Benzofuran compound as TRPM3 antagonist

Abstract

The present invention provides a compound represented by formula I, a tautomer thereof, a stereoisomer thereof, an oxide thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. The compound can be used as an antagonist of TRPM3.

Description

Benzofuran compounds as trpm3 antagonists

[0001] Priority information

[0002] The present disclosure claims priority to and the benefit of Chinese Patent Application No. 202410866369.4, filed June 28, 2024, Chinese Patent Application No. 202411174081.7, filed August 23, 2024, Chinese Patent Application No. 202411392941.4, filed September 30, 2024, Chinese Patent Application No. 202411657894.1, filed November 19, 2024, Chinese Patent Application No. 202510120872.X, filed January 24, 2025, and Chinese Patent Application No. 202510559317.7, filed April 29, 2025, and incorporates by reference the entire contents of each of the foregoing applications. TECHNICAL FIELD

[0003] The present invention belongs to the field of medicine, in particular, the present invention relates to a benzofuran compound as a transient receptor potential m 3 (TRPM3) antagonist and uses thereof. BACKGROUND

[0004] The TRP (transient receptor potential) superfamily consists of proteins with six transmembrane domains (6TM) that assemble as homo- or hetero-tetramers to form cation- permeable ion channels. The TRP superfamily consists of 27 cation channels, divided into 7 families: canonical TRP channels (TRPC), vanilloid receptor and related TRP channels (TRPV), melastatin-like TRP channels (TRPM), TRPA1, mucolipin-related TRP channels (TRPML), and polycystic kidney disease-related TRP proteins (TRPP), TRPN1.

[0005] Members of the TRP superfamily can be expressed in all mammalian organs and cell types, and great progress has been made in recent years in understanding their physiological roles. The sensitivity of TRP channels to a wide range of chemical and physical stimuli allows them to function as dedicated biosensors, involved in processes from vision to taste and touch. In particular, several members of the TRP superfamily exhibit very high sensitivity to temperature. These so-called ThermoTRPs are highly expressed in sensory neurons and / or skin keratinocytes, where they act as thermal sensors for detecting innocuous and noxious (painful) temperatures. TRP channel dysfunction is directly linked to the etiology of various genetic and acquired diseases.

[0006] TRPM subfamily members are divalent cation (Zn2+ , Mg 2+ , and Ca 2+ ) and Na + . TRPM channels are critical regulators of phosphatidylinositol PI(4,5)P2 channels. TRPM channels as important cellular sensors are involved in many physiological processes, including ion homeostasis, blood pressure, heart rhythm and immunity, central, etc. TRPM3 (transient receptor potential melastatin 3) is a Ca 2+ permeable non-selective cation channel expressed in nociceptive neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG). Neurosteroid pregnenolone sulfate is a known agonist of TRPM3. Neurosteroid pregnenolone sulfate causes pain in wild-type mice, but not in TRPM3 knockout mice. It has also recently been shown that complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain is eliminated in TRPM3 knockout mice. Thus, TRPM3 antagonists can be used as analgesics to counteract pain, such as inflammatory pain. The relationship between TRPM3 and epilepsy has also been demonstrated.

[0007] There is still an urgent need for new, alternative and / or better TRPM3 antagonists for the prevention or treatment of TRPM3-mediated diseases, especially pain, such as inflammatory pain and epilepsy. SUMMARY

[0008] The object of the present application is to provide a benzofuran compound as a TRPM3 antagonist, which has a structure as shown in the first aspect of the present application, and the use thereof, which can be used for the preparation of a medicament, a pharmaceutical composition or a preparation for treating and / or preventing a disease or a disorder associated with TRPM3; or treating and / or preventing a disease or a disorder associated with TRPM3.

[0009] In a first aspect of the present application, a compound represented by Formula I, a tautomer, a stereoisomer, an oxide, a pharmaceutically acceptable salt or a prodrug thereof is provided:

[0010] wherein R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)-NRa -S(=O)2-NR a -C(=O)R a -C(=O)OR a -C(=O)NR a R b ; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, Ci-C6alkyl, Ci-C6alkoxy;

[0011] L is selected from the group consisting of -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)(R a )-;

[0012] R2is selected from the group consisting of NR 21 R 22 ;

[0013] R 21 , R 22 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, oxo (=O), Ci-C6alkyl, Ci-C6deuteroalkyl, Ci-C6haloalkyl, Ci-C6alkylene-OH, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a , -S(=NR a )(=O)R a ;

[0014] or, R21 R 22 R a R a R a R a R a R a R a R a R a R R

[0015] R R

[0016] R R

[0017] R a R a R a R a R a R a R a R a R a R-C1-C6alkylene-S(=0)-, -C1-C6alkylene-S(=0)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-0-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-0-C0-C6alkylene, C0-C6alkyl-3-6 membered cycloalkyl-C0-C6alkyl, C0-C6alkyl-3-6 membered heterocycloalkyl-C0-C6alkyl, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6-8 membered aryl-C0-C6alkylene optionally substituted with 1, 2, 3, 4, 5 R m substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; m each R is independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0018] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0019] R4is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0020] or, two R4and the C atom to which they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0021] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0022] R a , R bEach group is independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0023] When M is selected from C1-C5 alkyleneoxy groups, the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and -L-R2 is selected from -C(=O)-NHR. 22 At that time, the R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are bonded with hydroxyl groups and -C(=NH)S(=O)2R a Substitution, or, the C1-C6 alkyl group is replaced by -OC(=O)NH2 and -C(=O)NR a R b Substitution, or, the C1-C6 alkyl group is replaced by a hydroxyl group and -S(=NRa)(=O)R a Substitution, or, the C1-C6 alkyl group is replaced by -S(=NRa)(=O)R a replace.

[0024] In a preferred embodiment of the present invention, compounds of Formula I, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs are provided:

[0025] Wherein, R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -S(=O)-NR a -、-S(=O)2-NR a -、-C(=O)R a -C(=O)OR a -C(=O)NR a R b; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, Ci-C6alkyl, Ci-C6alkoxy;

[0026] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)(R a )-;

[0027] R2is selected from NR 21 R 22 ;

[0028] R 21 , R 22 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, oxo (=O), Ci-C6alkyl, Ci-C6deuteroalkyl, Ci-C6haloalkyl, Ci-C6alkyl-OH, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a , -S(=NR a )(=O)R a ;

[0029] or, R 21 , R 224-8 membered heterocycloalkyl, 5-8 membered heteroaryl with the N atom of its attachment; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy;

[0030] R3is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0031] m is selected from 1, 2, 3;

[0032] M is selected from the group consisting of a bond, -O-, -S(=O)R a -, -S(=O)2R a -, -S(=O)NR a -, -S(=O)2NR a -, -C(=O)R a -, -C(=O)OR a -, -C(=O)NR a -, C1-C6alkylene, -C1-C6alkylene-S-, -C1-C6alkylene-NR a -, -C1-C6alkylene-S(=O)-, -C1-C6alkylene-S(=O)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-O-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-O-C0-C6alkylene, C0-C6alkylene-3-6 membered cycloalkyl-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-C0-C6alkylene, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6-8 membered aryl-C0-C6alkylene; said C1-C6alkylene, -C1-C6alkylene-S-, -C1-C6alkylene-NR a-C1-C6alkylene-S(=0)-, -C1-C6alkylene-S(=0)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-0-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-0-C0-C6alkylene, C0-C6alkyl-3-6 membered cycloalkyl-C0-C6alkyl, C0-C6alkyl-3-6 membered heterocycloalkyl-C0-C6alkyl, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6-8 membered aryl-C0-C6alkylene optionally substituted with 1, 2, 3, 4, 5 R m substituents; said R m each R4is independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0033] Ring A is selected from the group consisting of 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0034] R4is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0035] or, two R4and the C atom to which they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0036] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0037] R a , R beach independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0038] when M is selected from C1-C5alkyleneoxy, said C1-C5alkyleneoxy optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, C1-C6alkyl, C1-C6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -L-R2is selected from -C(=O)-NHR 22 ; said R 22 is selected from C1-C6alkyl, said C1-C6alkyl substituted with hydroxyl and -C(=NH)S(=O)2R a , or, said C1-C6alkyl substituted with -OC(=O)NH2and -C(=O)NR a ; said R b is selected from C1-C6alkyl, said C1-C6alkyl substituted with hydroxyl and -S(=NRa)(=O)R a .

[0039] In a preferred embodiment of the present application, there is provided a compound of Formula I, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0040] wherein R1is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)-NR a -, -S(=O)2-NR a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a ; and R b; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, Ci-C6alkyl, Ci-C6alkoxy;

[0041] L is selected from the group consisting of -C(=O)-, -S(=O)-, -S(=O)2-, a

[0042] R2is selected from the group consisting of NR 21 R 22 ;

[0043] R 21 , R 22 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, oxo (=O), Ci-C6alkyl, Ci-C6deuteroalkyl, Ci-C6haloalkyl, Ci-C6alkyl-OH, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a , -S(=NR a )(=O)R a ;

[0044] or, R 21 , R 22 ​4-8 membered heterocycloalkyl, 5-8 membered heteroaryl with the N atom of attachment; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy;

[0045] R3is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0046] m is selected from 1, 2, 3;

[0047] M is selected from -S(=O)NR a -, -S(=O)2NR a -, -C(=O)OR a -, C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-O-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-O-C0-C6alkylene; said C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-O-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-O-C0-C6alkylene is optionally substituted with 1, 2, 3, 4, 5 R m each independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; m each independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0048] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0049] R4is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0050] or, two R4and the C atom to which they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0051] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0052] R a , R b are each independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0053] when M is selected from C1-C5alkyleneoxy, said C1-C5alkyleneoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -L-R2is selected from -C(=O)-NHR 22 , -C(=O)-NR 22 , -C(=O)-OR a , -C(=O)-SR a , -C(=O)-S(=O)2R b , -C(=O)-S(=O)2NR a , -C(=O)-NR a , -C(=O)-NHS(=O)2R

[0054] In a preferred embodiment of the present application, there is provided a compound of Formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0055] wherein R1is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NRb C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)-NR a , -S(=O)2-NR a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b ; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, Ci-C6alkyl, Ci-C6alkoxy;

[0056] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)(R a )-;

[0057] R2is selected from NR 21 R 22 ;

[0058] R 21 , R 22 are each independently selected from the group consisting of: hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, oxo (=O), Ci-C6alkyl, Ci-C6deuteroalkyl, Ci-C6alkyl-OH, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a, -C(=O)R a ;

[0059] R 21 , R 22 and the N atom to which it is attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy;

[0060] R3is selected from the group consisting of: deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0061] m is selected from 1, 2, 3;

[0062] M is selected from the group consisting of: a bond, -O-, -S(=O)R a -, -S(=O)2R a -, -S(=O)NR a -, -S(=O)2NR a -, -C(=O)R a -, -C(=O)OR a -, -C(=O)NR a -, C1-C6alkylene, -C1-C6alkylene-S-, -C1-C6alkylene-NR a -, -C1-C6alkylene-S(=O)-, -C1-C6alkylene-S(=O)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-O-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-O-C0-C6alkylene, C0-C6alkylene-3-6 membered cycloalkyl-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-C0-C6alkylene, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6-8 membered aryl-C0-C6alkylene; said C1-C6alkylene, -C1-C6alkylene-S-, -C1-C6alkylene-NR a-C1-C6alkylene-S(=0)-, -C1-C6alkylene-S(=0)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3-6 membered cycloalkyl-0-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-0-C0-C6alkylene, C0-C6alkyl-3-6 membered cycloalkyl-C0-C6alkyl, C0-C6alkyl-3-6 membered heterocycloalkyl-C0-C6alkyl, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6-8 membered aryl-C0-C6alkylene optionally substituted with 1, 2, 3, 4, 5 R m substituents; said R m each R4is independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0063] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0064] R4is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0065] or, two R4and the C atom to which they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0066] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0067] R a , R beach independently selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0068] when M is selected from C1-C5alkyleneoxy, said C1-C5alkyleneoxy optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, C1-C6alkyl, C1-C6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -L-R2is selected from -C(=O)-NHR 22 22 , -OC(=O)NH2, and -C(=O)NR a R a R b .

[0069] In a preferred embodiment of the present application, there is provided a compound of Formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0070] wherein R1is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)-NR a , -S(=O)2-NR a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b ; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxyl; ​

[0071] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0072] R2is selected from NR 21 R 22 ;

[0073] R 21 , R 22 are each independently selected from hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a ;

[0074] or, R 21 , R 22 and the N atom to which they are attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy;

[0075] R3is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0076] m is selected from 1, 2, and 3;

[0077] M is selected from the bond, -O-, -S(=O)R a -、-S(=O)2R a -、-S(=O)NR a -、-S(=O)2NR a -、-C(=O)R a -、-C(=O)OR a -、-C(=O)NR a -, C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)-, -C1-C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyloxy group, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene, C0- C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene; wherein C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)-, -C1-C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyloxy group, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene, C0-C6 alkyl-3-6 membered cycloalkyl-C0-C6 alkyl, C0-C6 alkyl-3-6 membered heterocycloalkyl-C0-C6 alkyl, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene, optionally surrounded by 1, 2, 3, 4, or 5 Rs. m Replace; the R m Each is independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0078] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl;

[0079] R4is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0080] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0081] R a , R b are each independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0082] when M is selected from C1-C5alkyleneoxy, said C1-C5alkyleneoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from C1-C6alkyl, C1-C6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, said C1-C6alkyl, C1-C6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 R m , L-R2is selected from -C(=O)-NHR 22 ; 22 is selected from C1-C6alkyl, said C1-C6alkyl is substituted with hydroxyl and -C(=NH)S(=O)2R a .

[0083] In a preferred embodiment of the present application, there is provided a compound of Formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0084] wherein, R1is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NR b C(=O)R a , -SR a-S(=O)2R a -S(=O)2R a -S(=O)2R a -S(=O)2R a -C(=O)R a -C(=O)R a -C(=O)R a R b ; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl are optionally substituted by 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, Ci-C6alkyl, Ci-C6alkoxy;

[0085] L is selected from the group consisting of -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0086] R2is selected from the group consisting of NR 21 R 22 ;

[0087] R 21 , R 22 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl are optionally substituted by 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, Ci-C6alkyl, Ci-C6alkoxy, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)R a , -C(=NH)S(=O)2R a ;

[0088] or, R 21 , R 224-8 membered heterocycloalkyl, 5-8 membered heteroaryl with the N atom of attachment forming a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;

[0089] R3is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0090] m is selected from 1, 2, 3;

[0091] M is selected from the group consisting of a bond, -O-, -S(=O)R a -, -S(=O)2R a -, -S(=O)NR a -, -S(=O)2NR a -, -C(=O)R a -, -C(=O)OR a -, -C(=O)NR a -, C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)-, -C1-C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene; said C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a-C1-C6alkylene-S(=0)-, -C1-C6alkylene-S(=0)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkyl-3-6 membered cycloalkyl-C0-C6alkyl, C0-C6alkyl-3-6 membered heterocycloalkyl-C0-C6alkyl, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6-8 membered aryl-C0-C6alkylene optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0092] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0093] R4is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0094] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0095] R a , R b are each independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0096] when M is selected from C1-C5alkoxy, said C1-C5alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, LR2is selected from -C(=0)-NHR 22 , said R 22 is selected from C1-C6alkyl, said C1-C6alkyl is substituted with hydroxyl and -C(=NH)S(=0)2R asubstituted.

[0097] In a preferred embodiment of the present application, there is provided a compound of Formula I, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0098] wherein R1is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)-NR a -, -S(=O)2-NR a -, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b ; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxyl;

[0099] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0100] R2is selected from NR 21 R 22 ;

[0101] R 21 , R 22 are each independently selected from hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxyl, -C(=O)NR a R b , -OC(=O)Ra , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a ;

[0102] or, R 21 , R 22 and the N atom to which they are attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy;

[0103] R3is selected from the group consisting of: deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0104] m is selected from 1, 2, 3;

[0105] M is selected from the group consisting of: a bond, -O-, -S(=O)R a -, -S(=O)2R a -, -S(=O)NR a -, -S(=O)2NR a -, -C(=O)R a -, -C(=O)OR a -, -C(=O)NR a-C6alkylene, -Ci-C6alkylene-S-, -Ci-C6alkylene-S(=0)-, -Ci-C6alkylene-S(=0)2-, Ci-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, Ci-C6alkyleneoxy, Co-C6alkyl-3-6 membered cycloalkyl-Co-C6alkyl, Co-C6alkyl-3-6 membered heterocycloalkyl-Co-C6alkyl, Co-C6alkylene-5-8 membered heteroaryl-Co-C6alkylene, Co-C6alkylene-6-8 membered aryl-Co-C6alkylene; said Ci-C6alkylene, -Ci-C6alkylene-S-, -Ci-C6alkylene-S(=0)-, -Ci-C6alkylene-S(=0)2-, Ci-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, Ci-C6alkyleneoxy, Co-C6alkyl-3-6 membered cycloalkyl-Co-C6alkyl, Co-C6alkyl-3-6 membered heterocycloalkyl-Co-C6alkyl, Co-C6alkylene-5-8 membered heteroaryl-Co-C6alkylene, Co-C6alkylene-6-8 membered aryl-Co-C6alkylene are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, cyano, Ci-C6alkyl, Ci-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0106] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0107] R4is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said Ci-C6alkyl, Ci-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, cyano, Ci-C6alkyl, Ci-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0108] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0109] R a , R beach independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0110] when M is selected from C1-C5alkoxy, said C1-C5alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, L is not -C(=O)-, or LR2is selected from -C(=O)-NHR 22 , said R 22 is selected from C1-C6alkyl, said C1-C6alkyl is substituted with hydroxyl and -C(=NH)S(=O)2R a .

[0111] In a preferred embodiment of the application, there is provided a compound of Formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0112] wherein R1is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)-NR a -, -S(=O)2-NR a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b ; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0113] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0114] R2is selected from NR 21 R 22 ;

[0115] R 21 , R 22 each independently is selected from hydrogen, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a ;

[0116] or, R 21 , R 22 and the N atom to which they are attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy;

[0117] R3is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy;

[0118] m is selected from 1, 2, 3;

[0119] M is selected from a bond, -O-, -S(=O)R a -, -S(=O)2Ra - S(=0)2NR a - S(=0)2NR a - C(=0)R a - C(=0)OR a - C(=0)NR a - C(=0)NR a - C(=0)NR b - C(=0)NR

[0120] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl;

[0121] R4is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0122] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0123] R a , R beach independently selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0124] when M is selected from C1-C5alkoxy, said C1-C5alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, L is not -C(=O)-, or LR2is selected from -C(=O)-NHR 22 22 selected from C1-C6alkyl, said C1-C6alkyl is substituted with hydroxyl and -C(=NH)S(=O)2R a .

[0125] In a preferred embodiment of the application, the 3-14 membered heterocycloalkyl in ring A is selected from 3-14 membered heterocycloalkyl monocyclic rings, 7-14 membered heterocycloalkyl bicyclic rings containing 1, 2, 3 or 4 heteroatoms, said heteroatoms being selected from N, O, S; and said N and S atoms can be in their oxidized form. In a preferred embodiment of the application, the 3-14 membered heterocycloalkyl in ring A is selected from 3-14 membered heterocycloalkyl monocyclic rings, 7-14 membered heterocycloalkyl bicyclic rings containing 1, 2, 3 or 4 heteroatoms, said heteroatoms being selected from N, O, S.

[0126] In a preferred embodiment of the application, the 3-14 membered heterocycloalkyl in ring A is selected from 3-14 membered heterocycloalkyl monocyclic rings, 7-14 membered heterocycloalkyl bicyclic rings containing 1, 2, 3 or 4 heteroatoms, said heteroatoms being selected from N, O, S.

[0127] In a preferred embodiment of the application, the 3-14 membered heterocycloalkyl in ring A is selected from 3-14 membered heterocycloalkyl monocyclic rings, 7-14 membered heterocycloalkyl bicyclic rings containing 1, 2, 3 or 4 heteroatoms, said heteroatoms being selected from N, O, S.

[0128] In a preferred embodiment of the application, the 5-10 membered heteroaryl in ring A is selected from 5-10 membered heteroaryl monocyclic rings, 8-10 membered heteroaryl bicyclic rings containing 1, 2, 3 or 4 heteroatoms, said heteroatoms being selected from N, O, S; and said N and S atoms can be in their oxidized form.

[0129] In a preferred embodiment of the application, the 5-10 membered heteroaryl in ring A is selected from 5-10 membered heteroaryl monocyclic rings, 8-10 membered heteroaryl bicyclic rings containing 1, 2, 3 or 4 heteroatoms, said heteroatoms being selected from N, O, S.

[0130] ​In a preferred embodiment of the present application, the 6-10 membered aryl in ring A is selected from the group consisting of 6-10 membered aryl monocyclic, 7-10 membered aryl bicyclic.

[0131] In a preferred embodiment of the present application, the 3-14 membered heterocycloalkyl, 5-10 membered heteroaryl in ring A is selected from the group consisting of 3-14 membered heterocycloalkyl monocyclic, 7-14 membered heterocycloalkyl bicyclic, 5-10 membered heteroaryl monocyclic, 8-10 membered heteroaryl bicyclic, containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S; and the N and S atoms can be in their oxidized form.

[0132] In a preferred embodiment of the present application, the 3-14 membered heterocycloalkyl, 5-10 membered heteroaryl in ring A is selected from the group consisting of 3-14 membered heterocycloalkyl monocyclic, 7-14 membered heterocycloalkyl bicyclic, 5-10 membered heteroaryl monocyclic, 8-10 membered heteroaryl bicyclic, containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S.

[0133] In a preferred embodiment of the present application, the 3-14 membered heterocycloalkyl, 6-10 membered heteroaryl in ring A is selected from the group consisting of 3-14 membered heterocycloalkyl monocyclic, 7-14 membered heterocycloalkyl bicyclic, 6-10 membered heteroaryl monocyclic, 8-10 membered heteroaryl bicyclic, containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S; and the N and S atoms can be in their oxidized form.

[0134] In a preferred embodiment of the present application, the 3-14 membered heterocycloalkyl, 6-10 membered heteroaryl in ring A is selected from the group consisting of 3-14 membered heterocycloalkyl monocyclic, 7-14 membered heterocycloalkyl bicyclic, 6-10 membered heteroaryl monocyclic, 8-10 membered heteroaryl bicyclic, containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S.

[0135] In a preferred embodiment of the present application, the ring A is selected from the group consisting of wherein the dotted line represents a single or double bond; X1, X2, X3, X4, X5and X6are each independently selected from the group consisting of NR4, CR4, CR4R4, C, N, N oxide, O, S; ring B and ring D are each independently selected from the group consisting of phenyl ring, 7-10 aryl ring, 5-10 membered heteroaryl ring, 4-8 membered heterocycloalkyl, 4-8 membered cycloalkyl; the heteroatoms are selected from the group consisting of N, O, S; and the N and S atoms can be in their oxidized form.

[0136] In a preferred embodiment of the present application, the ring A is selected from the group consisting of wherein the dotted line represents a single or double bond; X1, X2, X3, X4, X5and X6are each independently selected from the group consisting of NR4, CR4, CR4R4, C, N, O, S; ring B and ring D are each independently selected from the group consisting of phenyl ring, 7-10 aryl ring, 5-10 membered heteroaryl ring, 4-8 membered heterocycloalkyl, 4-8 membered cycloalkyl.

[0137] In a preferred embodiment of the present application, said ring A is selected from wherein the dotted line represents a single or double bond; each of X1, X2, X3, X4, X5and X6is independently selected from NR4, CR4, N, O, S; each of ring B and ring D is independently selected from phenyl ring, 7-10 aromatic ring, 5-10 membered heteroaromatic ring, 4-8 membered heterocycloalkyl, 4-8 membered cycloalkyl.

[0138] In a preferred embodiment of the present application, said ring A is selected from wherein the dotted line represents a single or double bond; X1is selected from C, each of X2, X3, X4, X5and X6is independently selected from NR4, CR4, N, each of ring B and ring D is independently selected from phenyl ring, 5-6 membered heteroaromatic ring, 5-6 membered heterocycloalkyl, 5-6 membered cycloalkyl.

[0139] In a preferred embodiment of the present application, said ring A is selected from wherein is selected from wherein the dotted line represents a single or double bond; each of Y1, Y2, Y3, Y4, Y7, Y8, Y9, Y 10 is independently selected from NR4, CR4, CR4R4, N, N oxide, O, S; each of Y5and Y6is independently selected from NR4, CR4, C, N; or, two R4in CR4R4and the C atom to which they are attached form a 3-4 membered cycloalkyl, 3-4 membered heterocycloalkyl.

[0140] In a preferred embodiment of the present application, said ring A is selected from wherein is selected from wherein the dotted line represents a single or double bond; each of Y1, Y2, Y3, Y4, Y7, Y8, Y9, Y 10 is independently selected from NR4, CR4, CR4R4, N, O, S; each of Y5and Y6is independently selected from NR4, CR4, C, N; or, two R4in CR4R4and the C atom to which they are attached form a 3-4 membered cycloalkyl, 3-4 membered heterocycloalkyl.

[0141] In a preferred embodiment of the present application, said ring A is selected from wherein is selected from wherein the dotted line represents a single or double bond; each of Y1, Y2, Y3, Y4, Y7, Y8, Y9, Y 10 is independently selected from NR4, CR4, N, O, S; each of Y5and Y6is independently selected from NR4, CR4, N.

[0142] In a preferred embodiment of the present application, said ring A is selected from wherein is selected from wherein the dotted line represents a single or double bond; Y1, Y2, Y3, Y4, Y7, Y8, Y9, Y 10 each independently selected from NR4, CR4, N, O, S; Y5and Y6are each independently selected from NR4, CR4, N.

[0143] In a preferred embodiment of the present application, said ring A is selected from when is selected from wherein the dotted line represents a single or double bond; Y1, Y2, Y3, Y4are each independently selected from NR4, CR4, N, O, S; Y5and Y6are each independently selected from NR4, CR4, N.

[0144] In a preferred embodiment of the present application, said ring A is selected from wherein is selected from wherein the dotted line represents a single or double bond; Y1, Y2, Y3, Y4, Y7, Y8are each independently selected from C, CR4, CR4R4, NR4, N, N oxide; Y6is selected from N, CR4, C; Y9is selected from NR4, N, N oxide, CR4R4, CR4, O, S.

[0145] In a preferred embodiment of the present application, said ring A is selected from wherein is selected from wherein the dotted line represents a single or double bond; Y1, Y2, Y3, Y4, Y7, Y8are each independently selected from CR4, CR4R4, NR4, N; Y6is selected from N, CR4, C.

[0146] In a preferred embodiment of the present application, said ring A is selected from when is selected from wherein the dotted line represents a single or double bond; Y1, Y2, Y3, Y4, Y7, Y8are each independently selected from CR4, N.

[0147] In a preferred embodiment of the application, said ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuro-pyridine, benzene ring, indene, naphthalene, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyrimidopiperidine, pyridazinopiperidine, pyrazinopiperidine, benzotetrahydropyrrole, tetrahydronaphthridine, pyridocyclopentanospipro-cyclopropane, pyridotriazole, pyridotetrahydrofuran, triazolopiperazine, benzopyrazole, benzopyridine, pyridotetrahydropyrrole, indazol, benzimidazole, pyrimidopyrrole, pyridopyridine, pyridopyrrole, pyridazinopyrrole, thiazolocyclopentyl, and N-oxides thereof.

