CN118812519A - Substituted tetrahydrofurans as Nav1.8 inhibitors - Google Patents

Abstract

The present invention provides a compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; the compound has a good Nav1.8 inhibitory effect.

Description

Substituted tetrahydrofurans as Nav1.8 inhibitors

The present invention claims:

Priority to the prior application, patent application number 202310424854.1, filed with the State Intellectual Property Office of China on April 19, 2023, entitled “Substituted tetrahydrofuran as Nav1.8 inhibitors”;

Priority to the prior application, patent application number 202310566735.X, filed with the State Intellectual Property Office of China on May 18, 2023, entitled “Substituted Tetrahydrofurans as Nav1.8 Inhibitors”;

Priority to the prior application, patent application number 202311411427.6, filed with the State Intellectual Property Office of China on October 25, 2023, entitled “Substituted tetrahydrofuran as Nav1.8 inhibitors”;

Priority to the prior application, patent application number 202410050694.3, filed with the State Intellectual Property Office of China on January 12, 2024, entitled “Substituted tetrahydrofuran as Nav1.8 inhibitors”;

The entirety of said prior application is incorporated herein by reference.

Technical Field

The present invention belongs to the field of medicine and relates to substituted tetrahydrofuran as Nav1.8 inhibitor and its use. Specifically, the present invention relates to substituted tetrahydrofuran, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and pharmaceutical composition thereof as Nav1.8 inhibitor and its use in preparing medicine for treating, relieving or preventing pain.

Background Art

Pain is "an unpleasant feeling and emotional sensation, accompanied by actual or potential tissue damage, and it is a subjective feeling". Pain can serve as a warning signal to alert the body to potential dangers and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, strong or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living body. According to statistics, about one-fifth of the world's people suffer from moderate to severe chronic pain. The global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute, moderate and severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

Pain originates from the nociceptors in the peripheral nervous system. This is a free nerve ending that is widely distributed in the skin, muscles, joints and visceral tissues throughout the body. It can convert the thermal, mechanical or chemical stimulation it senses into nerve impulses (action potentials) and transmit them to the cell body part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and finally to the higher nerve centers, causing pain. The generation and conduction of action potentials in neurons depends on the voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane is depolarized, the sodium ion channels are activated, the channels open, causing sodium ions to flow in, further depolarizing the cell membrane, and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain.

Human sodium ions are a type of transmembrane ion channel protein, consisting of an α subunit with a molecular weight of 260kD and a β subunit with a molecular weight of 30-40kD. According to the different α subunits, it can be divided into 9 subtypes, namely Nav1.1~Nav1.9. Nav1.5, Nav1.8 and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is mainly present in myocardial cells, and Nav1.8 and Nav1.9 are present in the peripheral nervous system. Among them, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment.

The gene encoding Nav1.8 is SCN10A, which is located in the human chromosome 3p21-22 region and mainly encodes the α subunit. Studies have found that the homology of human and rat Nav1.8 genes is as high as 93%. Nav1.8 is mainly present in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rise of action potential is mainly composed of Nav1.8 current. In the model of neuropathic pain, nerve injury will increase the expression level of Nav1.8 in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After carrageenan was injected into the rat paw, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice cannot show normal visceral inflammatory pain. When the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathy. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy, which can be used to treat various types of pain, such as inflammatory pain, neuralgia, postoperative pain and cancer pain.

The major drawback of some known Nav's inhibitors is that their therapeutic window is poor, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce adverse reactions common to non-selective Nav's blockers. Therefore, the art still needs to develop new Nav1.8 selective inhibitors, preferably Nav channel inhibitors with better selectivity, more effective, increased metabolic stability, increased solubility and fewer side effects to Nav1.8.

Summary of the invention

The present invention aims to propose a Nav1.8 inhibitor, which can be used to prepare a drug for treating, relieving or preventing pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

In the first aspect of the present invention, the present invention provides a compound, which is a compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

in,

Ring A is selected from 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 6-membered heterocycloalkenyl, 9-10-membered aryl or 9-10-membered heteroaryl; the 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl is optionally substituted by one or more R ^a3 , when R ^a3 is multiple, they are the same or different;

R ^a3 is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl, -OR ¹¹ , -C(O)NR ⁹ R ¹⁰ , or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

Alternatively, two R ^a3 attached to the same atom combine to form =O;

Alternatively, two R ^{a3 groups} attached to adjacent atoms are combined with the atoms to which they are attached to form a fused 3-7 membered ring containing at most two heteroatoms selected from N, O and S;

X ^2a is selected from N, N ⁺ —O ^— or CR ^2a ;

X ^3a is selected from N, N ⁺ -O ^- or CR ^3a ;

X ^4a is selected from N, N ⁺ —O ^— or CR ^4a ;

X ^5a is selected from N, N ⁺ —O ^— or CR ^5a ; or N ⁺ —(C ₁ -C ₆ alkyl)Y ⁻ , wherein Y ⁻ is a monovalent anion;

X ^6a is selected from N, N ⁺ -O ^- or CR ^6a ;

R ^2a is selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ^3a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR ¹¹ , -COOH, -C(O)NR ⁹ R ¹⁰ , -C(═NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ , -S(O) ₂ R ⁷ , -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -S(O) ₂ NR ⁹ R ¹⁰ , -S(O)R ⁷ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , -C(O)NR ⁷ NR ⁹ R ¹⁰ , -C(O)-C(O)NR ⁹ R ¹⁰ , -C(O)NR ⁷ S(O) ₂ R ⁹ , -OS(O) ₂ NR ⁹ R ¹⁰ , -N＝S(O)R ⁹ R ¹⁰ , -SC(O)-NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ ; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl or -NR ⁹ C(O)C ₁ -C ₆ alkyl is optionally substituted by one or more R ¹² , C ₃ -C ₆ cycloalkyl, -NR ⁹ R ¹⁰ , -OR ¹¹ , -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R ¹² ;

R ^4a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C(O)NR ⁹ R ¹⁰ , -C(O)OH, -OR ¹¹ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl, or -S(O) ₂ R ⁷ ;

R ^5a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -S(O) ₂ R ⁷ ;

R ^6a is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

or R ^3a and R ^4a together with the atoms to which they are attached form a ring selected from the following formulae:

^R7 is selected from C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated alkyl, _C3 - _C6 cycloalkyl, C3 _{- C6} halocycloalkyl, or 3-7 membered heterocycloalkyl, wherein the _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted with one or more ^-OR11 or _C1 - _C6 alkyl;

R ⁸ is selected from H, -C(O)NR ⁹ R ¹⁰ or C ₁ -C ₆ alkyl;

R ⁹ and R ¹⁰ are each independently selected from H, C ₁ -C ₆ alkyl, 3-7 membered heterocycloalkyl, C ₃ -C ₆ cycloalkyl, -OR ¹¹ , -OH, -CN or -S(O) ₂ R ⁷ , wherein said C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, -OR ¹¹ ; or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl;

Each R ¹¹ is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl optionally substituted with -NH ₂ , 3-7 membered heterocycloalkyl optionally substituted with -OH, or 3-7 membered cycloalkyl optionally substituted with -OH;

Each R ¹² is independently selected from halogen, C ₁ -C ₆ alkyl or -OR ¹¹ ; or two R ¹² together with the atoms to which they are attached form an oxo group;

Each R ¹³ is independently selected from halogen, C ₁ -C ₆ alkyl or -CONH ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ , or two R ¹³ together with the atoms to which they are attached form oxo;

W is selected from a single bond, Imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole;

R ^4b1 and R ^4b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

R ^5b1 and R ^5b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

R ^6b is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy;

R ^7b is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy;

X ^3c is selected from N or CR ^3c ;

X ^4c is selected from N or CR ^4c ;

X ^5c is selected from N or CR ^5c ;

X ^6c is selected from N or CR ^6c ;

R ^2c is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy, -L ¹ -(C ₁ -C ₆ alkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkenylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkylene)-NR ¹⁶ R ¹⁷ , -L ¹ -(C ₁ -C ₆ alkylene)-N＝S(O)(C ₁ -C ₃ alkyl) ₂ , -L ¹ -(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C 3 alkyl) 2 ₆ alkyl) or L ¹ -L ² -R ¹⁴ , -NR ¹⁶ R ¹⁷ ;

R ¹⁴ is selected from C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C ₁ -C ₆ alkyl), -COOH, or -C(O)NR ¹⁶ R ¹⁷ , wherein the C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ¹⁵ is selected from H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁶ and R ¹⁷ are each independently H, -OH, C ₁ -C ₆ alkyl or 3-7 membered heterocycloalkyl;

R ^3c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy);

R ^4c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ^5c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and

R ^6c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxy;

L ¹ is a bond or O;

L ² is a bond or a C ₁ -C ₆ alkylene group;

and no more than 2 X ^2a , X ^3a , X ^4a , X ^5a and X ^6a are selected from N or N ⁺ -O ^- ;

and no more than one of X ^3c , X ^4c , X ^5c and X ^6c is N;

and R ^4a is not CH(OH)-R ^4a' , wherein R ^4a' is H or C 1 -C 5 alkyl optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl _, or -S ₍ O) ₂ R ⁷ .

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

in,

Ring A is selected from 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl; the 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl is optionally substituted by one or more R ^a3 , when R ^a3 is multiple, they are the same or different;

R ^a3 is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl, -OR ¹¹ , -C(O)NR ⁹ R ¹⁰ , or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

Alternatively, two R ^a3 attached to the same atom combine to form =O;

Alternatively, two R ^{a3 groups} attached to adjacent atoms are combined with the atoms to which they are attached to form a fused 3-7 membered ring containing at most two heteroatoms selected from N, O and S;

X ^2a is selected from N, N ⁺ —O ^— or CR ^2a ;

X ^3a is selected from N, N ⁺ -O ^- or CR ^3a ;

X ^4a is selected from N, N ⁺ —O ^— or CR ^4a ;

X ^5a is selected from N, N ⁺ —O ^— or CR ^5a ; or N ⁺ —(C ₁ -C ₆ alkyl)Y ⁻ , wherein Y ⁻ is a monovalent anion;

X ^6a is selected from N, N ⁺ -O ^- or CR ^6a ;

R ^2a is selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ^3a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR ¹¹ , -COOH, -C(O)NR ⁹ R ¹⁰ , -C(═NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ , -S(O) ₂ R ⁷ , -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -S(O) ₂ NR ⁹ R ¹⁰ , -S(O)R ⁷ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ ; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl or -NR ⁹ C(O)C ₁ -C ₆ alkyl is optionally substituted by one or more R ¹² , C ₃ -C ₆ cycloalkyl, -NR ⁹ R ¹⁰ , -OR ¹¹ , -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R ¹² ;

R ^4a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C(O)NR ⁹ R ¹⁰ , -C(O)OH, -OR ¹¹ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl, or -S(O) ₂ R ⁷ ;

R ^5a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -S(O) ₂ R ⁷ ;

R ^6a is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

or R ^3a and R ^4a together with the atoms to which they are attached form a ring selected from the following formulae:

^R7 is selected from C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated alkyl, _C3 - _C6 cycloalkyl, C3 _{- C6} halocycloalkyl, or 3-7 membered heterocycloalkyl, wherein the _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted with one or more ^-OR11 or _C1 - _C6 alkyl;

R ⁸ is selected from H, -C(O)NR ⁹ R ¹⁰ or C ₁ -C ₆ alkyl;

R ⁹ and R ¹⁰ are each independently selected from H, C ₁ -C ₆ alkyl, 3-7 membered heterocycloalkyl, C ₃ -C ₆ cycloalkyl, -OR ¹¹ , -OH, -CN or -S(O) ₂ R ⁷ , wherein said C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, -OR ¹¹ ; or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl;

Each R ¹¹ is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl optionally substituted with -OH, or 3-7 membered cycloalkyl optionally substituted with -OH;

Each R ¹² is independently selected from halogen, C ₁ -C ₆ alkyl or -OR ¹¹ ; or two R ¹² together with the atoms to which they are attached form an oxo group;

Each R ¹³ is independently selected from halogen, C ₁ -C ₆ alkyl or -CONH ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ , or two R ¹³ together with the atoms to which they are attached form oxo;

W is selected from Imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole;

R ^4b1 and R ^4b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

R ^5b1 and R ^5b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

R ^6b is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy;

R ^7b is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy;

X ^3c is selected from N or CR ^3c ;

X ^4c is selected from N or CR ^4c ;

X ^5c is selected from N or CR ^5c ;

X ^6c is selected from N or CR ^6c ;

R ^2c is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy, -L ¹ -(C ₁ -C ₆ alkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkenylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkylene)-NR ¹⁶ R ¹⁷ , -L ¹ -(C ₁ -C ₆ alkylene)-N＝S(O)(C ₁ -C ₃ alkyl) ₂ , -L ¹ -(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C 3 alkyl) 2 ₆ alkyl) or L ¹ -L ² -R ¹⁴ ;

R ¹⁴ is selected from C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C ₁ -C ₆ alkyl), -COOH, or -C(O)NR ¹⁶ R ¹⁷ , wherein the C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ¹⁵ is selected from H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁶ and R ¹⁷ are each independently H, -OH, C ₁ -C ₆ alkyl or 3-7 membered heterocycloalkyl;

R ^3c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy);

R ^4c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ^5c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and

R ^6c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxy;

L ¹ is a bond or O;

L ² is a bond or a C ₁ -C ₆ alkylene group;

and no more than 2 X ^2a , X ^3a , X ^4a , X ^5a and X ^6a are selected from N or N ⁺ -O ^- ;

and no more than one of X ^3c , X ^4c , X ^5c and X ^6c is N;

and R ^4a is not CH(OH)-R ^4a' , wherein R ^4a' is H or C 1 -C 5 alkyl optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl _, or -S ₍ O) ₂ R ⁷ .

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

in,

Ring A is selected from 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl; the 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl is optionally substituted by one or more R ^a3 , when R ^a3 is multiple, they are the same or different;

R ^a3 is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl, -OR ¹¹ , -C(O)NR ⁹ R ¹⁰ , or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

Alternatively, two R ^a3 attached to the same atom combine to form =O;

Alternatively, two R ^{a3 groups} attached to adjacent atoms are combined with the atoms to which they are attached to form a fused 3-7 membered ring containing at most two heteroatoms selected from N, O and S;

X ^2a is selected from N, N ⁺ —O ^— or CR ^2a ;

X ^3a is selected from N, N ⁺ -O ^- or CR ^3a ;

X ^4a is selected from N, N ⁺ —O ^— or CR ^4a ;

X ^5a is selected from N, N ⁺ —O ^— or CR ^5a ; or N ⁺ —(C ₁ -C ₆ alkyl)Y ⁻ , wherein Y ⁻ is a monovalent anion;

X ^6a is selected from N, N ⁺ -O ^- or CR ^6a ;

R ^2a is selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ^3a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR ¹¹ , -COOH, -C(O)NR ⁹ R ¹⁰ , -C(═NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ , -S(O) ₂ R ⁷ , -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -S(O) ₂ NR ⁹ R ¹⁰ , -S(O)R ⁷ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ ; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl or -NR ⁹ C(O)C ₁ -C ₆ alkyl is optionally substituted by one or more R ¹² , C ₃ -C ₆ cycloalkyl, -NR ⁹ R ¹⁰ , -OR ¹¹ , -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R ¹² ;

R ^4a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C(O)NR ⁹ R ¹⁰ , -C(O)OH, -OR ¹¹ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl, or -S(O) ₂ R ⁷ ;

R ^5a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -S(O) ₂ R ⁷ ;

R ^6a is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

or R ^3a and R ^4a together with the atoms to which they are attached form a ring selected from the following formulae:

^R7 is selected from C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated alkyl, _C3 - _C6 cycloalkyl, C3 _{- C6} halocycloalkyl, or 3-7 membered heterocycloalkyl, wherein the _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted with one or more ^-OR11 or _C1 - _C6 alkyl;

R ⁸ is selected from H, -C(O)NR ⁹ R ¹⁰ or C ₁ -C ₆ alkyl;

R ⁹ and R ¹⁰ are each independently selected from H, C ₁ -C ₆ alkyl, 3-7 membered heterocycloalkyl, C ₃ -C ₆ cycloalkyl, -OR ¹¹ , -OH, -CN or -S(O) ₂ R ⁷ , wherein said C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, -OR ¹¹ ; or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl;

Each R ¹¹ is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl optionally substituted with -OH, or 3-7 membered cycloalkyl optionally substituted with -OH;

Each R ¹² is independently selected from halogen, C ₁ -C ₆ alkyl or -OR ¹¹ ; or two R ¹² together with the atoms to which they are attached form an oxo group;

Each R ¹³ is independently selected from halogen, C ₁ -C ₆ alkyl or -CONH ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ , or two R ¹³ together with the atoms to which they are attached form oxo;

W is selected from Imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole;

R ^4b1 and R ^4b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

R ^5b1 and R ^5b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

X ^3c is selected from N or CR ^3c ;

X ^4c is selected from N or CR ^4c ;

X ^5c is selected from N or CR ^5c ;

X ^6c is selected from N or CR ^6c ;

R ^2c is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy, -L ¹ -(C ₁ -C ₆ alkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkenylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkylene)-NR ¹⁶ R ¹⁷ , -L ¹ -(C ₁ -C ₆ alkylene)-N＝S(O)(C ₁ -C ₃ alkyl) ₂ , -L ¹ -(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C 3 alkyl) 2 ₆ alkyl) or L ¹ -L ² -R ¹⁴ ;

R ¹⁴ is selected from C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C ₁ -C ₆ alkyl), -COOH, or -C(O)NR ¹⁶ R ¹⁷ , wherein the C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ¹⁵ is selected from H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁶ and R ¹⁷ are each independently H, -OH, C ₁ -C ₆ alkyl or 3-7 membered heterocycloalkyl;

R ^3c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy);

R ^4c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ^5c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and

R ^6c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxy;

L ¹ is a bond or O;

L ² is a bond or a C ₁ -C ₆ alkylene group;

and no more than 2 X ^2a , X ^3a , X ^4a , X ^5a and X ^6a are selected from N or N ⁺ -O ^- ;

and no more than one of X ^3c , X ^4c , X ^5c and X ^6c is N;

and R ^4a is not CH(OH)-R ^4a' , wherein R ^4a' is H or C 1 -C 5 alkyl optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl _, or -S ₍ O) ₂ R ⁷ .

