WO2021185305A1 - Indazole derivative and medical use thereof - Google Patents

Abstract

Disclosed are a compound as shown in general formula (I) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, intermediates thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating JAK-mediated diseases.

Description

An indazole derivative and its application in medicine Technical field

The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and intermediates and preparation methods thereof , And its application in the preparation of drugs for treating JAK-mediated diseases.

Background technique

Asthma is a chronic respiratory disease characterized by inflammation in the airway and increased airway responsiveness to various allergens. This disease causes degeneration, fibrosis, overreaction and remodeling of the patient’s airway, leading to Respiratory airflow is restricted. Approximately 300 million people worldwide suffer from asthma, and by 2025 it is expected that there will be an increase of 100 million patients. At present, most patients can control asthma symptoms through inhaled corticosteroids, combined with leukotrienes or long-acting beta agonists, but there are still some patients who cannot be relieved by the above methods, and such patients have high morbidity and death Rate.

Cytokines are a class of extracellular signaling molecules composed of interleukins, interferons, tumor necrosis factor superfamily, colony stimulating factors, chemokines, and growth factors. They generally regulate cell growth, differentiation and cell growth by binding to corresponding receptors. Effect, regulate the immune response. The levels of many cytokines play an important role in the pathology of asthma inflammation. For example, the method of targeting the interleukins IL-5 and IL-13 by antibodies has a good effect in the treatment of patients with severe asthma. In addition, more and more clinical pathological studies have shown that there are many cytokines related to the treatment of asthma, such as IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11 , IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon gamma (IFN gamma) and granulocyte macrophage colony stimulating factor (GM-CSF), these cytokines The signal is regulated by Janus family (JAKs) tyrosine kinases/signal transducers and transcription activator family (STATs) transcription factors.

The Janus family (JAKs) consists of four members, including JAK1, JAK2, JAK3 and TYK2. Cytokines trigger receptor dimerization by binding to the receptors in JAK, and promote the phosphorylation of JAK kinase tyrosine residues, thereby enabling JAK to activate. On the contrary, the phosphorylated JAKs kinase further binds and phosphorylates a variety of STAT proteins, induces their dimerization and fusion in the nucleus, directly regulates gene transcription and activates downstream disease signal factors. In addition to asthma, JAK-mediated cytokines are related to other respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial pneumonia, acute lung injury, acute respiratory distress syndrome, bronchial Inflammation, emphysema, bronchiolitis obliterans.

Since each member can regulate at least one cytokine related to asthma, it is of great significance to develop a new type of pan-JAKs inhibitor.

Summary of the invention

The purpose of the present invention is to provide a compound capable of inhibiting JAK kinase or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and intermediates and preparation methods thereof , And its application in the preparation of drugs for treating JAK kinase-mediated diseases.

The present invention provides a compound of general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein

选自

优选为

In some embodiments,

Selected from

Preferably

选自

In some embodiments,

Selected from

In certain embodiments, m is 1;

选自

以及m选自1； In some embodiments,

Selected from

And m is selected from 1;

In certain embodiments, R ¹ and R ² are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkane Oxy, C _2-6 alkenyl or C _2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, and alkynyl groups are optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 Or 4) Substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _{1-4 alkoxy;}

In certain embodiments, ^{each R 1 is} independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or propoxy;

In certain embodiments, ^{each R 1 is} independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, or isopropyl;

选自

In some embodiments,

Selected from

In certain embodiments, R ¹ is 2-ethyl, 5-fluoro, and 4-hydroxy; or R ¹ is 2-ethyl and 4-hydroxy;

In certain embodiments, ^{each R 2 is} independently selected from H or F;

In certain embodiments, R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, or isopropyl, R ^{2 is} selected from H or F, n2 is selected from 1, n1 Selected from 1, 2 or 3;

In certain embodiments, ^{each R 2 is} independently selected from H, F, OH, CF ₃ , methyl, or methoxy;

In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl , C _1-6 alkoxy, C _2-6 alkynyl, -COOH, -COOC _1-4 alkyl, -C(=O)NR ^a R ^b , C _3-12 carbocyclic group or 3 to 12 member Heterocyclyl, the alkyl, alkoxy, alkynyl, carbocyclic or heterocyclic group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, It is substituted by halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-12 carbocyclic group or 3 to 12-membered heterocyclic group, the heterocyclic group contains 1 to 4 Heteroatoms selected from O, S, N;

In certain embodiments, R ³ , R ⁴ , R ⁵ and R ^{6 are} not hydrogen at the same time;

In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl , Methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C( =O) NR ^a R ^b , wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piper The pyridine, phenyl, imidazolyl or benzimidazolyl is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _{Substituted by 1-4} alkoxy, C _3-6 carbocyclic group or 3 to 6-membered heterocyclic group, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl , Methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C( =O) NR ^a R ^b , wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piper The pyridine, phenyl, imidazolyl or benzimidazolyl is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -NH-cyclopropyl, methyl, ethyl, methoxy, ethoxy , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidinyl, oxetanyl, oxolanyl or oxanyl Substituent substituted;

In certain embodiments, R ^a and R ^b are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3 to 6 membered heterocyclyl, said alkyl, cycloalkane The group or heterocyclic group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy Substituents are substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N;

In certain embodiments, R ^a and R ^b are each independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclic Pentyl, azetidinyl, oxetanyl, oxetanyl or oxetanyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Group, azetidinyl, azetidinyl, azetidinyl, oxetanyl, oxetanyl or oxetanyl is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy substituents;

环丙基、环丁基、氮杂环己基、哌啶、苯基、咪唑基、苯并咪唑基、-COOH、-COOCH ₃、-C(＝O)NH ₂、-C(＝O)NHCH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)NHCH ₂CH ₃、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-氮杂环丁基、-C(＝O)NH-氮杂环戊基、-C(＝O)NH-氮杂环已基、-C(＝O)NH-氧杂环丁基、-C(＝O)NH-氧杂环戊基或-C(＝O)NH-氧杂环已基； In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl , Methoxy, ethynyl, propynyl, methoxymethyl, ethoxymethyl, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ 、-CH ₂ OH、-CH ₂ CH ₂ OH、

Cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NHCH ₂ CH ₃ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-ring Propyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH-azacyclic Butyl, -C(=O)NH-azacyclopentyl, -C(=O)NH-azacyclohexyl, -C(=O)NH-oxetanyl, -C(=O )NH-oxanyl or -C(=O)NH-oxanyl;

环丙基、N-甲基哌啶、咪唑基、苯并咪唑基、-COOH、-C(＝O)NH ₂、-C(＝O)NHCH ₃、-C(＝O)N(CH ₃) ₂或-C(＝O)NH-环丙基； In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl, isopropyl, ethynyl, propynyl, Methoxymethyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ OH,

Cyclopropyl, N-methylpiperidine, imidazolyl, benzimidazolyl, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ or -C(=O)NH-cyclopropyl;

In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, methoxy, -CH ₂ OH, ethynyl or propynyl;

In certain embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl, -CH ₂ OH, ethynyl, or propynyl ；

In certain embodiments, any R ³ , R ⁴ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further divided by 0 to 4 One (e.g. 0, 1, 2, 3 or 4) is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy The heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N;

In certain embodiments, alternatively, any R ⁵ , R ⁶ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 Substituted by alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, which is optionally further divided by 0 to 4 (e.g., 0, 1, 2 , 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, said The heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N;

In certain embodiments, any R ³ , R ⁴ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further divided by 0 to 4 One (for example, 0, 1, 2, 3 or 4) selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N;

In certain embodiments, any R ⁵ and R ⁶ together with the atoms to which they are attached form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further divided by 0 to 4 One (for example, 0, 1, 2, 3 or 4) selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In certain embodiments, any R ³ , R ⁵ and the atoms to which they are attached form a 4- to 6-membered heterocyclic ring, which is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) Substituted by a substituent selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy, and the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4 ) Heteroatoms selected from O, S, N;

In certain embodiments, any R ³ , R ⁴ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring, which is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 Or 4) Substituted by a substituent selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy;

In certain embodiments, n1 is selected from 0, 1, 2, 3, or 4, and n2 is selected from 0, 1, 2 or 3;

In certain embodiments, n1 is selected from 0, 1, 2, 3, or 4, and n2 is selected from 0 or 1;

In certain embodiments, n1 is selected from 2, 3, or 4, and n2 is selected from 0 or 1;

p and q are each independently selected from 0, 1, 2 or 3, and p+q≥1;

m is selected from 1, 2 or 3;

Provided that the compound is not

As the first embodiment of the present invention, the aforementioned compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein

R ¹ and R ² are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 Alkenyl or C _2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, and alkynyl groups are optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkoxy Group or C _2-6 alkynyl, -COOH, -COOC _1-4 alkyl, -C(=O)NR ^a R ^b , C _3-12 carbocyclic group or 3 to 12 membered heterocyclic group, wherein Alkyl, alkoxy, alkynyl, carbocyclyl or heterocyclyl is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen substituted C _{1- 4} alkyl group, C _1-4 alkoxy group, C _3-12 carbocyclic group or 3 to 12 membered heterocyclic group substituted by substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3 or 4) Heteroatoms selected from O, S and N;

R ^a and R ^b are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3 to 6 membered heterocyclic group, said alkyl, cycloalkyl or heterocyclic group optionally Ground is further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N (C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy substituent substituted, said The heterocyclic group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;

Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent Substitution, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;

Alternatively, any R ⁵ , R ⁶ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring or 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent Substitution, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;

Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 One (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;

n1 is selected from 0, 1, 2, 3 or 4;

n2 is selected from 0, 1, 2 or 3;

p and q are each independently selected from 0, 1, 2 or 3, and p+q≥1;

m is selected from 1, 2 or 3;

Provided that the compound is not

As a second embodiment of the present invention, the aforementioned compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein

R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

R ^{2 is} each independently selected from H, F, OH, CF ₃ , methyl or methoxy;

The definitions of other groups are the same as in the aforementioned first aspect of the present invention.

As the third embodiment of the present invention, the aforementioned compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl or isopropyl;

R ^{2 is} each independently selected from H or F;

选自

Selected from

m is selected from 1;

n1 is selected from 1, 2 or 3;

n2 is selected from 1.

As the fourth embodiment of the present invention, the aforementioned compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein the general formula The compound of (I) is selected from the compound of the general formula (Ia),

The definition of each substituent is the same as the aforementioned second embodiment of the present invention.

As the fifth embodiment of the present invention, the aforementioned compound of general formula (Ia) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl , Propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C(=O)NR ^a R ^b , where The methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, phenyl, imidazolyl or benzimidazolyl Optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring Group or a substituent of a 3- to 6-membered heterocyclic group, said heterocyclic group containing 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;

R ^a and R ^b are each independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidine Group, oxetanyl, oxetanyl or oxetanyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, azacyclohexyl, oxetanyl, oxolanyl or oxetanyl are optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4 ) Is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy substituents;

Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) is substituted by a substituent selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy, and the heterocyclic ring contains 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N;

Alternatively, any R ⁵ , R ⁶ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring or 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) is substituted by a substituent selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy, and the heterocyclic ring contains 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N;

Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms.

As the sixth embodiment of the present invention, the aforementioned compound of general formula (Ia) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

环丙基、环丁基、氮杂环己基、哌啶、苯基、咪唑基、苯并咪唑基、-COOH、-COOCH ₃、-C(＝O)NH ₂、-C(＝O)NHCH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)NHCH ₂CH ₃、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-氮杂环丁基、-C(＝O)NH-氮杂环戊基、-C(＝O)NH-氮杂环已基、-C(＝O)NH-氧杂环丁基、-C(＝O)NH-氧杂环戊基或-C(＝O)NH-氧杂环已基； R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl , Propynyl, methoxymethyl, ethoxymethyl, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH,

Cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NHCH ₂ CH ₃ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-ring Propyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH-azacyclic Butyl, -C(=O)NH-azacyclopentyl, -C(=O)NH-azacyclohexyl, -C(=O)NH-oxetanyl, -C(=O )NH-oxanyl or -C(=O)NH-oxanyl;

Alternatively, any R ³ , R ⁴ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring, and the carbocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4). Substituted by substituents of H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy;

Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms.

As the seventh embodiment of the present invention, the aforementioned compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein the general formula The compound described in (I) is selected from the compound described in general formula (Ia-1) or (Ib),

The definition of each substituent is the same as the aforementioned second embodiment of the present invention.

As an eighth embodiment of the present invention, the aforementioned compound of general formula (Ia-1) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or Eutectic,

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, cyclopropyl, Cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C(=O)NR ^a R ^b , wherein the methyl, ethyl , Propyl, isopropyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl or benzimidazolyl are optionally further substituted by 0 to 4 One (e.g. 0, 1, 2, 3 or 4) is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N (C _1-4 alkane Group) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 3 to 6-membered hetero Substituents of the cyclic group, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;

R ^a and R ^b are each independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidine Group, oxetanyl, oxetanyl or oxetanyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, azacyclohexyl, oxetanyl, oxolanyl or oxetanyl are optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4 ) Is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy substituents;

Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) is substituted by a substituent selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy, and the heterocyclic ring contains 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N;

Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms.

As the ninth embodiment of the present invention, the aforementioned compound of general formula (Ia-1) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or Eutectic,

环丙基、N-甲基哌啶、咪唑基、苯并咪唑基、-COOH、-C(＝O)NH ₂、-C(＝O)NHCH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)NH-环丙基； R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl, isopropyl, ethynyl, propynyl, methoxymethyl,- CH ₂ N(CH ₃ ) ₂ 、-CH ₂ OH、

Cyclopropyl, N-methylpiperidine, imidazolyl, benzimidazolyl, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NH-cyclopropyl;

Alternatively, any R ³ , R ⁴ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring, and the carbocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4). Substituted by substituents of H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy;

Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms.

As a tenth embodiment of the present invention, the following compound of general formula (Ic) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

Each R ^{2 is} independently selected from H, F, OH, CF ₃ , methyl or methoxy.

As the eleventh embodiment of the present invention, the aforementioned compound of general formula (Ic) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

R ^{1 is} selected from H or F;

R ^{2 is} selected from H or F.

The present invention relates to general formula (I), (Ia), (Ia-1), (Ib), the compound is not

Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ia-1), (Ib), (Ic) or its stereoisomers, deuterated products, solvates, pro Drug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the following structures:

The present invention relates to some embodiments of general formula (I) and (Ic), R ¹ and R ² are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl or C _2-6 alkynyl, the alkyl, alkoxy, alkenyl, and alkynyl groups are optionally further substituted by 0 to 4 One (e.g. 0, 1, 2, 3 or 4) is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy The substituents are substituted.

The present invention relates to some embodiments of general formula (I) and (Ic), R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy or propoxy.

The present invention relates to some embodiments of the general formulas (I) and (Ic), R ^{2 is} each independently selected from H, F, OH, CF ₃ , methyl or methoxy.

The present invention relates to some embodiments of the general formulas (I) and (Ic), ^{each of R 1 is} independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl or isopropyl.

The present invention relates to some embodiments of general formula (I) and (Ic), R ^{2 is} each independently selected from H or F.

The present invention relates to some embodiments of the general formulas (I) and (Ic), R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl or isopropyl, and R ^{2 is} selected From H or F, n2 is selected from 1, and n1 is selected from 1, 2 or 3.