[0148] In a preferred embodiment of the application, said ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuro-pyridine, benzene ring, indene, naphthalene, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyrimidopiperidine, pyridazinopiperidine, pyrazinopiperidine, benzotetrahydropyrrole, tetrahydronaphthridine, pyridocyclopentanospipro-cyclopropane, pyridotriazole, pyridotetrahydrofuran, triazolopiperazine, benzopyrazole, pyridotetrahydropyrrole, indazol, benzimidazole, pyrimidopyrrole, and N-oxides thereof.

[0149] In a preferred embodiment of the application, said ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuro-pyridine, benzene ring, indene, naphthalene, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyrimidopiperidine, pyridazinopiperidine, pyrazinopiperidine, benzotetrahydropyrrole, tetrahydronaphthridine, pyridocyclopentane spirocyclopropane, pyridotriazole, pyridotetrahydrofuran, triazolopiperazine, benzopyrazole.

[0150] In a preferred embodiment of the application, said ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuro-pyridine, benzene ring, indene, naphthalene, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyrimidopiperidine, pyridazinopiperidine, pyrazinopiperidine, benzotetrahydropyrrole.

[0151] In a preferred embodiment of the application, said ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuro-pyridine, benzene ring, indene, naphthalene, pyridopiperidine, pyrimidopiperidine, pyridazinopiperidine, pyrazinopiperidine, benzotetrahydropyrrole.

[0152] In a preferred embodiment of the application, said ring A is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrothiazolyl, dihydrotetrazolyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuropyridine, benzene ring, indene, naphthalene.

[0153] In a preferred embodiment of the application, said ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, benzopyridine, benzopyrazole, benzimidazole, tetrahydroquinoline, tetrahydroisoquinoline, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyridopyrimidine, pyridazinopyrrole, pyridofuran,

[0154] In a preferred embodiment of the application, said ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine,

[0155] In a preferred embodiment of the application, said ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine

[0156] In a preferred embodiment of the application, said ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine.

[0157] In a preferred embodiment of the application, said ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline.

[0158] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0159] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0160] In a preferred embodiment of the present application, said two R4form, with the C atom to which they are attached, a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0161] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0162] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy; said C1-C6alkyl, C1-C6alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0163] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran; said C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, amino, C1-C3alkyl, C1-C3alkoxy, oxo.

[0164] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran; said C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, oxo.

[0165] In a preferred embodiment of the present application, said R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran; said C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, oxo.

[0166] In a preferred embodiment of the present application, said R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran; said cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetanyl, tetrahydropyrrole, tetrahydrofuran are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, oxo.

[0167] In a preferred embodiment of the present application, said R4is selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran; said cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of halogen, hydroxy, C1-C3alkyl, oxo.

[0168] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C2-C4alkenyl, C2-C4alkynyl, cyclopropyl, cyclobutyl, azetidinyl; said C1-C3alkyl, C1-C3haloalkyl, C2-C4alkenyl, C2-C4alkynyl, cyclopropyl, cyclobutyl, azetidinyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of F, hydroxy, amino, C1-C3alkyl, C1-C3alkoxy, oxo.

[0169] In a preferred embodiment of the present application, said R4is selected from the group consisting of deuterium, hydrogen, halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C2-C4alkenyl, C2-C4alkynyl, cyclopropyl, cyclobutyl, azetidinyl, F substituted azetidinyl; said C2-C4alkenyl, C2-C4alkynyl, cyclopropyl, cyclobutyl, azetidinyl are optionally substituted with 1, 2, 3, 4, 5 F.

[0170] In a preferred embodiment of the present application, said R4is selected from the group consisting of hydrogen, halogen, C1-C3alkyl, C1-C3haloalkyl, C2-C4alkenyl, C2-C4alkynyl, cyclopropyl, cyclobutyl, azetidinyl, F substituted azetidinyl; said C2-C4alkenyl, C2-C4alkynyl, cyclopropyl, cyclobutyl, azetidinyl are optionally substituted with 1, 2, 3, 4, 5 F.

[0171] In a preferred embodiment of the present application, said R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl.

[0172] In a preferred embodiment of the present application, said R4is selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl.

[0173] In a preferred embodiment of the present application, said R4is selected from the group consisting of hydrogen, halogen, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl, azetidinyl, F substituted azetidinyl.

[0174] In a preferred embodiment of the present application, said R4is selected from the group consisting of halogen, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl, azetidinyl, F substituted azetidinyl.

[0175] In a preferred embodiment of the present application, said R4is selected from hydrogen, halogen, C1-C3alkyl, C1-C3haloalkyl.

[0176] In a preferred embodiment of the present application, said R4is selected from halogen, C1-C3alkyl, C1-C3haloalkyl.

[0177] In a preferred embodiment of the present application, said R4is selected from hydrogen, C1-C3alkyl, C1-C3haloalkyl.

[0178] In a preferred embodiment of the present application, said R4is selected from C1-C3alkyl, C1-C3haloalkyl.

[0179] In a preferred embodiment of the present application, said R4is selected from deuterium, hydrogen, F, Cl, cyano, methyl, -C(=O)NH2, -CF3, -CHF2, -CH2F,

[0180] In a preferred embodiment of the present application, said R4is selected from deuterium, hydrogen, F, cyano, methyl, -CF3, -CHF2, -CH2F,

[0181] In a preferred embodiment of the present application, said R4is selected from hydrogen, F, methyl, -CF3, -CHF2, -CH2F,

[0182] In a preferred embodiment of the present application, said R4is selected from hydrogen, F, -CF3, -CHF2, -CH2F,

[0183] In a preferred embodiment of the present application, said R4is selected from F, -CF3, -CHF2, -CH2F,

[0184] In a preferred embodiment of the present application, said R4is selected from F, -CF3, -CHF2, -CH2F.

[0185] In a preferred embodiment of the present application, said R4is selected from -CF3, -CHF2, -CH2F.

[0186] In a preferred embodiment of the present application, said n is selected from 0, 1, 2, 3, 4.

[0187] In a preferred embodiment of the present application, said n is selected from 0, 1, 2, 3.

[0188] In a preferred embodiment of the present application, said n is selected from 1, 2.

[0189] In a preferred embodiment of the present application, n is selected from 0, 1, 2.

[0190] In a preferred embodiment of the present application, n is selected from 1.

[0191] In a preferred embodiment of the present application, n is selected from 0, 1, 2. is selected from phenyl,

[0192] In a preferred embodiment of the present application, n is selected from 0, 1, 2. is selected from

[0193] In a preferred embodiment of the present application, n is selected from 0, 1, 2. is selected from

[0194] In a preferred embodiment of the present application, n is selected from 0, 1, 2. is selected from

[0195] In a preferred embodiment of the present application, n is selected from 0, 1, 2. is selected from

[0196] In a preferred embodiment of the present application, n is selected from 0, 1, 2. a -, -S(=0)2NR a -, -C(=0)NR a -, -C1-C6alkylene-S-, -C1-C6alkylene-NR a -, -C1-C6alkylene-S(=0)2-, C1-C6alkylene, C1-C6alkylenoxy, C0-C3alkylene-3-6 membered cycloalkyl-O-C0-C3alkylene, C0-C3alkylene-3-6 membered heterocycloalkyl-O-C0-C3alkylene, C2-C6alkenylene, C0-C3alkylene-3-6 membered cycloalkyl-C0-C3alkylene, C0-C3alkylene-3-6 membered heterocycloalkyl-C0-C3alkylene, C0-C3alkylene-5-8 membered heteroaryl-C0-C3alkylene; said -C1-C6alkylene-S-, -C1-C6alkylene-NR a-, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, C0-C3 alkylene-3-6 membered cycloalkyl-O-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-O-C0-C3 alkylene, C2-C6 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C3 alkylene-5-8 membered heteroaryl-C0-C3 alkylene, optionally surrounded by 1, 2, 3, 4, or 5 Rs. m replace.

[0197] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2R a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, C0-C3 alkylene-3-6 membered cycloalkyl-O-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-O-C0-C3 alkylene, C2-C6 alkenyl, C0-C3 alkyl-3-6 membered cycloalkyl-C0-C3 alkyl, C0-C3 alkyl-3-6 membered heterocycloalkyl-C0-C3 alkyl, C0-C3 alkylene-5-8 membered heteroaryl-C0-C3 alkylene; wherein -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, C0-C3 alkylene-3-6 membered cycloalkyl-O-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-O-C0-C3 alkylene, C2-C6 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C3 alkylene-5-8 membered heteroaryl-C0-C3 alkylene, optionally surrounded by 1, 2, 3, 4, or 5 Rs. m replace.

[0198] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-NR a, -Ci-C3alkylene-S(=0)2-, Ci-C3alkylene, Ci-C3alkylenoxy, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, C2-C4alkenylene, Co-C3alkyl-3-6 membered cycloalkyl-Co-C3alkyl, Co-C3alkyl-3-6 membered heterocycloalkyl-Co-C3alkyl, Co-C6alkylene-5-8 membered heteroaryl-Co-C6alkylene; said -Ci-C3alkylene-S-, -Ci-C3alkylene-NR a , -Ci-C3alkylene-S(=0)2-, Ci-C3alkylene, Ci-C3alkylenoxy, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, C2-C4alkenylene, Co-C3alkyl-3-6 membered cycloalkyl-Co-C3alkyl, Co-C3alkyl-3-6 membered heterocycloalkyl-Co-C3alkyl, Co-C6alkylene-5-8 membered heteroaryl-Co-C6alkylene optionally substituted with 1, 2, 3, 4, 5 R m substituents selected from the group consisting of halogen, cyano, -OR

[0199] In a preferred embodiment of the present application, said M is selected from the group consisting of -S(=0)NR a , -S(=0)2NR a , -C(=0)OR a , Ci-C6alkylenoxy, Co-C6alkylene-3-6 membered cycloalkyl-O-Co-C6alkylene, Co-C6alkylene-3-6 membered heterocycloalkyl-O-Co-C6alkylene; said Ci-C6alkylenoxy, Co-C6alkylene-3-6 membered cycloalkyl-O-Co-C6alkylene, Co-C6alkylene-3-6 membered heterocycloalkyl-O-Co-C6alkylene is optionally substituted with 1, 2, 3, 4, 5 R m substituents selected from the group consisting of halogen, cyano, -OR

[0200] In a preferred embodiment of the present application, said R m is selected from the group consisting of deuterium, halogen, Ci-C3alkyl, Ci-C3alkoxy.

[0201] In a preferred embodiment of the present application, said R m is selected from the group consisting of F, methyl.

[0202] In a preferred embodiment of the present application, said R m is selected from the group consisting of F.

[0203] In a preferred embodiment of the present application, said M is selected from the group consisting of a bond, -0-, -S(=0)2R a , -S(=0)2NR a , -C(=0)NR a , -Ci-C6alkylene-S-, -Ci-C6alkylene-NRa -, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, C2-C6 alkenyl, C0-C6 alkyl-3-6 membered cycloalkyl-C0-C6 alkyl, C0-C6 alkyl-3-6 membered heterocycloalkyl-C0-C6 alkyl, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene; wherein -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, C2-C6 alkenyl, C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, optionally surrounded by 1, 2, 3, 4, or 5 Rs. m replace.

[0204] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2R a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-NR a -、-C1-C6 alkylene-S(=O)2-、C1-C6 alkylene, C1-C6 haloalkylene, C1-C6 alkyleneoxy, C1-C6 haloalkyleneoxy, C2-C6 alkenyl, C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene.

[0205] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2R a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-S(=O)2-、C1-C6 alkylene、C1-C6 haloalkylene、C1-C6 alkyleneoxy、C1-C6 haloalkyleneoxy、3-6 membered cycloalkyl-O-、3-6 membered heterocycloalkyl-O-、C2-C6 alkenyl、C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene、C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene、C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene

[0206] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2R a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-S(=O)2-、C1-C6 alkylene、C1-C6 haloalkylene、C1-C6 alkyleneoxy、C1-C6 haloalkyleneoxy、C2-C6 alkenyl、C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene、C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene、C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene

[0207] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2R a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-S(=O)2-、C1-C6 alkylene、C1-C6 haloalkylene、C1-C6 alkyleneoxy、C2-C6 alkenyl、C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene、C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene、C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene

[0208] In a preferred embodiment of the present invention, M is selected from the following: -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-O-, -CHF-O-, -CF2-O-, cyclopropyl-O-, cyclobutyl-O-, oxacyclobutyl-O-, aziridine-O-, vinylene, propyleneene, CO-C3 alkylene-3-5 membered cycloalkyl-CO-C3 alkylene, CO-C3 alkylene-3-5 membered heterocycloalkyl-CO-C3 alkylene, CO-C3 alkylene-5-8 membered heteroaryl-CO-C3 alkylene.

[0209] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-NR a-、-C1-C3 alkylene-S(=O)2-、C1-C3 alkylene, C1-C3 haloalkylene, C1-C3 alkyleneoxy, C1-C3 haloalkyleneoxy, 3-6 membered cycloalkyl-O-、3-6 membered heterocycloalkyl-O-、C2-C4 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C6 alkylene-5-8 membered heteroaryl.

[0210] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-NR a -、-C1-C3 alkylene-S(=O)2-、C1-C3 alkylene, C1-C3 haloalkylene, C1-C3 alkyleneoxy, C1-C3 haloalkyleneoxy, C2-C4 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C6 alkylene-5-8 membered heteroaryl.

[0211] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-S(=O)2-、C1-C3 alkylene、C1-C3 haloalkylene、C1-C3 alkyleneoxy、C1-C3 haloalkyleneoxy、C2-C4 alkenyl、C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene、C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene、C0-C6 alkylene-5-8 membered heteroaryl.

[0212] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-S(=O)2-、C1-C3 alkylene、C1-C3 haloalkylene、C1-C3 alkyleneoxy、C2-C4 alkenyl、C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene、C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene、C0-C6 alkylene-5-8 membered heteroaryl.

[0213] In a preferred embodiment of the present application, the 5-8 membered heteroaryl in M contains 1, 2, 3 heteroatoms, which are the same or different; the heteroatoms are selected from N, O, S.

[0214] In a preferred embodiment of the present application, M is selected from a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-O-, -CHF-O-, -CF2-O-, cyclopropyl-O-, cyclobutyl-O-, oxetanyl-O-, azetidinyl-O-, ethenylene, propenylene, Co-C3alkylene-3-5 membered cycloalkyl-Co-C3alkylene, Co-C3alkylene-3-5 membered heterocycloalkyl-Co-C3alkylene, C0-C3alkylene-5-8 membered heteroaryl-C0-C3alkylene.

[0215] In a preferred embodiment of the present application, the 5-8 membered heteroaryl in M is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine.

[0216] In a preferred embodiment of the present application, M is selected from a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-O-, -CHF-O-, -CF2-O-, cyclopropyl-O-, cyclobutyl-O-, oxetanyl-O-, azetidinyl-O-, ethenylene, propenylene, Co-C3alkylene-3-5 membered cycloalkyl-Co-C3alkylene, Co-C3alkylene-3-5 membered heterocycloalkyl-Co-C3alkylene, furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine.

[0217] In a preferred embodiment of the present application, said M is selected from the group consisting of a bond, -0-, -S(=0)2NH-, -C(=0)NH-, -CH2-S-, -CH2-S(=0)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-0-, -CHF-0-, -CF2-0-, ethenylene, propenylene, Co-C3alkylene-3-5 membered cycloalkyl-Co-C3alkylene, Co-C3alkylene-3-5 membered heterocycloalkyl-Co-C3alkylene, furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine.

[0218] In a preferred embodiment of the present application, said M is selected from the group consisting of a bond, -0-, -S(=0)2NH-, -C(=0)NH-, -CH2-S-, -CH2-S(=0)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-0-, -CHF-0-, -CF2-0-, ethenylene, propenylene, Co-C3alkylene-3-5 membered cycloalkyl-Co-C3alkylene, Co-C3alkylene-3-5 membered heterocycloalkyl-Co-C3alkylene, furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine.

[0219] In a preferred embodiment of the present application, said M is selected from the group consisting of a bond, -0-, -S(=0)2NH-, -C(=0)NH-, -CH2-S-, -CH2-S(=0)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-0-, ethenylene, propenylene, Co-C3alkylene-3-5 membered cycloalkyl-Co-C3alkylene, Co-C3alkylene-3-5 membered heterocycloalkyl-Co-C3alkylene, furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine.

[0220] In a preferred embodiment of the present application, said 3-6 membered cycloalkyl in M is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0221] In a preferred embodiment of the present application, said 3-6 membered heterocycloalkyl in M contains 1, 2, 3 heteroatoms, which are identical or different; said heteroatoms are selected from the group consisting of N, O, S.

[0222] In a preferred embodiment of the present application, the 3-6 membered heterocycloalkyl in M is selected from the group consisting of oxiranyl, oxetanyl, oxetanyl, aziridinyl, azetidinyl, tetrahydropyrrole, piperidine, piperazine.

[0223] In a preferred embodiment of the present application, the 3-6 membered heterocycloalkyl in M is selected from the group consisting of oxiranyl, oxetanyl, oxetanyl, aziridinyl, azetidinyl.

[0224] In a preferred embodiment of the present application, M is selected from the group consisting of -S(=O)2NH-, -CH2-O-, -CF2-O-, In a preferred embodiment of the present application, M is selected from the group consisting of a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-, -CF2-O-, -CF2-NH-, -CH2-N(CH3)-,

[0225] In a preferred embodiment of the present application, M is selected from the group consisting of a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-, -CF2-O-,

[0226] In a preferred embodiment of the present application, M is selected from the group consisting of a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-, -CF2-O-,

[0227] In a preferred embodiment of the present application, M is selected from the group consisting of a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-, -CF2-O-,

[0228] In a preferred embodiment of the present invention, M is selected from the following: -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-.

[0229] In a preferred embodiment of the present invention, when L is selected from -C (=O)-, M is selected from -O-, and ring A is selected from... When ring B and ring D are each independently selected from benzene rings, 7-10 aromatic rings, 5-10 heteroaromatic rings, 4-8 heterocyclic alkyl groups, and 4-8 cycloalkyl groups, ring B is not a benzene ring.

[0230] In a preferred embodiment of the present invention, when L is selected from -C (=O)-, M is selected from -O-, and ring A is selected from... And when ring B is a benzene ring, ring A is not.

[0231] In a preferred embodiment of the present invention, when M is selected from C1-C5 alkyleneoxy groups, the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and -L-R2 is selected from -C(=O)-NHR. 22 At that time, the R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are coated with hydroxyl groups and -C(=NH)S(=O)2R a replace.

[0232] In a preferred embodiment of the present invention, when M is selected from C1-C5 alkyleneoxy groups, the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and -L-R2 is selected from -C(=O)-NHR. 22 At that time, the R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are converted by -OC(=O)NH2 and -C(=O)NR a R b replace.

[0233] In a preferred embodiment of the present application, when M is selected from C1-C5 alkyleneoxy, said C1-C5 alkyleneoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -L-R2 is selected from -C(=O)-NHR 22 , said R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl is substituted with -S(=NRa)(=O)R a ;

[0234] In a preferred embodiment of the present application, when M is selected from C1-C5 alkyleneoxy, said C1-C5 alkyleneoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -L-R2 is selected from -C(=O)-NHR 22 , said R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl is substituted with -S(=NRa)(=O)R a ;

[0235] In a preferred embodiment of the present application, when M is selected from C1-C5 alkyleneoxy, said C1-C5 alkyleneoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -L-R2 is selected from -C(=O)-NHR 22 , said R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl is substituted with -C(=NH)S(=O)2R a or -OC(=O)NH2;

[0236] In a preferred embodiment of the present application, the compound is selected from the following structures:

[0237] when L is selected from -C(=O)-, said R 21 is selected from hydrogen, R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl is substituted with -S(=NR a )(=O)R a ;

[0238] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the present application.

[0239] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0240] when L is selected from -C(=O)-, R 21 is selected from hydrogen, R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl being substituted by hydroxy and -S(=NRa)(=O)R a ;

[0241] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the application.

[0242] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0243] when L is selected from -C(=O)-, R 21 is selected from hydrogen, R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl being substituted by hydroxy and -C(=NH)S(=O)2R a ;

[0244] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the application.

[0245] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0246] when L is selected from -C(=O)-, R 21 is selected from hydrogen, R 22 is selected from C1-C6 alkyl, said C1-C6 alkyl being substituted by -OC(=O)NH2 and -C(=O)NR a R b ;

[0247] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the application.

[0248] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0249] when L is selected from -C(=O)-, R 21 is selected from hydrogen, R22 C1-C6alkyl substituted with hydroxy and -C(=NH)S(=O)2R a substituted;

[0250] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the application.

[0251] In a preferred embodiment of the application, the compound is selected from the following structures:

[0252] L is selected from -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-; a

[0253] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the application.

[0254] In a preferred embodiment of the application, the compound is selected from the following structures:

[0255] L is selected from -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0256] ring A, R1, R3, R4, R a , R 21 , R 22 , L, m and n are as defined in the first aspect of the application. In a preferred embodiment of the application, the compound is selected from the following structures:

[0257] wherein the dotted line represents a single or double bond;

[0258] X2, X3, X4, X5and X6are each independently selected from NR4, CR4, CR4R4, C, N, N oxide;

[0259] Y1, Y2, Y3, Y4, Y7, Y8are each independently selected from CR4, N, N oxide, CR4R4, NR4, C;

[0260] Y5and Y6are each independently selected from CR4, C, N;

[0261] Y9and Y 10 are each independently selected from CR4, N, N oxide, CR4R4, NR4, O, S. ​

[0262] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0263] wherein the dotted line represents a single or double bond;

[0264] X2, X3, X4, X5, and X6are each independently selected from the group consisting of NR4, CR4, CR4R4, C, N;

[0265] Y1, Y2, Y3, Y4, Y7, Y8, Y9, and Y 10 are each independently selected from the group consisting of CR4, N, CR4R4, NR4, C.

[0266] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0267] wherein the dotted line represents a single or double bond;

[0268] X2, X3, X4, X5, and X6are each independently selected from the group consisting of NR4, CR4, N;

[0269] Y1, Y2, Y3, Y4, Y7, and Y8are each independently selected from the group consisting of CR4, N.

[0270] In a preferred embodiment of the application, X1, X2, X3, X4, X5, and X6are each independently selected from the group consisting of NR4, CR4, N, O, S.

[0271] In a preferred embodiment of the application, at least one of X2, X3, X4, X5, and X6is selected from N.

[0272] In a preferred embodiment of the application, at most 4 of X2, X3, X4, X5, and X6are selected from N.

[0273] In a preferred embodiment of the application, at least one of Y1, Y2, Y3, Y4, Y7, and Y8is selected from N.

[0274] In a preferred embodiment of the application, at most 4 of Y1, Y2, Y3, Y4, Y7, and Y8are selected from N.

[0275] In a preferred embodiment of the application, Y9is selected from the group consisting of CR4R4, CR4, O.

[0276] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0277] M, R1, R2, R3, R4, L, m and n are as defined in the first aspect of the application.

[0278] In a preferred embodiment of the application, the compound is selected from the following structures:

[0279] wherein at least one of Y1, Y2, Y3, Y4and Y8is selected from N;

[0280] M, R1, R2, R3, R4, L, m and n are as defined in the first aspect of the application.

[0281] In a preferred embodiment of the application, the compound is selected from the following structures:

[0282] wherein ring B is selected from a 7-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 4-8 membered heterocycloalkyl ring, a 4-8 membered cycloalkyl ring;

[0283] ring D is selected from a benzene ring, a 7-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 4-8 membered heterocycloalkyl ring, a 4-8 membered cycloalkyl ring;

[0284] R1, R2, R3, R4, m and n are as defined in the first aspect of the application.

[0285] In a preferred embodiment of the application, the compound is selected from the following structures:

[0286] wherein when ring B is a benzene ring, is not is selected from a single bond or a double bond, and ring D is selected from a benzene ring, a 7-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 4-8 membered heterocycloalkyl ring, a 4-8 membered cycloalkyl ring;

[0287] R1, R2, R3, R4, m and n are as defined in the first aspect of the application.

[0288] In a preferred embodiment of the application, the compound is selected from the following structures:

[0289] ring A, R1, R3, R4, R m , R 21 , R 22 , m and n are as defined in the first aspect of the application.

[0290] In a preferred embodiment of the application, the L-R2is selected from L-NR 21 R 22 ;

[0291] the R 21 , R 22Each is independently selected from hydrogen, hydroxyl group, and -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl;

[0292] The C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, and 5-8 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -OC (=O)R a -C(=O)NR a R b -NR b C(=O)R a -S(=O)2R a -C(=NH)S(=O)2R a -S(=NR) a (=O)R a .

[0293] In a preferred embodiment of the present invention, L-R2 is selected from L-NR. 21 R 22 ;

[0294] The R 21 R 22 Each is independently selected from hydrogen, hydroxyl group, and -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl;

[0295] The C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, and 5-8 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkyl-OH, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -OC (=O)R a -C(=O)NR a R b -NR b C(=O)R a -S(=O)2R a, -C(=NH)S(=O)2R a .

[0296] In a preferred embodiment of the application, said L-R2is selected from L-NR 21 R 22 ;

[0297] said R 21 , R 22 is each independently selected from the group consisting of hydrogen, hydroxyl, -S(=O)2R a , C1-C6alkyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl;

[0298] said C1-C6alkyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, -C(=O)NR a R b , -NR b C(=O)R a , -S(=O)2R a , -C(=NH)S(=O)2R a .

[0299] In a preferred embodiment of the application, said R 21 , R 22 and the N atom to which they are attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C3alkyl, C1-C3haloalkyl.

[0300] In a preferred embodiment of the application, said R 21 , R 22 and the N atom to which they are attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl.

[0301] In a preferred embodiment of the application, said R 21 , R 22 and the N atom to which they are attached form a N-hydropyrrolidine, pyrrole, tetrahydropyrrole, piperidine, pyridine; said N-hydropyrrolidine, pyrrole, tetrahydropyrrole, piperidine, pyridine is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, F, Cl, methyl, CF3.

[0302] In a preferred embodiment of the application, said R 21 , R 22each independently selected from hydrogen, hydroxyl, C1-C6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, said C1-C6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, oxo (=0), C1-C6alkyl, C1-C6deuterated alkyl, C1-C6halogenated alkyl, C1-C6alkylene-OH, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, -OC(=0)R a , -C(=0)NR a R b , -C(=NH)S(=0)2R a , -S(=NR a )(=0)R a .

[0303] In a preferred embodiment of the application, said R 21 , R 22 each independently selected from hydrogen, hydroxyl, C1-C6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, said C1-C6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, oxo (=0), C1-C6alkyl, C1-C6deuterated alkyl, C1-C6halogenated alkyl, C1-C6alkyl-OH, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, -OC(=0)R a , -C(=0)NR a R b , -C(=NH)S(=0)2R a , -S(=NR a )(=0)R a .

[0304] In a preferred embodiment of the application, said R 21 , R 22each independently selected from hydrogen, hydroxyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, said C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, oxo (=0), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkyl-OH, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, -OC(=0)R a , -C(=0)NR a R b , -C(=NH)S(=0)2R a .

[0305] In a preferred embodiment of the application, said R 21 , R 22 each independently selected from hydrogen, hydroxyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, said C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: hydroxyl, halogen, C1-C6 alkyl, -C(=0)NR a R b , -C(=NH)S(=0)2R a .

