Carbocyclic or heterocyclic derivative, preparation method therefor and use thereof

Abstract

The present application relates to a substituted carbocyclic or heterocyclic derivative, a preparation method therefor, and a pharmaceutical use of a pharmaceutical composition containing the derivative or a deuterated derivative thereof. Specifically, the present application relates to a substituted carbocyclic or heterocyclic derivative as shown in general formula (I), (I-A) or (I-B), a preparation method therefor, and a pharmaceutically acceptable salt thereof, as well as a use thereof as a TRPM3 antagonist in the prevention and / or treatment of TRPM3-mediated related diseases, particularly in the field of pain. The definitions of the substituents in general formulas (I), (I-A) and (I-B) are the same as those in the description.

Description

Carbocyclic or heterocyclic derivatives, their preparation methods and uses Technical Field

[0001] This application relates to a substituted carbocyclic or heterocyclic derivative, a method for its preparation, a pharmaceutical composition containing the derivative or a deuterated derivative, and its use as a therapeutic agent or in a medicament for the prevention of TRPM3-mediated diseases. Background Technology

[0002] The transient receptor potential (TRP) channel superfamily comprises 27 members in humans and can be divided into six subfamilies based on protein sequence homology: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. Structurally, TRP channels have six transmembrane regions (S1-S6) and large N- and hydroxyl-terminal segments located within the cell. In most cases, fully functional TRP channels consist of four identical sequences forming a homotetramer, with the loop portion between S5 and S6 of each sequence forming the central pore of the channel. Functionally, TRP channels can be activated by physical factors such as temperature and pressure, and by chemical stimuli such as hydrogen ions and capsaicin, leading to the release of Na+. + Ca 2+ Mg 2+ When cations flow through the cell membrane, they alter the membrane potential of sensory neurons, leading to the generation of electrical signals.

[0003] Given the high expression of TRP channels in sensory neurons and their function in the perception of external signals, they have been a clear target for studying the mechanisms and inhibitory pathways of pain generation for many years. Representative subtypes include TRPV1, TRPA1, and TRPM8, and the development of inhibitors targeting these targets has experienced a boom, resulting in molecules such as AMG517, AMG333, and AMG9810. Despite showing promising analgesic effects in various preclinical animal models and even humans, progress in this pipeline has stalled due to issues such as impact on thermoregulation or the highly diverse functional mechanisms of the targets. These studies confirm that TRP channels play a crucial role in the generation and transmission of pain.

[0004] Although research on TRPM3 started relatively late, it is gradually showing its potential as a safe and effective analgesic target. TRPM3 can be activated by high temperatures, endogenous steroids such as pregnenolone, and synthetic molecules such as CIM0216, thereby mediating Ca2+ activation. 2+Ions flow across the cell membrane. TRPM3 is widely expressed in sensory neurons of the dorsal root ganglia or trigeminal ganglia in humans and rodents, and activation of μ-opioid receptors in the peripheral nervous system inhibits TRPM3 function (Dembla et al., eLife (2017)), suggesting that TRPM3 inhibition may serve as a mechanism for the analgesic effect of peripheral opioid receptor activation. Trpm3 knockout mice exhibit a loss of thermal pain sensitivity phenotype in CFA-induced inflammatory pain models (Vriens et al., Neuron (2021)). Inhibition of TRPM3 also shows good analgesic effects in neuropathic pain models such as partial ligation of the sciatic nerve (PSNL) and diabetic peripheral neuropathy (DPN), and inhibition of TRPM3 does not induce thermoregulation disorders like inhibition of TRPV1. In addition, stimulation of TRPM3 induces the secretion of calcitonin gene-related peptide (CGRP) by dorsal root ganglion or trigeminal ganglion cells, and administration of TRPM3 agonists to the dura mater or cheek in mice induces pain hypersensitivity and meningeal hyperexcitability, suggesting that TRPM3 may be involved in the development of migraines or head and facial pain (Kelemen et al., Biochemical Pharmacology (2021); Krivoshein et al., The Journal of Headache and Pain (2022)). The most advanced pipeline currently is Biohaven's BHV-2100, which has demonstrated excellent safety and pharmacokinetic data in Phase I clinical trials and will advance two Phase II clinical trials related to acute migraine and peripheral analgesia efficacy.

[0005] In summary, TRPM3 represents a novel target for peripheral nervous system analgesia with a well-defined biological mechanism and potential for safety and efficacy; however, the development of inhibitory molecules remains largely unexplored. Developing inhibitors targeting this target will help provide new and safer treatment options for pain patients. Summary of the Invention

[0006] To address the aforementioned technical problems, this application provides a substituted carbocyclic or heterocyclic derivative of general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof:

[0007] in:

[0008] X is selected from NH, O, S, or Se;

[0009] L is selected from H, D, halogen, haloalkyl, or cycloA;

[0010] Ring A is selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be further substituted by one or more R0;

[0011] T is selected from -NR x -、-CR x R y -, -O- or -S-, T is preferred;

[0012] U is selected from -NR z R w or -OR z U-Preferred-NR z R w ;

[0013] R0, R1, R2, R3, R4, R5, R6, R x R y Each is independently selected from hydrogen atom, deuterium, halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl or haloalkyl;

[0014] Alternatively, R1 and R2 together form =O, =S, =NR a R3 and R4 together form =O, =S, =NR a ;

[0015] Or, R1 and R2, R2 and R x R z R5 and R5, together with the atoms connected to them, form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein the 3-7 membered cycloalkyl and the 3-7 membered heterocycloalkyl are optionally further substituted by one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amide or =O.

[0016] R z R w Each group is independently selected from hydrogen atom, amino, hydroxyl, cyano, amide, alkoxy, alkyl, cycloalkyl, or heterocyclic group, wherein the amide, alkoxy, alkyl, cycloalkyl, or heterocyclic group is optionally further influenced by one or more R groups. 01 replace;

[0017] R 01 Whether identical or different, each is independently selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, carbonylalkyl, amide-substituted alkyl, thioamide-substituted alkyl, thioamide, amide, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, =O, =S, -C (=NR) a )NR b R c -C(=NR) a )Rb -C(=NR) a )NR b OR c -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -P(O)R a R b -S(=NR) a )(O)NR b R c or -OR a ;

[0018] s can be 0, 1, 2, or 3;

[0019] When L is selected from ring A, X is selected from O or S, T is selected from -O-, and R3 and R4 together form =O, at least one of the following conditions must be satisfied.

[0020] The condition is that,

[0021] (1) R1 and R2 are each independently selected from deuterium, halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, or R1 and R2 together form =O, =S, or =NR. a Alternatively, R1 and R2 together with the atoms they are connected to form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group, wherein the 3-7 membered cycloalkyl group or the 3-7 membered heterocycloalkyl group may optionally be further substituted by one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amide or =O.

[0022] (2)R 01 Selected from -C(=NR) a )NR b R c alkyl groups substituted with thioamide, thioamide groups, -C (=NR) a )R b -C(=NR) a )NR b OR c -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -P(O)R a R b or -S(=NR)a )(O)NR b R c ;

[0023] (3)R z Together with any two atoms in R5 connected to them, they form a 6-7 membered heterocyclic alkyl group, which may optionally be further substituted by one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amide or =O.

[0024] R a R b R c Each is independently selected from hydrogen atom, cyano, hydroxyl, amino, alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl or =O substituents;

[0025] Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, or =O.

[0026] A preferred embodiment of this application provides a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

[0027] in:

[0028] n is 0, 1, 2, or 3;

[0029] The definitions of R0, R1, R2, R3, R4, R5, R6, s, U, ring A, and T are as described in general formula (I).

[0030] A preferred embodiment of this application provides a compound of general formula (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (III) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0031] The definitions of R0, R3, R4, U, ring A, and n are as described in general formula (II).

[0032] A preferred embodiment of this application provides a compound of general formula (III) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (IV) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0033] Where: R0, R z R w The definitions of ring A and n are as described in general formula (II).

[0034] In some specific embodiments of this application, R3 and R4 together form =O.

[0035] In some specific embodiments of this application, U is -NR z R w .

[0036] In some specific embodiments of this application, U is -NR z R w R z For hydrogen ， R w It is an alkyl group, and the alkyl group is replaced by OH or amide groups.

[0037] In some specific embodiments of this application, U is -NR z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is replaced by OH, amide, or amino groups.

[0038] In some specific embodiments of this application, U is -NR z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is -C (=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b-P(O)R a R b or -S(=NR) a )(O)NR b R c replace.

[0039] In some specific embodiments of this application, U is -NR z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is -C (=NR) a )NR b R c replace.

[0040] In some specific embodiments of this application, R5 is an alkyl group, preferably a methyl group.

[0041] In some specific embodiments of this application, X is 0.

[0042] In some specific embodiments of this application, X is S.

[0043] In some specific embodiments of this application, X is Se.

[0044] In some specific embodiments of this application, T stands for -O-.

[0045] In some specific embodiments of this application, T stands for -CR x R y -, R x It is an alkyl group, R y It is a hydrogen atom.

[0046] In some specific embodiments of this application, T is -NR x -, R x alkyl.

[0047] In some specific embodiments of this application, L is cyclic A and is heteroaryl.

[0048] In some specific embodiments of this application, L is a cyclic A and a heteroaryl group, and the heteroaryl group is replaced by a haloalkyl group.

[0049] In some specific embodiments of this application, R1 is hydrogen and R2 is hydrogen.

[0050] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w .

[0051] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z Rw R z For hydrogen ， R w It is an alkyl group.

[0052] In some specific embodiments of this application, R6 is hydrogen or deuterium.

[0053] In some specific embodiments of this application, R6 is a halogen.

[0054] In some specific embodiments of this application, s is 1.

[0055] In some specific embodiments of this application, L is selected from ring A, X is selected from O or S, T is selected from -O- and when R3 and R4 together form =O, R1 is a halogen.