选自

The present invention relates to some embodiments of general formula (I) and (Ic),

Selected from

选自

m选自1。 The present invention relates to some embodiments of general formula (I),

Selected from

m is selected from 1.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkoxy or C _2-6 alkynyl, -COOH, -COOC _1-4 alkyl, -C (=O)NR ^a R ^b , C _3-12 carbocyclic group or 3-12 membered heterocyclic group, wherein the alkyl, alkoxy, alkynyl, carbocyclic or heterocyclic group is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N (C _{1 -4} alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-12 carbocyclic group or 3 to A 12-membered heterocyclic group is substituted by a substituent, and the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano , CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, Phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C(=O)NR ^a R ^b , wherein the methyl, ethyl, propyl, isopropyl, methoxy, acetylene Group, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl or benzimidazolyl is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N (C _1-4 alkyl) ₂ , NHC _3-6 ring Alkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 3- to 6-membered heterocyclic group substituted by substituents, The heterocyclic group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano , CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, Phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C(=O)NR ^a R ^b , wherein the methyl, ethyl, propyl, isopropyl, methoxy, acetylene Group, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl or benzimidazolyl is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -NH-Cyclopropyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, nitrogen Substituents of heterocyclohexyl, oxetanyl, oxolanyl or oxolanyl are substituted.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ^a and R ^b are each independently selected from H, C _1-6 alkyl, C _{3- 6} cycloalkyl or 3 to 6 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H , F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 Alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ^a and R ^b are each independently selected from H, methyl, ethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidinyl, oxetanyl, oxolanyl or oxetanyl, where all Said methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidinyl, oxetanyl, oxetanyl The pentyl or oxacyclohexyl group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH _2. NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkane The substituent of the oxy group is substituted.

环丙基、环丁基、氮杂环己基、哌啶、苯基、咪 唑基、苯并咪唑基、-COOH、-COOCH ₃、-C(＝O)NH ₂、-C(＝O)NHCH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)NHCH ₂CH ₃、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-氮杂环丁基、-C(＝O)NH-氮杂环戊基、-C(＝O)NH-氮杂环已基、-C(＝O)NH-氧杂环丁基、-C(＝O)NH-氧杂环戊基或-C(＝O)NH-氧杂环已基。 The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano , CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, methoxymethyl, ethoxymethyl, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH,

Cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NHCH ₂ CH ₃ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-ring Propyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH-azacyclic Butyl, -C(=O)NH-azacyclopentyl, -C(=O)NH-azacyclohexyl, -C(=O)NH-oxetanyl, -C(=O ) NH-oxolanyl or -C(=O)NH-oxolanyl.

环丙基、N-甲基哌啶、咪唑基、苯并咪唑基、-COOH、-C(＝O)NH ₂、-C(＝O)NHCH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)NH-环丙基。 The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano , CF ₃ , methyl, ethyl, isopropyl, ethynyl, propynyl, methoxymethyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ OH,

Cyclopropyl, N-methylpiperidine, imidazolyl, benzimidazolyl, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NH-cyclopropyl.

The present invention relates to some embodiments of general formula (I) and (Ia), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl Group, ethyl, methoxy, ethynyl, propynyl or -CH ₂ OH.

The present invention relates to some embodiments of the general formula (Ia-1), (Ib), R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl Group, ethynyl, propynyl or -CH ₂ OH.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or 3 To a 6-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, OH, cyano , CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), alternatively, any R ⁵ , R ⁶ and the atoms to which they are connected together form a C _3-6 membered carbon A ring or a 3- to 6-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, OH , Cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, and the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) Heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), alternatively, any R ³ , R ⁵ and the atoms to which they are connected together form a 4- to 6-membered heterocyclic ring , The heterocyclic ring is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _{Substituted by 1-4} alkyl or C _1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or 3 To a 6-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, _{1 , 2} , 3, or 4) from H, F, OH, cyano, CF 3, NH 2 , Methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), any R ⁵ , R ⁶ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or 3 To a 6-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 (for example, 0, _{1 , 2} , 3, or 4) from H, F, OH, cyano, CF 3, NH 2 , Methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), any R ³ , R ⁵ and the atoms to which they are connected together form a 4- to 6-membered heterocyclic ring, said The heterocycle is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy Substitution, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of the general formulas (I), (Ia), (Ia-1), (Ib), any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring, so The carbocyclic ring is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy Replaced.

The present invention relates to embodiments of the general formulas (Ia-1) and (Ib), wherein R ³ , R ⁴ , R ⁵ , and R ⁶ cannot be H at the same time.

Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ia-1), (Ib), (Ic) or its stereoisomers, deuterated products, solvates, pro Drug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the pharmaceutically acceptable salt is selected from L-tartrate.

The imidazo part of the tetrahydroimidazopyridine moiety in the structure of the compound of general formula (I), (Ia), (Ia-1), (Ib), (Ic) in the present invention exists in tautomeric form, including NS

According to IUPAC rules, these structures A and B produce different numbers of the atoms of the imidazole moiety: 2-(1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4, 5-c]pyridine (structure A) and 2-(1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (structure B) . It should be understood that although the structure is shown or named in a specific form, the present invention also includes its tautomers.

In the present invention, the compounds represented by the general formulas (I) and (I′) are tautomers, without other description, in the R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , m, When n1, n2, p, and q are the same, they belong to the same compound.

In the present invention, the compounds represented by the general formulas (Ia) and (Ia') are tautomers, and without other explanation, they belong to the same compound ^{if the R 3} , R ⁴ , R ⁵ , and R ^{6 are the same} .

In the present invention, the compounds represented by the general formulas (Ia-1) and (Ia-1') are tautomers, and without other explanation, in the case where R ³ , R ⁴ , R ⁵ , and R ^{6 are the} same, Belong to the same compound.

In the present invention, the compounds represented by the general formulas (Ib) and (Ib') are tautomers, and without other description, they belong to the same compound ^{if the R 3} , R ⁴ , R ⁵ , and R ^{6 are the same} .

In the present invention, the compounds represented by the general formulas (Ic) and (Ic') are tautomers, and without other description, they belong to the same compound ^{if the R 1} and R ^{2 are the same.}

The present invention relates to a pharmaceutical composition, including the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable a.

The present invention relates to a compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals for use in the preparation of drugs for the treatment of JAK-mediated diseases It is preferably used in the preparation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial pneumonia, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, spinal cord fibers The application of medicines for chemical, cancer, psoriasis, rheumatoid arthritis, hair loss, lupus erythematosus or scleroderma.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

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

"Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and more preferably It is an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And various branched chain isomers; the alkyl group may optionally be further selected from 0 to 6 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, Amido, alkenyl, alkynyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, 3 to 8 membered carbocyclic group, 3 to 8 membered heterocyclic group, 3 to An 8-membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group or a carboxylate substituent is substituted. The definition of the alkyl group appearing in this text is consistent with this definition.

"Alkenyl" refers to straight and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, etc. ; The alkyl group may optionally be further selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate group. The definition of the alkenyl group appearing in this text is consistent with this definition.

"Alkynyl" refers to a linear and branched monovalent unsaturated hydrocarbon group, which has at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butanyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl The alkyl group can optionally be further selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl Group, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituent. The definition of the alkynyl group appearing in this text is consistent with this definition.

"Alkoxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyl Oxy and cyclobutoxy. The alkoxy group may optionally be further selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate group. The definition of the alkoxy group appearing in this document is consistent with this definition.

"Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10- to 15-membered tricyclic ring system, the aromatic or non-aromatic ring is optionally monocyclic, bridged or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, or naphthalene ring. The carbocyclic ring may optionally be further selected from 0 to 5 F, Cl, Br, I, =0, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkyne Group, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituent. The definition of carbocyclic or carbocyclic group appearing in this text is consistent with this definition.

"Heterocyclic group" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S, preferably 3 to 8-membered heterocyclic group, the optionally substituted N, S in the heterocyclic ring can be Is oxidized into various oxidation states. The heterocyclic group can be connected to a hetero atom or a carbon atom, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane ethyl, aziridinyl, oxetanyl, and aza. Cyclobutyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, azepanyl, pyridyl, furanyl, thienyl, pyridine Pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl (azacyclohexyl), piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-Dithiol, dihydrofuranyl, dihydropyranyl, dithiopentyl, oxolanyl (tetrahydrofuranyl), tetrahydropyrrolyl (azacyclopentyl), tetrahydroimidazolyl, Tetrahydrothiazolyl, oxacyclohexyl (tetrahydropyranyl), benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octane Group, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The heterocyclic group may optionally be further selected from 0 to 5 F, Cl, Br, I, =0, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, Alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituents are substituted. The definition of heterocyclic group appearing in this text is consistent with this definition.

"Substituted by 0 to X substituents selected from..." means substituted by 0, 1, 2, 3.... X substituents selected from..., and X is selected from any integer between 1-10. For example, "substituted by 0 to 4 substituents selected from..." means substituted by 0, 1, 2, 3 or 4 substituents selected from... For example, "substituted by 0 to 5 substituents selected from" means substituted by 0, 1, 2, 3, 4, or 5 substituents selected from... For example, "hetero-bridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" means that the hetero-bridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F Substituted by the group.

XY-membered ring (X is selected from an integer less than Y and greater than or equal to 3, Y is selected from any integer between 4 and 12) including X+1, X+2, X+3, X+4.... Y-membered ring. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospiro rings or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, or 8-membered ring. , 9-membered or 10-membered heterocyclic ring.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example: "Alkyl group optionally substituted by F" means that the alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and that the free acid is combined with a non-toxic inorganic base or An organic base is a salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, where "other chemical components" refer to pharmaceutically acceptable compounds. Accepted carriers, excipients and/or one or more other therapeutic agents.

"Carrier" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives Agent and disintegrant.

A "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound by metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl groups.

"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.

"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.

"Stereoisomers" refer to isomers produced by the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Optional" or "optionally" or "selective" or "selectively" means that the event or condition described later can but does not necessarily occur, and the description includes the situation in which the event or condition occurs and its failures. What happened. For example, "heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but does not necessarily exist. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. Condition.

"IC50" is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a certain component in the process such as enzymes, receptors, cells, etc.).

Detailed ways

The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in chemical literature. "Commercially available chemicals" are obtained from formal commercial sources. Suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Medicine Stone, WuXi AppTec, and Bailingwei Technology, etc. company.

Reference books and monographs in the field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation methods for reference. These reference books and monographs include: "Synthetic Organic Chemistry", John Wiley&Sons, Inc., New York; SRSandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HOHouse, "Modern Synthetic Reactions", 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley&Sons, New York, 1992; J. March, "Advanced Organic Chemistry" :Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley&Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley&Sons, ISBN:0 -471-60180-2; Otera,J. (editor) "Modern Carbonyl Chemis try" (2000) Wiley-VCH, ISBN:3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN:0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2 ; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley&Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley&Sons, in over volumes; and "Chemistry of Functional Groups" John Wiley&Sons,in 73 volumes.

Specific and similar reactants can be selectively identified through the index of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society. These indexes are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, where many standard chemical supply plants (for example, those listed above) provide custom synthesis services. The reference for preparing and selecting medicinal salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). NMR is measured by (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetometers, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), internal standard It is tetramethylsilane (TMS);

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.20mm, and the size used for thin layer chromatography separation and purification products is 0.4mm -0.5mm;

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2 used in the following examples -Yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride was prepared according to the patent WO2018204238 method.

Synthesis of control compound L-tartrate:

1.1-[2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydro Imidazo[4,5-c]pyridin-5-yl]-2-morpholino-ethanone (reference compound)

1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-yl]-2-morpholino-ethanone

The first step: tert-butyl 2-morpholinoacetate (B-1)

tert-butyl 2-morpholinoacetate

Dissolve morpholine (A-1) (0.42g, 4.82mmol) in 20mL of THF, add potassium carbonate (1.37g, 9.91mmol) and tert-butyl bromoacetate (1.44g, 7.38mmol) at room temperature, and react at room temperature for 16h . The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100:1-1:1) to obtain tert-butyl 2-morpholine acetate (B -1) (0.5 g, yield: 52%).

LCMS m/z=202.3[M+1] ⁺

Step 2: Trifluoroacetate of 2-morpholinoacetic acid (C-1)

2-morpholinoacetic acid trifluoroacetate

Dissolve tert-butyl 2-morpholinoacetate (B-1) (0.32g, 1.59mmol) in 5mL trifluoroacetic acid and 5mL dichloromethane, and react at room temperature for 24h. The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate (0.35 g) of 2-morpholinoacetic acid (C-1).

LCMS m/z=146.2[M+1] ⁺

The third step: 1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6, 7-Tetrahydroimidazo[4,5-c]pyridin-5-yl]-2-morpholino-ethanone (reference compound)

1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-yl]-2-morpholino-ethanone

Dissolve the trifluoroacetate (0.35g) of the above crude 2-morpholinoacetic acid (C-1) in 10mL DMF, and then add HATU (0.81g, 2.13mmol), DIPEA (414mg, 3.20mmol) and 5-Ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazole[4,5-c]pyridin-2-yl)-1H-indole The hydrochloride (500 mg) of azol-6-yl)phenol (Intermediate 1) was reacted at room temperature for 16 hours, lithium hydroxide monohydrate (0.27 g, 6.43 mmol) was added, the temperature was raised to 65° C., and the mixture was stirred for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2N aqueous hydrochloric acid solution, 100 mL of water was added to the reaction solution, a large amount of solid was precipitated out, filtered, and 100 mL of methanol/dichloromethane (v/v=1: 10) was dissolved in the mixed solvent, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1) to obtain 1-[2-[6 -(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5- c] Pyridin-5-yl]-2-morpholino-ethanone (control compound) (400 mg, two-step yield from compound B-1: 48%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.98-6.78 (m, 3H), 4.80-4.66 (m, 2H), 4.01-3.92 (m, 2H), 3.78-3.63 ( m,4H), 3.40-3.33(m,2H), 2.97-2.75(m,2H), 2.60-2.48(m,6H), 1.07(t,3H).

LCMS m/z=523.2[M+1] ⁺

1-[2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydro L-tartrate of imidazo[4,5-c]pyridin-5-yl]-2-morpholino-ethanone (reference compound)

1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-yl]-2-morpholino-ethanone L-tartrate

The 1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetra Hydroimidazo[4,5-c]pyridin-5-yl]-2-morpholino-ethanone (reference compound) (see WO2018204238 for synthesis method) (0.200g, 0.383mmol) and L-tartaric acid (0.0574g, 0.383mmol) was dissolved in 1mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then add 50 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy- Phenyl)-4-fluoro-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl]-2-morpholino- L-tartrate (0.210 g, yield: 82%) of ethyl ketone (control compound).

¹ H NMR (400MHz, CD ₃ OD) δ 7.28-7.24 (m, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.87-6.82 (m, 1H), 4.72 (s, 2H) , 4.48 (s, 2H), 4.04 - 3.87 (m, 2H), 3.85 - 3.68 (m, 6H), 3.00 - 2.76 (m, 6H), 2.54 (q, 2H), 1.07 (t, 3H).