[0306] In a preferred embodiment of the application, said R 21 , R 22 each independently selected from hydrogen, hydroxyl, C1-C6 alkyl, said C1-C6 alkyl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: hydroxyl, halogen, C1-C6 alkyl, -C(=0)NR a R b , -C(=NH)S(=0)2R a .

[0307] In a preferred embodiment of the application, said L is selected from -C(=0)-, -S(=0)2-.

[0308] In a preferred embodiment of the application, said L-R2is selected from -C(=0)-NHR 22 , -S(=0)2-NHR 22 ; said R 22Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2, or 3 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkylene-OH, C1-C3 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC (=O)R a -C(=O)NR a R b -C(=NH)S(=O)2R a -S(=NH)(=O)R a .

[0309] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22 Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2, or 3 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkyl-OH, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC (=O)R a -C(=O)NR a R b -C(=NH)S(=O)2R a -S(=NH)(=O)R a .

[0310] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22 Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2, or 3 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 alkyl-OH, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC (=O)R a -C(=O)NR a R b -C(=NH)S(=O)2R a .

[0311] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally substituted by 1, 2, or 3 substituents selected from the following: hydroxyl, halogen, C1-C3 alkyl, -C(=O)NR a R b -C(=NH)S(=O)2R a .

[0312] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22 The group is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2, or 3 substituents selected from the following: hydroxyl, halogen, C1-C3 alkyl, -C(=O)NR. a R b -C(=NH)S(=O)2R a .

[0313] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22 The group is selected from C1-C6 alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents selected from the following: deuterium, F, hydroxyl, oxo (=O), trifluoroethyl, C1-C3 alkylene-OH, methoxy, cyclopropyl, cyclobutyl, -OC(=O)NH2, -C(=O)NH2, -C(=NH)S(=O)2CH3, methyl, deuterated methyl (-CD3), -S(=NH)(=O)CH3.

[0314] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22selected from the group consisting of C1-C6alkyl, 3-6 membered heterocycloalkyl, said C1-C6alkyl, 3-6 membered heterocycloalkyl optionally substituted with 1, 2, 3 substituents selected from the group consisting of deuterium, F, hydroxyl, oxo (=0), trifluoroethyl, C1-C3alkyl-OH, cyclopropyl, cyclobutyl, -OC(=0)NH2, -C(=0)NH2, -C(=NH)S(=0)2CH3, methyl, -CD3, -S(=NH)(=0)CH3.

[0315] In a preferred embodiment of the application, said L-R2is selected from the group consisting of -C(=0)-NHR 22 , -S(=0)2-NHR 22 ; said R 22 is selected from the group consisting of C1-C6alkyl, 3-6 membered heterocycloalkyl, said C1-C6alkyl, 3-6 membered heterocycloalkyl optionally substituted with 1, 2, 3 substituents selected from the group consisting of deuterium, hydroxyl, oxo (=0), C1-C3alkyl-OH, cyclopropyl, cyclobutyl, -OC(=0)NH2, -C(=0)NH2, -C(=NH)S(=0)2CH3, methyl, -CD3.

[0316] In a preferred embodiment of the application, said L-R2is selected from the group consisting of -C(=0)-NHR 22 , -S(=0)2-NHR 22 ; said R 22 is selected from the group consisting of C1-C6alkyl, 3-6 membered heterocycloalkyl, said C1-C6alkyl, 3-6 membered heterocycloalkyl optionally substituted with 1, 2, 3 substituents selected from the group consisting of hydroxyl, -C(=0)NH2, -C(=NH)S(=0)2CH3, methyl.

[0317] In a preferred embodiment of the application, said L-R2is selected from the group consisting of -C(=0)-NHR 22 , -S(=0)2-NHR 22 ; said R 22 is selected from the group consisting of C1-C6alkyl, said C1-C6alkyl optionally substituted with 1, 2, 3 substituents selected from the group consisting of hydroxyl, -C(=0)NH2, -C(=NH)S(=0)2CH3.

[0318] In a preferred embodiment of the application, said L-R2is selected from the group consisting of

[0319] In a preferred embodiment of the application, said L-R2is selected from the group consisting of

[0320] In a preferred embodiment of the application, said L-R2is selected from the group consisting of

[0321] In a preferred embodiment of the present application, said L-R2is selected from

[0322] In a preferred embodiment of the present application, said L-R2is selected from

[0323] In a preferred embodiment of the present application, said L-R2is selected from

[0324] In a preferred embodiment of the present application, said L-R2is selected from

[0325] In a preferred embodiment of the present application, said L-R2is selected from

[0326] In a preferred embodiment of the present application, said L-R2is selected from

[0327] In a preferred embodiment of the present application, said L-R2is selected from

[0328] In a preferred embodiment of the present application, said R3is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C3alkyl, C1-C3alkoxy; said C1-C3alkyl, C1-C3alkoxy is optionally substituted with 1, 2, 3 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy.

[0329] In a preferred embodiment of the present application, said R3is selected from hydrogen, halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy.

[0330] In a preferred embodiment of the present application, said R3is selected from hydrogen, F.

[0331] In a preferred embodiment of the present application, said R3is selected from hydrogen.

[0332] In a preferred embodiment of the present application, said R1is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy; said C1-C6alkyl, C1-C6alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy.

[0333] In a preferred embodiment of the present application, said R1is selected from the group consisting of hydrogen, halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy.

[0334] In a preferred embodiment of the present application, said R1is selected from the group consisting of hydrogen, methyl, F.

[0335] In a preferred embodiment of the present application, said R1is selected from the group consisting of hydrogen, methyl.

[0336] In a preferred embodiment of the present application, said compound is selected from the group consisting of the following structures:

[0337] In a preferred embodiment of the present application, said compound is selected from the group consisting of the following structures:

[0338] In a preferred embodiment of the present application, said compound is selected from the group consisting of the following structures:

[0339] In a preferred embodiment of the present application, said compound III-1 compound has the structure III-1a or III-1b:

[0340] In a preferred embodiment of the present application, said compound III-2 compound has the structure III-2a or III-2b:

[0341] In a preferred embodiment of the present application, said compound III-3 compound has the structure III-3a or III-3b:

[0342] In a preferred embodiment of the present application, said compound III-4 compound has the structure III-4a or III-4b:

[0343] In a preferred embodiment of the present application, said compound III-5 compound has the structure III-5a or III-5b:

[0344] In a preferred embodiment of the present application, said compound III-6 compound has the structure III-6a or III-6b:

[0345] In a preferred embodiment of the application, the compound III-7 is a compound having the structure III-7a or III-7b:

[0346] In a preferred embodiment of the application, the compound is selected from the group consisting of the following structures:

[0347] In a preferred embodiment of the application, the compound IV-1 has the structure IV-1a or IV-1b: selected from the group consisting of the following structures:

[0348] In a preferred embodiment of the application, the compound IV-2 has the structure IV-2a or IV-2b: selected from the group consisting of the following structures:

[0349] In a preferred embodiment of the application, the compound IV-3 has the structure IV-3a or IV-3b: selected from the group consisting of the following structures:

[0350] In a preferred embodiment of the application, the compound IV-3 has the structure IV-3a or IV-3b: selected from the group consisting of the following structures:

[0351] the ring A is selected from the group consisting of when the ring B and the ring D are each independently selected from the group consisting of a phenyl ring, a 7-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 4-8 membered heterocycloalkyl ring, a 4-8 membered cycloalkyl ring, the ring B is not a phenyl ring.

[0352] In a preferred embodiment of the application, the compound IV-3 has the structure IV-3a or IV-3b: selected from the group consisting of the following structures:

[0353] the ring A is selected from the group consisting of when the ring B and the ring D are each independently selected from the group consisting of a phenyl ring, a 7-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 4-8 membered heterocycloalkyl ring, a 4-8 membered cycloalkyl ring, the ring B is not a phenyl ring.

[0354] In a preferred embodiment of the application, the compound IV-4 has the structure IV-4a or IV-4b: selected from the group consisting of the following structures:

[0355] In a preferred embodiment of the application, the compound IV-5 has the structure IV-5a or IV-5b: selected from the group consisting of the following structures:

[0356] In a preferred embodiment of the present application, the compound IV-6 has the structure IV-6a or IV-6b:

[0357] In a preferred embodiment of the present application, the compound is selected from the group consisting of:

[0358] In a preferred embodiment of the present application, the compound of Formula I, tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug thereof, is characterized in that the compound comprises:

[0359] In a preferred embodiment of the present application, the compound of Formula I, tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug thereof, is characterized in that the compound comprises:

[0360] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a compound of Formula I, tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug thereof, as described in the first aspect; and a pharmaceutically acceptable carrier.

[0361] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a compound of Formula I, tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, as described in the first aspect; and a pharmaceutically acceptable carrier.

[0362] In a third aspect of the present application, use of a compound of Formula I, tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug thereof, as described in the first aspect, or a pharmaceutical composition as described in the second aspect, the use comprising:

[0363] as a TRPM3 antagonist;

[0364] and / or, preventing and / or treating a disease mediated by TRPM3;

[0365] and / or, preparing a medicament, pharmaceutical composition or formulation as a TRPM3 antagonist.

[0366] The third aspect of the present application, the use of the compound of formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect, the use comprises:

[0367] as a TRPM3 antagonist;

[0368] and / or, preventing and / or treating a disease mediated by TRPM3;

[0369] and / or, preparing a medicament, pharmaceutical composition or formulation as a TRPM3 antagonist.

[0370] The third aspect of the present application, the use of the compound of formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect, the use comprises:

[0371] as a TRPM3 antagonist;

[0372] and / or, preventing and / or treating a disease mediated by TRPM3;

[0373] and / or, preparing a medicament, pharmaceutical composition or formulation as a TRPM3 antagonist.

[0374] and / or, a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease in which TRPM3 is expressed and it is desirable or necessary to inhibit it.

[0375] The third aspect of the present application, the use of the compound of formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect, the use comprises:

[0376] as a TRPM3 antagonist;

[0377] and / or, preventing and / or treating a disease mediated by TRPM3;

[0378] and / or, preparing a medicament, pharmaceutical composition or formulation as a TRPM3 antagonist.

[0379] and / or, a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease in which TRPM3 is expressed and it is desirable or necessary to inhibit it.

[0380] The compound of formula I, a tautomer, a stereoisomer, an oxide, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect is expected to be useful in the prevention or treatment of a disease.

[0381] The compound of formula I, a tautomer, a stereoisomer, an oxide, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect is expected to be useful in the treatment of pain or epilepsy.

[0382] The compound of formula I, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect is expected to be useful in the treatment of pain or epilepsy.

[0383] Pain to be mentioned includes nociceptive pain, inflammatory pain, neuropathic pain, chronic pain.

[0384] The compound of formula I, a tautomer, a stereoisomer, an oxide, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect is useful for the treatment and / or prophylactic treatment of the aforementioned diseases.

[0385] The compound of formula I, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect is useful for the treatment and / or prophylactic treatment of the aforementioned diseases.

[0386] The fourth aspect of the present application provides a method for treating a disease, the disease being a TRPM3-mediated disease, the method comprising administering to a person suffering from or susceptible to said disease a therapeutically effective amount of the compound of formula I, a tautomer, a stereoisomer, an oxide, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect.

[0387] The fourth aspect of the present application provides a method for treating a disease, the disease being a TRPM3-mediated disease, the method comprising administering to a person suffering from or susceptible to said disease a therapeutically effective amount of the compound of formula I, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition of the second aspect as described in the first aspect.

[0388] The fourth aspect of the present application provides a method of treating a disease, which is a TRPM3-mediated disease, and / or a disease in which TRPM3 expression and inhibition is desired or necessary, the method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of a compound of Formula I, a tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition of the second aspect of the present application.

[0389] The fourth aspect of the present application provides a method of treating a disease, which is a TRPM3-mediated disease, and / or a disease in which TRPM3 expression and inhibition is desired or necessary, the method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of a compound of Formula I, a tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition of the second aspect of the present application.

[0390] Additional aspects and advantages of the application will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following description and the accompanying drawings or can be learned by practice of the application.

[0391] Terms and Definitions

[0392] Unless otherwise indicated, the definitions and terms recited in the specification and claims of this application, including the definitions of the examples, the exemplary definitions, the preferred definitions, the definitions recited in the tables, the definitions of the specific compounds in the examples, etc., can be combined and incorporated with each other in any manner. The compound structures after such combination and incorporation should be within the scope recited in the specification of this application.

[0393] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, publications, and other documents referenced herein are hereby incorporated by reference in their entirety. In the event of a conflict between the definitions and terms recited in this document and those contained in the documents incorporated by reference, the definitions and terms contained in this document control.

[0394] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" as used herein is inclusive, not exclusive. Additionally, the use of "including," "containing," "comprising," "having," and "involving" and variations thereof herein are not meant to be limiting to the subject matter claimed.

[0395] Definitions of standard chemical terminology can be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of the art are employed in practicing the present application, such as mass spectroscopy, NMR, IR and UV / VIS spectroscopy and pharmacological methods. Unless specific definitions are provided, the nomenclature utilized in connection with the description herein is understood in accordance with the nomenclature rules set forth in the relevant art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical formulation, and delivery, and treatment of patients. For example, reactions and purification can be performed according to the manufacturers' instructions or according to published procedures in the literature. In general, the techniques and procedures used can be found described in the multiple treatises and more specific literature articles referenced and discussed herein. In the present specification, groups and substituents are chosen to provide stable moieties and compounds.

[0396] When a substituent is described as being "substituted" it is meant to include not only the explicit substitution identified by the term but also the explicit substitution identified by the term written in the opposite direction, i.e., the explicit substitution identified by the term and the explicit substitution identified by the term written in the opposite direction are chemically equivalent. For example, CH2O is equivalent to OCH2. As used herein, "R1", "R1" and "R 1 " are synonymous in meaning and can be substituted for one another. Similar definitions apply to R2and other other symbols.

[0397] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or other literary material (including patents, patent applications, articles, books, treatises, manuals and papers) cited in this application are hereby incorporated by reference in their entirety into this document.

[0398] In addition to the foregoing, the following terms used in the specification and claims have the meanings indicated below, unless specified otherwise.

[0399] Where the specification and claims of this application state a range of values, for example, one or more of measurement, it is contemplated that any and every subset of values within the specified range is incorporated as if each were individually listed. For example, a range of 1 to 6 should be considered to include any number from 1 to 6, including individual numbers, such as one, three, 4, 5, 6, as well as ranges between the numbers, such as 1-5, 2-4, 3-6, etc.

[0400] In the present application, the term "one or more" when indicating the number of substituents means from one substitution to the maximum possible number of substitutions, i.e. from one hydrogen to all hydrogens are replaced by a substituent. The term "1-4" when indicating the number of substituents means 1, 2, 3 or 4 substitutions, i.e. 1, 2, 3 or 4 hydrogens are replaced by a substituent.

[0401] In the present application, "saturated, partially saturated or unsaturated" includes substituents saturated by hydrogen, substituents completely unsaturated by hydrogen and substituents partially saturated by hydrogen.

[0402] In the present application, the term "halogen" alone or as part of other substituents means fluorine, chlorine, bromine, iodine.

[0403] In the present application, the term "amino" alone or as part of other substituents means -NH2.

[0404] In the present application, the term "hydroxy" alone or as part of other substituents means -OH.

[0405] In the present application, the term "cyano" alone or as part of other substituents means -CN.

[0406] In the present application, the term "alkyl," alone or in part as part of other substituents, means a straight-chain or branched-chain hydrocarbon chain radical only composed of carbon and hydrogen atoms, free of unsaturation, having, for example, from 1 to 6 carbon atoms, and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, i-pentyl, neopentyl, and hexyl. Alkyl groups can be unsubstituted or substituted with one or more suitable substituents. Alkyl groups can also be isotopically enriched isomers of naturally abundant alkyl groups of carbon and / or hydrogen isotopes (i.e., deuterium or tritium). As used herein, the term "alkenyl" denotes a straight-chain or branched-chain monovalent hydrocarbon chain that contains one or more carbon-carbon double bonds. "Alkenyl" or "alkenylene" is intended to include both straight and branched-chain configurations and to have one or more carbon-carbon double bonds that can occur at any stable point along the chain. For example, "C2-C6alkenyl" (or C2-C6alkenylene) is intended to include alkenyl groups of 2, 3, 4, 5, 6 carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like. Examples of alkenylene groups include, but are not limited to, ethenylene, 1 -propenylene, 2-propenylene, 2-butenylene, 3-butenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 2-methyl-2-propenylene, 4-methyl-3-pentenylene, and the like.

[0407] In the present application, the term "alkynyl," alone or in part as part of other substituents, means a straight-chain or branched-chain monovalent hydrocarbon chain that contains one or more carbon-carbon triple bonds. "Alkynyl" or "alkynylene" is intended to include both straight and branched-chain configurations and to have one or more carbon-carbon triple bonds that can occur at any stable point along the chain. For example, "C2-C6alkynyl" (or C2-C6alkynylene) is intended to include alkynyl groups of 2, 3, 4, 5, 6 carbons; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like. For the avoidance of doubt, alkyl, alkenyl, and alkynyl groups as described herein can also be used as linking groups (i.e., groups that link two or more moieties of a compound as described), in which case such groups can be referred to as "alkylene," "alkenylene," and / or "alkynylene," respectively.

[0408] In the present application, the term "C1-C6alkyl", alone or as part of another substituent, is understood to mean a straight or branched chain saturated hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like or isomers thereof. In particular, the group has 1, 2, or 3 carbon atoms ("C1-C3alkyl"), for example methyl, ethyl, n-propyl, or isopropyl.

[0409] In the present application, the term "alkylene" is understood to mean a straight chain divalent hydrocarbon radical having 1-6 carbon atoms or a branched chain divalent hydrocarbon radical having 3-6 carbon atoms, unless otherwise specified, for example methylene, ethylene, propylene, 1-methylpropylene, butylene, and the like.

[0410] In the present application, the term "C1-C6alkoxy", alone or as part of another substituent, is understood to mean a straight or branched chain saturated hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms and an oxygen atom, which can be attached to any one of the carbon atoms of the C1-C6alkyl group. This includes, but is not limited to, methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), butoxy (C4H9-O-), ethyloxymethyl (C2H5-O-CH3).

[0411] In the present application, the term "Ci-C6-alkyleneoxy," either alone or as part of another substituent, is understood to mean a straight-chain or branched divalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms and an oxygen atom, which can be attached to any one of the carbon atoms of the straight-chain or branched Ci-C6-alkylene group. This includes, but is not limited to methyleneoxy (-CH2-O-), ethyleneoxy (-C2H4-O-), propyleneoxy (-C3H6-O-), butyleneoxy (-C4H8-O-), ethyleneoxy methylene (-C2H4-O-CH2-). The term "Co-C6-alkyleneoxy" is understood to mean the absence of an alkyleneoxy group or a straight-chain or branched divalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms and an oxygen atom, which can be attached to any one of the carbon atoms of the straight-chain or branched Ci-C6-alkylene group. The term "Co-C3-alkyleneoxy" is understood to mean the absence of an alkyleneoxy group or a straight-chain or branched divalent hydrocarbon radical having 1, 2, 3 carbon atoms and an oxygen atom, which can be attached to any one of the carbon atoms of the straight-chain or branched Ci-C3-alkylene group. This includes, but is not limited to methyleneoxy (-CH2-O-), ethyleneoxy (-C2H4-O-), propyleneoxy (-C3H6-O-), ethyleneoxy methylene (-C2H4-O-CH2-).

[0412] In the present application, "haloalkoxy," either alone or as part of another substituent, means an alkoxy group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkoxy group are replaced by fluorine, chlorine, bromine, or iodine.

[0413] In the present application, "haloalkyleneoxy," either alone or as part of another substituent, means an alkyleneoxy group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyleneoxy group are replaced by fluorine, chlorine, bromine, or iodine.

[0414] In the present application, the term "oxo," either alone or as part of another substituent, means that two hydrogens on a methylene group are replaced by an oxygen, i.e., the methylene group is replaced by a carbonyl group, represented by =0.

[0415] In the present application, the term "deuterated," either alone or as part of another substituent, means that any number (at least one) of the hydrogen atoms on an alkyl or alkylene group are replaced by deuterium.

[0416] In the present application, "deuteroalkyl" alone or as part of another substituent refers to branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more deuterium (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v + 1)). Examples of deuteroalkyl groups include, but are not limited to, trideuteromethyl, dideuteromethyl, monodeuteromethyl, pentadeuterioethyl, 2,2,2-trideuterioethyl, and heptadeuteriopropyl.

[0417] In the present application, "deuteroalkylene" alone or as part of another substituent refers to an alkylene group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkylene group are replaced with deuterium.

[0418] In the present application, "haloalkyl" alone or as part of another substituent refers to branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more halogen (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v + 1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptafluoropropyl.

[0419] In the present application, "haloalkylene" alone or as part of another substituent refers to branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more halogen (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v + 1)). Examples of haloalkylene groups include, but are not limited to, difluoromethylene, dichloromethylene, tetrafluoroethylene, tetrachloroethylene, 2,2-difluoroethylene, hexafluoropropylene, and hexachloropropylene.

[0420] In the present application, the term "aryl" or "aromatic ring" alone or as part of another substituent refers to a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, wherein at least one ring is aromatic. When one of the rings is non-aromatic, the group can be attached through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, and acenaphthyl.

[0421] In the present application, the term "6-14 membered aromatic ring" or "6-14 membered aryl" alone or as part of another substituent refers to a monocyclic or polycyclic carbocyclic ring having from 6 to 14 carbon atoms, wherein at least one ring is aromatic. The polycyclic carbocyclic ring can be bicyclic or tricyclic, wherein the bicyclic ring can be spiro, fused, and annulated. When one of the rings is non-aromatic, the group can be attached through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, and acenaphthyl.

[0422] In the present application, the term "heteroaromatic ring" when used alone or as part of another substituent refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, the remaining ring atoms being C, in which at least one ring is aromatic. The group can be carbon-based or heteroatom-based (i.e. it can be C-attached or N-attached, as is possible). When one of the rings is non-aromatic, the group can be attached through an aromatic ring, as well as through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" can be used interchangeably with the term "heteroaromatic ring", "heteroaryl" or "heteroaryl group".

[0423] In the present application, the term "5-14 membered heteroaromatic ring" when used alone or as part of another substituent is used interchangeably with "5-14 membered heteroaryl" and is understood to mean an aromatic ring group having 5-14 ring atoms and containing 1-5 heteroatoms independently selected from N, O, S and P. Where N atoms are optionally quaternized, N and S heteroatoms can optionally be oxidized (i.e. (N + -O - ) and S(O)p, p being 1 or 2). The term "5-8 membered heteroaromatic ring" is understood to mean an aromatic ring group having 5, 6, 7 or 8 ring atoms and containing 1-3 heteroatoms independently selected from N, O, S and P. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.

[0424] In the present application, the term "heterocycloalkyl" when used alone or as part of another substituent refers to a cycloalkyl in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by a heteroatom such as, but not limited to, N, O, S and P. The "heterocycloalkyl" can be saturated or unsaturated, but not aromatic. The "heterocycloalkyl" can also be a monocyclic, bicyclic or tricyclic ring, including bridged and spiro ring structures, containing 1, 2 or 3 rings. The term "3-14 membered heterocycloalkyl" is understood to mean a monocyclic, bicyclic or tricyclic ring having 3 to 14 atoms, wherein the heteroatoms are preferably selected from N, O and S, it being understood that when the total number of S atoms and O atoms in the heterocyclyl group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl groups include, but are not limited to: tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl, and the like.

[0425] In the present application, "haloheterocycloalkyl" when used alone or as part of another substituent refers to a heterocycloalkyl as described above wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced by fluorine, chlorine, bromine or iodine.

[0426] In the present application, the term "cycloalkyl" or "carbocyclic group" when used alone or as part of another substituent refers to a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C m -C n Cycloalkyl" is understood to mean a saturated or unsaturated, but not aromatic, carbocyclic ring having m to n atoms. For example, "3-14 membered cycloalkyl" refers to a cyclic alkyl group containing 3 to 14, 3 to 10, 3 to 6, or 3 to 5 carbon atoms, which can include 1 to 4 rings. A "5-8 membered cycloalkyl" contains 5-8 carbon atoms. Single, bi-, tri-, spiro, or bridged ring systems are included. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbyl groups such as decalin rings. The cycloalkyl group can be substituted with one or more substituents. In some embodiments, the cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group. The term "3-6 membered cycloalkyl" is understood to mean a saturated or unsaturated, but not aromatic, monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0427] In the present application, "haloalkyl," alone or in combination with other substituent(s), means an alkyl group as described above in which any number (one, two, three or more) of the hydrogen atoms attached to a carbon atom have been replaced with a halogen; i.e., a fluorinated, chlorinated, brominated or iodinated alkyl group. In the present application, "haloalkenyl," alone or in combination with other substituent(s), means an alkenyl group as described above in which any number (one, two, three or more) of the hydrogen atoms attached to a carbon atom have been replaced with a halogen; i.e., a fluorinated, chlorinated, brominated or iodinated alkenyl group.

[0428] In the present application, the term "monocyclic" alone or as part of other substituent(s), means a group having only one ring that can be saturated, unsaturated or partially saturated, which can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).

[0429] In the present application, the term "bicyclic" means a group having two connected rings. The bicyclic ring can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (e.g., norbornane and norbornene), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene). Bicyclic rings include (a) spiro compounds, in which the two rings share only one single atom (a spiro atom, which is often a quaternary carbon). Examples of spiro compounds include, but are not limited to:

[0430] Also included are spirocycloalkyls that share a spiro atom with a heterocycloalkyl, non-limiting examples of which include:

[0431] (b) fused bicyclic compounds, in which the two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and norbornane). Examples of fused bicyclic rings include, but are not limited to:

[0432] and (c) bridged bicyclic compounds, in which the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered as a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:

[0433] In the present application, the term "inert solvent" includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0434] The compounds provided herein, including intermediates useful in preparing the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), also include protected derivatives thereof. "Protected derivatives" are those compounds in which one or more of the reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, t-butyl, and the like, as well as isotopes thereof. Suitable protecting groups for amino and amido moieties include acetyl, trifluoroacetyl, t-butoxy carbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for hydroxyl moieties include benzyl and the like. Other suitable protecting groups are well known to those skilled in the art.

[0435] In the present application, the term "substituted" means that any one or more of the hydrogen atoms of the specified atom are optionally replaced with a substituent, including isotopes and variations of hydrogen. The valence of the specified atom is normal and the substituted compound is stable.

[0436] In the present application, the term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and the description includes both instances in which the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0437] In the present application, the term "optionally substituted" or "optionally substituted with" means that the specified group is unsubstituted or is substituted with one or more substituents independently selected from the possible substituents. For example, "aryl optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 "alkyl" means that the aryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 "alkyl", and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0438] In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0439] In the present application, the term "pharmaceutically acceptable acid addition salt" denotes a salt of a compound with an inorganic or organic acid which does not cause unacceptable adverse effects in a patient. A "pharmaceutically acceptable base addition salt" is a salt of a compound with an inorganic or organic base which does not cause unacceptable adverse effects in a patient. In addition to pharmaceutically acceptable salts, other salts possess utility in the purification or identification of the compounds of the application or in the preparation of other pharmaceutically acceptable salts.

[0440] In the present application, the term "amine salt" refers to the product obtained by neutralizing a primary, secondary, or tertiary alkylamine with an acid. The acid includes an inorganic or organic acid as described in the present application.