[0056] In some specific embodiments of this application, L is selected from ring A, X is selected from O or S, T is selected from -O-, and when R3 and R4 together form =O, R1 is deuterium. In some specific embodiments of this application, when R3 and R4 together form =O, U is -NR. z R w R z For hydrogen ， R w R5 is an alkyl group, and the alkyl group is substituted with OH or amide groups. R5 is methyl, X is O, T is -O-, L is a cyclic A and is a heteroaryl group, R1 is deuterium, and R2 is deuterium.

[0057] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen ， R w R5 is an alkyl group, and the alkyl group is substituted with OH or amide groups. R5 is methyl, X is O, T is -O-, L is a cyclic A and is a heteroaryl group, R1 is a halogen, and R2 is a halogen.

[0058] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen ， R w It is an alkyl group, with OH or amide substituents on the alkyl group, R5 is methyl, X is O, and T is -NR. x -, R x R1 is methyl, L is cyclic A and is heteroaryl, R1 is hydrogen, and R2 is hydrogen.

[0059] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w Rz For hydrogen ， R w It is an alkyl group, with OH or amide substituents on the alkyl group, R5 is methyl, X is O, and T is -NR. x -, R x R1 is a hydrogen atom, L is a ring A and is a heteroaryl group, R1 is hydrogen, and R2 is hydrogen.

[0060] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen ， R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, X is O, T is -O-, R x It is a hydrogen atom, L is a ring A and a heteroaryl group, and R1 and R2 together form =O.

[0061] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen ， R w It is an alkyl group, and the alkyl group is replaced by OH, R w For one or more R 01 Replaced by, R 01 -C(=NR) a )NR b R c R5 is methyl, X is S, T is -Se-, L is cyclic A and is heteroaryl, R1 is hydrogen, and R2 is hydrogen.

[0062] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen ， R w It is an alkyl group, and the alkyl group is replaced by OH, R w For one or more R 01 Replaced by, R 01 -C(=NR) a )NR b R c R5 is methyl, X is S, T is -O-, L is cyclic A and is heteroaryl, R1 is hydrogen, and R2 is hydrogen.

[0063] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen， R w It is an alkyl group, and the alkyl group is replaced by OH, R w For one or more R 01 Replaced by, R 01 -C(=NR) a )R b R5 is methyl, X is S, T is -Se-, L is cyclic A and is heteroaryl, R1 is hydrogen, and R2 is hydrogen.

[0064] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen ， R w It is an alkyl group, and the alkyl group is replaced by OH, R w For one or more R 01 Replaced by, R 01 -C(=NR) a )R b R5 is methyl, X is S, T is -O-, L is cyclic A and is heteroaryl, R1 is hydrogen, and R2 is hydrogen.

[0065] This application provides a substituted carbocyclic or heterocyclic derivative of general formula (IA) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0066] in:

[0067] Ring B is selected from a fused ring, which may optionally be further replaced by one or more R0;

[0068] X is selected from NH, O, S, or Se;

[0069] R0, R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, or haloalkyl.

[0070] Alternatively, R2 and R3 together form = 0;

[0071] U is selected from -NR x R y or -OR x U-Preferred-NR x R y ;

[0072] R x R yEach group is independently selected from hydrogen atom, amino, hydroxyl, cyano, amide, alkoxy, alkyl, cycloalkyl, or heterocyclic group, wherein the amide, alkoxy, alkyl, cycloalkyl, or heterocyclic group is optionally further influenced by one or more R groups. 01 replace;

[0073] R 01 Whether the groups are the same or different, they are each independently selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, carbonylalkyl, amide-substituted alkyl, thioamide-substituted alkyl, thioamide, amide, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, =O;

[0074] n is 0, 1, 2, or 3;

[0075] This application provides a substituted carbocyclic or heterocyclic derivative or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, represented by general formula (IB):

[0076] in:

[0077] Ring A is selected from cycloalkyl, heterocycloalkyl, fused ring, aryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, fused ring, aryl or heteroaryl may optionally be further substituted by one or more R0;

[0078] Ring B is selected from the following groups:

[0079] Q is selected from none or -CR1R2-;

[0080] T is selected from none, -NR x -、-CR x R y -, -O- or -S-, T is preferred;

[0081] U is selected from -NR z R w or -OR z U-Preferred-NR z R w ;

[0082] R0, R1, R2, R3, R4, R5, R x R y R z R wEach is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, amide-substituted alkyl, thioamide-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the hydroxyalkyl, amide-substituted alkyl, thioamide-substituted alkyl, amide, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl may optionally be further selected by one or more R 01 replace;

[0083] Alternatively, R1 and R2 together form =O, =S, or =NR. a R3 and R4 together form =O, =S, or =NR a ;

[0084] Or, R1 and R2, R2 and R x R z R5 and R5, together with the atoms they are connected to, form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein the 3-7 membered cycloalkyl and the 3-7 membered heterocycloalkyl are optionally further substituted by one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amide, =O.

[0085] R 01 Whether identical or different, each is independently selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, carbonylalkyl, amide-substituted alkyl, thioamide-substituted alkyl, thioamide, amide, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, =O, =S, -C (=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -P(O)R a R b -S(=NR) a )(O)NR b R c -OR a ;

[0086] R a R b R cEach of the following groups is independently selected from hydrogen atom, cyano, hydroxyl, amino, alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, hydroxyalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl or =O;

[0087] Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl or =O.

[0088] n is 0, 1, 2, or 3;

[0089] m can be 0, 1, 2, 3, 4, or 5.

[0090] In some specific embodiments of this application, T is -O- in general formula (IB).

[0091] In some specific embodiments of this application, in the general formula (IB), T represents no bond or a single bond.

[0092] In some specific embodiments of this application, in the general formula (IB), T is -NR. x -, R x It can be an alkyl group or a hydrogen atom.

[0093] In some specific embodiments of this application, in the general formula (IB), Q is either absent or a single bond.

[0094] In some specific embodiments of this application, in the general formula (IB), Q is -CR1R2-, and R1 and R2 are both hydrogen atoms.

[0095] In some specific embodiments of this application, in the general formula (IB), ring A is selected from aryl or heteroaryl.

[0096] In some specific embodiments of this application, in the general formula (IB), ring A is selected from aryl, and the aryl group is substituted with one or more halogens.

[0097] In some specific embodiments of this application, in general formula (IB), ring A is selected from aryl, said aryl is substituted by one or more haloalkyl or alkoxy groups, said alkoxy group is substituted by one or more halogens.

[0098] In some specific embodiments of this application, in general formula (IB), ring A is selected from heteroaryl groups, which are substituted by one or more halogens.

[0099] In some specific embodiments of this application, in general formula (IB), ring A is selected from heteroaryl groups, which are substituted by one or more haloalkyl groups.

[0100] In some specific embodiments of this application, in general formula (IB), ring A is selected from heteroaryl groups, which are substituted by one or more alkoxy groups, which are substituted by one or more halogens.

[0101] In some specific embodiments of this application, in general formula (IB), ring A is selected from fused rings, which are substituted by one or more halogens.

[0102] In some specific embodiments of this application, in general formula (IB), ring A is selected from fused rings, which are substituted by one or more haloalkyl groups.

[0103] In some specific embodiments of this application, in general formula (IB), ring A is selected from fused rings, said fused rings are substituted with one or more alkoxy groups, said alkoxy groups are substituted with one or more halogens.

[0104] In some specific embodiments of this application, in general formula (IB), R5 is selected from alkyl groups.

[0105] In some specific embodiments of this application, in general formula (IB), R5 is selected from halogens.

[0106] In some specific embodiments of this application, in general formula (IB), R5 is selected from alkyl halogenates.

[0107] In some specific embodiments of this application, in general formula (IB), R3 and R4 together form = 0.

[0108] In some specific embodiments of this application, in the general formula (IB), U is -NR. z R w R z Selected from hydrogen atoms, R w Selected from amide-substituted alkyl groups, wherein the alkyl group is substituted with one or more hydroxyl groups.

[0109] In some specific embodiments of this application, in the general formula (IB), U is -NR. z R w R z Selected from hydrogen atoms, R w Selected from hydroxyalkyl groups, wherein the hydroxyalkyl group is substituted with one or more amide groups.

[0110] In some specific embodiments of this application, in the general formula (IB), U is -NR. z R w R z Selected from hydrogen atoms, R w Selected from alkoxy groups, wherein the alkoxy group is substituted by one or more hydrogen atoms.

[0111] In some specific embodiments of this application, in the general formula (IB), U is -NR. z R w R z Selected from hydrogen atoms, R w The alkyl group is selected from thioamide-substituted alkyl groups, wherein the alkyl group is substituted with one or more hydroxyl groups.

[0112] This application provides a substituted carbocyclic or heterocyclic derivative of general formula (II-B), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof:

[0113] in:

[0114] R' is selected from hydrogen atom, deuterium, halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, cycloalkyl, heterocyclic;

[0115] The definitions of R0, R1, R2, R3, R4, R5, rings A, T, U, n, and m are shown in the general formula (IB).

[0116] In a preferred embodiment of this application, a compound of formula (I), (II), (III), (IV), (IB), or (II-B) or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof is provided, wherein ring A is selected from the following groups:

[0117] In one specific embodiment, ring A is selected from 5-6 aryl or 5-6 heteroaryl.

[0118] In one specific embodiment, ring A is selected from a thiazole ring or a pyridine ring.

[0119] In one specific embodiment, R0 is selected from halogens, alkyl groups, or haloalkyl groups.

[0120] In some specific embodiments of this application, R3 and R4 together form =O.

[0121] In some specific embodiments of this application, U is -NR z R w .

[0122] In some specific embodiments of this application, U is -NR z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is replaced by OH or amide groups.

[0123] In some specific embodiments of this application, R5 is a methyl group and m = 1.

[0124] In some specific embodiments of this application, R5 is a methyl group and m = 3.

[0125] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is replaced by OH or amide groups.

[0126] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is replaced by OH or amide group, R5 is methyl, and m=1.

[0127] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is replaced by OH or amide group, R5 is methyl, and m=3.

[0128] In some specific embodiments of this application, ring B is

[0129] In some specific embodiments of this application, T stands for -O-.