Example 1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (compound 1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(2-methylmorpholino)ethanone

The first step: 2-(2-Methylmorpholino) benzyl acetate (1b)

Benzyl 2-(2-methylmorpholino)acetate

Dissolve 2-methylmorpholine (1a) (0.50g, 4.94mmol) in 20mL THF, add potassium carbonate (1.37g, 9.91mmol) and benzyl bromoacetate (1.13g, 4.94mmol) at room temperature, and react at room temperature 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1-10:1) to obtain 2-(2-methylmorpholino)acetic acid Benzyl ester (1b) (0.4 g, yield: 32%).

¹ H NMR(400MHz,CD ₃ OD)δ7.40-7.26(m,5H), 5.16(s,2H), 3.82-3.76(m,1H), 3.71-3.58(m,2H), 3.28(s, 2H), 2.84-2.71(m, 2H), 2.36-2.26(m, 1H), 2.04-1.95(m, 1H), 1.09(d, 3H).

LCMS m/z=250.1[M+1] ⁺

Step 2: 2-(2-Methylmorpholino)acetic acid (1c)

2-(2-methylmorpholino)acetic acid

Benzyl 2-(2-methylmorpholino)acetate (1b) (0.40 g, 1.60 mmol) was dissolved in 25 mL of ethanol, 50 mg 10% palladium carbon was added, and the reaction was carried out at room temperature for 4 hours in a hydrogen balloon atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-(2-methylmorpholino)acetic acid (1c) (0.26 g).

LCMS m/z=160.3[M+1] ⁺

The third step: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro- 1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (Compound 1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(2-methylmorpholino)ethanone

Dissolve the above crude 2-(2-methylmorpholino)acetic acid (1c)(0.26g) in 10mL DMF, and then add O-(7-azabenzotriazol-1-yl)-N, N,N',N'-tetramethylurea hexafluorophosphate HATU (0.81g, 2.13mmol), N,N-diisopropylethylamine DIPEA (414mg, 3.20mmol) and 5-ethyl-2- Fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl) The hydrochloride (500mg) of phenol (Intermediate 1) was reacted at room temperature for 16h, lithium hydroxide monohydrate (0.27g, 6.43mmol) was added, the temperature was raised to 65°C, and the mixture was stirred for 3h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2N aqueous hydrochloric acid solution, 100mL of water was added to the reaction solution, a large amount of solids precipitated out, filtered, filter cake with 100mL dichloromethane/methanol (v/v) = 10 :1 was dissolved in a mixed solvent, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1) to obtain 1-(2-(6 -(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c] Pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (compound 1) (100 mg, two-step yield from compound 1b: 12%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.86-6.79 (m, 1H), 4.78 (s, 1H), 4.69 (s,1H),4.01-3.91(m,2H), 3.87-3.75(m,1H), 3.74-3.58(m,2H), 3.39-3.33(m,2H), 2.96-2.69(m,4H) ,2.54(q,2H),2.29–2.18(m,1H),1.97–1.88(m,1H),1.19–1.02(m,6H).

LCMS m/z=537.2[M+1] ⁺

Example 1-1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone L-tartrate (compound 1-1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(2-methylmorpholino)ethanone L-tartrate

The 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazole And [4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (Compound 1) (40mg, 0.075mmol) and L-tartaric acid (11.6mg, 0.077 mmol) was dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 30 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxybenzene) Yl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(2- L-tartrate salt of methylmorpholino)ethanone (compound 1-1) (25 mg, yield: 49%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.25 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.85 (d, 1H), 4.75-4.68 (m, 2H), 4.48 (s, 2H), 4.04--3.85 (m, 3H), 3.83--3.67 (m, 4H), 3.11-2.98 (m, 2H), 2.97--2.89 (m, 1H), 2.86-2.77 (m, 1H) , 2.63–2.48(m,3H), 2.33–2.18(m,1H), 1.22–1.11(m,3H), 1.07(t,3H).

LCMS m/z=537.2[M+1] ⁺

Example 2:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-(3-methylmorpholino)ethanone (Compound 2)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(3-methylmorpholino)ethanone

The first step: 2-(3-Methylmorpholino) benzyl acetate (2b)

Benzyl 2-(3-methylmorpholino)acetate

Dissolve 3-methylmorpholine (2a) (0.50g, 4.94mmol) in 20mL of THF, add potassium carbonate (1.37g, 9.91mmol) and benzyl bromoacetate (1.13g, 4.94mmol) at room temperature, and react at room temperature 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100:1-20:1) to obtain 2-(3-methylmorpholino)acetic acid Benzyl ester (2b) (0.54 g, yield: 44%).

¹ H NMR (400MHz, CD ₃ OD) δ7.41-7.27(m,5H), 5.16(s,2H), 3.77-3.71(m,1H), 3.67-3.56(m,3H), 3.56-3.49( m,1H), 3.23–3.15(m,1H), 2.79–2.73(m,1H), 2.72–2.61(m,2H), 0.94(d,3H).

LCMS m/z=250.3[M+1] ⁺

Step 2: 2-(3-Methylmorpholino)acetic acid (2c)

2-(3-methylmorpholino)acetic acid

Benzyl 2-(3-methylmorpholino)acetate (2b) (0.54 g, 2.17 mmol) was dissolved in 25 mL of ethanol, 50 mg of 10% palladium carbon was added, and the reaction was carried out at room temperature under a hydrogen balloon atmosphere for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-(3-methylmorpholino)acetic acid (2c) (0.34 g).

LCMS m/z=160.3[M+1] ⁺

The third step: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro- 1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(3-methylmorpholino)ethanone (Compound 2)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(3-methylmorpholino)ethanone

Dissolve the above crude 2-(3-methylmorpholino)acetic acid (2c) (0.32g) in 10mL DMF, and then add HATU (0.98g, 2.58mmol), DIPEA (500mg, 3.87mmol) and 5- Ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazole -6-yl)phenol (Intermediate 1) hydrochloride (600mg), react at room temperature for 16h. Lithium hydroxide monohydrate (0.27g, 6.43mmol) was added to the reaction solution, and the temperature was raised to 65°C and stirred for 3h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2N hydrochloric acid solution, 100 mL of water was added, a large amount of solid was precipitated, filtered, and the filter cake was used with 100 mL methanol/dichloromethane (v/v) = 1:10 The mixed solvent was dissolved, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10:1) to obtain 1-(2-(6-(2- Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5( 4H)-yl)-2-(3-methylmorpholino)ethanone (compound 2) (160 mg, two-step yield from compound 2b: 15%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.24 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.83 (d, 1H), 4.98-4.58 (m, 2H), 4.11 --4.00(m,1H), 3.98–3.84(m,2H), 3.82–3.54(m,3H), 3.37–3.26(m,1H), 3.23–3.14(m,1H), 2.98–2.89(m, 1H), 2.85-2.75 (m, 2H), 2.65-2.42 (m, 4H), 1.14-1.00 (m, 6H).

LCMS m/z=537.3[M+1] ⁺

Example 2-1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-(3-methylmorpholino)ethanone L-tartrate (compound 2-1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(3-methylmorpholino)ethanone L-tartrate

The 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazole And [4,5-c]pyridine-5(4H)-yl)-2-(3-methylmorpholino)ethanone (compound 2) (40mg, 0.075mmol) and L-tartaric acid (11.3mg, 0.075 mmol) was dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 20 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxybenzene Yl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(3- L-tartrate salt of methylmorpholino)ethanone (compound 2-1) (30 mg, yield: 52%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.56 (s, 1H), 12.35 (br.s, 1H), 9.88 (br.s, 1H), 7.22 (s, 1H), 7.05 (d, 1H) ), 6.92(d,1H), 6.83(d,1H), 4.68–4.41(m,2H), 4.21(s,3H), 3.95–3.86(m,1H), 3.86–3.70(m,2H), 3.70–3.55(m,2H), 3.53–3.40(m,1H), 3.18–3.07(m,1H), 3.06–2.98(m,1H), 2.82–2.75(m,1H), 2.70–2.59(m ,2H), 2.57-2.44(m,3H), 2.41--2.30(m,1H), 1.12-0.90(m,6H).

LCMS m/z=537.3[M+1] ⁺

Example 3:

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4 -Hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone ( Compound 3)

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

The first step: 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl) benzyl acetate (3b)

Benzyl 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetate

Dissolve (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (3a) (0.58g, 4.28mmol) in 20mL THF, add potassium carbonate (2.37) at room temperature g, 17.1mmol) and benzyl bromoacetate (0.98g, 4.28mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1-10:1) to obtain 2-((1S,4S)-2-oxygen Hetero-5-azabicyclo[2.2.1]hept-5-yl) benzyl acetate (3b) (0.5 g, yield: 47%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.41--7.28 (m, 5H), 5.22--5.12 (m, 2H), 4.43-4.36 (m, 1H), 4.01 (d, 1H), 3.68-3.57 (m ,2H), 3.55--3.43(m,2H), 3.11(dd,1H), 2.64--2.55(m,1H), 1.97--1.90(m,1H), 1.79--1.72(m,1H).

LCMS m/z=248.1[M+1] ⁺

The second step: 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetic acid (3c)

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetic acid

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl) benzyl acetate (3b) (500mg, 2.02mmol) was dissolved in 2mL ethyl acetate and Add 50 mg of 10% palladium on carbon to 2 mL of methanol, and react at room temperature for 4 hours in a hydrogen balloon atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetic acid (3c) (0.32g).

LCMS m/z=158.1[M+1] ⁺

The third step: 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5 -Fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl ) Ethyl ketone (compound 3)

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

Dissolve the above crude 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetic acid (3c) (300mg) in 4mL DMF, and then add HATU( 1.45g, 3.81mmol), DIPEA (492mg, 3.81mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[ 4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (894mg), react at room temperature for 16h. Heat the reaction solution to 65°C and add Lithium hydroxide monohydrate (0.48g, 11.4mmol) was reacted for 2h. The reaction solution was cooled to room temperature, quenched with 50mL of water, and then adjusted to pH 7 with 2N hydrochloric acid. A large amount of solid precipitated out, filtered, and the filter cake was filtered through Pre- HPLC (instrument and preparative column: Glison GX-281 is used to prepare the liquid phase. The preparative column model is Sunfire C18, 5μm, inner diameter*length=30mm*150mm. Preparation method: dissolve the crude product in methanol and filter it with a 0.45μm filter membrane to prepare Sample solution. Mobile phase system: acetonitrile/ammonia (0.05%). Gradient elution method: acetonitrile is eluted with a 5% gradient of 50%, elution time 15min), to obtain 2-((1S,4S)-2-oxa -5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indyl (Azol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 3) (120 mg, calculated in two steps from Compound 3b Rate: 12%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.22 (s, 1H), 6.93 (d, 1H), 6.88 (d, 1H), 6.84-6.76 (m, 1H), 4.74-4.66 (m, 2H) ,4.43–4.36(m,1H), 4.10–4.00(m,1H), 3.99–3.86(m,2H), 3.71–3.55(m,4H), 3.00–2.92(m,1H), 2.92–2.84( m,1H), 2.82–2.74(m,1H), 2.67–2.59(m,1H), 2.52(q,2H), 1.97–1.85(m,1H), 1.78–1.65(m,1H), 1.06( t,3H).

LCMS m/z=535.2[M+1] ⁺

Example 3-1:

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4 -Hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone L-tartrate (Compound 3-1)

2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone L-tartrate

The 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro- 4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 3) (50 mg, 0.093 mmol) and L-tartaric acid (14.0 mg, 0.093 mmol) were dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 20mL acetonitrile dropwise to the reaction solution, continue to stir for 1h, stand for 10min, filter, and dry the filter cake to obtain 2-((1S,4S)-2-oxa-5-azabicyclo[2.2. 1)hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6, The L-tartrate salt of 7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 3-1) (40 mg, yield: 63%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.59 (br.s, 1H), 12.39 (br.s, 1H), 7.23 (s, 1H), 7.05 (d, 1H), 6.92 (d, 1H) ), 6.83(d, 1H), 4.66–4.47(m, 2H), 4.46–4.37(m, 1H), 4.16(s, 2H), 3.99–3.91(m, 1H), 3.90–3.52(m, 6H) ), 3.05–2.92(m,1H), 2.87–2.60(m,3H), 2.55–2.44(m,2H), 1.98–1.84(m,1H), 1.74–1.65(m,1H), 1.03(t ,3H).

LCMS m/z=535.2[M+1] ⁺

Example 4:

2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4 -Hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone ( Compound 4)

2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

The first step: tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)acetate (4b)

Tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetate

Dissolve (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (4a) (0.70g, 5.16mmol) in 30mL THF, add potassium carbonate (1.43 g, 10.3mmol) and tert-butyl bromoacetate (1.01g, 5.18mmol), react at room temperature for 16h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0:1-1:1) to obtain 2-((1R,4R)- Tert-Butyl 2-oxa-5-azabicyclo[2.2.1]hept-5-yl)acetate (4b) (1.0 g, yield: 91%).

¹ H NMR(400MHz, CDCl ₃ ) δ4.44-4.38(m,1H), 4.04(d,1H), 3.72-3.62(m,2H), 3.46-3.30(m,2H), 3.15(d,1H) ), 2.62(d,1H), 1.99(d,1H), 1.78(d,1H), 1.47(s,9H).

LCMS m/z=214.3[M+1] ⁺

Step 2: 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetic acid (4c) trifluoroacetate

2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetic acid trifluoroacetate

Dissolve 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetic acid tert-butyl ester (4b) (400mg, 1.9mmol) in 2mL of dichloromethane Add 2ml of trifluoroacetic acid and react at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure to obtain crude 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetic acid (4c) trifluoroacetate (0.51 g).

LCMS m/z=158.3[M+1] ⁺

The third step: 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5 -Fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl ) Ethyl ketone (compound 4)

2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

Dissolve the above crude 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetic acid (4c) trifluoroacetate (0.51g) in 10mL DMF , And then add HATU (0.73g, 1.9mmol), DIPEA (0.66g, 5.1mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7- Tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (600mg), react at room temperature for 16h. Lithium hydroxide monohydrate (0.27g, 6.43mmol) was added to the solution, heated to 65°C and stirred for 3h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2N hydrochloric acid solution, and added to the reaction solution 100mL water, a large amount of solids precipitated, filtered, the filter cake was dissolved with 100mL methanol/dichloromethane (v/v) = 1:10 mixed solvent, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to Pre-HPLC (instrument And preparation column: use Glison GX-281 to prepare the liquid phase, the preparation column model is Sunfire C18, 5μm, inner diameter * length = 30mm*150mm. Preparation method: the crude product is dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45μm filter membrane, Prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: acetonitrile is eluted with a 5% gradient of 60%, and the elution time is 15 min). The obtained preparation solution is concentrated under reduced pressure, and then used The pH value of saturated sodium bicarbonate solution was adjusted to 9, the aqueous phase was extracted with a mixed solvent of 100 mL methanol/dichloromethane (v/v) = 1:10, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-((1R ,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl) -4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 4) (120mg , The two-step yield calculated from compound 4b: 12%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.94 (d, 1H), 6.88 (d, 1H), 6.82 (d, 1H), 4.76-4.65 (m, 2H), 4.44 --4.37(m,1H),4.10–4.01(m,1H), 4.00–3.88(m,2H), 3.70–3.57(m,4H),3.01–2.93(m,1H), 2.92–2.84(m, 1H), 2.83–2.75(m,1H), 2.67–2.60(m,1H), 2.54(q,2H), 1.97–1.87(m,1H), 1.78–1.68(m,1H), 1.07(t, 3H).

