Heterocyclic compound as well as preparation method and medical application thereof

Abstract

The invention relates to a heterocyclic compound, a preparation method thereof and application of the heterocyclic compound in medicine. Specifically, the invention relates to a heterocyclic compound as shown in a general formula (I), a preparation method of the heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound and application of the heterocyclic compound as a therapeutic agent, in particular to application of the heterocyclic compound as a Nav inhibitor and application of the heterocyclic compound in preparation of drugs for treating and / or relieving pain and pain-related diseases. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Heterocyclic compounds, preparation methods thereof and their applications in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to a heterocyclic compound, a method for preparing the same, and its use in medicine. In particular, the present disclosure relates to a heterocyclic compound represented by general formula (I), a method for preparing the same, and a pharmaceutical composition containing the same, as well as its use as a Nav inhibitor and its use in the preparation of a medicament for treating and / or alleviating pain and pain-related diseases. Background Art

[0002] Pain is a complex physiological and psychological process and one of the most common clinical symptoms. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience, accompanied by actual or potential tissue damage, which is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers and playing an indispensable protective role in 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, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life. Statistics show that approximately one in five people worldwide suffers from moderate to severe chronic pain.

[0003] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings that are widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They can convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies located in the dorsal root ganglia (DRG), ultimately transmitting them to higher nerve centers, causing pain. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane depolarizes, sodium ion channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and relieve pain.

[0004] Nav is a class of transmembrane ion channel proteins. These proteins are composed of a 260 kDa α subunit and a 30-40 kDa β subunit. Based on the identity of the α subunit, they can be divided into nine subtypes, Nav1.1 to Nav1.9. Different subtypes exhibit distinct tissue distributions and electrophysiological and pharmacological characteristics (Rush AM, et al. J. Physiol. 2007, 579, 1–14). Sodium channels are classified as TTX-sensitive (TTX-S) or TTX-insensitive (TTX-R) based on their ability to be effectively inhibited by nanomolar tetrodotoxin (TTX). Nav1.1, Nav1.2, Nav1.3, and Nav1.7 are TTX-S subtypes, with their encoding genes located on human chromosomes 2q23-24. They are abundantly expressed in neurons. Nav1.5, Nav1.8, and Nav1.9 are TTX-R subtypes, with their encoding genes located on human chromosomes 3p21-24. Among them, Nav1.5 is primarily found in cardiac myocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system (Goldin A.L., et al. Annu. Rev. Physiol. 2001, 63, 871–894). Nav1.4 and Nav1.6 are both TTX-S-type and are abundant in skeletal muscle and the central nervous system, respectively (Fozzard HA, et al. Physiol. Rev. 1996, 76, 887–926). The local anesthetic lidocaine relieves pain by inhibiting Nav. Non-selective Nav inhibitors, such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat chronic pain.

[0005] Nav1.8 is a TTX-R type protein encoded by the gene SCN10A. It is primarily found in trigeminal ganglion and DRG neurons and exhibits electrophysiological characteristics of slow inactivation and rapid recovery (Dib-Hajj SD, et al. Annu. Rev. Neurosci. 2010, 33, 325–347). In neurons expressing Nav1.8, the rise of the action potential is primarily composed of Nav1.8 currents. In some models of neuropathic pain, nerve injury increases Nav1.8 expression in axons and neuronal cell bodies (Sleeper AA, et al. J. Neurosci. 2000, 20, 7279–7289). Using Nav1.8 antisense oligonucleotides can significantly alleviate pain while simultaneously reducing Nav1.8 expression (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690–8696). Intra-paw injection of carrageenan in rats increases Nav1.8 expression in DRG neurons (Tanaka M., et al. G. NeuroReport 1998, 9, 967–972). Nav1.8 knockout mice fail to exhibit normal visceral inflammatory pain (Kerr BJ, et al. NeuroReport 2001, 12, 3077–3080). Gain-of-function mutations in the human Nav1.8 gene cause peripheral neuropathic pain (Faber CG, et al. Proc. Natl. Acad. Sci. USA 2012, 109, 19444–19449). Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy for a variety of pain types, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

[0006] Nav inhibitors used in clinical practice lack subtype selectivity and can only inhibit sodium channels expressed in the heart and central nervous system. Consequently, their therapeutic window is narrow and their scope of application is limited. Nav1.8 is primarily distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, improved pharmacokinetic properties, and fewer side effects.

[0007] Patent applications for disclosed Nav1.8 inhibitor compounds include WO2015089361A1, WO2021113627A1, WO2022129281 A1, WO2022121517A1, WO2019014352A1, WO2022256622A1, WO2022256676A1, WO2022256679A1, WO2022256842A1, and WO2022256702A1.

[0008] Summary of the Invention

[0009] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0010] in:

[0011] Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;

[0012] R A Selected from hydrogen, halogen, hydroxy, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4 、-alkylene-NR 3 R 4 , -O-alkylene-NR 3 R 4 、-C(=NR 5 )R 6 、-C(O)NR 3 R 4 、-C(O)R 6 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5 )(O)R 6 、=NR 5 、=CR 7 R 8 、-NR 5 C(O)R 6 、-NR 5 C(O)NR 3 R 4 、-P(O)R 7 R 8 、-C(O)NR 5 NR3 R 4 、-C(=NR 5 )NR 3 R 4 、-C(O)C(O)NR 3 R 4 、-S(=NR 5 )NR 3 R 4 、-S(=NR 5 )R 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-alkylene-heteroaryl and -O-alkylene-heterocyclyl, wherein the alkenyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by;

[0013] Each R B are the same or different and are each independently selected from halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0014] R 3 、R 4 and R 5 are the same or different and are each independently selected from hydrogen atom, alkyl, alkoxy, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 NR 22 C(O)R 23 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、S(O) v R 23 、S(O) v OR 23 、OS(O) v R 23 、S(O) v NR 20 R 21 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0015] or R 3 、R 4 and the nitrogen atom to which it is attached together form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 replaced by;

[0016] R 6 、R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 NR 22 C(O)R 23 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、S(O) v R 23 、S(O) v OR 23 、OS(O) v R 23 、S(O) v NR 20 R 21 , OR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0017] Each R 01 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, -NHalkyl, -N(alkyl), acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0018] Each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group and hydroxyalkyl group;

[0019] R' is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

[0020] X is O or S;

[0021] R a and R bare the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; each of the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy groups is independently optionally replaced by one or more R 02 replaced by;

[0022] R c and R d are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; each of the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy groups is independently optionally replaced by one or more R 02 replaced by;

[0023] or, R a 、R b and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; or, R c 、R d and the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R 02 replaced by;

[0024] R e is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;

[0025] Each R 02 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0026] X 1 CR X1 or N;

[0027] X 2 CR X2 or N;

[0028] X 3 CR X3 or N;

[0029] X 4 CR X4 or N;

[0030] X 5 CR X5 or N;

[0031] The condition is that X 1 、X 2 、X 3 、X 4 and X 5 Not all N at the same time;

[0032] R X1 、R X2 、R X3 、R X4 and R X5 are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, amide, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, -O-(CH2) n -cycloalkyl, -O-(CH2) s -heterocyclic, aryl and heteroaryl; wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by;

[0033] Each R 03 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0034] v is selected from 0, 1 and 2;

[0035] n is selected from 0, 1, 2, 3, 4 and 5;

[0036] s is selected from 0, 1, 2, 3, 4, and 5; and,

[0037] r is selected from 0, 1, 2, 3, 4 and 5.

[0038] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0039] in:

[0040] Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;

[0041] R A Selected from hydrogen, halogen, hydroxy, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4 、-alkylene-NR 3 R 4 , -O-alkylene-NR 3 R 4、-C(=NR 5 )R 6 、-C(O)NR 3 R 4 、-C(O)R 6 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5 )(O)R 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-alkylene-heteroaryl and -O-alkylene-heterocyclyl, wherein the alkenyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by;

[0042] Each R B are the same or different and are each independently selected from halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0043] R 3 、R 4 and R 5 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally replaced by one or more R 01 replaced by;

[0044] or R 3 、R 4 and the nitrogen atom to which it is attached together form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 replaced by;

[0045] R 6 is selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0046] Each R 01 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, -NHalkyl, -N(alkyl), acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0047] R' is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

[0048] X is O or S;

[0049] R a and R b are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy groups are optionally replaced by one or more R 02 replaced by;

[0050] The condition is that R a and R b Not simultaneously hydrogen;

[0051] R c and R d are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy groups are optionally replaced by one or more R 02 replaced by;

[0052] or, R a 、R b and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; or, R c 、R d and the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R 02 replaced by;

[0053] R e is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;

[0054] Each R 02 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0055] X 1 CR X1 or N;

[0056] X 2 CR X2 or N;

[0057] X 3 CRX3 or N;

[0058] X 4 CR X4 or N;

[0059] X 5 CR X5 or N;

[0060] The condition is that X 1 、X 2 、X 3 、X 4 and X 5 Not all N at the same time;

[0061] R X1 、R X2 、R X3 、R X4 and R X5 are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, amide, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, -O-(CH2) n -cycloalkyl, -O-(CH2) s -heterocyclic, aryl and heteroaryl; wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by;

[0062] Each R 03 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0063] v is selected from 0, 1 and 2;

[0064] n is selected from 0, 1, 2, 3, 4 and 5;

[0065] s is selected from 0, 1, 2, 3, 4, and 5; and,

[0066] r is selected from 0, 1, 2, 3, 4 and 5.

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 N, X 2 CR X2 , X 3 CR X3 , X 4 CR X4 , X 5 CRX5 ; or X 2 N, X 1 CR X1 , X 3 CR X3 , X 4 CR X4 , X 5 CR X5 ; or X 3 N, X 1 CR X1 , X 2 CR X2 , X 4 CR X4 , X 5 CR X5 ; or X 1 N, X 3 N, X 2 CR X2 , X 4 CR X4 , X 5 CR X5 ; or X 2 N, X 4 N, X 1 CR X1 , X 3 CR X3 , X 5 CR X5 ; or X 1 CR X1 , X 2 CR X2 , X 3 CR X3 , X 4 CR X4 , X 5 CR X5 ; R X1 、R X2 、R X3 、R X4 and R X5 As defined in general formula (I); preferably, X 1 CR X1 , X 2 CR X2 , X 3 CR X3 , X 4 CR X4 , X 5 CR X5 ; R X1 、R X2 、R X3 、RX4 and R X5 As defined in general formula (I); more preferably, X 1 CR X1 , X 2 CR X2 , X 3 CR X3 , X 4 CH, X 5 CH; R X1 、R X2 and R X3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 8-membered cycloalkyloxy and 4 to 7-membered heterocyclyloxy; the 3 to 8-membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 8-membered cycloalkyloxy and 4 to 7-membered heterocyclyloxy are each independently optionally substituted by one or more R 03 Replaced by; R 03 As defined in formula (I); most preferably, X 1 CR X1 , X 2 CR X2 , X 3 CR X3 , X 4 CH, X 5 CH; R X1 、R X2 and R X3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy.

[0068] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0069] in:

[0070] R a and R b Different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy; said 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy are optionally substituted by one or more R 02 replaced by;

[0071] R c and R d Different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy; said 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy are optionally substituted by one or more R 02 replaced by;

[0072] Cyclopentyl, R A 、R B , R', X, R X1 、R X2 、R X3 、R 02 and r are as defined in the general formula (I).

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof:

[0074] Among them, R', X, R a 、R b 、R c 、R d 、R X1 、R X2 and R X3 As defined in general formula (II).

[0075] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0076] wherein ring A is a phenyl group or a 5- or 6-membered heteroaryl group;

[0077] Q 1 C or N;

[0078] Q 2 Selected from CR A , N, NR" and C(O); Q 3 Selected from CR aa 、CHR aa , N, NR" and O; Y is selected from CR aa 、CHR aa , N, NR” and O;

[0079] --- is a single bond or a double bond;

[0080] R aa are the same or different and are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0081] R" are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0082] y is 0 or 1; p is 0 or 1;

[0083] R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 、R B and R A As defined in general formula (II).

[0084] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from R a 、R b 、R c 、R d and X are as defined in general formula (I); preferably, Selected from X, R a 、R b 、R c and R d As defined in general formula (II); further preferably, Selected from X is O or S, R a and R b Different, and each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy and 3 to 10-membered cycloalkyl, R c and R d Different, and each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy and 3 to 10 membered cycloalkyl; most preferably, for R a and R b Different, and each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl, R c and R d Different, and each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 alkyl halide;

[0085] In some embodiments, for R a and R b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 10 membered cycloalkyl; R c and R d Different, and each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3- to 10-membered cycloalkyl;

[0086] In some embodiments, for R a and R b Different, and each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 10 membered cycloalkyl; R c and R d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl and 3- to 10-membered cycloalkyl.

[0087] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring Cy is selected from 5-20 membered fused cycloalkyl, 5-20 membered fused heterocyclic group, 8-14 membered polycyclic aromatic group and 7-14 membered polycyclic heteroaromatic group; in some embodiments, ring Cy is 8-14 membered polycyclic heteroaromatic group; preferably, ring Cy is 9-10 membered bicyclic heteroaromatic group.

[0088] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring Cy is represented by Ring A and Ring B are the same or different and are each independently selected from a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 14-membered heteroaryl group. The * end is connected to -C(O)NR'-. Within the range allowed by the valence, R A and R B Connected to any position of ring A and ring B; preferably, ring Cy is represented by Ring A is phenyl or 5- or 6-membered heteroaryl, Ring B is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic group, phenyl and 5- or 6-membered heteroaryl, the * end is connected to -C(O)NR'-, and R is within the range allowed by the valence A and R B Connected to any position of ring A and ring B; further preferably, ring Cy is represented by Ring A is phenyl or 5- or 6-membered heteroaryl, Ring B is selected from 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclic group, phenyl and 5- or 6-membered heteroaryl, * end is connected to -C(O)NR'-, and R is within the range allowed by the valence A and R B Connected to any position of ring A and ring B; More preferably, ring Cy is represented by Ring A and Ring B are the same or different and are each independently a phenyl group or a 5- or 6-membered heteroaryl group, the * end is connected to -C(O)NR'-, and R is within the range allowed by the valence. A and R B Connect to any position of Ring A and Ring B;

[0089] In some embodiments, ring Cy is represented by Ring A is phenyl or 5- or 6-membered heteroaryl, Ring B is 5- or 6-membered heteroaryl, the * end is connected to -C(O)NR'-, and R is within the range allowed by the valence. A and R B Connected to any position of ring A and ring B; More preferably, ring Cy is selected from * end is connected to -C(O)NR'-, and R A and R BAttached to any position of the ring Cy; most preferably, the ring Cy is selected from * end is connected to -C(O)NR'-, and R A and R B Connect to any position of the ring Cy.

[0090] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein the ring Cy is Ring A is phenyl or 5- or 6-membered heteroaryl; Q 1 C or N, Q 2 is selected from CH, CH2, N, NH and C(O); Q 3 is selected from CH, CH2, N, NH and O; Y is selected from CH, CH2, N, NH and O; --- is a single bond or a double bond; y is 0 or 1; the * end is connected to -C(O)NR'-, and R is within the range allowed by the valence A and R B Connect to any position of the ring Cy.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein the ring Cy is selected from

[0092] In some embodiments, ring Cy is selected from * end is connected to -C(O)NR'-, and R A and R B Attached to any position of ring Cy; in some embodiments, ring Cy is selected from * end is connected to -C(O)NR'-, and R A and R B Attached to any position of ring Cy; in some embodiments, ring Cy is selected from

[0093] In some embodiments, ring Cy is selected from

[0094] In some embodiments, ring Cy is selected from In some embodiments, Cy is * end is connected to -C(O)NR'-, and R A and R B Connect to any position of the ring Cy.