[0130] In some specific embodiments of this application, R1 and R2 are hydrogen.

[0131] In some specific embodiments of this application, ring A is a 5-6 membered aryl group.

[0132] In some specific embodiments of this application, T is -O-, and R1 and R2 are hydrogen.

[0133] In some specific embodiments of this application, ring A is a 5-6 member heteroaryl group.

[0134] In some specific embodiments of this application, n is 1.

[0135] In some specific embodiments of this application, T is -O-, R1 and R2 are hydrogen, and ring A is a 5-6 membered heteroaryl group.

[0136] In some specific embodiments of this application, A is selected from

[0137] In some specific embodiments of this application, R0 is an alkyl group and n = 1.

[0138] In some specific embodiments of this application, R0 is methyl and n = 1.

[0139] In some specific embodiments of this application, R0 is a haloalkyl group.

[0140] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0141] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0142] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0143] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R wIt is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0144] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0145] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0146] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0147] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, R w It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0148] In some specific embodiments of this application, R3 and R4 together form = 0, and U is -NR. z R w R z For hydrogen, Rw It is an alkyl group, and the alkyl group is substituted with OH or amide groups, R5 is methyl, m=1, and ring B is... T is -O-, R1 and R2 are hydrogen, and A is... R0 is a methyl group, and n = 1.

[0149] In some specific embodiments of this application, R' is hydrogen, alkyl, haloalkyl, or deuteralkyl.

[0150] In some specific embodiments of this application, R' is methyl or deuterated methyl.

[0151] Furthermore, this application provides a pharmaceutical composition comprising an effective dose of the compound described in (I), (II), (III), (IV), (IA), (IB) or (II-B) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0152] This application provides the use of a compound of formula (I), (II), (III), (IV), (IA), (IB) or (II-B) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a TRPM3 antagonist.

[0153] This application also provides the use of compounds of general formula (I), (II), (III), (IV), (IA), (IB) or (II-B) or their stereoisomers, tautomers, deuterated derivatives or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of TRPM3-mediated diseases, wherein the TRPM3-mediated diseases are pain or pain-related diseases; wherein the TRPM3-mediated pain or pain-related diseases are selected from acute pain, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, primary pain or migraine.

[0154] This application further provides the use of the compound of general formula (I), (II), (III), (IV), (IA), (IB) or (II-B) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for the prevention and / or treatment of pain or pain-related diseases.

[0155] This application provides the use of a compound of formula (I), (II), (III), (IV), (IA), (IB) or (II-B) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of acute pain, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, primary pain or migraine.

[0156] The compounds of this application may optionally be in the form of a single optical isomer, a single enantiomer or a mixture of racemates, in the form of a tautomer, or in the form of a free base or an acid addition salt formed with a pharmacologically acceptable acid.

[0157] The compounds of this application may exist as tautomers. All tautomer forms of the compounds of this application are contemplated within the scope of this application.

[0158] Detailed description of the invention

[0159] Unless otherwise stated, some terms used in this application in the specification and claims are defined as follows:

[0160] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0161] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12 Cycloalkyl groups, more preferably C3-C8 cycloalkyl groups, and most preferably C3-C6 cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred. The cycloalkyl group may be optionally substituted or unsubstituted.

[0162] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more cyclic atoms are heteroatoms, such as oxygen, nitrogen, sulfur, boron atoms, etc., including monocyclic, polycyclic, fused-ring, bridged-ring, and spirocyclic groups. Preferably, it has a 5- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic group, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of “heterocyclic group” include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclic [3.2.1]octyl, piperazine, and hexahydropyrimidine. Heterocyclic groups may be substituted or unsubstituted.

[0163] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted.

[0164] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indolyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indolyl, benzisothiazolyl, benzo[oxazolyl], benzisothiazolyl. Heteroaryl groups may be substituted or unsubstituted. "Alkoxy" refers to an (alkyl-O-) group. Wherein, alkyl is defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0165] A "fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms. One or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated π-electron aromatic system. Conversely, at least one ring has a fully conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 quinary elements, more preferably 8 to 10 quinary elements.

[0166] "Hydroxy" refers to the -OH group.

[0167] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0168] "Amino" refers to -NH2.

[0169] “Cyano” refers to -CN.

[0170] "Nitro" refers to -NO2.

[0171] "Carboxyl group" refers to -C(O)OH.

[0172] "DMSO" refers to dimethyl sulfoxide.

[0173] “BOC” refers to tert-butoxycarbonyl.

[0174] “Tf” refers to trifluoromethanesulfonyl group.

[0175] “TBDPS” refers to tert-butyldiphenylsilyl.

[0176] "TFA" refers to trifluoroacetic acid.

[0177] "Hydroxyalkyl" refers to an alkyl group that is substituted with a hydroxyl group.

[0178] "Aminoalkyl" refers to an amino-substituted alkyl group.

[0179] "Halogenated alkyl" refers to alkyl groups that have been substituted with halogens.

[0180] "Alkylamino" refers to an amino group that is substituted with an alkyl group.

[0181] "Amide group" refers to -NH-CO-, -CO-NH-, -CO-NH2 or -CH2-CO-NH2.

[0182] "None" indicates a single bond, meaning the groups are directly connected.

[0183] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0184] Unless otherwise specified, the term "substituted" or "substituted" in this specification means that the group can be substituted by one or more substituents selected from the following groups: alkyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, and hydroxyalkyl.

[0185] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0186] Those skilled in the art will understand that salts of compounds of general formulas (I), (II), (III), (IV), (IA), (IB), or (II-B), including pharmaceutically acceptable salts, can be prepared. These salts can be prepared in situ during the final separation and purification of the compound, or by independently reacting a purified compound, in its free acid or free base form, with a suitable base or acid. Bases typically used to form pharmaceutically acceptable salts include organic or inorganic bases, and acids used to form pharmaceutically acceptable salts include organic or inorganic acids.

[0187] The pharmaceutically usable salts of this application can be synthesized from basic or acidic fractions using conventional chemical methods. Typically, these salts can be prepared by reacting the free acidic form of these compounds with a suitable stoichiometric amount of a base, or by reacting the free basic form of these compounds with a suitable stoichiometric amount of an acid. These reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Typically, a non-aqueous medium, such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is required where appropriate. A list of other suitable salts can be found in Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0188] "Deuterated derivatives" refer to compounds that contain deuterium bonded to carbon at at least one position, with the amount of carbon-bonded deuterium exceeding its natural content.

[0189] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0190] The pharmaceutical compositions disclosed in this application can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of this application can be prepared in solid form (non-limitingly including capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (non-limitingly including solutions, suspensions, or emulsions). The pharmaceutical compositions can undergo conventional pharmaceutical processes (e.g., sterilization) and / or can contain conventional inert diluents, lubricants, or buffers, as well as excipients such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0191] Typically, pharmaceutical compositions are tablets or capsules containing an active ingredient and

[0192] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc.;

[0193] b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; also included in tablets.

[0194] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; and if necessary.

[0195] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and / or

[0196] e) Absorbents, colorants, flavorings and sweeteners.

[0197] According to methods known in the art, tablets can be film-coated or enteric-coated.

[0198] Suitable compositions for oral administration include an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the form of tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions, and in order to provide a refined and palatable formulation, the composition may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for preparing tablets. These excipients are, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrants (e.g., corn starch, or alginate); binders (e.g., starch, gelatin, or gum arabic); and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets are either uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Oral formulations can be presented in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or in soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0199] Some injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting or emulsifiers, dissolution promoters, salts and / or buffers for adjusting osmotic pressure. Furthermore, they may contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain approximately 0.1-75% or approximately 1-50% of the active ingredient.

[0200] Since water may promote the degradation of certain compounds, this application also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of this application as active ingredients.

[0201] The anhydrous pharmaceutical compositions and dosage forms of this application can be prepared using anhydrous or low-water-content ingredients and low-water-content or low-humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions are packaged using materials known to prevent contact with water so that they can be contained in suitable formulation boxes. Examples of suitable packaging, without limitation, include airtight foil, plastics, unit-dose containers (e.g., tubular bottles), blister packs, and strip packs.

[0202] This application further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the decomposition rate of the compound of this application as an active ingredient. Such agents (referred herein as "stabilizers") include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers, or salt buffers.

[0203] For an individual weighing approximately 50-70 kg, the pharmaceutical composition or combination product of this application can be a unit dose of approximately 1-1000 mg of the active ingredient, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg, or approximately 0.5-100 mg, or approximately 1-50 mg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition, or combination product thereof depends on the individual's species, weight, age, and individual circumstances, the condition or disease being treated, or its severity. A physician, clinician, or veterinarian of general skill can readily determine the effective amount of each active ingredient required for the prevention, treatment, or inhibition of the development of a condition or disease.

[0204] The term "stereoisomer" for a compound having a given stereochemical configuration refers to its opposite enantiomers and any diastereomers including its geometrical isomers (Z / E). For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers will include its opposite enantiomers having an R,S,Z configuration, and its diastereomers having S,S,Z, R,R,Z, S,R,E, R,S,E, S,S,E, and R,R,E configurations. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any of the possible stereochemical configurations of the compound.

[0205] Compounds of general formulas (I), (II), (III), (IV), (IA), (IB), or (II-B), their stereoisomers, or tautomers or complexes of their stereoisomers, may be administered alone or in combination with one or more pharmaceutically active compounds. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends on the specific administration method, the effect of the excipient on solubility and stability, and the nature of the dosage form, etc. Available pharmaceutical compositions and methods of their preparation can be found, for example, in ARGennaro (ed.), Remington: Pharmaceutical Science and Practice (20th edition, 2000).

[0206] The compounds of this application may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this application, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this application.

[0207] Unless otherwise stated, the structure described in this application also includes all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this application, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this application.

[0208] The term "stereoisomer" refers to isomers formed by different spatial arrangements of atoms in a molecule. Stereoisomers can be classified into two main categories: cis-trans isomers and enantiomers, or further divided into enantiomers and diastereomers. Stereoisomers are a type of isomer. Stereoisomers are isomers formed when atoms or groups of atoms in a molecule are connected in the same order but arranged differently in space.

