CN117624166A

CN117624166A - Triazole derivative and preparation method and application thereof

Info

Publication number: CN117624166A
Application number: CN202210948132.1A
Authority: CN
Inventors: 邢莉; 刘海涛; 吴凡
Original assignee: Suzhou Langrui Biopharmaceutical Co ltd
Current assignee: Suzhou Langrui Biopharmaceutical Co ltd
Priority date: 2022-08-09
Filing date: 2022-08-09
Publication date: 2024-03-01

Abstract

The invention discloses a triazole compound shown in a 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, application of the triazole compound serving as a TRK kinase inhibitor, and a pharmaceutical composition containing the derivative.

Description

Triazole derivative and preparation method and application thereof

Technical Field

The application belongs to the field of medicines, and particularly relates to a triazole derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, application of the triazole derivative serving as a TRK kinase inhibitor and a pharmaceutical composition containing the triazole derivative.

Background

The tropomyosin-related kinase (TRK) family of enzymes is a transmembrane Receptor Tyrosine Kinase (RTK) comprising a homologous hinge region formed by folding multiple subunits, usually located between an N-terminal region and a C-terminal region, comprising an extracellular ligand binding domain, a transmembrane domain and an intracellular domain having kinase activity. Upon binding of Trk to cell membrane surface ligands, specific tyrosine sites are autophosphorylated by dimerization, activating downstream signaling pathways (Ras/MAPK, PI3K/AKT and plcγ pathways); TRK is a class of nerve growth factor receptors that regulate synaptic strength and plasticity of the mammalian nervous system. In this role, TRK family kinases regulate cellular differentiation, proliferation, metabolism, apoptosis, and pain. There are three members of the TRK family: tropomyosin-related kinase A (TRKA, encoded by the NTRK1 gene), tropomyosin-related kinase B (TRKB, encoded by the NTRK2 gene) and tropomyosin-related kinase CTRCC, encoded by the NTRK3 gene), all of which are involved in the development and progression of malignant tumors. The three subtypes of the TRK family differ in ligand, and are characterized by TRKA binding to NGF, TRKB binding to brain-derived neurotrophic factor (BDNF), and TRKC specific binding to neurotrophic factor (NT 3).

Similar to BCR-ABL gene fusion products that drive Chronic Myeloid Leukemia (CML), NTRK rearrangement and fusion gene products are observed in a variety of tumor types, unlike chronic myeloid leukemia, the incidence of NTRK fusion genes in each particular tumor type is generally rare. This presents great difficulties for patient identification and adequate recruitment for clinical trials. For example, the NTRK2 gene found fusion in 0.2% of lung adenocarcinomas; on the other hand, NTRK3 fusion genes have been found in almost all secretory breast cancers and breast analog secretory cancers (MASCs), which are an extremely rare salivary gland tumor (usually parotid gland tumor), and indeed, the decisive feature of MASCs is the NTRK gene fusion compared to other salivary gland cancers; in addition, NTRK fusion was found in approximately 50% of children's diffuse intrinsic bridge gliomas and non-brain stem glioblastomas. Within the major cancer subgroup, NTRK fusion occurs in 3.3% lung cancer, 2.2% colorectal cancer, 16.7% thyroid cancer, 2.5% glioblastoma, and 7.1% pediatric glioma in breast cancer. Finally, similar to the receptor tyrosine kinase RET (rearranged during transfection), NTRK fusion (in particular ETV6-NTRK 3) is common in papillary thyroid carcinomas induced after nuclear radiation of cernuoberi. Thus, it is an attractive treatment for TRK oncogenes, which can treat a wide variety of, often rare cancers.

The main approach to targeting TRK oncogenes is the use of small molecule kinase inhibitors. Since the gene fusion product is the major oncogene observed, gene fusion of the neurotrophic factor receptor tyrosine kinase (neurotrophic receptor tyrosine kinase, NTRK) results in loss of the extracellular domain of TRK, thereby triggering the development of a variety of tumors. Loss of the extracellular domain of TRK renders TRK-targeted antibody therapy ineffective, and other targeting strategies, such as antibody therapy, will not be effective because transmembrane tyrosine kinase fusion typically lacks an extracellular domain. In this case, the fusion protein is only susceptible to small molecule inhibition. In general, small molecules are designed to target the Adenosine Triphosphate (ATP) binding site of TRK to block catalytic activity. For example, some of the newly developed TRK small molecule inhibitors have been disclosed in the documents of chinese patent application CN102264736A, CN104520300a, etc., so that the development of TRK small molecule inhibitors is very significant.

Disclosure of Invention

According to one aspect of the present invention, it is an object of the present invention to provide a compound of formula i or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

Wherein:

W ¹ 、W ² 、W ³ 、W ⁴ 、W ⁵ 、W ⁶ 、W ⁷ each independently selected from carbon or nitrogen, and W ⁶ And W is ⁷ Not both carbon or nitrogen;

ring A is benzene ring, pyridine ring, hetero alkyl ring containing N atom;

R ¹ 、R ² 、R ³ each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ A cycloalkoxy group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted saturated or unsaturated 4-to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5-to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 4 groups selected from deuterium, hydroxy, halogen, cyano, sulfonyl, amino, C ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -OC (=o) C _1-4 Alkyl, -OC (=o) C ₃ ～C ₆ Substituents of cycloalkyl;

R ⁴ selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₆ Alkyl, saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, saturated or unsaturated C ₁ ～C ₆ Alkoxy, saturated or unsaturated C ₃ ～C ₆ A cycloalkoxy group;

R ⁵ selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₆ Alkyl, saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsaturated C ₁ ～C ₆ Alkoxy, saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy group, or R ⁵ Absence of;

X ¹ selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted C ₁ ～C ₆ Alkylamino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ A cycloalkoxy group, wherein the "substitution" refers to a substituent optionally containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, sulfonyl, amino;

L ¹ selected from hydrogen, deuterium, halogen, cyano, hydroxy, carboxyl, amino, amido, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkyl, substituted or unsubstituted C ₂ ～C ₈ Alkenyl, substituted or unsubstituted C ₂ ～C ₈ Alkynyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₄ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 14 membered heterocycloalkyl 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, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfonyl, C ₁ ～C ₄ Alkylsulfonyl, amino, amido, -NR ^a R ^b 、C ₁ ～C ₄ Alkyl, C ₁ ～C ₄ Hydroxyalkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -C (=o) C _1-4 Alkyl, -C (=O) NR ^a R ^b ，C _1-4 Alkylsulfonyl, C ₆ -C ₁₄ Aryl, a 4 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a 5 to 10 membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^a And R is ^b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group.

Preferably, R ¹ 、R ² 、R ³ Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, cyano, sulfonyl, amino, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₃ Alkoxy, C ₃ ～C ₆ Substituents for cycloalkoxy;

more preferably, R ¹ 、R ² 、R ³ Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsubstituted saturated or unsaturated C ₅ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₅ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally Ground R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C ₅ ～C ₆ Cycloalkyl, substituted or unsubstituted 4 to 7 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, cyano, sulfonyl, amino, C ₁ ～C ₃ Alkyl, C ₅ ～C ₆ Cycloalkyl, C ₁ ～C ₃ Alkoxy, C ₅ ～C ₆ Substituents for cycloalkoxy groups.

More preferably, R ¹ 、R ² 、R ³ Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C ₁ ～C ₄ Alkyl, C ₁ ～C ₄ Alkoxy, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 7 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted C ₃ ～C ₅ Cycloalkyl; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, amino and C ₁ ～C ₃ Substituents of alkyl groups.

More preferably, R ¹ 、R ² 、R ³ Each independently selected from hydrogen, deuterium, methyl, ethyl, propyl; optionally R ¹ And R is ² Forming, together with the N atom and the C atom to which they are attached, a hydroxy-substituted 5-or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, a halogen-substituted 5-or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O; optionally R ² And R is ³ Together with the C atom to which they are attached form cyclopropyl or cyclobutyl.

Preferably, R ⁴ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₄ Alkyl, saturated or unsaturated C ₅ ～C ₆ Cycloalkyl, saturated or unsaturated C ₁ ～C ₄ Alkoxy, saturated or unsaturatedC ₅ ～C ₆ A cycloalkoxy group;

more preferably, R ⁴ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₃ Alkyl, saturated or unsaturated C ₁ ～C ₃ An alkoxy group;

more preferably, R ⁴ Selected from hydrogen, deuterium, halogen, saturated or unsaturated C ₁ ～C ₃ Alkyl, saturated or unsaturated C ₁ ～C ₃ An alkoxy group;

preferably, R ⁵ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₄ Alkyl, saturated or unsaturated C ₅ ～C ₆ Cycloalkyl, substituted or unsaturated C ₁ ～C ₄ Alkoxy, saturated or unsaturated C ₅ ～C ₆ Cycloalkoxy group, or R ⁵ Absence of;

more preferably, R ⁵ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsaturated C ₁ ～C ₃ Alkoxy or R ⁵ Absence of;

more preferably, R ⁵ Selected from hydrogen, deuterium, halogen, saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsaturated C ₁ ～C ₃ Alkoxy or R ⁵ Absence of;

preferably X ¹ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkoxy, wherein said "substituted" means optionally containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, sulfonyl, amino;

more preferably X ¹ Selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkoxy, wherein said "substituted" means optionally containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, sulfonyl, amino;

more preferably X ¹ Selected from hydrogen, deuterium, halogen, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkoxy, wherein said "substituted" means optionally containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, hydroxy, carbonyl, amino;

preferably L ¹ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carboxyl, amino, amido, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkyl, substituted or unsubstituted C ₂ ～C ₄ Alkenyl, substituted or unsubstituted C ₂ ～C ₄ Alkynyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfonyl, C ₁ ～C ₄ Alkylsulfonyl, amino, amido, -NR ^a R ^b ，C ₁ ～C ₄ Alkyl, C ₁ ～C ₄ Hydroxyalkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -C (=o) C _1-4 Alkyl, -C (=O) NR ^a R ^b ，C _1-4 Alkylsulfonyl, C ₆ -C ₁₀ Aryl, 4-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, containing 1 to 3 optional groupsSubstituents for 5-to 10-membered heteroaryl groups from heteroatoms of N, O and S, wherein R ^a And R is ^b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group;

more preferably L ¹ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carboxyl, amino, amido, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 8 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfonyl, C ₁ ～C ₄ Alkylsulfonyl, amino, amido, -NR ^a R ^b ，C ₁ ～C ₃ Alkyl, C ₁ ～C ₃ Hydroxyalkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₃ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -C (=o) C _1-4 Alkyl, -C (=O) NR ^a R ^b ，C _1-3 Alkylsulfonyl, phenyl, 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituent of 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^a And R is ^b Each independently selected from the group consisting of hydrogen,deuterium, halogen, cyano, hydroxy, carbonyl, amino, C ₁ ～C ₃ Alkyl, C ₁ ～C ₄ An alkoxy group;

more preferably L ¹ One selected from the following groups

-OH

Preferably, the compound of formula I or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is represented by formula I-1, formula I-2 or formula I-3 below:

wherein the substituents W ⁵ 、W ⁶ 、W ⁷ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、X ¹ 、L ¹ Is defined as in formula 1 above.