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein the ring Cy is represented by Ring A is a 5-membered heteroaryl, Ring B is a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl, the * end is connected to -C(O)NR'-, R A is a hydroxyl group or an amino group.

[0096] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein the number of heteroatoms contained in ring Cy is no more than 5, preferably no more than 4, and more preferably no more than 3.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R A Selected from hydrogen atoms, hydroxyl groups, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, -NR 3 R 4 、-C 1-6 Alkylene-NR 3 R 4 、-OC 1-6 Alkylene-NR 3 R 4 , 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, 5- to 14-membered heteroaryl, -OC 1-6 Alkylene-5 to 14 heteroaryl and -OC 1-6 Alkylene-3 to 10-membered heterocyclic group, wherein the C 1-6 Alkylene, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl are each independently optionally substituted by one or more R 01 Replaced by; R 01 、R 3 and R 4 As defined in general formula (I);

[0098] Preferably, R A Selected from hydrogen atoms, hydroxyl groups, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, -NR 3 R 4 、-C 1-6 Alkylene-NR 3 R 4 and-OC1-6 Alkylene-NR 3 R 4 , the C 1-6 The alkylene group is optionally replaced by one or more R 01 Replaced by; R 01 、R 3 and R 4 As defined in general formula (I); further preferably, R A Selected from hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 More preferably, R A is hydroxy or amino; most preferably, R A is hydroxyl group;

[0099] In some embodiments, R A is a hydrogen atom, a hydroxyl group or an amino group, preferably a hydrogen atom or a hydroxyl group; in some embodiments, R A is selected from hydrogen atoms, halogens, hydroxyl groups, and amino groups; in some embodiments, R A is selected from hydrogen, halogen, hydroxy, amino, and =NH; in some embodiments, R A A hydrogen atom.

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein each R B are the same or different and are independently selected from halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy; preferably, each R B The same or different, and each independently selected from halogen, hydroxyl, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0101] In some embodiments, each R B are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, each R B are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl; more preferably, each R B are the same or different and are each independently selected from oxo and C 1-6 alkyl; in some embodiments, each R B are the same or different and are each independently selected from halogen, C 1-6Alkyl and halogenated C 1-6 alkyl; in some embodiments, each R B The same or different, and each independently halogen or C 1-6 alkyl.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, and r is selected from 0, 1 and 2.

[0103] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein Selected from W is N or CR W ;W 1 、W 2 and W 3 One of them is CR A , the remaining two are each independently N or CR 1B ;W 4 and W 5 One of them is CR A , the other is N or CR 2B ;W 6 Selected from O, S and NR 3B ;W 7 、W 8 、W 9 and W 10 One of them is CR A , the remaining three are independently N or CR 4B , and W 7 、W 8 、W 9 and W 10 At least one of them is N; W 11 and W 12 The same or different, and each independently N or CR 5B ;W 13 and W 14 The same or different, and each independently N or CR 6B ;W 17 、W 18 、W 19 and W 20 One of them is CR A , the remaining three are independently N or CR 7B ;W 15N or CR 8B , W 16 Selected from O, S and NR 9B ; Each R 1B 、R 2B 、R 4B 、R 5B 、R 6B 、R 7B 、R 8B 、R W and R 0 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 3B and R 9B are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R A As defined in general formula (I);

[0104] Preferably, Selected from W is N or CH; W 1 、W 2 and W 3 One of them is CR A , the remaining two are each independently N or CR 1B ;W 4 and W 5 One of them is CR A , the other is N or CR 2B ;W 6 Selected from O, S and NR 3B ;W 13 and W 14 The same or different, and each independently N or CR 6B ;W 15 N or CR 8B , W 16 Selected from O, S and NR 9B ;W 17 、W 18 、W 19 and W 20 One of them is CR A , the remaining three are independently N or CR 7B ; Each R 1B 、R 0 、R 2B 、R 6B 、R 7B and R 8B are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6Alkyl and halogenated C 1-6 Alkyl; R 9B and R 3B are each independently a hydrogen atom or a C 1-6 Alkyl; R A As defined in general formula (I);

[0105] More preferably, Selected from R A As defined in general formula (I);

[0106] More preferably, Selected from R A As defined in general formula (I); most preferably, Selected from

[0107] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein Selected from W 21 and W 22 Each independently is N or CR 5b ;W 23 N or CR 6b ;W 24 Selected from O, S and NR 7b ; Each R 1b 、R 2b 、R 3b 、R 4b 、R 5b and R 6b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 7b Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 Alkyl; t is selected from 0, 1 and 2, p is selected from 0, 1 and 2, and t and p are not 0 at the same time; preferably, Selected from

[0108] In some embodiments, Selected from W, W 1 、W 2 、W3 and R 0 As defined in formula (C3), W 4 、W 5 and W 6 As defined in formula (C4), W 13 、W 14 、W 17 、W 18 、W 19 and W 20 As defined in formula (C8), W 15 and W 16 As defined in formula (C11), W 21 、W 22 、R 1b 、W 2b 、R 3b 、W 4b , t and p are as defined in formula (C13-3); preferably, Selected from Among them, W 13 、W 14 、W 17 、W 18 、W 19 and W 20 As defined in formula (C8), W 15 and W 16 As defined in formula (C11), W 21 、W 22 、R 1b 、W 2b 、R 3b 、W 4b , t and p are as defined in formula (C13-3); more preferably, for Among them, W 13 、W 14 、W 17 、W 18 、W 19 and W 20 As defined in formula (C8), W 15 and W 16 As defined in formula (C11); further preferably, for W 13 、R A 、R 6B and R 7B As defined in formula (C8), W 15 and R 9B As defined in formula (C11).

[0109] In some embodiments of the present disclosure, the compound represented by formula (C8-1) or a pharmaceutically acceptable salt thereof, wherein W 13 N or CR 6B , R 6B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 13 is N or CH; more preferably N.

[0110] In some embodiments of the present disclosure, the compound represented by formula (C11-2) or a pharmaceutically acceptable salt thereof, wherein W 15 N or CR 8B , R 8B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 15 is N or CH; more preferably is CH.

[0111] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein for Ring A is phenyl or 5- or 6-membered heteroaryl; Q 1 C or N; Q 2 Selected from CR A , N, NR" and C(O); Q 3 Selected from CR aa 、CHR aa , N, NR" and O; Y is selected from CR aa 、CHR aa , N, NR" and O; --- is a single bond or a double bond;

[0112] R aa are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an amino group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, an alkenyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R″ are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0113] y is 0 or 1; p is 0 or 1; R B and R A As defined in general formula (I).

[0114] In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or fragment (A1), (A2), wherein is selected from phenyl, pyridyl, pyrrolyl, pyrazolyl and imidazolyl; preferably, Selected from

[0115] More preferably selected from The * end is connected to -C(O)NR'-, the # end is connected to Y, and the + end is connected to Q 2 connected.

[0116] In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or formula (A1), (A2), wherein Selected from R A As defined in general formula (I); preferably, for R A Selected from halogen, hydroxy and amino.

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or formula (A1), (A2), wherein Y is selected from CR aa , CH2, N and O, R aa As defined in general formula (III); preferably CH or CH2.

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or fragment (A1), (A2), wherein p is 0.

[0119] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Selected from R C is a hydrogen atom or R B , R A 、R B and r are as defined in formula (I);

[0120] In some embodiments, Selected from R C is a hydrogen atom or R B , R A and R B As defined in formula (I);

[0121] In some embodiments, Selected from R AAs defined in formula (I); in some embodiments, Selected from

[0122] Preferably, R A Selected from halogen, hydroxy and -NR 3 R 4 , R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl, and r is selected from 0, 1 and 2; * end is connected to -C(O)NR'-;

[0123] In some embodiments, Selected from

[0124] In some embodiments, Selected from In some embodiments, for

[0125] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Selected from R A Selected from hydrogen atoms, hydroxyl groups, amino groups, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy (preferably a hydrogen atom, a hydroxyl group or an amino group), the * end is connected to -C(O)NR'-; preferably, Selected from R A Selected from hydrogen atoms, hydroxyl groups, amino groups, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The hydroxyalkoxy group (preferably a hydrogen atom, a hydroxyl group or an amino group) is connected to -C(O)NR'- at the * end.

[0126] In some embodiments of the present disclosure, the compound represented by formula (C2) or (C3) or a pharmaceutically acceptable salt thereof, wherein W is CRW , R W Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably CH.

[0127] In some embodiments of the present disclosure, the compound represented by formula (C1), (C2) or (C3) or a pharmaceutically acceptable salt thereof, wherein W 2 CR A , W 1 and W 3 Each independently is N or CR 1B ; R A Selected from hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy, R 1B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 2 CR A , W 1 and W 3 All are N; or, W 2 CR A , W 1 N, W 3 CR 1B ; or, W 2 CR A , W 3 N, W 1 CR 1B ; R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy, R 1B For hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 2 CR A , W 1 and W 3 All are N; R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy.

[0128] In some embodiments of the present disclosure, the compound represented by formula (C4) or (C5) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, halogens and C 1-6 Alkyl, W 5 CR A , W 4 N, W 6 NR 3B ; R A Selected from hydroxyl, amino, C1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy, R 3B A hydrogen atom or C 1-6 Alkyl; preferably, R 0 is a hydrogen atom, W 5 CR A , W 4 N, W 6 NH; R A is a hydroxyl group or an amino group.

[0129] In some embodiments of the present disclosure, the compound represented by formula (C8), (C9) or (C10) or a pharmaceutically acceptable salt thereof, wherein W 13 is N, and W 14 CR 6B ; or, W 14 is N, and W 13 CR 6B ; or, W 13 and W 14 All CR 6B , R 6B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 13 is N, and W 14 CR 6B ; R 6B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; More preferably, W 13 is N, and W 14 For CH.

[0130] In some embodiments of the present disclosure, the compound represented by formula (C8), (C9) or (C10) or a pharmaceutically acceptable salt thereof, wherein W 13 is N, and W 14 CH; or, W 14 is N, and W 13 CH; or W 13 and W 14 All are CH.

[0131] In some embodiments of the present disclosure, the compound represented by formula (C8), (C9), (C10), (C11), (C11-1) or (C12) or a pharmaceutically acceptable salt thereof, wherein W 17 、W 18 、W 19 and W 20 One of them is CR A , one is N, and the remaining two are CR 7B , R 7BSelected from hydrogen atoms, halogens and C 1-6 Alkyl, R A As defined in general formula (I); preferably, W 17 、W 18 、W 19 and W 20 One of them is CR A , one is N, the remaining two are CH, R A Selected from hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy; preferably, W 17 、W 18 、W 19 and W 20 One of them is CR A , one is N, the remaining two are CH, R A is a hydroxyl group or an amino group.

[0132] In some embodiments of the present disclosure, the compound represented by formula (C8), (C9), (C10) or (C11-1) or a pharmaceutically acceptable salt thereof, wherein W 17 CR A , W 19 CR 7B , W 18 and W 20 One of them is N and the other is CR 7B , R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy, R 7B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 17 CR A , W 18 N, W 19 and W 20 All CR 7B , R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy, R 7B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; More preferably, W 17 CR A , W 18 N, W 19 and W 20 Both CH, R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy.

[0133] In some embodiments of the present disclosure, the compound represented by formula (C11) or (C12) or a pharmaceutically acceptable salt thereof, wherein W 20 CR A , W 19 N, W 17 and W 18 All CR 7B , R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy, R 7B Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 20 CR A , W 19 N, W 17 and W 18 Both CH, R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy.

[0134] In some embodiments of the present disclosure, the compound represented by formula (C11), (C11-1) or (C12) or a pharmaceutically acceptable salt thereof, wherein W 15 N or CR 8B , W 16 NR 9B , R 8B Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 9B A hydrogen atom or C 1-6 Alkyl; preferably, W 15 N or CH, W 16 is NH; more preferably, W 15 CH, W 16 For NH.

[0135] In some embodiments of the present disclosure, the compound represented by formula (C1) to (C12), (C11-1), (C11-2) or (C8-1) or a pharmaceutically acceptable salt thereof, wherein R A Selected from hydroxyl, amino, C 1-6 Hydroxyalkyl and C 1-6 Hydroxyalkoxy; preferably, R A is hydroxy or amino; most preferably, R A It is a hydroxyl group.

[0136] In some embodiments of the present disclosure, the compound represented by formula (C1) to (C12), (C11-1), (C11-2) or (C8-1) or a pharmaceutically acceptable salt thereof, wherein each R 1B、R 2B 、R 4B 、R 5B 、R 6B 、R 7B 、R 8B 、R W and R 0 are the same or different at each occurrence and are independently selected from hydrogen, halogen or C 1-6 Alkyl; preferably, R 1B 、R 2B 、R 4B 、R 5B 、R 6B 、R 7B 、R 8B 、R W and R 0 In each case it is a hydrogen atom.

[0137] In some embodiments of the present disclosure, the compound represented by formula (C1) to (C12), (C11-1), (C11-2) or (C8-1) or a pharmaceutically acceptable salt thereof, wherein R 3B and R 9B is the same or different at each occurrence and is independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 3B and R 9B In each case it is a hydrogen atom.

[0138] In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2) or (C13-3) or a pharmaceutically acceptable salt thereof, wherein W 21 is N, and W 22 CR 5b ; or, W 22 is N, and W 21 CR 5b ; or, W 21 and W 22 All CR 5b , R 5b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, W 21 is N, and W 22 CR 5b ; R 5b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; More preferably, W 21 is N, and W 22 For CH.

[0139] In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2) or (C13-3) or a pharmaceutically acceptable salt thereof, wherein W 21 is N, and W 22 CH; or, W 22 is N, and W 21 CH; or W 21 and W 22 All are CH.

[0140] In some embodiments of the present disclosure, the compound represented by formula (C14-1) or (C14-2) or a pharmaceutically acceptable salt thereof, wherein W 23 N or CR 6b , W 24 NR 7b , R 6b Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 7b A hydrogen atom or C 1-6 Alkyl; preferably, W 23 N or CH, W 24 is NH; more preferably, W 23 CH, W 24 For NH.

[0141] In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2), (C13-3), (C14-1) or (C14-2) or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1, and q is 1 or 2; preferably, t is 0, and q is 1 or 2.

[0142] In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2), (C13-3), (C14-1) or (C14-2) or a pharmaceutically acceptable salt thereof, wherein each R 1b 、R 2b 、R 3b 、R 4b 、R 5b and R 6b are the same or different at each occurrence and are independently selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 7b Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 1b 、R 2b 、R 3b 、R 4b 、R 5b 、R 6b and R 7b In each case it is a hydrogen atom.

[0143] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclic group; preferably, R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; further preferably, R a C 1-6 Alkyl or halogenated C 1-6 Alkyl; most preferably, R a is CH3 or CF3;

[0144] In some embodiments, R a C 1-6 Alkyl; preferably, R a For CH3.

[0145] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclic group; preferably, R b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; further preferably, R b C 1-6 Alkyl or halogenated C 1-6 Alkyl; most preferably, R b is CH3 or CF3;

[0146] In some embodiments, R b Halogenated C 1-6 Alkyl; preferably, R b It is CF3.

[0147] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R cSelected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclic group; preferably, R c Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; further preferably, R c A hydrogen atom or C 1-6 Alkyl; More preferably, R c is a hydrogen atom or CH3; most preferably, R c A hydrogen atom.