[0209] The term "substantially enantiomerically pure" refers to an enantiomeric purity greater than 90% at a given stereocenter. Therefore, the term "substantially enantiomerically pure" means greater than 80% ee (enantiomer excess). For compounds existing as stereoisomers, such stereoisomers can be substantially enantiomerically pure at the stereocenter, or preferably can have an enantiomeric purity greater than 97%, or more preferably greater than 99%. Detailed Implementation

[0210] The following embodiments are used to further describe this application, but these embodiments are not intended to limit the scope of this application.

[0211] Example

[0212] The examples provide preparation and related structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of this application and not intended to limit its scope. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0213] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0214] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm to 0.2mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm to 0.5mm in diameter.

[0215] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0216] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0217] CD3OD: Deuterated methanol.

[0218] CDCl3: Deuterated chloroform.

[0219] DMSO-d6: Deuterated dimethyl sulfoxide.

[0220] D2O: Heavy water.

[0221] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0222] The compound was purified using a C18 reversed-phase column for preparative or semi-preparative purification, silica gel column chromatography eluent system, and thin-layer chromatography. The eluent system was selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and water system; C: petroleum ether and ethyl acetate system. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding a small amount of acidic or basic reagents, such as trifluoroacetic acid, acetic acid, or triethylamine.

[0223] Example 1

[0224] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-1,2-dimethyl-5-((2-methylthiazo-5-yl)methoxy)-1H-indole

[0225] -3-Formamide

[0226] first step

[0227] 5-(chloromethyl)-2-methylthiazole

[0228] (2-methylthiazol-5-yl)methanol 1a (2 g, 15.48 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (3.68 g, 30.96 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated, and ethyl acetate (50 mL) was added. The mixture was washed twice with saturated sodium bicarbonate aqueous solution (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-(chloromethyl)-2-methylthiazol 1b (2.2 g), yield: 96.26%. This unpurified solution was directly used in the next reaction.

[0229] MS m / z (ESI): 147.8 [M+1]

[0230] Step 2

[0231] ethyl 1,2-dimethyl-5-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxylate

[0232] Ethyl 5-hydroxy-1,2-dimethyl-1H-indole-3-carboxylate 1c (300 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (628.56 mg, 1.93 mmol) and 5-(chloromethyl)-2-methylthiazole 1b (189.86 mg, 1.29 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give ethyl 1,2-dimethyl-5-((2-methylthiazol-5-yl)methoxy)-1H-indole-3-carboxylate 1d (400 mg), yield: 90.3%.

[0233] MS m / z(ESI): 345.1 [M+1]

[0234] 1 H NMR (400MHz, CDCl3) δ7.74(d,J=2.5Hz,1H),7.62(s,1H),7.22-7.17(m,1H),6.94-6.87(m,1H),5.27(s ,2H),4.40(q,J=7.2Hz,2H),3.73-3.59(m,3H),2.76(s,3H),2.73-2.67(m,3H),1.45(t,J=7.2Hz,3H).

[0235] Step 3

[0236] 1,2-Dimethyl-5-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxylic acid

[0237] Ethyl 1,2-dimethyl-5-((2-methylthiazol-5-yl)methoxy)-1H-indole-3-carboxylic acid 1d (100 mg, 290.34 g) was dissolved in 1.2 mL of a mixture of ethanol and water (ethanol:water = 5:1), and sodium hydroxide (174.19 mg, 4.36 mmol) was added. The mixture was stirred at 90 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was complete, 5 mL of water was added, and the pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 1,2-dimethyl-5-((2-methylthiazol-5-yl)methoxy)-1H-indole-3-carboxylic acid 1e (80 mg), yield: 87.09%. This product was used directly in the next reaction without purification.

[0238] MS m / z(ESI): 317.1 [M+1]

[0239] Step 4

[0240] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-1,2-dimethyl-5-((2-methylthiazo-5-yl)methoxy)-1H-indole-3-carboxamide

[0241] 1,2-Dimethyl-5-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxylic acid 1e (30 mg, 94.82 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (19.99 mg, 142.24 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea were added at 0 °C. Hexafluorophosphate (54.08 mg, 142.24 μmol), N,N-diisopropylethylamine (18.38 mg, 142.24 μmol), and 1-hydroxy-7-azobenzotriazole (12.91 mg, 94.82 μmol) were stirred at 25 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to obtain the crude product. The crude product was purified by chiral separation using SFC (column type: DAICEL CHIRALPAK AS, 250 mm × 30 mm, 10 μm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214 nm; column temperature: 40 °C) to obtain a single-configuration compound (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-1,2-dimethyl-5-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxamide 1 (10.55 mg), yield: 30.65%, retention time: 2.050 min, chiral purity: 98.68% ee.

[0242] MS m / z(ESI): 403.1 [M+1]

[0243] 1 H NMR (400MHz, CD3OD) δ7.67-7.63(m,1H),7.58-7.53(m,1H),7.33(d,J=8.9Hz,1H),6.93-6.86( m,1H),5.32(s,2H),4.71-4.68(m,1H),4.03-3.91(m,2H),3.71(s,3H),2.68(d,J=1.8Hz,6H).

[0244] Example 2

[0245] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxamide

[0246] first step

[0247] Cyclopropylmethane-d2-ol

[0248] Cyclopropane methyl carboxylate 2a (500 mg, 4.99 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum deuterated hydride (314 mg, 7.49 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, water, 15% sodium hydroxide solution, and water were slowly added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the solid was washed with dichloromethane. The filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give cyclopropylmethane-d2-ol 2b (300 mg), yield: 81.05%.

[0249] Step 2

[0250] 5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[0251] Cyclopropylmethane-d2-ol 2b (67 mg, 0.908 mmol) was dissolved in tetrahydrofuran (5 mL), and ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (100 mg, 0.454 mmol) and tributylphosphine (184 mg, 0.908 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (229 mg, 0.908 mmol) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at 65 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give ethyl 5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxylate 2d (80 mg), yield: 63.76%.

[0252] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=2.8Hz,1H),7.22(d,J=8.8Hz,1H),6.81(dd,J=8.8,2.4Hz,1H),4.33(q,J =7.2Hz,2H),2.67(s,3H),1.36(t,J=7.2Hz,3H),0.92-0.80(m,1H),0.62-0.53(m,2H),0.33-0.24(m,2H).

[0253] Step 3

[0254] 5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxylic acid

[0255] Ethyl 5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxylic acid 2d (80 mg, 0.290 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Sodium hydroxide (46 mg, 1.16 mmol) dissolved in water (1 mL) was added, and the mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to give 5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxylic acid 2e (60 mg), yield: 83.47%.

[0256] MS m / z(ESI): 249.2 [M+1]

[0257] Step 4

[0258] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxamide

[0259] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (51 mg, 0.363 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (156 mg, 1.21 mmol) was added. The reaction solution was stirred at 25 °C for 5 minutes. 5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxylic acid 2e (60 mg, 0.242 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (184 mg, 0.483 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative separation (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(cyclopropylmethoxy-d2)-2-methylbenzofuran-3-carboxamide 2 (53.73 mg), yield: 66.49%.

[0260] MS m / z(ESI): 335.2 [M+1]

[0261] 1H NMR (400MHz, DMSO-d6) δ7.57(d,J=7.6Hz,1H),7.47(s,1H),7.45(s,1H),7.30(d,J=2.8Hz,1H),7.18(s,1H),6.90(dd,J=8.8,2 .4Hz,1H),5.00(s,1H),4.53-4.43(m,1H),3.75(s,2H),2.64(s,3H),1.32-1.16(m,1H),0.62-0.52(m,2H),0.39-0.29(m,2H).

[0262] Example 3

[0263] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide

[0264] first step

[0265] 6-Methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0266] 5-Methoxypyridine-2-amine 3a (3 g, 24.17 mmol) and ethyl 2-chloro-3-oxobutyrate 3b (3.98 g, 24.17 mmol) were added to ethanol (60 mL) and reacted in a microwave oven at 120 °C for 0.6 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give ethyl 6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate 3c (1.8 g), yield: 31.80%.

[0267] MS m / z(ESI): 235.1 [M+1]

[0268] Step 2

[0269] ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate

[0270] Boron tribromide (6.785 g, 27.36 mmol) was slowly added to ethyl 6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate 3c (800 mg, 3.42 mmol) in dichloromethane (15 mL), and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, methanol (20 mL) was slowly added dropwise at 0 °C to quench the reaction. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system C) to give ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate 3d (400 mg), yield: 53.18%.

[0271] MS m / z(ESI): 221.1 [M+1]

[0272] Step 3

[0273] 2-Methyl-6-[(2-methylthiazolyl-5-yl)methoxy]imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0274] Ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate 3d (100 mg, 454.08 μmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (221.92 mg, 681.12 μmol) and 5-(chloromethyl)-2-methylthiazole 1b (73.74 mg, 499.49 μmol) were added. The mixture was stirred at 35 °C for 18 hours. After the reaction was completed, the reaction was quenched with water (30 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: system C) to obtain ethyl 2-methyl-6-[(2-methylthiazolyl-5-yl)methoxy]imidazo[1,2-a]pyridine-3-carboxylate 3e (140 mg), yield: 93.04%.

[0275] MS m / z(ESI): 331.9 [M+1]

[0276] Step 4

[0277] 2-Methyl-6-[(2-methylthiazolyl-5-yl)methoxy]imidazo[1,2-a]pyridine-3-carboxylic acid

[0278] Ethyl 2-methyl-6-[(2-methylthiazol-5-yl)methoxy]imidazo[1,2-a]pyridine-3-carboxylic acid ester 3e (70 mg, 211.23 μmol) was dissolved in 3.6 mL of a mixed solution (ethanol:water = 5:1), and sodium hydroxide (126.73 mg, 3.17 mmol) was added. The mixture was stirred at 90 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH of the solution was adjusted to 7 with 1 M hydrochloric acid, and the solution was concentrated under reduced pressure to give 2-methyl-6-((2-methylthiazol-5-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid 3f (60 mg), yield: 93.64%. This solution was used directly for the next reaction without purification.