[0441] In the present application, the term "stereoisomer" refers to isomers that have the same molecular formula but different structures resulting from the different ways in which their atoms are arranged in space. This includes enantiomers, diastereomers, and conformers.

[0442] In the present application, the term "oxide" refers to the optional oxidation of N and S heteroatoms in heterocycloalkyl, heteroaryl, heteroalkenyl, and the like rings (i.e., (N + -O - ) and S(O)p, p is 1 or 2).

[0443] Depending on the choice of starting materials and methods, the compounds of the application can be present in the form of one of the possible isomers or as a mixture of them, for example, as a mixture of racemic and non-racemic isomers, where appropriate, depending on the number of asymmetric carbon atoms. When describing compounds having optical activity, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to a single chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are used to designate the rotational orientation of plane-polarized light emitted by a compound, wherein (-) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0444] When bonds to a chiral carbon in the formula of the present application are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of the general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Wedge and dash bonds are used to represent the absolute configuration of a single stereogenic center.

[0445] In the present application, the term "tautomer" refers to isomers of a functional group that result from the rapid movement of an atom in a molecule between two positions. The compounds of the present application can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds. In the examples of the present application, a proton can occupy two or more positions in a ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazole, and 1H- and 2H-pyrazole. The tautomeric forms can be in equilibrium or spatially fixed in one form by appropriate substitution. For example:

[0446] The hydrogen of the nitrogen of the tetrazole can be on any one of the four nitrogens due to resonance.

[0447] In the present application, the term "pharmaceutical composition" refers to a preparation of a compound of the present application with a medium conventionally accepted in the art for the delivery of a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to the body and to facilitate absorption into the body to thereby produce the biological activity.

[0448] In the present application, the term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surface-active, wetting or dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that is approved by a relevant government regulatory agency or agency for use in humans or animals.

[0449] In the present application, the term "prodrug" refers to a compound that can be converted to a biologically active compound of the present application under physiological conditions or by solvolysis. Prodrugs of the present application are prepared by modifying functional groups in the compound in such a way that their functionality is temporarily destroyed by the prodrug moiety and thereafter capable of being regenerated in vivo. Prodrugs include compounds of the present application wherein one or more hydroxyl or amino groups are bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino group, respectively.

[0450] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0451] In the present application, the term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the kind of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. The excipients can enhance the handling properties of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and / or cohesiveness.

[0452] The terms "treat" and other similar synonyms as used herein include the following meanings:

[0453] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or at risk to developing the disease or condition but has not yet been diagnosed as having it;

[0454] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0455] (iii) relieving the disease or condition, i.e., causing the condition to regress; or

[0456] (iv) alleviating the symptoms of the disease or condition. Beneficial effects

[0457] The present inventors have made extensive and in-depth studies and unexpectedly developed a benzofuran compound as a TRPM3 antagonist, which has the structure shown in the present application. The compound of the present application can prevent or treat diseases or conditions associated with TRPM3, exhibits excellent pharmacokinetic properties, and has high safety and drug properties. DETAILED DESCRIPTION

[0458] The present application will be further described in conjunction with specific examples. It should be understood that the following description is merely the most preferred embodiment of the present application and should not be considered as a limitation to the scope of protection of the present application. Based on a full understanding of the present application, the experimental methods not specified in the following examples can be made by the skilled in the art according to the conventional conditions or according to the conditions recommended by the manufacturers, and non-essential modifications can be made to the technical solutions of the present application. Such modifications should be considered as included in the scope of protection of the present application.

[0459] The present application has the following definitions:

[0460] Symbols or units:

[0461] IC 50 : half maximal inhibitory concentration, the concentration at which an action (usually the biological activity or enzymatic activity of a substance) is inhibited by half

[0462] M: mol / L, for example n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M solution in n-hexane) means a solution of n-butyllithium with a molar concentration of 2.5 mol / L in n-hexane

[0463] N: normality, for example 2N hydrochloric acid means a hydrochloric acid solution with a normality of 2 mol / L

[0464] RT: retention time

[0465] Reagents:

[0466] DMF: N,N-dimethylformamide

[0467] DIPEA: N,N-diisopropylethylamine

[0468] EA: ethyl acetate, also written as EtOAc

[0469] PE: petroleum ether

[0470] THF: tetrahydrofuran

[0471] Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride

[0472] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)

[0473] Pd / C: palladium on carbon

[0474] HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0475] MeOH: methanol

[0476] DCM: dichloromethane

[0477] H2O: water

[0478] NBS: N-bromosuccinimide

[0479] Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0480] Xantphos: 4,5-bisdiphenylphosphino-9,9-dimethylxanthene

[0481] Test method:

[0482] LC-MS: liquid chromatography-mass spectrometry

[0483] TLC: thin layer chromatography

[0484] Example 1: Preparation of target compound I-2A

[0485] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((E)-2-(2- (trifluoromethyl)pyridin-3-yl)vinyl-1-yl)-1-benzofuran-3-carboxamide

[0486] The synthetic route of target compound I-2A is shown below:

[0487] First step: synthesis of 5-bromo-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0488] Dissolve 1,4-dibromo-2-iodobenzene (10 g, 27.0 mmol) in anhydrous THF (100 mL), then add copper(I) iodide (789 mg, 4.0 mmol), ethyl acetoacetate (4.3 g, 32.4 mmol) and potassium carbonate (11.46 g, 81.0 mmol) successively, stir at 100 °C for 16 hours under nitrogen protection. TLC monitoring shows that the reaction is completed, add water (100 mL) to the reaction solution, then extract with dichloromethane (100 mL) for three times, combine the organic phases, wash with saturated brine (40 mL), dry the organic phase with anhydrous sodium sulfate, filter, concentrate and dry the filtrate, separate the crude product by column chromatography (EA / PE = 10:1, V / V) to obtain 5-bromo-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (780 mg).

[0489] Second step: synthesis of 3-vinyl-2-(trifluoromethyl)pyridine

[0490] To a solution of 3-bromo-2-(trifluoromethyl)pyridine (2 g, 8.8 mmol) in 20 mL of dioxane / water (v / v = 4 / 1) was added Pd(dppf)Cl2(643 mg, 8.0 mmol), vinylboronic acid pinacol ester (1.49 g, 9.68 mmol) and potassium carbonate (1.83 g, 13.2 mmol) sequentially at room temperature. The reaction was heated at 100 °C for 16 h under nitrogen atmosphere. LC-MS showed the reaction was completed. The reaction was concentrated to give the crude product. Water (50 mL) was added to the crude product, which was extracted with dichloromethane (30 mL) for three times. The organic phase was combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was separated by column chromatography (PE / EA = 5 / 1, V / V) to give 3-vinyl-2-(trifluoromethyl)pyridine (1.4 g).

[0491] Step 3: Synthesis of ethyl 2-methyl-5-((E)-2-(2-(trifluoromethyl)pyridin-3- yl)vinyl)-1-benzofuran-3-carboxylate

[0492] To a solution of ethyl 5-bromo-2-methyl-1-benzofuran-3-carboxylate (500 mg, 1.7 mmol) and 3-vinyl-2-(trifluoromethyl)pyridine (294 mg, 1.7 mmol) in toluene (10 mL) was added bis(triphenylphosphine)palladium (87.2 mg, 0.17 mmol) and triethylamine (1.37 g, 13.6 mmol). The reaction was stirred at 80 °C for 16 h after purging with nitrogen for three times. The reaction was cooled to room temperature. The reaction was concentrated to give the crude product. Water (50 mL) was added to the crude product, which was extracted with dichloromethane (30 mL) for three times. The organic phase was combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was separated by column chromatography (PE / EA = 4 / 1, V / V) to give ethyl 2-methyl-5-((E)-2-(2-(trifluoromethyl)pyridin-3-yl)vinyl)-1-benzofuran-3-carboxylate (250 mg).

[0493] Step 4: Synthesis of 2-methyl-5-((E)-2-(2-(trifluoromethyl)pyridin-3-yl)vinyl)-1- benzofuran-3-carboxylic acid

[0494] The ethyl 2-methyl-5-((E)-2-(2-(trifluoromethyl)pyridin-3-yl)vinyl-1-yl)-1- benzofuran-3-carboxylate (80 mg, 0.2 mmol) was dissolved in THF / MeOH / H2O (V / V / V = 1 / 1 / 1, 6 mL) at room temperature, then lithium hydroxide (14.5 mg, 0.6 mmol) was added to the reaction solution, and stirred at room temperature overnight. LC-MS showed that the reaction was completed. The reaction solution was concentrated to obtain the crude product, which was dissolved in DCM / MeOH = 10 / 1 system, and 2N hydrochloric acid was used to adjust pH = 2-3, and concentrated to obtain the crude product (70 mg), which was directly used in the next step reaction.

[0495] Fifth step: synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((E)-2-(2- (trifluoromethyl)pyridin-3-yl)vinyl-1-yl)-1-benzofuran-3-carboxamide

[0496] The 2-methyl-5-((E)-2-(2-(trifluoromethyl)pyridin-3-yl)vinyl-1-yl)-1-benzofuran-3- carboxylic acid (70 mg, 0.2 mmol) was dissolved in DMF (2 mL) at room temperature, then L-serine amide hydrochloride (44.6 mg, 0.3 mmol), HATU (153.7 mg, 0.4 mmol) and DIPEA (62.5 mg, 0.5 mmol) were added in turn. Stirred at room temperature for 2 hours, LC-MS showed that the reaction was completed. Water (10 mL) was added to the crude product, and extracted with dichloromethane (30 mL) three times, the organic phase was combined, washed with saturated brine (10 mL) five times, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by high performance liquid chromatography to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((E)-2-(2-(trifluoromethyl)pyridin-3-yl)vinyl-1-yl)-1-benzofuran-3-carboxamide (19.2 mg).

[0497] LC-MS, M / Z (ESI): 434.4 [M+H] +

[0498] 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J = 4.8, 1.2 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.0, 4.8 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.57 (d, J = 16.0 Hz, 1H), 7.48 (s, 1H), 7.39 - 7.31 (m, 1H), 7.18 (s, 1H), 5.01 (t, J = 5.6 Hz, 1H), 4.50 (dt, J = 8.0, 5.2 Hz, 1H), 3.76 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0499] Example 2: Preparation of target compound I-8A

[0500] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,3-dihydro-1H-inden-1- yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0501] The synthetic route of target compound I-8A is shown as follows:

[0502] First step: synthesis of 5-((2,3-dihydro-1H-inden-1-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0503] At room temperature, 1-hydroxyindan (50 mg, 0.37 mmol) and 5-hydroxy-2- methyl-1-benzofuran-3-carboxylic acid ethyl ester (82 mg, 0.37 mmol) were added to tetrahydrofuran (5 mL), and after the addition of tributylphosphine (150 mg, 0.74 mmol), azobisdimethylvaleronitrile (187 mg, 0.74 mmol) was slowly added, and the reaction was carried out at room temperature overnight. After the reaction was completed, the reaction liquid was poured into ice water and extracted with ethyl acetate (50 mL) three times. The obtained organic phase was dried, filtered and rotary evaporated, and the crude product was purified by silica gel column (PE:EA (V / V) = 10:1) to obtain 5-((2,3-dihydro-1H-inden-1-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester (109 mg).

[0504] LC-MS, M / Z (ESI): 337.4 [M+H] +

[0505] Second step: synthesis of 5-((2,3-dihydro-1H-inden-1-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid

[0506] Compound 5-((2,3-dihydro-lH-inden-l-yl)oxy)-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (3) (109 mg, 0.32 mmol) was dissolved in THF / MeOH / H20 = 1 / 1 / 1 (6 mL) at room temperature. Then lithium hydroxide monohydrate (26.88 mg, 0.64 mmol) was added and stirring was continued at room temperature for 2 hours. TLC monitoring showed that the starting material was consumed after 2 hours. The reaction was stopped and the pH value was adjusted to acidic by adding hydrogen chloride solution (2 M). The solvent was removed under reduced pressure to give 5-((2,3-dihydro-lH-inden-l-yl)oxy)-2-methyl-l-benzofuran-3-carboxylic acid (100 mg), which was used directly in the next step.

[0507] LC-MS, M / Z (ESI): 294.3 [M+H] +

[0508] Step 3: Synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2,3-dihydro-lH- inden- 1 -yl)oxy)-2-methyl- 1 -benzofuran-3 -carboxamide

[0509] Compound 5-((2,3-dihydro-lH-inden-l-yl)oxy)-2-methyl-l-benzofuran-3-carboxylic acid (50.1 mg, 0.16 mmol), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), L-serine amide hydrochloride (22.4 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. Then N,N-diisopropylethylamine (61.9 mg, 0.48 mmol) was added and the reaction was continued at room temperature for 5 hours. TLC monitoring showed that the starting material was consumed after 5 hours. The reaction was filtered and the filtrate was purified by HPLC to give compound N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2,3-dihydro-lH-inden-l-yl)oxy)-2-methyl-l-benzofuran-3-carboxamide (7.1 mg, 0.018 mmol).

[0510] LC-MS, M / Z (ESI): 395.4 [M+H] +

[0511] 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.43 (t, J = 2.3 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 6.3 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.16 (s, 1H), 6.95 (dd, J = 8.9, 1.9 Hz, 1H), 5.86 - 5.80 (m, 1H), 5.00 (s, 1H), 4.45 (dt, J = 8.4, 5.0 Hz, 1H), 3.71 (s, 2H), 3.09 - 2.97 (m, 1H), 2.91 - 2.81 (m, 1H), 2.59 - 2.52 (m, 1H), 2.47 (s, 3H), 2.10 - 2.00 (m, 1H).

[0512] Example 3: Preparation of target compound I-9A

[0513] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(3,4-dihydroisoquinolin-2(1H)-yl)-2- methyl-1-benzofuran-3-carboxamide

[0514] The synthetic route of target compound I-9A is shown as follows:

[0515] First step: synthesis of 5-(3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0516] 1,2,3,4-tetrahydroisoquinoline (186 mg, 1.38 mmol) and 5-bromo-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester (300 mg, 1.06 mmol) were dissolved in N,N- dimethylformamide (5 mL), then Pd2(dba)3(192 mg, 0.212 mmol), Xphos (204 mg, 0.424 mmol), cesium carbonate (690 mg, 2.12 mmol) were added in turn under nitrogen protection, and the reaction solution was reacted at 90 degrees overnight. After the reaction was completed, water (5 mL) was added for quenching, and the mixture was extracted with ethyl acetate (10 mL) three times, and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-10:1) to obtain 5-(3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester (60 mg).

[0517] LC-MS, M / Z (ESI): 336.1 [M+H] +

[0518] Step 2: Synthesis of 5-(3,4-dihydroisoquinolin-2(lH)-yl)-2-methyl-l- benzofuran-3-carboxylic acid

[0519] Ethyl 5-(3,4-dihydroisoquinolin-2(lH)-yl)-2-methyl-l-benzofuran-3-carboxylate (65 mg, 0.194 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water = 1 mL: 0.5 mL: 1 mL, lithium hydroxide monohydrate (23 mg, 0.582 mmol) was added, the reaction was stirred at room temperature overnight. After the reaction was completed, concentrated and dried by rotary evaporation, then diluted with dilute hydrochloric acid to adjust to pH = 3 or so, then added DCM (3 mL) and extracted three times, separated, combined the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give 5-(3,4-dihydroisoquinolin-2(lH)-yl)-2-methyl-l- benzofuran-3-carboxylic acid (55 mg).

[0520] LC-MS, M / Z (ESI): 308.2 [M+H] +

[0521] Step 3: Synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-(3,4- dihydroisoquinolin-2(lH)-yl)-2-methyl-l-benzofuran-3-carboxamide

[0522] 5-(3,4-dihydroisoquinolin-2(lH)-yl)-2-methyl-l-benzofuran-3-carboxylic acid (55 mg, 0.178 mmol) and L-serine amide hydrochloride (37.5 mg, 0.267 mmol) were dissolved in N,N-dimethylformamide (2 mL), HATU (135 mg, 0.356 mmol) and N,N-diisopropylethylamine (57.6 mg, 0.445 mmol) were added in turn, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (3 mL) was added to quench, extracted with ethyl acetate (3 mL) three times, separated, combined the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a residue. The residue was purified by preparative reversed-phase high performance liquid chromatography to give N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-(3,4- dihydroisoquinolin-2(lH)-yl)-2-methyl-l-benzofuran-3-carboxamide (16 mg).

[0523] LC-MS, M / Z (ESI): 394.3 [M+H] +

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.22 - 7.17 (m, 2H), 7.15 - 7.13 (m, 2H), 7.05 (dd, J = 9.2, 2.4 Hz, 1H), 5.01 (t, J = 5.6 Hz, 1H), 4.45 (dt, J = 8.0, 4.8 Hz, 1H), 4.34 (s, 2H), 3.72 (dt, J = 8.8, 5.6 Hz, 2H), 3.50 (t, J = 6.0 Hz, 2H), 2.92 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H).

[0525] Example 4: Preparation of target compound I-1A

[0526] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2- (trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-1-benzofuran-3-carboxamide

[0527] The synthetic route of target compound I-1A is shown as follows:

[0528] First step: synthesis of 5-(benzylsulfanyl)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0529] Ethyl 5-bromo-2-methyl-1-benzofuran-3-carboxylate (800 mg, 2.82 mmol) and benzyl mercaptan (385 mg, 3.1 mmol) were dissolved in 1,4-dioxane (10 mL), Pd2(dba)3(258.6 mg, 0.28 mmol), Xantphos (326.7 mg, 0.56 mmol) and DIPEA (729.3 mg, 5.64 mmol) were added successively, the reaction system was replaced with nitrogen for three times, then heated to 110 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, the reaction solution was concentrated to obtain the crude product, water (50 mL) was added to the crude product, then extracted with dichloromethane (30 mL) for three times, the organic phases were combined, washed with saturated brine (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, and the crude product was separated by column chromatography (PE / EtOAc = 4 / 1, V / V) to obtain 5-(benzylsulfanyl)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0530] Step 2: Synthesis of ethyl 2-methyl-5-mercapto-l-benzofuran-3-carboxylate

[0531] Ethyl 5-(benzylsulfanyl)-2-methyl-l-benzofuran-3-carboxylate (400 mg, 1.22 mmol) was dissolved in toluene (6 mL) at room temperature, then aluminum chloride (409 mg, 3.05 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen protection. LC-MS showed the reaction was completed, then acetic acid was added to the reaction, and the reaction was concentrated to get the crude product. Water (20 mL) was added to the crude product, then dichloromethane (30 mL) was extracted three times, the organic phase was combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was separated by column chromatography (PE / EtOAc = 4 / 1, v / v) to get ethyl 2-methyl-5-mercapto-l-benzofuran-3-carboxylate.

[0532] Step 3: Synthesis of ethyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-l- benzofuran-3-carboxylate

[0533] Ethyl 2-methyl-5-mercapto-l-benzofuran-3-carboxylate (40 mg, 0.16 mmol), 3- (bromomethyl)-2-(trifluoromethyl)pyridine (48.6 mg, 0.2 mmol), potassium carbonate (44.2 mg, 0.32 mmol), and potassium iodide (2.8 mg, 0.016 mmol) were dissolved in acetonitrile (5 mL) at room temperature. The reaction was then reacted at 60°C for 12 hours. LC-MS showed that the reaction was completed, the reaction was concentrated to get the crude product, water (20 mL) was added to the crude product, then dichloromethane (30 mL) was extracted three times, the organic phase was combined, washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was separated by column chromatography (PE / EtOAc = 4 / 1, v / v) to get ethyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-l-benzofuran-3- carboxylate.

[0534] Step 4: Synthesis of 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-l- benzofuran-3-carboxylic acid

[0535] Ethyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-1- benzofuran-3-carboxylate (50 mg, 0.12 mmol) was dissolved in THF / MeOH / H20 (V / V / V = 1 / 1 / 1, 3 mL) at room temperature, then lithium hydroxide (9.1 mg, 0.36 mmol) was added. The reaction was stirred at room temperature overnight. LC-MS showed the reaction was completed, the reaction was concentrated to get the crude product, the crude product was dissolved in DCM / MeOH = 10 / 1 system, pH was adjusted to 2-3 with 2N hydrochloric acid, concentrated to get the crude product of 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-1- benzofuran-3-carboxylic acid, which was directly used in the next step without purification.

[0536] Fifth step: synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5- (((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-1-benzofuran-3-carboxamide

[0537] L-serylamide hydrochloride (24.0 mg, 0.15 mmol), HATU (82.8 mg, 0.2 mmol) and DIPEA (35.1 mg, 0.25 mmol) were added successively at room temperature. The reaction was stirred at room temperature for 2 hours, LC-MS showed the reaction was completed. Water (10 mL) was added to the reaction system, then extracted with dichloromethane (30 mL) for three times, the organic phase was combined, washed with saturated brine (10 mL), the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to get the crude product. The crude product was purified by high performance liquid chromatography to get N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)sulfanyl)-1-benzofuran-3-carboxamide.

[0538] LC-MS, M / Z (ESI): 454.4 [M+H] +

[0539] 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 4.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.0, 4.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 7.19 (s, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.49 - 4.44 (m, 1H), 4.35 (s, 2H), 3.73 (t, J = 5.2 Hz, 2H), 2.65 (s, 3H).

[0540] Example 5: Preparation of target compound I-17A

[0541] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5- yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0542] The synthetic route of target compound I-17A is shown as follows:

[0543] First step: synthesis of 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0544] Under ice bath condition, 6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol (73.6 mg, 0.54 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), then tri-tert-butylphosphine (183.6 mg, 0.9 mmol) and 5-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (100 mg, 0.45 mmol) were added in turn, and azodicarbonamide dipiperidine (ADDP) (229 mg, 0.9 mmol) was slowly added dropwise under nitrogen protection, after the addition was completed, it was stirred at room temperature overnight, TLC monitoring showed that the reaction was completed, water (10 mL) was added to the reaction solution, then extracted with dichloromethane (10 mL) for three times, the organic phase was combined, washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, the crude product was separated by column chromatography (EtOAc / PE = 5:1, V / V) to obtain 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0545] Step 2: Synthesis of 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid

[0546] Ethyl 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3- carboxylate (90 mg, 29.1 mmol) was dissolved in THF / MeOH / H2O (V / V / V = 1 / 1 / 1, 6 mL) at room temperature, then lithium hydroxide (20.9 mg, 87.3 mmol) was added. The reaction was stirred at room temperature overnight. LC-MS showed the reaction was completed. The reaction was concentrated to get the crude product, which was dissolved in DCM / MeOH = 10 / 1 system, pH = 2-3 was adjusted by 2N hydrochloric acid, and concentrated to get the crude product of 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid, which was directly used in the next step without purification.

[0547] Step 3: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H- cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0548] 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid (70 mg, 0.2 mmol) was dissolved in DMF (2 mL) at room temperature, then L-serine amide hydrochloride (44.6 mg, 0.22 mmol), HATU (152 mg, 0.4 mmol) and DIPEA (62.5 mg, 0.5 mmol) were added successively. The reaction was stirred at room temperature for 2 hours, LC-MS showed the reaction was completed. Water (10 mL) was added to the reaction system, then dichloromethane (30 mL) was extracted three times, the organic phase was combined, washed with saturated brine (10 mL) five times, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to get the crude product, which was purified by high performance liquid chromatography to get N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide.

[0549] LC-MS, M / Z (ESI): 396.4 [M+H] +

[0550] 1H NMR (400 MHz, DMSO-d4) δ 8.49 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.51 - 7.46 (m, 3H), 7.26 - 7.19 (m, 2H), 6.99 (dd, J = 8.8, 2.4 Hz, 1H), 5.92 (dd, J = 6.4, 3.6 Hz, 1H), 5.02 (t, J = 5.6 Hz, 1H), 4.50 - 4.45 (m, 1H), 3.78 - 3.70 (m, 2H), 3.16 - 3.07 (m, 1H), 2.99 - 2.90 (m, 1H), 2.70 - 2.60 (m, 4H), 2.16 - 2.08 (m, 1H).

[0551] Example 6: Preparation of target compound I-19A

[0552] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7- yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0553] The synthetic route of target compound I-19A is shown as follows:

[0554] First step: synthesis of 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol

[0555] Under ice-bath condition, 6,7-dihydro-5H-cyclopenta[c]pyridin-7-one (196.6 mg, 1.47 mmol) was dissolved in ethanol (10 mL), then sodium borohydride (72.7 mg, 1.92 mmol) was added, stirred at room temperature for 1 hour, TLC monitored the completion of the reaction, water (10 mL) was added to the reaction solution, then extracted with ethyl acetate (10 mL) for three times, the organic phase was combined, washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, the crude product was separated by column chromatography (EtOAc / PE = 1:2, V / V) to obtain 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol.

[0556] Second step: synthesis of 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0557] In an ice bath, 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (147.2 mg, 1.08 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), then tri-tert-butylphosphine (367.2 mg, 0.9 mmol) and ethyl 5-hydroxy-2-methyl-1-benzofuran-3-carboxylate (200 mg, 0.9 mmol) were added successively, and diazodicomethylpiperidine (458.6 mg, 1.8 mmol) was slowly added dropwise under nitrogen protection, and stirred at room temperature overnight, TLC monitoring reaction completion. Water (10 mL) was added to the reaction solution, then extracted with dichloromethane (10 mL) for three times, the organic phase was combined, washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried, and the crude product was separated by column chromatography (EtOAc / PE = 1:3, V / V) to obtain ethyl 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxylate.

[0558] Third step: synthesis of 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid

[0559] At room temperature, ethyl 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxylate (185.2 mg, 0.549 mmol) was dissolved in THF / MeOH / H2O (V / V / V = 1 / 1 / 1, 10 mL), then lithium hydroxide monohydrate (52.9 mg, 1.75 mmol) was added. Stirred at room temperature overnight, the reaction solution was concentrated to obtain the crude product, which was dissolved in a DCM / MeOH = 10 / 1 system, and the pH was adjusted to 2-3 with 2N hydrochloric acid, and concentrated to obtain 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid crude product, which was directly used in the next step reaction without purification.

[0560] Fourth step: synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0561] To a solution of 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid (140 mg, 0.4 mmol) in DMF (5 mL) was added L- serine hydrochloride (89.2 mg, 0.44 mmol), HATU (304 mg, 0.8 mmol) and DIPEA (125 mg, 1.0 mmol) successively at room temperature. The reaction mixture was stirred at room temperature for 2 h. LC-MS showed the reaction was completed. Water (10 mL) was added to the reaction mixture, which was extracted with dichloromethane (30 mL) for three times. The organic phase was combined and washed with saturated brine (10 mL) for five times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by high performance liquid chromatography to give N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H- cyclopenta[c]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide.

[0562] LC-MS, M / Z (ESI): 396.4 [M+H] +

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 12.5, 5.7 Hz, 2H), 7.38 (d, J = 4.9 Hz, 1H), 7.16 (s, 1H), 6.97 (dd, J = 8.9, 2.5 Hz, 1H), 5.94 (dd, J = 6.4, 3.4 Hz, 1H), 4.99 (s, 1H), 4.45 (ddd, J = 8.1, 5.0, 2.6 Hz, 1H), 3.71 (s, 1H), 3.15 - 3.01 (m, 1H), 2.90 (ddd, J = 17.2, 8.7, 4.8 Hz, 1H), 2.60 - 2.51 (m, 1H), 2.47 (dt, J = 3.6, 1.8 Hz, 3H), 2.17 - 2.05 (m, 1H).