[0148] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R d Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclic group; preferably, R d Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; More preferably, R d A hydrogen atom or C 1-6 Alkyl; further preferably, R d is a hydrogen atom or CH3; in some embodiments, R d C 1-6 Alkyl; in some embodiments, R d For CH3.

[0149] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R e Selected from hydrogen atoms, halogen, hydroxyl, cyano and C 1-6 Alkyl; preferably, R e A hydrogen atom.

[0150] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R a and Rb The same or different, and each independently is C 1-6 Alkyl or halogenated C 1-6 Alkyl; further preferably, R a C 1-6 Alkyl, and R b Halogenated C 1-6 Alkyl, most preferably, R a is CH3, and R b It is CF3.

[0151] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R a and R b Different, and each independently selected from hydrogen atom, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R a and R b Different, and each independently C 1-6 Alkyl or halogenated C 1-6 Alkyl; further preferably, R a C 1-6 Alkyl, and R b Halogenated C 1-6 Alkyl, most preferably, R a is CH3, and R b is CF3;

[0152] In some embodiments, R a Halogenated C 1-6 Alkyl, and R b C 1-6 Alkyl; preferably, R a is CF3, and R b For CH3.

[0153] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different and are each independently selected from hydrogen, CH3 and CF3; in some embodiments, R a and R b The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R a and R b The same or different, and each independently is a halogenated C 1-6 alkyl.

[0154] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R a and R b are different and are each independently selected from hydrogen, CH3 and CF3; in some embodiments, R a and R b Different, and each independently C 1-6 Alkyl; in some embodiments, R a and R b Different, and each independently is a halogenated C 1-6 alkyl.

[0155] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R a Halogenated C 1-6 Alkyl, R b is a hydrogen atom; in some embodiments, R a is a hydrogen atom, R b Halogenated C 1-6 Alkyl; in some embodiments, R a is a hydrogen atom, R b C 1-6 Alkyl; in some embodiments, R a C 1-6 Alkyl, R b A hydrogen atom.

[0156] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R c and R d are the same or different and are each independently selected from hydrogen atom, C 1-6 alkyl and 3 to 6 membered cycloalkyl; preferably, R c and R d The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; further preferably, R c is a hydrogen atom, and R d C 1-6 Alkyl; most preferably, R c is a hydrogen atom, and R d For CH3.

[0157] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R c and R d Different, and each independently selected from hydrogen atom, C 1-6alkyl and 3 to 6-membered cycloalkyl; preferably, R c and R d Different, and each independently a hydrogen atom or a C 1-6 Alkyl; further preferably, R c is a hydrogen atom, and R d C 1-6 Alkyl; most preferably, R c is a hydrogen atom, and R d is CH3; in some embodiments, R c and R d are different and are each independently a hydrogen atom or CH3.

[0158] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R c C 1-6 Alkyl, and R d is a hydrogen atom; or R c is CH3, and R d is a hydrogen atom; in some embodiments, R c is a 3- to 10-membered cycloalkyl group (preferably a cyclopropyl group), R d is a hydrogen atom; in some embodiments, R c is a hydrogen atom, R d is a 3- to 10-membered cycloalkyl group (preferably a cyclopropyl group).

[0159] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R c and R d are the same or different and are each independently a hydrogen atom or CH3; in some embodiments, R c and R d All are hydrogen atoms.

[0160] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein X is O.

[0161] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R' is a hydrogen atom or C 1-6 Alkyl; preferably, R' is a hydrogen atom.

[0162] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Hydroxyalkyl; preferably, R 3 and R 4 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; further preferably, R 3 and R 4 All are hydrogen atoms.

[0163] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Hydroxyalkyl; preferably, R 5 A hydrogen atom or C 1-6 Alkyl; further preferably, R 5 A hydrogen atom.

[0164] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Hydroxyalkyl; preferably, R 6 C 1-6 Alkyl; most preferably, R 6 For CH3.

[0165] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R X1 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3 to 6-membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 6-membered cycloalkyloxy and 4 to 7-membered heterocyclyloxy, wherein the 3 to 6-membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 6-membered cycloalkyloxy and 4 to 7-membered heterocyclyloxy are each independently optionally substituted by one or more R 03 Replaced by each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R X1 Selected from hydroxyl, C 1-6Alkoxy and halogenated C 1-6 Alkoxy; further preferably, R X1 C 1-6 Alkoxy; most preferably, R X1 It is a methoxy group.

[0166] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R X2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3 to 6 membered cycloalkyl and 4 to 7 membered heterocyclic group; preferably, R X2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; further preferably, R X2 is halogen; most preferably, R X2 is a fluorine atom.

[0167] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R X3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3 to 6 membered cycloalkyl and 4 to 7 membered heterocyclic group; preferably, R X3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; further preferably, R X3 is halogen; most preferably, R X3 is a fluorine atom.

[0168] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R X4 and R X5 are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy; preferably, R X4 and R X5 All are hydrogen atoms.

[0169] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1, 2 and 3; preferably, n is 0 or 1, and further preferably, n is 0.

[0170] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein s is selected from 0, 1, 2 and 3; preferably, s is 0 or 1, and further preferably s is 0.

[0171] In some embodiments of the present disclosure, for the compound represented by general formula (I), (II) or (II-1) or a pharmaceutically acceptable salt thereof, r is selected from 0, 1 and 2; preferably, r is 0 or 1, and most preferably, r is 0.

[0172] In some embodiments of the present disclosure, in the compound represented by general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, v is 1 or 2; preferably, v is 2.

[0173] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; R b Halogenated C 1-6 Alkyl; R c is a hydrogen atom; R d C 1-6 Alkyl; X is O;

[0174] R' is a hydrogen atom or C 1-6 Alkyl; Ring Cy is * end is connected to -C(O)NR'-, and R A and R B Connected to any position of the ring Cy; R A is hydroxyl or amino; R X1 C 1-6 Alkoxy; R X2 is halogen; R X3 is halogen; r is 0.

[0175] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; R b Halogenated C 1-6 Alkyl; R c is a hydrogen atom; R d C 1-6 Alkyl; X is O; R' is a hydrogen atom or C1-6 alkyl; Selected from R A is a hydrogen atom, a hydroxyl group or an amino group, and the * end is connected to -C(O)NR'-; R X1 C 1-6 Alkoxy; R X2 is halogen; R X3 It is a halogen.

[0176] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; R b Halogenated C 1-6 Alkyl; R c is a hydrogen atom; R d C 1-6 Alkyl; R X1 C 1-6 Alkoxy; R X2 is halogen; R X3 is a halogen; X is O; R' is a hydrogen atom or C 1-6 alkyl; Selected from R C is a hydrogen atom or R B , R A Selected from halogen, hydroxy and -NR 3 R 4 , R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl, and r is selected from 0, 1 and 2; the * end is connected to -C(O)NR'-.

[0177] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R a CH3; R b CF3; R c is a hydrogen atom; R d CH3; R X1 is methoxy; R X2 is halogen; R X3 is a halogen; X is O; R' is a hydrogen atom; Selected from

[0178] Table A Typical compounds of the present disclosure include, but are not limited to:

[0179] Another aspect of the present disclosure relates to a compound represented by formula (IA) or a salt thereof,

[0180] Among them, R 9 C 1-6 alkyl;

[0181] Cyclopentyl, R B , R', X, R a 、R b 、R c 、R d 、R e 、X 1 、X 2 、X 3 、X 4 、X 5 and r are as defined in the general formula (I).

[0182] Another aspect of the present disclosure relates to a compound represented by general formula (II-A) or a salt thereof,

[0183] Among them, R 9 C 1-6 alkyl;

[0184] Cyclopentyl, R B , R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 and r are as defined in general formula (II).

[0185] Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or a salt thereof,

[0186] in,

[0187] R 11 、R 12and R 13 are all amino protecting groups, preferably Boc;

[0188] R', X, R a 、R b 、R c 、R d 、R X1 、R X2 and R X3 As defined in general formula (II-1).

[0189] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0190] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0191] The compound represented by general formula (Ia) or its salt is subjected to condensation reaction with the compound represented by general formula (Ib) or its salt to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt, wherein:

[0192] R 10 is a halogen (preferably a chlorine atom) or OH;

[0193] Cyclopentyl, R A 、R B , R', R a 、R b 、R c 、R d 、R e ,X,X 1 、X 2 、X 3 、X 4 、X 5 and r are as defined in the general formula (I).

[0194] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0195] The compound represented by the general formula (IA) or its salt undergoes aminolysis or hydrolysis reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt, wherein:

[0196] R A is hydroxyl or amino; R 9 C 1-6 alkyl;

[0197] Cyclopentyl, R B, R', R a 、R b 、R c 、R d 、R e ,X,X 1 、X 2 、X 3 、X 4 、X 5 and r are as defined in the general formula (I).

[0198] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0199] The compound represented by general formula (IIa) or its salt is subjected to condensation reaction with the compound represented by general formula (Ib) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt, wherein:

[0200] R 10 is a halogen (preferably a chlorine atom) or OH;

[0201] Cyclopentyl, R A 、R B , R', R a 、R b 、R c 、R d , X, R X1 、R X2 、R X3 and r are as defined in general formula (II).

[0202] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0203] The compound represented by general formula (II-A) or its salt undergoes aminolysis or hydrolysis reaction to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt, wherein:

[0204] R A is hydroxyl or amino; R 9 C 1-6 alkyl;

[0205] Cyclopentyl, R B , R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 and r are as defined in general formula (II).

[0206] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0207] The compound represented by the general formula (II-1A) or a salt thereof is deprotected by removing the amino protecting group to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein:

[0208] R 11 、R 12 and R 13 are all amino protecting groups, preferably Boc;

[0209] R', X, R a 、R b 、R c 、R d 、R X1 、R X2 and R X3 As defined in general formula (II-1).

[0210] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0211] The compound represented by general formula (IIa) or its salt is subjected to condensation reaction with the compound represented by general formula (IIIb) or its salt (preferably hydrochloride or trifluoroacetate) to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt, wherein:

[0212] Among them, R 10 is a halogen (preferably a chlorine atom) or OH;

[0213] R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 、R B ,p,ring A,Q 1 , Q 2 , Q 3 、---、Y、R aa and y are as defined in formula (III).

[0214] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by Formula (I), (II), (II-1), (III) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0215] The present disclosure further relates to the use of a compound of formula (I), (II), (II-1), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.

[0216] The present disclosure further relates to the use of a compound of formula (I), (II), (II-1), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel, preferably, the voltage-gated sodium channel is Nav1.8.

[0217] The present disclosure further relates to the use of a compound of formula (I), (II), (II-1), (III) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or alleviating pain and pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0218] The present disclosure further relates to a method for inhibiting voltage-gated sodium channels, comprising administering to a patient in need thereof a compound of formula (I), (II), (II-1), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the voltage-gated sodium channel is Nav1.8.

[0219] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel, comprising administering to a patient in need thereof a compound of formula (I), (II), (II-1), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the voltage-gated sodium channel is Nav1.8.

[0220] The present disclosure further relates to a method for treating and / or alleviating pain and pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough and arrhythmia, which comprises administering to a patient in need thereof a compound of formula (I), (II), (II-1), (III) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; and the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0221] The present disclosure further relates to a compound represented by formula (I), (II), (II-1), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0222] The present disclosure further relates to a compound represented by formula (I), (II), (II-1), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.

[0223] The present disclosure further relates to a compound represented by the general formula (I), (II), (II-1), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel; preferably, the voltage-gated sodium channel is Nav1.8.

[0224] The present disclosure further relates to a compound of formula (I), (II), (II-1), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing pain and pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; and the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0225] The diseases or conditions described in the present disclosure are diseases or conditions that are treated and / or prevented by inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.

[0226] Preferably, the disease or condition mediated by voltage-gated sodium channels described in the present disclosure is pain and pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0227] The neuropathic pain described in the present disclosure is preferably selected from trigeminal neuralgia, post-herpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuralgia, burning syndrome, post-amputation pain, pain after spinal cord injury, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, primary small fiber neuropathy, primary sensory neuralgia and trigeminal autonomic cephalalgia.

[0228] The musculoskeletal pain described in the present disclosure is preferably selected from osteoarthritis pain, back pain, cold pain, burning pain and toothache.

[0229] The intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0230] The inflammatory pain described in the present disclosure is preferably selected from rheumatoid arthritis pain and vulvar pain.

[0231] Idiopathic pain as described in this disclosure includes fibromyalgia.

[0232] Acute pain as used in the present disclosure includes acute postoperative pain.

[0233] The postoperative pain in the present disclosure includes joint replacement pain, soft tissue surgery pain, bunionectomy pain, hernia repair pain and abdominoplasty pain; preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0234] The neuropathic pain is diabetic peripheral neuropathy or small fiber neuralgia.

[0235] The disease or disorder of the present disclosure is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic disorders, neurodegenerative disorders, psychiatric disorders, anxiety disorders, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0236] The pain and pain-related diseases of the present disclosure are selected from the group consisting of femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, muscle fiber pain, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Chuck-Mare-Duchesne neuropathy, hereditary sensory neuropathies, peripheral nerve injury, painful neuromas, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, Post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, phantom limb pain, intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendonitis, injury pain, movement pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, dental pain, multiple sclerosis (MS) pain, pain in depression, leprosy pain, Behcet's disease disease pain, adiposity dolorosa, phlebitis pain, Guillain-Barre pain, leg pain and dyskinesia, Haglund syndrome, erythromelalgia, Fabry's disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, hyperresponsive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or colic-induced pain.

[0237] The diseases or conditions of the present disclosure are selected from acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic disorders, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic cancer pain and breakthrough cancer pain), stroke (e.g., central neuropathic pain after stroke), cervical sprain related diseases, fragility fractures, spinal fractures, ankylosis Spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, pain from disc degeneration / herniation, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mast cell hyperplasia polyarthritis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuroarthropathy, temporomandibular joint disorder, joint replacement pain, non-cardiac chest pain, vulvar pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0238] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0239] As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0240] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0241] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0242] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0243] In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for tablet preparation, which are mixed together. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or may be coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0244] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0245] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0246] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0247] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0248] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0249] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0250] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0251] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0252] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0253] Terminology

[0254] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0255] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point. The substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0256] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0257] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0258] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0259] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0260] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., a monocyclic cycloalkyl) or a polycyclic ring system (i.e., a polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl), more preferably a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered cycloalkyl) or a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl) or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl).

[0261] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0262] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0263] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0264] Its connection point can be at any position;

[0265] wait.

[0266] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include: Its connection point can be at any position; wait.

[0267] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0268] Its connection point can be at any position.

[0269] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0270] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group) or a heterocyclic group having 3 to 10 ring atoms (i.e., a 3- to 10-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0271] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0272] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0273] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0274] wait.

[0275] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0276] wait.

[0277] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0278] wait.

[0279] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0280] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, a phenyl group. The polycyclic aromatic group is preferably an 8- to 14-membered polycyclic aromatic group, and non-limiting examples include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:

[0281] wait.

[0282] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0283] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0284] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0285] The polycyclic heteroaryl group is preferably a 7- to 14-membered polycyclic heteroaryl group or an 8- to 14-membered polycyclic heteroaryl group, more preferably a 9- to 10-membered bicyclic heteroaryl group; non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0286] wait.

[0287] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0288] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0289] The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0290] The term "alkynyl protecting group" refers to a readily removable group introduced into an alkynyl group in order to maintain the active hydrogen of an acetylene or terminal alkyne while other parts of the molecule react. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

[0291] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0292] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0293] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0294] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0295] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0296] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0297] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0298] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0299] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0300] The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

[0301] The term "methylidene" refers to =CH2.

