percentage inhibition rate as the Y-axis. The log(inhibitor) vs. response-variable slope function of GraphPad Prism 5 was used to fit the dose-response curve, thereby obtaining the IC50 value of each compound on the enzyme activity. 50 Value. The calculation formula is:

[0912] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0913] Where X represents the concentration of the analyte, Y represents the inhibition rate of the analyte at concentration X, Top refers to the maximum response, Bottom refers to the baseline response, and Hill Slope refers to the slope of the curve.

[0914] IC50 of various compounds on enzyme activity 50 The values ​​are shown in Tables 1 to 3 below.

[0915] Table 1. Effects of different compounds on the kinase TRKA WT In vitro inhibition experiment IC 50 Test results (nM)

[0916]

[0917]

[0918] Experimental results show that most of the compounds in this application exhibit activity against the kinase TRKA. WT In in vitro inhibition experiments, the inhibitory effects of these compounds were superior to those of compound Loxo-101, especially compounds I-3, I-4, I-9, I-10, I-17, I-19, I-26, I-33, I-34, I-35, I-36, I-38, I-59, I-60, I-61, I-62, I-63, I-92, I-93, and I-96, which were significantly better than Loxo-101.

[0919] Table 2. Effects of different compounds on the kinase TRKA F589L In vitro inhibition experiment IC 50 Test results (nM)

[0920] I-1 5.87 I-29 18.65 I-61 1.67 I-74 20.6 I-2 6.32 I-30 11.54 I-62 3.81 I-75 18.7 I-3 2.02 I-31 4.65 I-63 2.48 I-76 40.9 I-4 1.67 I-32 5.76 I-64 22.4 I-77 32.1 I-5 4.35 I-33 2.65 I-65 13.9 I-81 62.6 I-6 3.72 I-34 2.27 I-66 18.7 I-85 67 I-9 6.75 I-35 3.7 I-67 15.6 I-91 2.87 I-10 3.828 I-36 2.98 I-68 16.2 I-92 5.68 I-11 3.87 I-50 8.77 I-69 20.7 I-93 4.98 I-13 10.7 I-51 6.45 I-70 12.8 I-94 10.12 I-14 8.45 I-52 3.91 I-71 25.1 I-95 9.56 I-15 78.5 I-59 5.37 I-72 17.1 I-96 12.07 I-16 94.8 I-60 2.59 I-73 14.8 Loxo-101 43.1

[0921] Experimental results show that most of the compounds in this application exhibit activity against the kinase TRKA. F589L In in vitro inhibition experiments, the inhibitory effects of these compounds were superior to those of compound Loxo-101, especially compounds I-3, I-4, I-5, I-6, I-10, I-11, I-31, I-33, I-34, I-35, I-36, I-52, I-61, I-62, I-63, I-91, and I-93, which were significantly superior to Loxo-101.

[0922] Table 3. Effects of different compounds on TRKC kinase WT In vitro inhibition experiment IC 50 Test results (nM)

[0923] I-1 1.21 I-4 0.51 I-9 1.49 I-93 0.92 I-2 1.34 I-5 0.94 I-10 0.30 I-96 0.68 I-3 0.87 I-6 0.81 I-91 1.37 Loxo-101 1.7

[0924] Experimental results show that compounds I-3, I-4, I-5, I-6, I-10, I-93, and I-96 in this application have effects on the kinase TRKC. WT The inhibitory activity of the compound was significantly better than that of Loxo-101 in the in vitro inhibition experiment.

[0925] Experiment 2: Growth inhibitory effects of the compounds on three types of NTRK cells (Ba / F3-TPM3-NTRK1-WT, Ba / F3-TPM3-NTRK1-G595R, Ba / F3-TPM3-NTRK1-G667C).

[0926] Reagents:

[0927] RPMI 1640 medium L210KJ fetal bovine serum FSP500 PBS B310KJ Penicillin Streptomycin,Liquid(P / S) SV30010 Cell Titer-Glo (CTG) Kit G7573

[0928] Cell lines:

[0929] BaF3-NTRKA G595R RPMI 1640 + 10% FBS + 1% P / S BaF3-NTRKA G667C RPMI 1640 + 10% FBS + 1% P / S

[0930] Compound solution preparation: In a biosafety cabinet, the compounds of Examples 1-96 and compound Loxo-101 were pre-dissolved in 100% DMSO to prepare 10 mM stock solutions, which were then stored at -20°C. The above compound stock solutions were serially diluted with DMSO: A clean, sterile 96-well microplate with a V-bottom was placed in the biosafety cabinet. First, 4 μL of DMSO was added to well B2, and 10 μL of DMSO was added to wells B3-B11. Then, 6 μL of the 10 mM compound stock solution was added to well B2, and the mixture was mixed by pipetting up and down 10 times. At this point, the concentration of the compound in well B2 was 6 mM 100% DMSO. 5 μL of the solution was transferred from well B2 to well B3, and the mixture was mixed by pipetting up and down 10 times. This process was repeated until the concentration was reduced to B10. Well B11 contained only DMSO and no analyte compound.