[0279] MS m / z(ESI): 304.1 [M+1]

[0280] Step 5: (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide

[0281] 2-Methyl-6-((2-methylthiazolyl-5-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid 3f (50 mg, 164.83 μmol) was dissolved in N,N-dimethylformamide (1 mL), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (34.76 mg, 247.25 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (94.01 mg, 247.25 μmol), 1-hydroxy-7-azobenzotriazole (22.44 mg, 164.83 μmol) and N,N-diisopropylethylamine (63.91 mg, 494.50 μmol) were added. The mixture was stirred at 25 °C for 18 hours. The reaction was monitored by LC-MS, quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide 3 (12.88 mg), yield: 17.39%.

[0282] MS m / z(ESI): 390.1 [M+1]

[0283] 1H NMR (400MHz, CD3OD) δ = 9.09 (d, J = 1.8Hz, 1H), 7.82-7.73 (m, 3H), 5.45 (s, 2H ), 4.78-4.74 (m, 1H), 3.99 (dd, J = 1.6, 5.2Hz, 2H), 2.79 (s, 3H), 2.72 (s, 3H).

[0284] Example 4

[0285] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide

[0286] first step

[0287] 2-Methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0288] Ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate 3d (120 mg, 547.36 μmol) was dissolved in tetrahydrofuran (2 mL), and then tributylphosphine (155.04 mg, 766.30 μmol), (2-(trifluoromethyl)pyridin-3-yl)methanol 4a (145.42 mg, 821.03 μmol) and azodicarbonylpiperidine (193.34 mg, 766.30 μmol) were added sequentially. The mixture was stirred at 60 °C for 18 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography (eluent: system B) to give ethyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate 4b (150 mg), yield: 72.43%.

[0289] MS m / z(ESI): 380.0 [M+1]

[0290] Step 2

[0291] 2-Methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

[0292] Ethyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid 4b (150 mg, 395.43 μmol) was dissolved in 5 mL of a mixed solution (ethanol:water = 4:1), and sodium hydroxide (237.26 mg, 5.93 mmol) was added. The mixture was stirred at 90 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, the pH of the solution was adjusted to 7 with 1 M hydrochloric acid, filtered, and concentrated under reduced pressure to obtain 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid 4c (120 mg), yield: 86.39%. This product was used directly in the next reaction without purification.

[0293] MS m / z(ESI): 352.1 [M+1]

[0294] Step 3

[0295] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide

[0296] 2-Methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid 4c (100 mg, 284.67 μmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (60 mg, 427.01 μmol), 1-hydroxy-7-azobenzotriazole (38.75 mg, 284.67 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (162.36 mg, 427.01 μmol) and N,N-diisopropylethylamine (110.37 mg, 854.02 μmol). The mixture was stirred at 25 °C for 16 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative separation using a C18 reversed-phase column (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide 4 (43.44 mg), yield: 34.88%.

[0297] MS m / z(ESI): 438.1 [M+1]

[0298] 1 H NMR (400MHz, CD3OD) δ = 9.06 (d, J = 2.1Hz, 1H), 8.70 (d, J = 4.5Hz, 1H), 8.30 (d, J = 8.0Hz, 1H), 7.74 (dd, J = 4.8, 7.9Hz, 1H), 7.54(d,J=9.5Hz,1H),7.38(dd,J=2.4,9.7Hz,1H),5.35(s,2H),4.80-4.61(m,1H),3.98(t,J=5.1Hz,2H),2.74(s,3H).

[0299] Example 5

[0300] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxamide

[0301] first step

[0302] 2-Chloro-4-iodo-5-(methylthio)pyridine

[0303] 6-Chloro-4-iodopyridin-3-amine 5a (10 g, 39.30 mmol) was dissolved in dichloromethane (100 mL). 1,2-Dimethyldithionane 5b (8.22 g, 87.26 mmol) and tert-butyl nitrite (6.08 g, 58.95 mmol) were added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 2-chloro-4-iodo-5-(methylthio)pyridine 5c (1.9 g), yield: 16.93%.

[0304] MS m / z(ESI): 285.7 [M+1]

[0305] Step 2

[0306] 2-Chloro-5-(methylthio)-4-(prop-1-yn-1-yl)pyridine

[0307] 2-Chloro-4-iodo-5-(methylthio)pyridine 5c (1.9 g, 6.65 mmol), propyne (0.798 g, 19.96 mmol), bis(triphenylphosphine)palladium(II) dichloride (233.53 mg, 332.71 μmol), and cuprous iodide (126.73 mg, 665.42 μmol) were added to triethylamine (20 mL), and the mixture was stirred at 25 °C for 2 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was poured into water (40 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 2-chloro-5-(methylthio)-4-(prop-1-yn-1-yl)pyridine 5d (1 g), yield: 76.02%.

[0308] MS m / z(ESI): 197.8 [M+1]

[0309] Step 3

[0310] 5-Chloro-3-iodo-2-methylthiopheno[2,3-c]pyridine

[0311] A solution of elemental iodine (1.44 g, 5.67 mmol) in dichloromethane (20 mL) was added dropwise to a solution of 2-chloro-5-(methylthio)-4-(prop-1-yn-1-yl)pyridine 5e (800 mg, 4.05 mmol) in dichloromethane (30 mL) at room temperature. The mixture was stirred at room temperature for 14 hours. After the reaction was completed, the reaction was quenched with water (50 mL), extracted with dichloromethane (40 mL × 2), the organic phases were combined, washed with saturated sodium chloride aqueous solution (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 5-chloro-3-iodo-2-methylthiopheno[2,3-c]pyridine 5e (550 mg), yield: 43.9%.

[0312] MS m / z(ESI): 309.9 [M+1]

[0313] Step 4

[0314] methyl 5-chloro-2-methyl-thieno[2,3-c]pyridine-3-carboxylate

[0315] Under nitrogen protection at 0°C, a solution of isopropyl magnesium chloride and lithium chloride complex (387.08 mg, 2.67 mmol) was slowly added dropwise to a tetrahydrofuran (5 mL) solution of 5-chloro-3-iodo-2-methylthiopheno[2,3-c]pyridine 5e (550 mg, 1.78 mmol). After 0.5 hours, methyl chloroformate 5f (839.49 mg, 8.88 mmol) was added dropwise, and the reaction was carried out at 20°C for 14 hours. The reaction was detected by LC-MS. After the reaction was completed, the reaction solution was poured into 0.1M hydrochloric acid aqueous solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 5 g (180 mg) of methyl 5-chloro-2-methyl-thieno[2,3-c]pyridine-3-carboxylate, yield: 35%.

[0316] MS m / z(ESI): 242.1 [M+1]

[0317] Step 5

[0318] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy)thienro[2,3-c]pyridine-3-carboxylic acid methyl ester

[0319] 5 g (180 mg, 744.74 μmol) of methyl 5-chloro-2-methylthieno[2,3-c]pyridine-3-carboxylate was dissolved in toluene (5 mL). Then, (2-methylthiazol-5-yl)methanol 1a (192.41 mg, 1.49 mmol), cesium carbonate (606.63 mg, 1.86 mmol), tris(dibenzylacetone)palladium (136.39 mg, 148.95 μmol), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (126.50 mg, 297.90 μmol) were added. The mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (20 mL). The filtrate was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give methyl 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylate 5h (50 mg), yield: 17%.

[0320] MS m / z(ESI): 335.1 [M+1]

[0321] Step 6

[0322] 2-Methyl-5-[(2-methylthiazolyl-5-yl)methoxy]thienro[2,3-c]pyridine-3-carboxylic acid

[0323] Sodium hydroxide (17.94 mg, 448.55 μmol) was added to a 3.5 mL mixture of methyl 2-methyl-5-((2-methylthiazol-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylic acid 5h (50 mg, 149.52 μmol) (ethanol:water = 6:1). The mixture was stirred at 90 °C for 3 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (15 mL), the pH of the solution was adjusted to 5-6 with 1M hydrochloric acid, and the mixture was extracted with dichloromethane (20 mL × 2). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-methyl-5-((2-methylthiazol-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylic acid 5i (45 mg), yield: 84%. This product was used directly for the next reaction without purification.

[0324] MS m / z(ESI): 320.9 [M+1]

[0325] Step 7

[0326] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxamide

[0327] 2-Methyl-5-((2-methylthiazol-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylic acid 5i (45 mg, 140.46 μmol) was dissolved in N,N-dimethylformamide (2 mL), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (39.49 mg, 280.91 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80.11 mg, 210.68 μmol), N,N-diisopropylethylamine (72.61 mg, 561.82 μmol), and 1-hydroxy-7-azobenzotriazole (28.68 mg, 210.68 μmol) were added sequentially. The mixture was stirred at 20 °C for 14 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then preparatively separated using a C18 reversed-phase column (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)thieno[2,3-c]pyridine-3-carboxamide 5 (25.47 mg), yield: 44%. MS m / z (ESI): 407.1 [M+1]

[0328] 1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.15(d,J=8.0Hz,1H),7.76(s,1H),7.44(s,1H),7.25(s, 1H),7.13(s,1H),5.57(s,2H),4.52-4.47(m,1H),3.75-3.65(m,2H),2.68(s,3H),2.61(s,3H).

[0329] Example 6

[0330] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxamide

[0331] first step

[0332] 2-Methyl-5-[[2-(trifluoromethyl)-3-pyridyl]methoxy]thienro[2,3-c]pyridine-3-carboxylic acid methyl ester

[0333] 5 g (290 mg, 1.20 mmol) of methyl 5-chloro-2-methyl-thieno[2,3-c]pyridine-3-carboxylate, 4a (425.05 mg, 2.40 mmol) of (2-(trifluoromethyl)pyridin-3-yl)methanol, 219.75 mg (239.97 μmol) of tris(dibenzylideneacetone)palladium, 203.80 mg (479.95 μmol) of di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine, and 977.35 mg (3.00 mmol) of cesium carbonate were added to toluene (10 mL) and stirred at 100 °C for 12 hours under nitrogen protection. The reaction was monitored by TLC. After the reaction was completed, the mixture was filtered, washed with dichloromethane (20 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to obtain methyl 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylate 6a (190 mg), yield: 35%.