[0564] Example 7: Preparation of target compound I-28A

[0565] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0566] The synthetic route of target compound I-28A is shown below:

[0567] First Step: Synthesis of 3-(bromomethyl)-2-(trifluoromethyl)pyridine

[0568] The starting material 2-(trifluoromethyl)-3-pyridinemethanol (2 g, 11.3 mmol) was dissolved in dichloromethane (20 mL), and triphenylphosphine (5.92 g, 22.6 mmol) and carbon tetrabromide (7.48 g, 22.6 mmol) were added in batches at 0 °C, and then the reaction was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the reaction was concentrated by rotary evaporation to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-10:1) to obtain 3-(bromomethyl)-2-(trifluoromethyl)pyridine.

[0569] LC-MS, M / Z (ESI): 240.1 [M-H] +

[0570] Second Step: Synthesis of 3-((trifluoromethylsulfonyl)methyl)-2-(trifluoromethyl)pyridine

[0571] 3-(Bromomethyl)-2-(trifluoromethyl)pyridine (600 mg, 2.50 mmol) and sodium trifluoromethanesulfinate (780 mg, 5.0 mmol) were dissolved in acetonitrile (8 mL), and the reaction was replaced with nitrogen three times, warmed to 80 °C and stirred overnight. After the reaction was completed, the reaction was filtered with diatomite, and the filtrate was concentrated by rotary evaporation to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-5:1) to obtain 3-((trifluoromethylsulfonyl)methyl)-2-(trifluoromethyl)pyridine.

[0572] LC-MS, M / Z (ESI): 291.9 [M-H] +

[0573] Third Step: Synthesis of 3-(difluoro(trifluoromethylsulfonyl)methyl)-2-(trifluoromethyl)pyridine

[0574] To a solution of 3-(bromo(difluoro)methyl)-2-(trifluoromethyl)pyridine (200 mg, 0.737 mmol) in DMF (2 mL) was added N-fluorobenzenesulfonimide (400 mg, 1.74 mmol) and potassium phosphate tribasic (700 mg, 3.37 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL) three times. The organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated to get a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-10: 1) to get 3-(difluoro(trifluoromethylsulfonyl)methyl)-2- (trifluoromethyl)pyridine.

[0575] LC-MS, M / Z (ESI): 330.1 [M+H] +

[0576] Fourth step: synthesis of 3-(bromo(difluoro)methyl)-2-(trifluoromethyl)pyridine

[0577] To a solution of 3-(difluoro(trifluoromethylsulfonyl)methyl)-2-(trifluoromethyl)pyridine (420 mg, 1.273 mmol) in acetonitrile (5 mL) was added lithium bromide (554 mg, 6.365 mmol) at room temperature. The reaction mixture was stirred at 80 °C overnight. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL) three times. The organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated to get a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-8: 1) to get 3-(bromo(difluoro)methyl)-2-(trifluoromethyl)pyridine.

[0578] LC-MS, M / Z (ESI): 276.1 [M+H] +

[0579] Fifth step: synthesis of ethyl 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1- benzofuran-3-carboxylate

[0580] A mixture of 3-(bromo(difluoro)methyl)-2-(trifluoromethyl)pyridine (80 mg, 0.299 mmol) and 5-hydroxy-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (63.7 mg, 0.299 mmol) and potassium carbonate (80 mg, 0.598 mmol) was dissolved in acetonitrile (2 mL) and a catalytic amount of potassium iodide (4.8 mg, 0.03 mmol) was added. The reaction was heated to 85 °C and stirred overnight. After the reaction was complete, water (2 mL) was added to quench and the reaction was extracted with ethyl acetate (2 mL) three times. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-10: 1) to give 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l- benzofuran-3-carboxylic acid ethyl ester.

[0581] LC-MS, M / Z (ESI): 416.2 [M+H] +

[0582] Step 6: Synthesis of 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l- benzofuran-3-carboxylic acid

[0583] A mixture of 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l- benzofuran-3-carboxylic acid ethyl ester (65 mg, 0.156 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water = 1 mL: 0.5 mL: 1 mL and lithium hydroxide monohydrate (20 mg, 0.468 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was complete, it was concentrated and dried, then 2N hydrochloric acid was added to adjust the pH to about 3, and then DCM (3 mL) was added to extract three times. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l- benzofuran-3-carboxylic acid.

[0584] LC-MS, M / Z (ESI): 387.2 [M+H] +

[0585] Step 7: Synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-(difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l-benzofuran-3-carboxamide

[0586] L-serine hydrochloride (32 mg, 0.213 mmol) was dissolved in N,N- dimethylformamide (2 mL), HATU (118 mg, 0.284 mmol) and N,N- diisopropylethylamine (50 mg, 0.355 mmol) were added successively, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (3 mL) was added for quenching, and extraction was performed three times with ethyl acetate (3 mL). The organic phases were combined and washed five times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by reverse-phase high-performance liquid chromatography to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxamide.

[0587] LC-MS, M / Z (ESI): 457.2 [M+H] +

[0588] 1 H NMR (400 MHz, DMSO-d4) δ 8.97 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.0, 4.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.23 (dd, J = 8.8, 2.3 Hz, 1H), 7.16 (s, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.45 (dt, J = 8.0, 5.2 Hz, 1H), 3.71 (t, J = 5.6 Hz, 2H), 2.66 (s, 3H).

[0589] Example 8: Preparation of target compound I-30A

[0590] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(methyl((2- (trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxamide

[0591] The synthetic route of the target compound I-30A is shown below:

[0592] First step: synthesis of 5-(benzylamino)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0593] Into a 30 mL dry dichloromethane, 5-bromo-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (1.4 g, 4.94 mmol), benzylamine (1.6 g, 14.8 mmol), cesium carbonate (3.2 g, 10 mmol), Pd2(dba)3 (450 mg, 0.5 mmol), Xantphos (580 mg, 1 mmol) were added successively, and the mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. After the reaction was cooled, the mixture was directly concentrated to give a crude product, which was purified by silica gel column to give 5-(benzylamino)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0594] LC-MS, M / Z (ESI): 310.2 [M+H] +

[0595] Second Step: Synthesis of 5-amino-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0596] Into a 30 mL dry dichloromethane, 5-bromo-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (1.4 g, 4.94 mmol), benzylamine (1.6 g, 14.8 mmol), cesium carbonate (3.2 g, 10 mmol), Pd2(dba)3 (450 mg, 0.5 mmol), Xantphos (580 mg, 1 mmol) were added successively, and the mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. After the reaction was cooled, the mixture was directly concentrated to give a crude product, which was purified by silica gel column to give 5-(benzylamino)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0597] LC-MS, M / Z (ESI): 310.2 [M+H] +

[0598] Third Step: Synthesis of 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxylic acid ethyl ester

[0599] Into a 30 mL dry dichloromethane, 5-bromo-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (1.4 g, 4.94 mmol), benzylamine (1.6 g, 14.8 mmol), cesium carbonate (3.2 g, 10 mmol), Pd2(dba)3 (450 mg, 0.5 mmol), Xantphos (580 mg, 1 mmol) were added successively, and the mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. After the reaction was cooled, the mixture was directly concentrated to give a crude product, which was purified by silica gel column to give 5-(benzylamino)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0600] LC-MS, M / Z (ESI): 310.2 [M+H] +

[0601] Step 4: Synthesis of 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)- 1-benzofuran-3-carboxylic acid

[0602] Ethyl 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1- benzofuran-3-carboxylate (106 mg, 0.28 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water = 1 mL: 0.5 mL: 1 mL, and lithium hydroxide monohydrate (23 mg, 0.582 mmol) was added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, it was concentrated and dried in vacuo, then diluted with dilute hydrochloric acid to adjust the pH to about 3, and then extracted with DCM (3 mL) three times. The organic phase was separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-methyl-5-(((2- (trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxylic acid.

[0603] LC-MS, M / Z (ESI): 351.1 [M+H] +

[0604] Step 5: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5- (((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxamide

[0605] 2-methyl-5-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3- carboxylic acid (96.1 mg, 0.26 mmol) and L-serine amide hydrochloride (57.6 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (4 mL), and HATU (135 mg, 0.356 mmol) and N,N-diisopropylethylamine (57.6 mg, 0.445 mmol) were sequentially added. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (8 mL) was added to quench the reaction, and then extracted with ethyl acetate (5 mL) three times. The organic phase was separated, combined, washed with saturated brine (10 mL) five times, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative reverse-phase high-performance liquid chromatography to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2- (trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxamide.

[0606] LC-MS, M / Z (ESI): 436.8 [M+H] +

[0607] 1H NMR (400 MHz, DMSO-d4) δ 8.60 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.66 (dd, J = 7.8, 4.6 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.15 (s, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.56 (dd, J = 8.8, 2.4 Hz, 1H), 6.30 (t, J = 6.0 Hz, 1H), 4.98 (s, 1H), 4.49 (d, J = 5.2 Hz, 2H), 4.43 (dt, J = 7.8, 5.0 Hz, 1H), 3.70 (d, J = 2.8 Hz, 2H), 2.57 (d, J = 17.2 Hz, 3H).

[0608] Example 9: Preparation of target compound I-31A

[0609] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(methyl((2- (trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxamide

[0610] The synthetic route of target compound I-31A is shown below:

[0611] First step: synthesis of 2-methyl-5-(methyl((2-(trifluoromethyl)pyridin-3- yl)methyl)amino)-1-benzofuran-3-carboxylic acid ethyl ester

[0612] 2-methyl-5-({[2-(trifluoromethyl)pyridin-3-yl]methyl}amino)-1-benzofuran-3- carboxylic acid ethyl ester (188 mg, 0.5 mmol), cesium carbonate (325 mg, 1 mmol), iodomethane (211 mg, 1.5 mmol) were added into 5 mL of dry DMF successively, and the reaction was carried out at 50 °C for 4 hours under nitrogen protection. After the reaction solution was cooled, water was added, and the mixture was extracted with ethyl acetate twice. The organic phases were combined and concentrated to obtain a crude product, which was purified by silica gel column to obtain 2-methyl-5-(methyl((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxylic acid ethyl ester.

[0613] Second step: synthesis of 2-methyl-5-(methyl((2-(trifluoromethyl)pyridin-3- yl)methyl)amino)-1-benzofuran-3-carboxylic acid

[0614] Ethyl 2-methyl-5-(methyl{[2-(trifluoromethyl)pyridin-3-yl]methyl}amino)-1- benzofuran-3-carboxylate (122 mg, 0.31 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water = 1 mL: 0.5 mL: 1 mL, lithium hydroxide monohydrate (40 mg, 0.93 mmol) was added, the reaction was stirred at room temperature overnight. After the reaction was completed, it was concentrated and dried, then diluted with dilute hydrochloric acid to adjust pH = 3 or so, then extracted with DCM (3 mL) three times, separated, and the organic phase was combined. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 2-methyl-5-(methyl((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1- benzofuran-3-carboxylic acid.

[0615] LC-MS, M / Z (ESI): 365.1 [M+H] +

[0616] Third step: synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5- (methyl((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxamide

[0617] 2-methyl-5-(methyl((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3- carboxylic acid (108 mg, 0.29 mmol) and L-serine amide hydrochloride (62 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (5 mL), HATU (165 mg, 0.435 mmol) and N,N-diisopropylethylamine (116 mg, 0.9 mmol) were added in turn, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added to quench, and extracted with ethyl acetate (5 mL) three times, separated, and the organic phase was combined and washed with saturated brine (10 mL) five times, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative reverse-phase high-performance liquid chromatography to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(methyl((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-1-benzofuran-3-carboxamide.

[0618] LC-MS, M / Z (ESI): 450.9 [M+H] +

[0619] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.0, 4.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.23 - 7.11 (m, 2H), 6.61 (dd, J = 9.0, 2.6 Hz, 1H), 4.99 (s, 1H), 4.78 (s, 2H), 4.45 (dt, J = 8.0, 4.8 Hz, 1H), 3.72 (s, 2H), 3.08 (s, 3H), 2.61 (s, 3H).

[0620] Example 10: Preparation of target compound I-32A

[0621] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2- (trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3-carboxamide

[0622] The synthetic route of target compound I-32A is shown as follows;

[0623] First step: synthesis of 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3- yl)ethyl)-1-benzofuran-3-carboxylic acid ethyl ester

[0624] 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)vinyl)-1-benzofuran-3-carboxylic acid ethyl ester (150 mg, 0.4 mmol) was dissolved in methanol (10 mL), palladium on carbon (15 mg, 10 wt%) was added, and the reaction was replaced with hydrogen three times. After stirring at room temperature overnight, the reaction was filtered with celite, and then concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-5:1) to obtain 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3-carboxylic acid ethyl ester.

[0625] LC-MS, M / Z (ESI): 378.3 [M+H] +

[0626] Second step: synthesis of 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3- yl)ethyl)-1-benzofuran-3-carboxylic acid

[0627] Ethyl 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3- carboxylate (80 mg, 0.212 mmol) was dissolved in THF / MeOH / H20 (V / V / V = 1 / 1 / 1, 6 mL), then lithium hydroxide (27 mg, 0.636 mmol) was added, and stirred at room temperature overnight. After the reaction was completed, the crude product was concentrated. The crude product was dissolved in DCM / MeOH = 10 / 1 system, and 2N hydrochloric acid was used to adjust pH = 2-3, and concentrated to obtain 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3-carboxylic acid crude product, which was directly used in the next step without purification.

[0628] LC-MS, M / Z (ESI): 350.3 [M+H] +

[0629] Third step: N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2- (trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3-carboxamide

[0630] 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3-carboxylic acid (70 mg, 0.2 mmol) was dissolved in DMF (2 mL), then L-serine hydrochloride (42 mg, 0.3 mmol), HATU (150 mg, 0.4 mmol) and DIPEA (64.5 mg, 0.5 mmol) were added in turn. Stirred at room temperature for 2 hours. After the reaction was completed, water (3 mL) was added to quench, extracted with ethyl acetate (3 mL) three times, separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by reverse phase high performance liquid chromatography to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)ethyl)-1-benzofuran-3-carboxamide.

[0631] LC-MS, M / Z (ESI): 436.4 [M+H] +

[0632] 1H NMR (400 MHz, DMSO-d6) δ 8.54 (t, J = 6.0 Hz, 1H), 7.97 (t, J = 10.0 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.44 (t, J = 14.0 Hz, 2H), 7.19 - 7.11 (m, 2H), 4.99 (t, J = 5.6 Hz, 1H), 4.44 (dt, J = 8.0, 5.2 Hz, 1H), 3.72 (t, J = 5.6 Hz, 2H), 3.10 - 3.02 (m, 2H), 2.95 (dd, J = 10.4, 5.6 Hz, 2H), 2.62 (d, J = 4.0 Hz, 3H).

[0633] Example 11: Preparation of target compound I-3A

[0634] N-(3-(((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)-2-methyl-1- benzofuran-5-yl)-2-(trifluoromethyl)pyridine-3-carboxamide

[0635] The synthetic route of target compound I-3A is shown as follows:

[0636] First step: synthesis of ethyl 2-methyl-5-((2-(trifluoromethyl)pyridine-3- carbonyl)amino)-1-benzofuran-3-carboxylate

[0637] Ethyl 5-amino-2-methyl-1-benzofuran-3-carboxylate (130 mg, 0.6 mmol), 2- (trifluoromethyl)pyridine-3-carboxylic acid (137 mg, 0.72 mmol), 2-(7- azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (300 mg, 0.78 mmol), N,N-diisopropylethylamine (312 mg, 2.4 mmol) were added to N,N- dimethylformamide (3 mL) at room temperature and reacted for 2 h. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL) twice, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, which was purified by silica gel column (petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain ethyl 2-methyl-5-((2-(trifluoromethyl)pyridine-3-carbonyl)amino)-1- benzofuran-3-carboxylate.

[0638] LC-MS, M / Z (ESI): 393.3 [M+H] +

[0639] Step 2: Synthesis of 2-methyl-5-((2-(trifluoromethyl)pyridine-3-carbonyl)amino)- 1-benzofuran-3-carboxylic acid

[0640] Ethyl 2-methyl-5-((2-(trifluoromethyl)pyridine-3-carbonyl)amino)-1- benzofuran-3-carboxylate (210 mg, 0.53 mmol) was dissolved in a mixture solution of tetrahydrofuran: methanol: water = 2 mL: 1 mL: 2 mL (10 mL), and lithium hydroxide monohydrate (60 mg, 1.6 mmol) was added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, it was concentrated and dried in vacuo, and then diluted with dilute hydrochloric acid solution to adjust the pH to about 3, and then extracted with dichloromethane (3 mL) three times, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-methyl-5-((2-(trifluoromethyl)pyridine-3-carbonyl)amino)-1- benzofuran-3-carboxylic acid.

[0641] LC-MS, M / Z (ESI): 365.3 [M+H] +

[0642] Step 3: Synthesis of N-(3-(((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)- 2-methyl-1-benzofuran-5-yl)-2-(trifluoromethyl)pyridine-3-carboxamide

[0643] 2-methyl-5-((2-(trifluoromethyl)pyridine-3-carbonyl)amino)-1-benzofuran-3- carboxylic acid (148 mg, 0.4 mmol) and L-serine amide hydrochloride (68 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (197 mg, 0.52 mmol) and N,N- diisopropylethylamine (208 mg, 1.6 mmol) were sequentially added. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (8 mL) was added to quench, and extracted with ethyl acetate (4 mL) three times, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative reverse phase high performance liquid chromatography (column: YMC-Triart Prep C18 7 μm 30 mm x 40 cm); mobile phase A: 0.1% FA; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient: 30%-80%, 6 minutes) to obtain N-(3-(((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)-2-methyl-1- benzofuran-5-yl)-2-(trifluoromethyl)pyridine-3-carboxamide.

[0644] LC-MS, M / Z (ESI): 448.0 [M+H] +

[0645] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.86 (dd, J = 7.8, 4.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.47 (s, 1H), 7.17 (s, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.48 (dt, J = 7.8, 5.2 Hz, 1H), 3.73 (t, J = 5.4 Hz, 2H), 2.67 (s, 3H).

[0646] Example 12: Preparation of target compound I-6A

[0647] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2- (trifluoromethyl)pyridin-3-yl)cyclopropyl)-1-benzofuran-3-carboxamide

[0648] The synthetic route of target compound I-6A is shown as follows:

[0649] First step: synthesis of ethyl 2-(4-bromo-2-formyloxyphenoxy)propanoate

[0650] Dissolve 5-bromo-2-hydroxybenzaldehyde (5 g, 24.0 mmol) in acetonitrile (50 mL), then add ethyl 2-bromopropionate (6.75 g, 37.3 mmol) and potassium carbonate (6.87 g, 48.0 mmol) successively, and stir at room temperature for 16 hours. TLC monitoring shows that the reaction is completed. Concentrate the reaction solution to obtain the crude product, add water (100 mL) to the reaction solution, and then extract with dichloromethane (100 mL). Combine the organic phases, wash with saturated brine (40 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. Separate the crude product by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to obtain ethyl 2-(4-bromo-2-formyloxyphenoxy)propanoate.

[0651] Second step: synthesis of 2-(4-bromo-2-formyloxyphenoxy)propanoic acid

[0652] Ethyl 2-(4-bromo-2-formylphenoxy)propanoate (6 g, 19.9 mmol) was dissolved in 60 mL of tetrahydrofuran / methanol / water (V / V / V = 1 / 1 / 1) at room temperature, then lithium hydroxide (1.43 g, 59.7 mmol) was added, stirred at room temperature for 16 hours, LC-MS showed that the reaction was completed. The reaction solution was concentrated to obtain the crude product, water (30 mL) was added to the crude product, then the pH value was adjusted to 2-3 with concentrated hydrochloric acid, then extracted with dichloromethane / methanol = 10 / 1 (100 mL), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain 2-(4-bromo-2-formylphenoxy)propanoic acid, which was directly used in the next step without purification.

[0653] Third step: synthesis of 5-bromo-2-methyl-1-benzofuran

[0654] 2-(4-bromo-2-formylphenoxy)propanoic acid (5 g, 18.3 mmol) and sodium acetate (4.5 g, 54.9 mmol) were dissolved in acetic anhydride (50 mL) solution, then heated to 145°C and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was concentrated to obtain the crude product, water (50 mL) was added to the crude product, then extracted with dichloromethane (50 mL) three times, the organic phase was combined, washed with saturated brine (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain 5-bromo-2-methyl-1-benzofuran.

[0655] Fourth step: synthesis of 3-((E)-2-(2-methyl-1-benzofuran-5-yl)vinyl)-2- (trifluoromethyl)pyridine

[0656] 5-bromo-2-methyl-1-benzofuran (2.0 g, 9.5 mmol) and 3-vinyl-2- (trifluoromethyl)pyridine (1.8 g, 10.4 mmol) were dissolved in toluene (30 mL), then bis(triphenylphosphine)palladium (488 mg, 0.9 mmol) and triethylamine (7.69 g, 76 mmol) were added, the reaction system was replaced with nitrogen three times, then heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, the reaction solution was concentrated to obtain the crude product, water (50 mL) was added to the crude product, then extracted with dichloromethane (30 mL) three times, the organic phase was combined, washed with saturated brine (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain 3-((E)-2-(2-methyl-1-benzofuran-5-yl)vinyl)-2- (trifluoromethyl)pyridine.

[0657] Step 5: Synthesis of 3-(2-(2-methyl-l-benzofuran-5-yl)cyclopropyl)-2- (trifluoromethyl)pyridine

[0658] Trimethylsulfoxonium iodide (7.18 g, 33.0 mmol) and sodium tert-butoxide (3.17 g, 33.0 mmol) were dissolved in anhydrous dimethylsulfoxide (20 mL) at room temperature, then the reaction was stirred for 1 hour under nitrogen protection, then 3-((E)-2-(2-methyl-l-benzofuran-5-yl)vinyl)-2- (trifluoromethyl)pyridine (1 g, 3.3 mmol) was dissolved in dimethylsulfoxide (5 mL) and added to the reaction solution, then stirred at 80 °C overnight. LC-MS showed that the reaction was completed. Water (30 mL) was added to the crude product, then extracted with dichloromethane (30 mL) for three times, the organic phases were combined, washed with saturated brine (10 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain 3-(2-(2-methyl-l-benzofuran-5-yl)cyclopropyl)-2- (trifluoromethyl)pyridine.

[0659] Step 6: Synthesis of 3-(2-(3-bromo-2-methyl-l-benzofuran-5-yl)cyclopropyl)-2- (trifluoromethyl)pyridine

[0660] 3-(2-(2-methyl-l-benzofuran-5-yl)cyclopropyl)-2-(trifluoromethyl)pyridine (500 mg, 1.5 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at room temperature, then N-bromosuccinimide (320.4 mg, 1.8 mmol) was added. Stirring at room temperature for 2 hours, LC-MS showed that the reaction was completed. The reaction solution was concentrated to obtain the crude product, water (10 mL) was added to the crude product, then extracted with dichloromethane (20 mL) for three times, the organic phases were combined, washed with saturated brine (10 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain 3-(2-(3-bromo-2-methyl-l-benzofuran-5-yl)cyclopropyl)-2- (trifluoromethyl)pyridine.

[0661] Methyl 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1- benzofuran-3-carboxylate (150 mg, 0.4 mmol) was dissolved in tetrahydrofuran / methanol / water (V / V / V = 1 / 1 / 1, 6 mL) at room temperature, then lithium hydroxide (28.8 mg, 1.2 mmol) was added. It was stirred at room temperature overnight, LC-MS showed the reaction was completed. The reaction solution was concentrated to get the crude product, the crude product was dissolved in dichloromethane / methanol = 10 / 1 system, pH value was adjusted to 2-3 with 2N hydrochloric acid solution, concentrated to get the crude product 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1- benzofuran-3-carboxylic acid, which was used directly in the next step reaction without purification.

[0662] Eighth step: synthesis of 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1- benzofuran-3-carboxylic acid

[0663] Methyl 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1- benzofuran-3-carboxylate (150 mg, 0.4 mmol) was dissolved in tetrahydrofuran / methanol / water (V / V / V = 1 / 1 / 1, 6 mL) at room temperature, then lithium hydroxide (28.8 mg, 1.2 mmol) was added. It was stirred at room temperature overnight, LC-MS showed the reaction was completed. The reaction solution was concentrated to get the crude product, the crude product was dissolved in dichloromethane / methanol = 10 / 1 system, pH value was adjusted to 2-3 with 2N hydrochloric acid solution, concentrated to get the crude product 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1- benzofuran-3-carboxylic acid, which was used directly in the next step reaction without purification.

[0664] Ninth step: synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2- (trifluoromethyl)pyridin-3-yl)cyclopropyl)-1-benzofuran-3-carboxamide

[0665] At room temperature, 2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1-benzofuran-3-carboxylic acid (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of L-seramide hydrochloride (91.6 mg, 0.49 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (315 mg, 0.66 mmol), and N,N-diisopropylethylamine (134.0 mg, 0.82 mmol). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. Add water (10 mL) to the crude product, then extract with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Then, precipitate the crude product by high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(2-(2-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = acetonitrile, B = water + 0.5% formic acid, and a gradient of 30% acetonitrile.

[0666] LC-MS, M / Z (ESI): 448.0 [M+H] +

[0667] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,J=4.0Hz,1H),7.86(d,J=8.0Hz,1H),7.71–7 .64(m,2H),7.61(s,1H),7.50(d,J=8.8Hz,2H),7.19(s,1H),7.16(dd,J=8.8 ,1.6Hz,1H),5.00(td,J=5.6,2.0Hz,1H),4.50–4.44(m,1H),3.74(t,J=5.2H z,2H),2.65(s,3H),2.44-2.37(m,2H),1.76–1.70(m,1H),1.67-1.61(m,1H).

[0668] Example 13: Preparation of target compound I-22A

[0669] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopentan[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxamide

[0670] A synthetic route of the target compound I-22A is shown below:

[0671] First Step: Synthesis of methyl 4-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylate

[0672] Under nitrogen, zinc metal (3.5 g, 53.5 mmol) and 1,2-dibromoethane (0.23 mL, 2.7 mmol) were mixed in tetrahydrofuran (30 mL) and the reaction was stirred at 80 °C for 2 hours. After cooling to room temperature, trimethylchlorosilane (0.06 mL, 0.52 mmol) was added and stirred for 30 minutes. Ethyl 3-iodopropionate (10 g, 43.8 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction and stirred at 40 °C for 4 hours. Cuprous cyanide (3.2 g, 35.7 mmol) and lithium chloride (3.05 g, 72 mmol) were mixed in tetrahydrofuran (10 mL) and then added dropwise to the reaction at 0 °C and stirred for 30 minutes. The reaction was then cooled to -78 °C and ethyl chloroformate (3.3 mL, 33.8 mmol) and methyl nicotinate (4.63 g, 33.8 mmol) in tetrahydrofuran (10 mL) were added dropwise under nitrogen. The reaction was then slowly warmed to room temperature and stirred for 12 hours. Saturated sodium carbonate solution (30 mL) was added to the reaction and extracted with ethyl acetate (50 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. Xylene (20 mL) and sulfur (3.3 g, 104 mmol) were added to the crude product and heated to 140 °C for 12 hours. After the reaction was completed, the reaction was filtered after cooling to room temperature and the filtrate was concentrated. Purification by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) gave methyl 4-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylate.