LCMS m/z=535.2[M+1] ⁺

Example 4-1:

2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4 -Hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone L-tartrate (Compound 4-1)

2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone L-tartrate

The 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro- 4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 4) (40 mg, 0.075 mmol) and L-tartaric acid (11.3 mg, 0.075 mmol) were dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 20mL acetonitrile dropwise to the reaction solution, continue to stir for 1h, stand for 10min, filter, and dry the filter cake to obtain 2-((1R,4R)-2-oxa-5-azabicyclo[2.2. 1)hept-5-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6, The L-tartrate salt of 7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 4-1) (30 mg, yield: 58%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.58 (br.s, 1H), 12.38 (br.s, 1H), 7.22 (s, 1H), 7.05 (d, 1H), 6.92 (d, 1H) ), 6.87–6.79(m,1H), 4.64–4.47(m,2H), 4.43–4.37(m,1H), 4.12(s,2H), 3.97–3.90(m,1H), 3.88–3.66(m ,5H),3.59–3.53(m,1H),3.00–2.91(m,1H), 2.83–2.60(m,3H),2.56–2.44(m,2H),1.94-1.83(m,1H),1.73 --1.63(m,1H),1.03(t,3H).

LCMS m/z=535.2[M+1] ⁺

Example 5:

Cis-2-(2,6-Dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indole (Azol-3-yl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 5)

Cis-2-(2,6-dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7 -dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

The first step: cis-tert-butyl-2-(2,6-dimethylmorpholino)acetate (5b)

Cis-tert-butyl 2-(2,6-dimethylmorpholino)acetate

Dissolve cis-2,6-dimethylmorpholine (5a) (0.49g, 4.25mmol) in 20mL THF, add potassium carbonate (2.37g, 17.1mmol) and tert-butyl bromoacetate (0.83g) at room temperature , 4.26mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100:1-1:1) to obtain cis-2-(2,6-di Tert-butyl methylmorpholino)acetate (5b) (0.78 g, yield: 80%).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.81-3.69 (m, 2H), 3.09 (s, 2H), 2.84-2.76 (m, 2H), 1.92 (t, 2H), 1.47 (s, 9H), 1.15(d,6H).

LCMS m/z=230.3[M+1] ⁺

Step 2: Trifluoroacetate of cis-2-(2,6-dimethylmorpholino)acetic acid (5c)

Cis-2-(2,6-dimethylmorpholino)acetic acid trifluoroacetate

Dissolve tert-butyl cis-2-(2,6-dimethylmorpholino)acetate (5b) (0.73g, 3.18mmol) in 5mL dichloromethane and 5mL trifluoroacetic acid, and react at room temperature for 16h. The reaction solution was concentrated to obtain crude trifluoroacetate (0.55 g) of cis-2-(2,6-dimethylmorpholino)acetic acid (5c).

LCMS m/z=174.3[M+1] ⁺

The third step: cis-2-(2,6-dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro -1H-indazol-3-yl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 5)

Cis-2-(2,6-dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7 -dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

Dissolve the above crude cis-2-(2,6-dimethylmorpholino)acetic acid (5c) trifluoroacetate (0.55g) in 5mL DMF, and then add HATU (1.62g, 4.26mmol) ), DIPEA (1.10g, 8.51mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5- c] Pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (1.0g), react at room temperature for 16h. The reaction solution was heated to 65° C., and lithium hydroxide monohydrate (0.53 g, 12.6 mmol) was added to react for 2 hours. The reaction solution was cooled to room temperature, quenched with 50 mL of water, adjusted to pH 7 with 2N dilute hydrochloric acid, a large amount of solids precipitated, filtered, and the filter cake was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)= 100:1-10:1) to give cis-2-(2,6-dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxybenzene Yl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 5) (0.15g, two-step yield calculated from compound 5b: 9%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.82 (d, 1H), 4.77 (s, 1H), 4.69 (s) ,1H), 4.00--3.91(m, 2H), 3.77--3.60(m, 2H), 3.37--3.32(m, 2H), 2.95--2.73(m, 4H), 2.54(q, 2H), 1.89--1.77 (m,2H),1.17-1.02(m,9H).

LCMS m/z=551.2[M+1] ⁺

Example 5-1:

Cis-2-(2,6-Dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indole (Azol-3-yl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone L-tartrate (compound 5-1)

Cis-2-(2,6-dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7 -dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone L-tartrate

The cis-2-(2,6-dimethylmorpholino)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- Indazol-3-yl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 5) (50mg, 0.09mmol) and L- Tartaric acid (13.5mg, 0.09mmol) was dissolved in 1mL tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then add 20 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain cis-2-(2,6-dimethylmorpholino)-1-(2 -(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-3H-imidazo[4,5 -c] L-tartrate of pyridine-5(4H)-yl)ethanone (Compound 5-1) (50 mg, yield: 79%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.27--7.23 (m, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.84 (d, 1H), 4.75 - 4.67 (m, 2H) ,4.47(s,2H),4.04–3.87(m,2H), 3.86–3.63(m,4H), 3.10–2.98(m,2H), 2.97–2.87(m,1H), 2.86–2.77(m, 1H), 2.54(q,2H), 2.25-2.05(m,2H), 1.19-1.12(m,6H), 1.07(t,3H).

LCMS m/z=551.2[M+1] ⁺

Example 6:

2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-Fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one (Compound 6 )

2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one

The first step: tert-butyl 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)acetate (6b)

tert-butyl 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)acetate

Dissolve 6-oxa-3-azabicyclo[3.1.1]heptane 4-toluenesulfonate (6a) (1.5g, 5.53mmol) in 30mL THF, add potassium carbonate (1.5g, 11mmol) at room temperature ) And tert-butyl bromoacetate (1.1g, 5.64mmol) at room temperature for 16h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0:1-1:1) to obtain 2-(6-oxa-3 -Azabicyclo[3.1.1]heptan-3-yl) tert-butyl acetate (6b) (1.0 g, yield: 85%).

¹ H NMR (400MHz, CDCl ₃ ) δ4.51 (d, 2H), 3.38 (s, 2H), 3.26-3.14 (m, 2H), 3.13-3.00 (m, 3H), 2.42 (d, 1H), 1.49(s,9H).

LCMS m/z=214.3[M+1] ⁺

Step 2: Trifluoroacetate of 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)acetic acid (6c)

2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)acetic acid trifluoroacetate

Dissolve 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)acetic acid tert-butyl ester (6b) (400mg, 1.9mmol) in 2mL dichloromethane, add 2ml trifluoro Acetic acid, react at room temperature for 20h. The reaction solution was concentrated under reduced pressure to obtain crude 2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)acetic acid (6c) trifluoroacetate (0.51 g).

LCMS m/z=158.3[M+1] ⁺

The third step: 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyl (Phenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethane-1- Ketone (Compound 6)

2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one

Dissolve the trifluoroacetate (0.51g) of the above 2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)acetic acid (6c) in 10mL DMF, and then add HATU successively (0.73g, 1.9mmol), DIPEA (0.66g, 5.1mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazole) And [4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (600mg), react at room temperature for 16h. Lithium hydroxide monohydrate (0.27g, 6.43mmol) was added to the reaction solution, and the temperature was raised to 65°C and stirred for 3h. The reaction solution was cooled to room temperature and concentrated directly under reduced pressure. The residue was adjusted to pH 8 with 2N hydrochloric acid solution, and 100 mL of water was added to precipitate a large amount of solids. After filtration, 100 mL of methanol/dichloromethane (v/v) = 1 was used for the filter cake. Dissolve the mixed solvent of :10, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (dichloromethane/methanol (v/v)=100:1-10:1) to obtain 2-( 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro -1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one (Compound 6) (0.20 g, the two-step yield calculated from compound 6b: 20%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.24 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.86-6.80 (m, 1H), 4.87-4.67 (m, 2H) ,4.57–4.45(m,2H),4.03–3.94(m,2H),3.70–3.57(m,2H), 3.25–3.18(m,1H), 3.18–3.10(m,1H), 3.10–2.84( m,4H), 2.84–2.76(m,1H), 2.54(q,2H), 2.43–2.25(m,1H), 1.07(t,3H).

LCMS m/z=535.2[M+1] ⁺

Example 6-1:

2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one L- Tartrate (Compound 6-1)

2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-oneL-tartrate

2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl) -4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one (compound 6) (50mg, 0.093mmol) and L-tartaric acid (14mg, 0.093mmol) were dissolved in 1mL tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then add 20 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 2-(6-oxa-3-azabicyclo[3.1.1] hept-3- Yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7- The L-tartrate salt of tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one (compound 6-1) (35 mg, yield: 55%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.26 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.87-6.81 (m, 1H), 4.81-4.70 (m, 2H) ,4.59-4.50(m,2H),4.48(s,2H),4.04-3.92(m,2H),3.90-3.74(m,2H),3.40-3.33(m,1H),3.30-3.25(m, 1H), 3.18-2.98(m, 3H), 2.96-2.77(m, 2H), 2.54(q, 2H), 2.42-2.24(m, 1H), 1.07(t, 3H).

LCMS m/z=535.2[M+1] ⁺

Example 7:

2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 7)

2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

The first step: tert-butyl 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)acetate (7b)

tert-butyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)acetate

Dissolve 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (7a) (1.0g, 6.68mmol) in 20mL THF, add potassium carbonate (1.85g, 13.4mmol) and Tert-Butyl bromoacetate (1.96g, 10.0mmol), react at room temperature for 3h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100:1-1:1) to obtain 2-(8-oxa-3-nitrogen) Heterobicyclo[3.2.1]oct-3-yl)acetic acid tert-butyl ester (7b) (1.42 g, yield: 94%).

¹ H NMR (400MHz, CDCl ₃ ) δ 4.33-4.21 (m, 2H), 3.05 (s, 2H), 2.68-2.58 (m, 2H), 2.57-2.47 (m, 2H), 2.11-1.95 (m ,2H),1.94-1.77(m,2H),1.46(s,9H).

LCMS m/z=228.2[M+1] ⁺

Step 2: Trifluoroacetate of 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)acetic acid (7c)

2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)acetic acid trifluoroacetate

Dissolve 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)acetic acid tert-butyl ester (7b) (0.73g, 3.21mmol) in 5mL dichloromethane and 5mL trifluoro In acetic acid, react at room temperature for 16h. The reaction solution was concentrated to obtain crude 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)acetic acid (7c) trifluoroacetate (0.8 g).

LCMS m/z=172.1[M+1] ⁺

The third step: 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyl (Phenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 7 )

2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

Dissolve the above crude 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)acetic acid (7c) trifluoroacetate (0.8g) in 5mL DMF, and then add in sequence HATU (1.62g, 4.26mmol), DIPEA (1.10g, 8.51mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H- Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (1.0g), reacted at room temperature for 16h. The reaction solution was heated to 65° C., and lithium hydroxide monohydrate (0.544 g, 12.96 mmol) was added to react for 2 hours. The reaction solution was cooled to room temperature, quenched with 50 mL of water, and then adjusted to pH 7 with 2N hydrochloric acid. A large amount of solids were precipitated out, filtered, and the filter cake was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)= 100:1-10:1) to obtain 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2-(6-(2-ethyl-5 -Fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl ) Ethanone (Compound 7) (0.3 g, two-step yield calculated from Compound 7b: 17%).

¹ H NMR(400MHz, CD ₃ OD)δ7.23(s,1H), 6.98-6.92(m,1H), 6.89(d,1H), 6.86-6.78(m,1H), 4.87(s,1H) ,4.68(s,1H),4.33–4.17(m,2H),4.05–3.90(m,2H), 3.30–3.22(m,2H), 2.98–2.74(m,2H), 2.72–2.49(m, 4H), 2.45-2.31(m, 2H), 2.08-1.64(m, 4H), 1.07(t, 3H).

LCMS m/z=549.2[M+1] ⁺

Example 7-1:

2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)- 4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone L-tartrate (compound 7-1)

2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H- indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone L-tartrate

The 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl) -4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (Compound 7) (50mg , 0.09mmol) and L-tartaric acid (13.5mg, 0.09mmol) were dissolved in 1mL tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then add 20 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 2-(8-oxa-3-azabicyclo[3.2.1]oct-3- Yl)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H -L-tartrate salt of imidazo[4,5-c]pyridine-5(4H)-yl)ethanone (compound 7-1) (25 mg, yield: 40%).

¹ H NMR(400MHz,DMSO-d ₆ )δ13.56(br.s,1H), 9.88(br.s,1H), 7.25-7.20(m,1H), 7.06(d,1H), 6.92(d ,1H), 6.83(d,1H), 4.71(s,1H), 4.50(s,1H), 4.29(s,2H), 4.26–4.12(m,2H), 3.90–3.75(m,2H), 3.24–3.16(m, 2H), 2.84–2.74(m, 1H), 2.67–2.42(m, 5H), 2.35–2.21(m, 2H), 1.91–1.82(m, 1H), 1.79–1.71(m ,1H), 1.70-1.63(m,1H), 1.62-1.52(m,1H), 1.03(t,3H).

LCMS m/z=549.2[M+1] ⁺

Example 8:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydroimidazole And [4,5-c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone (Compound 8)

1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-1,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone

The first step: tert-butyl 2-[(2R)-2-methylmorpholin-4-yl]acetate (8b)

tert-butyl 2-[(2R)-2-methylmorpholin-4-yl]acetate

Dissolve (R)-2-methylmorpholine (8a) (0.70g, 6.92mmol) in 30mL THF, add potassium carbonate (1.91g, 13.8mmol) and tert-butyl bromoacetate (1.35g, 6.92mmol) at room temperature mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0:1-1:1) to obtain 2-[(2R)-2-methyl Morpholin-4-yl] tert-butyl acetate (8b) (1.4 g, yield: 94%).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.89-3.64 (m, 3H), 3.11 (s, 2H), 2.88-2.73 (m, 2H), 2.41--2.29 (m, 1H), 2.07-1.96 (m ,1H), 1.47(s,9H), 1.14(d,3H).

LCMS m/z=216.3[M+1] ⁺

Step 2: 2-[(2R)-2-Methylmorpholin-4-yl]acetic acid (8c) trifluoroacetate

2-[(2R)-2-methylmorpholin-4-yl]acetic acid trifluoroacetate

Dissolve 2-[(2R)-2-methylmorpholin-4-yl]acetic acid tert-butyl ester (8b) (1.40g, 6.5mmol) in 5mL dichloromethane, add 10mL trifluoroacetic acid, and react at room temperature for 20h . The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate (1.78 g) of 2-[(2R)-2-methylmorpholin-4-yl]acetic acid (8c).

LCMS m/z=160.3[M+1] ⁺

The third step: 1-(2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7 -Tetrahydroimidazo[4,5-c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone (Compound 8)

1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-1,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone

Dissolve the above crude 2-[(2R)-2-methylmorpholin-4-yl]acetic acid (8c) trifluoroacetate (1.78g) in 30mL DMF, and then add HATU (3.25g, 8.55 mmol), DIPEA (2.21g, 17.1mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5 -c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (2.0g), after reacting at room temperature for 16h, lithium hydroxide monohydrate (2.7g, 64.3mmol), the temperature was raised to 65°C and stirred for 3h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2N aqueous hydrochloric acid solution, 300mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, and the obtained solid was used 300mL of methanol/dichloromethane (v/v=1: 10) was dissolved in the mixed solvent, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1) to obtain 1-(2-[6 -(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydroimidazo[4,5-c ]Pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone (Compound 8) (1.1 g, two-step yield from Compound 8b: 32%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.86-6.79 (m, 1H), 4.78 (s, 1H), 4.69 (s, 1H), 4.01-3.92 (m, 2H), 3.87-3.75 (m, 1H), 3.74-3.58 (m, 2H), 3.41--3.34 (m, 2H), 2.95-2.70 (m, 4H) ,2.54(q,2H), 2.30-2.19(m,1H), 1.98-1.88(m,1H), 1.17-1.02(m,6H).