Preferably, the compound of formula I or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is represented by 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:

wherein the substituents W ⁵ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、X ¹ 、L ¹ Is defined as in formula 1 above.

Preferably, the compound 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 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 is selected from the group consisting of:

/>

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

According to a third aspect of the present invention, it is a further object of the present invention to provide the use of a compound according to the present invention or an isotopically labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for use in the treatment or prevention of a disease or condition mediated by TRK or a TRK mutation in a subject in need thereof.

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

More preferably, the disease or condition mediated by TRK or a TRK mutation is selected from the group consisting of surgical pain, inflammatory pain, neuropathic pain, alzheimer's disease, parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, salivary gland tumor, bile duct cancer, interstitial tumor, brain tumor, and hematological malignancy.

According to a fourth aspect of the present invention, it is a further object of the present invention to provide a kit of parts for the administration of a compound of formula I according to the present invention or an isotopically labelled compound thereof, or an optical isomer, a geometrical isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention, together with a container and instructions for use.

According to a fifth aspect of the present invention, it is a further object of the present invention to provide a method of treating a disease or condition mediated by TRK or a TRK mutation, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I according to the present 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 the pharmaceutical composition according to the present invention.

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.

As used herein, the terms "comprising," "including," "having," "containing," or any other similar language, are intended to cover a non-exclusive inclusion, as an open-ended connection (open-ended transitional phrase). For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….

All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.

If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.

In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.

In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is also meant that the claim of X as X1 and/or X2 have been fully described. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3" and Y is described as "selected from the group consisting of Y1, Y2, and Y3," then the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

Definition of the definition

"alkyl" refers to a group ("C") that is a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms _1–8 Alkyl "). In some embodiments, the alkyl hasHaving 1 to 7 carbon atoms ("C _1-7 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C _1-6 Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C _1-5 Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C _1-4 Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C _1-3 Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C _1-6 Alkyl "). C (C) _1–6 Examples of alkyl groups include methyl (C) ₁ ) Ethyl (C) ₂ ) Propyl (C) ₃ ) (e.g., n-propyl, isopropyl), butyl (C) ₄ ) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C) ₅ ) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl) and hexyl (C) ₆ ) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C ₇ ) N-octyl (C) ₈ ) Etc. Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl is unsubstituted C _1-8 Alkyl (e.g. unsubstituted C ₁ Alkyl radicals, e.g. -CH ₃ ). In certain embodiments, the alkyl is substituted C _1-8 Alkyl (e.g. substituted C ₁ Alkyl radicals, e.g. -CF ₃ )。

"alkoxy" means a monovalent-O-alkyl group in which the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups in this disclosure typically contain 1-6 carbon atoms ("C1-C6 alkoxy") or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy") or substituted (a "substituted alkoxy") with one or more substituents. In certain embodiments, the alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, the alkoxy is a substituted C1 to C6 alkoxy.

"cycloalkyl" means a non-aromatic ring system having 3 to 8 ring carbon atoms ("C _3-8 Cycloalkyl ") and zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C _3-8 Cycloalkyl "). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 8 ring carbon atoms ("C _5-8 Cycloalkyl "). Exemplary C _3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C) ₃ ) Cyclopropenyl (C) ₃ ) Cyclobutyl (C) ₄ ) Cyclobutenyl (C) ₄ ) Cyclopentyl (C) ₅ ) Cyclopentenyl (C) ₅ ) Cyclohexyl (C) ₆ ) Cyclohexenyl (C) ₆ ) Cyclohexadienyl (C) ₆ ) Etc. Exemplary C _3-8 Cycloalkyl groups include, but are not limited to, C described above _3-6 Cycloalkyl group and cycloheptyl (C) ₇ ) Cycloheptenyl (C) ₇ ) Cycloheptadienyl (C) ₇ ) Cycloheptatrienyl (C) ₇ ) Cyclooctyl (C) ₈ ) Cyclooctenyl (C) ₈ ) Etc. Each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents, unless otherwise specified. In certain embodiments, cycloalkyl is unsubstituted C _3-8 Cycloalkyl; in certain embodiments, cycloalkyl is substituted C _3-8 Cycloalkyl groups.

"heterocycloalkyl" refers to a group of a 5-to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-to 14-membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as the valence permits. The heterocyclic group may be a single ring ("monocyclic heterocyclic group") or a fused, bridged or spiro ring system, for example a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or may be partially unsaturated. "heterocyclic group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic system. Each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted by one or more substituents ("substituted heterocycloalkyl"), unless otherwise specified. In certain embodiments, the heterocycloalkyl is an unsubstituted 5-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 5-14 membered heterocycloalkyl.

"aryl" or "aromatic ring group" refers to a group ("C") of a single or multiple ring (e.g., bi-or tri-cyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system _6-14 Aryl "). In some embodiments, aryl groups have 6 ring carbon atoms ("C ₆ Aryl "; for example, phenyl). In some embodiments, aryl groups have 10 ring carbon atoms ("C ₁₀ Aryl "; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C ₁₄ Aryl "; for example, anthracyl). "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the point of attachment is on the aromatic ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, unless otherwise indicated. In certain embodiments, aryl is unsubstituted C _6-14 Aryl groups. In certain embodiments, aryl is substituted C _6-14 Aryl groups.

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

"halogen" or "halo" means fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

"substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is substituted with an allowable substituent, e.g., a substituent that upon substitution forms a stable compound, e.g., a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein which result in the formation of stable compounds. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

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

The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) may be obtained by contacting neutral forms of such compounds with sufficient amounts of an acid in pure solution or in a suitable inert solvent, examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; the organic acids include acids such as benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, sulfanilic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, folinic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

As used herein, the modifier term "about" refers to a change in value that may occur, for example, by routine testing and processing; unintentional errors in passing such tests and processing; differences in source or purity by the manufacture of the components used in the present invention; etc. As used herein, a "about" a particular value also includes the particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include equivalents to the listed amounts. In one embodiment, the term "about" means within 20% of the reported numerical value.

As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or disorder and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptom associated therewith. As used herein, the term "treatment" or the like may include "prophylactic treatment" referring to reducing the likelihood of recurrence of a disease or disorder or a previously controlled disease or disorder in a subject that is free of, or at risk of, suffering from, or susceptible to recurrence of the disease or disorder. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The compounds represented by formula I or isotopically-labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, and pharmaceutical compositions comprising the compounds provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterilizing devices for injection or instillation.

The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. For example, the unit dose of the formulation comprises from 0.05 to 2000mg of the compound of formula I or a pharmaceutically acceptable salt thereof, preferably the unit dose of the formulation comprises from 0.1mg to 1000mg of the compound of formula I.

The compounds and pharmaceutical compositions of the present invention represented by formula I may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Most preferably orally. The most preferable daily dosage is 0.01-200mg/kg body weight, and can be administered at one time, or 0.01-100mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.

In the present invention, the term "effective amount" may refer to an effective amount of dosage and period of time required to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or the condition of the disease at the time of treatment, the constitution of the particular target organ to be administered, the individual size of the patient, or the severity of the disease or symptoms. One of ordinary skill in the art will be able to determine empirically the effective amount of a particular compound without undue experimentation.

Typical formulations are prepared by mixing a compound of 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 materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The particular carrier, diluent or excipient used will depend upon the manner and purpose of use of the compounds of the present invention. The solvent is generally selected based on the solvent that one of ordinary skill in the art would consider to be safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG 300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make or use the drug in an acceptable form.

When the compound of formula I according to the present invention is 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 the invention of formula (I) may be administered to a subject separately or together in any known form of oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration.

These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make the pharmaceutical composition acceptable for manufacture or use.

The medicament of the invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular formulations. In solid dosage forms, the compounds or pharmaceutical compositions of the invention are admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starches, lactose, sucrose, mannitol, silicic acid and the like; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; humectants such as glycerin and the like; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, and the like; solution retarders such as paraffin and the like; absorption promoters such as quaternary ammonium compounds and the like; adsorbents such as kaolin, bentonite, and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using lactose as well as high molecular weight polyethylene glycols and the like as excipients.

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 pharmaceutical compositions thereof, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide; oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these, etc.

In addition to these inert diluents, the compositions can also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and perfuming agents.

As for the suspension, in addition to the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or a mixture of several of these substances, or the like, may be further contained.

The compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same may be administered in other topically administrable dosage forms, including ointments, powders, sprays and inhalants. The medicament may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and with any preservative, buffer or propellant required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

In addition, kits (e.g., pharmaceutical packaging) are also encompassed by the present disclosure. Kits are provided that can include a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampoule, bottle, syringe, and/or sub-packaging or other suitable container). In some embodiments, the provided kits may optionally further comprise a second container comprising a pharmaceutically acceptable excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical compositions or compounds described herein disposed in the first container and the second container are combined to form one unit dosage form.

In certain embodiments, the kits described herein further comprise instructions contained in the kit for using the compounds or pharmaceutical compositions. The kits described herein may also include information required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kits and instructions provide for treating a TRK mutation mediated disease and/or preventing a TRK mutation mediated disease in a subject in need thereof. The kits described herein may comprise one or more additional pharmaceutical agents as separate compositions.

The invention is described in further detail below in connection with specific examples, but the invention is not limited to the following examples, which are intended to better illustrate certain embodiments of the invention and are not to be construed as limiting the scope of the invention in any way. The conditions not specified in the examples are conventional conditions. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

The compounds of formula I of the present application may be synthesized by a variety of methods familiar to those skilled in the art of organic synthesis. Some exemplary methods for synthesizing compounds of formula I are given in the following specific examples, which are well known in the art of synthetic chemistry. Obviously, referring to the exemplary schemes in this patent, one skilled in the art can readily design synthetic routes for other compounds of formula I by appropriate adjustments of reactants, reaction conditions, and protecting groups.