[0302] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0303] The term "hydroxy" refers to -OH.

[0304] The term "mercapto" refers to -SH.

[0305] The term "amino" refers to -NH2.

[0306] The term "cyano" refers to -CN.

[0307] The term "nitro" refers to -NO2.

[0308] The term "oxo" or "oxo" refers to "=0".

[0309] The term "carbonyl" refers to C=O.

[0310] The term "acetyl" refers to -C(O)CH3.

[0311] The term "amido" refers to -C(O)NH2.

[0312] The term "carboxy" refers to -C(O)OH.

[0313] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0314] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0315] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, meaning it can be Z, E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0316] In the chemical structures of the compounds described herein, the bond to the stereogenic center of the compound is like In the formula (a), represents the relative configuration of the stereogenic center; wherein, compound 1a of Example 1 is a mixture of 1b-1 and 1b-2.

[0317] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another. It includes all possible tautomers, that is, in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0318] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0319] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0320] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0321] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0322] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0323] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0324] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0325] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0326] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0327] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0328] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0329] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustrative purposes only and are not limiting.

[0330] Synthesis method of the disclosed compound

[0331] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0332] Option 1

[0333] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0334] The compound represented by general formula (Ia) or its salt is subjected to condensation reaction with the compound represented by general formula (Ib) or its salt under alkaline conditions to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt.

[0335] R 10 is a halogen (preferably a chlorine atom) or OH;

[0336] Among them, when R 10 When it is OH, the reaction occurs in the presence of a condensing agent;

[0337] Cyclopentyl, R A 、R B , R', R a 、R b 、R c 、R d 、R e ,X,X 1 、X 2 、X 3 、X 4 、X 5 and r are as defined in the general formula (I).

[0338] Option 2

[0339] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0340] The compound represented by the general formula (IA) or its salt undergoes an aminolysis reaction in the presence of an aminating agent to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt, wherein:

[0341] R A is amino, R 9 C 1-6 Further, when the solvent contains water, the compound represented by the general formula (IA) or its salt also undergoes hydrolysis reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt, at which time R A is a hydroxyl group or an amino group;

[0342] Or the compound represented by general formula (IA) or its salt undergoes hydrolysis reaction under alkaline conditions to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt, wherein R9 C 1-6 Alkyl, R A is hydroxyl group;

[0343] Cyclopentyl, R B , R', R a 、R b 、R c 、R d 、R e ,X,X 1 、X 2 、X 3 、X 4 、X 5 and r are as defined in the general formula (I).

[0344] Option 3

[0345] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0346] The compound represented by general formula (IIa) or its salt is subjected to a condensation reaction with the compound represented by general formula (Ib) or its salt under alkaline conditions to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt, wherein:

[0347] R 10 is a halogen (preferably a chlorine atom) or OH;

[0348] Among them, when R 10 When it is OH, the reaction occurs in the presence of a condensing agent;

[0349] Cyclopentyl, R A 、R B , R', R a 、R b 、R c 、R d , X, R X1 、R X2 、R X3 and r are as defined in general formula (II).

[0350] Option 4

[0351] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0352] The compound represented by general formula (II-A) or its salt undergoes aminolysis reaction in the presence of an aminating agent to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt, wherein:

[0353] R A is amino, R 9C 1-6 Further, when the solvent contains water, the compound represented by the general formula (II-A) or its salt also undergoes hydrolysis reaction to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt, at which time R A is a hydroxyl group or an amino group;

[0354] Or the compound represented by general formula (II-A) or its salt undergoes hydrolysis reaction under alkaline conditions to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt, wherein R 9 C 1-6 Alkyl, R A is hydroxyl group;

[0355] Cyclopentyl, R B , R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 and r are as defined in general formula (II).

[0356] Plan 5

[0357] The present disclosure provides a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0358] The compound represented by the general formula (II-1A) or a salt thereof is subjected to acidic conditions to remove the amino protecting group to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein:

[0359] R 11 、R 12 and R 13 are all amino protecting groups, preferably Boc;

[0360] R', X, R a 、R b 、R c 、R d 、R X1 、R X2 and R X3 As defined in general formula (II-1).

[0361] Plan 6

[0362] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0363] The compound represented by general formula (IIa) or its salt is subjected to a condensation reaction with the compound represented by general formula (IIIb) or its salt (preferably hydrochloride or trifluoroacetate) under alkaline conditions to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt, wherein:

[0364] Among them, R 10 is a halogen (preferably a chlorine atom) or OH;

[0365] When R 10 When it is OH, the reaction occurs in the presence of a condensing agent;

[0366] R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 、R B ,p,ring A,Q 1 , Q 2 , Q 3 、---、Y、R aa and y are as defined in formula (III).

[0367] In the condensation reaction in the above synthesis scheme, when R 10 When is halogen, the condensation reaction is optionally carried out in the presence of a catalyst, and the catalyst is preferably 4-dimethylaminopyridine.

[0368] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine (DIPEA), n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, ammonia water, cesium fluoride and potassium hydroxide.

[0369] When the condensation reaction is carried out in the above synthesis scheme, the reagent providing alkaline conditions is preferably triethylamine or N,N-diisopropylethylamine; when R 10 When OH is NH, the reagent providing alkaline conditions is preferably N,N-diisopropylethylamine. When the hydrolysis reaction occurs in the above synthesis scheme, the reagent providing alkaline conditions is an aqueous solution of the above-mentioned organic bases and inorganic bases, preferably an aqueous solution of DIPEA.

[0370] The condensing agent described in the above reaction includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, Methyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; preferably HATU.

[0371] In the above synthesis scheme, the reagents providing acidic conditions include but are not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf, preferably trifluoroacetic acid.

[0372] The aminating agent described in the above reaction includes but is not limited to: liquid ammonia, ammonia water, urea, ammonium salt (source of NH3), ammonia 1,4-dioxane and organic amine; preferably ammonia 1,4-dioxane.

[0373] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0374] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0375] Example

[0376] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0377] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0378] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489.

[0379] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0380] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0381] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0382] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0383] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0384] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0385] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0386] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0387] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0388] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0389] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0390] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0391] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0392] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0393] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0394] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0395] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0396] Example 1-P1 and Example 1-P2

[0397] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydropyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P1

[0398] (2R,3S,4S,5R)-N-(7-aminopyrazolo[1,5-c]pyrimidin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P2

[0399] first step

[0400] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-1

[0401] (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-2

[0402] rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (12 g, 33.87 mmol, prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627") was separated by chiral column (Waters SFC 150, chromatographic column: DAICEL 40*250mm, 10μm; mobile phase A: Supercritical CO2, mobile phase B: IPA), gradient ratio: A:B 90:10, flow rate: 120mL / min) to obtain the title products 1b-1 (5.5g, yield: 45.8%) and 1b-2 (5.08g, yield: 42.3%).

[0403] Single configuration compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%):

[0404] MS m / z(ESI):353.2[M-1].

[0405] Chiral HPLC analysis: retention time 2.414 minutes, purity: 99% (chromatographic column: DAICEL 100*3mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: IPA (0.1% DEA), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5mL / min).

[0406] Single configuration compound (longer retention time) 1b-2 (5.08 g, yield: 42.3%):

[0407] MS m / z(ESI):353.2[M-1].

[0408] Chiral HPLC analysis: retention time 2.724 minutes, purity: 99% (chromatographic column: DAICEL 100*3mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: IPA (0.1% DEA), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5mL / min).

[0409] Step 2

[0410] Ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-3-carboxylate 1e

[0411] Ethyl (E)-3-(dimethylamino)-2-(2-(methylthio)pyrimidin-4-yl)acrylate 1c (5 g, 18.7 mmol, prepared by the method disclosed in the literature "Journal of Chemical Information and Modeling, 2021, vol. 61, #1, p. 467–480") was dissolved in dichloromethane (50 mL). A solution of 2,4,6-trimethylbenzenesulfonylhydroxylamine 1d (5.47 g, 25.43 mmol, Shanghai Hanhong) in dichloromethane (50 mL) was added dropwise on an ice bath. The reaction mixture was stirred for 3 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 1e (140mg, yield: 3%).

[0412] MS m / z(ESI):238.2[M+1].

[0413] Step 3

[0414] 7-(Methylthio)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid 1f

[0415] Compound 1e (130 mg, 547 μmol) was dissolved in a mixture of tetrahydrofuran / methanol / water (1 / 1 / 0.5) (5 mL). Lithium hydroxide (115 mg, 2.74 mmol) was added and stirred for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 1f (100 mg). This product was used directly in the next reaction without purification. MS m / z (ESI): 210.2 [M+1].

[0416] Step 4

[0417] tert-Butyl (7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl)carbamate 1g

[0418] Compound 1f (100 mg, 478 μmol) was dissolved in tert-butanol (0.2 mL) and toluene (5 mL), and diphenylphosphoryl azide (DPPA) (127.8 mg, 525.7 μmol) and triethylamine (144 mg, 1.42 mmol) were added. The mixture was stirred at 90°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give 1 g (8 mg, 5.97%) of the title compound.

[0419] MS m / z(ESI):281.2[M+1].

[0420] Step 5

[0421] 7-(Methylthio)pyrazolo[1,5-c]pyrimidin-3-amine hydrochloride 1h

[0422] Compound 1g (8 mg, 28 μmol) was dissolved in 1 mL of dichloromethane, and 0.5 mL of 4M HCl dioxane solution was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1h (5 mg), which was used directly in the next reaction without purification.

[0423] MS m / z(ESI):181.2[M+1].

[0424] Step 6

[0425] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1i

[0426] Compound 1h (5 mg, 27 μmol) and compound 1b-1 (13 mg, 36 μmol) were dissolved in 0.5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (14 mg, 110 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (16 mg, 44 μmol) were added under ice-cooling. The temperature was maintained for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to give the title compound 1i (10 mg, yield: 52.7%).

[0427] MS m / z(ESI):517.2[M+1].

[0428] Step 7

[0429] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-(methylsulfonyl)pyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1j

[0430] Compound 1i (10 mg, 19.3 μmol) was dissolved in dichloromethane (0.5 mL), and m-chloroperbenzoic acid (10 mg, 57.9 μmol, Shanghai Titan) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1j (20 mg). The product was used directly in the next step without purification.

[0431] MS m / z(ESI):549.2[M+1].

[0432] Step 8

[0433] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydropyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P1

[0434] (2R,3S,4S,5R)-N-(7-aminopyrazolo[1,5-c]pyrimidin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P2

[0435] Compound 1j (10 mg, 18.2 μmol) was added to 10 mL of 0.4 M ammonia in 1,4-dioxane (containing a small amount of water), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 1-P1 (2 mg, 22.59%) and compound 1-P2 (2 mg, 22.5%).

[0436] Compound 1-P1:

[0437] MS m / z(ESI):487.2[M+1].

[0438] 1 H NMR (500 MHz, MeOD): δ 8.19 (s, 1H), 7.16 (ddd, 1H), 7.02 (dd, 2H), 6.59 (d, 1H), 5.13 (d, 1H), 4.33 (dd, 1H), 4.02 (d, 3H), 2.82 (p, 1H), 1.69 (s, 3H), 0.90-0.75 (m, 3H). Compound 1-P2:

[0439] MS m / z(ESI):486.2[M+1].

[0440] 1 H NMR (500MHz, MeOD): δ8.19(s,1H),7.40(d,1H),7.17(ddd,1H),7.06-6.97(m,1H),6.82(d, 1H),5.14(d,1H),4.34(dd,1H),4.02(d,3H),2.82(p,1H),1.70(s,3H),0.89-0.77(m,3H).

[0441] Example 2

[0442] (2R,3S,4S,5R)-N-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0443] first step

[0444] tert-Butyl (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)(tert-butoxycarbonyl)carbamate 2b

[0445] 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 2a (1 g, 4.71 mmol, Shanghai Shaoyuan) was dissolved in a mixed solvent of dichloromethane (25 mL), methanol (10 mL) and tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol, Shanghai Shaoyuan) was added. The reaction was stirred for 24 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to give the title compound 2b (500 mg, yield: 25%).

[0446] MS m / z(ESI):212.9[M-199].

[0447] Step 2

[0448] tert-Butyl (tert-butoxycarbonyl)(7-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)carbamate 2c

[0449] Compound 2b (500 mg, 1.21 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl carbamate (180 mg, 1.54 mmol, Shanghai Shaoyuan) was added, methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (BrettPhos Pd G3) (50 mg, 55.16 μmol, sigma), cesium carbonate (800 mg, 2.4 mmol), nitrogen was replaced, and the reaction was carried out at 100°C for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 2c (300 mg, yield: 55%).

[0450] MS m / z(ESI):450.2[M+1].

[0451] Step 3

[0452] [1,2,4]triazolo[1,5-a]pyridine-2,7-diamine bis(2,2,2-trifluoroacetic acid) salt 2d

[0453] Compound 2c (100 mg, 222.4 μmol) was dissolved in dichloromethane (5 mL), and 5 mL of trifluoroacetic acid (1 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 2d (83 mg), which was used directly in the next reaction without purification.

[0454] MS m / z(ESI):150.2[M+1].

[0455] Step 4

[0456] (2R,3S,4S,5R)-N-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0457] Compound 1b-1 (21 mg, 29 μmol) and crude compound 2d (30 mg, 79.8 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (25 mg, 193 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (34 mg, 89 μmol) were added under ice-cooling. The reaction was maintained at the temperature for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 2 (2.5 mg, yield: 8.6%).

[0458] MS m / z(ESI):486.2[M+1].

[0459] 1 H NMR (500MHz, DMSO-d6): δ10.53(s,1H),8.43-8.41(m,1H),7.74-7.73(m,1H),7.20-7.11(m,2H),7.01-6.99(m,1H), 5.91(s,2H),5.09-5.01(m,1H),4.27-4.25(m,1H),3.95(s,3H),2.79-2.76(m,1H),1.60(s,3H),0.74-0.72(m,3H).

[0460] Example 3

[0461] (2R,3S,4S,5R)-N-(2-amino-1H-benzo[d]imidazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0462] first step

[0463] tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-6-nitro-1H-benzo[d]imidazole-1-carboxylate 3b

[0464] 6-Nitro-1H-benzo[d]imidazol-2-amine 3a (1 g, 5.6 mmol, Shanghai Hanhong) was dissolved in tetrahydrofuran (50 mL), and di-tert-butyl dicarbonate (4 g, 18.3 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) were added. The reaction mixture was stirred for 3 hours, and the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 3b (1.2 g, yield: 44%).

[0465] Step 2

[0466] tert-Butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate 3c

[0467] Compound 3b (400 mg, 836 μmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and 10% palladium carbon catalyst (wet) (100 mg) was added. The mixture was stirred under a hydrogen atmosphere for 14 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 3c (300 mg).

[0468] Step 3

[0469] tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)-1H-benzo[d]imidazole-1-carboxylate 3d

[0470] Compound 1b-1 (20 mg, 56.4 μmol) and crude compound 3c (35 mg, 78 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (25 mg, 193 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (28 mg, 73.6 μmol) were added under ice-cooling. The temperature was maintained for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 3d (21 mg, yield: 47%).

[0471] MS m / z(ESI):785.2[M+1].

[0472] Step 4

[0473] (2R,3S,4S,5R)-N-(2-amino-1H-benzo[d]imidazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0474] Compound 3d (20 mg, 25.4 μmol) was dissolved in dichloromethane (2 mL), and 2 mL of trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 3 (3 mg, yield: 24%).