[0673] Second Step: Synthesis of 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

[0674] Sodium hydride (2.57 g, 64.3 mmol, 60%) was added to dry tetrahydrofuran (30 mL) at room temperature, followed by the addition of a solution of methyl 4-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylate (3.31 g, 13.9 mmol) in tetrahydrofuran (20 mL). The reaction was heated to reflux and stirred for 4 h. After the reaction was complete, the temperature was allowed to drop to room temperature and the reaction was concentrated. The residue was added to 12 M hydrochloric acid solution (50 mL) at 0 °C, followed by heating to 110 °C for 1 h. Saturated sodium carbonate solution (30 mL) was added to the reaction, which was filtered, and the filtrate was extracted with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to give 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one.

[0675] Third step: synthesis of 1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

[0676] Sodium hydride (2.57 g, 64.3 mmol, 60%) was added to dry tetrahydrofuran (30 mL) at room temperature, followed by the addition of a solution of methyl 4-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylate (3.31 g, 13.9 mmol) in tetrahydrofuran (20 mL). The reaction was heated to reflux and stirred for 4 h. After the reaction was complete, the temperature was allowed to drop to room temperature and the reaction was concentrated. The residue was added to 12 M hydrochloric acid solution (50 mL) at 0 °C, followed by heating to 110 °C for 1 h. Saturated sodium carbonate solution (30 mL) was added to the reaction, which was filtered, and the filtrate was extracted with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to give 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one.

[0677] Fourth step: synthesis of 1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol

[0678] To a solution of 1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (260 mg, 1.29 mmol) in ethanol (10 mL) was added sodium borohydride (72.7 mg, 1.92 mmol) under ice-bath condition. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL) for three times. The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (2:1, v / v)) to give 1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol.

[0679] Fifth step: synthesis of ethyl 2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxylate

[0680] To a solution of 1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (130 mg, 0.64 mmol) in anhydrous tetrahydrofuran (5 mL) was added tri-tert-butylphosphine (I) (262.1 mg, 0.64 mmol) and ethyl 5-hydroxy-2-methyl-1-benzofuran-3-carboxylate (142.8 mg, 0.64 mmol) under ice-bath condition. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL) for three times. The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (3:1, v / v)) to give ethyl 2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxylate.

[0681] Sixth step: synthesis of 2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxylic acid

[0682] At room temperature, ethyl 2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxylic acid (212 mg, 0.52 mmol) was dissolved in tetrahydrofuran / methanol / water (V / V / V = 1 / 1 / 1, 10 mL), and then lithium hydroxide monohydrate (52.9 mg, 1.75 mmol) was added. The mixture was stirred overnight at room temperature, and the reaction solution was concentrated to obtain the crude product. The crude product was dissolved in a dichloromethane / methanol = 10 / 1 system, and the pH was adjusted to 2-3 with 2N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxylic acid, which was used directly in the next reaction without purification.

[0683] Step 7: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxamide

[0684] At room temperature, crude 2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxylic acid (240 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of L-seramide hydrochloride (142.5 mg, 0.71 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (486.4 mg, 1.28 mmol), and N,N-diisopropylethylamine (200 mg, 1.6 mmol). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. Add water (10 mL) to the reaction system, then extract three times with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Filter the crude product through high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)oxy)-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = acetonitrile, B = water + 0.5% formic acid, gradient: 30.0% acetonitrile.

[0685] LC-MS, M / Z (ESI): 464.4 [M+H] +

[0686] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.9 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.38 (s, 1H), 7.17 (s, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.06 (s, 1H), 4.99 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 8.0, 3.3 Hz, 1H), 3.72 (t, J = 5.3 Hz, 2H), 3.24 - 3.12 (m, 1H), 3.03 (ddd, J = 17.6, 8.9, 2.8 Hz, 1H), 2.62 (s, 3H), 2.54 (dt, J = 14.9, 7.5 Hz, 1H), 2.27 - 2.16 (m, 1H).

[0687] Example 14: Preparation of target compound I-23A

[0688] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((7,7-difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0689] The synthetic route of target compound I-23A is shown below:

[0690] First step: synthesis of 7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine

[0691] 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (3.0 g, 22.5 mmol) was added to dichloromethane (30 mL), diethylamine sulfide trifluoride (10.8 g, 67.5 mmol) was added dropwise under ice water bath, after the addition was completed, the reaction was carried out at room temperature for 24 hours. The reaction solution was directly poured into 50 mL saturated aqueous sodium bicarbonate solution to quench, filtered to remove diatomite, the filter cake was washed with dichloromethane, the filtrate was separated, the organic phase was washed with saturated ammonium chloride, separated, dried, filtered, and rotary evaporated to give 7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine.

[0692] LC-MS, M / Z (ESI): 156.3 [M+H] +

[0693] Step 2: Synthesis of 5-bromo-7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine

[0694] To 7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine (870 mg, 5.6 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (1.5 g, 8.4 mmol), azobisisobutyronitrile (180 mg, 1.12 mmol) and the reaction mixture was heated at 100 °C for 2 h. After cooling, the reaction mixture was concentrated and purified by silica gel column (petroleum ether / ethyl acetate (V / V) = 10 / 1) to give 5-bromo-7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine.

[0695] LC-MS, M / Z (ESI): 234.2 [M+H] +

[0696] Step 3: Synthesis of 5-((7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-5- yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0697] To 5-bromo-7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine (380 mg, 1.62 mmol), 5-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (358 mg, 1.62 mmol), potassium carbonate (670 mg, 4.8 mmol) were added to acetonitrile (5 mL) and the reaction mixture was heated at 50 °C for 16 h. After cooling, the reaction mixture was filtered through celite and the solid was washed with ethyl acetate twice. The filtrate was concentrated to give a crude product which was purified by silica gel column (petroleum ether / ethyl acetate (V / V) = 4 / 1) to give 5-((7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0698] LC-MS, M / Z (ESI): 374.2 [M+H] +

[0699] Step 4: Synthesis of 5-((7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-5- yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid

[0700] To a solution of 5-((7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2- methyl-1-benzofuran-3-carboxylic acid ethyl ester (430 mg, 1.15 mmol) in tetrahydrofuran: methanol: water = 2 mL: 1 mL: 2 mL (10 mL) was added lithium hydroxide monohydrate (130 mg, 3.45 mmol) and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was concentrated and dried, then diluted with dilute hydrochloric acid solution to adjust the pH to about 3, then extracted with dichloromethane (3 mL) three times, separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-((7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid as a crude product, which was used directly in the next step.

[0701] LC-MS, M / Z (ESI): 346.2 [M+H] +

[0702] Fifth step: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((7,7-difluoro- 6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0703] To a solution of 5-((7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-2- methyl-1-benzofuran-3-carboxylic acid (350 mg, 1.0 mmol) and L-serine amide hydrochloride (168 mg, 1.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7- azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (500 mg, 1.3 mmol) and N,N-diisopropylethylamine (520 mg, 4.0 mmol) sequentially, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (15 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL) three times, separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative reverse phase high performance liquid chromatography (column: YMC-Triart Prep C18 7 μm 30 mm x 40 cm; mobile phase A: water + 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient: 30%-80%, 6 minutes) to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((7,7-difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide.

[0704] LC-MS, M / Z (ESI): 432.2 [M+H] +

[0705] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (dd, J = 4.8, 1.2 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.57 - 7.44 (m, 3H), 7.21 (s, 1H), 7.04 (dd, J = 8.8, 2.6 Hz, 1H), 6.03 (td, J = 6.8, 2.4 Hz, 1H), 5.02 (td, J = 5.6, 1.8 Hz, 1H), 4.49 (dt, J = 8.0, 5.0 Hz, 1H), 3.75 (t, J = 5.4 Hz, 2H), 3.46 - 3.35 (m, 1H), 2.77 - 2.58 (m, 4H).

[0706] Example 15: Preparation of target compound I-25A

[0707] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)- 2-methyl-1-benzofuran-3-carboxamide

[0708] The synthetic route of target compound I-25A is shown below:

[0709] First Step: Synthesis of 5-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0710] Dissolve 5,6,7,8-tetrahydro-l,6-naphthyridine (309 mg, 2.3 mmol) and 5-bromo-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (500 mg, 1.77 mmol) in N,N-dimethylformamide (8 mL), add tris(dibenzylideneacetone)dipalladium(0) (324 mg, 0.345 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (338 mg, 0.708 mml) and cesium carbonate (1.15 mg, 3.54 mmol) successively, replace the reaction solution with nitrogen for three times, then heat to 85 °C and stir overnight. After the reaction is completed, quench with water (10 mL) and extract with ethyl acetate (10 mL) three times, separate the organic phase and combine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain a residue. Purify the residue by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-3: 1) to obtain 5-(7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester.

[0711] LC-MS, M / Z (ESI): 337.3 [M+H] +

[0712] Second Step: Synthesis of 5-(7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-2-methyl-l- benzofuran-3-carboxylic acid

[0713] Dissolve 5-(7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (300 mg, 0.89 mmol) in tetrahydrofuran / methanol / water (V / V / V = 2 / 1 / 2, 6 mL), then add lithium hydroxide (110 mg, 3.56 mmol) and stir at room temperature overnight. After the reaction is completed, concentrate to obtain a crude product. Dissolve the crude product in a dichloromethane / methanol = 10 / 1 system, adjust the pH value to 2-3 with a 2N hydrochloric acid solution, and concentrate to obtain a crude 5-(7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-2-methyl-l-benzofuran-3-carboxylic acid, which is used directly in the next step without purification.

[0714] LC-MS, M / Z (ESI): 309.3 [M+H] +

[0715] Third Step: Synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-(7,8-dihydro-l,6- naphthyridin-6(5H)-yl)-2-methyl-l-benzofuran-3-carboxamide

[0716] To a solution of 5-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-methyl-1- benzofuran-3-carboxylic acid (25 mg, 0.081 mmol) in N,N-dimethylformamide (2 mL) was added L-serine hydrochloride (20 mg, 0.121 mmol), 2-(7-azobenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (60 mg, 0.162 mmol) and N,N- diisopropylethylamine (30 mg, 0.243 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, water (3 mL) was added to quench the reaction and extracted with ethyl acetate (3 mL) three times. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to get a residue. The residue was purified by preparative reverse phase high performance liquid chromatography (column: YMC-Triart Prep C18 7 pm 30 mm x 40 cm); mobile phase A: water + 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient: 15% to 65% in 6 min) to get N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(7,8-dihydro-1,6- naphthyridin-6(5H)-yl)-2-methyl-1-benzofuran-3-carboxamide.

[0717] LC-MS, M / Z (ESI): 395.2 [M+H] +

[0718] 1 H NMR (400 MHz, DMSO-d6) d 8.34 (d, J = 4.0 Hz, 1H), 8.22 (s, 1H), 7.64 - 7.58 (m, 2H), 7.48 (s, 1H), 7.41 (dd, J = 14.4, 5.6 Hz, 2H), 7.19 (dd, J = 7.6, 4.8 Hz, 2H), 7.09 (dd, J = 9.2, 2.4 Hz, 1H), 4.48 - 4.43 (m, 1H), 4.37 (s, 2H), 3.73 (d, J = 3.2 Hz, 2H), 3.61 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H).

[0719] Example 16: Preparation of the target compound I-27A

[0720] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0721] The synthetic route of the target compound I-27A is shown below:

[0722] First Step: Synthesis of 2-bromo-3-(bromomethyl)pyridine

[0723] (2-bromopyridin-3-yl)methanol (6 g, 31.9 mmol) was dissolved in dichloromethane (60 mL), and triphenylphosphine (16.7 g, 63.8 mmol) and carbon tetrabromide (21.1 g, 63.8 mmol) were added in batches at 0 °C, and then the reaction was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the reaction was rotary evaporated and concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 10 / 1) to obtain 2-bromo-3-(bromomethyl)pyridine.

[0724] Second Step: Synthesis of 2-bromo-3-((trifluoromethylsulfonyl)methyl)pyridine

[0725] 2-bromo-3-(bromomethyl)pyridine (7.0 g, 28.1 mmol) and sodium trifluoromethanesulfinate (8.76 g, 56.2 mmol) were dissolved in acetonitrile (70 mL), and the reaction was replaced with nitrogen three times, warmed to 80 °C and stirred overnight. After the reaction was completed, the reaction was filtered with diatomite, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 10 / 1) to obtain 2-bromo-3-((trifluoromethylsulfonyl)methyl)pyridine (5 g, yield: 58.3%).

[0726] Third Step: Synthesis of 2-bromo-3-(difluoro(trifluoromethylsulfonyl)methyl)pyridine

[0727] 2-bromo-3-((trifluoromethylsulfonyl)methyl)pyridine (5.0 g, 16.4 mmol) was dissolved in N,N-dimethylformamide (50 mL), and N-fluorobenzenesulfonimide (10.84 g, 34.44 mmol) and potassium phosphate tribasic (10.43 g, 49.2 mmol) were added in sequence, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (50 mL) was added to quench, and extracted with ethyl acetate (50 mL) three times, and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 10 / 1) to obtain 2-bromo-3-(difluoro(trifluoromethylsulfonyl)methyl)pyridine.

[0728] Fourth Step: Synthesis of 2-bromo-3-(bromodifluoromethyl)pyridine

[0729] Dissolve 2-bromo-3-(difluoro(trifluoromethylsulfonyl)methyl)pyridine (3.5 g, 10.2 mmol) in acetonitrile (30 mL), add lithium bromide (4.42 g, 51.0 mmol), and slowly warm the reaction to 80 °C with stirring overnight. After the reaction is complete, add water (20 mL) and extract with ethyl acetate (30 mL) three times, separate the layers, and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue by column chromatography (petroleum ether: ethyl acetate (V / V) = 10 / 1) to give 2-bromo-3-(bromodifluoromethyl)pyridine.

[0730] Fifth Step: Synthesis of 5-((2-bromopyridin-3-yl) difluoromethoxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0731] Dissolve 2-bromo-3-(bromodifluoromethyl)pyridine (1.0 g, 3.5 mmol) and 5-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (774 mg, 3.5 mmol) and potassium carbonate (967.4 mg, 7.0 mmol) in acetonitrile (10 mL), then add potassium iodide (58.45 mg, 0.35 mmol), and heat the reaction to 85 °C with stirring overnight. After the reaction is complete, quench with water (20 mL) and extract with ethyl acetate (20 mL) three times, separate the layers, and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue by column chromatography (petroleum ether: ethyl acetate (V / V) = 5 / 1) to give 5-((2-bromopyridin-3-yl) difluoromethoxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0732] Sixth Step: Synthesis of 5-((2-cyclopropylpyridin-3-yl) difluoromethoxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0733] Ethyl 5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate (80 mg, 0.2 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water = 1 mL: 1 mL: 1 mL (10 mL), and lithium hydroxide monohydrate (14.4 mg, 0.6 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was concentrated to give a crude product. The crude product was dissolved in dichloromethane / methanol = 10 / 1, and the pH was adjusted to 2-3 with 2N hydrochloric acid solution. The crude product, ethyl 5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate, was used in the next reaction without purification.

[0734] Step 7: Synthesis of 5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylic acid

[0735] Ethyl 5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate (80 mg, 0.2 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water = 1 mL: 1 mL: 1 mL (10 mL), and lithium hydroxide monohydrate (14.4 mg, 0.6 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was concentrated to give a crude product. The crude product was dissolved in dichloromethane / methanol = 10 / 1, and the pH was adjusted to 2-3 with 2N hydrochloric acid solution. The crude product, ethyl 5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate, was used in the next reaction without purification.

[0736] Step 8: Synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2- cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxamide

[0737] 5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)2-methyl-1-benzofuran-3-carboxylic acid (60 mg, 0.16 mmol) and L-seramide hydrochloride (36.8 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (2 mL). Then, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (121.6 mg, 0.32 mmol) and N,N-diisopropylethylamine (51.6 mg, 0.4 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. Water (10 mL) was added to the reaction system, followed by three extractions with dichloromethane (30 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to high-performance liquid chromatography (HPLC) (Column: SunFire). TM Prep C18 OBD TM N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-cyclopropylpyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = water + 0.5% formic acid, B = acetonitrile, and a gradient of 30.0% acetonitrile.

[0738] LC-MS, M / Z (ESI): 446.4 [M+H] +

[0739] 1 H NMR (400MHz, DMSO-d6) δ8.58(dd,J=4.8,1.4Hz,1H),8.05(dd,J=8.0,1.6Hz,1H),7.74-7.2(m,2H),7.63(d,J=8.8Hz,1H),7.50(s,1H),7.30– 7.26(m,2H),7.19(s,1H),5.01(t,J=5.2Hz,1H),4.49-4.44(m,1H),3. 74(t,J=4.0Hz,2H),2.67(s,3H),2.64–2.60(m,1H),1.14–1.06(m,4H).

[0740] Example 17: Preparation of target compound I-29A

[0741] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-(3,3-difluoroazacyclobutan-1-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0742] A synthetic route of the target compound I-29A is shown below:

[0743] First Step: Synthesis of 5-((2-(3,3-difluoroazetidin-l-yl)pyridin-3-yl)di(fluoro)methoxy)- 2-methyl-l-benzofuran-3-carboxylic acid ethyl ester

[0744] Ethyl 5-((2-bromopyridin-3-yl)di(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxylate (300 mg, 0.7 mmol) was dissolved in 1,4-dioxane (6 mL) at room temperature, then 3,3-difluoroazetidine hydrochloride (136 mg, 1.05 mmol), tris(dibenzylideneacetone)dipalladium (64.5 mg, 0.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (82 mg, 0.14 mmol) and cesium carbonate (458 mg, 1.4 mmol) were added successively. The reaction was stirred at 110 °C for 16 hours under nitrogen protection. LC-MS showed that the reaction was completed, the reaction solution was concentrated to obtain the crude product, water (30 mL) was added to quench the reaction, extracted with dichloromethane (30 mL) for three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain ethyl 5-((2-(3,3-difluoroazetidin-l-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate.

[0745] Second Step: Synthesis of 5-((2-(3,3-difluoroazetidin-l-yl)pyridin-3-yl)di(fluoro)methoxy)- 2-methyl-l-benzofuran-3-carboxylic acid

[0746] Ethyl 5-((2-(3,3-difluoroazetidin-l-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate (180 mg, 0.41 mmol) was dissolved in a mixed solution of tetrahydrofuran:methanol:water = 1 mL: 1 mL: 1 mL (10 mL), lithium hydroxide monohydrate (29.5 mg, 1.23 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was dissolved in a dichloromethane / methanol = 10 / 1 system, the pH value was adjusted to 2-3 with 2N hydrochloric acid solution, and concentrated to obtain the crude product ethyl 5-((2-(3,3-difluoroazetidin-l-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-l- benzofuran-3-carboxylate, which was directly used in the next step reaction without purification.

[0747] Step 3: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-(3,3-difluoroazacyclobutane-1-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0748] Ethyl 5-((2-(3,3-difluoroazacyclobutan-1-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxylate (150 mg, 0.36 mmol) and L-seramide hydrochloride (80.6 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (2 mL). Then, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (278 mg, 0.73 mmol) and N,N-diisopropylethylamine (117.9 mg, 0.91 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. Add water (10 mL) to the crude product, then extract three times with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Then, precipitate the crude product by high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-(3,3-difluoroazacyclobutane-1-yl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = water + 0.5% formic acid, B = acetonitrile, and a gradient of 30.0% acetonitrile.

[0749] LC-MS, M / Z (ESI): 497.2 [M+H] +

[0750] 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.48 (s, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 7.18 (s, 1H), 6.95 (dd, J = 8.0, 4.8 Hz, 1H), 5.00 (t, J = 5.2 Hz, 1H), 4.57 (t, J = 12.4 Hz, 4H), 4.49 - 4.44 (m, 1H), 3.73 (t, J = 5.2 Hz, 2H), 2.68 (s, 3H).

[0751] Example 18: Preparation of target compound I-33A

[0752] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-(2- (trifluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-1-benzofuran-3-carboxamide

[0753] The synthetic route of target compound I-33A is shown below:

[0754] First step: synthesis of tert-butyl 3-((4-methylphenyl-1-sulfonyl)oxy)azetidine-1-carboxylate

[0755] Tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.8 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature, then p-toluenesulfonyl chloride (1.65 g, 8.6 mmol) was added. Stirring at room temperature for 2 hours, TLC monitoring reaction completion. Water (10 mL) was added to the reaction solution, then extracted with ethyl acetate (10 mL) for three times, the organic phase was combined, washed with saturated brine (10 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, the crude product was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to obtain tert-butyl 3-((4-methylphenyl-1-sulfonyl)oxy)azetidine-1-carboxylate.

[0756] Second step: synthesis of tert-butyl 3-((3-carboxyethyl-2-methyl-1-benzofuran-5-yl)oxy)azetidine-1-carboxylate

[0757] To a solution of 3-((4-methylphenyl-1-sulfonyl)oxy)azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 3.97 mmol), 5-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (0.72 g, 3.24 mmol), potassium carbonate (1.34 g, 9.6 mmol) in acetonitrile (10 mL) was added at 80 °C and stirred overnight. The reaction mixture was cooled to room temperature and filtered through celite. The solid was washed with ethyl acetate twice and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 4 / 1) to give 3-((3-carboxylic acid ethyl ester-2-methyl-1-benzofuran-5-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester.

[0758] Step 3: Synthesis of 5-((azetidin-3-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0759] To a solution of 3-((3-carboxylic acid ethyl ester-2-methyl-1-benzofuran-5-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.2 mmol) in anhydrous tetrahydrofuran (20 mL) was added 2N hydrochloric acid solution (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by thin layer chromatography. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL) three times. The organic phase was combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and dried. The crude product was purified by column chromatography (dichloromethane / methanol (V / V) = 10:1) to give 5-((azetidin-3-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (425 mg, yield: 48.3%)

[0760] Step 4: Synthesis of 2-methyl-5-((1-(2-(trifluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-1-benzofuran-3-carboxylic acid ethyl ester

[0761] To a solution of 5-((azetidin-3-yl)oxy)-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (270 mg, 0.98 mmol) in N,N-dimethylformamide (6 mL) was added 3-bromo-2-trifluoromethylpyridine (266.3 mg, 1.18 mmol), 2-dicyclohexylphosphino-2',6'-dιisopropoxy-l,l'-biphenyl-2- yl) palladium(II) (83.7 mg, 0.10 mmol) and cesium carbonate (955.5 mg, 2.94 mmol) sequentially at room temperature. The reaction was stirred at 120 °C under nitrogen for 16 hours. LC-MS showed the reaction was complete. The reaction was concentrated to give a crude product. Water (30 mL) was added to the crude product and the mixture was extracted with ethyl acetate (10 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (3: 1, v / v) to give 2-methyl-5-((l-(2-(trifluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-l- benzofuran-3-carboxylic acid ethyl ester.

[0762] Fifth Step: Synthesis of 2-methyl-5-((l-(2-(trifluoromethyl)pyridin-3-yl)azetidin-3- yl)oxy)-l-benzofuran-3-carboxylic acid

[0763] To a solution of 2-methyl-5-((l-(2-(trifluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-l- benzofuran-3-carboxylic acid ethyl ester (330 mg, 0.78 mmol) in tetrahydrofuran: methanol: water = 1:1:1 (10 mL) was added lithium hydroxide monohydrate (56.1 mg, 2.34 mmol) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was complete, the reaction was concentrated to give a crude product. The crude product was dissolved in dichloromethane / methanol = 10 / 1 system and the pH value was adjusted to 2-3 with 2N hydrochloric acid solution. The crude product 2-methyl-5-((l-(2-(trifluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-l- benzofuran-3-carboxylic acid was obtained by concentration and was used directly in the next reaction without purification.

[0764] Sixth Step: Synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((l-(2- (trifluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-l-benzofuran-3-carboxamide

[0765] 2-Methyl-5-((1-(2-(trifluoromethyl)pyridin-3-yl)azacyclobutan-3-yl)oxy)-1-benzofuran-3-carboxylic acid (340 mg, 0.87 mmol) and L-seramide hydrochloride (200.1 mg, 1.36 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (661.2 mg, 1.74 mmol) and N,N-diisopropylethylamine (280.6 mg, 2.17 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. LC-MS showed the reaction was complete. Water (10 mL) was added to the crude product, followed by extraction three times with dichloromethane (30 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to high-performance liquid chromatography (HPLC) (Column: SunFire). TM Prep C18 OBD TM N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((1-(2-(trifluoromethyl)pyridin-3-yl)azacyclobutane-3-yl)oxy)-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = water + 0.5% formic acid, B = acetonitrile, and a gradient of 30.0% acetonitrile.

[0766] LC-MS, M / Z (ESI): 479.4 [M+H] +

[0767] 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=3.5Hz,1H),7.81(m,1H),7.68(d,J=8.0Hz,1H),7.5 6(s,1H),7.47(d,J=9.0Hz,1H),7.45–7.42(m,1H),7.38(d,J=2.7Hz,1H),7.17–7.14( m,1H),7.12(d,J=8.6Hz,1H),6.86(dd,J=8.9,2.6Hz,1H),5.21(dd,J=11.1,5.6Hz,1H ),5.11(m,1H),3.95(dd,J=8.6,6.7Hz,1H),3.73(dd,J=10.8,5.2Hz,2H),2.58(s,3H).

[0768] Example 19: Preparation of target compound I-34A

[0769] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-(difluoromethyl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0770] The synthetic route for the target compound I-34A is shown below:

[0771] Step 1: Synthesis of 3-bromo-2-(difluoromethyl)pyridine

[0772] 3-Bromopyridin-2-carboxaldehyde (6.0 g, 32.2 mmol) was dissolved in dichloromethane (80 mL), and diethylaminotrifluoride (10.4 g, 64.4 mmol) was added dropwise at 0 °C. Under nitrogen protection, the reaction mixture was stirred at 0 °C for 2 hours, then quenched with a saturated sodium bicarbonate solution in an ice bath. The mixture was then extracted three times with dichloromethane (30 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1-5:1) to give 3-bromo-2-(difluoromethyl)pyridine.

[0773] LC-MS, M / Z (ESI): 210.1 [M+H] +

[0774] Step 2: Synthesis of methyl 2-(difluoromethyl)pyridine-3-carboxylate

[0775] 3-Bromo-2-(difluoromethyl)pyridine (1.0 g, 4.81 mmol) was dissolved in triethylamine:methanol = 1:8 (V:V) (18 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (351 mg, 0.481 mmol) was added. The reaction solution was replaced three times with carbon monoxide, and then heated to 60 °C and stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to obtain a crude product. Water (5 mL) was added to the crude product, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and evaporated to dryness. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 5 / 1) to obtain methyl 2-(difluoromethyl)pyridine-3-carboxylate.

[0776] LC-MS, M / Z (ESI): 188.1 [M+H] +

[0777] Step 3: Synthesis of (2-(difluoromethyl)pyridin-3-yl)methanol

[0778] Methyl 2-(difluoromethyl)pyridine-3-carboxylate (1.75 g, 9.36 mmol) was dissolved in tetrahydrofuran (20 mL) and lithium aluminum hydride (420 mg, 11.2 mmol) was added portionwise at 0 °C under nitrogen protection. The reaction was stirred at room temperature overnight. After the reaction was completed, water (0.5 mL), 10% sodium hydroxide solution (1 mL), water (1 mL), ethyl acetate and anhydrous sodium sulfate were added successively. The reaction was filtered through a five-hole funnel and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-1:1) to give (2-(difluoromethyl)pyridin-3-yl)methanol.