[0931] Preparation of 6X compound solution (6-fold dilution, where X represents the dilution factor) (initial concentration 10 μM): Place a clean, sterile 96-well microplate with a V-bottom in a biosafety cabinet; add 99 μL of cell culture medium to each well from B2 to G11; use a 12-channel pipette to add 1 μL of the compound solution prepared in the previous step to the corresponding well; pipette up and down 10 times in each well to mix; at this point, the highest concentration of the compound is 60 μM.

[0932] Cell treatment with compound: Remove the seeded cell culture plate from the incubator; add 20 μL of compound solution to each well, selecting the lowest possible transfer speed, ensuring the solution adheres to the wall and avoids contact with the bottom of the culture plate; gently agitate the cell culture plate to mix the compound solution, then return the cell culture plate to the incubator and continue culturing for 72 hours.

[0933] At this point, the highest concentration of the compound used for treatment was 10 μM. After 72 hours of cell treatment, a Cell TiterGlo (CTG) assay was performed. First, the cell culture plate was removed from the CO2 incubator and placed at room temperature for 30 minutes to ensure uniform temperature throughout the plate. The Cell TiterGlo reagent, prepared according to the instructions, was then removed and allowed to thaw at room temperature. Next, 60 μL of Cell TiterGlo reagent was added to each well containing cells, and the plate was incubated on a horizontal shaker at 225 rpm for 1 hour in the dark at room temperature. Then, the plate was read using a Tecan Spark microplate reader according to the chemiluminescence method, following the instructions. The IC50 values ​​of some compounds for different cell lines were recorded. 50 See Tables 4 to 6 below:

[0934] Table 4. In vitro inhibitory effects of different compounds on Ba / F3-TPM3-NTRK1-WT cells (IC50) 50 Test results (nM)

[0935]

[0936]

[0937] Experimental results show that compounds I-9, I-10, I-92, I-94, and I-95 in this application exhibit significantly better inhibitory activity than compound Loxo-101 in in vitro inhibition experiments of Ba / F3-TPM3-NTRK1-WT cells.

[0938] Table 5. In vitro inhibitory effects of different compounds on Ba / F3-TPM3-NTRK1-G595R cells (IC50) 50 Test results (nM)

[0939]

[0940] Experimental results show that most of the compounds in this application have significantly better inhibitory effects on Ba / F3-TPM3-NTRK1-G595R cells in vitro than compound Loxo-101, especially compounds I-1, I-2, I-2, I-3, I-5, I-6, I-9, I-10, I-17, I-19, I-21, I-25, I-26, I-27, I-38, I-75, I-91, I-93, I-94, I-95, and I-96.

[0941] Table 6. In vitro inhibitory effects of different compounds on Ba / F3-TPM3-NTRK1-G667C cells (IC50) 50 Test results (nM)

[0942]

[0943] Experimental results show that the inhibitory ability of the compound in this application in the in vitro inhibition experiment of Ba / F3-TPM3-NTRK1-G667C cells is comparable to that of compound Loxo-101.

[0944] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound represented by Formula I-1, Formula I-2 or Formula I-3, or an optical isomer thereof or a pharmaceutically acceptable salt thereof: Formula I-1 Formula I-2 Formula I-3 in: W 5 W 6 W 7 Each is independently selected from carbon or nitrogen, and W 6 and W 7 It cannot be either carbon or nitrogen at the same time; Ring A is a benzene ring or a pyridine ring; R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated C1-C6 alkyl, substituted or unsubstituted saturated C1-C6 alkoxy, and optionally R 2 and R 3 Together with the C atoms that connect them, they form substituted or unsubstituted saturated C3-C6 cycloalkyl groups; wherein "substituted" means selectively containing 1 to 4 substituents selected from deuterium, hydroxyl, halogen, cyano, amino, C1-C4 alkyl, and C1-C4 alkoxy. R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated C1~C6 alkyl, and saturated C1~C6 alkoxy groups; R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated C1-C6 alkyl, or R 5 It does not exist; X 1 The group is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted saturated C1-C6 alkyl, substituted or unsubstituted saturated C1-C6 alkoxy, wherein "substituted" means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, and amino. L 1 Selected from one of the following groups 。 2. The compound according to claim 1, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, It is represented by the following formulas: I-1-a, I-1-b, I-2-a, I-2-b, I-3-a, or I-3-b: Formula I-1-a Formula I-1-b Formula I-2-a Formula I-2-b Formula I-3-a Formula I-3-b Among them, the substituent rings A and W 5 R 1 R 2 R 3 R 4 R 5 X 1 L 1 The definition is the same as in claim 1.