LCMS m/z=537.2[M+1] ⁺

Example 8-1:

1-(2-[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydroimidazole And [4,5-c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone L-tartrate (Compound 8-1)

1-[2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-fluoro-1H-indazol-3-yl]-1,4,6,7-tetrahydroimidazo[4,5 -c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone L-tartrate

The 1-(2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro Imidazo[4,5-c]pyridin-5-yl]-2-[(2R)-2-methylmorpholin-4-yl]ethanone (Compound 8) (200mg, 0.373mmol) and L-tartaric acid (56mg, 0.373mmol) was dissolved in 2mL tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then add 60mL acetonitrile dropwise to the reaction solution, continue to stir for 1h, stand for 10min, filter, and dry the filter cake to obtain 1-(2-[6-(2-ethyl-5-fluoro-4-hydroxybenzene Yl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl]-2-[(2R)- The L-tartrate salt of 2-methylmorpholin-4-yl]ethanone (compound 8-1) (200 mg, yield: 78%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.25 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.85 (d, 1H), 4.75-4.68 (m, 2H), 4.48 (s,2H),4.06-3.85(m,3H),3.84-3.66(m,4H),3.11-2.98(m,2H),2.97-2.89(m,1H),2.85-2.78(m,1H) , 2.64–2.48(m,3H), 2.33–2.18(m,1H), 1.19–1.11(m,3H), 1.07(t,3H).

LCMS m/z=537.2[M+1] ⁺

Example 9:

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro- 1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (Compound 9)

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4 ,5-c]pyridin-5(4H)-yl)-2-(2-methylmorpholino)ethanone

The first step: (S)-2-(2-Methylmorpholino) tert-butyl acetate (9b)

(S)-tert-butyl 2-(2-methylmorpholino)acetate

Dissolve (S)-2-methylmorpholine (9a) (0.50g, 4.94mmol) in 20mL THF, add potassium carbonate (1.37g, 9.91mmol) and tert-butyl bromoacetate (1.44g, 7.38) at room temperature mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100:1-1:1) to obtain (S)-2-(2-methyl) Morpholino tert-butyl acetate (9b) (0.5 g, yield: 47%).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.89-3.64 (m, 3H), 3.10 (s, 2H), 2.86-2.72 (m, 2H), 2.37-2.26 (m, 1H), 2.04-1.95 (m ,1H), 1.47(s,9H), 1.14(d,3H).

LCMS m/z=216.2[M+1] ⁺

Step 2: (S)-2-(2-Methylmorpholino)acetic acid (9c) trifluoroacetate

(S)-2-(2-methylmorpholino)acetic acid trifluoroacetate

(S)-2-(2-Methylmorpholino)-tert-butyl acetate (9b) (0.35g, 1.62mmol) was dissolved in 5mL trifluoroacetic acid and 5mL dichloromethane, and reacted at room temperature for 24h. The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate (0.35 g) of (S)-2-(2-methylmorpholino)acetic acid (9c).

LCMS m/z=160.2[M+1] ⁺

The third step: (S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7 -Dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (Compound 9)

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4 ,5-c]pyridin-5(4H)-yl)-2-(2-methylmorpholino)ethanone

Dissolve the above crude (S)-2-(2-methylmorpholino)acetic acid (9c) trifluoroacetate (0.35g) in 10mL DMF, and then add HATU(0.81g, 2.13mmol), DIPEA (414mg, 3.20mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine -2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (500mg), after 16 hours of reaction at room temperature, lithium hydroxide monohydrate (0.27g, 6.43mmol) was added, and the temperature was increased To 65°C, stir for 3h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2N aqueous hydrochloric acid solution, 100 mL of water was added to the reaction solution, a large amount of solid was precipitated out, filtered, and 100 mL of methanol/dichloromethane (v/v=1: 10) was dissolved in the mixed solvent, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1) to obtain (S)-1-( 2-(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4, 5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (compound 9) (100 mg, two-step yield from compound 9b: 12%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.92 (d, 1H), 6.86 (d, 1H), 6.85-6.79 (m, 1H), 4.79 (s, 1H), 4.69 (s,1H),4.02–3.90(m,2H), 3.87–3.74(m,1H), 3.74–3.58(m,2H), 3.39–3.32(m,2H), 2.95–2.68(m,4H) ,2.54(q,2H),2.28-2.17(m,1H),1.96-1.86(m,1H),1.15-1.02(m,6H).

LCMS m/z=537.3[M+1] ⁺

Example 9-1:

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro- L-tartrate of 1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (Compound 9-1)

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4 ,5-c]pyridin-5(4H)-yl)-2-(2-methylmorpholino)ethanone L-tartrate

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro -1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(2-methylmorpholino)ethanone (Compound 9) (50mg, 0.093mmol) and L-tartaric acid ( 13.9 mg, 0.093 mmol) was dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 30 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain (S)-1-(2-(6-(2-ethyl-5-fluoro- 4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2 -L-tartrate of (2-methylmorpholino)ethanone (compound 9-1) (45 mg, yield: 70%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.25 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.84 (d, 1H), 4.76-4.68 (m, 2H), 4.47 (s,2H),4.03-3.83(m,3H),3.81-3.62(m,4H),3.11-2.88(m,3H),2.86-2.77(m,1H),2.60-2.44(m,3H) ,2.27-2.14(m,1H),1.19-1.11(m,3H),1.07(t,3H).

LCMS m/z=537.2[M+1] ⁺

Example 10:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)ethyl Ketone (Compound 10)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethanone

The first step: 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl) tert-butyl acetate (10b)

tert-butyl 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)acetate

Dissolve (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (10a) (0.6g, 5.3mmol) in 20mL THF, add potassium carbonate (1.46g, 10.6mmol) at room temperature React with tert-butyl bromoacetate (1.5g, 7.7mmol) at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=100:1-1:1) to obtain 2-((3aR,6aS)-tetrahydro -1H-furo[3,4-c]pyrrole-5(3H)-yl) tert-butyl acetate (10b) (0.6 g, yield: 50%).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.81--3.72 (m, 2H), 3.62 (dd, 2H), 3.20 (s, 2H), 3.03 - 2.91 (m, 2H), 2.90 - 2.81 (m, 2H) ), 2.39(dd, 2H), 1.46(s, 9H).

LCMS m/z=228.3[M+1] ⁺

Step 2: 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)acetic acid (10c) trifluoroacetate

2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)acetic acid trifluoroacetate

Dissolve 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)acetic acid tert-butyl ester (10b) (0.6g, 2.64mmol) in 5mL In dichloromethane and 5mL trifluoroacetic acid, the reaction was carried out at room temperature for 16h. The reaction solution was concentrated under reduced pressure to obtain crude 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)acetic acid (10c) trifluoroacetic acid Salt (0.6g).

LCMS m/z=172.3[M+1] ⁺

The third step: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro- 1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) -Yl) ethyl ketone (compound 10)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethanone

Dissolve the above crude 2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)acetic acid (10c) in trifluoroacetate (0.6g) In 10mL DMF, add HATU (1.62g, 4.26mmol), DIPEA (1.10g, 8.51mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6 ,7-Tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (1.0g), react at room temperature 16h. Lithium hydroxide monohydrate (0.89 g, 21.21 mmol) was added to the reaction solution, the temperature was raised to 65° C., and the mixture was stirred for 3 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2mol/L hydrochloric acid aqueous solution, 100mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, and the obtained solid was used 100mL of dichloromethane/methanol (v/v) = 10:1 mixed solvent dissolved, dried with anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10:1) to obtain 1-(2- (6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5- c]pyridine-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)ethanone (Compound 10) (0.2g, two-step yield calculated from compound 10b: 14%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.82 (d, 1H), 4.78 (s, 1H), 4.69 (s) ,1H), 4.00–3.92(m,2H), 3.86–3.76(m,2H), 3.64–3.39(m,4H), 2.98–2.64(m,6H), 2.60–2.42(m,4H), 1.07 (t,3H).

LCMS m/z=549.2[M+1] ⁺

Example 10-1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)ethyl Ketone L-tartrate (Compound 10-1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethanone L-tartrate

The 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazole And [4,5-c]pyridine-5(4H)-yl)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl) Ethyl ketone (compound 10) (50 mg, 0.09 mmol) and L-tartaric acid (13.5 mg, 0.09 mmol) were dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 20 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxybenzene Yl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-((3aR ,6aS)-Tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)ethanone L-tartrate (Compound 10-1) (25 mg, yield: 40%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.24 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.83 (d, 1H), 4.73 (s, 1H), 4.62 (s) ,1H), 4.42(s,2H), 4.16–3.92(m,3H), 3.90–3.62(m,5H), 3.53–3.39(m,2H), 3.14–3.01(m,2H), 2.98–2.77 (m,4H),2.54(q,2H),1.07(t,3H).

LCMS m/z=549.3[M+1] ⁺

Example 11:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (Compound 11)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone

The first step: tert-butyl 2-(2-hydroxymethyl)morpholino)acetate (11b)

tert-butyl 2-(2-(hydroxymethyl)morpholino)acetate

Dissolve 2-hydroxymethylmorpholine hydrochloride (11a) (1.33g, 8.66mmol) in 40mL THF, add potassium carbonate (2.99g, 21.64mmol) and tert-butyl bromoacetate (2.54g, 13.02) at room temperature mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1-10:1) to obtain 2-(2-hydroxymethyl)morpholino ) Tert-Butyl acetate (11b) (1.1 g, yield: 55%).

¹ H NMR(400MHz, CDCl ₃ ) δ3.93-3.86(m,1H), 3.81-3.68(m,2H), 3.66-3.54(m,2H), 3.12(s,2H), 2.86-2.74(m ,2H),2.41-2.31(m,1H),2,18(t,1H),1.47(s,9H)

LCMS m/z=232.3[M+1] ⁺

The second step: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7 -Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (Compound 11)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone

Dissolve tert-butyl 2-(2-hydroxymethyl)morpholino)acetate (11b) (0.60 g, 2.59 mmol) in 7 mL of dichloromethane, add 10 mL of trifluoroacetic acid, and react at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure to obtain 0.2 g of residue. Dissolve 0.2g residue in 5mL DMF, then add HATU (1.31g, 3.45mmol), DIPEA (815mg, 6.31mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-( 4,5,6,7-Tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (0.81 g) After 16 hours of reaction at room temperature, lithium hydroxide monohydrate (0.85 g, 20.26 mmol) was added, the temperature was raised to 65° C., and the mixture was stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2mol/L hydrochloric acid aqueous solution, 70mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, and the obtained solid was used 100mL of dichloromethane/methanol (v/v) =1:1 mixed solvent was dissolved, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1) to obtain 1-(2- (6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[ 4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (compound 11) (127 mg, yield calculated from compound 11b: 9%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.82 (d, 1H), 4.86-4.66 (m, 2H), 4.02 --3.92 (m, 2H), 3.92 - 3.79 (m, 1H), 3.76 - 3.42 (m, 4H), 3.41 - 3.33 (m, 2H), 2.98 - 2.68 (m, 4H), 2.54 (q, 2H) , 2.32-2.21(m,1H), 2.08-1.99(m,1H), 1.07(t,3H).

LCMS m/z=553.2[M+1] ⁺

Example 11-1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone L-tartrate (Compound 11-1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone L-tartrate

The 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro -5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (Compound 11) (50mg, 0.091mmol) and L-tartaric acid ( 13.6 mg, 0.091 mmol) was dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 30 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxybenzene) Yl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2 -(Hydroxymethyl)morpholino)ethanone L-tartrate (Compound 11-1) (31 mg, yield: 48%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.25 (d, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.84 (d, 1H), 4.78-4.68 (m, 2H), 4.48 (s, 2H), 4.04--3.88 (m, 3H), 3.84--3.64 (m, 4H), 3.62--3.48 (m, 2H), 3.18--2.98 (m, 2H), 2.98--2.76 (m, 2H) ,2.65--2.30(m,4H),1.07(t,3H).

LCMS m/z=553.2[M+1] ⁺

Example 12:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one (Compound 12)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one

The first step: 2-ethynylmorpholine (12b) trifluoroacetate

2-ethynylmorpholine trifluoroacetate

Dissolve tert-butyl 2-ethynylmorpholine-4-carboxylate (12a) (see WO2014117274 for synthesis method) (320 mg, 1.51 mmol) in 4 mL of dichloromethane and 2 mL of trifluoroacetic acid, and react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate (423 mg) of 2-ethynylmorpholine (12b).

LCMS m/z=112.1[M+1] ⁺

The second step: tert-butyl 2-(2-ethynylmorpholino)acetate (12c)

tert-butyl 2-(2-ethynylmorpholino)acetate

Dissolve the trifluoroacetate (423mg) of crude 2-ethynylmorpholine (12b) in 5mL THF, add potassium carbonate (0.52g, 3.76mmol) and tert-butyl bromoacetate (0.44g, 2.26mmol) at room temperature ), react at room temperature for 16h. The reaction solution was filtered and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=100:1-1:1) to obtain 2-(2-ethynylmorpholino) Tert-butyl acetate (12c) (0.20 g, two-step yield from compound 12a: 59%).

¹ H NMR (400MHz, CDCl ₃ ) δ 4.43-4.35 (m, 1H), 3.98-3.89 (m, 1H), 3.75-3.66 (m, 1H), 3.20-3.07 (m, 2H), 2.96-2.88 (m,1H), 2.75-2.66(m,1H), 2.57-2.42(m,3H), 1.46(s,9H).

LCMS m/z=226.1[M+1] ⁺

The third step: the trifluoroacetate salt of 2-(2-ethynylmorpholino)acetic acid (12d)

2-(2-ethynylmorpholino)acetic acid trifluoroacetate

Dissolve tert-butyl 2-(2-ethynylmorpholino)acetate (12c) (422mg, 1.87mmol) in 4mL dichloromethane and 3mL trifluoroacetic acid, and react at room temperature for 16h. The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate (0.6 g) of 2-(2-ethynylmorpholino)acetic acid (12d).

LCMS m/z=170.1[M+1] ⁺

The fourth step: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7 -Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one (Compound 12)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one

Dissolve the above crude 2-(2-ethynylmorpholino)acetic acid (12d) trifluoroacetate (0.6g) in 8mL DMF, then add HATU (950mg, 2.50mmol), DIPEA (647mg, 5.00 mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl) The hydrochloride (585 mg) of -1H-indazol-6-yl)phenol (Intermediate 1) was reacted at room temperature for 16 hours. Lithium hydroxide monohydrate (0.52 g, 12.39 mmol) was added to the reaction solution, the temperature was raised to 65° C., and the mixture was stirred for 3 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2mol/L hydrochloric acid aqueous solution, 100mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, and the obtained solid was used 100mL of dichloromethane/methanol (v/v) = 10:1 mixed solvent dissolved, dried with anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10:1) to obtain 1-(2- (6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[ 4,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one (compound 12) (0.4 g, two-step yield from compound 12c: 39%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.25--7.18 (m, 1H), 6.98--6.90 (m, 1H), 6.88 (d, 1H), 6.80 (dd, 1H), 4.86--4.63 (m, 2H), 4.45--4.27(m,1H), 4.05---3.80(m,3H), 3.70--3.52(m,1H), 3.43--3.27(m,2H), 3.02--2.72(m,4H), 2.66-- 2.30(m,5H),1.05(t,3H).