[0334] MS m / z(ESI): 383.0 [M+1]

[0335] Step 2

[0336] 2-Methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thienro[2,3-c]pyridin-3-carboxylic acid

[0337] 2-Methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylic acid methyl ester 6a (80 mg, 209.23 μmol) was dissolved in 3.5 mL of a mixture of ethanol and water (ethanol:water = 6:1), and sodium hydroxide (25.11 mg, 627.69 μmol) was added. The mixture was stirred at 90 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the solution was diluted with water (15 mL), the pH of the solution was adjusted to 3 with 1 M hydrochloric acid, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylic acid 6b (70 mg), yield: 60%. This was used directly for the next reaction without purification.

[0338] MS m / z(ESI): 369.1 [M+1]

[0339] Step 3

[0340] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxamide

[0341] 2-Methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxylic acid 6b (70 mg, 190.05 μmol), (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (53.43 mg, 380.09 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (108.39 mg, 285.07 μmol), N,N-diisopropylethylamine (98.25 mg, 760.19 μmol), and 1-hydroxy-7-azobenzotriazole (38.80 mg, 285.07 μmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 20 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and washed with N,N-dimethylformamide (2 mL), concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)thieno[2,3-c]pyridine-3-carboxamide 6 (21 mg), yield: 24%.

[0342] MS m / z (ESI): 455.2 [M+1]

[0343] 1 H NMR (500MHz, DMSO-d6) δ8.75(s,1H),8.69(d,J=4.5Hz,1H),8.18(t,J=8.5Hz,2H),7.74(dd,J=8.0,5.0Hz,1H),7.45( s,1H),7.34(s,1H),7.14(s,1H),5.61(s,2H),4.52-4.50(m,1H),3.76-3.72(m,1H),3.70-3.66(m,1H),2.69(s,3H).

[0344] Example 7

[0345] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxamide

[0346] first step

[0347] 8-Fluoro-1,2,3,4-Tetrahydroisoquinoline

[0348] 8-Fluoroisoquinoline 7a (300 mg, 2.04 mmol) and platinum dioxide (462 mg, 2.04 mmol) were dissolved in 3 mL of acetic acid and stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 8-fluoro-1,2,3,4-tetrahydroisoquinoline 7b (152 mg), yield: 49.32%.

[0349] MS m / z(ESI): 152.0 [M+1].

[0350] Step 2

[0351] ethyl 5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxylate

[0352] Ethyl 5-bromo-2-methylbenzofuran-3-carboxylate 7c (284 mg, 1.01 mmol) was dissolved in anhydrous dioxane (5 mL), and cesium carbonate (982 mg, 3.02 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (93 mg, 0.20 mmol), tris(dibenzylideneacetone)palladium (92 mg, 0.10 mmol), and 8-fluoro-1,2,3,4-tetrahydroisoquinoline 7b (152 mg, 1.01 mmol) were added. The reaction was monitored by LC-MS. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give ethyl 5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxylate 7d (115 mg), yield: 32.37%.

[0353] MS m / z (ESI): 354.1 [M+1]

[0354] Step 3

[0355] 5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxylic acid

[0356] Ethyl 5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxylic acid 7d (115 mg, 0.32 mmol) was dissolved in a mixed solution of methanol (3 mL), tetrahydrofuran (3 mL), and water (3 mL). Lithium hydroxide (24 mg, 0.96 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to 5.0 with 1 N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7e (75 mg) of 5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxylic acid, yield: 61.40%.

[0357] MS m / z(ESI): 326.1 [M+1]

[0358] Step 4

[0359] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxamide

[0360] 5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxylic acid 7e (17 mg, 55.31 μmol) was dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (35.74 mg, 276.56 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (31.55 mg, 82.97 μmol), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (8.64 mg, 82.97 μmol) were added. The reaction solution was stirred at 25 °C for 1 hour. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was preparatively classified by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(8-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2-methylbenzofuran-3-carboxamide 7 (21.09 mg), yield: 22.24%.

[0361] MS m / z(ESI): 412.3 [M+1]

[0362] 1 H NMR (400MHz, DMSO-d6) δ7.64(d,J=8.0Hz,1H),7.52-7.39(m,3H),7.27-7.17(m,2H),7.11(dd,J=9.2,2.4Hz,1H),7.06-7.02(m,2H),5.01( t,J=5.6Hz,1H),4.48(dt,J=8.0,4.0Hz,1H),4.35(s,2H),3.76(t,J=5.4Hz,2H),3.53(t,J=5.8Hz,2H),2.99(t,J=5.8Hz,2H),2.64(s,3H).

[0363] Example 8

[0364] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzo[b]selenophen-3-carboxamide

[0365] first step

[0366] (2-Iodo-4-methoxyphenyl)(methyl)selenosilane

[0367] 2-Iodo-4-methoxyaniline 8a (6.5 g, 26.1 mmol) was dissolved in dichloromethane (70 mL). Dimethyl diselenide (9.81 g, 52.2 mmol) and tert-butyl nitrite (4.04 g, 39.2 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (2-iodo-4-methoxyphenyl)(methyl)selenoline 8b (8 g), yield: 93.73%.

[0368] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=2.8Hz,1H),7.22(d,J=8.4Hz,1H),6.88(dd,J=8.4,2.8Hz,1H),3.78(s,3H),2.32(s,3H).

[0369] Step 2

[0370] (4-Methoxy-2-(prop-1-yn-1-yl)phenyl)(methyl)selenoethane

[0371] (2-Iodo-4-methoxyphenyl)(methyl)selenoline 8b (5 g, 15.3 mmol), cuprous iodide (146 mg, 0.76 mmol), and dichlorobis(triphenylphosphine)palladium(II) (1.07 g, 1.53 mmol) were dissolved in triethylamine (50 mL), and propyne (1.84 g, 45.87 mmol) was added. The mixture was stirred at 15 °C for 14 hours, and the reaction was monitored by TLC. The reaction was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (4-methoxy-2-(prop-1-yn-1-yl)phenyl)(methyl)selenoline 8c (3.6 g), yield: 98.45%.

[0372] 1 H NMR (400MHz, CDCl3) δ7.23(d,J=8.4Hz,1H),6.95(d,J=2.4Hz,1H),6.80(dd,J=8.8,2.8Hz,1H),3.78(s,3H),2.32(s,3H),2.14(s,3H).

[0373] Step 3

[0374] 3-Iodo-5-methoxy-2-methylbenzo[b]selenophenol

[0375] (4-Methoxy-2-(prop-1-yn-1-yl)phenyl)(methyl)selenosilane 8c (5 g, 15.3 mmol) was dissolved in dichloromethane (40 mL), and elemental iodine (4.20 g, 16.6 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, and the reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 3-iodo-5-methoxy-2-methylbenzo[b]selenophenol 8d (3.4 g), yield: 42.33%.

[0376] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=8.4Hz,1H),7.26(s,1H),6.90(dd,J=8.8,2.8Hz,1H),3.92(s,3H),2.64(s,3H).

[0377] Step 4

[0378] methyl 5-methoxy-2-methylbenzo[b]selenophen-3-carboxylate

[0379] 0.1 g (0.28 mmol) of 3-iodo-5-methoxy-2-methylbenzo[b]selenophenol 8d was dissolved in 6 mL of a mixed solution (N,N-dimethylformamide:methanol = 2:1), and palladium acetate (6.40 mg, 0.03 mmol) and triphenylphosphine (14.9 mg, 0.06 mmol) were added. The mixture was stirred at 80 °C for 16 hours under carbon monoxide (50 psi), and the reaction was monitored by LCMS. After the reaction was completed, the mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give methyl 5-methoxy-2-methylbenzo[b]selenophene-3-carboxylate 8e (85 mg), yield: 65.33%.

[0380] MS m / z(ESI): 285.0 [M+1]

[0381] Step 5

[0382] methyl 5-hydroxy-2-methylbenzo[b]selenophen-3-carboxylate

[0383] 0.08 g (0.28 mmol) of methyl 5-methoxy-2-methylbenzo[b]selenophen-3-carboxylate 8e was dissolved in dichloromethane (2 mL), and boron tribromide (354 mg, 1.41 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give methyl 5-hydroxy-2-methylbenzo[b]selenophen-3-carboxylate 8f (40 mg), yield: 50.96%.

[0384] 1 H NMR (500MHz, CDCl3) δ7.91(d,J=2.5Hz,1H),7.61(d,J=8.5Hz,1H),6.89(dd,J=8.5,2.5Hz,1H),3.96(s,3H),2.88(s,3H).

[0385] Step 6

[0386] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzo[b]selenophen-3-carboxylic acid methyl ester

[0387] 8f of methyl 5-hydroxy-2-methylbenzo[b]selenophen-3-carboxylate (40 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), and cesium carbonate (96.8 mg, 0.30 mmol) and 5-(chloromethyl)-2-methylthiazole 1b (24.1 mg, 0.16 mmol) were added. The mixture was stirred at 30 °C for 14 hours, and the reaction was monitored by LC-MS. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 8 g (20 mg) of methyl 2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzo[b]selenophen-3-carboxylate, yield: 79.48%.