[0475] MS m / z(ESI):485.2[M+1].

[0476] 1 H NMR (500MHz, DMSO-d6): δ10.65(br,1H),9.99(s,1H),7.50(s,1H),7.22-7.11(m,2H),7.05-6.96(m,2H),6.12 (s,2H),5.10-4.96(m,1H),4.31-4.21(m,1H),3.96(s,3H),2.80-2.68(m,1H),1.59(s,3H),0.76-0.72(m,3H).

[0477] Example 4

[0478] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0479] first step

[0480] 6-Bromo-1-chloropyrrolo[1,2-a]pyrazine 4b

[0481] 1-Chloropyrrolo[1,2-a]pyrazine 4a (1.53 g, 10 mmol, Shanghai Bidex) was dissolved in tetrahydrofuran (30 mL), and dibromohydantoin (1.41 g, 5 mmol) was added under ice-cooling. The reaction mixture was kept at the temperature for 1 hour. Ethyl acetate was added to the reaction solution to dilute it, and the mixture was washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent B to give the title compound 4b (1.86 g, yield: 80%).

[0482] MS m / z(ESI):230.9[M+1].

[0483] Step 2

[0484] 6-Bromopyrrolo[1,2-a]pyrazin-1(2H)-one 4c

[0485] Compound 4b (1.74 g, 7.5 mmol) was dissolved in methanol (15 mL), and concentrated hydrochloric acid (15 mL) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, neutralized with sodium bicarbonate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 4c (1.48 g, yield: 92%).

[0486] MS m / z(ESI):213.0[M+1].

[0487] Step 3

[0488] 6-((Diphenylmethylene)amino)pyrrolo[1,2-a]pyrazin-1(2H)-one 4d

[0489] Compound 4c (427 mg, 2 mmol) was dissolved in toluene (11 mL), and benzophenone imine (727 mg, 4 mmol, Shanghai Shaoyuan), tris(dibenzylideneacetone)dipalladium (184 mg, 201 μmol, Shanghai Titan), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg, 401 μmol, Shanghai Titan), and sodium tert-butoxide (578 mg, 6 mmol) were added. The atmosphere was replaced with nitrogen, and the reaction was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 4d (550 mg, yield: 87.5%).

[0490] MS m / z(ESI):314.0[M+1].

[0491] Step 4

[0492] 6-Aminopyrrolo[1,2-a]pyrazin-1(2H)-one 4e

[0493] Compound 4d (40 mg, 127 μmol) was dissolved in 1 mL of methanol, and 0.2 mL of 4 M hydrochloric acid in 1,4-dioxane was added. The mixture was stirred for 1.5 hours. The reaction solution was neutralized with saturated sodium bicarbonate solution and concentrated under reduced pressure to obtain the crude title compound 4e (19 mg). The product was used directly in the next reaction without purification.

[0494] MS m / z(ESI):150.2[M+1].

[0495] Step 5

[0496] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0497] Compound 1b-1 (35 mg, 100 μmol) and crude compound 4e (30 mg, 201 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (65 mg, 501 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (57 mg, 150 μmol) were added under ice-cooling. The reaction temperature was maintained for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 4 (8 mg, yield: 16%).

[0498] MS m / z(ESI):486.2[M+1].

[0499] 1 H NMR (500MHz, MeOD): δ7.18(t,1H),7.05(d,1H),7.00(q,1H),6.85(d,1H),6.57(d,1H),6.48 (d,1H),5.16(d,1H),4.32(q,1H),4.00(s,3H),2.84-2.78(m,1H),1.69(s,3H),0.84(d,3H).

[0500] Example 5

[0501] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0502] first step

[0503] 7-Methoxy-3-nitro-1H-pyrrolo[2,3-c]pyridine 5b

[0504] 7-Methoxy-1H-pyrrolo[2,3-c]pyridine 5a (1 g, 6.7 mmol, Shanghai Bidex) was dissolved in concentrated sulfuric acid (5 mL). Potassium nitrate (820 mg, 8.1 mmol) was added portionwise under ice bath and the reaction was maintained at the temperature for 2 hours. The reaction solution was poured into ice water to precipitate a yellow solid. The solid was filtered and the filter cake was washed with water and dried to obtain the crude title compound 5b (1 g). The product was used directly in the next reaction without purification.

[0505] MS m / z(ESI):194.2[M+1].

[0506] Step 2

[0507] 3-Nitro-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 5c

[0508] Compound 5b (200 mg, 1 mmol) was dissolved in 2 mL of 4 M hydrochloric acid 1,4-dioxane solution and stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, and a yellow solid precipitated. The solid was filtered and the filter cake was washed with ethanol and dried to obtain the crude title compound 5c (100 mg). The product was used directly in the next reaction without purification.

[0509] MS m / z(ESI):180.1[M+1].

[0510] Step 3

[0511] 3-Amino-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 5d

[0512] Compound 5c (50 mg, 279 μmol) was dissolved in 5 mL of isopropanol, and Raney nickel (100 mg) and 1 mL of hydrazine hydrate were added. The mixture was stirred at 85°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 5d (40 mg). The product was used directly in the next reaction without purification.

[0513] MS m / z(ESI):150.1[M+1].

[0514] Step 4

[0515] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0516] Compound 1b-1 (40 mg, 112.9 μmol) and crude compound 5d (40 mg, 268.1 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (50 mg, 386 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (70 mg, 184 μmol) were added under ice-cooling. The reaction was maintained at the temperature for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 5 (12 mg, yield: 21%).

[0517] MS m / z(ESI):486.2[M+1].

[0518] 1 H NMR (500MHz, DMSO-d6): δ11.76(br,1H),10.94-10.90(m,1H),10.20(br,1H),7.58(s,1H),7.19-7.12(m,2H),6.90-6.85(m,1 H),6.59-6.55(m,1H),5.16-5.12(m,1H),4.28-4.24(m,1H),3.95(s,3H),2.78-2.74(m,1H),1.59(s,3H),0.76-0.72(m,3H).

[0519] Example 6

[0520] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0521] first step

[0522] 3-Aminopyrazolo[1,5-a]pyrimidin-7(4H)-one 6b

[0523] 3-Nitropyrazolo[1,5-a]pyrimidine-7-ol 6a (5 mg, 27.7 μmol, prepared by the method disclosed in Example 2 on page 6 of the specification of patent application "US006099593A") was dissolved in 1 mL of methanol and 1 mL of tetrahydrofuran, and 10% palladium carbon catalyst (wet) (5 mg) was added. The mixture was replaced with hydrogen and stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 6b (4 mg). The product was used directly in the next reaction without purification.

[0524] MS m / z(ESI):151.1[M+1].

[0525] Step 2

[0526] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0527] Compound 1b-1 (12 mg, 33.8 μmol) and crude compound 6b (4 mg, 26.6 μmol) were dissolved in 0.5 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (13 mg, 101.6 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (75 mg, 40.6 μmol) were added under ice-cooling. The reaction temperature was maintained for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 6 (5 mg, yield: 30.3%).

[0528] MS m / z(ESI):487.2[M+1].

[0529] 1 H NMR (500MHz, CD3OD): δ7.94(s,1H),7.78(d,1H),7.25-7.14(m,1H),7.00(q, 1H),5.82(d,1H),5.16(d,1H),4.31(dd,1H),4.02(t,3H),2.83(t,1H),1.71(s,3H),0.83(d,3H).

[0530] Example 7

[0531] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0532] first step

[0533] (E)-3-(2-Methoxyvinyl)-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 7b

[0534] (Methoxymethyl)triphenylphosphine chloride (1.51 g, 4.4 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (20 mL), and potassium tert-butoxide (996.5 mg, 8.9 mmol) was added under ice bath, and the temperature was maintained with stirring for 0.5 hours. 4-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde 7a (1.0 g, 4.45 mmol, prepared by the method disclosed in Scheme 22 on page 107 of the specification of the patent application "WO2020150545") was added, and the reaction was naturally restored to room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 7b (600 mg, yield: 53.3%).

[0535] MS m / z(ESI):254.2[M+1].

[0536] Step 2

[0537] 2-(4-Nitro-1H-pyrazol-3-yl)acetaldehyde hydrochloride 7c

[0538] Compound 7b (150 mg, 5923 μmol) was dissolved in tetrahydrofuran (2 mL), and 6 M hydrochloric acid (1 mL) was added. The mixture was stirred at 60° C. for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 7c (100 mg), which was used directly in the next step without purification.

[0539] MS m / z(ESI):154.2[M-1].

[0540] Step 3

[0541] N-(4-Methoxybenzyl)-2-(4-nitro-1H-pyrazol-3-yl)ethan-1-amine 7d

[0542] The crude compound 7c (114.9 mg, 599.7 μmol) was dissolved in methanol (8 mL), and p-methoxybenzylamine (164.6 mg, 1.29 mmol) was added, and the reaction was stirred for 1 hour. Sodium borohydride (66.6 mg, 1.8 mmol) was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 7d (25 mg, yield: 15%).

[0543] MS m / z(ESI):277.2[M+1].

[0544] Step 4

[0545] 6-(4-Methoxybenzyl)-3-nitro-5,6-dihydropyrazolo[1,5-c]pyrimidin-7(4H)-one 7e

[0546] Compound 7d (60 mg, 217.1 μmol) was dissolved in acetonitrile (5 mL), and N,N-carbonyldiimidazole (CDI) (52.81 mg, 325.7 μmol) and triethylamine (65.92 mg, 651.4 μmol) were added. The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 7e (28 mg, yield: 42%).

[0547] MS m / z(ESI):303.2[M+1].

[0548] Step 5

[0549] 3-Amino-6-(4-methoxybenzyl)-5,6-dihydropyrazolo[1,5-c]pyrimidin-7(4H)-one 7f

[0550] Compound 7e (12 mg, 39.7 μmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and 10% palladium-carbon hydrogenation catalyst (dry) (10 mg) was added. The mixture was replaced with hydrogen and stirred for 14 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 7f (10 mg), which was used directly in the next step without purification.

[0551] MS m / z(ESI):273.2[M+1].

[0552] Step 6

[0553] 3-Amino-5,6-dihydropyrazolo[1,5-c]pyrimidin-7(4H)-one 7g

[0554] The crude compound 7f (10 mg, 36.7 μmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.25 mL) and trifluoromethanesulfonic acid (0.25 mL) were added under ice bath, and the reaction was stirred at the maintained temperature for 2 hours. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate solution and then concentrated under reduced pressure. A mixed solvent of dichloromethane / methanol (V / V = 9 / 1) was added to the residue, washed, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 7g (5 mg), which was used directly in the next step without purification.

[0555] MS m / z(ESI):153.2[M+1].

[0556] Step 7

[0557] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,5,6,7-tetrahydropyrazole

[0558] [1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 7

[0559] Compound 1b-1 (10 mg, 28 μmol) and crude compound 7g (5 mg, 32.8 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (10.9 mg, 84.6 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (12.8 mg, 33.8 μmol) were added under ice-cooling. The reaction was maintained at the temperature for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 7 (3 mg, yield: 21%).

[0560] MS m / z(ESI):489.2[M+1].

[0561] 1 H NMR (500MHz, CD3OD): δ7.81(s,1H),7.13(ddd,1H),6.98(td,1H),5.07(d,1H),4.26(d d,1H),3.99(d,3H),3.49(t,2H),2.96(t,2H),2.78(p,1H),1.66(s,3H),0.81(dq,3H).

[0562] Example 8

[0563] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 8

[0564] first step

[0565] (3-Bromo-1H-pyrrol-2-yl)methanol 8b

[0566] Methyl 3-bromo-1H-pyrrole-2-carboxylate 8a (8 g, 39.2 mmol, Nanjing Yaoshi) was dissolved in tetrahydrofuran (150 mL), and a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (24 mL) was added dropwise under ice-bath. The mixture was stirred and allowed to return to room temperature for 2 hours. Sodium sulfate decahydrate was added to the reaction solution under ice-bath to quench the reaction, filter, and concentrate the filtrate under reduced pressure to give the crude title compound 8b (5 g), which was used directly in the next step without purification.

[0567] MS m / z(ESI):174.0[M-1].

[0568] Step 2

[0569] 3-Bromo-1H-pyrrole-2-carbaldehyde 8c

[0570] The crude compound 8b (5 g, 28.4 mmol) was dissolved in dichloromethane (100 mL), and manganese dioxide (24.7 g, 284.1 mmol) was added. The mixture was stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 8c (4 g), which was used directly in the next step without purification.

[0571] MS m / z(ESI):172.0[M-1].

[0572] Step 3

[0573] 3-Bromo-1-p-toluenesulfonyl-1H-pyrrole-2-carbaldehyde 8d

[0574] Sodium hydride (766.3 mg, 20 mmol, 60% purity) was suspended in tetrahydrofuran (150 mL), and crude compound 8c (2.9 g, 16.7 mmol) was added. After stirring for 30 minutes, p-toluenesulfonyl chloride (3.5 g, 18.35 mmol) was added and the reaction was stirred for 14 hours. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 8d (5.1 g, yield: 93.2%).

[0575] MS m / z(ESI):328.1[M+1].

[0576] Step 4

[0577] (E)-3-Bromo-2-(2-methoxyvinyl)-1-p-toluenesulfonyl-1H-pyrrole 8e

[0578] (Methoxymethyl)triphenylphosphine chloride (4.17 g, 12.1 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (150 mL), and potassium tert-butoxide (1.36 g, 12.1 mmol) was added under ice bath, and the reaction was stirred at the maintained temperature for 0.5 hour. Compound 8d (2 g, 6.09 mmol) was added, and the reaction was allowed to return to room temperature naturally for 14 hours. Water was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 8e (1.4 g, yield: 64%).

[0579] MS m / z(ESI):356.2[M+1].

[0580] Step 5

[0581] 2-(3-Bromo-1-p-toluenesulfonyl-1H-pyrrol-2-yl)acetaldehyde 8f

[0582] Compound 8e (1.4 g, 3.93 mmol) was dissolved in tetrahydrofuran (30 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was stirred for 1 hour. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 8f (1.3 g), which was used directly in the next reaction without purification.

[0583] MS m / z(ESI):340.0[M-1].

[0584] Step 6

[0585] 2-(3-Bromo-1-toluenesulfonyl-1H-pyrrol-2-yl)-N-(4-methoxybenzyl)ethan-1-amine 8g

[0586] The crude compound 8f (1 g, 2.92 mmol) was dissolved in methanol (30 mL), and p-methoxybenzylamine (601 mg, 4.38 mmol, Shanghai Shaoyuan) was added, and the reaction was stirred for 1 hour. Sodium cyanoborohydride (275 mg, 4.38 mmol) was added, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8g (466 mg, yield: 34.4%).

[0587] MS m / z(ESI):463.2[M+1].

[0588] Step 7

[0589] 2-(3-Bromo-1H-pyrrol-2-yl)-N-(4-methoxybenzyl)ethan-1-amine 8h

[0590] Compound 8g (466 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL), and a methanol solution of sodium methoxide (50%) (1.1 g, 10 mmol) was added under ice-bath. The mixture was stirred and allowed to return to room temperature for 4 hours. The pH of the reaction solution was adjusted to neutral with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 8h (287 mg, yield: 92%).

[0591] MS m / z(ESI):309.2[M+1].