LCMS m/z=547.3[M+1] ⁺

Example 12-1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)e-1-one L-tartrate (Compound 12-1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one L-tartrate

The 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro -5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-ethynylmorpholino)ethan-1-one (Compound 12) (50mg, 0.09mmol) and L-tartaric acid ( 13.5 mg, 0.09 mmol) was dissolved in 1 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Then add 20 mL of acetonitrile dropwise to the reaction solution, continue to stir for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxybenzene Yl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2 -Ethynylmorpholino)ethan-1-one L-tartrate (Compound 12-1) (30 mg, yield: 48%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.26 (s, 1H), 6.95 (d, 1H), 6.92-6.83 (m, 2H), 4.92-4.82 (m, 1H), 4.78-4.66 (m, 1H), 4.50(s, 2H), 4.46–4.32(m, 1H), 4.08–3.84(m, 3H), 3.77–3.55(m, 1H), 3.50–3.35(m, 2H), 3.05–2.75( m, 4H), 2.72--2.38 (m, 5H), 1.07 (t, 3H).

LCMS m/z=547.3[M+1] ⁺

Example 13:

(R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7 -Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (Compound 13)

(R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H -imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone

The first step: tert-butyl (R)-2-(2-hydroxymethyl)morpholino)acetate (13b)

(R)-tert-butyl 2-(2-(hydroxymethyl)morpholino)acetate

Dissolve (R)-2-hydroxymethylmorpholine hydrochloride (13a) (5.00g, 32.55mmol) in 40mL THF, add potassium carbonate (11.41g, 82.56mmol) and tert-butyl bromoacetate ( 9.52g, 48.81mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1-10:1) to obtain (R)-2-(2-hydroxymethyl ) Morpholino)-tert-butyl acetate (13b) (6.1 g, yield: 81%).

LCMS m/z=232.3[M+1] ⁺

The second step: (R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4 ,6,7-Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (Compound 13)

(R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H -imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone

(R)-2-(2-Hydroxymethyl)morpholino)acetic acid tert-butyl ester (13b) (3.8g, 16.4mmol) was dissolved in 20mL of dichloromethane, 15mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 16h. The reaction solution was directly concentrated under reduced pressure to obtain 6.2 g of residue. Dissolve 6.2g residue in 25mL DMF, then add HATU (8.28g, 21.8mmol), DIPEA (7.04g, 54.5mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3- (4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride ( 4.12g), after reacting at room temperature for 16h, lithium hydroxide monohydrate (1.68g, 40.00mmol) was added, the temperature was raised to 55°C, and the mixture was stirred for 2h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 8 with 2mol/L hydrochloric acid aqueous solution, 100mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, and the obtained solid was used 100mL of dichloromethane/methanol (v/v) =1:1 mixed solvent is dissolved, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1) to obtain (R)-1 -(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H -Imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (compound 13) (2.1g, yield calculated from compound 13b: 23% ).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.82 (d, 1H), 4.86-4.66 (m, 2H), 4.02 --3.92(m,2H),3.92–3.79(m,1H),3.76–3.42(m,4H),3.42–3.33(m,2H),3.02–2.68(m,4H),2.54(q,2H) , 2.34–2.21(m,1H), 2.08–1.99(m,1H), 1.07(t,3H).

LCMS m/z=553.2[M+1] ⁺

Example 13-1:

(R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7 -Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone L-tartrate (Compound 13-1)

(R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H -imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone L-tartrate

(R)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6, 7-Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone (Compound 13) (1.5g, 2.71mmol) And L-tartaric acid (0.41g, 2.71mmol) were dissolved in 10mL tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then add 40mL acetonitrile dropwise to the reaction solution, continue to stir for 1h, let stand for 10min, precipitate the oil, pour out the supernatant, add 30mL water to the residue to dissolve, freeze-dry to obtain (R)-1-(2 -(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)-2-(2-(hydroxymethyl)morpholino)ethanone L-tartrate (Compound 13-1) (1.7g, yield: 89%) .

¹ H NMR (400MHz, CD ₃ OD) δ 7.25 (d, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.85 (d, 1H), 4.76-4.69 (m, 2H), 4.48 (s,2H),4.04-3.88(m,3H),3.83-3.63(m,4H),3.62-3.46(m,2H),3.12-2.96(m,2H),2.96-2.77(m,2H) , 2.61–2.47(m,3H), 2.43–2.28(m,1H), 1.07(t,3H).

LCMS m/z=553.2[M+1] ⁺

Example 14

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-(1,4-oxazepin-4-yl)ethanone (Compound 14)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(1,4-oxazepan-4-yl)ethanone

The first step: tert-butyl 2-(1,4-oxazepin-4-yl)acetate (14b)

tert-butyl 2-(1,4-oxazepan-4-yl)acetate

Dissolve 1,4-oxazepine hydrochloride (14a) (750mg, 5.5mmol) in 10mL THF, add potassium carbonate (1.5g, 11mmol) and tert-butyl bromoacetate (1.1g) at room temperature , 5.6mmol), react at room temperature for 16h. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100:1-1:1) to obtain 2-(1,4-oxazepine) Cycloheptan-4yl) tert-butyl acetate (14b) (0.48 g, yield: 41%).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.81 (t, 2H), 3.78-3.73 (m, 2H), 3.33 (s, 2H), 2.95-2.83 (m, 4H), 1.99-1.89 (m, 2H) ), 1.47(s, 9H).

The second step: 2-(1,4-oxazepin-4-yl)acetic acid (14c) hydrochloride

2-(1,4-oxazepan-4-yl)acetic acid hydrochloride

Dissolve tert-butyl 2-(1,4-oxazepin-4-yl)acetate (14b) (480mg, 2.2mmol) in 2mL dichloromethane, add 10mL 4mol/L hydrochloric acid 1.4-dioxane The solution was reacted at room temperature for 16h. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride (0.44 g) of crude 2-(1,4-oxazepin-4-yl)acetic acid (14c).

LCMS m/z=160.1[M+1] ⁺

The third step: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro- 1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(1,4-oxazepin-4-yl)ethanone (Compound 14)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(1,4-oxazepan-4-yl)ethanone

Dissolve the above crude 2-(1,4-oxazepin-4-yl)acetic acid (14c) hydrochloride (0.44g) in 10mL DMF, and then add HATU (970mg, 2.6mmol), DIPEA (660mg, 5.1mmol) and 5-ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine -2-yl)-1H-indazol-6-yl)phenol (Intermediate 1) hydrochloride (600mg), react at room temperature for 16h. The pH of the reaction solution was adjusted to 7 with 2mol/L hydrochloric acid, and then 100mL of water was added to precipitate a large amount of solids. The resulting solid was dissolved in 30mL of methanol, and then lithium hydroxide monohydrate (0.22g, 5.24mmol) was added, and the temperature was raised to 50. ℃, stir for 1h. Concentrate most of the solvent in the reaction solution under reduced pressure, cool to 0°C, adjust the pH to 7 with 2mol/L hydrochloric acid solution, add 100mL of water to the reaction solution, precipitate a large amount of solid, filter, the solid obtained is dried in an oven for 6h, the crude product is silica gel Column chromatography was separated and purified (dichloromethane/methanol (v/v) = 10:1) to obtain 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro -1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)-2-(1,4-oxazepine Cycloheptan-4-yl)ethanone (Compound 14) (0.4 g, two-step yield from Compound 14b: 34%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 6.95 (d, 1H), 6.89 (d, 1H), 6.83 (d, 1H), 4.90-4.64 (m, 2H), 4.01 --3.92(m,2H), 3.86–3.63(m,4H), 3.60–3.48(m,2H), 2.97–2.72(m,6H), 2.54(q,2H), 2.00–1.82(m,2H) ,1.07(t,3H).

LCMS m/z=537.3[M+1] ⁺

Example 14-1:

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo [4,5-c]pyridine-5(4H)-yl)-2-(1,4-oxazepin-4-yl)ethanone L-tartrate (Compound 14-1)

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c ]pyridin-5(4H)-yl)-2-(1,4-oxazepan-4-yl)ethanone L-tartrate

The 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazole And [4,5-c]pyridine-5(4H)-yl)-2-(1,4-oxazepin-4-yl)ethanone (Compound 14) (275mg, 0.513mmol) and L -Tartaric acid (0.077g, 0.513mmol) was dissolved in 2mL tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1h. Then 60 mL of acetonitrile was added dropwise to the reaction solution, stirring was continued for 1 h, standing for 10 min, filtered, the filter cake was dried, then dissolved in 20 mL of water, and lyophilized to obtain 1-(2-(6-(2-ethyl- 5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)- Yl)-2-(1,4-oxazepin-4-yl)ethanone L-tartrate (Compound 14-1) (0.31 g, yield: 88%).

¹ H NMR(400MHz, D ₂ O) δ7.00--6.60(m,2H), 6.60--6.05(m,2H), 4.70--4.25(m,6H), 4.20--3.40(m,10H), 2.90-- 2.50(m,2H),2.42-1.95(m,4H),1.00-0.60(m,3H).

LCMS m/z=537.3[M+1] ⁺

Example 15:

(S)-1-(2-(6-(2-Ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one (Compound 15)

(S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one

The first step: 1-(4'-(benzyloxy)-2'-ethyl-3,5-difluoro-[1,1'-biphenyl]-4-yl)-2,2-diethyl Oxyethyl-1-one (15b)

1-(4'-(benzyloxy)-2'-ethyl-3,5-difluoro-[1,1'-biphenyl]-4-yl)-2,2-diethoxyethan-1-one

Combine 2-(4-(benzyloxy)-2-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (15a) (for synthesis method see WO2020173400) (45g, 133.0mmol) and 1-(4-bromo-2,6-difluorophenyl)-2,2-diethoxye-1-one (see WO2018204238 for synthesis method) (43g, 133.1mmol ) Is dissolved in a mixed solvent of 500mL toluene, 50mL water and 50mL ethanol, and potassium carbonate (36.7g, 266mmol) is added, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride is added under nitrogen protection Palladium dichloromethane complex (3.25g, 3.98mmol), heated to 120°C and reacted for 4h. The reaction solution was cooled to room temperature, poured into 0.5L water, extracted with ethyl acetate (2L×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v /v)=100:3-10:1) to obtain 1-(4'-(benzyloxy)-2'-ethyl-3,5-difluoro-[1,1'-biphenyl]-4 -Yl)-2,2-diethoxyethane-1-one (15b) (45 g, yield: 74%).

The second step: 6-(4-(benzyloxy)-2-ethylphenyl)-3-(diethoxymethyl)-4-fluoro-1H-indazole (15c)

6-(4-(benzyloxy)-2-ethylphenyl)-3-(diethoxymethyl)-4-fluoro-1H-indazole

Add 1-(4'-(benzyloxy)-2'-ethyl-3,5-difluoro-[1,1'-biphenyl]-4-yl)-2,2-diethoxyethyl -1-One (15b) (27.70g, 60.94mmol) was dissolved in 140mL of THF, hydrazine hydrate (14mL, 288.05mmol) was added at room temperature, and the temperature was raised to 100°C for 16h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding 100 mL ethyl acetate. The organic phase was washed with 0.1 mol/L aqueous hydrochloric acid solution (50 mL×2) and separated. The organic phase was dried over anhydrous sodium sulfate and reduced under reduced pressure. After concentration, the crude product was slurried with 100 mL methyl tert-butyl ether for 30 min, filtered with suction, and the filter cake was collected to obtain 6-(4-(benzyloxy)-2-ethylphenyl)-3-(diethoxymethyl )-4-fluoro-1H-indazole (15c) (26 g, yield: 95%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.25 (br.s, 1H), 7.51-7.45 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.31 (m, 1H), 7.19 --7.13 (m, 2H), 7.00 (d, 1H), 6.91 (dd, 1H), 6.81-6.74 (m, 1H), 5.82 (s, 1H), 5.15 (s, 2H), 3.77-3.66 (m , 2H), 3.65--3.54 (m, 2H), 2.55 (q, 2H), 1.16 (t, 6H), 1.04 (t, 3H).

The third step: 6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazole-3-carbaldehyde (15d)

6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazole-3-carbaldehyde

Dissolve 6-(4-(benzyloxy)-2-ethylphenyl)-3-(diethoxymethyl)-4-fluoro-1H-indazole (15c) (6.50g, 14.49mmol) In a mixed solvent of 80 mL of dichloromethane/acetone (v/v=1:1), 4 mol/L aqueous hydrochloric acid (1 mL) was added at room temperature, and reacted at room temperature for 30 minutes. A large amount of solids were observed during the reaction. The reaction solution was concentrated under reduced pressure to obtain a crude solid product. 50 mL of methyl tert-butyl ether was added to the crude product to be slurried for 30 minutes, filtered with suction and the filter cake was collected to obtain 6-(4-(benzyloxy)-2-ethylphenyl )-4-fluoro-1H-indazole-3-carbaldehyde (15d) (5.37 g, yield: 99%).

LCMS m/z=375.2[M+1] ⁺ .

The fourth step: 5-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazol-3-yl)-5H-imidazo[ 4,5-c)pyridine (15e)

5-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazol-3-yl)-5H-imidazo[4,5-c]pyridine

Dissolve 6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazole-3-carbaldehyde (15d) (5.37g, 14.35mmol) in 40mL DMF, at room temperature Add solid sodium bisulfite (2.26g, 21.72mmol) and 1-benzyl-4-imino-1,4-dihydropyridine-3-amine hydrobromide (3.17g) (see WO2018204238 for synthesis method), The temperature was raised to 150°C and reacted for 3h. The reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, and the filter cake was collected to obtain crude 5-benzyl-2-(6-(4-(benzyloxy)-2-ethyl Phenyl)-4-fluoro-1H-indazol-3-yl)-5H-imidazo[4,5-c]pyridine (15e) (9.5 g).

LCMS m/z=554.2[M+1] ⁺

The fifth step: 5-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazol-3-yl)-4,5,6 ,7-Tetrahydro-3H-imidazo[4,5-c]pyridine (15f)

5-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4, 5-c]pyridine

The crude product from the previous step 5-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazol-3-yl)-5H-imidazo[ 4,5-c]pyridine (15e) (9.5g) was dissolved in a mixed solvent of 50mL methanol/tetrahydrofuran (v/v)=1:1, sodium borohydride (5.43g, 143.5mmol) was added at room temperature, and the reaction was carried out at room temperature. 19h. Add 50mL of water to the reaction solution, continue to stir for 10 minutes, extract with ethyl acetate (100mL×3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is subjected to Pre-HPLC (instrument and preparation column: Glison GX-281) To prepare the liquid phase, the model of the preparation column is Sunfire C18, 5μm, inner diameter×length=30mm×150mm). Preparation method: The crude product is dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: acetonitrile is eluted with a 5% gradient of 60%, and the elution time is 15min), the obtained preparation solution is concentrated under reduced pressure, and then the pH value is adjusted to 9 with saturated sodium bicarbonate solution, and the water phase is 100mL methanol/dichloride Methane (v/v) = 1:10 mixed solvent extraction, drying with anhydrous sodium sulfate, and concentration under reduced pressure to obtain 5-benzyl-2-(6-(4-(benzyloxy)-2-ethylbenzene Yl)-4-fluoro-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (15f) (320mg, calculated from compound 15d The total yield of the two steps: 4%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.52-7.46(m,2H), 7.45-7.31(m,7H), 7.31-7.24(m,1H), 7.22-7.15(m,2H), 7.00 (d, 1H), 6.91 (dd, 1H), 6.72 (dd, 1H), 5.15 (s, 2H), 3.72 (s, 2H), 3.44 (s, 2H), 2.82-2.74 (m, 2H), 2.69--2.62(m,2H), 2.58(q,2H), 1.05(t,3H).