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

in,

Ring A is selected from 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl; the 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl is optionally substituted by one or more R ^a3 , when R ^a3 is multiple, they are the same or different;

R ^a3 is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl, -OR ¹¹ , -C(O)NR ⁹ R ¹⁰ , or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

Alternatively, two R ^a3 attached to the same atom combine to form =O;

Alternatively, two R ^{a3 groups} attached to adjacent atoms are combined with the atoms to which they are attached to form a fused 3-7 membered ring containing at most two heteroatoms selected from N, O and S;

X ^2a is selected from N, N ⁺ —O ^— or CR ^2a ;

X ^3a is selected from N, N ⁺ -O ^- or CR ^3a ;

X ^4a is selected from N, N ⁺ —O ^— or CR ^4a ;

X ^5a is selected from N, N ⁺ —O ^— or CR ^5a ; or N ⁺ —(C ₁ -C ₆ alkyl)Y ⁻ , wherein Y ⁻ is a monovalent anion;

X ^6a is selected from N, N ⁺ -O ^- or CR ^6a ;

R ^2a is selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ^3a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR ¹¹ , -COOH, -C(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -S(O) ₂ R ⁷ , -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -S(O) ₂ NR ⁹ R ¹⁰ , -S(O)R ⁷ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ ; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl or -NR ⁹ C(O)C ₁ -C ₆ alkyl is optionally substituted by one or more R ¹² , C ₃ -C ₆ cycloalkyl, -NR ⁹ R ¹⁰ , -OR ¹¹ , -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R ¹² ;

R ^4a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C(O)NR ⁹ R ¹⁰ , -C(O)OH, -OR ¹¹ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl, or -S(O) ₂ R ⁷ ;

R ^5a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -S(O) ₂ R ⁷ ;

R ^6a is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

or R ^3a and R ^4a together with the atoms to which they are attached form a ring selected from the following formulae:

^R7 is selected from C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated alkyl, _C3 - _C6 cycloalkyl, C3 _{- C6} halocycloalkyl, or 3-7 membered heterocycloalkyl, wherein the _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted with one or more ^-OR11 or _C1 - _C6 alkyl;

R ⁸ is selected from H or C ₁ -C ₆ alkyl;

R ⁹ and R ¹⁰ are each independently selected from H, C ₁ -C ₆ alkyl, 3-7 membered heterocycloalkyl, C ₃ -C ₆ cycloalkyl, -OR ¹¹ , -OH, -CN or -S(O) ₂ R ⁷ , wherein said C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, -OR ¹¹ ; or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl;

Each R ¹¹ is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl optionally substituted with -OH, or 3-7 membered cycloalkyl optionally substituted with -OH;

Each R ¹² is independently selected from halogen, C ₁ -C ₆ alkyl or -OR ¹¹ ; or two R ¹² together with the atoms to which they are attached form an oxo group;

Each R ¹³ is independently selected from halogen, C ₁ -C ₆ alkyl or -CONH ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ , or two R ¹³ together with the atoms to which they are attached form oxo;

W is selected from Imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole;

R ^4b1 and R ^4b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

R ^5b1 and R ^5b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

X ^3c is selected from N or CR ^3c ;

X ^4c is selected from N or CR ^4c ;

X ^5c is selected from N or CR ^5c ;

X ^6c is selected from N or CR ^6c ;

R ^2c is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy, -L ¹ -(C ₁ -C ₆ alkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkenylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkylene)-NR ¹⁶ R ¹⁷ , -L ¹ -(C ₁ -C ₆ alkylene)-N＝S(O)(C ₁ -C ₃ alkyl) ₂ , -L ¹ -(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C 3 alkyl) 2 ₆ alkyl) or L ¹ -L ² -R ¹⁴ ;

R ¹⁴ is selected from C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C ₁ -C ₆ alkyl), -COOH, or -C(O)NR ¹⁶ R ¹⁷ , wherein the C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ¹⁵ is selected from H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁶ and R ¹⁷ are each independently H, -OH, C ₁ -C ₆ alkyl or 3-7 membered heterocycloalkyl;

R ^3c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy);

R ^4c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ^5c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and

R ^6c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxy;

L ¹ is a bond or O;

L ² is a bond or a C ₁ -C ₆ alkylene group;

p is 1, 2, or 3;

and no more than 2 X ^2a , X ^3a , X ^4a , X ^5a and X ^6a are selected from N or N ⁺ -O ^- ;

and no more than one of X ^3c , X ^4c , X ^5c and X ^6c is N;

and R ^4a is not CH(OH)-R ^4a' , wherein R ^4a' is H or C 1 -C 5 alkyl optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl _, or -S ₍ O) ₂ R ⁷ .

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

in,

Ring A is selected from 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl; the 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl is optionally substituted by one or more R ^a3 , when R ^a3 is multiple, they are the same or different;

R ^a3 is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl, -OR ¹¹ , -C(O)NR ⁹ R ¹⁰ , or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

Alternatively, two R ^a3 attached to the same atom combine to form =O;

Alternatively, two R ^{a3 groups} attached to adjacent atoms are combined with the atoms to which they are attached to form a fused 3-7 membered ring containing at most two heteroatoms selected from N, O and S;

X ^2a is selected from N, N ⁺ —O ^— or CR ^2a ;

X ^3a is selected from N, N ⁺ -O ^- or CR ^3a ;

X ^4a is selected from N, N ⁺ —O ^— or CR ^4a ;

X ^5a is selected from N, N ⁺ —O ^— or CR ^5a ; or N ⁺ —(C ₁ -C ₆ alkyl)Y ⁻ , wherein Y ⁻ is a monovalent anion;

X ^6a is selected from N, N ⁺ -O ^- or CR ^6a ;

R ^2a is selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ^3a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR ¹¹ , -COOH, -NR ⁹ C(O)C ₁ -C ₆ alkyl, -S(O) ₂ R ⁷ , -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -S(O)R ⁷ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ ; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl or -NR ⁹ C(O)C ₁ -C ₆ alkyl is optionally substituted by one or more R ¹² , C ₃ -C ₆ cycloalkyl, -NR ⁹ R ¹⁰ , -OR ¹¹ , -CN, or 3-7 membered heterocycloalkyl optionally substituted with one or more R ¹² ;

R ^4a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C(O)NR ⁹ R ¹⁰ , -C(O)OH, -OR ¹¹ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl, or -S(O) ₂ R ⁷ ;

R ^5a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -S(O) ₂ R ⁷ ;

R ^6a is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

or R ^3a and R ^4a together with the atoms to which they are attached form a ring selected from the following formulae:

^R7 is selected from _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated alkyl or 3-7 membered heterocycloalkyl, wherein the _C1 - _C6 alkyl or 3-7 membered heterocycloalkyl is optionally substituted with one or more ^-OR11 or _C1 - _C6 alkyl;

R ⁸ is selected from H or C ₁ -C ₆ alkyl;

R ⁹ and R ¹⁰ are each independently selected from H, C ₁ -C ₆ alkyl, 3-7 membered heterocycloalkyl, C ₃ -C ₆ cycloalkyl, -OH, -CN or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ ; or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl;

Each R ¹¹ is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl optionally substituted with -OH, or 3-7 membered cycloalkyl optionally substituted with -OH;

Each R ¹² is independently selected from halogen, C ₁ -C ₆ alkyl or -OR ¹¹ ; or two R ¹² together with the atoms to which they are attached form an oxo group;

Each R ¹³ is independently selected from halogen, C ₁ -C ₆ alkyl or -CONH ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ , or two R ¹³ together with the atoms to which they are attached form oxo;

W is selected from Imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole;

R ^4b1 and R ^4b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

R ^5b1 and R ^5b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ;

X ^3c is selected from N or CR ^3c ;

X ^4c is selected from N or CR ^4c ;

X ^5c is selected from N or CR ^5c ;

X ^6c is selected from N or CR ^6c ;

R ^2c is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, -L ¹ -(C ₁ -C ₆ alkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkenylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkylene)-NR ¹⁶ R ¹⁷ , -L ¹ -(C ₁ -C ₆ alkylene)-N＝S(O)(C ₁ -C ₃ alkyl) ₂ , or L ¹ -L ² -R ¹⁴ ;

R ¹⁴ is selected from C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C ₁ -C ₆ alkyl), -COOH, or -C(O)NR ¹⁶ R ¹⁷ , wherein the C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ¹⁵ is selected from H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁶ and R ¹⁷ are each independently H, -OH, C ₁ -C ₆ alkyl or 3-7 membered heterocycloalkyl;

R ^3c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy);

R ^4c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ^5c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and

R ^6c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxy;

L ¹ is a bond or O;

L ² is a bond or a C ₁ -C ₆ alkylene group;

p is 1, 2, or 3;

and no more than 2 X ^2a , X ^3a , X ^4a , X ^5a and X ^6a are selected from N or N ⁺ -O ^- ;

and no more than one of X ^3c , X ^4c , X ^5c and X ^6c is N;

and R ^4a is not CH(OH)-R ^4a' , wherein R ^4a' is H or C 1 -C 5 alkyl optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl _, or -S ₍ O) ₂ R ⁷ .

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that the compound represented by formula (II) is

in,

R ^6b is selected from H, halogen, C ₁ -C ₆ alkyl; preferably, R ^6b is selected from H, F, Cl, methyl, ethyl; more preferably, R ^6b is selected from H, F, methyl;

R ^7b is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; preferably, R ^7b is selected from H, F, Cl, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy; more preferably, R ^7b is selected from H, F, methyl, trifluoromethyl, methoxy;

And R ^6b and R ^7b are not H at the same time.

In an optional embodiment of the present invention, R ^2c is C ₁ -C ₆ alkoxy; preferably, R ^2c is methoxy, ethyloxy, n-propyloxy, isopropyloxy, and more preferably, R ^2c is methoxy.

In an optional embodiment of the present invention, R ^3c is halogen; preferably, R ^3c is F or Cl; more preferably, R ^3c is F.

In an optional embodiment of the present invention, R ^4c is halogen; preferably, R ^4c is F or Cl; more preferably, R ^4c is F.

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is

In an optional embodiment of the present invention, R ^2c is C ₁ -C ₆ deuterated alkoxy; preferably, R ^2c is -O-CD ₃ .

In an optional embodiment of the present invention, R ^4c is halogen; preferably, R ^4c is F or Cl; more preferably, R ^4c is F.

In an optional embodiment of the present invention, R ^5c is halogen; preferably, R ^5c is F or Cl; more preferably, R ^5c is F.

In an optional embodiment of the present invention, R ^5b1 and R ^5b2 are each independently selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogens.

In an optional embodiment of the present invention, R ^4b1 is H.

In an optional embodiment of the present invention, R ^4b2 is C ₁ -C ₆ alkyl; preferably, R ^4b2 is methyl, ethyl, n-propyl, isopropyl; more preferably, R ^4b2 is methyl.

In an optional embodiment of the present invention, R ^5b1 and R ^5b2 are each independently selected from methyl or trifluoromethyl;

Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with 1-2 halogens.

In an optional embodiment of the present invention, R ^5b1 is methyl and R ^5b2 is trifluoromethyl.

In an optional embodiment of the present invention, W is * indicates connection to ring A.

In an optional embodiment of the present invention, W is selected from imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole.

In an optional embodiment of the present invention, W is * indicates connection to ring A.

In an optional embodiment of the present invention, W is a single bond.

In an optional embodiment of the present invention, R ^5b1 and R ^5b2 together with the atoms to which they are attached form a C ₃ -C ₆ saturated ring, wherein the C ₃ -C ₆ saturated ring is optionally substituted by 1-2 halogens, wherein the halogens are F or Cl; preferably, the halogens are F.

In an optional embodiment of the present invention, R ^5b1 and R ^5b2 together with the atoms to which they are attached form (like ), (like ), (like ),

In an optional embodiment of the present invention, R ^5b1 and R ^5b2 together with the atoms to which they are attached form

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, Ring A is

Wherein, the R ^2a is selected from halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In an optional embodiment of the present invention, X ^5a is CH.

In an optional embodiment of the present invention, R ^2a is halogen; preferably, R ^2a is F or Cl; more preferably, R ^2a is F.

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, ^X2a , ^X5a and ^X6a are CH.

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, ^X2a , ^X5a and ^X6a are CH.

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, X ^4a is N or CR ^4a ; preferably, R ^4a is halogen; more preferably, R ^4a is F.

In an optional embodiment of the present invention, R ⁷ is a C ₁ -C ₆ deuterated alkyl group; preferably, R ⁷ is a C ₁ -C ₃ deuterated alkyl group; more preferably, R ⁷ is a deuterated methyl group, such as a trideuterated methyl group.

In an optional embodiment of the present invention, ^R9 is H and ^R10 is H.

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, ^X2a , ^X5a and ^X6a are CH.

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, R ^a3 is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; preferably, R ^3a is selected from H or C ₁ -C ₃ alkyl; more preferably, R ^a3 is methyl.

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, ^Ra3 is selected from ^-OR11 , -C(O) ^NR9R10 or _-S (O) ^2R7 , ^R7 , ^R9 , ^R10 and ^R11 are independently defined as above; preferably, ^Ra3 is -C(O ⁾ _NH2 .

In an optional embodiment of the present invention, Ring A is

In an optional embodiment of the present invention, R ^a3 is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; preferably, R ^3a is selected from H or C ₁ -C ₃ alkyl; more preferably, R ^a3 is H.

Ring A is

in;

X ^4a is N ⁺ -O ^- , N or CR ^4a ; preferably, R ^4a is H or halogen; more preferably, R ^4a is H or F;

R ^3a is selected from -S(O) ₂ -NH ₂ , -N=S(O)(CH ₃ ) ₂ , -S-CONH ₂ , -OS(O) ₂ -NH ₂ , -CONHNH ₂ , -COCONH ₂ , -CONH, -S(O) ₂ -R ⁷ , -CONH-R ¹⁰ , -C(=NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ ,

R ^5a is selected from H or halogen; preferably, R ^5a is H or F;

R ⁷ is C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ⁷ is cyclopropyl or cyclobutyl;

R ⁹ is H or C ₁ -C ₆ alkyl; preferably, R ⁹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ⁹ is H or methyl;

R ¹⁰ is H, -OR ¹¹ or C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more halogen, -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ¹⁰ is H, -OR ¹¹ , cyclopropyl or cyclobutyl, the cyclopropyl and cyclobutyl are optionally substituted by one or more -OH;

R ¹¹ is H or C ₁ -C ₆ alkyl; preferably, R ¹¹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ¹¹ is H or methyl. In an optional embodiment of the present invention, ring A is selected from

In an optional embodiment of the present invention,

Ring A is

in;

X ^4a is N or CR ^4a ; preferably, R ^4a is H or halogen; more preferably, R ^4a is H or F;

R ^3a is selected from -S(O) ₂ -NH ₂ , -S(O) ₂ -R ⁷ , -CONH-R ¹⁰ , -C(═NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ or

R ⁷ is C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ⁷ is cyclopropyl or cyclobutyl;

R ⁹ is H or C ₁ -C ₆ alkyl; preferably, R ⁹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ⁹ is H or methyl;

R ¹⁰ is H, -OR ¹¹ or C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more halogen, -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ¹⁰ is H, -OR ¹¹ , cyclopropyl or cyclobutyl, the cyclopropyl and cyclobutyl are optionally substituted by one or more -OH;

R ¹¹ is H or C ₁ -C ₆ alkyl; preferably, R ¹¹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ¹¹ is H or methyl.

In an optional embodiment of the present invention, ring A is selected from

In an optional embodiment of the present invention, Ring A is

in;

X ^4a is N or CR ^4a ; preferably, R ^4a is halogen; more preferably, R ^4a is F;

R ^3a is selected from -S(O) ₂ -NH ₂ , -S(O) ₂ -R ⁷ , -CONH-R ¹⁰ , -N(R ⁹ )-COR ¹⁰ or

R ⁷ is C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl is optionally substituted with one or more -OR ¹¹ or C ₁ -C ₆ alkyl;

R ⁹ is H or C ₁ -C ₆ alkyl;

R ¹⁰ is a C _{3 -C 6} cycloalkyl group, which is optionally substituted by one or more halogens or _{C 1} -C ₆ alkyl groups.

In an optional embodiment of the present invention, ring A is selected from

In an optional embodiment of the present invention, R ^2a is selected from H, F.

In an optional embodiment of the present invention, R ^3a is selected from

In an optional embodiment of the present invention, R ^4a is selected from H, F.

In an optional embodiment of the present invention, R ^2c is C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, -O-(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -O-(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl); R ¹⁵ is selected from H, methyl, ethyl, propyl.

In an optional embodiment of the present invention, R ^2c is methoxy, dimethylamino, trideuterated methoxy,

In an optional embodiment of the present invention, R ¹¹ is NH _2- substituted pyrimidinyl, for example

In an optional embodiment of the present invention, for Better, for Better, for

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

wherein Ring A, W, R ^2c , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , X ^3c , X ^4c , X ^5c , and X ^6c are independently defined as above.

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

wherein Ring A, W, R ^2c , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , X ^3c , X ^4c , X ^5c , and X ^6c are independently defined as above.

In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

Wherein, R ^3a , R ^4a , R ^2c , R ^3c , R ^4c , R ^4b1 , R ^4b2 , R ^5b1 , and R ^5b2 are independently defined as above. In an optional embodiment of the present invention, the compound has any of the following structures, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of any of the following structures:

In the second aspect of the present invention, a pharmaceutical composition is proposed, which comprises a therapeutically effective amount of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

In the third aspect of the present invention, the present invention proposes the use of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of drugs related to inhibiting voltage-gated sodium ion channels, wherein the voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8.

According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug, the drug can be used to treat, relieve or prevent pain, and the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

In a fourth aspect, the present invention provides a method for inhibiting voltage-gated sodium ion channels, or preventing and/or treating diseases related to voltage-gated sodium ion channels, comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect of the present invention.

The voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8. The voltage-gated sodium ion channel-related diseases are pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

Beneficial Effects

According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

Provided are Nav1.8 inhibitors with novel structures, excellent pharmacokinetic properties, and good efficacy or drugability, which can be used to effectively treat Nav1.8-related diseases and conditions.

Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

Definition and explanation of terms

Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

Those skilled in the art will appreciate that, according to the conventions used in the art, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.

The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.

The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, D-isomers, L-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.

The prefix "Cu _{- Cv} " indicates that the following group has from u to v carbon atoms. For example, "C1 _{- C6} alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

As used herein, the term "halogen" refers to F, Cl, Br or I.