The invention is further illustrated by the following examples; but these examples do not limit the scope of the invention. All reactants used in each example were obtained commercially unless otherwise stated; the instruments and equipment used in the synthesis experiments and the product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.

In the following examples, the structure of exemplary compounds of the present invention is 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 was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6) as solvent, deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) The internal standard is Tetramethylsilane (TMS).

An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC determination uses agilent 1200DAD high pressure liquid chromatograph. The thin layer chromatography silica gel plate is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier. In addition, without specific description, all reactions of the invention are carried out under continuous magnetic stirring in dry nitrogen or argon atmosphere, the solvent is dry solvent, and the reaction temperature is in degrees celsius.

Further, abbreviations used in the examples have the following meanings: NIS is N-iodosuccinimide; TMS, trimethylsilyl; pdCl ₂ (PPh ₃ ) ₂ Bis (triphenylphosphine) palladium dichloride; cuI: cuprous iodide; KF is potassium fluoride; cuSO ₄ Copper sulfate; VCNa, sodium ascorbate; pd (Pd) ₂ (dba) ₃ Tris (dibenzylideneacetone) dipalladium; BINAP 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; cs (cells) ₂ CO ₃ : cesium carbonate; na (Na) ₂ CO ₃ : sodium carbonate; naBH ₄ Sodium borohydride; BBr (BBr) ₃ Boron tribromide; LAH, lithium aluminum hydride; naOH: sodium hydroxide; BOC: t-butoxycarbonyl; EA: ethyl acetate; PE is petroleum ether; meOH: methanol; etOH: ethanol; DIEA: n, N-diisopropylethylamine; DMSO: dimethyl sulfoxide; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; dioxane: a dioxane; DMF: n, N-dimethylformamide; NMP: n-methylpyrrolidone; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; TLC: thin layer chromatography; structure: structural formula.

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

Step A: 6-chloro-3-iodoimidazo [1,2-b ] pyridazine (2)

6-chloroimidazo [1,2-b ] pyridazine (Compound 1, 50g,0.33 mol) was placed in methanol (2L), NIS (146.51 g,0.65 mol) was added, stirred at 70℃for 24 hours, then extracted with water (2L), and after filtration, the cake was slurried with petroleum ether and ethyl acetate (10:1) to give Compound 2 (60 g, yield: 66%) as a brown solid.

LCMS(m/z):280[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ＝7.89(d,J＝9.4,1H),7.85(s,1H),7.11(d,J＝9.4,1H).

And (B) step (B): 6-chloro-3- ((trimethylsilyl) ethynyl) imidazo [1,2-b ] pyridazine (3)

6-chloro-3-iodoimidazole [1,2-b ]]Pyridazine (Compound 2, 50g,0.18 mol) was placed in tetrahydrofuran (750 mL), and ethynyl trimethylsilane (21.09 g,0.21 mol) was added sequentially, pdCl ₂ (PPh ₃ ) ₂ (12.56 g,0.02 mol), cuprous iodide (3.41 g,0.02 mol) and triethylamine (90.51 g,0.89 mol), stirred at 25℃for 12 hours, then extracted with water (1.5L) and extracted 3 times with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give Compound 3 as a gray solid (25 g, yield: 56%).

LCMS(m/z):250[M+H] ⁺ .

Step C: n- (1- (2, 5-difluorophenyl) ethyl) -3-ethynylimidazo [1,2-b ] pyridazin-6-ylamine (5)

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

LCMS(m/z):299[M+H] ⁺ .

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

N- [1- (2, 5-difluorophenyl) ethyl ] -3-ethynylimidazo [1,2-b ] pyridazine-6-methylamine (compound 5, 50mg,0.17 mmol) is placed in tetrahydrofuran (1 mL) and water (1 mL), 3-azido-1-propanol (compound 6, 14.59mg,0.17 mmol), copper sulfate (20.95 mg,0.08 mmol), sodium erythorbate (66.41 mg,0.33 mmol) are added in sequence, and stirred at 15℃for 16 hours, then direct liquid chromatography produces compound I-1 (8.1 mg, yield: 15%) as a white solid.

LCMS(m/z):386[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )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).

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

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

6-chloro-3-iodoimidazole [1,2-b ]]Pyridazine (Compound 2, 20g,0.07 mol) was placed in tetrahydrofuran (400 mL), and ethynyl trimethylsilane (8.44 g,0.08 mol), pd (PPh ₃ ) ₂ Cl ₂ (5.03 g, 0.007mol), cuprous iodide (1.36 g,0.07 mol) and triethylamine (36.23 g,0.36 mol), stirred at 25℃for 12 hours, then extracted with water (1L) and extracted 3 times with ethyl acetate (300 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 7 (8.5 g, yield: 47%) as a white solid.

LCMS(m/z):250[M+H] ⁺ .

And (B) step (B): 6-chloro-3- ((trimethylsilyl) ethynyl) imidazo [1,2-b ] pyridazine (8)

6-chloro-3- [2- (trimethylsilyl) ethynyl ] imidazo [1,2-b ] pyridazine (compound 7,8g,0.03 mol) was placed in tetrahydrofuran and methanol 1:1 (80 mL) was added potassium carbonate (8.85 g,0.06 mol) in portions, stirred at 15℃for 1 hour under nitrogen protection, then extracted with water (40 mL), extracted 3 times with methylene chloride (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 8 (6 g, yield: 85%) as a white solid.

LCMS(m/z):178[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )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).

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

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

LCMS(m/z):265[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )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).

Step D2- (4- (6- ((1- (2-chloro-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -1H-1,2, 3-triazol-1-yl) ethyl-1-ol (I-2)

2- (4- { 6-chloroimidazo [1, 2-b)]Pyridazin-3-yl } -1,2, 3-triazol-1-yl) ethanol (Compound 9, 60mg,0.23 mmol)) was placed in 1, 4-dioxane (5 mL), and 1- (2-chloro-5-fluorophenyl) ethylamine (Compound 10, 39.36mg,0.23 mmol) and cesium carbonate (221.59 mg,0.68 mmol) Pd were added sequentially ₂ (dba) ₃ (20.76 mg,0.02 mmol) and BINAP (12.4 mg,0.02 mmol) were stirred under nitrogen at 100deg.C for 12 hours, then separated by direct liquid chromatography to give I-2 (4.5 mg, yield: 5%) as a white solid.

LCMS(m/z):402[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 3:2- (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-3)

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

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

LCMS(m/z):170[M+H] ⁺ .

And (B) step (B): 3-ethynyl-N- (1- (5-fluoro-2-methoxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-ylamine (13)

6-chloro-3- [2- (trimethylsilyl) ethynyl ] imidazo [1,2-b ] pyridazine (compound 7,1g,4.00 mmol) was placed in DMSO (10 mL), 1- (5-fluoro-2-methoxyphenyl) ethylamine (compound 12,1g,5.9 mmol), cesium carbonate (3.91 g,12 mmol) were added sequentially, stirred at 100℃for 16 hours, then diluted with water (10 mL) and extracted 3 times with dichloromethane (10 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography gave compound 13 (100 mg, yield: 9%) as a white solid after concentration.

LCMS(m/z):311[M+H] ⁺ .

Step C: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-3)

Compound I-3 was synthesized by the method described in example 1 with reference to compound I-1, starting from compound 13 instead of compound 5.

LCMS(m/z):398[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 4: 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-4)

Step A:2- (1-aminoethyl) -4-fluorophenol (14)

Compound 14 was synthesized by the method of referring to compound 12 using compound 1- (5-fluoro-2-hydroxyphenyl) ethanone as a starting material instead of compound 11.

LCMS(m/z):156[M+H] ⁺ .

¹ HNMR(DMSO-d6,400MHz)δ10.24(s,1H),8.48(br.s.,3H),7.31(dd,J＝2.9,9.7Hz,1H),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).

And (B) step (B): 2- (1- ((3-ethynylimidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) -4-fluorophenol (15)

Compound 15 was synthesized by the method described with reference to compound 13 using compound 14 as a starting material instead of compound 12.

LCMS(m/z):297[M+H] ⁺ .

Step C: preparation of 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-4)

Compound I-4 was synthesized by the method of referring to compound I-3 using compound 15 instead of compound 13 as a raw material.

LCMS(m/z):384[M+H] ⁺ .

¹ H NMR(400MHz,DMSO_d ₆ )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).

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)

Step A1- (3, 5-difluoro-2-methoxyphenyl) ethyl-1-amine (16)

The method of synthetic reference WO2019063748 for compound 16.

LCMS(m/z):188[M+H] ⁺ .

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).

Step B2- (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)

Compound I-5 was synthesized by the method of referring to compound I-2 using compound 16 as a starting material instead of compound 10.

LC-MS(m/z):416(M+H) ⁺

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)

To a solution of compound I-5 (120 mg,0.29 mmol) in methylene chloride (6 mL) was added dropwise a solution of boron tribromide (217.13 mg,0.87 mmol) in methylene chloride (2 mL) at room temperature, and after completion of the addition, the reaction mixture was stirred at room temperature for about 16 hours, and after completion of the reaction, an aqueous solution of saturated sodium hydrogencarbonate was added to the reaction mixture, which was filtered and the filtrate was purified by preparative chromatography to give compound I-6 (11 mg, yield: 21.93%) as a white solid.

LCMS(m/z):402(M+H) ⁺ .

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),6.81-6.76(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).

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)

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

Compound 17 reference CN 112110938.

LCMS(m/z):182[M+H] ⁺ .

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).

And (B) 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)

Compound I-7 was synthesized by the method of referring to compound I-2 using compound 17 as a starting material instead of compound 10.

LCMS(m/z):410[M+H] ⁺ .

¹ H NMR:(400MHz,MeOD-d ₄ )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).

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)

The compound I-8 is synthesized by taking the compound I-7 as a raw material instead of the compound I-5 and referring to the method of the compound I-6.

LCMS(m/z):396[M+H] ⁺ .

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)

Step A: (5-fluoro-2-methoxyphenyl) methanamine (18)

The method of synthesis reference US2018127356 of compound 18.

LCMS(m/z):156[M+H] ⁺ .