LCMS m/z=558.3[M+1] ⁺

The sixth step: 3-ethyl-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H- Indazol-6-yl)phenol (15g) hydrochloride

3-ethyl-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol hydrochloride

The 5-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-4-fluoro-1H-indazol-3-yl)-4,5,6,7- Tetrahydro-3H-imidazo[4,5-c]pyridine (15f) (320mg, 0.57mmol) was added to 20mL methanol/tetrahydrofuran (v/v) = 1:1 mixed solvent, and 12mol/L hydrochloric acid was added sequentially (0.5 mL) and 10% palladium-carbon (400 mg), put the reaction system under a hydrogen atmosphere (pressure of 50 psi), and raise the temperature to 50° C. to react for 19 hours. The reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain crude 3-ethyl-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4 ,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (15g) hydrochloride (230mg).

LCMS m/z=378.3[M+1] ⁺

The seventh step: (S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7 -Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one (Compound 15)

(S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one

Dissolve the above crude (S)-2-(2-methylmorpholino)acetic acid (9c) trifluoroacetate (310mg) in 5mL DMF, and then add HATU (433mg, 1.14mmol), DIPEA ( 735mg, 5.69mmol) and the crude product of the previous step 3-ethyl-4-(4-fluoro-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2- Hydrochloride (230mg) of -1H-indazol-6-yl)phenol (15g) was reacted at room temperature for 16h, lithium hydroxide monohydrate (42mg, 1.0mmol) was added, and the temperature was raised to 55°C for 2h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, the preparation column model was Sunfire C18, 5μm, inner diameter×length=30mm×150mm). Preparation method: The crude product is dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: acetonitrile is eluted with a 5% gradient of 60%, and the elution time is 15min), the obtained preparation solution is concentrated under reduced pressure, and then the pH value is adjusted to 9 with saturated sodium bicarbonate solution, and the water phase is 100mL methanol/dichloride Methane (v/v) = 1:10 mixed solvent extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl) -4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methyl Glymorpholino)ethan-1-one (compound 15) (15 mg, total yield of two steps from compound 15f: 5%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.24-7.19 (m, 1H), 7.06 (d, 1H), 6.85-6.78 (m, 1H), 6.77 (d, 1H), 6.68 (dd, 1H) , 4.78 (s, 1H), 4.69 (s, 1H), 4.00-3.89 (m, 2H), 3.87-3.55 (m, 3H), 3.38-3.31 (m, 2H), 2.94-2.87 (m, 1H) , 2.85–2.67(m,3H), 2.57(q,2H), 2.27–2.15(m,1H), 1.96–1.85(m,1H), 1.16–1.02(m,6H).

LCMS m/z=519.3[M+1] ⁺

Example 15-1:

(S)-1-(2-(6-(2-Ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one L-tartrate (Compound 15-1)

(S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one L-tartrate

(S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro -5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one (Compound 15) (15mg, 0.029mmol) and L-tartaric acid ( 4.2 mg, 0.028 mmol) was dissolved in 0.5 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Add 10 mL of acetonitrile dropwise to the reaction solution, continue stirring for 1 h, let stand for 10 min, filter, and dry the filter cake to obtain (S)-1-(2-(6-(2-ethyl-4-hydroxyphenyl) -4-fluoro-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methyl Glymorpholino)ethan-1-one L-tartrate (Compound 15-1) (15 mg, yield: 77%).

¹ H NMR (400MHz, CD ₃ OD) δ 7.23 (s, 1H), 7.07 (d, 1H), 6.83 (dd, 1H), 6.77 (d, 1H), 6.69 (dd, 1H), 4.76-4.69 (m,2H),4.46(s,2H),4.03-3.81(m,3H),3.80-3.64(m,2H),3.63-3.54(m,2H),3.03-2.88(m,3H),2.85 --2.77 (m, 1H), 2.58 (q, 2H), 2.51 - 2.38 (m, 1H), 2.22 - 2.08 (m, 1H), 1.18 - 1.30 (m, 6H).

LCMS m/z=519.3[M+1] ⁺

Example 16:

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one (compound 16)

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one

The above crude product (S)-2-(2-methylmorpholino)acetic acid (9c) trifluoroacetate (2.2g) and 5-ethyl-2-fluoro-4-(3-(4, 5,6,7-Tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol hydrochloride (see WO2017079205 for synthesis method) (600mg) After 16 hours of reaction at room temperature, lithium hydroxide monohydrate (210 mg, 5.0 mmol) was added, and the temperature was raised to 55° C. to react for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, the preparation column model was Sunfire C18, 5μm, inner diameter×length=30mm×150mm). Preparation method: The crude product is dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: acetonitrile is eluted with a 5% gradient of 60%, and the elution time is 15 min). The obtained preparation is concentrated under reduced pressure, and then the pH value is adjusted to 9 with saturated sodium bicarbonate solution. The aqueous phase is 200 mL methanol/dichloride. Methane (v/v) = 1:10 mixed solvent extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (S)-1-(2-(6-(2-ethyl-5-fluoro-4- Hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methyl Glymorpholino)ethan-1-one (compound 16) (360 mg, total yield of two steps from compound 9b: 7%).

¹ H NMR (400MHz, CD ₃ OD) δ 8.26 (dd, 1H), 7.42 - 7.38 (m, 1H), 7.18 - 7.11 (m, 1H), 6.97 - 6.91 (m, 1H), 6.88 (d, 1H), 4.86--4.67(m, 2H), 4.02--3.91(m, 2H), 3.87--3.56(m, 3H), 3.40--3.33(m, 2H), 2.96--2.68(m, 4H), 2.53( q, 2H), 2.29-2.18 (m, 1H), 1.98-1.87 (m, 1H), 1.16-0.99 (m, 6H).

LCMS m/z=519.3[M+1] ⁺

Example 16-1:

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one L-tartrate (Compound 16-1)

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4 ,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one L-tartrate

(S)-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro -5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methylmorpholino)ethan-1-one (compound 16) (360mg, 0.695mmol) and L-tartaric acid ( 104 mg, 0.693 mmol) was dissolved in 3.6 mL of tetrahydrofuran/water (v/v=1:1) mixed solvent, and stirred at room temperature for 1 h. Add 60mL acetonitrile dropwise to the reaction solution, continue to stir for 1h, stand for 10min, filter, and dry the filter cake to obtain (S)-1-(2-(6-(2-ethyl-5-fluoro-4- Hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-(2-methyl Glymorpholino)ethan-1-one L-tartrate (Compound 16-1) (350 mg, yield: 75%).

¹ H NMR (400MHz, CD ₃ OD) δ 8.25 (d, 1H), 7.41 (s, 1H), 7.16 (dd, 1H), 6.93 (d, 1H), 6.89 (d, 1H), 4.73 (s , 2H), 4.48 (s, 2H), 4.04--3.84 (m, 3H), 3.82--3.64 (m, 4H), 3.09-2.96 (m, 2H), 2.96--2.78 (m, 2H), 2.59--2.45 (m,3H), 2.29-2.14(m,1H), 1.19-1.01(m,6H).

LCMS m/z=519.3[M+1] ⁺

Biological test case

Test Example 1: Inhibitory activity on JAK1, JAK2, JAK3 kinase

Use Cisbio's HTRF KinEASE-TK kit (article number: 62TK0PEC) for detection. The specific method is as follows:

Dilute the compound with 1x the following kinase buffer to make it 2.5 times the final concentration; dilute the enzymes JAK1, JAK2 and JAK3 (Carna; 08-144, 08-045 and 08-046) to 15μg/ mL, 0.185μg/mL, 1.665μg/mL; Dilute ATP to 19.6μM (JAK1), 19.8μM (JAK2), 7.15μM (JAK3); Dilute TK Substrate-biotin stock solution Into 10μM.

Carry out 10μL kinase reaction with 1x kinase buffer: Example compound or 1x kinase buffer 4μL+TK substrate biotin 2μL+JAK enzyme 2μL+ATP 2μL, mix and incubate at room temperature for 2 hours (JAK1) or 30 minutes (JAK2 and After JAK3), add 5 μL Streptavidin-XL665 (500 nM) and 5 μL TK Antibody-cryptate (1x), and continue to incubate at room temperature for 1 hour. The fluorescence value of 665nm and 620nm was measured by a microplate reader (PHERAstar FSX). Signal ratio Ratio calculated according to formula (1), calculated using the Origin 9.2 analysis and IC _50.

Ratio=[Signal 665]/[Signal 620]*10 ⁴ formula (1)

The inhibitory activity of the JAK1, JAK2, and JAK3 kinases of the compounds of the present invention was determined by the above experiment.

Table 1. Inhibitory activity of the compounds of the present invention on JAK1, JAK2 and JAK3 kinases

Serial number Compound JAK1(nM) JAK2(nM) JAK3(nM) 1 Compound 5-1 0.16 2.36 0.21 2 Compound 6-1 0.32 2.65 0.34 3 Compound 8-1 0.29 1.35 0.45 4 Compound 9-1 0.50 3.07 0.32 5 Compound 14-1 0.67 1.65 0.13

Conclusion: The compounds of the present invention have inhibitory effects on JAK1, JAK2 and JAK3 kinases. For example, the compounds shown in Table 1 have excellent inhibitory effects.

Test Example 2: IL-13 induces p-STAT6 expression in mouse lung tissue

Male Balb/C mice (18-22g) purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. were adapted to the experimental environment for at least 3 days. On the day of the experiment, the animals were anesthetized with isoflurane. The vehicle (10% DMSO + 10% 1,3-propanediol + 80% normal saline) or the test compound (50 μL/head) is administered to the anesthetized animal by intratracheal administration at the required dose. After the animal recovers, it is returned to the breeding cage. One hour after the administration, the animals were anesthetized again, and the vehicle or 0.03 μg IL-13 (R&D, Cat#413-ML-025) was administered by intratracheal administration at 50 μL/only. After the animal recovers, it is returned to the breeding cage. One hour after IL-13 (Thermo, Cat#700247) was administered, the lung tissues of the mice were collected, and the expression level of p-STAT6 was detected by the wes instrument (ProteinSimple). The drug efficacy of the test compound is expressed by the inhibition rate (%) of p-STAT6 expression, the inhibition rate of the normal group (no test compound and IL-13) is 100%, and the inhibition rate of the vehicle group (only IL-13) The rate is 0%.

Table 2. Inhibition rate of compounds at a dose of 100 μg on IL-13-induced p-STAT6 expression in mouse lung tissue

Serial number Compound IL-13 induced mouse lung tissue p-STAT6 expression model inhibition rate% 1 Control compound L-tartrate 70.45 2 Compound 5-1 80.49 3 Compound 8-1 83.83 4 Compound 9-1 87.80

Conclusion: The compound of the present invention has a better inhibitory rate on IL-13-induced p-STAT6 expression in mouse lung tissue than the control compound L-tartrate at a dose of 100 μg. For example, compounds 5-1, 8-1, and 9-1 are in The inhibitory rate of IL-13-induced p-STAT6 expression in mouse lung tissues at a dose of 100 μg was higher than 80%.

The compound of the present invention has a good inhibitory activity on IL-13-induced p-STAT6 expression in mouse lung tissue at a dose of 200 μg. For example, compounds 1-1 and 6-1 have a good inhibitory activity on IL-13-induced mouse lung at a dose of 200 μg. The inhibition rate of p-STAT6 expression in tissues is ≥90%.

Test Example 3: Experiment of IL-2 and anti-CD3 inducing human PBMC to secrete IFNγ

The Ficoll density gradient centrifugation method was used to separate human PBMC from whole blood from healthy volunteers. PBMC cells were cultured in RPMI-1640 medium (Gibco, Cat#22400089) containing 10% fetal bovine serum (Hyclone, Cat#SH30406.05) and 1X penicillin-streptomycin solution (Gibco, Cat#15140122). Inoculate 2×10 ⁵ cells (50μL) per well in a 96-well plate, incubate for 1 hour at 37°C and 5% CO ₂ and add different concentrations (2 times the final concentration, 100μL/well) to be tested Compound. Then incubate for 1 hour at 37°C and 5% CO _{2 and} add 50μL of IL-2 (Biotech, Cat#202-IL-050) with a final concentration of 100ng/mL and anti- CD3 (BD Pharmingen, Cat#555329) premixed solution, and transferred to the cell incubator for 24 hours. Thereafter, centrifuge at 4°C and 500g for 5 minutes, take 150 μL of the supernatant, and detect the IFNγ concentration according to the instructions of the Elisa kit (R&D, Cat#SIF50). The data obtained using the Origin 9.2 software (DoseResp function) fit IC ₅₀ values of test compounds.

_{Table 3. The IC 50} value of the compound's inhibitory activity against IL-2 and anti-CD3 inducing human PBMC to secrete IFNγ

Serial number Compound IC ₅₀ (nM) 1 Control compound L-tartrate 13.19 2 Compound 10-1 6.95 3 Compound 14-1 4.60 4 Compound 15-1 7.60

Conclusion: The compounds 10-1, 14-1 and 15-1 of the present invention have better inhibitory activity on IL-2 and anti-CD3 inducing human PBMC to secrete IFNγ than the control compound L-tartrate.

Test Example 4: IL-13 induces STAT6 phosphorylation in BEAS-2B cells

BEAS-2B cells (ATCC) were cultured in DMEM medium (ATCC, Cat#30- 2002). 7500 cells per well (20μL) were seeded in a 384-well plate (Perkin Elmer, Catalog#6007680) and cultured overnight at 37°C and 5% CO2. The test compound was dissolved in DMSO, and diluted gradually to 3000 times the final concentration, and then diluted 1000 times with the culture medium. Aspirate 10 μL of the medium, add 5 μL of the test compound, and incubate for 1 hour at 37° C. and 5% CO2. Add 5μL of IL-13 to each well (final concentration is 40ng/mL), and incubate for 30 minutes at 37°C and 5% CO2. AlphaLISA kit (Perkin Elmer, Catalog#ALSU-PST6-A500) was used to detect the level of p-STAT6. The specific operation is as follows: After removing the culture medium (containing the test compound and IL-13), add 10 μL 1×Lysis Buffer to each well, seal the plate, and shake for 10 minutes. Add 2.5μL Acceptor Mix to each well, seal the plate, shake for 2 minutes in the dark and incubate at room temperature for 2 hours. After that, add 2.5μL Donor Mix to each well, seal the plate, shake for 2 minutes in the dark, and incubate at room temperature for 2 hours. Use Envision microplate reader's AlphaScreen method (Ex 680/Em 570) for detection. The data obtained using the Origin 9.2 software (DoseResp function) fit IC ₅₀ values of test compounds.