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms attached to the rest of the molecule by means of a single bond. For example, "C ₁ -C ₆ "alkyl" is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon atoms and hydrogen atoms, containing one or more carbon-carbon double bonds, and having a specific number of carbon atoms, which is connected to the rest of the molecule by means of a single bond. For example, a " _C2 - _C6 alkenyl" radical is an alkenyl radical having between 2, 3, 4, 5 or 6 carbon atoms. It should be understood that in the case where the alkenyl radical contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl radical is, for example, selected from vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged or spiro) saturated hydrocarbon group consisting only of carbon and hydrogen atoms, having a specific number of carbon ring atoms, and connected to the rest of the molecule by a single bond. For example, "C ₃ -C ₈ cycloalkyl" is a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. The cycloalkyl group is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.

As used herein, the term "heterocycloalkyl" refers to a stable, non-aromatic, monocyclic or bicyclic (fused, bridged or spirocyclic) saturated hydrocarbon group consisting of carbon, hydrogen and one or more heteroatoms (such as nitrogen, oxygen and sulfur), which has a specified number of ring atoms and is connected to the rest of the molecule by a single bond. For example, a "3-9-membered heterocycloalkyl" is a cycloalkyl group having 3, 4, 5, 6, 7, 8 or 9 atoms and having at least one heteroatom such as nitrogen, oxygen and sulfur. The heterocycloalkyl may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl.

As used herein, the term "heterocycloalkenyl" refers to a stable non-aromatic ring structure (monocyclic or polycyclic) containing at least one double bond, containing one or more heteroatoms independently selected from O, N and S and specifying the number of ring atoms. The non-aromatic ring structure may have 4 to 10 ring members, and in particular 4 to 7 ring members. The fused heterocyclic ring system may contain carbocyclic rings and need only contain one heterocyclic ring.

As used herein, the term "fused 3-7 membered ring containing up to two heteroatoms selected from N, O and S" when applied to the ring formed by two ^Ra groups attached to adjacent atoms together with the atoms to which they are attached refers to a saturated, unsaturated or aromatic ring fused to a heteroaryl, heterocycloalkyl or aryl ring and containing up to two heteroatoms selected from N, O and S.

As used herein, the term "haloalkyl" refers to an alkyl group having a specific number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halogen. For example, a "C ₁ -C ₆ haloalkyl" group is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halogen group.

As used herein, the term "alkoxy" refers to a radical of the formula ^-ORa , wherein ^Ra is an alkyl radical having the specified number of carbon atoms. For example, a " _C1 - _C6alkoxy " radical is a radical of the formula ^-ORa , wherein ^Ra is an alkyl radical having 1, 2, 3, 4, 5 or 6 carbon atoms.

As used herein, the term "haloalkoxy" refers to an alkoxy group having a specific number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen. For example, "C ₁ -C ₆ haloalkoxy" refers to an alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen groups.

As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having the specified number of carbon atoms, which is attached to the remainder of the molecule by two single bonds. For example, a "C ₁ -C ₆ alkylene" group is an alkylene radical having 1, 2, 3, 4, 5 or 6 carbon atoms.

As used herein, the term "alkenylene" refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having a specific number of carbon atoms, which is connected to the rest of the molecule by two single bonds. For example, a "C ₁ -C ₆ alkenylene" group is an alkenylene radical having 1, 2, 3, 4, 5 or 6 carbon atoms.

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, containing no unsaturation, and having a specified number of carbon atoms, which is attached to the rest of the molecule by a single bond, and wherein the bond between any two other carbon atoms is a triple bond. For example, " _C2 - _C6alkynyl " refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms, wherein the bond between any two carbon atoms is a triple bond. The alkynyl group is selected from, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent- In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

As used herein, the term "aryl" refers to a stable, aromatic, monocyclic or bicyclic ring group having a specified number of ring atoms. For example, a "9-10 membered aryl" is an aryl group having 9 or 10 carbons. The aryl group is, for example, selected from indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl or naphthyl.

As used herein, the term "heteroaryl" refers to a stable aromatic monocyclic or bicyclic group having a specified number of ring atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. For example, "5-10 membered heteroaryl" refers to a group having 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O and S. And it may be benzo-fused. The heteroaryl is, for example, selected from indolyl, isoindolyl, quinolyl, quinazoline, indolizinyl, imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl.

As used herein, the term "monovalent anion" refers to an anion with a single unit negative charge. In some embodiments, the monovalent anion is pharmaceutically acceptable. As used herein, the term "pharmaceutically acceptable monovalent anion" refers to those that are suitable for contact with the tissues of humans and lower animals within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable monovalent anions include any monovalent anions that are components of pharmaceutically acceptable salts described herein. Illustratively, the monovalent anion can be a halide, such as chloride or bromide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Exemplary carboxylates include halogenated carboxylates, such as acetate and trifluoroacetate.

As used herein, labels such as "*4" and "*3" such as those shown in the structures below designate the atom to which the corresponding R groups (in this case, the R ^4a and R ^3a groups, respectively) are attached.

As used herein, in any chemical structure or formula, the bold or hashed direct bonds ( ), such as

middle,

Indicates the relative stereochemistry of a stereogenic center with respect to other stereogenic centers to which it is connected with bold or hashed direct bonds.

As used herein, in any chemical structure or formula, a bold or hashed wedge-shaped bond ( ), such as in

middle,

Indicates the absolute stereochemistry of a stereogenic center, and the relative stereochemistry of that stereogenic center with respect to the other stereogenic center to which it is connected by bold or hashed wedge bonds.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur.

In addition, it should be noted that, unless otherwise clearly indicated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently the same or different specific groups. In more detail, the description method "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

DETAILED DESCRIPTION

The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Example 1: Preparation of target compound I-2/I-2A

Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxydeoxy-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-2)

Synthesis of (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxydeoxy-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-2A)

The synthetic route of the target compound I-2/I-2A is as follows:

Step 1: Synthesis of (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxydeoxy-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxalanine-2-carboxamide

At room temperature, (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxylic acid (400 mg, 1.13 mmol) was dissolved in dichloromethane (4.00 mL), cooled to 0°C, and oxalyl chloride (287 mg, 2.26 mmol) was added dropwise. After stirring for 2 hours, the reaction solution was concentrated to dryness, and dichloromethane (4.00 mL) was added to dissolve it. Triethylamine (171 mg, 1.69 mmol) and 6-amino-2,3-dihydro-1H-isoindol-1-one (201 mg, 1.35 mmol) were added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, water (5.00 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (5.00 mL*3). The organic phase was washed with a saturated sodium chloride solution (10.0 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was separated by reverse phase chromatography on a Waters Xbridge 150*25mm*5um; gradient 33%-63% B over min, (mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 33%-63%) to obtain (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxyylidene-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (120 mg, yield 21.7%).

LC-MS, M/Z (ESI): 485.2 (M+H ⁺ )

Step 2: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxydeoxy-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-2)

Synthesis of (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxydeoxy-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-2A)

(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxydeoxy-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (120 mg, 206 umol) was prepared by chiral separation, chromatographic column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); isocratic elution mode (mobile phase: CO ₂ -isopropanol (0.1% ammonia water); B%: 50%,) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxyylidene-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-2) (26.6 mg, 22.1% yield) and (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxyylidene-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-2A) (22.4 mg, 18.6% yield) were obtained respectively.

Compound I-2 retention time 1.598min: LC-MS, M/Z (ESI): 485.2 (M+1) ⁺

¹ H NMR(400MHz,METHANOL-d4)δ8.01(d,1H),7.80(dd,1H),7.52(d,1H),7.10-7.18(m,1H),6.93-7.02(m,1H) ,5.07(d,1H),4.41(s,2H),4.33(dd,1H),4.00(d,3H),2.79(t,1H),1.67(s,3H),0.78-0.86(m,3H ).

Compound I-2A retention time 2.003min: ¹ H NMR (400MHz, METHANOL-d4) δ8.01 (d, 1H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.09-7.18 (m, 1H), 6.92-7.04 (m, 1H), 5.07 (d, 1H), 4.42 (s, 2H), 4.33 (dd, 1H), 4.00 (d, 3H), 2.79 (t, 1H), 1.67 (s, 3H), 0.78-0.86 (m, 3H).

Example 2: Preparation of target compound I-9/I-9A

Synthesis of 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (I-9)

Synthesis of 6-[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (I-9A)

The synthetic route of the target compound I-9/I-9A is as follows:

Step 1: Synthesis of (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(isoquinolin-6-yl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxamide

At room temperature, (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxylic acid (600 mg, 1.69 mmol) was dissolved in dichloromethane (6.00 mL), cooled to 0°C, and oxalyl chloride (430 mg, 3.39 mmol) was added dropwise. After stirring for 2 hours, the reaction solution was concentrated to dryness, and dichloromethane (6.00 mL) was added to dissolve it. Triethylamine (257 mg, 2.54 mmol) and 6-amino-isoquinoline (293 mg, 2.03 mmol) were added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, water (10.00 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (5.00 mL*3). The organic phase was washed with saturated sodium chloride solution (10.0 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was separated by chromatography (petroleum ether: ethyl acetate 5:1 to 1:1) to obtain (4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(isoquinolin-6-yl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxamide (275 mg, crude product).

LC-MS, M/Z (ESI): 481.2 (M+H ⁺ )

Step 2: Synthesis of 6-[(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide

At 0°C, (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(isoquinolin-6-yl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (270 mg, 562 umol) was dissolved in dichloromethane (6.00 mL), and m-chloroperbenzoic acid (228 mg, 1.12 mmol) was added in batches, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, saturated sodium sulfite solution (5.00 mL) was added to quench, and the mixture was extracted with dichloromethane (5.00 mL*3). The organic phase was washed with saturated sodium chloride solution (10.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was directly concentrated and subjected to reverse phase preparation column: Waters Xbridge 150*25mm*5um; (mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 30%-60%, 7min) to obtain 6-[(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanyl-2-amido]isoquinoline-2-nitrogen oxide (120 mg, 42.4% yield).

LC-MS, M/Z(ESI):497.2(M+1) ⁺

Step 3: Synthesis of 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (I-9)

Synthesis of 6-[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (I-9A)

6-[(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (120 mg, 242 umol) was chirally separated and prepared on a column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 um); isocratic elution mode (mobile phase: CO ₂ -ethanol (0.1% ammonia water); B%: 25%,) and then 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (I-9) (51.4 mg, 42.8% yield) and 6-[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-amido]isoquinoline-2-nitrogen oxide (I-9A) (52.4 mg, 43.6% yield) were obtained respectively.

Compound I-9 retention time 1.683 min: LC-MS, M/Z (ESI): 497.2 (M+H ⁺ )

¹ H NMR(400MHz,METHANOL-d4)δ8.93(s,1H),8.43(s,1H),8.15(dd,1H),7.95(d,1H),7.90(d,1H),7.84(dd ,1H),7.11-7.19(m,1H),6.94-7.04(m,1H),5.12(d,1H),4.36(dd,1H),4.00(d,3H),2.81(quin,1H), 1.68(s,3H),0.83(br dd,3H).

Compound I-9A retention time 1.842min: ¹ H NMR (400MHz, METHANOL-d4) δ8.94 (s, 1H), 8.43 (s, 1H), 8.15 (dd, 1H), 7.93-7.99 (m, 1H), 7.91 (d, 1H), 7.85 (dd, 1H), 7.12-7.19 (m, 1H), 6.94-7.04 (m, 1H), 5.12 (d, 1H), 4.36 (dd, 1H), 4.00 (d, 3H), 2.81 (quin, 1H), 1.68 (s, 3H), 0.80-0.87 (m, 3H). Example 3: Preparation of target compound I-12

(2R,3S,4S,5R)-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-12).

The route of target compound I-12 is as follows:

Step 1: Ethyl 4,5-difluoro-2-methoxyphenylacetate

4,5-difluoro-2-methoxyphenylboronic acid (25.0g, 133mmol) was dissolved in tetrahydrofuran (400mL). Under nitrogen atmosphere, tri-o-tolylphosphane (4.05g, 13.30mmol), benzyl (triethyl) ammonium chloride (3.03g, 13.3mmol), potassium fluoride (23.8g, 399mmol) and tris (dibenzylideneacetone) dipalladium (3.65g, 3.99mmol) were added respectively. The reaction liquid was replaced with nitrogen three times, and then ethyl bromoacetate (34.00g, 199mmol) was added. The reaction liquid was stirred at 25°C for 1 hour. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain ethyl 4,5-difluoro-2-methoxyphenylacetate (8.00g, yield: 26.1%).

Step 2: 2-(4,5-difluoro-2-methoxyphenyl)acetic acid

Ethyl 4,5-difluoro-2-methoxyphenylacetate (10.0 g, 43.4 mmol) was dissolved in tetrahydrofuran (130 mL) and water (65.0 mL), and lithium hydroxide monohydrate (9.11 g, 217 mmol) was added in batches. The reaction solution was stirred at 50°C for 12 hours. After the reaction was completed, hydrochloric acid (1N) was used to adjust the pH to 3-4, and then extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated sodium chloride solution (30.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was directly used in the next step: 2-(4,5-difluoro-2-methoxyphenyl)acetic acid (8.00 g, yield: 91.1%).

LC-MS,M/Z(ESI):201.1(MH) ⁺

Step 3: (R)-3-(4,5-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one

2-(4,5-difluoro-2-methoxyphenyl)acetic acid (1 g, 4.95 mmol) was dissolved in acetonitrile (16.0 mL), 1,1-carbonyldiimidazole (882.31 mg, 5.44 mmol) was slowly added to the reaction solution at 0°C, and the reaction solution was stirred at 25°C for 1 hour. Potassium carbonate (1.37 g, 9.89 mmol) and (3R)-4,4,4-trifluoro-3-hydroxy-3-methyl-butane-2-one (1.65 g, 7.42 mmol) were then added to the reaction solution, and the reaction solution was finally stirred at 45°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude yellow liquid product, which was separated and purified by column chromatography (mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain (R)-3-(4,5-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (1.30 g, yield: 81.5%).

LC-MS, M/Z(ESI):323.0(M+H) ⁺

Step 4: (3S,4S,5R)-3-(4,5-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

(R)-3-(4,5-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (1.30 g, 4.03 mmol) was dissolved in isopropanol (10.0 mL). Palladium/carbon (1.29 g, 1.21 mmol, 10% purity) was slowly added under nitrogen atmosphere. Hydrogen was replaced three times. The reaction solution was stirred at 40°C for 48 hours under hydrogen atmosphere (3.00 MPa). After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was directly used in the next step, (3S,4S,5R)-3-(4,5-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (1.00 g, yield: 76.4%).

LC-MS, M/Z(ESI):325.0(M+H) ⁺

Step 5: (3S,4S,5R)-3-(4,5-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

(3S,4S,5R)-3-(4,5-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (1.00 g, 3.08 mmol) was dissolved in dichloromethane (10.0 mL). Boron tribromide (2M, 4.63 mL) was slowly added dropwise at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0°C, and then extracted with dichloromethane (10mL*3). The organic phase was washed with a saturated sodium chloride solution (30.0mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was directly used in the next step, (3S,4S,5R)-3-(4,5-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (900mg, yield: 94.0%).

LC-MS, M/Z(ESI):311.0(M+H) ⁺

Step 6: (3S,4S,5R)-3-(4,5-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

(3S,4S,5R)-3-(4,5-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (900 mg, 2.90 mmol) was dissolved in acetonitrile (10.0 mL), deuterated iodomethane (1.24 g, 8.70 mmol) and potassium carbonate (801.92 mg, 5.80 mmol) were added respectively, and the reaction solution was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) at 0°C, and then extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was directly used in the next step, (3S,4S,5R)-3-(4,5-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (650 mg, yield: 68.0%).

LC-MS, M/Z(ESI):328.0(M+H) ⁺

Step 7: (2R,3S,4S,5R)-3-[4,5-difluoro- ^2- ( _2H3 )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxalan-2-ol

(3S,4S,5R)-3-(4,5-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (500 mg, 1.53 mmol) was dissolved in anhydrous toluene (10.0 mL). Diisobutylaluminum hydride (1M, 2.29 mL) was slowly added dropwise at -30°C under a nitrogen atmosphere, and the reaction solution was stirred at -30°C for 2 hours. After the reaction was completed, water (1.00 mL) was added to the reaction solution at 0°C to quench the reaction, and then filtered and concentrated to obtain a crude product, which was directly used in the next step, (2R,3S,4S,5R)-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-ol (450 mg, yield: 89.5%).

LC-MS, M/Z(ESI):312.1(M+H) ⁺

Step 8: (2S,3S,4S,5R)-3-[4,5-difluoro- ^2- ( _2H3 )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxalan-2-yl acetate

(2R,3S,4S,5R)-3-[4,5-difluoro-2-( ^2H3 ₎ methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-ol (425 mg, 1.29 mmol) was dissolved in dichloromethane (5.00 mL), and triethylamine (261 mg, 2.58 mmol), 4-dimethylaminopyridine (15.7 mg, 129 μmol) and acetic anhydride (197 mg, 1.94 mmol) were added respectively, and the reaction solution was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 0°C to obtain a colorless liquid. The crude product was separated and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1-5:1) to obtain (2S,3S,4S, _{5R)-3-[4,5-difluoro-2-(2H3} ⁾ methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxalan-2-yl acetate (400 mg, yield: 83.5%).

Step 9: (2R,3S,4S,5R)-3-[4,5-difluoro- ^2- ( _2H3 )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxaline-2-carbonitrile

(2S,3S,4S,5R)-3-[4,5-difluoro-2-( ^2H3 ₎ methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl acetate (400 mg, 1.08 mmol) was dissolved in anhydrous toluene (4.00 mL). Boron trifluoride etherate (183 mg, 1.29 mmol) and trimethylsilyl cyanide (160 mg, 1.62 mmol) were added at -30°C, and the reaction solution was stirred at -30°C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1-5:1) to obtain (2R,3S,4S,5R)-3-[4,5-difluoro-2-( ^2H3 ) _{methoxyphenyl} ]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carbonitrile (240 mg, yield: 65.8%).

Step 10: (2R,3S,4S,5R)-3-[4,5-difluoro- ^2- ( _2H3 )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxylic acid

(2R,3S,4S,5R)-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carbonitrile (240 mg, 709 μmol) was dissolved in ethanol (2.00 mL) and water (1.00 mL), potassium hydroxide (119 mg, 2.13 mmol) was added, and the reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 3-4 with hydrochloric acid (1N), then extracted with ethyl acetate (10 mL*3), the organic phase was washed with saturated sodium chloride solution (30.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain (2R,3S,4S,5R)-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxylic acid (100 mg, yield: 39.5%).