3. The compound of formula I according to claim 1 or 2, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated C1-C4 alkyl, substituted or unsubstituted saturated C1-C4 alkoxy, and optionally R 2 and R 3 Together with the C atoms that connect them, they form substituted or unsubstituted saturated C3-C6 cycloalkyl groups; wherein "substituted" means selectively containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, amino, C1-C3 alkyl, and C1-C3 alkoxy.

4. The compound of formula I according to claim 1 or 2, or an optical isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated C1-C3 alkyl, substituted or unsubstituted saturated C1-C3 alkoxy, and optionally R 2 and R 3 Together with the C atoms that connect them, they form substituted or unsubstituted saturated C5-C6 cycloalkyl groups; wherein "substituted" means selectively containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, cyano, amino, C1-C3 alkyl, and C1-C3 alkoxy.

5. The compound of formula I according to claim 1 or 2, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, and optionally R 2 and R 3 Together with the C atoms that connect them, they form substituted or unsubstituted C3-C5 cycloalkyl groups; wherein "substituted" means selectively containing 1 to 3 substituents selected from deuterium, hydroxyl, halogen, amino and C1-C3 alkyl groups.

6. The compound of formula I according to claim 1 or 2, or its optical isomer or pharmaceutically acceptable salt thereof, characterized in that, R 1 R 2 R 3 Each is independently selected from hydrogen, deuterium, methyl, ethyl, and propyl; R may be selected from... 2 and R 3 Together with the C atoms that connect them, they form cyclopropyl or cyclobutyl groups.

7. The compound of formula I according to claim 1 or 2, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, R 4 It is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated C1~C4 alkyl, and saturated C1~C4 alkoxy.

8. The compound of formula I according to claim 1 or 2, or its optical isomer or pharmaceutically acceptable salt thereof, characterized in that, R 4 It is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated C1~C3 alkyl, and saturated C1~C3 alkoxy.

9. The compound of formula I according to claim 1 or 2, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, R 4 It is selected from hydrogen, deuterium, halogen, saturated C1~C3 alkyl, and saturated C1~C3 alkoxy.

10. The compound of formula I according to claim 1 or 2, or its optical isomer or a pharmaceutically acceptable salt thereof, characterized in that, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated C1-C4 alkyl, or R 5 It does not exist.

11. The compound of formula I according to claim 1 or 2, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated C1-C3 alkyl or R 5 It does not exist.

12. The compound of formula I according to claim 1 or 2, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, R 5 Selected from hydrogen, deuterium, halogen, saturated C1-C3 alkyl groups or R 5 It does not exist.

13. The compound of formula I according to claim 1 or 2, or its optical isomer or a pharmaceutically acceptable salt thereof, characterized in that, X 1 The group is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted saturated C1-C4 alkyl, substituted or unsubstituted saturated C1-C4 alkoxy, wherein "substituted" means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, and amino.

14. The compound of formula I according to claim 1 or 2, or its optical isomer or pharmaceutically acceptable salt thereof, characterized in that, X 1 The group is selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated C1-C3 alkyl, substituted or unsubstituted saturated C1-C3 alkoxy, wherein "substituted" means selectively containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, and amino.

15. The compound of formula I according to claim 1 or 2, or its optical isomer or a pharmaceutically acceptable salt thereof, characterized in that, X 1 The group is selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated C1-C3 alkyl, substituted or unsubstituted saturated C1-C3 alkoxy, wherein "substituted" means selectively containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, hydroxyl, and amino.

16. The compound according to claim 1 or 2, or its optical isomer or a pharmaceutically acceptable salt thereof, characterized in that, It is selected from the following compounds: 。 17. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 16, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. Use of the compound of any one of claims 1 to 16, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament as a TRK kinase inhibitor for the treatment or prevention of a disease or condition mediated by TRK or a TRK mutation in a subject in need.

19. The use according to claim 18, characterized in that, The diseases or conditions mediated by TRK or TRK mutations are selected from one or more of cancer, neurodegenerative diseases, inflammation, and pain.

20. The use according to claim 18, characterized in that, The diseases or conditions mediated by TRK or TRK mutations are selected from surgical pain, inflammatory pain, neuropathic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, cholangiocarcinoma, stromal tumor, brain tumor, and hematologic malignancies.

21. A kit comprising the compound of any one of claims 1 to 16, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17, and a container and instructions for use.

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