[0592] Step 8

[0593] 5-Bromo-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2-c]pyrimidin-1(2H)-one 8i

[0594] Compound 8h (287 mg, 928.2 μmol) was dissolved in tetrahydrofuran (20 mL), and N,N-carbonyldiimidazole (CDI) (451.5 mg, 2.8 mmol) was added. After stirring for 30 minutes, sodium hydride (106.7 mg, 2.8 mmol, 60% purity) was added. The reaction was stirred for 14 hours. Water was added to the reaction solution to quench the reaction, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 8i (126 mg, yield: 40.5%).

[0595] MS m / z(ESI):335.2[M+1].

[0596] Step 9

[0597] 5-((Diphenylmethylene)amino)-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2-c]pyrimidin-1(2H)-one 8j

[0598] Compound 8i (40 mg, 119.3 μmol) and benzophenone imine (43.2 mg, 238.6 μmol) were dissolved in toluene (10 mL), and tris(dibenzylideneacetone)palladium (10.92 mg, 11.9 μmol, Shanghai Titan), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (13.8 mg, 23.9 μmol, Shanghai Titan) and sodium tert-butoxide (34.4 mg, 358 μmol) were added. The atmosphere was replaced with nitrogen, and the reaction was stirred at 100° C. for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8j (44 mg, yield: 84.6%).

[0599] MS m / z(ESI):436.2[M+1].

[0600] Step 10

[0601] 5-((Diphenylmethylene)amino)-3,4-dihydropyrrolo[1,2-c]pyrimidin-1(2H)-one 8k

[0602] Compound 8j (20 mg, 45.9 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) and trifluoromethanesulfonic acid (0.3 mL) were added under ice-bath. The reaction mixture was stirred and maintained at the temperature for 2 hours. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate solution and then concentrated under reduced pressure. A mixed solvent of dichloromethane / methanol (V / V = 9 / 1) was added to the residue, washed, and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 8k (14 mg), which was used directly in the next step without purification.

[0603] MS m / z(ESI):316.2[M+1].

[0604] Step 11

[0605] 5-Amino-3,4-dihydropyrrolo[1,2-c]pyrimidin-1(2H)-one 8l

[0606] Compound 8k (14 mg, 44.4 μmol) was dissolved in methanol (1 mL), and 0.3 mL of 4 M hydrochloric acid 1,4-dioxane solution was added. The mixture was stirred and reacted for 2 hours. The reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (5 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 8l (6 mg), which was used directly in the next step without purification.

[0607] MS m / z(ESI):152.2[M+1].

[0608] Step 12

[0609] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2,3,4-tetrahydropyrrole

[0610] [1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 8

[0611] Compound 1b-1 (20 mg, 56 μmol) and crude compound 8l (8.5 mg, 56 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (22 mg, 269 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (25.7 mg, 67.7 μmol) were added under ice bath. The temperature was maintained for 2 hours. The reaction solution was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 8 (1.5 mg, yield: 5.4%).

[0612] MS m / z(ESI):488.2[M+1].

[0613] 1 H NMR (500MHz, CD3OD): δ7.15-7.10(m,2H),7.01-6.96(m,1H),6.28(d,1H),5.06(d,,1H),4.2 9-4.26(m,1H),4.02(d,3H),3.43-3.41(m,2H),2.79(t,3H),1.67(s,3H),0.83-0.78(m,3H).

[0614] Example 9

[0615] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0616] first step

[0617] 1-(3-Bromo-1H-pyrrol-2-yl)-N-(4-methoxybenzyl)methanamine 9a

[0618] Compound 8c (441 mg, 2.53 mmol) was dissolved in methanol (20 mL), and p-methoxybenzylamine (414 mg, 3 mmol, Shanghai Bidex), acetic acid (152 mg, 2.53 mmol) and sodium acetate borohydride (1.07 g, 5.06 mmol) were added. The reaction was stirred for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 9a (544 mg, yield: 72.7%).

[0619] MS m / z(ESI):295.2[M+1].

[0620] Step 2

[0621] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydro-1H-pyrrole)

[0622] 9-[1,2-c]imidazol-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0623] The synthetic route of Example 8 was followed from step 8 to step 12, and the starting compound 8h in step 8 was replaced by compound 9a to obtain the title compound 9 (1 mg, yield: 9.35%).

[0624] MS m / z(ESI):474.2[M+1].

[0625] 1 H NMR (500MHz, CD3OD): δ7.15-7.09(m,1H),7.02-6.96(m,2H),6.33(d,1H),5.01(d,1H) ,4.51(d,1H),4.26(dd,2H),4.01(d,3H),2.79(t,2H),1.66(s,3H),0.83-0.78(m,3H).

[0626] Example 10

[0627] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10

[0628] first step

[0629] 5-((Benzhydrylene)amino)-2-(methoxymethyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one 10b

[0630] 5-Bromo-2-(methoxymethyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one 10a (500 mg, 1.9 mmol, was prepared by the method of “Journal of the Chemical Society. Perkin Transactions 1(2001), 2002, #4, p.471-475), benzophenone imine (704.9 mg, 3.88 mmol) was dissolved in toluene (10 mL), and tris(dibenzylideneacetone)palladium (178 mg, 194.4 μmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (224.8 mg, 388.9 μmol) and sodium tert-butoxide (560.7 mg, 5.83 mmol) were added. The atmosphere was replaced with nitrogen, and the reaction was stirred at 100°C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 10b (375 mg, yield: 53.9%).

[0631] MS m / z(ESI):358.2[M+1].

[0632] Step 2

[0633] 5-Amino-2-(methoxymethyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one 10c

[0634] Compound 10b (90 mg, 251.8 μmol) was dissolved in tetrahydrofuran (2 mL), and 1 M hydrochloric acid (0.5 mL) and water (0.2 mL) were added. The mixture was stirred for 2 hours. The pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 10c (50 mg), which was used directly in the next step without purification.

[0635] MS m / z(ESI):194.2[M+1].

[0636] Step 3

[0637] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(methoxymethyl)-1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10d

[0638] Compound 1b-1 (91 mg, 258.8 μmol) and crude compound 10c (50 mg, 258.8 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (100 mg, 776 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 310 μmol) were added under ice-cooling. The temperature was maintained for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 10d (135 mg, 98.5%).

[0639] MS m / z(ESI):530.2[M+1].

[0640] Step 4

[0641] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10

[0642] Compound 10d (80 mg, 151.1 μmol) was dissolved in 2 M hydrochloric acid isopropanol solution (4 mL), and the reaction was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 10 (1 mg, yield: 1.3%).

[0643] MS m / z(ESI):486.2[M+1].

[0644] 1H NMR (500MHz, CD3OD): δ7.47(s,1H),7.17(ddd,1H),7.01(td,1H),6.81(d,1H),6.66(d,1H),6.4 1(d,1H),5.11(d,1H),4.33(dd,1H),4.02(d,3H),2.81(p,1H),1.69(s,3H),0.86-0.82(m,3H).

[0645] Example 11

[0646] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-5,6-dihydroimidazo[1,5-c]pyrimidin-1-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 11

[0647] first step

[0648] Ethyl 2-((diphenylmethylene)amino)-2-(2-(methylthio)pyrimidin-4-yl)acetate 11b

[0649] Ethyl 2-((diphenylmethylene)amino)acetate (3.66 g, 13.7 mmol, Shanghai Shaoyuan) was dissolved in dimethyl sulfoxide (30 mL), and sodium hydride (955 mg, 24.9 mmol, 60% purity) was added in batches under ice bath, and the temperature was maintained for reaction for 1 hour. A solution of 4-chloro-2-(methylthio)pyrimidine 11a (2.0 g, 12.4 mmol, Shanghai Bid) in dimethyl sulfoxide (5 mL) was added, and the reaction was stirred for 14 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 11b (2.2 g, yield: 45.1%).

[0650] MS m / z(ESI):392.2[M+1].

[0651] Step 2

[0652] 2-Amino-2-(2-(methylthio)pyrimidin-4-yl)acetic acid 11c

[0653] Compound 11b (2.2 g, 5.6 mmol) was dissolved in tetrahydrofuran (20 mL), concentrated hydrochloric acid (4 mL) was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 11c (1.1 g, yield: 86%).

[0654] MS m / z(ESI):228.2[M+1].

[0655] Step 3

[0656] 2-Formamido-2-(2-(methylthio)pyrimidin-4-yl)acetic acid 11d

[0657] Formic acid (2 mL) and acetic anhydride (2 mL) were mixed and reacted at 50°C for 1 hour. After cooling to room temperature, the mixture was dropwise added to a dichloromethane solution (20 mL) of compound 11c (1.1 g, 4.8 mmol) and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent B to give the title compound 11d (1.1 g, yield: 89%).

[0658] MS m / z(ESI):256.2[M+1].

[0659] Step 4

[0660] Ethyl 5-(methylthio)imidazo[1,5-c]pyrimidine-1-carboxylate 11e

[0661] Compound 11d (1.1 g, 4.3 mmol) was dissolved in 1,4-dioxane (20 mL), and phosphorus oxychloride (3 mL) was added. The reaction was carried out at 110°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 7-8 with aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 11e (820 mg, yield: 80%).

[0662] MS m / z(ESI):238.2[M+1].

[0663] Step 5

[0664] Ethyl 5-oxo-5,6-dihydroimidazo[1,5-c]pyrimidine-1-carboxylate 11f

[0665] Compound 11e (800 mg, 3.37 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and lithium hydroxide (283 mg, 6.74 mmol) was added. The mixture was stirred for 2 hours, and the pH was adjusted to about 7 with 2M hydrochloric acid. The precipitated solid was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 11f (390 mg), which was used directly in the next reaction without purification.

[0666] MS m / z(ESI):208.2[M+1].

[0667] Step 6

[0668] 5-Oxo-5,6-dihydroimidazo[1,5-c]pyrimidine-1-carboxylic acid 11g

[0669] The crude compound 11f (1 g, 4.8 mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL), and lithium hydroxide (497 mg, 11.8 mmol) was added. The mixture was refluxed for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove most of the solvent. The pH was adjusted to about 7 with 2M hydrochloric acid. The precipitated solid was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 11 g (590 mg), which was used directly in the next reaction without purification.

[0670] MS m / z(ESI):180.2[M+1].

[0671] Step 7

[0672] tert-Butyl (5-oxo-5,6-dihydroimidazo[1,5-c]pyrimidin-1-yl)carbamate 11h

[0673] The crude compound 11g (500mg, 2.79mmol) was dissolved in tert-butanol (5mL) and toluene (10mL), and diphenylphosphoryl azide (1.02g, 4.19mmol, Shanghai Shaoyuan) and triethylamine (848mg, 8.38mmol) were added. The mixture was replaced with nitrogen and reacted at 90°C for 14 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system A to give the title compound 11h (300mg, yield: 42.94%).

[0674] MS m / z(ESI):251.2[M+1].

[0675] Step 8

[0676] 1-Aminoimidazo[1,5-c]pyrimidin-5(6H)-one 2,2,2-trifluoroacetate 11i

[0677] Compound 11h (230 mg, 919 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 11i (230 mg), which was used directly in the next step without purification. MS m / z (ESI): 151.2 [M+1].

[0678] Step 9

[0679] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-5,6-dihydroimidazo[1,5-c]pyrimidin-1-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 11

[0680] Compound 1b-1 (150 mg, 423 μmol) and crude compound 11i (113 mg, 426.3 μmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (274 mg, 2.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (242 mg, 636.4 μmol) were added under ice bath. The temperature was maintained for 2 hours, and the reaction solution was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 11 (25 mg, yield: 12.1%).

[0681] MS m / z(ESI):487.2[M+1].

[0682] 1 H NMR (500MHz, DMSO-d6): δ11.07(br,1H),10.55(br,1H),8.30(s,1H),7.23-7.19(m,2H),6.66-6.64(m,1H),6.52-6 .51(m,1H),5.16-5.14(m,1H),4.25-4.21(m,1H),3.95(s,3H),2.78-2.72(m,1H),1.60(s,3H),0.73-0.71(m,3H).

[0683] Example 12

[0684] (2R,3S,4S,5R)-N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 12

[0685] first step

[0686] 7-Chloro-3-nitro-1H-pyrrolo[2,3-c]pyridine 12a

[0687] Compound 5c (1 g, 5.58 mmol) was dissolved in phosphorus oxychloride (10 mL), and N,N-diisopropylethylamine (2 g, 15.47 mmol) was added. The mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate and dried to obtain the crude title compound 12a (800 mg), which was used directly in the next step without purification.

[0688] MS m / z(ESI):198.2[M+1].

[0689] Step 2

[0690] 7-Chloro-1H-pyrrolo[2,3-c]pyridin-3-amine 12b

[0691] The crude compound 12a (100 mg, 506.12 μmol) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). Iron powder (300 mg, 5.37 mmol) and 2 mL of saturated ammonium chloride solution were added. The mixture was stirred at 70°C for 2 hours. The reaction solution was filtered while hot, and the filtrate was concentrated under reduced pressure to give the crude title compound 12b (50 mg), which was used directly in the next step without purification.

[0692] MS m / z(ESI):168.2[M+1].

[0693] Step 3

[0694] (2R,3S,4S,5R)-N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 12

[0695] Compound 1b-1 (40 mg, 112.9 μmol) and crude compound 12b (50 mg, 298 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (50 mg, 386 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (65 mg, 171 μmol) were added under ice-cooling. The reaction temperature was maintained for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 12 (12 mg, yield: 21%).

[0696] MS m / z(ESI):504.2[M+1].

[0697] 1 H NMR (500MHz, DMSO-d6): δ11.89(s,1H),10.50(s,1H),7.98-7.90(m,2H),7.70(s,1H),7.21-7.12(m,2H) ,5.18-5.12(m,1H),4.31-4.27(m,1H),3.95(s,3H),2.78-2.74(m,1H),1.60(s,3H),0.76-0.72(m,3H).

[0698] Example 13

[0699] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 13

[0700] first step

[0701] 7-Fluoro-1H-pyrrolo[2,3-c]pyridine 13b

[0702] 2-Fluoro-3-nitropyridine 13a (5 g, 35.2 mmol, Shanghai Bidex) was dissolved in tetrahydrofuran (20 mL). A 1 M solution of vinylmagnesium bromide in tetrahydrofuran (105 mL) was added dropwise at -78°C and the temperature was slowly raised to -20°C for 2 hours. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 13b (800 mg, yield: 16.7%).

[0703] MS m / z(ESI):137.2[M+1].

[0704] Step 2

[0705] 7-Fluoro-3-nitro-1H-pyrrolo[2,3-c]pyridine 13c

[0706] Compound 13b (200 mg, 1.47 mmol) was dissolved in concentrated sulfuric acid (5 mL), and potassium nitrate (150 mg, 1.48 mmol) was added portionwise at 0°C. The reaction was continued at the same temperature for 2 hours. Water was added to the reaction solution, stirred for 30 minutes, and filtered. The filter cake was washed with water and dried to obtain the crude title compound 13c (100 mg), which was used directly in the next step without purification.

[0707] MS m / z(ESI):182.2[M+1].

[0708] Step 3

[0709] 7-Fluoro-1H-pyrrolo[2,3-c]pyridin-3-amine 13d

[0710] The crude compound 13c (20 mg, 110.42 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and 10% palladium-carbon catalyst (10 mg) was added. The mixture was replaced with hydrogen and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 13d (20 mg), which was used directly in the next step without purification.

[0711] MS m / z(ESI):152.2[M+1].

[0712] Step 4

[0713] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 13

[0714] Compound 1b-1 (30 mg, 84.6 μmol) and crude compound 13d (20 mg, 132 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (33 mg, 255 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (100 mg, 262 μmol) were added under ice-cooling. The reaction temperature was maintained for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 13 (5 mg, yield: 12%).