LC-MS,M/Z(ESI):356.1(MH) ⁺

Step 11: (2R,3S,4S,5R)-N-[2-(Benzylmercapto)pyridin-4-yl]-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxamide

(2R,3S,4S,5R)-3-[4,5-difluoro-2-( ^2H3 ₎ methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxylic acid (100mg, 282μmol) was dissolved in dichloromethane (2.00mL), and N,N-dimethylformamide (2.06mg, 28.2μmol) and oxalyl chloride (53.7mg, 423μmol) were added at 0℃, and the reaction solution was stirred at 25℃ for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. Then the above crude product was dissolved in dichloromethane (2.00mL), and 2-benzylthiopyridin-4-amine (61.0mg, 282μmol) and triethylamine (85.6mg, 846μmol) were added at 0℃, and the reaction solution was stirred at 25℃ for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by prep-TLC (mobile phase was petroleum ether:ethyl acetate = 1:1, raw material Rf = 0.00 product Rf = 0.43) to obtain (2R,3S,4S,5R)-N-[2-(benzylmercapto)pyridin-4-yl]-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (80 mg, yield: 51%).

Step 12: (2R,3S,4S,5R)-3-[4,5-difluoro-2-( _2H3 )methoxyphenyl]-4,5-dimethyl-N-(2-sulfamoylpyridin- ⁴ -yl)-5-(trifluoromethyl)oxolane-2-carboxamide (I-12)

(2R,3S,4S,5R)-N-[2-(Benzylmercapto)pyridin-4-yl]-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (50.0 mg, 90.0 μmol) was dissolved in acetonitrile (1.50 mL), acetic acid (0.50 mL) and water (0.50 mL), 3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione in acetonitrile (0.50 mL) was slowly added dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a yellow oil. The above yellow oil was dissolved in acetonitrile (1.00 mL), and ammonia water (2.00 g, 18.8 mmol) was slowly added dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography, the separation method was: Waters Xbridge 150*25mm*5um; mobile phase: [H ₂ O(NH4HCO3)-ACN]; gradient: 40%-70% B over 9min to obtain (2R,3S,4S,5R)-3-[4,5-difluoro-2-( ² H ₃ )methoxyphenyl]-4,5-dimethyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)oxolane-2-carboxamide (2.78 mg, yield 16.2%).

¹ H NMR (400 MHz, METHANOL-d ₄ )δ＝8.54(d, J＝5.50 Hz, 1H)8.28(d, J＝1.88 Hz, 1H)7.77(dd, J＝5.50, 2.14 Hz, 1H)7.32(dd, J＝11.38, 9.00 Hz, 1H)6.98(dd, J＝12.52, 6.88 Hz, 1H)4.80(d, J＝9.51 Hz, 1H)3.73-3.88(m, 1H)2.61-2.85(m, 1H)1.61(s, 3H)1.04(dd, J＝7.08, 1.44 Hz, 3H) Example 4: Preparation of target compound I-13

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-sulfamoylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-13).

The route of target compound I-13 is as follows:

Step 1: 5-amino-2-fluorobenzenesulfonamide

Palladium/carbon (241 mg, 227 μmol, 10% purity) was added to a methanol solution (10.0 mL) of 5-nitro-2-fluorobenzenesulfonamide (500 mg, 2.27 mmol), and the mixture was replaced with hydrogen three times. The reaction solution was stirred for 12 hours under hydrogen (50 Psi) and a temperature of 80°C. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product: 5-amino-2-fluorobenzenesulfonamide (400 mg, yield: 92.6%), which was used directly in the next step without purification.

LC-MS,M/Z(ESI):189.1(MH) ⁺

Step 2: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-sulfamoylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-13)

5-amino-2-fluorobenzenesulfonamide (257 mg, 1.35 mmol) and (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (400 mg, 1.13 mmol) were dissolved in N, N-dimethylformamide (4.00 mL). Under a nitrogen atmosphere, triethylamine (571 mg, 5.65 mmol) and n-butylphosphonic anhydride (2.44 g, 3.39 mmol, 50% ethyl acetate solution) were slowly added dropwise, and the reaction solution was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (15 mL), and then extracted with ethyl acetate (10.0 mL*3). The organic phase was washed with a saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography to obtain I-13. Purification method: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H ₂ O(NH4HCO3)-ACN]; gradient: 40%-70% B over 20min; (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-aminosulfonylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (227 mg, yield: 37.2%).

¹ H NMR (400MHz, CD ₃ OD) δ = 8.15 (dd, J = 6.38, 2.64Hz, 1H), 7.83 (ddd, J = 8.96, 4.20, 2.76Hz, 1H), 7.27 (t, J = 9.40Hz ,1H),7.10-7.18(m,1H),6.96-7.05(m,1H),5.07(d,J＝10.51Hz,1H),4.32(dd,J＝10.4,8.07Hz,1H),4.01( d,J＝2.26Hz,3H),2.74-2.87(m,1H),1.68(s,3H),0.75-0.90(m,3H).

Example 5: Preparation of target compound I-21

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-N-(3-hydroxycyclobutyl)methylpicolinamide (I-21).

The route of target compound I-21 is as follows:

Step 1: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-o-picolinic acid

Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methyl pyridinium ester (300 mg, 614.25 μmol) was dissolved in methanol (4.00 mL) and water (1.00 mL), and then sodium hydroxide (73.70 mg, 1.84 mmol) was added, and the reaction solution was stirred at 25 ° C for 2 hours. After the reaction is completed, the pH value of the reaction solution is adjusted to 3-4 using hydrochloric acid (1N), and then extracted with ethyl acetate (10.0 mL*3). The organic phase is washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude yellow liquid: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-1-picolinic acid (250 mg, yield: 85.8%).

LC-MS,M/Z(ESI):473.1(MH) ⁺

Step 2: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-N-(3-hydroxycyclobutyl)methylpicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-o-pyridinecarboxylic acid (100 mg, 210 μmol) and triethylamine (42.6 mg, 421 μmol) were dissolved in tetrahydrofuran (2.00 mL), and then isobutyl chloroformate (43.2 mg, 316 μmol) was added dropwise at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Finally, 3-amino-cyclobutane-1-ol (36.7 mg, 421 μmol) was added to the reaction solution and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain a crude yellow liquid product: the crude product was separated and purified by reverse phase high performance liquid chromatography to obtain a white solid. Purification method: Waters Xbridge 150*25mm*5um; mobile phase: [H ₂ O(NH4HCO3)-ACN]; gradient: 35%-65% B over 15min; 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-N-(3-hydroxycyclobutyl)methylpicolinamide (9.23 mg, yield: 8.06%) was obtained.

¹ H NMR (400MHz, CD ₃ OD) δ = 8.51 (d, J = 5.50Hz, 1H) 8.21-8.31 (m, 1H) 7.86-7.94 (m, 1H) 7.08-7.20 (m, 1H) 6.94-7.04 (m,1H)5.09(d,J＝10.40Hz,1H)4.59(s,2H)4.34(m,1H)4.03-4.09(m,1H)4.01(d,J＝2.26Hz,3H)2.76-2.85 (m,2H)2.33(s,1H)2.00-2.05(m,1H)1.68(s,3H)0.78-0.92(m,3H)

Example 6: Preparation of target compound I-25

4-((2R,3S,4S,5R)-3-(2-(2,2-difluoro-3-hydroxypropoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (I-25).

The synthetic route of the target compound I-25 is as follows:

Step 1: 2,2-Difluoro-3-hydroxypropyl 4-methylbenzenesulfonate

2,2-difluoropropane-1,3-diol (2.00 g, 17.8 mmol) and triethylamine (5.42 g, 53.5 mmol) were dissolved in dichloromethane (10.0 mL). Under nitrogen atmosphere, p-toluenesulfonyl chloride (3.40 g, 17.8 mmol) was slowly added dropwise at 0°C. The reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was slowly quenched by adding sodium bicarbonate aqueous solution at 0°C until no bubbles were generated. Then it was extracted with dichloromethane (20.0 mL*3), the organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude yellow liquid. The crude product was separated and purified by reverse phase high performance liquid chromatography to obtain a colorless liquid: 2,2-difluoro-3-hydroxypropyl 4-methylbenzenesulfonate (1.20 g, yield: 25%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.84 (d, J = 8.40Hz, 2H), 7.51 (d, J = 8.14Hz, 2H), 5.67 (t, J = 6.24Hz, 1H), 4.37 (t,J＝13.8Hz,2H),3.63(td,J＝13.57,6.24Hz,2H),2.51(dt,J＝3.60,1.80Hz,1H),2.44(s,3H).

Step 2: 4-((2R,3S,4S,5R)-3-(2-(2,2-difluoro-3-hydroxypropoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (350 mg, 761 μmol) and 2,2-difluoro-3-hydroxypropyl 4-methylbenzenesulfonate (243 mg, 914 μmol) were dissolved in N,N dimethylformamide (4.00 mL), and potassium carbonate (210 mg, 1.52 mmol) was added. The reaction was stirred at 130 ° C for 1 hour in a microwave reactor. After the reaction was completed, the reaction solution was diluted with water (10.0 mL), and then extracted with ethyl acetate (10.0 mL*3). The organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude yellow liquid. The crude product was separated and purified by reverse phase high performance liquid chromatography, and the separation method was as follows: chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: [ _H2O (NH4HCO3)-ACN]; gradient: 40%-70% B over 9min to obtain: 4-((2R,3S,4S,5R)-3-(2-(2,2-difluoro-3-hydroxypropoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (16.3 mg, yield: 3.67%).

¹ H NMR (400MHz, CD ₃ OD) δppm 8.50 (d, J = 5.64Hz, 1H) 8.27 (d, J = 2.14Hz, 1H) 7.91 (dd, J = 5.44, 2.20Hz, 1H) 7.17-7.23 ( m,1H)7.03-7.11(m,1H)5.11(d,J＝10.52Hz,1H)4.51-4.63(m,2H)4.37-4.49(m,2H)3.86 1(t,J＝13.0Hz,2H )2.81-2.92(m,1H)1.68(s,3H)0.80-0.89(m,3H)

Example 7: Preparation of target compound I-26

Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-[4-fluoro-3-(N-hydroxycarbamimidoyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (I-26)

The synthetic route of the target compound I-26 is as follows:

Step 1: Synthesis of (2R,3S,4S,5R)-N-(3-cyano-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (26B)

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxylic acid (26A) (100 mg, 282 μmol, 1.00 eq) was dissolved in N,N-dimethylformamide (1 mL), and butylphosphonic anhydride (50% in ethyl acetate) (406 mg, 1.13 mmol, 4.00 eq), triethylamine (85.6 mg, 846 μmol, 117 μL, 3.00 eq) and 5-amino-2-fluorobenzonitrile (49.9 mg, 366 μmol, 1.30 eq) were added and stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) at 0°C, extracted with ethyl acetate (10 mL×3), dried and concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1, R _f was 0.47) to give a yellow oily product (2R, 3S, 4S, 5R)-N-(3-cyano-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (26B) (60.0 mg, 127 μmol, 45.0% yield).

LC-MS, M/Z (ESI): 473.1 [M+H ⁺ ]

Step 2: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-[4-fluoro-3-(N-hydroxycarbamimidoyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)oxalanine-2-carboxamide (I-26)

(2R,3S,4S,5R)-N-(3-cyano-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (26B) (40.0 mg, 84.6 μmol, 1.00 eq) was dissolved in anhydrous ethanol (1 mL), hydroxylamine hydrochloride (8.83 mg, 127 μmol, 1.50 eq) and triethylamine (17.1 mg, 169 μmol, 23.5 μL, 2.00 eq) were added, and the mixture was stirred at 70 °C for 4 hours. After the reaction was complete, the reaction solution was purified by HPLC (chromatographic column: C18150×25mm×10μm; mobile phase: A=water+0.1% formic acid, B=acetonitrile; gradient: 32%-62%, 9min) to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-[4-fluoro-3-(N-hydroxycarbamimidoyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (I-26) (13.0 mg, 25.7μmol, 30.3% yield).

¹ H NMR (400MHz, DMSO-d) δ10.32 (s, 1H), 9.62 (s, 1H), 7.75 (dd, J = 2.6, 6.4Hz, 1H), 7.68-7.59 (m, 1H), 7.24 -7.09(m,3H),5.78(s,2H),5.04(d,J＝10.4Hz,1H),4.23(dd,J＝8.0,9.9Hz,1H),3.94(d,J＝1.6Hz, 3H),2.75(quin,J＝7.3Hz,1H),1.59(s,3H),0.72(brd,J＝6.4Hz,3H)

LC-MS, M/Z (ESI): 506.1 [M+H ⁺ ]

Example 8: Preparation of target compound I-27

Synthesis of (2R,3S,4S,5R)-N-(3-carbamimidophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-27)

The synthetic route of the target compound I-27 is as follows:

Step 1: Synthesis of (2R,3S,4S,5R)-N-(3-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1) (200 mg, 564 μmol) was dissolved in N,N-dimethylformamide (2 mL), and tri-n-butylphosphonic anhydride (50% in ethyl acetate) (813 mg, 1.13 mmol, 50% purity), triethylamine (171 mg, 1.69 mmol, 235 μL) and 3-aminobenzonitrile (73.3 mg, 621 μmol) were added, and the mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) at 0°C, extracted with ethyl acetate (20 mL*3), dried and concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to give (2R, 3S, 4S, 5R)-N-(3-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (160 mg, 352 μmol, 62.3% yield).

LC-MS, M/Z (ESI): 453.1 (MH ⁺ )

Step 2: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-hydroxycarbamimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-N-(3-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2) (70.0 mg, 154 μmol) was dissolved in anhydrous ethanol (2 mL), hydroxylamine hydrochloride (32.1 mg, 462 μmol) and triethylamine (62.3 mg, 616 μmol, 85.7 μL) were added, and stirred at 80°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-hydroxycarbamimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (72.0 mg, 147 μmol, 95.8% yield).

LC-MS, M/Z (ESI): 488.3 (M+H ⁺ )

Step 3: Synthesis of (2R,3S,4S,5R)-N-(3-carbamimidophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

Wet palladium on carbon (78.6 mg, 73.8 μmol, 10% purity) was dissolved in glacial acetic acid (3 mL), and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-hydroxycarbamimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (3) (72.0 mg, 147 μmol) and ammonium formate (46.5 mg, 738 μmol) dissolved in glacial acetic acid (2 mL) were added, and the mixture was stirred at 120°C for 5 hours. After the reaction was complete, the reaction solution was filtered and concentrated, and purified by high performance liquid chromatography (chromatographic column: C18 150*25mm*10um; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 20%-50%, 9min) to obtain (2R,3S,4S,5R)-N-(3-carbamimidophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (36.9 mg, 77.6 μmol, 52.5% yield).

LC-MS, M/Z (ESI): 472.2 (M+H ⁺ )

¹ H NMR(400MHz, DMSO-d)δ10.50-10.92(m,1H)9.39-10.36(m,2H)8.46(s,1H)8.10(s,1H)7.87(d,J＝8.75Hz,1H )7.50-7.58(m,1H)7.43-7.48(m,1H)7.13-7.23(m,2H)5.13(d,J＝10.38Hz,1H)4.26(dd,J＝10.38,7.75Hz,1H)3.95 (d,J＝2.00Hz,3H)2.76(br t,J＝7.50Hz,1H)1.60(s,3H)0.73(br d,J＝6.75Hz,3H)

Example 9: Preparation of target compound I-29

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-hydroxypicolinamide (I-29)

The route of target compound I-29 is as follows:

Step 1: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-hydroxypicolinamide (I-29)

Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (150 mg, 307 μmol) was dissolved in methanol (1.5 mL) and water (1.5 mL). Under a nitrogen atmosphere, potassium hydroxide (64.6 mg, 921 μmol) and hydroxylamine hydrochloride (42.7 mg, 614 μmol) were slowly added, and the reaction solution was stirred at 25°C for 24 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A=water+0.1% FA, B=acetonitrile; gradient: 43%-73%, 1min) to obtain 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-hydroxypicolinamide (15.0 mg, yield 10%).

H NMR (400MHz, CD ₃ OD) δ8.46(d,J＝5.50Hz,1H),8.21(d,J＝2.00Hz,1H),7.88(dd,J＝5.50,2.14Hz,1H),7.07 -7.17(m,1H),6.95-7.02(m,1H),5.08(d,J＝10.38Hz,1H),4.33(dd,J＝10.20,8.20Hz,1H),4.00(d,J＝2.24 Hz,3H),2.73-2.87(m,1H),1.67(s,3H),0.77-0.92(m,3H).

Example 10: Preparation of target compound I-37

1-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-4-oxyylidene-1,4-dihydropyridine-3-carboxamide (I-37).

The route of target compound I-37 is as follows:

Step 1: 4-Oxylidene-4H-pyran-3-carboxylic acid ethyl ester

Ethyl formate (16.0 g, 215 mmol) was dissolved in tetrahydrofuran (50.0 mL). Potassium tert-butoxide (1 M, 53.9 mL) was slowly added dropwise at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 0.5 hours. Then, a solution of (E)-ethyl 2-((dimethylamino)methylene)-3-oxybutylene ester (5.00 g, 26.9 mmol) in tetrahydrofuran (50.0 mL) was slowly added dropwise to the reaction solution at 0°C. Finally, the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was slowly added dropwise to hydrochloric acid (1N.80.0 mL) at 0°C for quenching, and then extracted with ethyl acetate (50.0 mL*3). The organic phase was washed with saturated sodium chloride solution (80.0 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase was petroleum ether: ethyl acetate = 1:1 to 0:1) to obtain 4-oxyylidene-4H-pyran-3-carboxylic acid ethyl ester (2.00 g, yield: 44.06%).

¹ H NMR (400MHz, CHLOROFORM-d) δppm 8.37-8.64 (m, 1H) 7.73 (dd, J＝5.88, 1.00Hz,

1H)6.38-6.51(m,1H)4.23-4.45(m,2H)1.23-1.42(m,3H)

Step 2: 1-((tert-Butyloxycarbonyl)amino)-4-oxydeoxy-1,4-dihydropyridine-3-carboxylic acid ethyl ester

Tert-butyloxycarbonylhydrazine (1.36 g, 10.2 mmol) and ethyl 4-oxy-4H-pyran-3-carboxylate (1.15 g, 6.84 mmol) were dissolved in ethanol (15.0 mL), and the reaction solution was stirred at 80 ° C for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was stirred with methyl tert-butyl ether (20.0 mL) for 2 hours for pulping and purification to obtain ethyl 1-((tert-butyloxycarbonyl)amino)-4-oxy-1,4-dihydropyridine-3-carboxylate (1.50 g, yield: 77.6%).