_{Table 4. The IC 50} value of the compound's inhibitory activity against IL-13-induced STAT6 phosphorylation in BEAS-2B cells

Serial number Compound IC ₅₀ (nM) 1 Control compound L-tartrate 49.11 2 Compound 14-1 2.22 3 Compound 16-1 15.73

Conclusion: The compounds 14-1 and 16-1 of the present invention have better inhibitory activity on IL-13-induced STAT6 phosphorylation in BEAS-2B cells than the control compound L-tartrate.

Test Example 5: Mouse lung blood ratio experiment

5.1. Experimental animals: BALB/c mice, ~25g, male, 10-12 weeks old, 30, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

5.2. Test plan:

I.T. inhaled administration

Before and after the administration, 0.10 mL of blood was taken from the orbit with isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Blood sampling time points: 5min, 15min, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h. Before analysis and testing, all plasma samples were stored at -80°C.

The time points of tissue sample collection in the administration group: 5min, 0.5h, 1h, 4h and 24h. After the animal was bled and euthanized, the lung tissue was taken, washed with normal saline, homogenized with 50% methanol at a ratio of m/v=1:8, and stored in a -80° refrigerator for analysis.

5.3. The results of the lung blood ratio measured for the compounds of the present invention are shown in Table 5 below.

Table 5. Results of test compound mouse lung blood ratio

Conclusion: The mouse lung blood ratio of compound 14-1 of the present invention is better than the control compound L-tartrate.

Test Example 6: Rat lung blood ratio experiment

6.1. Experimental animals: SD rats, 180-220g, male, 6-8 weeks old, 30 animals, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

6.2. Test plan:

I.T. inhaled administration

Before and after the administration, 0.10 mL of blood was taken from the orbit with isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Blood sampling time points: 5min, 0.5h, 1h, 4h and 24h. Before analysis and testing, all plasma samples were stored at -80°C.

The time points of tissue sample collection in the administration group: 5min, 0.5h, 1h, 4h and 24h. After the animal was bled and euthanized, the lung tissue was taken, washed with normal saline, homogenized with 50% methanol at a ratio of m/v=1:8, and stored in a -80° refrigerator for analysis.

6.3. The results of the lung blood ratio measured for the compounds of the present invention are shown in Table 6 below.

Table 6. Results of test compound rat lung blood ratio

Conclusion: The rat lung blood ratio of compound 14-1 of the present invention is better than that of the control compound L-tartrate.

Test Example 7: Rat PK experiment

7.1. Experimental animals: SD rats, 180-220g, male, 6-8 weeks old, 12, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

7.2. Test plan:

I.V.: intravenous administration; I.G.: intragastric administration

Before and after the administration of isoflurane anesthesia, 0.10 mL of blood was taken from the orbit, placed in an EDTAK ₂ centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Blood sampling time points: 0, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h. Before analysis and testing, all plasma samples were stored at -80°C.

The results of plasma exposure, apparent volume of distribution and in vivo clearance rate of the compound of the present invention after intravenous administration in rats are shown in Table 7 below.

Table 7. Rat PK for intravenous administration of test compound

The results of plasma exposure and half-life of the compound of the present invention after intragastric administration in rats are shown in Table 8 below.

Table 8. Rat PK for oral administration of test compound

Conclusion: Compared with the control compound L-tartrate, the compounds 9-1 and 14-1 of the present invention have lower plasma system exposure and higher in vivo clearance after intravenous administration in rats. Compound 9-1 After intragastric administration in rats, it has a lower plasma system exposure and a shorter half-life, indicating that the drug of the present invention has a lower exposure after entering the systemic plasma system, and avoids possible safety problems caused by in vivo system exposure (Reference: J. Med. Chem., 2017, 60, 767-786).

Test Example 8: Test compound for stability of liver microsomes

The total volume of the incubation system is 100 μL, and the medium is 100 mM phosphate buffer (PBS, pH 7.4), including liver microsomal protein with a final concentration of 0.50 mg/mL, 1.00 μM test substance and 1.00 mM NADPH, using a 37°C water bath. Incubate, add the same volume of ice-cold acetonitrile to terminate the reaction after 0, 5, 15, 30, and 60 minutes. The negative control was incubated with heat-inactivated liver microsomes of the corresponding species, and the incubation time points were 0 and 60 min, respectively. The LC/MS/MS method was used to detect the remaining content of the test substance. All incubated samples are double samples.

The stability results of the liver microsomes of the compound of the present invention are shown in Table 9 below.

Table 9. Liver microsomal stability of test compounds

Conclusion: Compared with the control compound L-tartrate, the compounds 9-1 and 14-1 of the present invention have a higher clearance rate and shorter half-life in liver microsomes, indicating that compounds 9-1 and 14-1 are in Metabolism in the liver is faster, and the exposure to the systemic plasma system after being metabolized by the liver is lower, avoiding possible safety problems caused by exposure to the system in the body.

Test Example 9: Rat skin application experiment

9.1. Experimental animals: SD rats, 200-250g, male, 10-12 weeks old, 18 animals/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

9.2. Test plan:

*Calculated by mass percentage of free alkali.

9.3. Ointment prescription:

Ingredient Chinese name Ingredient English name content Compound Compound 0.5%* Ethylhexyl Hydroxystearate Ethylhexyl Hydroxystearate 5% Medium chain triglycerides Medium chain triglyceride 5% Vaseline Vaseline 79.5% N-methylpyrrolidone N-Methylpyrrolidone 10%

*Calculated by mass percentage of free alkali.

After administration, 0.50 mL of blood was taken from the orbit with isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Plasma collection time point: 3, 7, 24, 48, 72, 96h. Before analysis and testing, all plasma samples were stored at -80°C.

Time points for collection of dermal and epidermal tissue samples: 3, 7, 24, 48, 72, 96h. After the animal is bled and euthanized, take the skin of the smeared area, wash it with soap and water, then wash it with water, then separate the dermis and epidermis, and homogenize with 50% acetonitrile according to the ratio of m/v=1:10 and then -80° refrigerator Save for analysis.

The dermal and plasma exposure results of the compound of the present invention after being applied to the skin of rats are shown in Table 10 and Table 11 below.

Table 10. Rat PK administered by skin application of test compound (salt)

Table 11. Rat PK administered by skin application of test compound (free base)

Conclusion: The results of the dermis/plasma ratio of the compounds 9-1, 14-1 and 14 of the present invention after being applied to the skin of rats are better than the control compound L-tartrate.

Test Example 10: Safety pharmacological experiment on the effect of intravenous administration on cardiovascular function in awake Beagle dogs

10.1. Test animals: Beagle dogs, 4/male, 4/female, male (♂): 7.06～8.16kg, female (♀): 6.44～7.60kg, 10～15 months old, 8 dogs/compound, purchase At Beijing Max Biotechnology Co., Ltd.

10.2. Test plan:

Administration method: The animal uses a 10 mL syringe and an intravenous infusion needle to administer the compound to the animal's forelimb intravenously, and the administration is completed within 1-2 minutes. The dosage of each animal is determined according to the weight measured recently before the drug. The cross-dosing method is adopted in two rounds, and the first and second rounds of dosing are separated by 1 day.

I.V.: intravenous administration;

Use the Digital Respiratory Telemetry System 2 (Data Science International Inc., USA) to collect animal ECG, blood pressure, and body temperature indicators. Turn on the telemetry system and implant before administration to record various animal indicators. Administer the drug at least 1.5 hours after the system is turned on. Collect animal index data about 24 hours after administration. In order to prevent possible system data overflow during the acquisition process, it can be properly shut down and then restarted. The switching process shall not affect the value of the set data point. The switching system time is recorded. About 25 hours after the medication, after the data collection is over, turn off the telemetry system. The testing indicators and time points are as follows:

ECG indicators: heart rate (bpm), RR interval (ms), PR interval (ms), QRS time limit (ms), R wave voltage (mV), QT interval (ms), QTcF interval (ms), ST segment voltage (mV), Tp-e interval (ms), T wave height (mV), P wave width (ms).

The recorded QT interval will be analyzed using QTcF correction. QTc Fridericia’s correction formula QTcF=QT/RR1/3.

Blood pressure indicators: systolic blood pressure (mmHg), diastolic blood pressure (mmHg), mean arterial pressure (mmHg), pulse pressure difference (mmHg).

Other indicators: body temperature (℃).

Detection time point: within 1h before the drug, 5min(±1min), 0.25h(±5min), 0.5h(±5min), 1h(±10min), 1.5h(±10min), 2h(±10min) after administration , 4h(±15min), 6h(±20min), 8h(±30min), 12h(±45min), 24h(±1h).

The results of the effects of the compound of the present invention on the cardiovascular function of awake Beagle dogs administered by intravenous injection are shown in Table 12 and Table 13 below.

Table 12. Symptoms of the effect of intravenous injection of 5 mg/kg test compound on awake Beagle dogs

Allergic reactions include: ear itching, redness and swelling around the eyes and ears;

Table 13. Symptoms of the effect of 15 mg/kg test compound administered intravenously on awake Beagle dogs

Conclusion: Under the conditions of this experiment, at a dose of 5 mg/kg, the control compound L-tartrate can produce side effects such as allergic reactions, increased heart rate, lower blood pressure, and changes in RR, PR, and QT intervals. The compound of the present invention, for example, Compound 9-1 does not have the above side effects; at a dose of 15 mg/kg, the control compound L-tartrate can produce side effects such as lateral lying, weakness, increased heart rate, lower blood pressure, and changes in RR, PR, and QT intervals, while the compound of the present invention For example, compound 9-1 does not have the above side effects. In summary, the side effects of the control compound L-tartrate administered to Beagle dogs by intravenous injection were stronger than those of compound 9-1.

Claims (16)

A compound of general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein

R ¹ and R ² are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 Alkenyl or C _2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl and alkynyl groups are optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, cyano , CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , NH ₂ , OH, C _1-6 alkyl, C _1-6 alkoxy Group or C _2-6 alkynyl, -COOH, -COOC _1-4 alkyl, -C(=O)NR ^a R ^b , C _3-12 carbocyclic group or 3 to 12 membered heterocyclic group, wherein Alkyl, alkoxy, alkynyl, carbocyclyl or heterocyclyl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-12 carbocyclic group or a substituent of 3 to 12 membered heterocyclic group, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N; R ^a and R ^b are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3 to 6 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally Ground is further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N (C _1-4 alkyl) ₂ , NHC _{3 -6} cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O , S, N heteroatoms; Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 H , F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, wherein the heterocyclic ring contains 1 to 4 Heteroatoms selected from O, S, N; Alternatively, any R ⁵ , R ⁶ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 H , F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, wherein the heterocyclic ring contains 1 to 4 Heteroatoms selected from O, S, N; Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, Substituents substituted by cyano, CF ₃ , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; n1 is selected from 0, 1, 2, 3 or 4; n2 is selected from 0, 1, 2 or 3; p and q are each independently selected from 0, 1, 2 or 3, and p+q≥1; m is selected from 1, 2 or 3; Provided that the compound is not

The compound according to claim 1 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy; Each R ^{2 is} independently selected from H, F, OH, CF ₃ , methyl or methoxy. The compound according to claim 2 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein R ^{1 is} each independently selected from H, F, OH, CF ₃ , methyl, ethyl, propyl or isopropyl; R ^{2 is} each independently selected from H or F;

Selected from

m is selected from 1; n1 is selected from 1, 2 or 3; n2 is selected from 1. The compound according to claim 2 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound of general formula (I) is selected from the group consisting of The compound of formula (Ia),

The compound according to claim 4 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl , Propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C(=O)NR ^a R ^b , where Said methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, phenyl, imidazolyl or benzimidazolyl Optionally further 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _{Substituents of 3-6} cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 3 to 6-membered heterocyclic group Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; R ^a and R ^b are each independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidine Group, oxetanyl, oxetanyl or oxetanyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azepanyl, azacyclohexyl, oxetanyl, oxolanyl or oxetanyl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I , OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen substituted C _{1 -4} substituted by alkyl or C _1-4 alkoxy substituents; Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 H , F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; Alternatively, any R ⁵ , R ⁶ and the atoms to which they are attached together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 H , F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N. The compound according to claim 5 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , NH ₂ , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl , Propynyl, methoxymethyl, ethoxymethyl, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH,

Cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NHCH ₂ CH ₃ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-ring Propyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH-azacyclic Butyl, -C(=O)NH-azacyclopentyl, -C(=O)NH-azacyclohexyl, -C(=O)NH-oxetanyl, -C(=O )NH-oxanyl or -C(=O)NH-oxanyl; Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring, and the carbocyclic ring is optionally further substituted by 0 to 4 selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents; Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N. The compound according to claim 2 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound of general formula (I) is selected from the group consisting of The compound represented by formula (Ia-1) or (Ib),

The compound according to claim 7 or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, cyclopropyl, Cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl, benzimidazolyl, -COOH, -COOCH ₃ or -C(=O)NR ^a R ^b , wherein the methyl, ethyl , Propyl, isopropyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclohexyl, piperidine, phenyl, imidazolyl or benzimidazolyl are optionally further substituted by 0 to 4 One is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 3 to 6-membered heterocyclic group substituted by substituents, the hetero The cyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R ^a and R ^b are each independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidine Group, oxetanyl, oxetanyl or oxetanyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azepanyl, azacyclohexyl, oxetanyl, oxolanyl or oxetanyl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I , OH, cyano, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, C _1-4 alkyl, halogen substituted C _{1 -4} substituted by alkyl or C _1-4 alkoxy substituents; Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 H , F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N. The compound according to claim 8 or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from H, F, cyano, CF ₃ , methyl, ethyl, isopropyl, ethynyl, propynyl, methoxymethyl,- CH ₂ N(CH ₃ ) ₂ 、-CH ₂ OH、

Cyclopropyl, N-methylpiperidine, imidazolyl, benzimidazolyl, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NH-cyclopropyl; Alternatively, any R ³ , R ⁴ and the atoms to which they are connected together form a C _3-6 membered carbocyclic ring, and the carbocyclic ring is optionally further substituted by 0 to 4 selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents; Alternatively, any R ³ , R ⁵ and the atoms to which they are attached together form a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is optionally further selected from H, F, OH, cyano, CF ₃ , NH ₂ , methyl or methoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N. The compound according to claim 2 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound of general formula (I) is selected from the group consisting of Formula (Ic),

The compound according to claim 10 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, R ^{1 is} selected from H or F; R ^{2 is} selected from H or F. The compound according to claim 1, or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the following structures:

The compound according to claim 12 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the pharmaceutically acceptable salt is selected from L -Tartrate. A pharmaceutical composition, comprising the compound according to any one of claims 1-12 or its stereoisomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceuticals Acceptable carrier. The compound according to any one of claims 1-12, or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, is used in the preparation and treatment of JAK-mediated diseases The application of drugs. The application according to claim 15, wherein the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial pneumonia, acute lung injury, acute respiratory distress syndrome, bronchitis, lung Emphysema, bronchiolitis obliterans, spinal fibrosis, cancer, psoriasis, rheumatoid arthritis, hair loss, lupus erythematosus or scleroderma.