¹ H NMR(400MHz,MeOD-d ₄ )δ＝7.15-7.11(2H,m),7.06-7.03(1H,m),4.06(2H,s),3.88(3H,s)

Step B2- (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)

Compound I-9 was synthesized by the method of referring to compound I-2 using compound 18 instead of compound 10 as a raw material.

LCMS(m/z):384[M+H] ⁺ .

Example 10: 4-fluoro-2- (((3- (1- (2-hydroxyethyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) methyl) phenol (I-10)

Step A: preparation of 2- (aminomethyl) -4-fluorophenol (20)

5-fluoro-2-hydroxyphenylethyl (compound 19,2g,14.59 mmol) was placed in tetrahydrofuran (25 mL), lithium aluminum hydride (1.11 g,29.17 mmol) was added at 0℃under nitrogen protection, stirring was continued at 0℃for 0.5 hours, then methanol (20 mL) was used for dilution and filtration after extraction, and the filtrate was concentrated and separated by reversed phase liquid chromatography to give compound 20 (2.5 g, yield: 91.57%) as a yellow solid.

LCMS(m/z):142[M+H] ⁺ .

¹ H NMR:(400MHz,D ₂ O)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).

And (B) step (B): 4-fluoro-2- (((3- (1- (2-hydroxyethyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) methyl) phenol (I-10)

Compound I-10 was synthesized by the method of referring to compound I-2 using compound 20 instead of compound 10 as a raw material.

LCMS(m/z):370[M+H] ⁺ .

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)

Step A1- (5-fluoro-2-methoxypyridin-3-yl) ethyl-1-amine (21)

Compound 21 was synthesized by the method described in reference WO 2017004342.

LCMS(m/z):171[M+H] ⁺ .

Step B2- (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)

Compound I-11 was synthesized by the method of referring to compound I-2 using compound 21 as a starting material instead of compound 10.

LCMS(m/z):399[M+H] ⁺ .

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)

The compound I-12 is synthesized by taking the compound I-11 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):385[M+H] ⁺ .

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

Step A2- (5-fluoro-2-methoxyphenyl) propyl-2-amine (22)

The method of synthesis reference US2016221948 for compound 22.

LCMS(m/z):184[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ1.55(s,6H),6.99-7.12(m,2H),7.18-7.27(m,1H),7.41-7.46(m,1H)

Step B2- (4- (6- ((2- (5-fluoro-2-methoxyphenyl) propan-2-yl) amino) imidazo [1,2-B ] pyridazin-3-yl) -1H-1,2, 3-triazol-1-yl) ethyl-1-ol (I-13)

/>

Compound I-13 was synthesized by the method of referring to compound I-2 using compound 22 as a starting material instead of compound 10.

LCMS(m/z):412[M+H] ⁺ .

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) propan-2-yl) phenol (I-14)

The compound I-14 is synthesized by taking the compound I-13 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):398[M+H] ⁺ .

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)

Step A5-chloro-3- ((triethylsilyl) ethynyl) pyrazolo [1,5-a ] pyrimidine (24)

Compound 24 was synthesized by the method described with reference to compound 3, starting from compound 23 instead of compound 2.

LCMS(m/z):250[M+H] ⁺ .

Step B3-ethynyl-N- (1- (5-fluoro-2-methoxyphenyl) ethyl) pyrazolo [1,5-a ] pyrimidin-5-amine (25)

Compound 25 was synthesized by the method described with reference to compound 13 starting from compound 12 and compound 24 (instead of compound 7).

LCMS(m/z):311[M+H] ⁺ .

Step C2- (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)

Compound I-15 was synthesized by the method described in example 1 with reference to compound I-1, starting from compound 25 instead of compound 5.

LCMS(m/z):398[M+H] ⁺ .

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

Step A2- (1- ((3-ethynyl pyrazolo [1,5-a ] pyrimidin-5-yl) amino) ethyl) -4-fluorophenol (26)

Compound 26 was synthesized by the method described with reference to compound 15 starting from compound 14 and compound 24.

LCMS(m/z):297[M+H] ⁺ .

Step B4-fluoro-2- (1- ((3- (1- (2-hydroxyethyl) -1H-1,2, 3-triazol-4-yl) pyrazolo [1,5-a ] pyrimidin-5-yl) amino) ethyl) phenol (I-16)

Compound I-16 was synthesized by the method described with reference to compound I-4 using compound 26 as a starting material instead of compound 15.

LCMS(m/z):384[M+H] ⁺ .

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)

Step A (R) -1- (5-fluoro-2-methoxyphenyl) ethane-1-amine (27)

The synthesis of compound 27 was prepared according to the method of reference Journal of Medicinal Chemistry (1974), 17 (7), 708-15.

LCMS(m/z):170[M+H] ⁺ .

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)

Compound I-17 was synthesized by the method of substituting compound 27 for compound 12 and referring to compound I-3.

LCMS(m/z):398[M+H] ⁺ .

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)

Step A (S) -1- (5-fluoro-2-methoxyphenyl) ethane-1-amino (28)

The synthesis of compound 28 was prepared as described in reference Journal of Medicinal Chemistry (1974), 17 (7), 708-15.

LCMS(m/z):170[M+H] ⁺ .

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)

Compound I-18 was synthesized by the method of substituting compound 28 for compound 12 and referring to compound I-3.

LCMS(m/z):398[M+H] ⁺ .

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)

Step A (R) -2- (1-aminoethyl) -4-fluorophenol (29)

Compound 29 was synthesized by the method of reference compound 27.

LCMS(m/z):156[M+H] ⁺

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).

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)

Compound I-19 was synthesized by the method of referring to compound I-4 using compound 29 instead of compound 14 as a raw material.

LCMS(m/z):384[M+H] ⁺ .

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)

Step A (S) -2- (1-aminoethyl) -4-fluorophenol (30)

Compound 30 was synthesized by the method of reference compound 28.

LCMS(m/z):156[M+H] ⁺ .

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)

Compound I-20 was synthesized by the method of referring to compound I-4 using compound 30 instead of compound 14 as a raw material.

LCMS(m/z):384[M+H] ⁺ .

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)

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

Compound 31 was synthesized by the method of reference compound 27.

LCMS(m/z):171[M+H] ⁺ .

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)

Compound I-21 was synthesized by the method of substituting compound 31 for compound 21 and referring to compound I-11.

LCMS(m/z):399[M+H] ⁺ .

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)

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

Compound 32 was synthesized by the method of reference compound 28.

LCMS(m/z):171[M+H] ⁺ .

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)

Compound I-22 was synthesized by the method of referring to compound I-11 using compound 32 instead of compound 21 as a raw material.

LCMS(m/z):399[M+H] ⁺ .

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)

The compound I-23 is synthesized by taking the compound I-21 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):385[M+H] ⁺ .

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)

The compound I-24 is synthesized by taking the compound I-22 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):385[M+H] ⁺ .

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) propan-2-ol (I-25)

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

Reference RSC Advances; vol.6; nb.91; (2016); compound 33 was synthesized by the method of p.88859-88867.

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) propan-2-ol (I-25)

Compound I-25 was synthesized by the method of referring to compound I-17 using compound 33 as a starting material instead of compound 6.

LCMS(m/z):412[M+H] ⁺ .

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)

Compound I-26 was synthesized by the method of referring to compound I-19 using compound 33 as a starting material instead of compound 6.

LCMS(m/z):398[M+H] ⁺ .

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) propan-2-ol (I-27)

Compound I-27 was synthesized by the method of referring to compound I-21 using compound 33 as a starting material instead of compound 6.

LCMS(m/z):413[M+H] ⁺ .

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)

Compound I-28 was synthesized by the method of referring to compound I-23 using compound 33 as a starting material instead of compound 6.

LCMS(m/z):399[M+H] ⁺ .

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) ethan-1-ol (I-29)

Step A5-bromo-3-iodopyrazolo [1,5-a ] pyridine (34)

The compound 5-bromopyrazolo [1,5-a ] pyridine is taken as a raw material, and reference is made to Journal of Medicinal Chemistry; vol.61; nb.10; (2018); compound 34 was synthesized by the method of p.4386-4396.

LCMS(m/z):279[M+H] ⁺ .

Step B2- (4- (5-bromopyrazolo [1,5-a ] pyridin-3-yl) -1H-1,2, 3-triazol-1-yl) ethan-1-ol (35)

Compound 35 was synthesized by the method of substituting compound 34 for compound 2 and referring to compound 9.

LCMS(m/z):308[M+H] ⁺ .

Step C2- (4- (5- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) pyrazolo [1,5-a ] pyridin-3-yl) -1H-1,2, 3-triazol-1-yl) ethan-1-ol (I-29)

Compound I-29 was synthesized by the method of referring to compound I-2, using compound 35 instead of compound 9 as a raw material, and compound 12 instead of compound 10 as a raw material.

LCMS(m/z):397[M+H] ⁺ .

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),4.25(s,3H),3.82-3.79(m,2H),1.43(d,J＝6.8Hz,1H).

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)

Compound I-30 was synthesized by the method of referring to compound I-2, using compound 35 as a raw material instead of compound 9, and compound 14 as a raw material instead of compound 10.

LCMS(m/z):383[M+H] ⁺ .

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).

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

Compound I-31 was synthesized by the method of referring to compound I-25 using compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine as a starting material instead of compound 27.

LCMS(m/z):438[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-32)

The compound I-32 is synthesized by taking the compound I-31 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):424[M+H] ⁺

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) pyrrolidin-3-ol (I-33)

Compound I-33 was synthesized by the method of referring to compound I-25 using compound (3 s,5 s) -5- (5-fluoro-2-methoxyphenyl) pyrrolidin-3-ol as a starting material instead of compound 27.

LCMS(m/z):454[M+H] ⁺ .

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

Compound I-34 was synthesized by the method of referring to compound I-25 using compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine instead of compound 27 as a raw material.

LCMS(m/z):456[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-35)

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The compound I-35 is synthesized by taking the compound I-34 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):442[M+H] ⁺ .

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

Compound I-36 was synthesized by the method of referring to compound I-25 using compound (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine instead of compound 27 as a raw material.

LCMS(m/z):439[M+H] ⁺ .

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) pyrrolidin-2-yl) pyridin-2 (1H) -one (I-37)

The compound I-37 is synthesized by taking the compound I-36 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):425[M+H] ⁺ .

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

Compound I-38 was synthesized by the method of referring to compound I-25 using compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine as a starting material instead of compound 27.