LC-MS, M/Z(ESI):283.0(M+H) ⁺

Step 3: 1-amino-4-oxydeoxy-1,4-dihydropyridine-3-carboxylic acid ethyl ester

1-((tert-Butyloxycarbonyl)amino)-4-oxyylidene-1,4-dihydropyridine-3-carboxylic acid ethyl ester (200 mg, 708 μmol) was dissolved in HCl/1,4-dioxane (2M, 708 μL), and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, 1-amino-4-oxyylidene-1,4-dihydropyridine-3-carboxylic acid ethyl ester, which was directly used in the next step (120 mg, yield: 92.7%).

LC-MS, M/Z(ESI):183.2(M+H) ⁺

Step 4: 1-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-4-oxyylidene-1,4-dihydropyridine-3-carboxylic acid ethyl ester

(3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (200 mg, 564 μmol) and N,N-dimethylformamide (4.13 mg, 56.4 μmol) were dissolved in dichloromethane (4.00 mL), and oxalyl chloride (143 mg, 1.13 mmol) was slowly added dropwise at 0°C under a nitrogen atmosphere, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. Then the crude product was dissolved in dichloromethane (2.00 mL), slowly added dropwise to a dichloromethane (2.00 mL) solution of 1-amino-4-oxyylidene-1,4-dihydropyridine-3-carboxylic acid ethyl ester (100 mg, 548 μmol) at 0°C, and finally triethylamine (69.3 mg, 536 μmol) was added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product: 1-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-4-oxyylidene-1,4-dihydropyridine-3-carboxylic acid ethyl ester, which was directly used in the next step. (200 mg, yield: 71.2%).

LC-MS, M/Z(ESI):519.2(M+H) ⁺

Step 5: 1-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-4-oxyylidene-1,4-dihydropyridine-3-carboxamide (I-37)

1-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-4-oxyylidene-1,4-dihydropyridine-3-carboxylic acid ethyl ester (120 mg, 231 μmol) was dissolved in ammonia methanol (7M, 1.32 mL) solution, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain. The crude product was separated and purified by reverse phase high performance liquid chromatography to obtain I-37. Purification method: Chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 8%-38% B over 15min: 1-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)-4-oxyylidene-1,4-dihydropyridine-3-carboxamide (38.7 mg, yield: 32.3%).

¹ H NMR (400MHz, CD ₃ OD) δ = 8.42 (d, J = 2.64Hz, 1H) 7.75 (dd, J = 7.76, 2.64Hz, 1H) 7.11-7.26 (m, 1H) 6.91-7.05 (m, 1H)6.57(d,J＝7.75Hz,1H)5.23(d,J＝10.78Hz,1H)4.53-4.68(m,2H)4.32(dd,J＝10.70,8.10Hz,1H)4.03(d,J ＝2.38Hz,3H)2.75-2.89(m,1H)2.71-2.96(m,1H)1.71(s,3H)0.71-0.99(m,3H)

Example 11: Preparation of target compound I-39

2-Aminocarbonyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(methylsulfonyl)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)pyridine-1-oxide (I-39).

The synthetic route of the target compound I-39 is as follows:

Step 1: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (420mg, 887μmol) was dissolved in dichloromethane (10.0mL). Boron tribromide (666mg, 2.66mmol, 256.46μL) was slowly added dropwise at 0℃ under nitrogen atmosphere. The reaction solution was stirred at 25℃ for 2 hours. After the reaction was completed, the reaction solution was slowly added to a saturated sodium bicarbonate aqueous solution at 0℃ for quenching until no bubbles were generated. Then it was extracted with dichloromethane (10.0mL*3), the organic phase was washed with a saturated sodium chloride solution (20.0mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1-1:1) to obtain: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (120 mg, yield: 29%).

LC-MS, M/Z(ESI):460.1(M+H) ⁺

Step 2: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(methylthio)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (100 mg, 217 μmol) and 1-chloro-2-methylmercapto-ethane (48.1 mg, 435 μmol) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (90.2 mg, 653 μmo) was added. The reaction solution was stirred at 80 ° C for 12 hours. After the reaction was completed, the reaction solution was quenched with water (10.0 mL), and then extracted with ethyl acetate (10.0 mL*3). The organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by prep-column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1) to obtain 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(methylthio)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (70 mg, yield: 60%).

LC-MS, M/Z(ESI):534.1(M+H) ⁺

Step 3: 2-aminocarbonyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(methylsulfonyl)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)pyridine 1-oxide

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(methylthio)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (20.0 mg, 37.49 μmol) was dissolved in dichloromethane (1.00 mL), and then m-chloroperoxybenzoic acid (17.8 mg, 82.4 μmol, 80% purity) was added, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, sodium sulfite (5.00 mL) was added to the reaction solution to quench, and then extracted with dichloromethane (10.0 mL*3), and the organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography, the separation method was: YMC-Actus Triart C18150*30mm*7um; mobile phase: [water(FA)-ACN]; gradient: 38%-68% B over 10min to obtain: 2-aminoformyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(methylsulfonyl)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide (8.30 mg, yield: 36.5%).

LC-MS, M/Z(ESI):566.2(M+H) ⁺

¹ H NMR (400MHz, CD ₃ OD) δ = 8.50 (d, J = 6.00Hz, 1H), 8.30 (d, J = 1.75Hz, 1H), 7.89 (dd, J = 5.50, 2.14Hz, 1H), 7.18-7.26(m,1H),7.03-7.14(m,1H),5.07(d,J＝10.6Hz,1H),4.61-4.65(m,1H),4.47-4.57(m,2H),3.66( t,J＝5.26Hz,2H)3.07(s,3H),2.77-2.92(m,1H),1.72(s,3H),0.79-0.92(m,3H).

Example 12: Preparation of target compound I-40

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(hydrazinecarbonyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-40).

The route of target compound I-40 is as follows:

Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(hydrazinecarbonyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-40)

Methyl 4-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpyridinium ester (2.00 g, 17.8 mmol) was dissolved in ethanol (4.00 mL), and hydrazine hydrate (72.3 mg, 1.23 mmol, 85% purity) was slowly added dropwise under a nitrogen atmosphere, and the reaction solution was stirred at 80° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product of a yellow liquid. The crude product was separated and purified by reverse phase high performance liquid chromatography to obtain I-40. Purification method: Chromatographic column: Phenomenex luna C18 150*25mm*10um; Mobile phase: [water(FA)-ACN]; Gradient: 43%-73% B over 1min (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(hydrazinecarbonyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (53.0 mg, yield: 17.4%).

¹ H NMR (400MHz, CD ₃ OD) δ = 8.48 (d, J = 5.50Hz, 1H) 8.24 (d, J = 1.88Hz, 1H) 7.88 (dd, J = 5.50, 2.13Hz, 1H) 7.09-7.19 (m,1H)6.93-7.06(m,1H)5.09(d,J＝10.4Hz,1H)4.55-4.65(m,2H)4.34(dd,J＝10.4,8.08Hz,1H)4.01(d,J ＝2.38Hz,3H)2.76-2.87(m,1H)1.67(s,3H)0.72-0.89(m,3H)

Example 13: Preparation of target compound I-41

Synthesis of (2R,3S,4S,5R)-N-(2-((4-aminopyrimidin-2-yl)oxy)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-41)

The synthetic route of the target compound I-41 is as follows:

Step 1: Synthesis of tert-butyl N-[(tert-butoxy)carbonyl]-N-[2-(methylthio)pyrimidin-4-yl]carbamate

Dissolve 2-methylmercapto-4-aminopyrimidine (5.00 g, 35.4 mmol) and BOC anhydride (8.50 g, 38.9 mmol, 8.95 mL) in dichloromethane (50 mL), add 4-dimethylaminopyridine (216 mg, 1.77 mmol) and triethylamine (7.17 g, 70.8 mmol, 9.86 mL), purge with nitrogen for one minute and stir at 25 ° C for 12 hours. After the reaction is complete, the reaction solution is concentrated to obtain tert-butyl N-[(tert-butoxy)carbonyl]-N-[2-(methylthio)pyrimidin-4-yl]carbamate (10.0 g, 29.2 mmol, 82.7% yield).

LC-MS, M/Z (ESI): 342.0 (M+H ⁺ )

Step 2: Synthesis of tert-butyl N-[(tert-butoxy)carbonyl]-N-(2-methylsulfonylpyrimidin-4-yl)carbamate

Under a nitrogen atmosphere at 0°C, dissolve tert-butyl N-[(tert-butoxy)carbonyl]-N-[2-(methylthio)pyrimidin-4-yl]carbamate (5.00 g, 14.6 mmol) in dichloromethane (50 mL), add m-chloroperbenzoic acid (5.95 g, 29.2 mmol, 85% purity), slowly raise the temperature to 25°C, and stir for 2 hours. After the reaction is complete, the reaction solution is poured into sodium bicarbonate (50 mL) under a nitrogen atmosphere at 0°C, the pH is adjusted to 7, extracted with dichloromethane (50 mL*3), and the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated directly to obtain a crude product, which is purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 12:1/5:1) to obtain tert-butyl N-[(tert-butoxy)carbonyl]-N-(2-methylsulfonylpyrimidin-4-yl)carbamate (760 mg, 2.04 mmol, 13.9% yield).

LC-MS, M/Z (ESI): 374.0 (M+H ⁺ )

Step 3: Synthesis of tert-butyl-N-[(tert-butoxy)carbonyl]-N-[2-({4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-amide]pyridin-2-yl}oxy)pyrimidin-4-yl]carbamate

tert-Butyl N-[(tert-butoxy)carbonyl]-N-(2-methylsulfonylpyrimidin-4-yl)carbamate (3) (150 mg, 401 μmol) was dissolved in N,N-dimethylformamide (2 mL), and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-hydroxypyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (188 mg, 421 μmol, 1.05 eq) and potassium carbonate (111 mg, 803 μmol) were added. The reaction mixture was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL) and filtered to obtain tert-butyl-N-[(tert-butoxy)carbonyl]-N-[2-({4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-amide]pyridin-2-yl}oxy)pyrimidin-4-yl]carbamate (5) (140 mg, 189 μmol, 47.1% yield).

LC-MS,M/Z(ESI):640.2(M-100+H ⁺ )

Step 4: Synthesis of (2R,3S,4S,5R)-N-(2-((4-aminopyrimidin-2-yl)oxy)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-41)

Tert-butyl-N-[(tert-butoxy)carbonyl]-N-[2-({4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-amido]pyridin-2-yl}oxy)pyrimidin-4-yl]carbamate (5) (140 mg, 189 μmol, 1.00 eq) was dissolved in HCl/ethyl acetate (2 mL) and stirred at 25°C for 3 hours. After the reaction was complete, the reaction solution was poured into sodium bicarbonate (15 mL), the pH was adjusted to 7, and the product was extracted with dichloromethane (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by HPLC (chromatographic column: Phenomenex luna C18250*50mm*15um; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 32%-62%, 9 min) to obtain (2R,3S,4S,5R)-N-(2-((4-aminopyrimidin-2-yl)oxy)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (21.3 mg, 39.48 μmol, 20.86% yield).

LC-MS, M/Z (ESI): 540.1 (M+H ⁺ )

¹ H NMR (400MHz, CDCl ₃ -d) δ8.58 (s, 1H), 8.23 (d, J = 5.88Hz, 1H), 7.53 (d, J = 7.63Hz, 1H), 6.85-6.93 (m, 1H),7.02-7.10(m,1H),6.79(dd,J＝7.69,2.06Hz,1H),6.70(d,J＝1.88Hz,1H),6.45(d,J＝5.88Hz,1H), 5.60(br s,2H),5.00(d,J＝10.76Hz,1H),4.12(dd,J＝10.57,8.19Hz,1H),4.01(d,J＝2.63Hz,3H),2.76(t,J＝7.69 Hz,1H),1.67(s,3H),0.78(br dd,J＝5.07,2.19Hz,3H).

Example 14: Preparation of target compound I-42

Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxamide (I-42)

The synthetic route of the target compound I-42 is as follows:

Step 1: Synthesis of methyl 4-amino-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate

Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (300 mg, 846 μmol) in N,N-dimethylformamide (3 mL), add tri-n-butylphosphonic anhydride (50% in ethyl acetate) (1.22 g, 3.39 mmol), triethylamine (257 mg, 2.54 mmol, 353 μL) and methyl 4,5-diaminopicolinate (169 mg, 1.02 mmol), and stir at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL) at 0°C, extracted with ethyl acetate (30 mL*3), dried and concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1/1:1) to give 4-amino-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid methyl ester (320 mg, 635 μmol, 75.0% yield).

LC-MS, M/Z (ESI): 504.1 (M+H ⁺ )

Step 2: Synthesis of methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazole[4,5-c]pyridine-6-carboxylate

Methyl-4-amino-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid (300 mg, 595 μmol) was dissolved in glacial acetic acid (3 mL), concentrated sulfuric acid (1.5 mL) was added, and the mixture was stirred at 110°C for 3 hours. After the reaction was completed, the reaction solution was poured into sodium bicarbonate (50 mL) at 0°C, extracted with ethyl acetate (30 mL*3), dried and concentrated to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazole[4,5-c]pyridine-6-carboxylic acid methyl ester (6) (140 mg, 288 μmol, 48.4% yield).

LC-MS, M/Z (ESI): 486.1 (M+H ⁺ )

Step 3: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxamide

Methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazole[4,5-c]pyridine-6-carboxylate (110 mg, 226 μmol) was dissolved in aqueous ammonia (1 mL) and stirred at 70°C for 2 hours. After the reaction was complete, the reaction solution was purified by HPLC (chromatographic column: C18 150*25mm*10μm; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 38%-68%, 9min) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxamide (20.3 mg, 43.1 μmol, 19.0% yield).

LC-MS, M/Z (ESI): 469.1 (MH ⁺ )

¹ H NMR (400MHz, DMSO-d ₆ ) δ13.3 (s, 1H) 8.88 (s, 1H) 8.18 (d, J = 0.75Hz, 1H) 8.07 (brs, 1H) 7.55 (br d, J = 1.88 Hz,1H)7.06-7.24(m,2H)5.84(d,J＝11.01Hz,1H)4.50(dd,J＝10.94,7.57Hz,1H)3.95(d,J＝2.13Hz,3H)2.89(t ,J＝7.50Hz,1H)1.66(s,3H)0.81(br d,J＝6.25Hz,3H)

Example 15: Preparation of target compound I-43

Synthesis of 4-((2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (I-43)

The synthetic route of the target compound I-43 is as follows:

Step 1: Synthesis of ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Int.9) (5.00 g, 14.1 mmol) in dichloromethane (40 mL), add N,N-dimethylformamide (10.3 mg, 141 μmol) and oxalyl chloride (5.37 g, 42.3 mmol) at 0°C under nitrogen atmosphere, and stir at 25°C for 2 hours. Then, spin dry, dissolve in dichloromethane (20 mL), add anhydrous ethanol (3.25 g, 70.6 mmol) and triethylamine (4.28 g, 42.3 mmol), and stir at 25°C for 1 hour. After the reaction was completed, the reaction mixture was dried and concentrated to give ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.50 g, 14.1 mmol, 99.9% yield).

LC-MS, M/Z (ESI): 383.1 (M+H ⁺ )

Step 2: Synthesis of ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (6.00g, 15.7mmol) in dichloromethane (120mL), add aluminum chloride (10.5g, 78.5mmol), react at 20℃ and stir for 12 hours. After the reaction is complete, slowly add the reaction solution into sodium bicarbonate (300mL) solution, extract with dichloromethane/methanol (10/1100*3mL), dry, filter and concentrate to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (2.70g, 7.33mmol, 46.7% yield).

LC-MS, M/Z (ESI): 369.2 (M+H ⁺ )

Step 3: Synthesis of ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (1.32 g, 3.58 mmol) in dichloromethane (13 mL), add triethylamine (725 mg, 7.17 mmol) and trifluoromethanesulfonic anhydride (1.11 g, 3.94 mmol), and stir the reaction at 25 °C for 12 hours. After the reaction was completed, the mixture was dried and concentrated to give a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 100:0/40:1) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (730 mg, 1.46 mmol, 40.7% yield).

LC-MS, M/Z (ESI): 501.0 (M+H ⁺ )

Step 4: Synthesis of (2R,3S,4S,5R)-3-(2-((diphenylmethylene)amino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

Ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.0 mg, 60.0 μmol) was dissolved in toluene (2 mL), and then benzophenone imine (16.3 mg, 89.9 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.47 mg, 6.00 μmol) and potassium phosphate (50.9 mg, 240 μmol) were added, and then tris(dibenzylideneacetone)dipalladium (5.49 mg, 6.00 μmol) was added under nitrogen atmosphere, and the reaction was stirred at 110°C under nitrogen atmosphere for 3 hours. After the reaction was complete, the reaction solution was directly spin-dried to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 100:0/400:1) to obtain (2R, 3S, 4S, 5R)-3-(2-((diphenylmethylene)amino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (260 mg, 489 μmol, 47.9% yield).

LC-MS, M/Z (ESI): 532.1 (M+H ⁺ )

Step 5: Synthesis of ethyl (2R,3S,4S,5R)-3-(2-amino-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

Ethyl (2R,3S,4S,5R)-3-(2-((diphenylmethylene)amino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (300 mg, 226 μmol) was dissolved in tetrahydrofuran (3 mL), hydrochloric acid (1M, 1.47 mL) was added, and the reaction was stirred at 25°C for 3 hours. After the reaction was complete, ammonia water (0.5 mL) was added under nitrogen atmosphere at 0°C, and the crude product was concentrated to obtain a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 4:1) to obtain ethyl (2R,3S,4S,5R)-3-(2-amino-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (50.0 mg, 136 μmol, 60.2% yield).

LC-MS, M/Z (ESI): 368.3 (M+H ⁺ )

Step 6: Synthesis of ethyl (2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

Under a nitrogen atmosphere, wet palladium carbon (113 mg, 106 μmol) was dissolved in ethyl acetate (1 mL), and formaldehyde (37%) (86.2 mg, 1.06 mmol, 79.1 μL) was added. Then, ethyl (2R, 3S, 4S, 5R)-3-(2-amino-3, 4-difluorophenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (39.0 mg, 106 μmol) dissolved in methanol (6 mL) was added. The reaction was replaced with hydrogen three times, and the mixture was stirred at 50 psi, 25 °C for 24 hours. After the reaction was complete, the crude product was filtered and concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 4:1) to give (2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (15.0 mg, 37.9 μmol, 35.7% yield).