[0715] MS m / z(ESI):488.2[M+1].

[0716] 1 H NMR (500MHz, DMSO-d6): δ7.89(s,1H),7.64-7.63(m,1H),7.50-7.47(m,1H),7.18-7.15(m,1H),7.02-6.97(m ,1H),5.18-5.12(m,1H),4.38-4.35(m,1H),4.01(s,3H),2.83-2.80(m,1H),1.69(s,3H),0.86-0.83(m,3H).

[0717] Example 14

[0718] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydroisoxazolo[4,5-b]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 14

[0719] first step

[0720] Methyl 3-(benzyloxy)-4-((tert-butoxycarbonyl)amino)picolinate 14b

[0721] Methyl 3-(benzyloxy)-4-bromopicolinate 14a (1.8 g, 5.58 mmol, prepared by the method disclosed in the literature "Journal of Medicinal Chemistry, 2020, vol. 63, #14, p. 7491-7507") and tert-butyl carbamate (1.97 g, 16.8 mmol, Shanghai Titan) were dissolved in 1,4-dioxane (50 mL), and tris(dibenzylideneacetone)dipalladium (512 mg, 559 μmol), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (647 mg, 1.1 mmol), and cesium carbonate (4.56 g, 14 mmol) were added. The reaction was stirred at 115 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 14b (2 g, yield: 99.8%).

[0722] MS m / z(ESI):359.2[M+1].

[0723] Step 2

[0724] Methyl 4-((tert-Butoxycarbonyl)amino)-3-hydroxypicolinate 14c

[0725] Compound 14b (2 g, 5.58 mmol) was dissolved in 40 mL of methanol, and 10% palladium-carbon catalyst (wet) (1.2 g) was added. The mixture was replaced with hydrogen and stirred for 4 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 14c (1.42 g). The product was used directly in the next reaction without purification.

[0726] MS m / z(ESI):269.1[M+1].

[0727] Step 3

[0728] tert-Butyl (3-hydroxy-2-(hydroxycarbamoyl)pyridin-4-yl)carbamate 14d

[0729] The crude compound 14c (1.42 g, 5.29 mmol) was dissolved in 25 mL of ethanol, and 50% aqueous hydroxylamine solution (3.49 g, 52.9 mmol) was added. The mixture was stirred for 16 hours. Water was added to the reaction solution, stirred for 10 minutes, and then filtered. The filter cake was dried to obtain the crude title compound 14d (1.03 g). The product was used directly in the next reaction without purification.

[0730] MS m / z(ESI):270.1[M+1].

[0731] Step 4

[0732] tert-Butyl (3-oxo-2,3-dihydroisoxazolo[4,5-b]pyridin-7-yl)carbamate 14e

[0733] Compound 14d (900 mg, 3.34 mmol) and triethylamine (406 mg, 4.01 mmol) were dissolved in tetrahydrofuran (25 mL), and thionyl chloride (438 mg, 3.68 mmol) was added dropwise at -78°C. The mixture was naturally returned to room temperature and stirred for 0.5 hour. The reaction solution was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 14e (839 mg). The product was used directly in the next reaction without purification.

[0734] MS m / z(ESI):252.2[M+1].

[0735] Step 5

[0736] 7-Aminoisoxazolo[4,5-b]pyridin-3(2H)-one hydrochloride 14f

[0737] The crude compound 14e (800 mg, 3.18 mmol) was dissolved in 30 mL of 4 M hydrochloric acid 1,4-dioxane solution and stirred for 14 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 14f (410 mg), which was used directly in the next step without purification.

[0738] MS m / z(ESI):152.2[M+1].

[0739] Step 6

[0740] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-dihydroisoxazolo[4,5-b]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 14

[0741] Compound 1b-1 (500 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (360 mg, 2.83 mmol) and 1 drop of N,N-dimethylformamide were added under ice-bath. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (1.38 g, 10.67 mmol) and 4-dimethylaminopyridine (265 mg, 2.15 mmol) were added. The crude compound 14f (400 mg, 2.13 mmol, Shanghai Hanhong) was added under ice-bath. The mixture was stirred for 14 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL / min) to give the title compound 14 (55mg, yield: 5.29%).

[0742] MS m / z(ESI):488.2[M+1].

[0743] 1 H NMR (500MHz, CDCl3): δ9.07(bs,1H),8.23(d,1H),7.12(d,1H),7.08-7.05(m,1H),6.88(q, 1H),5.07(d,1H),4.13(dd,1H),3.97(s,3H),2.77-2.71(m,1H),1.67(s,3H),0.77(d,3H).

[0744] Example 15

[0745] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 15

[0746] first step

[0747] Methyl 4-(bis(tert-butoxycarbonyl)amino)-3-methylpicolinate 15b

[0748] Methyl 4-amino-3-methylpicolinate 15a (1.5 g, 9.02 mmol, prepared by the method disclosed in the literature "Heterocycles, 2013, vol. 87, #6, p. 1279-1287"), di-tert-butyl dicarbonate (5.9 g, 27.03 mmol), triethylamine (4.56 g, 45.06 mmol), and 4-dimethylaminopyridine (1.11 g, 9.01 mmol) were dissolved in dichloromethane (40 mL) and stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 15b (1.25 g, yield: 37.8%).

[0749] MS m / z(ESI):367.2[M+1].

[0750] Step 2

[0751] Methyl 4-(bis(tert-butoxycarbonyl)amino)-3-(bromomethyl)picolinate 15c

[0752] Compound 15b (1.25 g, 3.41 mmol) was dissolved in carbon tetrachloride (30 mL), and N-bromosuccinimide (729 mg, 4.10 mmol) and azobisisobutyronitrile (56 mg, 341.03 μmol) were added. The mixture was reacted at 100°C for 14 hours. The reaction solution was cooled to room temperature and quenched by adding saturated sodium thiosulfate solution. The mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 15c (1.28 g, yield: 84.2%).

[0753] MS m / z(ESI):445.2[M+1].

[0754] Step 3

[0755] Methyl 4-(bis(tert-butoxycarbonyl)amino)-3-(cyanomethyl)picolinate 15d

[0756] Compound 15c (1.28 g, 2.87 mmol) was dissolved in acetonitrile (20 mL), and cesium fluoride (2.18 g, 14.35 mmol) and trimethylsilyl cyanide (1.42 g, 14.31 mmol) were added. The mixture was stirred at 50°C for 14 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 15d (417 mg, yield: 37%).

[0757] MS m / z(ESI):392.2[M+1].

[0758] Step 4

[0759] tert-Butyl (tert-butoxycarbonyl)(8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)carbamate 15e

[0760] Compound 15d (417 mg, 1.06 mmol) was dissolved in methanol (10 mL), sodium borohydride (242 mg, 6.4 mmol) was added at 0°C, and cobalt chloride hexahydrate (153 mg, 643.04 μmol, Chinese medicine) was slowly added. The reaction was stirred for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered out and concentrated under reduced pressure to give the crude title compound 15e (200 mg). The product was used directly in the next reaction without purification.

[0761] MS m / z(ESI):364.2[M+1].

[0762] Step 5

[0763] 4-Amino-6,7-dihydro-1,7-naphthyridin-8(5H)-one 15f

[0764] The crude compound 15e (200 mg, 550 μmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (5 mL), and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to give the title compound 15f (20 mg, yield: 22%).

[0765] MS m / z(ESI):164.2[M+1].

[0766] Step 6

[0767] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 15

[0768] Compound 1b-1 (45 mg, 127 μmol) and compound 15f (20 mg, 128 μmol) were dissolved in 2 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (164 mg, 1.26 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (77 mg, 202 μmol) were added under ice-cooling. The reaction temperature was maintained for 2 hours. The reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 15 (4 mg, yield: 6.3%).

[0769] MS m / z(ESI):500.2[M+1].

[0770] 1 H NMR (500MHz, CDCl3): δ7.89(s,1H),7.05(s,1H),6.81(dd,1H),6.58(s,1H),5.88-5.60(m,1H),4.84 (d,1H),4.65(s,2H),4.10(d,1H),3.96(s,3H),3.55(s,2H),2.67(t,1H),1.57(s,3H),0.75(d,3H).

[0771] Example 16

[0772] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 16

[0773] first step

[0774] 7-Amino-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one 16b

[0775] 7-Nitro-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one 16a (30 mg, 144.1 μmol, prepared by the method disclosed in Example 9 on page 34 of the specification of patent application "WO2007004959") was dissolved in methanol (4 mL), and 10% palladium carbon hydrogenation catalyst (dry) (15 mg) was added. The mixture was replaced with hydrogen and stirred for 14 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 16b (25 mg), which was used directly in the next step without purification.

[0776] MS m / z(ESI):179.2[M+1].

[0777] Step 2

[0778] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 16

[0779] Compound 1b-1 (45 mg, 127.5 μmol) was dissolved in 3 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (57.7 mg, 446.3 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (72.7 mg, 191.3 μmol) were added under ice-cooling. The mixture was stirred at the temperature for 10 minutes, and then crude compound 16b (25 mg, 140.3 μmol) was added. The temperature was maintained for another 2 hours, and the reaction solution was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-42%, flow rate: 30mL / min) to obtain the title compound 16 (15mg, yield: 22.8%).

[0780] MS m / z(ESI):515.2[M+1].

[0781] 1 H NMR (500MHz, CD3OD): δ7.89(d,1H),7.71(dd,1H),7.13(t,1H),6.99(dd,2H),5.03(d,1 H),4.36-4.26(m,3H),3.99(t,3H),3.41(d,2H),2.78(t,1H),1.66(s,3H),0.81(d,3H).

[0782] Example 17

[0783] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindoline]-6'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p1

[0784] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindoline]-5'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p2

[0785] first step

[0786] (2R,3S,4S,5R)-N-(3,4-dicyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 17b

[0787] Compound 1b-1 (1.25 g, 3.52 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (1.33 g, 10.5 mmol) and 5 drops of N,N-dimethylformamide were added under ice-bath. The temperature was maintained for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (1.36 g, 10.5 mmol), 4-dimethylaminopyridine (2 mg, 16.2 μmol), and 4-aminophthalonitrile 17a (400 mg, 2.13 mmol, Shanghai Shaoyuan) were added under ice-bath. The reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 17b (900 mg, yield: 53.7%).

[0788] MS m / z(ESI):480.2[M+1].

[0789] Step 2

[0790] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindoline]-6'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p1

[0791] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindoline]-5'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p2

[0792] Compound 17b (200 mg, 417.2 μmol) was dissolved in diethyl ether (5 mL), and tetraisopropyl titanate (261 mg, 918.3 μmol, Shanghai Titan) was added at -78°C. A 2.0 M solution of ethylmagnesium bromide in tetrahydrofuran (690.3 μL) was added dropwise. The mixture was stirred at 0°C for 1 hour and then returned to room temperature for 16 hours. Methanol was added to the reaction solution for quenching, and the solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (1‰ trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give the title compound (15 mg, yield: 5.7%).

[0793] Single configuration compound (shorter retention time): (15 mg, yield: 5.7%).

[0794] MS m / z(ESI):510.2[M+1].

[0795] HPLC analysis: retention time 1.835 minutes, purity: 95% (chromatographic column: HALO C18, 2.7 μm, 3.0*30 mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0796] 1 H NMR (500MHz, CD3OD): δ8.57(d,1H),7.73(dd,1H),7.35(d,1H),7.17-7.13(m,1H),7.01-6.95(m,1H),5.10(d,1H) ),4.33(dd,1H),4.10(d,3H),2.82-2.76(m,1H),1.83-1.80(m,2H),1.71-1.69(m,2H),1.68(s,3H),0.83(d,3H).

[0797] Single configuration compound (longer retention time): (15 mg, yield: 5.7%).

[0798] MS m / z(ESI):510.2[M+1].

[0799] HPLC analysis: retention time 2.057 minutes, purity: 98% (chromatographic column: HALO C18, 2.7 μm, 3.0*30 mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0800] 1 H NMR (500MHz, CD3OD): δ8.02(d,1H),7.77(d,1H),7.71(dd,1H),7.14-7.10(m,1H),6.99-6.94(m,1H),5.09(d,1H),4.3 3-4.29(m,1H),4.00-3.99(m,3H),2.82-2.76(m,1H),1.83-1.80(m,2H),1.68-1.66(m,2H),1.65(s,3H),0.81(d,3H).

[0801] Example 18

[0802] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(cis-(1R,2S)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (cis isomer mixture) 18-p1

[0803] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(trans-(1S,2S)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (trans isomer mixture) 18-p2

[0804] first step

[0805] Tert-butyl (1-oxo-2,3-dihydro-1H-inden-5-yl)carbamate 18b

[0806] 5-Chloro-2,3-dihydro-1H-indene-1-one 18a (1 g, 6 mmol, Shanghai Shaoyuan) was dissolved in 1,4-dioxane (11 mL), and tert-butyl carbamate (843.7 mg, 7.2 mmol, Shanghai Shaoyuan), palladium acetate (67.4 mg, 300 μmol, Shanghai Titan), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (285.7 mg, 600 μmol, Shanghai Titan), cesium carbonate (4.9 g, 15 mmol) were added. The mixture was replaced with nitrogen and stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 18b (1.4 g, yield: 94.3%).

[0807] MS m / z(ESI):248.2[M+1].

[0808] Step 2

[0809] 5-Amino-2-fluoro-2,3-dihydro-1H-inden-1-one 18c

[0810] Compound 18b (110 mg, 444.8 μmol) was dissolved in methanol (3 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (315.1 mg, 889.6 μmol) was added. The mixture was stirred at 70°C for 48 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 18c (48 mg, yield: 65.3%).

[0811] MS m / z(ESI):166.2[M+1].

[0812] Step 3

[0813] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(cis-(1R,2S)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (cis mixture) 18-p1

[0814] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(trans-(1S,2S)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (trans mixture) 18-p2

[0815] Compound 1b-1 (200 mg, 564.5 μmol) and compound 18c (93.2 mg, 564.5 μmol) were dissolved in 2 mL N,N-diisopropylethylamine (73 mg, 564.5 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (257.6 mg, 677.4 μmol) were added to N,N-dimethylformamide under ice bath, and the reaction was restored to room temperature for 0.5 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dissolved in methanol (5 mL). Sodium borohydride (60.6 mg, 564.5 μmol) was added, and the reaction was stirred for 1 hour. After that, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL / min) to obtain the title compound (24.4mg, yield: 8.5%), (5.6mg, yield: 2%).

[0816] Cis isomer mixture or trans isomer mixture (shorter retention time) (24.4 mg, yield: 8.5%):

[0817] MS m / z(ESI):504.2[M+1].

[0818] HPLC analysis: retention time 2.57 minutes, purity: 97% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD3OD): δ7.50(s,1H),7.40(dd,1H),7.33(d,1H),7.15-7.12(m,1H),7.01-6.93(m,1H),5.29-5.11(m, 1H),5.07-4.92(m,2H),4.30(dd,1H),3.98(d,3H),3.15-3.00(m,2H),2.78(q,1H),1.66(s,3H),0.93-0.76(m,3H).

[0819] Cis isomer mixture or trans isomer mixture (longer retention time) (5.6 mg, yield: 2%):

[0820] MS m / z(ESI):504.2[M+1].

[0821] HPLC analysis: retention time 2.62 minutes, purity: 94% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD3OD): δ7.50(d,1H),7.41(dd,1H),7.32(d,1H),7.15-7.12(m,1H),7.05-6.91(m,1H),5.07-5.00(m,2H),4 .30(dd,1H),3.99(d,3H),3.03-2.89(m,1H),2.78(q,1H),2.19(t,1H),2.08-1.99(m,1H),1.66(s,3H),0.82-0.81(m,3H).