LCMS(m/z):457[M+H] ⁺ .

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) pyrrolidin-2-yl) pyridin-2 (1H) -one (I-39)

The compound I-39 is synthesized by taking the compound I-38 as a raw material instead of the compound I-5 and referring to a method of the compound I-6.

LCMS(m/z):443[M+H] ⁺ .

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)

Step A1-azido-2-fluoroethane (36)

A solution of 2-fluoroethanol (1.0 g,15.6 mmol) in pyridine (8 mL) was cooled to 0deg.C, a solution of p-toluenesulfonyl chloride (5.95 g,31.2 mmol) in pyridine (10 mL) was added dropwise, the reaction mixture was stirred continuously at 0deg.C for about 3 hours, after completion of the reaction, the reaction mixture was poured into an ice water mixture, precipitation was observed, suction filtration was performed, and the obtained solid was washed with an aqueous solution of saturated sodium carbonate and dried to obtain 2-fluoroethyl-4-methylbenzenesulfonic acid. 2-fluoroethyl-4-methylbenzenesulfonate was dissolved in dry DMF (15 mL). Sodium azide (1.1 g,16.9 mmol) was added portionwise to the solution. Stirred at room temperature for 48 hours. The resulting solid was filtered to give 1-azido-2-fluoroethane (579 mg).

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

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)

Compound I-40 was synthesized by the method of substituting compound 36 for compound 6 and referring to compound I-19.

LCMS(m/z):386[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-41)

Step A (R) -1-azido-2-fluoropropane (37)

Compound 37 was synthesized by the method described with reference to compound 36 starting from compound (R) -2-fluoropropane-1-ol instead of 2-fluoroethanol.

And (B) 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) pyrrolidin-2-yl) phenol (I-41)

Compound I-40 was synthesized by the method of referring to compound I-32 using compound 37 as a starting material instead of compound 33.

LCMS(m/z):426[M+H] ⁺ .

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)

Compound I-42 was synthesized by the method of reference to Compound I-27 using commercially available azidoacetic acid instead of the compound at the 6-position starting material.

LCMS(m/z):413[M+H] ⁺ .

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 ] pyridazin-6-amine (I-43)

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) formate tert-butyl ester

Compound 38 was synthesized by the method of reference compound I-17 using commercially available N-Boc-2-azidoethylamine instead of starting at compound 6.

LCMS(m/z):497[M+H] ⁺ .

And (B) 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 ] pyridazin-6-amine (I-43)

Compound 38 (20 mg) was dissolved in dissolved methylene chloride (5 mL), trifluoroacetic acid (2 mL) was added, the reaction mixture was further stirred at room temperature for about 1 hour, after completion of the reaction, a saturated aqueous sodium carbonate solution was added to the reaction system, the pH was adjusted to about 8-9, methylene chloride (5 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain Compound I-43.

LCMS(m/z):397[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-44)

Step A: 2-azido-N-methylethan-1-amine (39)

N-methylamino-1-ethylbromohydrogen bromide (2.5 g,12.5 mmol) and sodium azide (1.5 g,23 mmol) were dissolved in water (25 mL). Heated at 75℃for 15 hours. The reaction mixture was cooled in an ice bath and sodium hydroxide (4 g) was added. The solution phase was separated and the organic phase was removed. The aqueous phase was extracted twice with diethyl ether and the organic layers combined. Dried over magnesium sulfate and concentrated to give the product (1.3 g).

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

LCMS(m/z):101[M+H] ⁺ .

And (B) 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) pyrrolidin-2-yl) phenol (I-44)

Compound I-44 was synthesized by the method of referring to compound I-35 using compound 39 as a starting material instead of compound 33.

LCMS(m/z):441[M+H] ⁺ .

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)

Step A: 2-azido-N, N-dimethylethane-1-amine (40)

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. Stirred at 80℃for 24 hours. The mixture was cooled. 1M sodium hydroxide solution was added and the mixture was adjusted to ph=10. The mixture was extracted three times with dichloromethane. The mixed extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound 40.

¹ H NMR:(400MHz,CDCl ₃ )δ＝3.41(t,J＝6.2Hz,2H),2.56(t,J＝6.2Hz,2H),2.32(s,6H).

LCMS(m/z):115[M+H] ⁺ .

And (B) 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)

Compound I-45 was synthesized by the method of referring to compound I-19 using compound 40 instead of compound 6 as a raw material.

LCMS(m/z):411[M+H] ⁺ .

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)

Step A2-azidoacetamide (41)

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℃overnight. After the reaction was completed, it was cooled to room temperature, and the product was extracted with ethyl acetate (3×10 mL). The organic phases are combined and washed with a small amount of saturated sodium solution, the organic phases are dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the product.

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

LCMS(m/z):101[M+H] ⁺ .

Compound I-46 was synthesized by the method described with reference to compound I-17 using compound 41 as a starting material instead of compound 6.

LCMS(m/z):411[M+H] ⁺ .

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

Compound I-47 was synthesized by the method described with reference to compound I-21 starting from commercially available 1-azido-2-methanesulfonylethane instead of compound 6.

LCMS(m/z):461[M+H] ⁺ .

Example 48: (R) -2- (1- ((3- (1- (2- (1H-imidazo l-5-yl) ethyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) -4-fluorophenol (I-48)

Step A5- (2-azidoethyl) -1H-imidazole (42)

Compound 42 was synthesized by the method described in literature Nature (London, unitekingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):138[M+H] ⁺ .

And (B) step (B): (R) -2- (1- ((3- (1- (2- (1H-imidazo l-5-yl) ethyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) -4-fluorophenol (I-48)

LCMS(m/z):434[M+H] ⁺ .

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)

Step A azidocyclopropane (43)

Compound 43, reference Chemical Biology and Drug Design; (2016); p.398-403.

LCMS(m/z):84[M+H] ⁺ .

And (B) 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)

Compound I-49 was synthesized by the method described with reference to compound I-19 using compound 43 as a starting material instead of compound 6.

LCMS(m/z):380[M+H] ⁺ .

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) cyclopropan-1-ol (I-50)

Step A1-azidocyclopropane-1-ol (44)

Compound 44 is synthesized by the method described in reference Recueil des Travaux Chimiques des Pays-Bas,1974, vol.93, p.287-289.

LCMS(m/z):100[M+H] ⁺ .

And (B) 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) cyclopropan-1-ol (I-50)

Compound I-50 was synthesized by the method of substituting compound 44 for compound 6-position starting material, and referring to compound I-21.

LCMS(m/z):411[M+H] ⁺ .

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)

Step A1- (azidomethylene) cyclopropan-1-ol (45)

Compound 45 was synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):114[M+H] ⁺ .

And (B) 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)

Compound I-51 was synthesized by the method of referring to compound I-19 using compound 45 instead of compound 6 as a raw material.

LCMS(m/z):410[M+H] ⁺ .

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)

Step A (1-azidocyclopropyl) methanol (46)

Compound 46 is synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):114[M+H] ⁺ .

And (B) 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)

Compound I-52 was synthesized by the method described with reference to compound I-19 using compound 46 as a starting material instead of compound 6.

LCMS(m/z):410[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-53)

Step A2-azidocyclopropane-1-ol (47)

Compound 47 is synthesized according to the method of Nature (London, united kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):100[M+H] ⁺ .

And (B) 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) pyrrolidin-2-yl) phenol (I-53)

Compound I-53 was synthesized by the method of referring to compound I-35 using compound 47 as a starting material instead of compound 33.

LCMS(m/z):440[M+H] ⁺ .

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)

Step A azidocyclobutane (48)

Compound 48 is synthesized as described in Synthesis,1971, p.325-326.

LCMS(m/z):98[M+H] ⁺ .

And (B) 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)

Compound I-54 was synthesized by the method described with reference to compound I-19 using compound 48 as a starting material instead of compound 6.

LCMS(m/z):394[M+H] ⁺ .

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

Step A3-azidoethane (49)

Compound 49 is synthesized according to the method of reference Journal of Organic Chemistry (1983), 48 (18), 2953-2956.

LCMS(m/z):98[M+H] ⁺ .

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

Compound I-55 was synthesized by the method of referring to compound I-19 using compound 49 as a starting material instead of compound 6.

LCMS(m/z):396[M+H] ⁺ .

Example 56: (R) -3- (1- (azetidin-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)

Step A3-azidoazetidine (50)

Compound 50 was synthesized according to the method of reference Journal of Organic Chemistry (1983), 48 (18), 2953-2956.

LCMS(m/z):99[M+H] ⁺ .

And (B) step (B): (R) -3- (1- (azetidin-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)

Compound I-56 was synthesized by the method of referring to compound I-17 using compound 50 as a starting material instead of compound 6.

LCMS(m/z):409[M+H] ⁺ .

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)

Step A3-azidocyclobutan-1-ol (51)

Compound 51 was synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):114[M+H] ⁺ .

And (B) 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)

Compound I-57 was synthesized by the method of referring to compound I-19 using compound 51 as a starting material instead of compound 6.

LCMS(m/z):410[M+H] ⁺ .

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

Step A4-azidoazetidin-2-one (52)

Compound 52 was synthesized according to the method of document Science of Synthesis (2005), 21, 325-386.

LCMS(m/z):113[M+H] ⁺ .

And (B) step (B): 4- (4- (6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -1H-1,2, 3-triazol-1-yl) azetidin-2-one (I-58)

Compound I-58 was synthesized by the method of referring to compound I-35 using compound 52 as a starting material instead of compound 33.

LCMS(m/z):453[M+H] ⁺ .

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

Step A (1R, 2R) -2-azidocyclopentan-1-ol (53)

Compound 53 was synthesized according to the method of reference Synthesis (2002), (15), 2254-2258.

¹ H NMR:(400MHz,CDCl ₃ )δ4.10(m,1H),3.72(m,1H),2.10(m,2H),1.72-1.60(m,4H).

LCMS(m/z):128[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- ((3- (1- ((1R, 2R) -2-hydroxycyclopentyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-59)

The compound 53 is used as a raw material to replace the compound 6, and the method for preparing the compound I-59 is used for preparing the compound I-19.

LCMS(m/z):424[M+H] ⁺ .

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

Step A (1R, 2S) -2-azidocyclopentan-1-ol (54)

Compound 54 was synthesized according to the method of reference Science of Synthesis (2007), 29, 193-249.