LC-MS, M/Z (ESI): 396.1 (M+H ⁺ )

Step 7: Synthesis of (2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

Dissolve (2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (15.0 mg, 37.9 μmol) in anhydrous ethanol (1 mL) and water (0.5 mL), add sodium hydroxide (1M, 379 μL), and stir at 30°C for 2 hours. After the reaction is complete, add dilute hydrochloric acid (1M, 0.5 mL) at 0°C to adjust the pH to 2, extract with ethyl acetate (5 mL*3), filter and concentrate to obtain (2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (11.0 mg, 29.9 μmol, 78.9% yield).

LC-MS, M/Z (ESI): 368.2 (M+H ⁺ )

Step 8: Synthesis of methyl 4-((2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpyridinium ester

Dissolve (2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (8.00 mg, 21.8 μmol) in dichloromethane (5 mL), add N,N-dimethylformamide (159 μg, 2.18 μmol) and oxalyl chloride (5.53 mg, 43.6 μmol), react at 25°C and stir for 1 hour. Then spin dry and dissolve in dichloromethane (1 mL), add 4-amino-2-pyridinecarboxylic acid methyl ester (3.65 mg, 24.0 μmol) and triethylamine (6.61 mg, 65.3 μmol) dissolved in dichloromethane (2 mL), react at 25°C and stir for 1 hour. After the reaction was complete, the reaction mixture was dried and concentrated to give methyl 4-((2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpyridinium ester (9.00 mg, 18.0 μmol, 82.4% yield).

LC-MS, M/Z (ESI): 502.4 (M+H ⁺ )

Step 9: Synthesis of 4-((2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (I-43)

Methyl 4-((2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methyl pyridinium ester (9.00 mg, 18.0 μmol) was dissolved in ammonia methanol solution (1 mL) and the reaction was stirred at 20°C for 1 hour. After the reaction was complete, the reaction solution was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18150*25mm*10um; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 50%-80%, 9min) to obtain 4-((2R,3S,4S,5R)-3-(2-(dimethylamino)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazylamino)methylpicolinamide (0.62 mg, 1.25 μmol, 6.96% yield).

LC-MS, M/Z (ESI): 487.1 (M+H ⁺ )

¹ H NMR (400MHz, DMSO-d) δ10.77 (s, 1H), 8.48 (d, 1H, J = 5.5Hz), 8.27 (d, 1H, J = 1.8Hz), 8.0-8.1 (m, 1H ),7.81(dd,1H,J＝1.8,5.8Hz),7.61(br s,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),5.05(d,1H,J＝ 10.6Hz),4.50(br dd,1H,J＝7.4,10.4Hz),2.77(br d,1H,J＝7.5Hz),2.72(s,6H),1.60(s,3H),0.74(br d ,3H,J＝6.3Hz)

Example 16: Preparation of target compound I-44

Synthesis of (2R,3S,4S,5R)-N-(3-(2-amino-2-oxoacetyl)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-44)

The synthetic route of the target compound I-44 is as follows:

Step 1: Synthesis of (2R,3S,4S,5R)-N-(3-acetyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 282 μmol) in N,N-dimethylformamide (2 mL), add n-butylphosphonic anhydride (50% in ethyl acetate) (406 mg, 564 μmol, 50% purity), triethylamine (85.6 mg, 846 μmol, 117 μL) and 5-amino-2-fluoroacetophenone (47.5 mg, 310 μmol), and stir at 25°C for 2 hours. After the reaction was complete, the mixture was dried and concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 2:1) to give (2R, 3S, 4S, 5R)-N-(3-acetyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (97.0 mg, 198 μmol, 70.2% yield).

LC-MS, M/Z (ESI): 490.1 (M+H ⁺ )

Step 2: Synthesis of (2R,3S,4S,5R)-N-(3-(2-amino-2-oxoacetyl)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-44)

(2R,3S,4S,5R)-N-(3-acetyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (56.0 mg, 114 μmol) was dissolved in dimethyl sulfoxide (2 mL), iodine (23.2 mg, 91.5 μmol, 18.4 μL) and formamidine hydrochloride (10.1 mg, 125 μmol) were added, and the mixture was stirred at 110°C for 11 hours. After the reaction was complete, the reaction solution was purified by HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 45%-75%, 65min) to obtain (2R,3S,4S,5R)-N-(3-(2-amino-2-oxyylideneacetyl)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30.0mg). The obtained product was separated and purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IG 250×30 mm ID, 10 um particle size; mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 15%, isocratic elution mode) to give (2R,3S,4S,5R)-N-(3-(2-amino-2-oxoacetyl)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (12.8 mg, 24.3 μmol, 21.2% yield).

LC-MS, M/Z (ESI): 519.3 (M+H ⁺ )

¹ H NMR (400MHz, DMSO-d) δ10.48 (s, 1H), 8.26 (s, 1H), 8.12 (dd, 1H, J = 2.8, 6.3Hz), 7.9-8.0 (m, 2H), 7.3 -7.4(m,1H),7.1-7.2(m,2H),5.06(d,1H,J＝10.4Hz),4.24(dd,1H,J＝7.7,10.2Hz),3.95(d,3H,J ＝2.0Hz),2.76(t,1H,J＝7.6Hz),1.60(s,3H),0.72(br d,3H,J＝6.4Hz)

Example 17: Preparation of target compound I-45

Synthesis of (2R,3S,4S,5R)-N-(2-(2-amino-2-oxoacetyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-45)

The synthetic route of the target compound I-45 is as follows:

Step 1: Synthesis of methyl 2-(4-((tert-butoxycarbonyl)amino)pyridin-2-yl)-2-oxoacetate

Dissolve tert-butyl (2-bromopyridin-4-yl)carbamate (1.80 g, 6.59 mmol) in tetrahydrofuran (18 mL), add n-butyl lithium (2.50 M, 7.91 mL) at -78 °C under nitrogen atmosphere, and stir for 1 hour at -78 °C. Then, dissolve dimethyl oxalate (1.63 g, 13.8 mmol) in tetrahydrofuran (5 mL), add to the above reaction solution at -78 °C under nitrogen atmosphere, slowly heat to 0 °C and stir for 1 hour. After the reaction was completed, the reaction solution was poured into an aqueous ammonium chloride solution (50 mL) under a nitrogen atmosphere at 0°C, extracted with ethyl acetate (40 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 100:1/7:1) to obtain a yellow oily substance 2-(4-((tert-butoxycarbonyl)amino)pyridin-2-yl)-2-oxoacetate (340 mg, 1.21 mmol, 18.4% yield).

LC-MS,M/Z(ESI):225.2(M-56+H ⁺ )

Step 2: Synthesis of methyl 2-(4-aminopyridin-2-yl)-2-oxoacetate

Dissolve methyl 2-(4-((tert-butoxycarbonyl)amino)pyridin-2-yl)-2-oxoacetate (340 mg, 1.21 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (1 mL), and stir at 20°C for 3 hours. After the reaction is complete, concentrate directly to obtain a crude product, which is purified by HPLC (chromatographic column: Welch Xtimate C18 150*25mm*5um; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 1%-20%, 10 min) to obtain methyl 2-(4-aminopyridin-2-yl)-2-oxoacetate (170 mg, 943 μmol, 77.7% yield).

LC-MS, M/Z (ESI): 181.3 (M+H ⁺ )

Step 3: Synthesis of methyl-2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-oxoacetate

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1) (200 mg, 564 μmol) was dissolved in dichloromethane (5 mL). N,N-dimethylformamide (4.13 mg, 56.4 μmol, 4.34 μL) and oxalyl chloride (143 mg, 1.13 mmol, 98.8 μL) were added under nitrogen atmosphere at 0°C. The reaction was stirred at 25°C for 1 hour. Then, the mixture was dried and dissolved in dichloromethane (2 mL), and then added dropwise to a mixed solution of methyl 2-(4-aminopyridin-2-yl)-2-oxoylidene acetate (3c-1) (81.3 mg, 451 μmol) and triethylamine (285 mg, 2.82 mmol, 392 μL) in dichloromethane (3 mL), and stirred at 25°C for 1 hour. After the reaction was complete, the mixture was dried and concentrated to obtain a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 1:2) to obtain methyl-2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-oxoacetate (50.0 mg, 96.8 μmol, 17.1% yield).

LC-MS, M/Z (ESI): 515.1 (MH ⁺ )

Step 4: Synthesis of (2R,3S,4S,5R)-N-(2-(2-amino-2-oxoacetyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-45)

Methyl-2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-oxoacetate (3-1) (50.0 mg, 96.8 μmol) was dissolved in ammonia methanol solution (3 mL) and stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 60%-90%, 9min) to obtain (2R,3S,4S,5R)-N-(2-(2-amino-2-oxoacetyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2.41 mg, 4.53 μmol, 4.68% yield, 94.3% purity).

LC-MS, M/Z (ESI): 500.1 (MH ⁺ )

¹ H NMR (400MHz, CDCl ₃ -d) δ10.5-11.0(m,1H),8.2-8.7(m,1H),7.5-8.1(m,3H),7.0-7.3(m,2H),5.0 -5.2(m,1H),4.1-4.4(m,1H),3.9-4.0(m,3H),2.7-2.9(m,1H),1.60(s,3H),0.72(br d,3H,J =6.5Hz)

Example 18: Preparation of target compound I-46

Synthesis of N-(cyclopropylsulfonyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (I-46)

The synthetic route of the target compound I-46 is as follows:

Step 1: Synthesis of methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1) (300 mg, 847 μmol) was dissolved in N,N-dimethylformamide (6 mL), butylphosphonic anhydride (50% in ethyl acetate) (1.22 g, 1.69 mmol, 50% purity), N,N-diisopropylethylamine (328 mg, 2.54 mmol, 442 μL) and methyl 4-amino-2-picolinate (155 mg, 1.02 mmol) were added, and the mixture was stirred at 25°C for 12 hours. After the reaction was complete, the crude product was dried and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 5:1/1:1) to obtain methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (160 mg, 328 μmol, 38.7% yield). LC-MS, M/Z (ESI): 489.1 (M+H ⁺ )

Step 2: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid

Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (160 mg, 328 μmol) was dissolved in anhydrous ethanol (3 mL), and a solution of sodium hydroxide (65.5 mg, 1.64 mmol) in water (1 mL) was added and stirred at 25°C for 2 hours. After the reaction was complete, dilute hydrochloric acid (0.1 M, 3.28 mL) was added, and the reaction solution was poured into water (15 mL), extracted with ethyl acetate (5 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid (140 mg, 295 μmol, 90.1% yield).

LC-MS, M/Z (ESI): 475.0 (M+H ⁺ )

Step 3: Synthesis of N-(cyclopropylsulfonyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (I-46)

4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid (3) (70.0 mg, 148 μmol) was dissolved in N,N-dimethylformamide (1 mL), 1,1-carbonyldiimidazole (162 mg, 1.61 mmol) was added, and the mixture was stirred at 70°C for 1 hour to obtain solution 1. Sodium hydroxide (23.61 mg, 590.25 μmol, 60% purity) was dissolved in N,N-dimethylformamide (1 mL), cyclopropanesulfonamide (71.5 mg, 590 μmol) was added, and the mixture was stirred at 20°C for 1 hour to obtain solution 2. Solution 1 was added dropwise to solution 2, and the mixture was stirred at 20°C for 1 hour. After the reaction was completed, the reaction solution was poured into an aqueous ammonium chloride solution (10 mL) under a nitrogen atmosphere, extracted with ethyl acetate (5 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated directly to obtain a crude product, which was purified by high performance liquid chromatography (chromatographic column: Phenomenexluna C18150*25 mm*10 um; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 58%-78%, 10 min) to obtain N-(cyclopropylsulfonyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (18.3 mg, 31.3 μmol, 21.2% yield).

LC-MS, M/Z (ESI): 578.2 (M+H ⁺ )

¹ H NMR (400MHz, DMSO-d) δ10.86 (s, 1H), 8.57 (d, 1H, J = 5.5Hz), 8.37 (d, 1H, J = 1.8Hz), 7.96 (dd, 1H, J ＝2.0,5.6Hz),7.1-7.2(m,2H),5.13(d,1H,J＝10.1Hz),4.26(dd,1H,J＝7.8,9.9Hz),3.95(d,3H,J＝ 2.0Hz),3.0-3.1(m,1H),2.78(br t,1H,J＝7.6Hz),1.61(s,3H),1.14(br d,2H,J＝4.0Hz),1.0-1.1( m,2H),0.73(br d,3H,J＝5.9Hz)

Example 19: Preparation of target compound I-47

Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-fluoro-5-sulfamoylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-47)

The synthetic route of the target compound I-47 is as follows:

Step 1: Synthesis of benzyl(3-fluoro-5-nitrophenyl)sulfane

3,5-Difluoronitrobenzene (1C) (2.00 g, 12.6 mmol) and potassium carbonate (1.91 g, 13.8 mmol) were dissolved in N,N-dimethylformamide (20 mL), and benzyl mercaptan (1C-1) (1.56 g, 12.6 mmol, 1.48 mL) was added under nitrogen atmosphere at 0°C, and the reaction was stirred at 20°C for 3 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) under nitrogen atmosphere at 0°C, extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude benzyl (3-fluoro-5-nitrophenyl) sulfane (3.00 g, 11.4 mmol, 90.6% yield).

Step 2: Synthesis of 3-(benzylthio)-5-fluoroaniline

Benzyl (3-fluoro-5-nitrophenyl) sulfane (2.90 g, 11.0 mmol) was dissolved in anhydrous ethanol (30 mL) and water (5 mL), and iron powder (3.08 g, 55.1 mmol) and ammonium chloride (5.89 g, 110 mmol) were added, and the mixture was stirred at 70°C for 12 hours. After the reaction was complete, the crude product was filtered and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 50:1/20:1) to obtain a yellow solid 3-(benzylthio)-5-fluoroaniline (900 mg, 3.86 mmol, 35.0% yield).

LC-MS, M/Z (ESI): 234.2 (M+H ⁺ )

Step 3: Synthesis of (2R,3S,4S,5R)-N-(3-(benzylthio)-5-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (117 mg, 330 μmol) in N,N-dimethylformamide (3 mL), add n-butylphosphonic anhydride (50% in ethyl acetate) (476 mg, 661 μmol, 50% purity), N,N-diisopropylethylamine (128 mg, 991 μmol, 173 μL) and 3-(phenylmethylthio)-5-fluoroaniline (92.5 mg, 396 μmol), and stir at 25°C for 12 hours. After the reaction was complete, the mixture was dried and concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 2:1) to give (2R, 3S, 4S, 5R)-N-(3-(benzylthio)-5-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (130 mg, 228 μmol, 69.1% yield).

LC-MS, M/Z (ESI): 568.2 (MH ⁺ )

Step 4: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-fluoro-5-sulfamoylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-47)

Dissolve (2R,3S,4S,5R)-N-(3-(benzylthio)-5-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (120 mg, 211 μmol) in tetrahydrofuran (1 mL) and acetonitrile (0.5 mL), add glacial acetic acid (88.6 mg, 1.47 mmol, 84.4 μL) and water (53.1 mg, 2.95 mmol, 53.1 μL) dropwise at 0°C, add 1,3-dichloro-5,5-dimethylhydantoin (58.1 mg, 295 μmol), and stir at 0°C for 2 hours. Then add ammonia water (2.64 g, 21.1 mmol, 2.90 mL, 28% purity) at 0°C, and stir at 0°C for 2 hours. After the reaction was complete, the reaction solution was directly spin-dried to obtain a crude product, which was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: solvent A=water+0.1% ammonium bicarbonate, B=acetonitrile; gradient: 50%-80%, 9min) to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-fluoro-5-sulfamoylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30.1 mg, 56.7 μmol, 26.8% yield).

LC-MS, M/Z (ESI): 527.1 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.6 (s, 1H), 7.9-8.1 (m, 1H), 7.75 (td, 1H, J=2.0, 10.9 Hz), 7.49 (br s, 2H), 7.3-7.3 (m, 1H), 7.1-7.2 (m, 2H), 5.08 (d, 1H, J=10.3 Hz), 4.24 (dd, 1H, J=7.8, 10.1 Hz), 3.95 (d, 3H, J=2.1 Hz), 2.77 (t, 1H, J=7.6 Hz), 1.60 (s, 3H), 0.73 (br d, 3H, J=6.3 Hz) Example 20: Preparation of Target Compound I-48

5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-fluorophenylsulfamate (I-48)

The route of target compound I-48 is as follows:

Step 1: tert-Butyl (4-fluoro-3-hydroxyphenyl)carbamate

5-Amino-2-fluorophenol (1.00 g, 7.87 mmol) was dissolved in tetrahydrofuran (25 mL), and then di-tert-butyl dicarbonate (2.58 g, 11.8 mmol) was slowly added, and the reaction solution was stirred at 70°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and directly concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 2:1) to obtain tert-butyl (4-fluoro-3-hydroxyphenyl)carbamate (900 mg, yield 50%).

¹ H NMR (400MHz, CDCl3) δ7.04 (br d, J＝6.38Hz, 1H), 6.87 (t, J＝8.8Hz, 1H), 6.66-6.68 (m, 1H), 6.47 (s, 1H) ,6.05(br s,1H),5.72-6.26(s,1H),1.43(s,9H).

Step 2: 5-((tert-Butyloxycarbonyl)amino)-2-fluorophenylsulfamate

Dissolve sulfamoyl chloride (822 mg, 5.81 mmol) in acetonitrile (5 mL), slowly add formic acid (284 mg, 5.91 mmol) at 0 ° C, and stir the reaction solution at 0 ° C for 30 minutes. The reaction solution was diluted with acetonitrile (5 mL), and the reaction solution was stirred at 25 ° C for 2 hours. Then, a solution of tert-butyl (4-fluoro-3-hydroxyphenyl) (600 mg, 2.64 mmol) in N, N-dimethylacetamide (5 mL) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), and then extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain crude 5-((tert-butoxycarbonyl)amino)-2-fluorophenylaminosulfonate (400 mg, yield: 49.5%). The crude product was used directly in the next step.

LC-MS, M/Z (ESI): 329.0 (M+Na ⁺ )

Step 3: 5-amino-2-fluorophenylsulfamate

5-((tert-Butyloxycarbonyl)amino)-2-fluorophenylsulfamate (600 mg, 1.96 mol) was dissolved in ethyl acetate (2 mL), and then hydrochloric acid/ethyl acetate (30 mL, 2 M) was added, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, it was directly concentrated to obtain crude 5-amino-2-fluorophenylsulfamate (400 mg, yield: 99%).