[0779] LC-MS, M / Z (ESI): 160.1 [M+H] +

[0780] Fourth step: synthesis of 3-(bromomethyl)-2-(difluoromethyl)pyridine

[0781] (2-(Difluoromethyl)pyridin-3-yl)methanol (500 mg, 3.12 mmol) was dissolved in dichloromethane (7 mL) and carbon tetrabromide (2.0 g, 6.24 mmol) and triphenylphosphine (1.6 g, 6.24 mmol) were added successively. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added and the mixture was extracted with ethyl acetate (30 mL) three times. The organic phase was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated and dried. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 5 / 1) to give 3-(bromomethyl)-2-(difluoromethyl)pyridine.

[0782] LC-MS, M / Z (ESI): 223.1 [M+H] +

[0783] Fifth step: synthesis of 2-(difluoromethyl)-3-((trifluoromethylsulfonyl)methyl)pyridine

[0784] To a solution of 3-(bromomethyl)-2-(difluoromethyl)pyridine (300 mg, 0.212 mmol) in acetonitrile (5 mL) was added sodium trifluoromethylsulfinate (420 mg, 0.424 mmol) and the reaction was purged with nitrogen three times. The reaction was heated to 80 °C and stirred overnight. After the reaction was completed, water (5 mL) was added and the reaction was extracted with dichloromethane (30 mL) three times. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and dried. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 5 / 1) to give 2-(difluoromethyl)-3-((trifluoromethylsulfonyl)methyl)pyridine.

[0785] LC-MS, M / Z (ESI): 276.1 [M+H] +

[0786] Step 6: Synthesis of 2-(difluoromethyl)-3-(difluoro(trifluoromethylsulfonyl)methyl)pyridine

[0787] To a solution of 2-(difluoromethyl)-3-((trifluoromethylsulfonyl)methyl)pyridine (184 mg, 0.667 mmol) in N,N-dimethylformamide (4 mL) was added N-fluorobenzene sulfonimide (441 mg, 1.4 mmol) and potassium phosphate tribasic (424 mg, 2.0 mmol) at 0 °C. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, water (5 mL) was added and the reaction was extracted with ethyl acetate (20 mL). The organic phase was combined and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and dried. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 5 / 1) to give 2-(difluoromethyl)-3-(difluoro(trifluoromethylsulfonyl)methyl)pyridine.

[0788] LC-MS, M / Z (ESI): 312.1 [M+H] +

[0789] Step 7: Synthesis of ethyl 5-((2-(difluoromethyl)pyridin-3-yl)bis(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxylate

[0790] Dissolve 2-(difluoromethyl)-3-(difluoro(trifluoromethylsulfonyl)methyl)pyridine (170 mg, 0.545 mmol) and 5-hydroxy-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (120 mg, 0.545 mmol) in acetonitrile (5 mL), add potassium carbonate (150 mg, 1.09 mmol) and potassium iodide (91 mg, 0.545 mmol), replace the reaction with nitrogen three times, warm to 85 °C, and stir overnight. After the reaction is completed, add water (5 mL), extract with ethyl acetate (20 mL) three times, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and dry in vacuo to obtain 5-((2-(difluoromethyl)pyridin-3-yl)bis(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester.

[0791] LC-MS, M / Z (ESI): 398.3 [M+H] +

[0792] Eighth step: synthesis of 5-((2-(difluoromethyl)pyridin-3-yl)bis(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxylic acid

[0793] Dissolve 5-((2-(difluoromethyl)pyridin-3-yl)bis(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (170 mg, 0.427 mmol) in tetrahydrofuran / methanol / water (V / V / V = 2 / 1 / 2, 6 mL), then add lithium hydroxide (72 mg, 1.71 mmol), and stir at room temperature overnight. After the reaction is completed, concentrate to obtain the crude product. Dissolve the crude product in a dichloromethane / methanol = 10 / 1 system, adjust the pH value to 2-3 with a 2N hydrochloric acid solution, and concentrate to obtain the crude 5-((2-(difluoromethyl)pyridin-3-yl)bis(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxylic acid, which is directly used in the next step without purification.

[0794] LC-MS, M / Z (ESI): 370.3 [M+H] +

[0795] Ninth step: synthesis of N-((2S)-l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2-(difluoromethyl)pyridin-3-yl)bis(fluoro)methoxy)-2-methyl-l-benzofuran-3-carboxamide

[0796] The starting material 5-((2-(difluoromethyl)pyridin-3-yl)di(fluoro)methoxy)-2- methyl-1-benzofuran-3-carboxylic acid (170 mg, 0.495 mmol) was dissolved in N,N- dimethylformamide (4 mL), then L-serine hydrochloride (97.5 mg, 0.74 mmol), 2-(7- azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (348 mg, 0.99 mmol) and N,N-diisopropylethylamine (149 mg, 1.24 mmol) were added successively. Stirring was carried out at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added for quenching, and extraction was carried out with ethyl acetate (3 mL) three times, and the organic phase was separated and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative reverse phase high performance liquid chromatography (column: YMC-Triart Prep C18 7 μm 30 mm x 40 cm); mobile phase A: water + 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient: 15%-65%, 9 minutes) to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2- (difluoromethyl)pyridin-3-yl)di(fluoro)methoxy)-2-methyl-1-benzofuran-3-carboxamide.

[0797] LC-MS, M / Z (ESI): 456.1 [M+H] +

[0798] 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 4.8 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.77 (ddd, J = 15.2, 7.6, 3.6 Hz, 3H), 7.64 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.36 - 7.21 (m, 2H), 7.16 (s, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.45 (dt, J = 8.0, 5.2 Hz, 1H), 3.71 (t, J = 5.6 Hz, 2H), 2.66 (s, 3H).

[0799] Example 20: Preparation of the target compound I-35

[0800] N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-5-((difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide

[0801] The synthetic route of the target compound I-35 is shown below:

[0802] First Step: Synthesis of 3-((tert-butyl-dimethyl)silyloxy)-2-(((4- methoxyphenyl)methyl)amino)-2-methylpropanenitrile

[0803] To a solution of 1-(tert-butyldimethylsilyloxy)-2-propanone (2.5 g, 13.2 mmol) in ethanol (25 mL) was added 4-methoxybenzylamine (1.9 mL, 14.6 mmol) at room temperature. Then trimethylsilyl cyanide (1.9 mL, 15.9 mmol) and ammonium chloride (0.21 g, 3.98 mmol) were added to the reaction mixture. The reaction was stirred at 80 °C for 16 h, and the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to give 3-((tert-butyl-dimethyl)silyloxy)-2-(((4-methoxyphenyl)methyl)amino)-2-methylpropanenitrile.

[0804] Second Step: Synthesis of O-(tert-butyldimethylsilyl)-N2-((4-methoxyphenyl)methyl)-2- methylserinamide

[0805] To a solution of 3-((tert-butyldimethylsilyloxy)-2-(((4-methoxyphenyl)methyl)amino)-2- methylpropanenitrile (2.5 g, 7.47 mmol) in dimethyl sulfoxide (20 mL) was added potassium carbonate (7.2 g, 52.5 mmol) at room temperature. Then hydrogen peroxide (3.5 mL, 74.75 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 16 h, and the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL) three times. The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to give O-(tert-butyldimethylsilyl)-N2-((4-methoxyphenyl)methyl)-2-methylserinamide.

[0806] Third Step: Synthesis of O-(tert-butyldimethylsilyl)-2-methylserinamide

[0807] O-(tert-butyldi(methyl)silyl)-N2-((4-methoxyphenyl)methyl)-2-methylsarcosine (0.72 g, 2.0 mmol) was dissolved in methanol (10 mL) at room temperature, then palladium hydroxide (0.375 g) was added. The reaction was stirred at room temperature for 4 hours under the pressure of hydrogen balloon, then the reaction was filtered and the filtrate was concentrated to give the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to give O-(tert-butyldi(methyl)silyl)-2-methylsarcosine.

[0808] Fourth Step: Synthesis of N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-5-(difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l-benzofuran-3-formamide

[0809] O-(tert-butyldi(methyl)silyl)-N2-((4-methoxyphenyl)methyl)-2-methylsarcosine (0.72 g, 2.0 mmol) was dissolved in methanol (10 mL) at room temperature, then palladium hydroxide (0.375 g) was added. The reaction was stirred at room temperature for 4 hours under the pressure of hydrogen balloon, then the reaction was filtered and the filtrate was concentrated to give the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate (V / V) = 10:1) to give O-(tert-butyldi(methyl)silyl)-2-methylsarcosine.

[0810] Fifth Step: Synthesis of N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-5-(difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-l-benzofuran-3-formamide

[0811] N-(1-amino-3-((tert-butyldi(methyl)silyl)oxy)-2-methyl-1-oxopropan-2-yl)-5- (difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3- carboxamide (330 mg, 0.55 mmol) was dissolved in tetrahydrofuran at room temperature, then tetrabutylammonium fluoride (1 M in tetrahydrofuran) (1.67 mL, 1.67 mmol) was added. The reaction was stirred at room temperature for 3 hours. LC-MS showed the reaction was complete. Water (10 mL) was added to the reaction, which was then extracted with ethyl acetate (10 mL) three times. The organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was separated by high performance liquid chromatography (Column: SunFire™ Prep C18 OBD™ 5 μm, 30 X 150 mm, mobile phase: A = water + 0.5% formic acid, B = acetonitrile, gradient: 30.0% acetonitrile) to give N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-5-(difluoro(2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxamide.

[0812] LC-MS, M / Z (ESI): 488.4 [M+H] +

[0813] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 4.5 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 8.1, 4.8 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.20 (dd, J = 8.9, 1.9 Hz, 1H), 7.13 (s, 1H), 5.29 - 5.24 (m, 1H), 2.63 (s, 3H), 1.45 (s, 3H).

[0814] Example 21: Preparation of target compound I-36

[0815] 5-(Difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-N-(1-methylpiperidin-4-yl)-1- benzofuran-3-carboxamide

[0816] The synthetic route of target compound I-36 is shown below:

[0817] Step 1: Synthesis of 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-N-(1-methylpiperidin-4-yl)-1-benzofuran-3-carboxamide

[0818] At room temperature, 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of 1-methylpiperidin-4-amine (44.1 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (196.3 mg, 0.5 mmol), and N,N-diisopropylethylamine (83.3 mg, 0.65 mmol). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. Add water (10 mL) to the reaction solution, then extract three times with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Filter the crude product through high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-N-(1-methylpiperidin-4-yl)-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = water + 0.5% formic acid, B = acetonitrile, and a gradient of 20.0% acetonitrile.

[0819] LC-MS, M / Z (ESI): 484.3 [M+H] +

[0820] 1 H NMR (400MHz, DMSO-d6) δ9.00(d,J=4.4Hz,1H),8.59(d,J=8.0Hz,1H),8.06(d,J=7. 6Hz,1H),7.98(dd,J=8.0,4.8Hz,1H),7.65(d,J=8.8Hz,1H),7.58(d,J=1.6Hz,1H) ,7.24(dd,J=8.8,2.0Hz,1H),3.81–3.75(m,1H),2.79(d,J=12.0Hz,2H),2.61(s,3 H),2.21(s,3H),2.08(t,J=10.8Hz,2H),1.83(d,J=10.0Hz,2H),1.66–1.55(m,2H).

[0821] Example 22: Preparation of target compound I-37

[0822] 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-N-(1,3-dihydroxypropane-2-yl)-2-methyl-1-benzofuran-3-carboxamide

[0823] The synthetic route for the target compound I-37 is shown below:

[0824] Step 1: Synthesis of 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-N-(1,3-dihydroxypropane-2-yl)-2-methyl-1-benzofuran-3-carboxamide

[0825] At room temperature, 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of 2-aminopropane-1,3-diol (35.2 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (196.3 mg, 0.5 mmol), and N,N-diisopropylethylamine (83.3 mg, 0.65 mmol). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. Add water (10 mL) to the crude product, then extract three times with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Then, precipitate the crude product by high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-N-(1,3-dihydroxypropane-2-yl)-2-methyl-1-benzofuran-3-carboxamide was obtained by separation using a mobile phase of 5 μm, 30 x 150 mm, A = water + 0.5% formic acid, B = acetonitrile, and a gradient of 40.0% acetonitrile.

[0826] LC-MS, M / Z (ESI): 461.19 [M+H] +

[0827] 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 4.0 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 7.98 (dd, J = 8.0, 4.8 Hz, 1H), 7.74 - 7.56 (m, 3H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 4.73 (s, 2H), 4.02 - 3.95 (m, 1H), 3.54 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H).

[0828] Example 23: Preparation of target compound I-18A

[0829] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H- cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0830] The synthetic route of target compound I-18A is shown as follows;

[0831] First step: synthesis of 6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol

[0832] Under ice-bath condition, 6,7-dihydro-5H-cyclopenta[c]pyridin-5-one (250 mg, 1.87 mmol) was dissolved in ethanol (10 mL), then sodium borohydride (105.4 mg, 2.78 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by thin layer chromatography. Water (10 mL) was added to the reaction, then extracted with ethyl acetate (10 mL) for three times. The organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2:1, V / V) to give 6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol.

[0833] Second step: synthesis of 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0834] Compound 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester (320 mg, 0.94 mmol) was dissolved in THF / MeOH / H20 = 1 / 1 / 1 (6 mL) at room temperature. Then lithium hydroxide monohydrate (79 mg, 1.88 mmol) was added and stirred at room temperature for 2 hours. TLC monitoring showed that the starting material was consumed. The pH value was adjusted to 2-3 by adding hydrogen chloride solution (2N) and the reaction mixture was concentrated under reduced pressure to give 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid, which was used directly in the next step.

[0835] LC-MS, M / Z (ESI): 338.4 [M+H] +

[0836] Third step: synthesis of 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2- methyl-1-benzofuran-3-carboxylic acid

[0837] Compound 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester (320 mg, 0.94 mmol) was dissolved in THF / MeOH / H20 = 1 / 1 / 1 (6 mL) at room temperature. Then lithium hydroxide monohydrate (79 mg, 1.88 mmol) was added and stirred at room temperature for 2 hours. TLC monitoring showed that the starting material was consumed. The pH value was adjusted to 2-3 by adding hydrogen chloride solution (2N) and the reaction mixture was concentrated under reduced pressure to give 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid, which was used directly in the next step.

[0838] LC-MS, M / Z (ESI): 293.3 [M+H] +

[0839] Fourth step: synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7- dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0840] Compound 5-((6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid (300 mg, 0.96 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (546 mg, 1.44 mmol), L-serine amide hydrochloride (134.4 mg, 0.96 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, then N,N-diisopropylethylamine (371.4 mg, 2.88 mmol) was added and the reaction was allowed to proceed at room temperature for 5 hours. TLC monitoring showed that the starting material was consumed after 5 hours. The reaction mixture was filtered and directly purified by preparative liquid chromatography (column: C18 150 x 30 mm; solvent: A = water + 0.05 volume of formic acid (99%), B = acetonitrile; gradient: 25% - 55% in 7 minutes) to give N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H- cyclopenta[c]pyridin-5-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide.

[0841] LC-MS, M / Z (ESI): 396.4 [M+H] +

[0842] 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.36 (d, J = 5.0 Hz, 2H), 7.45 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 6.96 (dd, J = 8.9, 2.4 Hz, 1H), 5.86 - 5.81 (m, 1H), 4.45 (dd, J = 7.8, 4.8 Hz, 1H), 3.72 (d, J = 5.0 Hz, 2H), 3.09 - 2.98 (m, 2H), 2.97 - 2.83 (m, 2H), 2.58 (s, 3H), 2.09 - 1.93 (m, 2H)

[0843] Example 24: Preparation of target compound I-20A

[0844] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H-cyclopenta[b]pyridin- 7-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0845] The synthetic route of target compound I-20A is shown below:

[0846] Step 1: Synthesis of 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester

[0847] 5-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine (200 mg, 1.48 mmol) and 5- hydroxy-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (328 mg, 1.48 mmol) were added into tetrahydrofuran (10 mL) at room temperature, then tributylphosphonium (600 mg, 2.96 mmol) was added, and diazodicomethylpiperidine (748 mg, 2.96 mmol) was added slowly. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (50 ml) three times. The obtained organic phase was dried, filtered and rotary evaporated. The crude product was purified by silica gel column (petroleum ether: ethyl acetate V / V = 10:1) to obtain 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester.

[0848] LC-MS, M / Z (ESI): 337.4 [M+H] +

[0849] Step 2: Synthesis of 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid

[0850] 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester (280 mg, 0.83 mmol) was dissolved in tetrahydrofuran / methanol / water = 1 / 1 / 1 (6 mL) solvent system at room temperature. Then lithium hydroxide monohydrate (69.8 mg, 1.66 mmol) was added, and the stirring was continued at room temperature overnight. TLC monitoring showed that the starting material was completely reacted, and the stirring was stopped. Hydrogen chloride solution (2N) was added to the reaction system to adjust the pH value to 2-3, and concentrated under reduced pressure to obtain 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid, which was directly used in the next reaction.

[0851] LC-MS, M / Z (ESI): 294.3 [M+H]+

[0852] Step 3: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H- cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide

[0853] Compound 5-((6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1- benzofuran-3-carboxylic acid (270 mg, 0.92 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (527 mg, 1.36 mmol), L-serine amide hydrochloride (127.6 mg, 0.91 mmol) were dissolved in N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (352.8 mg, 2.73 mmol) was added. The reaction was stirred at room temperature for 5 hours. TLC monitoring showed that the starting material was consumed. The reaction mixture was filtered and purified directly by preparative liquid chromatography (column: C18 150 x 30 mm; mobile phase A = water + 0.05 volume formic acid (99%), mobile phase B = acetonitrile; gradient: 25% - 55% in 7 minutes) to give N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((6,7-dihydro-5H- cyclopenta[b]pyridin-7-yl)oxy)-2-methyl-1-benzofuran-3-carboxamide.

[0854] LC-MS, M / Z (ESI): 395.4 [M+H] +

[0855] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 4.5 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.43 (dd, J = 10.0, 5.5 Hz, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.15 (s, 1H), 6.98 (dd, J = 8.9, 2.4 Hz, 1H), 5.68 (s, 1H), 5.23 - 5.20 (m, 1H), 4.48 - 4.41 (m, 2H), 3.74 - 3.69 (m, 2H), 3.07 - 2.97 (m, 2H), 2.92 - 2.82 (m, 2H), 2.59 (s, 3H), 2.07 (ddd, J = 13.1, 8.2, 4.0 Hz, 2H).

[0856] Example 25: Preparation of target compound I-26A

[0857] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(7-(trifluoromethyl)-3,4- dihydro-2,6-naphthyridin-2(1H)-yl)-1-benzofuran-3-carboxamide

[0858] The synthetic route of the target compound I-26A is shown below:

[0859] First Step: Synthesis of 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6- naphthalen-2(lH)-yl)-l-benzofuran-3-carboxylic acid ethyl ester

[0860] The starting material 7-(trifluoromethyl)-l,2,3,4-tetrahydro-2,6-quinoline (200 mg, 0.99 mmol) and 5-bromo-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (215 mg, 0.759 mmol) were dissolved in N,N-dimethylformamide (8 mL), and then tris(dibenzylideneacetone)dipalladium(0) (139 mg, 0.152 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (144 mg, 0.304 mml) and cesium carbonate (493 mg, 1.518 mmol) were added successively. The reaction solution was replaced with nitrogen three times, and then heated to 85 °C and stirred overnight. After the reaction was completed, water (10 mL) was added to quench the reaction, and then extracted with ethyl acetate (10 mL) three times. The organic phase was separated, and then dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-3: 1) to obtain 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6-naphthalen-2(lH)-yl)-l-benzofuran-3-carboxylic acid ethyl ester.

[0861] LC-MS, M / Z (ESI): 405.3 [M+H] +

[0862] Second Step: Synthesis of 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6- naphthalen-2(lH)-yl)-l-benzofuran-3-carboxylic acid

[0863] The starting material 7-(trifluoromethyl)-l,2,3,4-tetrahydro-2,6-quinoline (200 mg, 0.99 mmol) and 5-bromo-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (215 mg, 0.759 mmol) were dissolved in N,N-dimethylformamide (8 mL), and then tris(dibenzylideneacetone)dipalladium(0) (139 mg, 0.152 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (144 mg, 0.304 mml) and cesium carbonate (493 mg, 1.518 mmol) were added successively. The reaction solution was replaced with nitrogen three times, and then heated to 85 °C and stirred overnight. After the reaction was completed, water (10 mL) was added to quench the reaction, and then extracted with ethyl acetate (10 mL) three times. The organic phase was separated, and then dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-3: 1) to obtain 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6-naphthalen-2(lH)-yl)-l-benzofuran-3-carboxylic acid ethyl ester.

[0861] LC-MS, M / Z (ESI): 405.3 [M+H] +

[0862] Second Step: Synthesis of 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6- naphthalen-2(lH)-yl)-l-benzofuran-3-carboxylic acid

[0863] The starting material 7-(trifluoromethyl)-l,2,3,4-tetrahydro-2,6-quinoline (200 mg, 0.99 mmol) and 5-bromo-2-methyl-l-benzofuran-3-carboxylic acid ethyl ester (215 mg, 0.759 mmol) were dissolved in N,N-dimethylformamide (8 mL), and then tris(dibenzylideneacetone)dipalladium(0) (139 mg, 0.152 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (144 mg, 0.304 mml) and cesium carbonate (493 mg, 1.518 mmol) were added successively. The reaction solution was replaced with nitrogen three times, and then heated to 85 °C and stirred overnight. After the reaction was completed, water (10 mL) was added to quench the reaction, and then extracted with ethyl acetate (10 mL) three times. The organic phase was separated, and then dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 1-3: 1) to obtain 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6-naphthalen-2(lH)-yl)-l-benzofuran-3-carboxylic acid ethyl ester.

[0864] LC-MS, M / Z (ESI): 377.3 [M+H] +

[0865] Step 3: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(7- (trifluoromethyl)-3,4-dihydro-2,6-naphthridin-2(lH)-yl)-l-benzofuran-3-carboxamide

[0866] To a solution of 2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6-naphthalene-2(lH)- yl)-l-benzofuran-3-carboxylic acid (50 mg, 0.132 mmol) in N,N-dimethylformamide (2 mL) was added L-serine amide hydrochloride (28 mg, 0.198 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.265 mmol) and N,N-diisopropylethylamine (51.5 mg, 0.397 mmol) successively. The mixture was stirred at room temperature for 2 h. After completion of the reaction, water (3 mL) was added to quench the reaction and extracted with ethyl acetate (3 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by preparative reverse phase high performance liquid chromatography (column: YMC-Triart Prep C18 7 μm 30 mm x 40 cm); mobile phase A: 0.1% FA; mobile phase B: acetonitrile; flow rate: 42 ml / min; gradient: 15% - 45% for 8 min) to give N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(7-(trifluoromethyl)-3,4-dihydro-2,6-naphthridin-2(lH)-yl)-l-benzofuran-3-carboxamide.

[0867] LC-MS, M / Z (ESI): 463.4 [M+H] +

[0868] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 - 7.45 (m, 3H), 7.20 (d, J = 6.4 Hz, 2H), 4.54 (s, 2H), 4.48 - 4.40 (m, 1H), 3.74 (s, 2H), 3.64 - 3.62 (m, 2H), 3.08 (s, 2H), 2.62 (s, 3H), 2.01 - 1.87 (m, 1H).

[0869] Example 26: Preparation of target compound I-38

[0870] (3,3-Difluoroazacyclobutane-1-yl)(5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-yl)methyl ketone

[0871] The synthetic route for the target compound I-38 is shown below:

[0872] Step 1: Synthesis of (3,3-difluoroazacyclobutane-1-yl)(5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-yl) methyl ketone

[0873] At room temperature, 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of 3,3-difluoroazacyclobutane (34.4 mg, 0.37 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (196.3 mg, 0.5 mmol), and N,N-diisopropylethylamine (83.3 mg, 0.65 mmol). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. Add water (10 mL) to the reaction system, then extract with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Filter the crude product through high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM (3,3-difluoroazacyclobutane-1-yl)(5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-yl) methyl ketone was isolated by 5 μm, 30X 150 mm, Phase: ACN / H2O (0.5% FA) 45% CAN.

[0874] LC-MS, M / Z (ESI): 463.2 [M+H] +

[0875] 1H NMR (400MHz, DMSO-d6) δ9.01(d,J=4.4Hz,1H),8.61(d,J=8.0Hz,1H),7.99(dd,J=8.4,4.8Hz,1H),7.70( d,J=9.2Hz,1H),7.57(d,J=2.0Hz,1H),7.28(dd,J=9.2,2.4Hz,1H),4.54(t,J=12.8Hz,4H),2.61(s,3H).

[0876] Example 27: Preparation of target compound I-39

[0877] 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-N-(4-(hydroxymethyl)oxacyclohexane-4-yl)-2-methyl-1-benzofuran-3-carboxamide

[0878] The synthetic route for the target compound I-39 is shown below:

[0879] Step 1: Synthesis of 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-N-(4-(hydroxymethyl)oxacyclohexane-4-yl)-2-methyl-1-benzofuran-3-carboxamide

[0880] At room temperature, 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of (4-aminooxacyclohexane-4-yl)methanol (35.2 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (196.3 mg, 0.5 mmol), and N,N-diisopropylethylamine (83.3 mg, 0.65 mmol). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. Add water (10 mL) to the reaction system, then extract with dichloromethane (30 mL). Combine the organic phases, wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Filter the crude product through high-performance liquid chromatography (HPLC). TM Prep C18 OBD TM 5-(difluoro(2-(trifluoromethyl)pyridin-3-yl)methoxy)-N-(4-(hydroxymethyl)oxacyclohexane-4-yl)-2-methyl-1-benzofuran-3-carboxamide) was isolated by 5 μm, 30 x 150 mm, Phase: ACN / H2O (0.5% FA) 40% ACN.

[0881] LC-MS, M / Z (ESI): 500.2 [M+H] +

[0882] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 4.4 Hz, 1H), 8.59 (d, J = 7.6 Hz, 1H), 7.98 (dd, J = 8.0, 4.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.24 (dd, J = 8.8, 2.0 Hz, 1H), 4.88 (t, J = 5.6 Hz, 1H), 3.74 - 3.69 (m, 2H), 3.69 - 3.48 (m, 4H), 2.65 (s, 3H), 2.16 (d, J = 13.6 Hz, 2H), 1.66 - 1.59 (m, 2H).

[0883] Example 28: Preparation of the target compound I-40A

[0884] N-((2S)-1-amino-3-hydroxy-propan-2-yl)-5-((2-(trifluoromethyl)pyridin-3- yl)methoxy)-1-benzofuran-3-carboxamide

[0885] The synthetic route of the target compound I-40A is shown below:

[0886] First Step: Synthesis of 5-bromo-2-hydroxy-2,3-dihydro-1-benzofuran-3-carboxylic acid ethyl ester

[0887] 5-bromo-2-hydroxybenzaldehyde (1.5 g, 7.463 mmol) was dissolved in dichloromethane (25 mL), diethyl tetrafluoroborate (120 mg, 0.746 mmol) was added, then ethyl hydrazine (1.4 g, 11.941 mmol) was added dropwise at below 38 °C, the reaction was stirred at room temperature for 0.5 hours. TLC monitoring showed that the raw material was consumed, and the crude product of 5-bromo-2-hydroxy-2,3-dihydro-1-benzofuran-3-carboxylic acid ethyl ester was obtained by concentration under reduced pressure. The next step reaction was carried out directly without purification.