LCMS(m/z):128[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- ((3- (1- ((1R, 2S) -2-hydroxycyclopentyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-60)

Compound I-60 was synthesized by the method of referring to compound I-19 using compound 54 as a starting material instead of compound 6.

LCMS(m/z):424[M+H] ⁺ .

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

Step A (3S, 4S) -4-azidopyrrolidin-3-ol (55)

Compound 55 is described in Organic Letters; vol.10; nb.8; (2008); synthesis by the method of p.1617-1619.

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).

LCMS(m/z):129[M+H] ⁺ .

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

Compound I-61 was synthesized by the method described with reference to compound I-34 using compound 55 as a starting material instead of compound 33.

LCMS(m/z):483[M+H] ⁺ .

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

Step A (1S, 3R) -3-azidocyclopentan-1-ol (56)

Compound 56 was synthesized by the method described in document WO 2011086053.

¹ H NMR:(400MHz,CDCl ₃ )δ:4.25-4.30(m,1H),3.95-3.80(m,6H).

LCMS(m/z):128[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- ((3- (1- ((1R, 3S) -3-hydroxycyclopentyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-62)

Compound I-62 was synthesized by the method of substituting compound 56 for compound 6-position starting material and referring to compound I-19.

LCMS(m/z):424[M+H] ⁺ .

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

Step A (1R, 3R) -3-azidocyclopentan-1-ol (57)

Compound 57 is synthesized by the method of reference WO 2011086053.

¹ H NMR:(400MHz,CDCl ₃ )δ:4.27-4.35(m,1H),3.90-3.65(m,6H).

LCMS(m/z):128[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- ((3- (1- ((1R, 3R) -3-hydroxycyclopentyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-63)

Compound I-63 was synthesized by the method of referring to compound I-19 using compound 57 as a starting material instead of compound 6.

LCMS(m/z):424[M+H] ⁺ .

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)

Step A (S) -3-azidothetrahydrofuran (58)

Compound 58 is synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):114[M+H] ⁺ .

And (B) 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)

Compound I-64 was synthesized by the method of referring to compound I-19 using compound 58 as a starting material instead of compound 6.

LCMS(m/z):410[M+H] ⁺ .

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 ] pyridazin-6-amine (I-65)

Step A (R) -3-azidothetrahydrofuran (59)

Compound 59 was synthesized by the method described in literature Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):114[M+H] ⁺ .

And (B) 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 ] pyridazin-6-amine (I-65)

Compound I-65 was synthesized by the method of referring to compound I-21 using compound 59 as a starting material instead of compound 6.

LCMS(m/z):425[M+H] ⁺ .

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

Step A3-azidopyrrolidine (60)

Compound 60 is synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):113[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (1- (pyrrolidin-3-yl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-66)

Compound I-66 was synthesized by the method described with reference to compound I-26 using compound 60 instead of compound 33 as the starting material.

LCMS(m/z):453[M+H] ⁺ .

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

Step A (1R, 2R) -2-azidocyclohexan-1-ol (61)

Compound 61 is referred to the document RSC advance; vol.5; nb.112; (2015); synthesized by the method of p.92387-92393.

¹ H NMR:(400MHz,CDCl ₃ )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)

LCMS(m/z):142[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- ((3- (1- ((1R, 2R) -2-hydroxycyclohexane) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-67)

Compound I-67 was synthesized by the method of referring to compound I-19 using compound 61 instead of compound 6 as a raw material.

LCMS(m/z):438[M+H] ⁺ .

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)

Step A (1 r,4 r) -4-azidocyclohexan-1-ol (62)

Compound 62 is described in reference Advanced Synthesis andCatalysis; vol.354; nb.8; (2012); synthesis by the method of p.1417-1421.

¹ H NMR:(500MHz,CDCl ₃ )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).

LCMS(m/z):142[M+H] ⁺ .

And (B) 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)

Compound I-68 was synthesized by the method of referring to compound I-21 using compound 62 as a starting material instead of compound 6.

LCMS(m/z):453[M+H] ⁺ .

Example 69: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (1- (6- (hydroxymethyl) tetrahydroxy-2H-pyran-3-yl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-69)

Step A (5-azidothydro-2H-pyran-2-yl) methanol (63)

Compound 63 was synthesized by the method described in Nature (London, united kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):158[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (1- (6- (hydroxymethyl) tetrahydroxy-2H-pyran-3-yl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-69)

Compound I-69 was synthesized by the method of referring to compound I-35 using compound 63 as a starting material instead of compound 33.

LCMS(m/z):498[M+H] ⁺ .

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

Step A (1R, 3R) -3-azidocyclohexan-1-ol (64)

Compound 64 was synthesized by the method described in Nature (London, united kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):142[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- ((3- (1- ((1R, 3R) -3-hydroxycyclohexane) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-70)

Compound I-70 was synthesized by the method of substituting compound 64 for compound 6-position starting material, referring to compound I-19.

LCMS(m/z):438[M+H] ⁺ .

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 ] pyridazin-6-amine (I-71)

Step A (1R, 2R) -2-azidocyclohexane-1-amine (65)

Compound 65 was synthesized by the method described in reference Materials Today Communications (2020), 22,100747.

¹ H NMR:(400MHz,CDCl ₃ )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).

LCMS(m/z):141[M+H] ⁺ .

And (B) 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 ] pyridazin-6-amine (I-71)

Compound I-71 was synthesized by the method of referring to compound I-17 using compound 65 as a starting material instead of compound 6.

LCMS(m/z):451[M+H] ⁺ .

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)

Step A4-azidothydro-2H-pyran (66)

Compound 66 was synthesized by the method described in WO 2011/41399.

¹ H NMR:(400MHz,CDCl ₃ )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)

LCMS(m/z):128[M+H] ⁺ .

Compound I-72 was synthesized by the method of substituting compound 66 for compound 6-position starting material, and referring to compound I-19.

LCMS(m/z):424[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-73)

Step A (R) -3-azidopiperidine (67)

Compound 67 was synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):127[M+H] ⁺ .

And (B) 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) pyrrolidin-2-yl) phenol (I-73)

Compound I-73 was synthesized by the method of referring to compound I-35 using compound 67 instead of compound 33 as a raw material.

LCMS(m/z):467[M+H] ⁺ .

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)

Step A4-azidopiperidine (68)

Compound 68 was synthesized by the method described in reference European Journal of Medicinal Chemistry,2018, vol.145, p.191-205.

¹ H NMR(300MHz,CDCl ₃ )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,CDCl ₃ )δ54.3,40.6,27.4.

LCMS(m/z):127[M+H] ⁺ .

And (B) 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)

Compound I-74 was synthesized by the method described with reference to compound I-19 using compound 68 as a starting material instead of compound 6.

LCMS(m/z):423[M+H] ⁺ .

Example 75: 4-fluoro-2- ((R) -1- (3- (1- ((S) -tetrahydrogen-2H-pyran-3-yl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-75)

Step A (S) -3-azidothydro-2H-pyran (69)

Compound 69 was synthesized by the method described in literature Nature (London, unitekingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):128[M+H] ⁺ .

And (B) step (B): 4-fluoro-2- ((R) -1- (3- (1- ((S) -tetrahydrogen-2H-pyran-3-yl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-75)

Compound I-75 was synthesized by the method of referring to compound I-32 using compound 69 as a starting material instead of compound 33.

LCMS(m/z):450[M+H] ⁺ .

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)

Step A3-azidoaniline (70)

Compound 70 is synthesized by the method described in reference to Organic & Biomolecular Chemistry (2016), 14 (24), 5761-5767.

¹ H NMR(300MHz,CDCl ₃ )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,CDCl ₃ )147.7,140.8,130.3,111.6,108.8,105.2.

LCMS(m/z):135[M+H] ⁺ .

And (B) 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)

Compound I-76 was synthesized by the method of referring to compound I-19 using compound 70 instead of compound 6 as a raw material.

LCMS(m/z):431[M+H] ⁺ .

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)

Step A3-azidopyridin-2-amine (71)

Compound 71 was synthesized by the method described in reference Tetrahedron Letters (2015), 56 (47), 6606-6609.

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.

LCMS(m/z):136[M+H] ⁺ .

And (B) 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)

Compound I-77 was synthesized by the method of referring to compound I-19 using compound 71 as a starting material instead of compound 6.

LCMS(m/z):432[M+H] ⁺ .

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)

Step A5-azidopyridin-2-amine (72)

Compound 72 was synthesized by the method described in reference Letters in Drug Design & Discovery (2011), 8 (5), 401-405.

LCMS(m/z):136[M+H] ⁺ .

And (B) step (B): (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

Compound I-78 was synthesized by the method of referring to compound I-19 using compound 72 as a starting material instead of compound 6.

LCMS(m/z):432[M+H] ⁺ .

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)

Step A4-azidoaniline (73)

Compound 73 was synthesized according to the method of reference Organic & Biomolecular Chemistry (2016), 14 (24), 5761-5767.

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

LCMS(m/z):135[M+H] ⁺ .

And (B) 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)

Compound I-79 was synthesized by the method of referring to compound I-19 using compound 73 as a starting material instead of compound 6.

LCMS(m/z):431[M+H] ⁺ .

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)

Step A4-azidobenzeneamine (74)

Compound 74 is synthesized by the method described in WO 2021/5222.

LCMS(m/z):149[M+H] ⁺ .

And (B) 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)

Compound I-80 was synthesized by the method of referring to compound I-19 using compound 74 as a starting material instead of compound 6.

LCMS(m/z):445[M+H] ⁺ .

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) pyridin-3-hydroxy (I-81)

Step A5-azidopyridin-3-ol (75)

Compound 75 was synthesized by the method described in WO 2009143507.

LCMS(m/z):137[M+H] ⁺ .

And (B) 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) pyridin-3-hydroxy (I-81)

Compound I-81 was synthesized by the method of referring to compound I-19 using compound 75 as a starting material instead of compound 6.

LCMS(m/z):433[M+H] ⁺ .

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

Step A1-azido-4-methoxybenzene (76)

Compound 76 was synthesized by the method described in document WO 2009143507.

LCMS(m/z):150[M+H] ⁺ .

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

Compound I-82 was synthesized by the method described with reference to compound I-34 using compound 76 as a starting material instead of compound 33.

LCMS(m/z):504[M+H] ⁺ .

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)

Step A3-azidophenol (77)

Compound 77 was synthesized by the method of reference Synlett (2005), (14), 2209-2213.

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.