LC-MS, M/Z (ESI): 207.1 (M+H ⁺ )

Step 4: 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-fluorophenylsulfamate

5-Amino-2-fluorophenylsulfamate (349 mg, 1.69 mmol) and (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (400 mg, 1.13 mmol) were dissolved in N, N-dimethylformamide (6 mL), and then N, N-diisopropylethylamine (1.09 g, 8.47 mmol) and n-butylphosphonic anhydride (1.63 g, 2.26 mmol, 50% content) were slowly added, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), and then extracted with ethyl acetate (10 mL*3), and the organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A=water+0.1%FA, B=acetonitrile; gradient: 53%-83%, 1min) to obtain a relatively pure product, and then separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Waters Xbridge 150* _25mm *5um; mobile phase: solvent A=water+0.1% _NH3H2O , B=acetonitrile; gradient: 28%-58%, 9min) to obtain 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-fluorophenylsulfamate (2.00 mg, yield: 0.30%)

¹ H NMR (400MHz, MeOD) δ7.79 (dd, J＝7.00, 2.64Hz, 1H), 7.45-7.49 (m, 1H), 7.21 (t, J＝9.46Hz, 1H), 7.13 (br t, J＝6.24Hz,1H),6.96-7.03(m,1H),5.04(d,J＝10.52Hz,1H),4.89-4.91(m,1H),4.59(s,1H),4.30(dd,J ＝10.38,8.38Hz,1H),4.00(d,J＝2.25Hz,3H),2.79(t,J＝7.57Hz,1H),1.66(s,3H),1.30(s,1H),0.79-0.85 (m,3H).

Example 21: Preparation of target compound I-49

(2R,3S,4S,5R)-N-(3-((1H-imidazol-2-yl)oxy)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-49)

The route of target compound I-49 is as follows:

Step 1: 2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

2-Chloroimidazole (800 mg, 614.25 μmol) was dissolved in tetrahydrofuran (4 mL), and sodium hydride (73.70 mg, 1.84 mmol) was slowly added at 0 ° C under nitrogen protection, and the reaction solution was stirred at 25 ° C for 1 hour. Then 2-(trimethylsilyl)ethoxymethyl chloride was slowly added dropwise to the reaction solution. Finally, the reaction solution was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was slowly added to saturated ammonium chloride (5 mL) at 0 ° C and nitrogen protection for quenching, and then extracted with ethyl acetate (10 mL*3), the organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 2:1) to obtain the target compound 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.20 g, yield: 66%)

Step 2: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (600 mg, 1.69 mmol) and 5-amino-2-fluorophenol (258 mg, 2.03 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then N,N-diisopropylethylamine (1.09 g, 8.47 mmol) and n-butylphosphonic anhydride (50% ethyl acetate solution, 3.66 g, 5.08 mmol) were slowly added, and the reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, water (30 mL) was added to the reaction solution to quench it, and then it was extracted with ethyl acetate (10.0 mL*3). The organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude yellow solid. The crude product was purified by prep-TLC (mobile phase: ethyl acetate: petroleum ether = 1:1) to obtain (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (620 mg, yield: 79%).

LC-MS, M/Z (ESI): 464.1 (M+H ⁺ )

Step 3: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (250 mg, 539 μmol) and 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (188 mg, 809 μmol) were dissolved in N,N-diisopropylethylamine (2 mL), and the reaction solution was stirred at 140°C for 72 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), and then extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude yellow solid product, which was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A=water+0.1% FA, B=acetonitrile; gradient: 68%-98%, 1min) to give a white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25.0 mg, yield 7.02%).

LC-MS, M/Z (ESI): 660.2 (M+H ⁺ )

Step 4: (2R,3S,4S,5R)-N-(3-((1H-imidazol-2-yl)oxy)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-49)

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20.0 mg, 30.3 μmol) was dissolved in dichloromethane (2 mL) and ethanol (0.2 mL), and then trifluoroacetic acid (36.4 mg, 303 μmol) was added, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, it was directly concentrated to obtain a crude product as a yellow solid. The crude product was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A=water+0.1% FA, B=acetonitrile; gradient: 43%-73%, 1 min) to obtain (2R,3S,4S,5R)-N-(3-((1H-imidazole-2-yl)oxy)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (3.00 mg, yield: 18.4%).

LC-MS, M/Z (ESI): 530.3 (M+H ⁺ )

¹ H NMR (400MHz, CD ₃ OD) δ7.59-7.69(m,1H),7.35-7.46(m,1H),7.20(dd,J＝10.2,9.08Hz,1H),7.09-7.15(m, 1H),6.94-7.04(m,1H),6.65-6.80(m,2H),4.98-5.10(m,1H),4.29(dd,J＝10.32,8.08Hz,1H),4.00(d,J＝ 2.26Hz,3H),2.74-2.83(m,1H),1.66(s,3H),0.77-0.86(m,3H).

Example 22: Preparation of target compound I-50

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-{[dimethyl(oxo)-λ6-sulfylidene]amino}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-50)

The route of target compound I-50 is as follows:

Step 1: Synthesis of tert-butyl N-(2-{[dimethyl(oxo)-λ6-thio]amino}pyridin-4-yl)carbamate

Tert-butyl (2-bromopyridin-4-yl)carbamate (500 mg, 1.83 mmol), iminodimethyl-16-sulfone (205 mg, 2.20 mmol) and cesium carbonate (1.19 g, 3.66 mmol) were dissolved in 1,4-dioxane (10 mL), and then tris(dibenzylideneacetone)dipalladium (168 mg, 183 μmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (212 mg, 366 μmol) were added, and the reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, the reaction solution was poured into water (40 mL) at 0°C, and then extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 10:1/0:1) to obtain tert-butyl N-(2-{[dimethyl(oxo)-λ6-thio]amino}pyridin-4-yl)carbamate (275 mg, 964 μmol, 52.6% yield).

LC-MS, M/Z: 286.0 (M+H ⁺ )

Step 2: Synthesis of [(4-aminopyridin-2-yl)imino]dimethyl-λ6-sulfone

Dissolve tert-butyl N-(2-{[dimethyl(oxo)-λ6-imino]amino}pyridin-4-yl)carbamate (257 mg, 900 μmol) in dichloromethane (2.00 mL), then add trifluoroacetic acid (1.54 g, 13.5 mmol, 1 mL) at 0°C, and stir the reaction solution at 25°C for 2 hours. After the reaction is completed, pour the reaction solution into a saturated sodium bicarbonate aqueous solution (40 mL) at 0°C, then extract with dichloromethane:methanol=10:1 (50 mL*5), wash the organic phase with a saturated sodium chloride solution (20 mL), dry it over anhydrous sodium sulfate, and filter and concentrate to obtain a crude product [(4-aminopyridin-2-yl)imino]dimethyl-λ6-sulfone (120 mg, 648 μmol, 71.9% yield). The crude product is used directly in the next step.

LC-MS, M/Z: 185.9 (MH ⁺ )

Step 3: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-{[dimethyl(oxo)-λ6-sulfylidene]amino}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-50)

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (90.0 mg, 254 μmol) and [(4-aminopyridin-2-yl)imino]dimethyl-λ6-sulfone (4) (47.1 mg, 254 μmol) were dissolved in acetonitrile (3 mL), and then N,N-diisopropylethylamine (98.5 mg, 762 μmol, 133 μL) was added. n-Butylphosphoric anhydride (50% ethyl acetate solution) (366 mg, 508 μmol, 50% content) was dropped into the reaction solution at 0°C, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) under a nitrogen atmosphere at 0°C, extracted with ethyl acetate (15 mL*3), the organic phase was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Welch Xtimate C18 150*25mm*5um; mobile phase: solvent A=water+0.1% FA, B=acetonitrile; gradient: 25%-45%, 10min) to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-{[dimethyl(oxo)-λ6-thioyl]amino}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20.0 mg, 38.24 μmol, 15.0% yield, 99.7% purity).

¹ H NMR (400MHz, CDCl ₃ ) δ8.38 (s, 1H), 8.09 (d, J = 5.8Hz, 1H), 7.17-7.12 (m, 1H), 7.11-7.04 (m, 1H), 6.94- 6.85(m,2H),4.98(d,J＝10.9Hz,1H),4.12-4.04(m,1H),4.00(d,J＝2.6Hz,3H),3.34(s,6H),2.70-2.75 (m,1H),1.66(s,3H),0.84-0.74(m,3H)

Example 23: Preparation of target compound I-51

S-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-fluorophenyl)thiocarbamate (I-51)

The route of target compound I-51 is as follows:

Step 1: 2-Fluoro-5-nitrobenzenesulfonyl chloride

Dissolve p-fluoronitrobenzene (30.0 g, 212 mmol) in chlorosulfonic acid (10 mL), replace with nitrogen three times, and stir the reaction solution at 100 ° C for 12 hours. After the reaction is completed, cool to room temperature, slowly add the reaction solution to water (1 L) at 0 ° C for quenching, and then extract with ethyl acetate (300 mL * 3), wash the organic phase with saturated sodium chloride solution (500 mL) and dry it with anhydrous sodium sulfate, filter and concentrate to obtain a crude product. The crude product is separated and purified by column chromatography (mobile phase is petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 2-fluoro-5-nitrobenzenesulfonyl chloride (20.0 g, yield: 39.2%).

Step 2: 5-Amino-2-fluorobenzenethiol

2-Fluoro-5-nitrobenzenesulfonyl chloride (20.0 g, 83.5 mmol) was dissolved in concentrated hydrochloric acid (100 mL), and tin dichloride-dihydrate (94.2 g, 417 mmol) was slowly added in batches, replaced with nitrogen three times, and the reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (1 L) at 0 ° C for quenching, and then extracted with dichloromethane (1 L * 3), and the organic phase was washed with a saturated sodium chloride solution (500 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase was petroleum ether: ethyl acetate = 10:1-1:1) to obtain 5-amino-2-fluorobenzenethiol (3.00 g, yield: 25.1%).

Step 3: 3,3'-disulfide bis(4-fluoroaniline)

5-Amino-2-fluorobenzenethiol (3.00 g, 20.9 mmol) was dissolved in dimethyl sulfoxide (30 mL), replaced with nitrogen three times, and the reaction solution was stirred at 80 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was diluted with water (100 mL) at 0 ° C, and then extracted with ethyl acetate (30 mL * 3). The organic phase was washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase was petroleum ether: ethyl acetate = 10: 1-1: 1) to obtain 3,3'-disulfide bis (4-fluoroaniline) (1.20 g, yield: 20.1%).

¹ H NMR (400MHz, DMSO-d6) δ6.93 (t, J＝9.20Hz, 2H), 6.76 (dd, J＝6.50, 2.76Hz, 2H),

6.49(ddd,J＝8.70,4.12,2.80Hz,2H),5.18(s,4H).

Step 4: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-N-[3-[[5-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-2-fluoro-phenyl]disulfide]-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (500 mg, 1.41 mmol) and N,N-dimethylformamide (10.3 mg, 141 μmol) were dissolved in dichloromethane (10 mL). Under nitrogen protection, oxalyl chloride (358 mg, 2.82 mmol) was slowly added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 25°C for 1 hour. After the reaction is completed, the reaction solution is directly concentrated (diluted with dichloromethane several times and then concentrated), then diluted in dichloromethane (10mL), slowly added dropwise to a dichloromethane (10mL) solution of 3,3'-disulfanyldi(4-fluoroaniline) and triethylamine (428mg, 4.23mmol) at 0°C, and the reaction solution is stirred at 25°C for 12 hours. After the reaction is completed, it is diluted with water (20mL), then extracted with dichloromethane (10mL*3), the organic phase is washed with a saturated sodium chloride solution (10mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1-2:1) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-N-[3-[[5-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-2-fluoro-phenyl]disulfide]-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (450 mg, yield: 33.3%).

LC-MS, M/Z (ESI): 957.1 (M+H ⁺ )

Step 5: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-mercaptophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-N-[3-[[5-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-2-fluoro-phenyl]disulfide]-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (430 mg, 449 μmol) was dissolved in tetrahydrofuran (8 mL). Under nitrogen protection, tributylphosphine (272 mg, 1.35 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (10 mL*3), the organic phase was washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1-1:1) to obtain (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-mercaptophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (340 mg, yield: 78.9%).

LC-MS, M/Z (ESI): 480.0 (M+H ⁺ )

¹ H NMR (400MHz, DMSO-d6) δ10.25(s,1H),7.78(dd,J＝7.00,2.50Hz,1H),7.30(ddd,J＝8.86,4.42,2.64Hz,1H),7.07 -7.23(m,3H),5.05(d,J＝10.40Hz,1H),4.21-4.25(m,1H),3.95(d,J＝2.14Hz,3H),2.50-2.83(m,1H), 1.59(s,3H),0.72(br d,J＝5.88Hz,3H).

Step 6: S-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-fluorophenyl)thiocarbamate (I-51)

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-mercaptophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (257 mg, 1.35 mmol) was dissolved in acetonitrile (4 mL). Chlorosulfonic acid isocyanate (571 mg, 5.65 mmol) was slowly added dropwise at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, water (1 mL) was slowly added dropwise at 0°C. Finally, the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, it was directly concentrated to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A=water+0.1%TFA, B=acetonitrile; gradient: 48%-78%, 9min) to obtain S-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-fluorophenyl)thiocarbamate (5.00 mg, yield: 2.27%).

¹ H NMR (400MHz, DMSO-d6) δ10.34 (s, 1H), 7.81 (dd, J = 6.50, 2.64Hz, 2H), 7.51-7.78 (m, 2H), 7.25 (t, J = 8.8Hz ,1H),7.07-7.20(m,2H),5.05(d,J＝10.38Hz,1H),4.23(dd,J＝10.14,7.64Hz,1H),3.94(d,J＝2.14Hz,3H) ,2.68-2.86(m,1H),1.59(s,3H),0.72(brd,J＝6.00Hz,3H).

Example 24: Preparation of target compound I-52

Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-52)

The synthetic route of target compound I-52 is as follows:

Step 1: Synthesis of 2-hydrazino-5-nitropyridine

At room temperature, 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol) was dissolved in ethanol (50 mL), cooled to 0°C, and then hydrazine hydrate (5.57 g, 94.6 mmol, 85% w/w) was added dropwise, and then heated to 60°C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was rinsed with ethanol (10 mL*3) and dried to obtain 2-hydrazine-5-nitropyridine (4.60 g, yield 94.6%).

LC-MS, M/Z (ESI): 155.1 (M+H ⁺ )

Step 2: Synthesis of tert-butyl 2-(5-nitropyridin-2-yl)hydrazine-1-carboxylate

2-Hydrazino-5-nitropyridine (1.00 g, 6.49 mmol) was dissolved in dioxane (20 mL) and N,N-dimethylformamide (1 mL), and triethylamine (1.74 g, 17.2 mmol) and di-tert-butyl carbonate (2.38 g, 10.8 mmol) were added, and the reaction solution was stirred at 110°C for 1 hour. After the reaction was completed, water (20 mL) was added to quench, and ethyl acetate (10 mL*3) was used for extraction. The organic phase was washed with saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a crude product. The crude product was purified by chromatography column (petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain tert-butyl 2-(5-nitropyridin-2-yl)hydrazine-1-carboxylate (1.56 g, 92.1% yield).

Step 3: Synthesis of tert-butyl 2-(5-aminopyridin-2-yl)hydrazine-1-carboxylate

Dissolve tert-butyl 2-(5-nitropyridin-2-yl)hydrazine-1-carboxylate (1.50 g, 8.90 mmol) in ethanol (15 mL), add 10% palladium carbon (150 mg, 141 umol) under argon protection, replace hydrogen three times, and stir the reaction solution at 30 Psi and 25 ° C for 12 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated and dried to obtain tert-butyl 2-(5-aminopyridin-2-yl)hydrazine-1-carboxylate (1.20 g, 90.9% yield).

LC-MS, M/Z (ESI): 225.1 (M+H ⁺ )

Step 4: Synthesis of tert-butyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1-carboxylate

At room temperature, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (300 mg, 846 umol) was dissolved in dichloromethane (6 mL), cooled to 0°C, and oxalyl chloride (161 mg, 1.27 mmol) was added dropwise. After stirring for 2 hours, the reaction solution was concentrated to dryness, and dichloromethane (6 mL) was added to dissolve. Triethylamine (171 mg, 1.69 mmol) and tert-butyl 2-(5-aminopyridin-2-yl)hydrazine-1-carboxylate (208 mg, 931 umol) were added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (5 mL*3). The organic phase was washed with a saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was purified by chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain tert-butyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1-carboxylate (110 mg, 23.1% yield).

LC-MS, M/Z (ESI): 561.2 (M+H ⁺ )

Step 5: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-hydrazinopyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

At room temperature, tert-butyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1-carboxylate (100 mg, 178 umol) was dissolved in ethyl acetate (2 mL), and ethyl acetate hydrochloride (2 mL, 2M) was added, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-hydrazinopyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (100 mg, crude product).

LC-MS, M/Z (ESI): 461.2 (M+H ⁺ )

Step 6: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-52)

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-hydrazinopyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (90.0 mg, 195 μmol) was dissolved in tetrahydrofuran (2 mL), and carbonyldiimidazole (38.0 mg, 234 μmol) and triethylamine (39.5 mg, 390 μmol) were added, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, water (5 mL) was added to quench, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phase was washed with a saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25 mm*5 um; mobile phase: solvent A = water + 0.1% NH ₃ ·H ₂ O, B = acetonitrile; gradient: 23%-53%, 10 min) to obtain (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (I-52) (24.8 mg, yield 23.8%)

LC-MS, M/Z (ESI): 487.2 (M+H ⁺ )

¹ H NMR (400MHz, CD ₃ OD) δ8.50 (s, 1H), 7.28 (d, J = 2Hz, 1H), 7.17-7.22 (m, 1H), 7.09-7.15 (m, 1H), 6.94- 7.02(m,1H),5.06(d,J＝10.4Hz,1H),4.31(dd,J＝10.4Hz,8.8Hz,1H),4.00(d,J＝2.4Hz,3H),2.75-2.82( m,1H),1.66(s,3H),0.80-0.82(m,3H).

Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

All reagents except NaOH and KOH for acid-base titration were purchased from Sigma (St. Louis, MO). The final concentrations of the test compounds were prepared on the day and dissolved in the extracellular solution. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl ₂ , 1.8; MgCl ₂ , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 1 μM TTX. The intracellular solution (mM) was: aspartic acid, 140; magnesium chloride, 2; ethylene glycol tetraacetic acid (EGTA), 11; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10. The pH was adjusted to 7.4 with cesium hydroxide.