[0822] Example 19

[0823] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 19

[0824] first step

[0825] 7-Methoxy-5-methyl-1H-pyrrolo[2,3-c]pyridine 19b

[0826] 7-Chloro-5-methyl-1H-pyrrolo[2,3-c]pyridine 19a (4 g, 24 mmol, prepared by the method disclosed in Example P1 on page 9 of the specification of patent application "US2007185154") and 30% sodium methoxide methanol solution (40 mL) were mixed and reacted in a microwave at 110°C for 4 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 19b (1.1 g, 28.2%).

[0827] MS m / z(ESI):163.2[M+1].

[0828] Step 2

[0829] 7-Methoxy-5-methyl-3-nitro-1H-pyrrolo[2,3-c]pyridine 19c

[0830] Compound 19b (1.1 g, 6.78 mmol) was dissolved in concentrated sulfuric acid (10 mL), and potassium nitrate (686 mg, 6.78 mmol) was added portionwise under ice bath. The temperature was maintained for 2 hours. The reaction solution was poured into ice water, and the pH was adjusted to neutral with 2 M sodium hydroxide solution. The product was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to give the title compound 19c (300 mg, yield: 21.3%).

[0831] Step 3

[0832] 5-Methyl-3-nitro-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 19d

[0833] Compound 19c (180 mg, 1.35 mmol) was dissolved in 3 mL of 1,4-dioxane and 3 mL of concentrated hydrochloric acid. The mixture was stirred at 85°C for 4 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with water and dried to obtain the crude title compound 19d (261 mg). The product was used directly in the next reaction without purification.

[0834] MS m / z(ESI):194.0[M+1].

[0835] Step 4

[0836] 3-Amino-5-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 19e

[0837] The crude compound 19d (261 mg, 1.35 mmol) was dissolved in isopropanol (3 mL), and Raney nickel (230 mg) and hydrazine hydrate (1.5 mL) were added. The mixture was stirred at 85°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 19e (220 mg). The product was used directly in the next reaction without purification.

[0838] MS m / z(ESI):163.9[M+1].

[0839] Step 5

[0840] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 19

[0841] Compound 1b-1 (131 mg, 369.77 μmol) and crude compound 19e (50 mg, 306.4 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (199 mg, 1.53 mmol) and 50% 1-propylphosphoric acid cyclic anhydride in ethyl acetate (391 mg, 614 mmol, Shanghai Bidex) were added. The reaction was stirred for 2 hours, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound 19 (80 mg, yield: 52.2%).

[0842] MS m / z(ESI):500.2[M+1].

[0843] 1 H NMR (500MHz, CD3OD): δ7.60(s,1H),7.16-7.13(m,1H),7.01-6.96(m,1H),6.34(s,1H),5.12(d, 1H),4.33(dd,1H),4.00-3.99(m,3H),2.82-2.75(m,1H),2.28(s,3H),1.67(s,3H),0.83(d,3H).

[0844] Biological evaluation

[0845] Test Example 1: Determination of the inhibitory activity of the disclosed compounds on Nav1.8

[0846] The purpose of this experiment is to investigate the effects of compounds on the Nav1.8 ion channel in vitro. The Nav1.8 ion channel is stably expressed in HEK293 cells. After the Nav1.8 current stabilizes, the magnitude of the Nav1.8 current before and after compound application is compared to determine the compound's effect on the Nav1.8 channel.

[0847] 1 Experimental materials and instruments

[0848] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp700A (Axon instrument)

[0849] 2) Digital-to-analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon instruments)

[0850] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0851] 4) Inverted microscope: TL4 (Olympus)

[0852] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0853] 6) Microelectrode glass capillary: B12024F (Wuhan Weitan Scientific Instrument Co., Ltd.)

[0854] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0855] 8)TTX AF3014 (Affix Scientific)

[0856] 2 Experimental steps

[0857] 2.1 Compound preparation

[0858] All compounds used to prepare intracellular and extracellular solutions, except NaOH and KOH for acid-base titration, were purchased from Sigma (St. Louis, MO). The extracellular solution (mM) consisted of: NaCl, 137; KCl, 4; CaCl₂, 1.8; MgCl₂, 1; HEPES, 10; and glucose, 10; pH 7.4 (NaOH titration). The intracellular solution (mM) consisted of: aspartic acid, 140; MgCl₂, 2; EGTA, 11; and HEPES, 10; pH 7.2 (CsOH titration). All test and control compound solutions contained 1 μM TTX.

[0859] The test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular fluid to prepare the required concentration.

[0860] 2.2 Manual patch clamp test process

[0861] 1) After the compound is prepared into a solution of the specified concentration, the solution is added to each channel in order from low to high concentration, and each channel is marked.

[0862] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and place the electrode tip in contact with the cell. Set the three-way valve of the vacuum device to the three-way position. Then, apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue applying negative pressure to rupture the cell membrane, creating a current path.

[0863] 3) After the cell membrane current stabilizes, perfuse at different concentrations. If the current remains stable for at least one minute, switch to the next concentration. Each concentration should be perfused for no more than five minutes.

[0864] 4) Clean the perfusion tank. Rinse the cells in descending order of concentration, rinsing for 20 seconds at each concentration. Finally, rinse with extracellular solution for 1 minute.

[0865] 2.3 Test voltage equation (resting) and results

[0866] Cells were clamped at -80 mV and then depolarized to 10 mV with a 10-millisecond square wave to elicit Nav1.8 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was measured and, after stabilization, the test compound was perfused. Once the response stabilized, the strength of the blockade was calculated.

[0867] 3. Data Analysis

[0868] Data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Management will review the results. Current stability refers to the current variation within a limited range over time. The magnitude of this stable current is used to calculate the effect of the compound at that concentration.

[0869] The inhibitory activity of the disclosed compounds on Nav1.8 was determined by the above test, and the measured IC 50 See Table 1 for values.

[0870] Table 1. IC values ​​of the compounds disclosed herein for inhibition of Nav1.8 channel activity 50

[0871] Conclusion: The compounds disclosed in the present invention have a significant inhibitory effect on the activity of Nav1.8 channels.

[0872] Test Example 2: Pharmacokinetic Evaluation

[0873] 1. SD rat experiment

[0874] 1. Abstract

[0875] SD rats were used as test animals, and the plasma drug concentrations at different time points after gavage (ig) of the example compounds were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in SD rats was studied and their pharmacokinetic characteristics were evaluated.

[0876] 2. Experimental plan

[0877] 2.1 Investigational Drugs

[0878] Example 5 compound.

[0879] 2.2 Experimental animals

[0880] Four SD rats, half male and half female, were provided by Weitonglihua Experimental Animal Technology Co., Ltd. After fasting overnight, they were gavaged and given the drug.

[0881] 2.3 Drug preparation

[0882] A certain amount of the example compounds were weighed respectively, and 5% DMSO + 5% Tween 80 + 90% normal saline were added to prepare a 0.2 mg / mL colorless clear solution.

[0883] 2.4 Administration

[0884] The dosage was 2 mg / kg, and the administration volume was 10.0 mL / kg.

[0885] 3. Operation

[0886] Before dosing and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after dosing, collect 0.2 mL of blood from the eye socket and place it in an EDTA-K2 anticoagulant tube. Centrifuge at 10,000 rpm for 1 minute (4°C). Plasma is separated within 1 hour and stored at -20°C until testing. The entire process from blood collection to centrifugation should be performed in an ice bath. Eat 2 hours after dosing.

[0887] To determine the test compound content in SD rat plasma after administration of various drug concentrations, 25 μL of SD rat plasma samples were collected at various times post-dose, vortexed, and mixed with 250 μL of an acetonitrile solution containing the internal standard (SHR3162 100 ng / mL). The mixture was then centrifuged at 3700 rpm for 10 minutes. The supernatant was mixed with water in a 1:1 ratio, and 0.5 μL of the supernatant was then sampled for LC / MS / MS analysis.

[0888] 4. Pharmacokinetic parameter results

[0889] Table 2. Pharmacokinetic parameters of the disclosed compounds in SD rats

[0890] Conclusion: The disclosed compounds have high blood concentration, high exposure, and high bioavailability in SD rats, and have obvious pharmacokinetic advantages.

[0891] 2. Mouse Experiment

[0892] 1. Abstract

[0893] CD-1 mice were used as test animals. LC / MS / MS was used to determine the plasma drug concentrations at different time points after gavage (ig) of the Example compounds in CD-1 mice. The pharmacokinetic behavior of the disclosed compounds in CD-1 mice was studied and their pharmacokinetic characteristics were evaluated.

[0894] 2. Experimental plan

[0895] 2.1 Investigational Drugs

[0896] Example 5 and Example 1-P1 compounds.

[0897] 2.2 Experimental animals

[0898] Eighteen male CD-1 mice were provided by Weitonglihua Laboratory Animal Technology Co., Ltd. They were divided into two groups and given the drug by gavage.

[0899] 2.3 Drug preparation

[0900] A certain amount of the example compounds were weighed respectively, and 25% PEG400 + 75% (10% TPGS + 1% HPMC K100LV) was added to prepare a 10 mg / mL solution (Example 1-P1: white suspension; Example 5: colorless slightly opaque solution).

[0901] 2.4 Administration

[0902] The dosage was 100 mg / kg, and the administration volume was 10.0 mL / kg.

[0903] 3. Operation

[0904] Before dosing and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after dosing, collect 0.1 mL of blood from the eye socket and place it in an EDTA-K2 anticoagulant tube. Centrifuge at 10,000 rpm for 1 minute (4°C). Plasma is separated within 1 hour and stored at -20°C until testing. The entire process from blood collection to centrifugation should be performed in an ice bath. Eat 2 hours after dosing.

[0905] Determination of the test compound content in CD-1 mouse plasma after administration of various drug concentrations: 20 μL of CD-1 mouse plasma samples were collected at various times post-dose, vortexed, and mixed with 250 μL of an acetonitrile solution containing an internal standard (Example 1-P1: verapamil 100 ng / mL; Example 5: tolbutamide 100 ng / mL). The mixture was then centrifuged at 3700 rpm for 15 minutes. The supernatant from Example 5 was mixed with water (1:1 ratio), and 1 μL of the supernatant was analyzed by LC / MS / MS.

[0906] In Example 1-P1 group, 120 μL of the supernatant was mixed with 50 μL of water, and 3 μL of the supernatant was used for LC / MS / MS analysis.

[0907] 4. Pharmacokinetic parameter results

[0908] Table 3. Pharmacokinetic parameters of the disclosed compounds in CD-1 mice

[0909] Conclusion: The disclosed compounds have high blood concentrations, high exposure, and low clearance in CD-1 mice, and have obvious pharmacokinetic advantages.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl; R A Selected from hydrogen, halogen, hydroxy, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4 、-alkylene-NR 3 R 4 , -O-alkylene-NR 3 R 4 、-C(=NR 5 )R 6 、-C(O)NR 3 R 4 、-C(O)R 6 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5 )(O)R 6 、=NR 5 、=CR 7 R 8 、-NR 5 C(O)R 6 、-NR 5 C(O)NR 3 R 4 、-P(O)R 7 R 8 、-C(O)NR 5 NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-C(O)C(O)NR 3 R 4 、-S(=NR 5 )NR 3 R 4 、-S(=NR 5 )R 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-alkylene-heteroaryl and -O-alkylene-heterocyclyl, wherein the alkenyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by; Each R B are the same or different and are each independently selected from halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 3 、R 4 and R 5 are the same or different and are each independently selected from hydrogen atom, alkyl, alkoxy, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 NR 22 C(O)R 23 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、S(O) v R 23 、S(O) v OR 23 、OS(O) v R 23 、S(O) v NR 20 R 21 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by; or R 3 、R 4 and the nitrogen atom to which it is attached together form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 replaced by; R 6 、R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 NR 22 C(O)R 23 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、S(O) v R 23 、S(O) v OR 23 、OS(O) v R 23 、S(O) v NR 20 R 21 , OR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 01 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, -NHalkyl, -N(alkyl), acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group and hydroxyalkyl group; R' is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group; X is O or S; R a and R b are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are each independently optionally replaced by one or more R 02 replaced by; R c and R d are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are each independently optionally replaced by one or more R 02 replaced by; or, R a 、R b and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; or, R c 、R d and the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R 02 replaced by; R e is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl; Each R 02 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; X 1 CR X1 or N; X 2 CR X2 or N; X 3 CR X3 or N; X 4 CR X4 or N; X 5 CR X5 or N; The condition is that X 1 、X 2 、X 3 、X 4 and X 5 Not all N at the same time; R X1 、R X2 、R X3 、R X4 and R X5 are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, amide, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, -O-(CH2) n -cycloalkyl, -O-(CH2) s -heterocyclic, aryl and heteroaryl; wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by; Each R 03 are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; v is selected from 0, 1 and 2; n is selected from 0, 1, 2, 3, 4 and 5; s is selected from 0, 1, 2, 3, 4, and 5; and, r is selected from 0, 1, 2, 3, 4 and 5.

2. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: in: R a and R b Different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy; said 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy are optionally substituted by one or more R 02 replaced by; R c and R d Different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy; said 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy are optionally substituted by one or more R 02 replaced by; Cyclopentyl, R A 、R B , R', X, R X1 、R X2 、R X3 、R 02 and r as defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the ring Cy is selected from Preferably, ring Cy is selected from More preferably * end is connected to -C(O)NR'-, and R A and R B Connect to any position of the ring Cy.

4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Selected from R C is a hydrogen atom or R B , R A and R B As defined in claim 1; Preferably selected from More preferably selected from Most preferably 5. The compound of any one of claims 1 to 4, wherein R a C 1-6 Alkyl; preferably, R a For CH3.

6. The compound of any one of claims 1 to 5, wherein R b Halogenated C 1-6 Alkyl; preferably, R b It is CF3.

7. The compound of any one of claims 1 to 6, wherein R c is a hydrogen atom, and R d C 1-6 Alkyl; preferably, R c is a hydrogen atom, and R d For CH3. 8 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein X is O.

9. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R A is selected from hydrogen, halogen, hydroxy, amino and =NH; preferably, R A is a hydrogen atom, a hydroxyl group or an amino group; more preferably, R A A hydrogen atom. 10 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R′ is a hydrogen atom.

11. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R B are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl; preferably, each R B The same or different, and each independently halogen or C 1-6 alkyl.

12. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R X1 C 1-6 Alkoxy; preferably, R X1 It is a methoxy group.

13. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R X2 is halogen; preferably, R X2 is a fluorine atom.

14. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R X3 is halogen; preferably, R X3 is a fluorine atom.

15. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is selected from the following compounds:

16. A compound represented by general formula (II-A) or general formula (II-1A) or a salt thereof: in, R 9 C 1-6 alkyl; R 11 、R 12 and R 13 are all amino protecting groups, preferably Boc; Cyclopentyl, R B , R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 and r as defined in claim 2.

17. A compound or a salt thereof selected from the group consisting of:

18. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by general formula (II-A) or its salt undergoes aminolysis or hydrolysis reaction to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt, wherein: R A is hydroxyl or amino; R 9 C 1-6 alkyl; Cyclopentyl, R B , R', X, R a 、R b 、R c 、R d 、R X1 、R X2 、R X3 and r as defined in claim 2.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.

8.

21. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the preparation of a medicament for treating and / or alleviating pain and pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

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