LCMS(m/z):136[M+H] ⁺ .

And (B) 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)

Compound I-83 was synthesized by the method of referring to compound I-19 using compound 77 as a starting material instead of compound 6.

LCMS(m/z):432[M+H] ⁺ .

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)

Step A2-azidophenol (78)

Compound 78 is described in reference European Journal of Medicinal Chemistry; vol.210; (2021); 112988.

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.

LCMS(m/z):136[M+H] ⁺ .

And (B) 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)

Compound I-84 was synthesized by the method of referring to compound I-19 using compound 78 instead of compound 6 as a raw material.

LCMS(m/z):432[M+H] ⁺ .

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)

Step A2-azidoacetonitrile (79)

Compound 79 is synthesized by the method of reference ChemPhysChem (2020), 21 (11), 1126-1133.

And (B) 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)

Compound I-85 was synthesized by the method of referring to compound I-19 using compound 79 as a starting material instead of compound 6.

LCMS(m/z):379[M+H] ⁺ .

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)

Step A2- (azidomethyl) -5-methylfuran (80)

Compound 80 was synthesized by the method described in Nature (London, united kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):138[M+H] ⁺ .

And (B) 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)

Compound I-86 was synthesized by the method of referring to compound I-19 using compound 80 as a starting material instead of compound 6.

LCMS(m/z):434[M+H] ⁺ .

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-fluoropyrrolidin-2-yl) -4-fluorophenol (I-87)

Step A4- (azidomethyl) -1H-pyrazole (81)

Compound 81 is synthesized by the method described in Nature (London, united kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):124[M+H] ⁺ .

And (B) 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-fluoropyrrolidin-2-yl) -4-fluorophenol (I-87)

/>

Compound I-87 was synthesized by the method of referring to compound I-35 using compound 81 as a starting material instead of compound 33.

LCMS(m/z):464[M+H] ⁺ .

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)

Step A4- (azidomethyl) -1-methyl-1H-pyrazole (82)

Compound 82 is synthesized by the method described in Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):138[M+H] ⁺ .

And (B) 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)

Compound I-88 was synthesized by the method described with reference to compound I-19 using compound 82 as a starting material instead of compound 6.

LCMS(m/z):434[M+H] ⁺ .

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

Step A4- (azidomethyl) -1-methyl-d ₃ -1H-pyrazole (83)

Compound 83 is synthesized by the method described in the literature Nature (London, united Kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):141[M+H] ⁺ .

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

Compound I-89 was synthesized by the method of referring to compound I-19 using compound 83 instead of compound 6 as a raw material.

LCMS(m/z):437[M+H] ⁺ .

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

Step A4- (azidomethyl) -2-methylthiophene (84)

Compound 84 is synthesized by the method described in Nature (London, united kingdom) (2019), 574 (7776), 86-89.

LCMS(m/z):154[M+H] ⁺ .

Step B (R) -N- (1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) -3- (1- ((5-methylthiophene-3-yl) methyl) -1H-1,2, 3-triazol-4-yl) imidazo [1,2-B ] pyridazin-6-amine (I-90)

Compound I-90 was synthesized by the method of referring to compound I-21 using compound 84 as a starting material instead of compound 6.

LCMS(m/z):465[M+H] ⁺ .

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)

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

Compound 85 was synthesized using the commercially available compounds 3-amino-6-chloroimidazo [1,2-B ] pyridazine and methyl 4, 4-dimethoxyacetoacetate as starting materials, by the method of reference Synlett,2020,31,175-178.

LCMS(m/z):293[M+H] ⁺ .

Step B2- (1- (6-chloroimidazo [1,2-B ] pyridazin-3-yl) -1H-1,2, 3-triazol-4-yl) ethan-1-ol (86)

Methyl 2- (1- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) -1H-1,2, 3-triazol-4-yl) acetate (compound 85, 293mg,1 mmol) was placed in tetrahydrofuran (5 mL), lithium aluminum (47.4 mg,2.14 mmol) was added, stirred at 25℃for 1 hour, then extracted with saturated ammonium chloride solution (5 mL) and extracted 2 times 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).

LCMS(m/z):265[M+H] ⁺ .

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)

Compound I-91 was synthesized by the method of referring to compound I-2, using compound 86 instead of compound 9 as a raw material, and compound 29 instead of compound 10 as a raw material.

LCMS(m/z):384[M+H] ⁺ .

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) pyrrolidin-2-yl) phenol (I-92)

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

Compound 87 was synthesized by the method of referring to compound I-2, using compound 86 as a raw material instead of compound 9, and compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine as a raw material instead of compound 10.

LCMS(m/z):424[M+H] ⁺ .

And (B) 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) pyrrolidin-2-yl) phenol (I-92)

Compound I-92 was synthesized by using compound 87 as a starting material instead of compound I-5 and referring to compound I-6.

LCMS(m/z):410[M+H] ⁺

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) pyrrolidin-2-yl) phenol (I-93)

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

Compound 88 is synthesized by a method of referring to compound I-2, using compound 86 instead of compound 9 as a raw material and compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine instead of compound 10 as a raw material.

LCMS(m/z):442[M+H] ⁺ .

And (B) 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) pyrrolidin-2-yl) phenol (I-93)

Compound I-93 was synthesized by using compound 88 as a starting material instead of compound I-5 and referring to compound I-6.

LCMS(m/z):428[M+H] ⁺

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) ethan-1-ol (I-94)

Compound I-94 was synthesized by the method of referring to compound I-2, using compound 86 instead of compound 9 as a raw material, and compound 31 instead of compound 10 as a raw material.

LCMS(m/z):399[M+H] ⁺ .

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

Compound I-95 was synthesized by the method of referring to compound I-2, using compound 86 instead of compound 9 as a raw material, and compound (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine instead of compound 10 as a raw material.

LCMS(m/z):425[M+H] ⁺ .

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

Compound I-96 was synthesized by the method of referring to compound I-2, using compound 86 instead of compound 9 as a raw material, and compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine instead of compound 10 as a raw material.

LCMS(m/z):443[M+H] ⁺ .

Example 97: biological evaluation

Test one: experiments on inhibition of the activity of the compounds on TRKA, TRKA (F589L), TRKA (G595R/G667C), TRKC (G696A) kinase, respectively

The experimental method comprises the following steps: compound preparation the compounds of examples 1-96 and Loxo-101 were each pre-dissolved in 100% DMSO to prepare 10mM stock solutions and stored frozen at-20 ℃.

The chemical structure of compound Loxo-101 is as follows and is commercially available and can be prepared with particular reference to WO 2010/48314.

Kinase reaction process: preparing a 1 XKinase buffer; preparing a compound concentration gradient: the test concentrations of the compounds of test examples 1-96 and of the compound Loxo-101 were 1000nM, and 100% DMSO solutions diluted 100-fold to final concentrations in 384 well plates were used to dilute the compounds 3-fold with precision to give 10 concentrations (1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.4, 0.16, 0.15 and 0.05 nM). The 250nL of 100-fold final concentration of compound was transferred to the destination plate OptiPlate-384F using a dispenser Echo 550; preparing a Kinase solution with a final concentration of 2.5 times by using a 1 XKinase buffer; mu.L of 2.5-fold final concentration Kinase solution was added to each of the compound wells and the positive control wells, and 10. Mu.L of 1 XKinase buffer was added to the negative control wells; centrifuging at 1000rpm for 30 seconds, shaking and uniformly mixing a reaction plate, and incubating at room temperature for 10 minutes; a mixed solution of ATP and Kinase substrate 22 was prepared at 5/3 times the final concentration using a 1 XKinase buffer; adding 15 mu L of a mixed solution of ATP and a substrate with 5/3 times of the final concentration, and initiating a reaction; centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating at room temperature for corresponding time; adding 30 mu L of stop detection solution to stop kinase reaction, centrifuging at 1000rpm for 30 seconds, and shaking and mixing uniformly; the conversion was read with Caliper EZ Reader.

Data analysis: the calculation formula is as follows:

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

wherein: conversion% _sample is a Conversion reading of the sample; convertion% _min: negative control Kong Junzhi, representing conversion reading without enzyme wells; convesion% _max: positive control Kong Bizhi mean represents conversion readings for wells without compound inhibition. A fitted dose-response curve, using the log of the concentration as X-axis and the percentage inhibition as Y-axis, using log (inhibitor) vs. response-Variable slope fitted dose-response curve of analytical software GraphPad Prism 5 to obtain IC of each compound to enzyme activity ₅₀ Values. The calculation formula is:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))。

where X represents the concentration of the test compound, Y represents the inhibition rate of the test compound at the concentration of X, top represents the maximum response, bottom represents the baseline response, hill Slope represents the Slope of the curve, i.e., the Slope.

IC of the respective Compounds on enzymatic Activity ₅₀ The values are shown in tables 1 to 3 below.

TABLE 1 different compounds vs. kinase TRKA ^WT In vitro inhibition test IC of (C) ₅₀ Test results (nM)

Experimental results indicate that most of the compounds in the application are expressed in kinase TRKA ^WT The inhibition capacity in the in vitro inhibition experiments of (a) is better than that of the compound Loxo-101, in particular to that of the 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 are obviously better than that of the compound Loxo-101.

TABLE 2 different compounds vs. kinase TRKA ^F589L In vitro inhibition test IC of (C) ₅₀ Test results (nM)

Compounds of formula (I)	TRKA ^F589L	Compounds of formula (I)	TRKA ^F589L	Compounds of formula (I)	TRKA ^F589L	Compounds of formula (I)	TRKA ^F589L
								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

Experimental results indicate that most of the compounds in the application are expressed in kinase TRKA ^F589L The inhibition capacity in the in vitro inhibition experiments of (a) is better than that of the compound Loxo-101, in particular to that of the 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 are obviously better than that of the compound Loxo-101.

TABLE 3 different compounds vs. kinase TRKC ^WT In vitro inhibition test IC of (C) ₅₀ Test results (nM)

Compounds of formula (I)

TRKC ^WT

Compounds of formula (I)

TRKC ^WT

Compounds of formula (I)

TRKC ^WT

Compounds of formula (I)

TRKC ^WT

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

Experimental results show that the compounds I-3, I-4, I-5, I-6, I-10, I-93, I-96 are used in the kinase TRKC ^WT The inhibition capacity in the in vitro inhibition experiments of (a) is obviously better than that of the compound Loxo-101.