[0388] MS m / z(ESI): 382.0 [M+1]

[0389] Step 7

[0390] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzo[b]selenophen-3-carboxylic acid

[0391] 8 g (0.02 g, 0.05 mmol) of methyl 2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzo[b]selenophen-3-carboxylic acid was dissolved in 0.6 mL of a mixture of ethanol and water (ethanol:water = 5:1). Sodium hydroxide (6.31 mg, 0.16 mmol) was added, and the mixture was stirred at 90 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, 15 mL of water was added, and the pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8 h (19 mg) of 2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzo[b]selenophen-3-carboxylic acid, which was directly used in the next reaction without purification. MS m / z (ESI): 367.9 [M+1]

[0392] Step 8

[0393] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzo[b]selenophen-3-carboxamide

[0394] 2-Methyl-5-((2-methylthiazol-5-yl)methoxy)benzo[b]selenophen-3-carboxylic acid 8h (19 mg, 0.05 mmol), (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (14.6 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (29.6 mg, 0.08 mmol), 1-hydroxy-7-azabenzotriazole (1... 0.6 mg (0.08 mmol), N,N-diisopropylethylamine (26.8 mg, 0.21 mmol), stirred at 20 °C for 12 hours, the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered, and the filtrate was preparatively separated by a C18 reversed-phase column (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzo[b]selenophene-3-carboxamide 8 (7.73 mg), yield: 33.60%.

[0395] MS m / z(ESI): 454.0 [M+1]

[0396] 1H NMR (500MHz, DMSO-d6) δ8.14(d,J=8.0Hz,1H),7.83(d,J=9.0Hz,1H),7.71(s,1H),7.58(d,J=2.5Hz,1H),7.42(s,1H),7.16(s,1H), 6.95(dd,J=9.0,2.5Hz,1H),5.31(s,2H),4.46-4.58(m,1H),3.73(d,J=5.0Hz,1H),3.69(d,J=7.0Hz,1H),2.65(s,3H),2.63(s,3H).

[0397] Example 9

[0398] (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indene-1-carboxamide

[0399] first step

[0400] 2-(4-methoxypyridin-2-yl)ethyl acetate

[0401] Diisopropylaminolithium (6.96 g, 64.96 mmol) was added dropwise to a tetrahydrofuran (60 mL) solution of 4-methoxy-2-methylpyridine 9a (4 g, 32.48 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Diethyl carbonate 9b (4.34 g, 36.70 mmol) was then added, and the mixture was stirred at room temperature for 15.5 h. The reaction was monitored by LCMS. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (60 mL), extracted with ethyl acetate (60 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 2-(4-methoxypyridine-2-yl)ethyl acetate 9c (5.5 g), yield: 86.74%.

[0402] 1 H NMR (400MHz, CDCl3) δ8.36(d,J=5.6Hz,1H),6.81(s,1H),6.72-6.69(m,1H),4.20-4.09(m,2H),3.83(s,2H),3.77(s,3H),1.27-1.23(m,3H).

[0403] Step 2

[0404] 7-Methoxy-2-methyl-indene-1-carboxylic acid ethyl ester

[0405] 9c (5.5 g, 28.17 mmol) of 2-(4-methoxypyridin-2-yl)ethyl acetate, 9d (6.81 g, 73.60 mmol) of 1-chloroprop-2-one, and 11.83 g (140.87 mmol) of sodium bicarbonate were dissolved in acetone (80 mL). The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 9e (2 g) of 7-methoxy-2-methyl-indene-1-carboxylate, yield: 30.43%.

[0406] MS m / z(ESI): 233.9 [M+1]

[0407] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=7.2Hz,1H),7.52(d,J=2.4Hz,1H),6.85(s,1H),6 .39-6.36(m,1H),4.37-4.32(m,2H),3.86(s,3H),2.42(s,3H),1.42-1.38(m,3H).

[0408] Step 3

[0409] 7-Hydroxy-2-methyl-indene-1-carboxylic acid ethyl ester

[0410] 7-Methoxy-2-methyl-medium-nitrogen indene-1-carboxylate 9e (2.3 g, 9.86 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium methanethiol (2.07 g, 24.65 mmol) was added. The mixture was stirred at 80 °C for 7 hours. The reaction was monitored by LC-MS. After the reaction was complete, the solution was diluted with water (30 mL), and the pH of the solution was adjusted to 5 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7-hydroxy-2-methyl-medium-nitrogen indene-1-carboxylate 9f (0.7 g), yield: 32.38%. This product was used directly for the next reaction without purification. MS m / z (ESI): 219.9 [M+1]

[0411] 1H NMR(400MHz, CDCl3) δ7.92(d,J=2.4Hz,1H),7.52(d,J=7.2Hz,1H),6.84(s, 1H),6.48-6.45(m,1H),4.37-4.31(m,2H),2.39(s,3H),1.45-1.41(m,3H).

[0412] Step 4

[0413] 2-Methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-indene-1-carboxylic acid ethyl ester

[0414] Ethyl 7-hydroxy-2-methylindene-1-carboxylate 9f (0.35 g, 1.60 mmol), (2-(trifluoromethyl)pyridin-3-yl)methanol 4a (339.32 mg, 1.92 mmol), and (E)-diazepine-1,2-diylbis(piperidin-1-yl ketone) were dissolved in tetrahydrofuran (20 mL), and tributylphosphine (419.89 mg, 2.08 mmol) was added. The mixture was stirred at 60 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 9 g (0.44 g) of ethyl indene-1-carboxylate of 2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy), yield: 72.85%.

[0415] MS m / z(ESI): 378.9 [M+1]

[0416] 1 H NMR (400MHz, CDCl3) δ8.68(s,1H),8.13(d,J=7.6Hz,1H),7.79(d,J=7.6Hz,1H),7.58-7.54(m,2H) ,6.91(s,1H),6.49-6.46(m,1H),5.34(s,2H),4.36-4.30(m,2H),2.44(s,3H),1.39-1.35(s,3H).

[0417] Step 5

[0418] 2-Methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indene-1-carboxylic acid

[0419] 9 g (0.34 g, 898.65 μmol) of ethyl indene-1-carboxylic acid from 2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy) was dissolved in 8 mL of a mixed solution (ethanol:water = 4:1), and sodium hydroxide (539.15 mg, 13.48 mmol) was added. The mixture was stirred at 90 °C for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the solution was diluted with 2 mL of ice water and the pH was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 3), and concentrated under reduced pressure to obtain 9 h (0.3 g) of ethyl indene-1-carboxylic acid from 2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy) in 9 h (yield: 95.30%). This product was used directly in the next reaction without purification.

[0420] MS m / z(ESI): 350.9 [M+1]

[0421] Step 6

[0422] (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indene-1-carboxamide

[0423] 2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy) indin-1-carboxylic acid 9h (0.2 g, 570.95 μmol) and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (120.39 mg, 856.43 μmol) were dissolved in N,N-dimethylacetamide (4 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (238.80 mg, 628.05 μmol), 1-hydroxy-7-azobenzotriazole (85.48 mg, 628.05 μmol) and N,N-diisopropylethylamine (368.96 mg, 2.85 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the reaction solution was separated by C18 reversed-phase column (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-7-((2-(trifluoromethyl)pyridin-3-yl)methoxy) indene-1-carboxamide 9 (0.06 g), yield: 24.08%.

[0424] MS m / z(ESI): 437.1 [M+1]

[0425] 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.28-8.22(m,2H),7.81-7.78(m,1H),7.63(s,1H),7.46(s,1H),7.24(s,1H),7. 16(s,1H),6.86(d,J=7.6Hz,1H),6.53-6.51(m,1H),5.29(s,2H),4.46-4.43(m,1H),3.78-3.66(m,2H),2.43(s,3H).

[0426] Example 10

[0427] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)-2H-isoindole-1-carboxamide

[0428] first step

[0429] 2-((2-bromo-4-methoxybenzyl)(methyl)amino)methyl acetate

[0430] 2-(methylamino)acetic acid methyl ester hydrochloride 10b (4.87 g, 34.88 mmol) was dissolved in dichloromethane (50 mL), and sodium acetate (2.86 g, 34.88 mmol) was added. The mixture was stirred at 25 °C for 30 min. 2-bromo-4-methoxy-benzaldehyde 10a (5 g, 23.25 mmol) and acetic acid (1.40 g, 23.25 mmol) were added, and the mixture was stirred at 25 °C for another 30 min. Finally, sodium borohydride acetate (9.86 g, 46.50 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 2-((2-bromo-4-methoxybenzyl)(methyl)amino)acetic acid methyl ester 10c (5.8 g), yield: 82.55%.

[0431] MS m / z(ESI): 302.0 [M+1]

[0432] Step 2

[0433] methyl 6-methoxy-2-methyl-2H-isoindole-1-carboxylate

[0434] 10c (4 g, 13.24 mmol) of methyl 2-((2-bromo-4-methoxybenzyl)(methyl)amino)acetate was dissolved in dioxane (5 mL), and phenol (373.75 mg, 3.97 mmol), methanesulfonic acid [2,2-bis(diphenylphosphine)-1,1-binaphthyl](2-amino-1,1-biphenyl-2-yl)palladium(II) (657.53 mg, 661.89 μmol), and potassium phosphate (8.43 g, 39.71 mmol) were added. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 10d (200 mg) of methyl 6-methoxy-2-methyl-isoindole-1-carboxylate, yield: 6.89%. MS m / z(ESI): 220.1 [M+1].

[0435] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=9.1Hz,1H),7.39(d,J=2.1Hz,1H),6.94(t,J=7 .2Hz,1H),6.79(dd,J=2.3,8.9Hz,1H),4.21(s,3H),3.97(s,3H),3.91(s,3H).

[0436] Step 3

[0437] methyl 6-hydroxy-2-methyl-2H-isoindole-1-carboxylate

[0438] 10d of methyl 6-methoxy-2-methyl-isoindole-1-carboxylate (150 mg, 684.19 μmol) was dissolved in 1.5 mL of dichloromethane. Boron tribromide (514.22 mg, 2.05 mmol) was added at -78 °C. The mixture was stirred at 0 °C for 3 hours under nitrogen protection. The reaction was monitored by LC-MS. The reaction was quenched with 10 mL of ice water, extracted with 30 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 10e of methyl 6-hydroxy-2-methyl-isoindole-1-carboxylate (120 mg), yield: 85.47%. The methyl 6-hydroxy-2-methyl-isoindole-1-carboxylate was directly used in the next step of the reaction without purification.