The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM and redissolved in the extracellular fluid on the day of the test to prepare the required concentration.

Electrophysiological experimental steps:

Transfer the cells to the perfusion tank and perfuse with extracellular solution. The intracellular solution was thawed on the day of the experiment. The electrodes were pulled with PC-10 (Narishige, Japan). Whole-cell patch clamp recording was performed, and the noise was filtered at one-fifth of the sampling frequency. 1/4 of the length of the electrode tube was added to the electrode, and the electrode was installed on the probe. Set the required protocol, adjust the interface to Membrane test, and adjust the stage to Bath. Apply positive pressure to the electrode, touch the tip of the electrode to the cell, adjust the three-way valve of the suction device to the three-way state, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Adjust the stage to Patch, control the leak within -200pA, and continue to apply negative pressure to rupture the cell membrane and form a current path. Open the suction device and the extracellular solution valve to perfuse, observe the cell current, and start adding drugs when the cell current is stable (at least 3 sweeps of the current curve overlap). Add drugs from low concentration to high concentration, and the drug addition time for each concentration should be no less than 2min, and wait until the current is stable before changing the concentration.

The test article is administered by perfusion using a perfusion system that uses its own gravity. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude the ups and downs of the initial current. The average of the peak current amplitudes recorded in the last 10 times during the initial recording period is used as the current peak of the negative control. After the initial current stabilizes, the test sample is administered from a low concentration until the peak current recorded in 10 times stabilizes again or after continuous administration for 5 minutes, the peak current after administration is "unchanged" from that before administration. We define the following two situations as "stable" or "unchanged": 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA and the CV value is less than 10%, 2) or the average of the peak current for 10 consecutive scans is between 200pA and 50pA and the CV value is less than 30%. Then the next higher concentration is administered for testing.

The peak current average of the last 10 scans for each concentration is used as the peak current for data analysis. If a steady state cannot be reached within 5 minutes, the peak current average of the last 10 scans at this time is used as the peak current for data analysis. At the same time, the cell should be discarded and no longer used for detection of higher concentrations. At least two cells are tested for each concentration of the compound.

Voltage pulse procedure:

The cells were clamped at -80 mV and then depolarized to 10 mV with a 10 ms square wave to obtain NaV1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was measured, and after it stabilized, the test compound was perfused. When the response stabilized, the intensity of the blockade was calculated.

Data processing and fitting

Data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the current variation over time within a limited range. By plotting the dose-effect relationship between the drug's gradient dilution series concentration and the stable current value generated by its action on HEK293/Nav1.8,

Then the inhibitory activity (IC ₅₀ ) of the drug on Nav1.8 ion channel was calculated.

Compounds IC ₅₀ (nM) 1nM inhibition rate I-6 1.99 / I-13 0.41 73% I-26 0.15 91% I-27 / 83% I-30 / 71% I-43 / 88% I-47 0.43 /

The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims (11)

1. A compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, Ring A is selected from 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 6-membered heterocycloalkenyl, 9-10-membered aryl or 9-10-membered heteroaryl; the 5-membered heteroaryl, 3-7-membered heterocycloalkyl, 9-10-membered aryl or 9-10-membered heteroaryl is optionally substituted by one or more R ^a3 , when R ^a3 is multiple, they are the same or different; R ^a3 is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl, -OR ¹¹ , -C(O)NR ⁹ R ¹⁰ , or -S(O) ₂ R ⁷ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, -C(O)C ₁ -C ₆ alkyl is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ; Alternatively, two R ^a3 attached to the same atom combine to form =O; Alternatively, two R ^{a3 groups} attached to adjacent atoms are combined with the atoms to which they are attached to form a fused 3-7 membered ring containing at most two heteroatoms selected from N, O and S; X ^2a is selected from N, N ⁺ —O ^— or CR ^2a ; X ^3a is selected from N, N ⁺ -O ^- or CR ^3a ; X ^4a is selected from N, N ⁺ —O ^— or CR ^4a ; X ^5a is selected from N, N ⁺ —O ^— or CR ^5a ; or N ⁺ —(C ₁ -C ₆ alkyl)Y ⁻ , wherein Y ⁻ is a monovalent anion; X ^6a is selected from N, N ⁺ -O ^- or CR ^6a ; R ^2a is selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; R ^3a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl, -CN, -OR ¹¹ , -COOH, -C(O)NR ⁹ R ¹⁰ , -C(═NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ , -S(O) ₂ R ⁷ , -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -S(O) ₂ NR ⁹ R ¹⁰ , -S(O)R ⁷ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , -C(O)NR ⁷ NR ⁹ R ¹⁰ , -C(O)-C(O)NR ⁹ R ¹⁰ , -C(O)NR ⁷ S(O) ₂ R ⁹ , -OS(O) ₂ NR ⁹ R ¹⁰ , -N＝S(O)R ⁹ R ¹⁰ , -SC(O)-NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ ; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-9 membered heterocycloalkyl, 5-membered heteroaryl or -NR ⁹ C(O)C ₁ -C ₆ alkyl is optionally substituted by one or more R ¹² , C ₃ -C ₆ cycloalkyl, -NR ⁹ R ¹⁰ , -OR ¹¹ , -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R ¹² ; R ^4a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C(O)NR ⁹ R ¹⁰ , -C(O)OH, -OR ¹¹ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O)(NR ⁹ )R ⁷ , -S(O)NR ⁹ R ¹⁰ , -NR ⁷ C(O)NR ⁹ R ¹⁰ , or -P(O)(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl, or -S(O) ₂ R ⁷ ; R ^5a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -S(O) ₂ R ⁷ ; R ^6a is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; or R ^3a and R ^4a together with the atoms to which they are attached form a ring selected from the following formulae: ^R7 is selected from C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated alkyl, _C3 - _C6 cycloalkyl, C3 _{- C6} halocycloalkyl, or 3-7 membered heterocycloalkyl, wherein the _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted with one or more ^-OR11 or _C1 - _C6 alkyl; R ⁸ is selected from H, -C(O)NR ⁹ R ¹⁰ or C ₁ -C ₆ alkyl; R ⁹ and R ¹⁰ are each independently selected from H, C ₁ -C ₆ alkyl, 3-7 membered heterocycloalkyl, C ₃ -C ₆ cycloalkyl, -OR ¹¹ , -OH, -CN or -S(O) ₂ R ⁷ , wherein said C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, -OR ¹¹ ; or R ⁹ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl; Each R ¹¹ is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl optionally substituted with -NH ₂ , 3-7 membered heterocycloalkyl optionally substituted with -OH, or 3-7 membered cycloalkyl optionally substituted with -OH; Each R ¹² is independently selected from halogen, C ₁ -C ₆ alkyl or -OR ¹¹ ; or two R ¹² together with the atoms to which they are attached form an oxo group; Each R ¹³ is independently selected from halogen, C ₁ -C ₆ alkyl or -CONH ₂ , wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OR ¹¹ , or two R ¹³ together with the atoms to which they are attached form oxo; W is selected from a single bond, Imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole; R ^4b1 and R ^4b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl; R ^5b1 and R ^5b2 are each independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl; Alternatively, R ^5b1 and R ^5b2 together with _the atoms to which they are attached form a C _{3 -C 6} saturated ring, which is optionally substituted with one or more halogen, -OR ¹¹ , -CN or -NR ⁹ R ¹⁰ ; R ^6b is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy; R ^7b is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy; X ^3c is selected from N or CR ^3c ; X ^4c is selected from N or CR ^4c ; X ^5c is selected from N or CR ^5c ; X ^6c is selected from N or CR ^6c ; R ^2c is selected from H, -OH, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ haloalkoxy, -L ¹ -(C ₁ -C ₆ alkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkenylene)-OR ¹⁵ , -L ¹ -(C ₁ -C ₆ alkylene)-NR ¹⁶ R ¹⁷ , -L ¹ -(C ₁ -C ₆ alkylene)-N＝S(O)(C ₁ -C ₃ alkyl) ₂ , -L ¹ -(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C 3 alkyl) 2 ₆ alkyl) or L ¹ -L ² -R ¹⁴ , -NR ¹⁶ R ¹⁷ ; R ¹⁴ is selected from C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)O(C ₁ -C ₆ alkyl), -COOH, or -C(O)NR ¹⁶ R ¹⁷ , wherein the C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy; R ¹⁵ is selected from H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ¹⁶ and R ¹⁷ are each independently H, -OH, C ₁ -C ₆ alkyl or 3-7 membered heterocycloalkyl; R ^3c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy); R ^4c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ^5c is selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and R ^6c is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxy; L ¹ is a bond or O; L ² is a bond or a C ₁ -C ₆ alkylene group; and no more than 2 X ^2a , X ^3a , X ^4a , X ^5a and X ^6a are selected from N or N ⁺ -O ^- ; and no more than one of X ^3c , X ^4c , X ^5c and X ^6c is N; and R ^4a is not CH(OH)-R ^4a' , wherein R ^4a' is H or C 1 -C 5 alkyl optionally substituted with one or more halogen, -OR ¹¹ , 3-7 membered heterocycloalkyl, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl _, or -S ₍ O) ₂ R ⁷ . 2. The compound represented by formula (II) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R ^2c is C ₁ -C ₆ alkoxy; preferably, R ^2c is methoxy, ethyloxy, n-propyloxy, isopropyloxy, more preferably, R ^2c is methoxy; and/or, R ^3c is halogen; preferably, R ^3c is F or Cl; more preferably, R ^3c is F; and/or, R ^4c is halogen; preferably, R ^4c is F or Cl; more preferably, R ^4c is F; Preferably, R ^2c is -L ¹ -(C ₁ -C ₆ haloalkylene)-OR ¹⁵ or -L ¹ -(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C ₆ alkyl); Preferably, R ^2c is -O-(CH ₂ CF ₂ CH ₂ )-OH or -O-(CH ₂ CH ₂ )-S(O) ₂ CH ₃ ; and/or, R ^3c is halogen; preferably, R ^3c is F or Cl; more preferably, R ^3c is F; and/or, R ^4c is halogen; preferably, R ^4c is F or Cl; more preferably, R ^4c is F; Preferably, R ^2c is C ₁ -C ₆ alkoxy, C ₁ -C ₆ deuterated alkoxy, -O-(C ₁ -C ₆ haloalkylene)-OR ¹⁵ , -O-(C ₁ -C ₆ alkylene)-S(O) ₂ (C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl); R ¹⁵ is selected from H, methyl, ethyl, propyl; Preferably, R ^2c is methoxy, dimethylamino, trideuterated methoxy, 3. The compound represented by formula (II) according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R ^5b1 and R ^5b2 are each independently selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; Alternatively, R ^5b1 and R ^5b2 together with the atoms to which they are attached form a C ₃ -C ₆ saturated ring, wherein the C ₃ -C ₆ saturated ring is optionally substituted with one or more halogens; and/or, R ^4b1 is H; and/or, R ^4b2 is C ₁ -C ₆ alkyl; preferably, R ^4b2 is methyl, ethyl, n-propyl, isopropyl; more preferably, R ^4b2 is methyl; Preferably, R ^5b1 and R ^5b2 are each independently selected from methyl or trifluoromethyl; Alternatively, R ^5b1 and R ^5b2 together with the atoms to which they are attached form a C ₃ -C ₆ saturated ring, and the C ₃ -C ₆ saturated ring is optionally substituted by 1-2 halogens; preferably, the halogen is F or Cl; Preferably, R ^5b1 and R ^5b2 together with the atoms to which they are attached form (like ), (like ), (like ), 4. The compound represented by formula (II) according to any one of claims 1 to 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that R ^2a is selected from H, F; Preferably, R ^3a is selected from Preferably, R ^4a is selected from H and F. 5. The compound represented by formula (II) according to any one of claims 1 to 4, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that W is * indicates connection with ring A; Preferably, for Better, for Better, for Preferably, R ¹¹ is NH ₂ -substituted pyrimidinyl, for example 6. The compound represented by formula (II) according to any one of claims 1 to 5, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Ring A is Preferably, ring A is Wherein, R ^2a is selected from halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; Preferably, X ^5a is CH; and/or, R ^2a is halogen; preferably, R ^2a is F or Cl; more preferably, R ^2a is F; Preferably, ring A is Preferably, ring A is Preferably, ring A is Preferably, X ^4a is N or CR ^4a ; Preferably, R ^4a is halogen; More preferably, R ^4a is F; and/or, R ⁷ is C ₁ -C ₆ deuterated alkyl; preferably, R ⁷ is C ₁ -C ₃ deuterated alkyl; more preferably, R ⁷ is deuterated methyl, such as trideuterated methyl; and/or, R ⁹ is H, R ¹⁰ is H; Preferably, ring A is Preferably, X ^2a , X ^5a and X ^6a are CH; Preferably, ring A is in; X ^4a is N or CR ^4a ; preferably, R ^4a is H or halogen; more preferably, R ^4a is H or F; R ^3a is selected from -S(O) ₂ -NH ₂ , -S(O) ₂ -R ⁷ , -CONH-R ¹⁰ , -C(═NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ or R ⁷ is C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ⁷ is cyclopropyl or cyclobutyl; R ⁹ is H or C ₁ -C ₆ alkyl; preferably, R ⁹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ⁹ is H or methyl; R ¹⁰ is H, -OR ¹¹ or C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more halogen, -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ¹⁰ is H, -OR ¹¹ , cyclopropyl or cyclobutyl, the cyclopropyl and cyclobutyl are optionally substituted by one or more -OH; R ¹¹ is H or C ₁ -C ₆ alkyl; preferably, R ¹¹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ¹¹ is H or methyl; Preferably, ring A is Preferably, ring A is R ^a3 is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; preferably, R ^3a is selected from H or C ₁ -C ₃ alkyl; more preferably, R ^a3 is methyl; Preferably, ring A is ^Ra3 is selected ^{from -OR11} , -C(O) ^NR9R10 or ^-S (O) _2R7 , ^R7 , ^R9 , ^R10 and ^R11 are independently defined as above; preferably, ^Ra3 is -C(O) _NH2 ; Preferably, ring A is R ^a3 is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; preferably, R ^3a is selected from H or C ₁ -C ₃ alkyl; more preferably, R ^a3 is H; Preferably, ring A is in; X ^4a is N ⁺ -O ^- , N or CR ^4a ; preferably, R ^4a is H or halogen; more preferably, R ^4a is H or F; R ^3a is selected from -S(O) ₂ -NH ₂ , -N=S(O)(CH ₃ ) ₂ , -S-CONH ₂ , -OS(O) ₂ -NH ₂ , -CONHNH ₂ , -COCONH ₂ , -CONH, -S(O) ₂ -R ⁷ , -CONH-R ¹⁰ , -C(=NH)-NR ⁹ R ¹⁰ , -N(R ⁹ )-COR ¹⁰ , R ^5a is selected from H or halogen; preferably, R ^5a is H or F; R ⁷ is C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ⁷ is cyclopropyl or cyclobutyl; R ⁹ is H or C ₁ -C ₆ alkyl; preferably, R ⁹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ⁹ is H or methyl; R ¹⁰ is H, -OR ¹¹ or C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is optionally substituted by one or more halogen, -OR ¹¹ or C ₁ -C ₆ alkyl; preferably, R ¹⁰ is H, -OR ¹¹ , cyclopropyl or cyclobutyl, the cyclopropyl and cyclobutyl are optionally substituted by one or more -OH; R ¹¹ is H or C ₁ -C ₆ alkyl; preferably, R ¹¹ is H, methyl, ethyl, n-propyl or isopropyl; more preferably, R ¹¹ is H or methyl. 7. The compound represented by formula (II) according to any one of claims 1 to 6, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Ring A is selected from 8. The compound represented by formula (II) according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound represented by formula (II) is wherein ring A, W, R ^2c , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , X ^3c , X ^4c , X ^5c , and X ^6c are independently defined as in any one of claims 1 to 7; Preferably, the compound represented by formula (II) is wherein ring A, W, R ^2c , R ^3c , R ^4c , R ^4b1 , R ^4b2 , R ^5b1 , and R ^5b2 are independently defined as in any one of claims 1 to 7; wherein ring A, W, R ^2c , R ^4c , R ^4b1 , R ^4b2 , R ^5b1 , and R ^5b2 are independently defined as in any one of claims 1 to 7; Preferably, R ^2c is C ₁ -C ₆ deuterated alkoxy; Preferably, R ^2c is -O-CD ₃ ; and/or, R ^4c is halogen; preferably, R ^4c is F or Cl; more preferably, R ^4c is F; and/or, R ^5c is halogen; preferably, R ^5c is F or Cl; more preferably, R ^5c is F; Preferably, the compound represented by formula (II) is wherein ring A, W, R ^2c , R ^3c , R ^4c , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , and R ^7b are independently defined as in any one of claims 1 to 7; Preferably, R ^6b is selected from H, halogen, C ₁ -C ₆ alkyl; preferably, R ^6b is selected from H, F, Cl, methyl, ethyl; more preferably, R ^6b is selected from H, F, methyl; R ^7b is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; preferably, R ^7b is selected from H, F, Cl, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy; more preferably, R ^7b is selected from H, F, methyl, trifluoromethyl, methoxy; and R ^6b and R ^7b are not H at the same time; Preferably, the compound represented by formula (II) is: wherein ring A, W, R ^2c , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , X ^3c , X ^4c , X ^5c , and X ^6c are independently defined as in any one of claims 1 to 7; Preferably, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: wherein ring A, W, R ^2c , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , X ^3c , X ^4c , X ^5c , and X ^6c are independently defined as in any one of claims 1 to 7; Preferably, the compound represented by formula (II) is: wherein R ^3a , R ^4a , R ^2c , R ^3c , R ^4c , R ^4b1 , R ^4b2 , R ^5b1 , and R ^5b2 independently have the meanings as defined in any one of claims 1 to 7. 9. The compound represented by formula (II) according to any one of claims 1 to 8, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound represented by formula (II) is selected from the following compounds: 10. A pharmaceutical composition, characterized in that it comprises a compound represented by formula (II) according to any one of claims 1 to 9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable excipient. 11. Use of the compound of formula (II) as described in any one of claims 1 to 9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition as described in claim 10 in the preparation of a drug for inhibiting voltage-gated sodium ion channels and/or in the preparation of a drug for treating, alleviating or preventing pain; Preferably, the voltage-gated sodium ion channel is Nav1.8; Preferably, the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.