Experiment II: the compound has growth inhibition effect on three cells of NTRK (Ba/F3-TPM 3-NTRK1-WT, ba/F3-TPM3-NTRK1-G595R, ba/F3-TPM3-NTRK 1-G667C).

Reagent:

Reagents	Catalog#
		RPMI 1640 medium	L210KJ
Fetal bovine serum	FSP500
		PBS	B310KJ
Penicillin Streptomycin,Liquid(P/S)	SV30010
		Cell Titer-Glo (CTG) kit	G7573

Cell line:

Cell line	Culture conditions
		BaF3-NTRKA G595R	RPMI 1640+10％FBS+1％P/S
BaF3-NTRKA G667C	RPMI 1640+10％FBS+1％P/S

compound solution preparation: the compounds of examples 1-96 and Loxo-101 were each pre-dissolved in 100% DMSO in a biosafety cabinet to prepare 10mM stock solution, which was frozen at-20 ℃; the stock solution of the compound is subjected to gradient dilution with DMSO: a clean and sterile 96-well microplate with a V-shaped bottom is placed in a biosafety cabinet, 4 mu L of DMSO is firstly added into a B2 well, 10 mu L of DMSO is added into a B3-B11 well, then 6 mu L of 10mM compound storage solution is added into the B2 well, the mixture is blown up and down for 10 times to uniformly mix, at the moment, the concentration of the compound in the B2 well is 6mM,100% DMSO is obtained, 5 mu L of solution is transferred into the B3 well, blown up and down for 10 times, uniformly mixing is carried out, and the mixture is sequentially diluted until the mixture is diluted to the B10 and B11 wells, and no compound to be tested is added.

Preparation of 6X compound solution (6-fold dilution, X represents dilution factor) (initial final concentration is 10. Mu.M), and placing a clean and sterile 96-well microplate with V-shaped bottom in a biosafety cabinet; adding 99 mu L of cell culture medium into each hole of the B2-G11, adding 1 mu L of the compound solution in each hole prepared in the previous step of compound solution preparation into the corresponding hole by using a 12-channel pipettor, and blowing the solution in each hole up and down for 10 times by using the pipettor to mix uniformly; the highest concentration of the compound at this time was 60. Mu.M;

compound-treated cells: taking the inoculated cell culture plate out of the incubator; adding 20 mu L of compound solution from each hole into the corresponding cell culture hole, selecting the lowest pipetting speed during sample adding, attaching to the wall and avoiding contacting the bottom of the culture plate; gently shaking the cell culture plate to homogenize the compound solution, and then placing the cell culture plate back into the incubator for continuous culture for 72hr;

the treatment concentration of the compound was at this point at most 10. Mu.M. After 72hr treatment of the cells, cell TiterGlo (CTG) assay was performed. First, the cell culture plate is removed from the CO ₂ Taking out the culture plate from the incubator, and placing the culture plate at room temperature for 30 minutes to ensure that the temperature of the culture plate is uniform; taking out a Cell TiterGlo reagent prepared in advance according to the specification, standing at room temperature, and melting; then 60. Mu.L of Cell TiterGlo reagent was added to each Cell-containing well Placing a horizontal shaking table under the condition of light room temperature at 225rpm, and incubating for 1hr; reading the plate according to the method in the specification by using a Tecan Spark enzyme-labelling instrument according to a chemiluminescence method, and performing IC (integrated circuits) on part of compounds for different cell lines ₅₀ Tables 4 to 6 below each show:

TABLE 4 in vitro inhibition experiments of different compounds on cells Ba/F3-TPM3-NTRK1-WT IC ₅₀ Test results (nM)

Experimental results show that the inhibition capacity of the compounds I-9,I-10, I-92, I-94 and I-95 in the in-vitro inhibition experiment of the cell Ba/F3-TPM3-NTRK1-WT is obviously better than that of the compound Loxo-101.

TABLE 5 in vitro inhibition experiments of different compounds on cells Ba/F3-TPM3-NTRK1-G595R IC ₅₀ Test results (nM)

Experimental results show that the inhibition capability of most of the compounds in the application in vitro inhibition experiments of Ba/F3-TPM3-NTRK1-G595R of cells is obviously better than that of the compounds Loxo-101, especially the compounds I-1, 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 are more prominent.

TABLE 6 in vitro inhibition experiments of different compounds on cells Ba/F3-TPM3-NTRK1-G667C IC ₅₀ Test results (nM)

Experimental results show that the inhibition capacity of the compound in the application in an in vitro inhibition experiment of the cell Ba/F3-TPM3-NTRK1-G667C is equivalent to that of the compound Loxo-101.

The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A compound of formula i or an isotopically-labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

wherein:

ring A is benzene ring, pyridine ring, hetero alkyl ring containing N atom;

R ¹ 、R ² 、R ³ each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ A cycloalkoxy group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted saturated or unsaturated 4-to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5-to 14-membered group containing 1 to 3 heteroatoms selected from N, O and S Heteroaryl, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 4 groups selected from deuterium, hydroxy, halogen, cyano, sulfonyl, amino, C ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -OC (=o) C _1-4 Alkyl, -OC (=o) C ₃ ～C ₆ Substituents of cycloalkyl;

X ¹ selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted C ₁ ～C ₆ Alkylamino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkoxy groupSubstituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ A cycloalkoxy group, wherein the "substitution" refers to a substituent optionally containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, sulfonyl, amino;

L ¹ selected from hydrogen, deuterium, halogen, cyano, hydroxy, carboxyl, amino, amido, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkyl, substituted or unsubstituted C ₂ ～C ₈ Alkenyl, substituted or unsubstituted C ₂ ～C ₈ Alkynyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₆ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₄ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 14 membered heterocycloalkyl 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, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfonyl, C ₁ ～C ₄ Alkylsulfonyl, amino, amido, -NR ^a R ^b 、C ₁ ～C ₄ Alkyl, C ₁ ～C ₄ Hydroxyalkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -C (=o) C _1-4 Alkyl, -C (=O) NR ^a R ^b ，C _1-4 Alkylsulfonyl, C ₆ -C ₁₄ Aryl, a 4 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a 5 to 10 membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^a And R is ^b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ CycloalkoxyA radical, C containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group.

2. A compound according to claim 1 or an isotopically labelled compound, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, characterized in that it is represented by the following formula I-1, formula I-2 or formula I-3:

wherein the substituents W ⁵ 、W ⁶ 、W ⁷ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、X ¹ 、L ¹ Is as defined in claim 1.

3. The compound of claim 1, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, characterized in that it is represented by the following 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:

Wherein the substituents W ⁵ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、X ¹ 、L ¹ Is as defined in claim 1.

4. A compound of formula I or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, as claimed in any one of claims 1 to 3,

more preferably, R ¹ 、R ² 、R ³ Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsubstituted saturated or unsaturatedC of (2) ₅ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₅ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C ₅ ～C ₆ Cycloalkyl, substituted or unsubstituted 4 to 7 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, cyano, sulfonyl, amino, C ₁ ～C ₃ Alkyl, C ₅ ～C ₆ Cycloalkyl, C ₁ ～C ₃ Alkoxy, C ₅ ～C ₆ Substituents for cycloalkoxy;

more preferably, R ¹ 、R ² 、R ³ Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C ₁ ～C ₄ Alkyl, C ₁ ～C ₄ Alkoxy, optionally R ¹ And R is ² Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 7 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, optionally R ² And R is ³ Form, together with the C atom to which they are attached, a substituted or unsubstituted C ₃ ～C ₅ Cycloalkyl; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, amino and C ₁ ～C ₃ Substituents of alkyl;

5. A compound of formula I or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, as claimed in any one of claims 1 to 3,

preferably, R ⁴ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₄ Alkyl, saturated or unsaturated C ₅ ～C ₆ Cycloalkyl, saturated or unsaturated C ₁ ～C ₄ Alkoxy, saturated or unsaturated C ₅ ～C ₆ A cycloalkoxy group;

More preferably, R ⁵ Selected from hydrogenDeuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsaturated C ₁ ～C ₃ Alkoxy or R ⁵ Absence of;

preferably L ¹ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carboxyl, amino, amido, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkyl, substituted or unsubstituted C ₂ ～C ₄ Alkenyl, substituted or unsubstituted C ₂ ～C ₄ Alkynyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substitutedOr unsubstituted saturated or unsaturated C ₁ ～C ₄ Alkoxy, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfonyl, C ₁ ～C ₄ Alkylsulfonyl, amino, amido, -NR ^a R ^b ，C ₁ ～C ₄ Alkyl, C ₁ ～C ₄ Hydroxyalkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -C (=o) C _1-4 Alkyl, -C (=O) NR ^a R ^b ，C _1-4 Alkylsulfonyl, C ₆ -C ₁₀ Aryl, 4 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituent of 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^a And R is ^b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino ₁ ～C ₄ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₄ Alkoxy, C ₃ ～C ₆ A cycloalkoxy group;

more preferably L ¹ Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carboxyl, amino, amido, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkyl, substituted or unsubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkyl, substituted or unsubstituted saturated or unsaturated C ₁ ～C ₃ Alkoxy, substituted or unsubstitutedSubstituted saturated or unsaturated C ₃ ～C ₆ Cycloalkoxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 8 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfonyl, C ₁ ～C ₄ Alkylsulfonyl, amino, amido, -NR ^a R ^b ，C ₁ ～C ₃ Alkyl, C ₁ ～C ₃ Hydroxyalkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₃ Alkoxy, C ₃ ～C ₆ Cycloalkoxy, -C (=o) C _1-4 Alkyl, -C (=O) NR ^a R ^b ，C _1-3 Alkylsulfonyl, phenyl, 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituent of 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^a And R is ^b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C ₁ ～C ₃ Alkyl, C ₁ ～C ₄ An alkoxy group;

more preferably L ¹ One selected from the following groups

6. A compound according to any one of claims 1 to 5, or an isotopically labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, selected from the group consisting of:

7. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 6, or an isotopically-labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for use in the treatment or prevention of a disease or condition mediated by TRK or a TRK mutation in a subject in need thereof;

preferably, the disease or disorder mediated by TRK or a TRK mutation is selected from one or more of cancer, neurodegenerative disease, inflammation, pain;

9. A kit of parts comprising a compound according to any one of claims 1 to 6 or an isotopically labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 7, together with a container and instructions for use.

10. A method of treating a disease or disorder mediated with TRK or a TRK mutation, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 6 or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 7.