[0888] Second Step: Synthesis of 5-bromo-1-benzofuran-3-carboxylic acid ethyl ester

[0889] To a solution of 5-bromo-2-hydroxy-2,3-dihydro-1-benzofuran-3-carboxylic acid ethyl ester (1.5 g, 5.226 mmol) was added dropwise concentrated sulfuric acid (2.5 mL) and the reaction was allowed to proceed at room temperature for 30 minutes. The mixture was diluted with dichloromethane and sodium bicarbonate (15 g) was added portionwise. The mixture was stirred at room temperature for 1 hour, filtered and the filtrate was concentrated and dried in vacuo. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1, V / V) to give 5-bromo-1-benzofuran-3-carboxylic acid ethyl ester.

[0890] LC-MS, M / Z (ESI): 269.1 [M+H] + .

[0891] Third step: synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- benzofuran-3-carboxylic acid ethyl ester

[0892] To a solution of 5-bromo-1-benzofuran-3-carboxylic acid ethyl ester (100 mg, 0.373 mmol) in 1,4-dioxane (3 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (27 mg, 0.037 mmol), pinacol diboronic acid (114 mg, 0.447 mmol) and potassium acetate (73 mg, 0.746 mmol) sequentially. The reaction was purged with nitrogen three times and heated to 90 °C and stirred overnight. After completion of the reaction, water (5 mL) and ethyl acetate (5 mL) were added and the organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and dried in vacuo. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1 to 10:1) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-3-carboxylic acid ethyl ester.

[0893] LC-MS, M / Z (ESI): 317.1 [M+H] + .

[0894] Fourth step: synthesis of 5-hydroxy-1-benzofuran-3-carboxylic acid ethyl ester

[0895] Ethyl 5-hydroxy-l-benzofuran-3-carboxylate (150 mg, 0.728 mmol) was dissolved in tetrahydrofuran (10 mL), 2-(trifluoromethyl)-3-pyridinemethanol (157 mg, 0.873 mmol) and tributylphosphine (292 mg, 1.456 mmol) were added, the reaction was purged with nitrogen three times, stirred at room temperature for 10 minutes, then azobisdimethylvaleronitrile (375 mg, 1.456 mmol) was added in batches, the reaction was stirred at room temperature overnight. After the reaction was completed, water (5 mL) was added, then extracted with ethyl acetate (10 mL), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, the crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1, V / V) to obtain ethyl 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-l-benzofuran-3-carboxylate.

[0896] LC-MS, M / Z (ESI): 207.1 [M+H] + .

[0897] Fifth step: synthesis of ethyl 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-l- benzofuran-3-carboxylate

[0898] Ethyl 5-hydroxy-l-benzofuran-3-carboxylate (150 mg, 0.728 mmol) was dissolved in tetrahydrofuran (10 mL), 2-(trifluoromethyl)-3-pyridinemethanol (157 mg, 0.873 mmol) and tributylphosphine (292 mg, 1.456 mmol) were added, the reaction was purged with nitrogen three times, stirred at room temperature for 10 minutes, then azobisdimethylvaleronitrile (375 mg, 1.456 mmol) was added in batches, the reaction was stirred at room temperature overnight. After the reaction was completed, water (5 mL) was added, then extracted with ethyl acetate (10 mL), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and dried, the crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1, V / V) to obtain ethyl 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-l-benzofuran-3-carboxylate.

[0899] LC-MS, M / Z (ESI): 366.3 [M+H] + .

[0900] Sixth step: synthesis of 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-l- benzofuran-3-carboxylic acid

[0901] Ethyl 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzofuran-3-carboxylate (140 mg, 0.382 mmol) was dissolved in tetrahydrofuran / methanol / water (V / V / V = 2 / 1 / 2, 5 mL), then lithium hydroxide monohydrate (78 mg, 1.91 mmol) was added, and stirred at room temperature overnight. After the reaction was completed, the crude product was concentrated. The crude product was dissolved in a dichloromethane / methanol = 10 / 1 system, and the pH was adjusted to 2-3 with a 2N hydrochloric acid solution, and concentrated to obtain the crude product 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzofuran-3-carboxylic acid, which was directly used in the next reaction without purification.

[0902] LC-MS, M / Z (ESI): 337.2 [M+H] + .

[0903] Step 7: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzofuran-3-carboxamide

[0904] Ethyl 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzofuran-3-carboxylate (140 mg, 0.382 mmol) was dissolved in tetrahydrofuran / methanol / water (V / V / V = 2 / 1 / 2, 5 mL), then lithium hydroxide monohydrate (78 mg, 1.91 mmol) was added, and stirred at room temperature overnight. After the reaction was completed, the crude product was concentrated. The crude product was dissolved in a dichloromethane / methanol = 10 / 1 system, and the pH was adjusted to 2-3 with a 2N hydrochloric acid solution, and concentrated to obtain the crude product 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzofuran-3-carboxylic acid, which was directly used in the next reaction without purification.

[0905] LC-MS, M / Z (ESI): 424.2 [M+H] +

[0906] 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.4 Hz, 1H), 8.67 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.0, 4.8 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.10 (s, 1H), 7.05 (dd, J = 9.2, 2.8 Hz, 1H), 5.30 (s, 2H), 4.91 (t, J = 5.6 Hz, 1H), 4.45 (dd, J = 13.6, 5.6 Hz, 1H), 3.72 - 3.62 (m, 2H).

[0907] Example 29: Preparation of target compound I-41A

[0908] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(difluoro(6-methyl-2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0909] The synthetic route of target compound I-41A is shown below:

[0910] First Step: Synthesis of methyl 6-methyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0911] Methyl 6-methyl-2-(trifluoromethyl)pyridine-3-carboxylate (1.2 g, 4.8 mmol) was dissolved in THF (20 mL) at room temperature, then 1M BH3-THF (20 mL, 20 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. LC-MS showed that the reaction was completed. The reaction was quenched by the addition of methanol (20 mL). The reaction was concentrated to remove the solvent, and then water (20 mL) was added. The reaction was extracted with dichloromethane (20 mL), and the organic phase was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain the crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1, V / V) to obtain (6-methyl-2- (trifluoromethyl)pyridin-3-yl)methanol (1.0 g, yield: 85%).

[0912] Second Step: Synthesis of (6-methyl-2-(trifluoromethyl)pyridin-3-yl)methanol

[0913] Methyl 6-methyl-2-(trifluoromethyl)pyridine-3-carboxylate (1.2 g, 5.4 mmol) was dissolved in tetrahydrofuran / ethanol = 1 / 1 (V / V, 20 mL) at room temperature, then sodium borohydride (416 mg, 10.8 mmol) and calcium chloride (1190 mg, 10.8 mmol) were added successively. Then stirred for 16 hours, LC-MS showed that the reaction was completed. The reaction solution was filtered to obtain the filtrate, which was concentrated to obtain the crude product, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate = 4 / 1, V / V) to obtain (6-methyl-2-(trifluoromethyl)pyridin-3-yl)methanol.

[0914] Third step: synthesis of 3-(bromomethyl)-6-methyl-2-(trifluoromethyl)pyridine

[0915] (6-methyl-2-(trifluoromethyl)pyridin-3-yl)methanol (790 mg, 4.1 mmol) was dissolved in dichloromethane (10 mL), and triphenylphosphine (2.71 g, 8.2 mmol) and carbon tetrabromide (2.14 g, 8.2 mmol) were added in batches at 0°C, then the reaction solution was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10 / 1, v / v) to obtain 3-(bromomethyl)-6-methyl-2-(trifluoromethyl)pyridine.

[0916] Fourth step: synthesis of 6-methyl-3-((trifluoromethylsulfonyl)methyl)-2- (trifluoromethyl)pyridine

[0917] 3-(bromomethyl)-6-methyl-2-(trifluoromethyl)pyridine (950 mg, 3.7 mmol) and sodium trifluoromethanesulfinate (1.15 g, 7.4 mmol) were dissolved in acetonitrile (10 mL), then the reaction solution was replaced with nitrogen three times, warmed to 80°C and stirred overnight. After the reaction was completed, the reaction solution was filtered with diatomite, and the filtrate was concentrated and rotary evaporated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10 / 1, v / v) to obtain 6-methyl-3-((trifluoromethylsulfonyl)methyl)-2-(trifluoromethyl)pyridine.

[0918] Fifth step: synthesis of 3-(difluoro(trifluoromethylsulfonyl)methyl)-6-methyl-2- (trifluoromethyl)pyridine

[0919] Dissolve 6-methyl-3-((trifluoromethylsulfonyl)methyl)-2- (trifluoromethyl)pyridine (570 mg, 1.85 mmol) in N,N-dimethylformamide (10 mL), add N-fluorobenzenesulfonimide (1.22 g, 3.88 mmol) and potassium phosphate tribasic (1.17 g, 5.55 mmol) successively, and stir the reaction mixture at room temperature overnight. After completion of the reaction, quench with ammonium chloride (10 mL), extract with ethyl acetate (20 mL), separate the layers, and combine the organic layers. Dry the organic layers over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 10 / 1, v / v) to obtain 3-(difluoro(trifluoromethylsulfonyl)methyl)-6-methyl-2- (trifluoromethyl)pyridine.

[0920] Step 6: Synthesis of 5-(difluoro(6-methyl-2-(trifluoromethyl)pyridin-3-yl)methoxy)-2- methyl-1-benzofuran-3-carboxylic acid ethyl ester

[0921] Dissolve 3-(difluoro(trifluoromethylsulfonyl)methyl)-6-methyl-2- (trifluoromethyl)pyridine (520 mg, 1.51 mmol) and 5-hydroxy-2-methyl-1- benzofuran-3-carboxylic acid ethyl ester (332.2 mg, 1.51 mmol) and potassium carbonate (417.3 mg, 3.02 mmol) in acetonitrile (10 mL), and then add potassium iodide (252.1 mg, 1.51 mmol). Heat the reaction mixture to 85°C, and stir overnight. After completion of the reaction, confirm by LC-MS, concentrate the reaction mixture to obtain a crude product, and then add water (20 mL) to the crude product, extract with ethyl acetate (40 mL), separate the layers, and combine the organic layers. Dry the organic layers over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 5 / 1, v / v) to obtain 5-(difluoro(6-methyl-2- (trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid ethyl ester.

[0922] Step 7: Synthesis of 5-(difluoro(6-methyl-2-(trifluoromethyl)pyridin-3-yl)methoxy)-2- methyl-1-benzofuran-3-carboxylic acid

[0923] Ethyl 5-(difluoro(6-methyl-2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid (390 mg, 0.9 mmol) was dissolved in a 1 / 1 / 1 (6 mL) mixture of tetrahydrofuran / methanol / water. Lithium hydroxide monohydrate (64.8 mg, 2.7 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product. The crude product was dissolved in a 10 / 1 system of dichloromethane / methanol, and the pH was adjusted to 2-3 with 2N hydrochloric acid solution. The crude product was then concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 15 / 1, v / v) to obtain 5-(difluoro(6-methyl-2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid.

[0924] Step 8: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(difluoro(6-methyl-2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxamide

[0925] 5-(difluoro(6-methyl-2-(trifluoromethyl)pyridin-3-yl)methoxy)-2-methyl-1-benzofuran-3-carboxylic acid (100 mg, 0.25 mmol) and L-seramide hydroch...

Claims

1. The compound represented by Formula I, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs: in, R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -S(=O)-NR a -、-S(=O)2-NR a -、-C(=O)R a -C(=O)OR a -C(=O)NR a R b The C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy. L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)(R a )-; R2 is selected from NR 21 R 22 ; R 21 R 22 Each is independently selected from hydrogen, deuterium, hydroxyl, and -SR. a -S(=O)R a -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkylene-OH, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -C(=O)NR a R b -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -C(=O)R a -C(=O)OR a -C(=NH)S(=O)2R a -S(=NR) a (=O)R a ; Or, R 21 R 22 The N atom attached thereto forms a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group; the 4-8 membered heterocyclic alkyl group or the 5-8 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy; R3 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy; m is selected from 1, 2, and 3; M is selected from the bond, -O-, -S(=O)R a -、-S(=O)2R a -、-S(=O)NR a -、-S(=O)2NR a -、-C(=O)R a -、-C(=O)OR a -、-C(=O)NR a -, C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)-, -C1-C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyloxy group, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene, C0- C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene; wherein C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)-, -C1-C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyloxy group, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene, C0-C6 alkyl-3-6 membered cycloalkyl-C0-C6 alkyl, C0-C6 alkyl-3-6 membered heterocycloalkyl-C0-C6 alkyl, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene, optionally surrounded by 1, 2, 3, 4, or 5 Rs. m Replace; the R m Each is independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl; R4 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 ynyl, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 ynyl, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; Alternatively, the two R4 atoms and their attached C atoms form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; R a R b Each group is independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; When M is selected from C1-C5 alkyleneoxy groups, the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and -L-R2 is selected from -C(=O)-NHR. 22 At that time, the R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are bonded with hydroxyl groups and -C(=NH)S(=O)2R a Substitution, or, the C1-C6 alkyl group is replaced by -OC(=O)NH2 and -C(=O)NR a R b Substitution, or, the C1-C6 alkyl group is replaced by a hydroxyl group and -S(=NRa)(=O)R a Substitution, or, the C1-C6 alkyl group is replaced by -S(=NRa)(=O)R a replace.

2. The compound of Formula I as claimed in claim 1, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs, characterized in that, Where M is selected from -S(=O)NR a -、-S(=O)2NR a -、-C(=O)OR a - C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene; wherein the C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene are optionally surrounded by 1, 2, 3, 4, or 5 R... m Replace; the R m Each is independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; When M is selected from C1-C5 alkyleneoxy groups, the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and -L-R2 is selected from -C(=O)-NHR. 22 At that time, the R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are bonded with hydroxyl groups and -C(=NH)S(=O)2R a Substitution, or, the C1-C6 alkyl group is replaced by -OC(=O)NH2 and -C(=O)NR a R b Substitution, or, the C1-C6 alkyl group is replaced by a hydroxyl group and -S(=NRa)(=O)R a Substitution, or, the C1-C6 alkyl group is replaced by -S(=NRa)(=O)R a replace; The rings A, R1, R2, R3, R4, L, m, and n have the definitions described in claim 1.

3. The compound of Formula I as described in claims 1 and 2, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs, characterized in that, The Selected from 3-14 membered heterocyclic alkyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups substituted with n R4 groups; And / or, ring A is selected from 3-14 membered heterocyclic alkyl monocyclic rings, 7-14 membered heterocyclic alkyl bicyclic rings, 6-10 membered aryl monocyclic rings, 7-10 membered aryl bicyclic rings, 5-10 membered heterocyclic aryl monocyclic rings, and 8-10 membered heterocyclic aryl bicyclic rings; the 3-14 membered heterocyclic alkyl monocyclic rings, 7-14 membered heterocyclic alkyl bicyclic rings, 5-10 membered heterocyclic aryl monocyclic rings, and 8-10 membered heterocyclic aryl bicyclic rings contain 1, 2, 3, or 4 heteroatoms; the heteroatoms are selected from N, O, and S; and the N and S atoms can be in their oxide form; And / or, ring A is selected from The dashed lines represent single or double bonds; X1, X2, X3, X4, X5, and X6 are each independently selected from NR4, CR4, CR4R4, C, N, N oxides, O, and S; ring B and ring D are each independently selected from benzene rings, 7-10 aromatic rings, 5-10 heteroaromatic rings, 4-8 heterocyclic alkyl groups, and 4-8 cycloalkyl groups; the heteroatoms are selected from N, O, and S; and the N and S atoms can be in oxide form. And / or, ring A is selected from ,in Selected from The dashed lines represent single or double bonds; Y1, Y2, Y3, Y4, Y7, Y8, Y9, Y 10 Each is independently selected from NR4, C, CR4, CR4R4, N, N oxide, O, S; Y5 and Y6 are each independently selected from NR4, CR4, C, N; or, the two R4 atoms in CR4R4 and their attached C atoms form a 3-4 membered cycloalkyl or a 3-4 membered heterocycloalkyl. And / or, ring A is selected from ,in Selected from The dashed lines represent single or double bonds; Y1, Y2, Y3, Y4, Y7, and Y8 are each independently selected from C, CR4, CR4R4, NR4, N, and N oxides; Y6 is selected from N, CR4, and C; Y9 is selected from NR4, N, N oxides, CR4R4, CR4, O, and S. And / or, ring A is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyridazine, pyrazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazolium, dihydrotriazole, dihydrotetrazolium, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazolium, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, etc. Phosphine, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuran-pyridine, benzene ring, indene, naphthalene, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyrimidinidine, pyrazinidine, pyrazinidine, benzotetrahydropyrrole, tetrahydronaphthyl, pyridocyclopentane-spirocyclopropane, pyridotriazole, pyridotetrahydrofuran, triazole-piperazine, benzopyrazole, benzopyridine, pyridotetrahydropyrrole, indazole, benzimidazole, pyrimidinidine, pyridopyrrole, pyrazinidine, thiazolylcyclopentyl, and their N oxides; And / or, ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, benzopyridine, benzopyrazole, benzimidazole, tetrahydroquinoline, tetrahydroisoquinoline, pyridocyclopentyl, pyridocyclohexyl, pyridopiperidine, pyridopyridine, pyridazinopyrrole, pyridofuran, And / or, R4 is selected from deuterium, hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 ynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 ynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; And / or, R4 is selected from deuterium, hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclopropyl, oxecyclobutyl, azircyclobutyl, tetrahydropyrrole, tetrahydrofuran; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclopropyl, oxecyclobutyl, azircyclobutyl, tetrahydropyrrole, tetrahydrofuran are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, oxo; And / or, R4 is selected from deuterium, hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 ynyl, cyclopropyl, cyclobutyl, and aziridine; wherein the C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 ynyl, cyclopropyl, cyclobutyl, and aziridine are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: F, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, and oxo; And / or, the R4 is selected from deuterium, hydrogen, F, Cl, cyano, methyl, -C(=O)NH2, -CF3, -CHF2, -CH2F, And / or, n is selected from 0, 1, 2, 3, 4; And / or, the Selected from benzene, 4. The compound of Formula I as claimed in claim 1, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs, characterized in that, The M is selected from bond, -O-, -S(=O)2R a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, C0-C3 alkylene-3-6 membered cycloalkyl-O-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-O-C0-C3 alkylene, C2-C6 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C3 alkylene-5-8 membered heteroaryl-C0-C3 alkylene; wherein -C1-C6 alkylene-S-, -C1-C6 alkylene-NR a -, -C1-C6 alkylene-S(=O)2-, C1-C6 alkylene, C1-C6 alkyleneoxy, C0-C3 alkylene-3-6 membered cycloalkyl-O-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-O-C0-C3 alkylene, C2-C6 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C3 alkylene-5-8 membered heteroaryl-C0-C3 alkylene, optionally surrounded by 1, 2, 3, 4, or 5 Rs. m replace; And / or, the M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-NR a -, -C1-C3 alkylene-S(=O)2-, C1-C3 alkylene, C1-C3 alkyleneoxy, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, C2-C4 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene; wherein -C1-C3 alkylene-S-, -C1-C3 alkylene-NR a -, -C1-C3 alkylene-S(=O)2-, C1-C3 alkylene, C1-C3 alkyleneoxy, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, C2-C4 alkenyl, C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene, C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, optionally with 1, 2, 3, 4, or 5 selected from R m replace; And / or, the M is selected from -S(=O)NR a -、-S(=O)2NR a -、-C(=O)OR a - C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene; wherein the C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-O-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-O-C0-C6 alkylene are optionally surrounded by 1, 2, 3, 4, or 5 R... m replace; And / or, the R m Selected from deuterium, halogens, C1-C3 alkyl groups, and C1-C3 alkoxy groups; And / or, the R m Selected from F; And / or, the 5-8 membered heteroaryl group in M ​​contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S; And / or, M is selected from the following: -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-O-, -CHF-O-, -CF2-O-, cyclopropyl-O-, cyclobutyl-O-, oxacyclobutyl-O-, aziridine-O-, vinylene, propyleneene, CO-C3 alkylene-3-5 membered cycloalkyl-CO-C3 alkylene, CO-C3 alkylene-3-5 membered heterocycloalkyl-CO-C3 alkylene, CO-C3 alkylene-5-8 membered heteroaryl-CO-C3 alkylene; And / or, the 5-8 heteroaryl group in M ​​is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyridazine, and triazine; And / or, the 3-6 membered cycloalkyl group in M ​​is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; And / or, the 3-6 membered heterocyclic alkyl group in M ​​contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S; And / or, the 3-6 membered heterocyclic alkyl group in M ​​is selected from oxetyl, oxetyl, oxetyl, aziridine, tetrahydropyrrole, piperidine, and piperazine; And / or, M is selected from the following: -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-, -CF2-O-, -CF2-NH-, -CH2-N(CH3)-, And / or, M is selected from -S(=O)2NH-, -CH2-O-, -CF2-O-, 5. The compound of Formula I as claimed in claims 1 and 2, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs, characterized in that, The compound is selected from the following structures: The rings A, R1, R3, R4, R a R 21 R 22 R, L, m, and n have the definitions of claim 1, wherein R 21 R 22 L satisfies any one of the following conditions: a) When L is selected from -C(=O)-, R 21 Selected from hydrogen, R 22 When selected from C1-C6 alkyl groups, the C1-C6 alkyl groups are bonded with hydroxyl groups and -C(=NH)S(=O)2R a replace; b) L is selected from -S(=O)-, -S(=O)2-, -P(=O)(R a )-; c) When L is selected from -C(=O)-, R 21 Selected from hydrogen, R 22 When selected from C1-C6 alkyl groups, the C1-C6 alkyl groups are separated by -OC(=O)NH2 and -C(=O)NR. a R b replace; d) When L is selected from -C(=O)-, R 21 Selected from hydrogen, R 22 When selected from C1-C6 alkyl groups, the C1-C6 alkyl group is bonded with a hydroxyl group and -S(=NRa)(=O)R a replace; e) When L is selected from -C(=O)-, R 21 Selected from hydrogen, R 22 When selected from C1-C6 alkyl groups, the C1-C6 alkyl group is -S (=NR) a (=O)R a replace.

6. The compound, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs as claimed in claim 3, characterized in that, The compound is selected from the following structures: The dashed lines represent single or double bonds. X2, X3, X4, X5, and X6 are each independently selected from NR4, CR4, CR4R4, C, N, and N oxides; Y1, Y2, Y3, Y4, Y7, and Y8 are each independently selected from CR4, N, N oxides, CR4R4, NR4, and C; Y9 and Y 10 Each is independently selected from CR4, N, N oxides, CR4R4, NR4, O, and S; And / or, at least one of X2, X3, X4, X5, and X6 is selected from N; And / or, at least one of Y1, Y2, Y3, Y4, Y7 and Y8 is selected from N; And / or, compounds of formula II-2A, II-2B, II-2K, II-2L, II-2M, and II-2N have the following structures: Among them, at least one of Y1, Y2, Y3, Y4 and Y8 is selected from N; M, R1, R2, R3, R4, L, m, and n have the definitions described in claim 1.

7. The compound, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs as described in claim 1 or claim 6, characterized in that, The L-R2 is selected from L-NR. 21 R 22 ; The R 21 R 22 Each is independently selected from hydrogen, hydroxyl group, and -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl; The C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, and 5-8 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkylene-OH, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -OC (=O)R a -C(=O)NR a R b -NR b C(=O)R a -S(=O)2R a -C(=NH)S(=O)2R a -S(=NR) a (=O)R a ; And / or, R 21 R 22 The N atom attached thereto forms a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group; the 4-8 membered heterocyclic alkyl group or the 5-8 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the following: hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl; And / or, R 21 R 22 The N atom attached thereto forms N-heterocyclic butane, pyrrole, tetrahydropyrrole, piperidine, or pyridine; wherein the N-heterocyclic butane, pyrrole, tetrahydropyrrole, piperidine, or pyridine is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, F, Cl, methyl, CF3. And / or, the R 21 R 22 Each of the following groups is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, and 5-8 membered heteroaryl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, and 5-8 membered heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkylene-OH, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl, -OC (=O)R a -C(=O)NR a R b -C(=NH)S(=O)2R a -S(=NR) a (=O)R a ; And / or, the L is selected from -C(=O)-, -S(=O)2-; And / or, the L-R2 is selected from -C(=O)-NHR 22 -S(=O)2-NHR 22 The R 22 Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2, or 3 substituents selected from the following: deuterium, hydroxyl, halogen, oxo (=O), C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkylene-OH, C1-C3 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OC (=O)R a -C(=O)NR a R b -C(=NH)S(=O)2R a -S(=NH)(=O)R a ; And / or, the L-R2 is selected from -C(=O)-NHR 22 -S(=O)2-NHR 22 The R 22 The group is selected from C1-C6 alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C1-C6 alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents selected from the following: deuterium, F, hydroxyl, oxo (=O), trifluoroethyl, C1-C3 alkylene-OH, methoxy, cyclopropyl, cyclobutyl, -OC(=O)NH2, -C(=O)NH2, -C(=NH)S(=O)2CH3, methyl, deuterated methyl (-CD3), -S(=NH)(=O)CH3; And / or, the L-R2 is selected from And / or, the L-R2 is selected from 8. The compound, its tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug as claimed in claim 1 or any one of claims 5-6, characterized in that, The R3 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C3 alkyl, and C1-C3 alkoxy; the C1-C3 alkyl and C1-C3 alkoxy are optionally substituted by 1, 2, or 3 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy. And / or, the R3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; And / or, the R3 is selected from hydrogen, F, and.

9. The compound, its tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug as claimed in claim 1 or any one of claims 5-6, characterized in that, R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C1-C6 alkoxy; the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy. And / or, R1 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; And / or, R1 is selected from hydrogen, methyl, and F.

10. The compound, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs as claimed in claim 1, characterized in that, The compound includes:

10. [Deleted, 91 detailed rules, 05.09.2025] 11. [Detailed Rules 91, 05.09.2025] The compound, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts, or prodrugs as claimed in claim 1, are characterized in that, The compound includes:

12. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: a compound as described in any one of claims 1-11, its tautomers, stereoisomers, oxides, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

13. Use of the compound, tautomer, stereoisomer, oxide, pharmaceutically acceptable salt, or prodrug, or pharmaceutical composition of claim 11, as described in any one of claims 1-11, wherein the use comprises: As a TRPM3 antagonist; And / or, to prevent and / or treat TRPM3-mediated diseases; And / or, to prepare a drug, pharmaceutical composition or formulation as a TRPM3 antagonist.

14. The use as described in claim 13, characterized in that, The illness is either pain or epilepsy.

15. The use as described in claim 14, wherein the disease is nociceptive pain, inflammatory pain, neuropathic pain, chronic pain, or epilepsy.

16. A method for treating a disease, characterized in that, The disease is a TRPM3-mediated disease, and / or a disease in which TRPM3 expression and antagonism are desired or necessary; The method comprises: administering a therapeutically effective dose of any of the compounds described in 1-11, their tautomers, stereoisomers, oxides, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 12 to a person who has or is susceptible to the disease.

17. The method as described in claim 16, characterized in that, The illness is either pain or epilepsy; And / or, the disease is nociceptive pain, inflammatory pain, neuropathic pain, chronic pain, or epilepsy.

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