[0439] MS m / z(ESI): 206.1 [M+1]

[0440] Step 4

[0441] 2-Methyl-6-((2-methylthiazolyl-5-yl)methoxy)-2H-isoindole-1-carboxylic acid methyl ester

[0442] 50 mg (243.65 μmol) of methyl 6-hydroxy-2-methyl-isoindole-1-carboxylate 10e was dissolved in dimethyl sulfoxide (1 mL), and 5-(chloromethyl)-2-methylthiazolium 1b (53.95 mg, 365.48 μmol) and cesium carbonate (238.16 mg, 730.96 μmol) were added. The mixture was stirred at 40 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 2-methyl-6-((2-methylthiazol-5-yl)methoxy)-2H-isoindole-1-carboxylate 10f (25 mg), yield: 32.43%.

[0443] MS m / z(ESI): 317.0 [M+1].

[0444] Step 5

[0445] 2-Methyl-6-((2-methylthiazolyl-5-yl)methoxy)-2H-isoindole-1-carboxylic acid

[0446] 10 f (20 mg, 63.22 μmol) of methyl 2-methyl-6-((2-methylthiazol-5-yl)methoxy)-2H-isoindole-1-carboxylic acid was dissolved in 1.2 mL of a mixed solution (ethanol:water = 5:1), and sodium hydroxide (25.28 mg, 632.16 μmol) was added. The mixture was stirred at 90 °C for 0.5 h. The reaction was monitored by LC-MS. After the reaction was completed, water (10 mL) was added, and the pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 10 g (10 mg) of 2-methyl-6-((2-methylthiazol-5-yl)methoxy)-2H-isoindole-1-carboxylic acid, yield: 52.32%. This product was used directly in the next reaction without purification.

[0447] MS m / z(ESI): 302.8 [M+1]

[0448] Step 6

[0449] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)-2H-isoindole-1-carboxamide

[0450] 10 g (10 mg, 33.07 μmol) of 2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-2H-isoindole-1-carboxylic acid was dissolved in N,N-dimethylformamide (0.5 mL), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (4.65 mg, 33.07 μmol), N,N-diisopropylethylamine (4.27 mg, 33.07 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (12.58 mg, 33.07 μmol) were added. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-2H-isoindole-1-carboxamide 10 (1.59 mg), yield: 12.38%.

[0451] MS m / z(ESI): 389.1 [M+1]

[0452] 1 H NMR (400MHz, CDCl3) δ7.70(s,1H),7.52(d,J=8.9Hz,1H),7.24(s,1H),7.21(d,J=1.3Hz,1H),7.06(d,J=6.2Hz,1H),6.90(d,J=1.1Hz,1H),6.79(d d,J=2.1,9.0Hz,1H),5.53(s,1H),5.31(s,2H),4.70(d,J=2.7Hz,1H),4. 35(dd,J=2.9,11.5Hz,1H),4.22(s,3H),3.86-3.79(m,1H),2.70(s,3H).

[0453] Example 11

[0454] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-7-((2-methylthiazolyl-5-yl)methoxy)indene-1-carboxamide

[0455] first step

[0456] 2-Methyl-7-((2-methylthiazolyl-5-yl)methoxy)-indene-1-carboxylic acid ethyl ester

[0457] Under nitrogen protection, ethyl 7-hydroxy-2-methylindene-1-carboxylate 9f (0.3 g, 1.37 mmol), (2-methylthiazol-5-yl)methanol 1a (229.8 mg, 1.78 mmol), and (E)-diazepine-1,2-diylbis(piperidin-1-yl methyl ketone) (448.84 mg, 1.78 mmol) were dissolved in tetrahydrofuran (9 mL), and tributylphosphine (359.91 mg, 1.78 mmol) was added. The mixture was stirred at 60°C for 16 hours (78 mmol), and the reaction was monitored by LCMS. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give ethyl indene-1-carboxylate 11a (0.1 g), yield: 22.12%.

[0458] MS m / z(ESI): 330.9 [M+1]

[0459] Step 2

[0460] 2-Methyl-7-((2-methylthiazolyl-5-yl)methoxy)indene-1-carboxylic acid

[0461] Ethyl indene-1-carboxylic acid 11a of 2-methyl-7-((2-methylthiazol-5-yl)methoxy) was dissolved in 2.0 mL of a mixed solution (ethanol:water = 3:1), and sodium hydroxide (181.58 mg, 5.45 mmol) was added. The mixture was stirred at 90 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, 5 mL of water was added, and the pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11b of indene-1-carboxylic acid of 2-methyl-7-((2-methylthiazol-5-yl)methoxy) (yield: 98.35%). This unpurified solution was directly used in the next step of the reaction.

[0462] MS m / z(ESI): 302.9 [M+1]

[0463] Step 3

[0464] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-7-((2-methylthiazolyl-5-yl)methoxy)indene-1-carboxamide

[0465] 11b of 2-methyl-7-((2-methylthiazol-5-yl)methoxy) indene-1-carboxylic acid (0.09 g, 297.67 μmol) and (S)-2-amino-3-hydroxypropionamide hydrochloride (50.21 mg, 357.20 μmol) were dissolved in N,N-dimethylacetamide (2 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (124.50 mg, 327.44 μmol), 1-hydroxy-7-azobenzotriazole (44.57 mg, 327.44 μmol), and N,N-diisopropylethylamine (153.89 mg, 1.19 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then separated by C18 reversed-phase column chromatography (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-7-((2-methylthiazolyl-5-yl)methoxy) indene-1-carboxamide 11 (7.4 mg), yield: 6.4%.

[0466] MS m / z(ESI): 389.1 [M+1]

[0467] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=7.6Hz,1H),7.74(s,1H),7.63(d,J=2.8Hz,1H),7.46(s,1H),7.21-7.16(m,2H),6.86(m,J=2 .8Hz,1H),6.47-6.44(m,1H),5.31(s,2H),5.03-5.00(m,1H),4.46-4.43(m,1H),3.78-3.66(m,2H),2.64(s,3H),2.43(s,3H).

[0468] Example 12

[0469] (R)-N-(3-hydroxy-1-(hydroxyamino)-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0470] first step

[0471] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0472] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 12a (100 mg, 256.79 μmol, prepared according to patent WO2022112352) was dissolved in dichloromethane (2 mL), and imidazole (34.96 mg, 513.58 μmol) and tert-butyldiphenylchlorosilane (105.87 mg, 385.18 μmol) were added. The mixture was stirred at 20 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL), and the organic phase was separated. The organic phase was washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 12b (60 mg), yield: 37.22%. It was carried out directly in the next step of the reaction without purification.

[0473] MS m / z(ESI): 628.1 [M+1]

[0474] Step 2: (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0475] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 12b (60 mg, 95.57 μmol) was dissolved in tetrahydrofuran (1 mL), and 2,2,2-trifluoroacetic anhydride (50.18 mg, 238.92 μmol) and triethylamine (38.68 mg, 382.27 μmol) were added. The mixture was stirred at 20 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL), and the organic phase was separated. The organic phase was washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 12c (20 mg), yield: 34.32%. It was directly used in the next reaction without purification.

[0476] MS m / z(ESI): 610.1 [M+1]

[0477] Step 3

[0478] (R)-N-(3-((tert-butyldiphenylsilyl)oxy)-1-(hydroxyamino)-1-iminopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-carboxamide

[0479] (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamide 12c (20 mg, 32.80 μmol) was dissolved in ethanol (2 mL), and hydroxylamine hydrochloride (4.56 mg, 65.59 μmol) and potassium carbonate (13.60 mg, 98.39 μmol) were added. The mixture was stirred at 90 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give (R)-N-(3-((tert-butyldiphenylsilyl)oxy)-1-(hydroxyamino)-1-iminopropane-2-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamide 12d (10 mg), yield: 47.43%. This product was used directly in the next reaction without purification.

[0480] MS m / z(ESI): 643.1 [M+1]

[0481] Step 4: (R)-N-(3-hydroxy-1-(hydroxyamino)-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0482] (R)-N-(3-((tert-butyldiphenylsilyl)oxy)-1-(hydroxyamino)-1-iminopropan-2-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamide 12d (10 mg, 15.56 μmol) was dissolved in tetrahydrofuran (0.8 mL), and tetrabutylammonium fluoride (12.2 mg, 46.67 μmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction was monitored by LCMS, and the mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (eluent: system B) to give (R)-N-(3-hydroxy-1-(hydroxyamino)-1-iminopropan-2-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamide 12 (3.1 mg), yield: 47.68%.

[0483] MS m / z (ESI): 405.1 [M+1]

[0484] 1H NMR(500MHz,CD3OD)δ7.67(s,1H),7.45-7.40(m,2H),7.02(d,J=9.0Hz,1H), 5.34(s,2H),4.82(s,1H),4.09-4.03(m,1H),4.01-3.97(m,1H),2.71(s,6H).

[0485] Example 13

[0486] (R)-N-(1-amino-3-hydroxy-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0487] first step

[0488] (R)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-iminopropan-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0489] Ammonium chloride (52.63 mg, 983.92 μmol) was added to a toluene solution of triethylaluminum (112.33 mg, 983.92 μmol) (3 mL). The mixture was stirred at 0–25 °C for 3 hours. Then, a toluene solution of (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 12c (100 mg, 163.99 μmol) (5 mL) was slowly added. The mixture was stirred at 90 °C for 5 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give (R)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 13a (60 mg), yield: 58.37%. This unpurified product was directly used in the next reaction. MS m / z (ESI): 627.3 [M+1]

[0490] Step 2

[0491] (R)-N-(1-amino-3-hydroxy-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide

[0492] (R)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamide 13a (40 mg, 63.81 μmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride (10.46 mg, 40.00 μmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, and the residue was purified by preparative separation on a C18 reversed-phase column (eluent: system B) to give (R)-N-(1-amino-3-hydroxy-1-iminopropyl-2-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamide 13 (2.53 mg), yield: 10.21%.

[0493] MS m / z(ESI): 389.1 [M+1]

[0494] 1 H NMR(400MHz,CD3OD)δ7.66(s,1H),7.41-7.46(m,2H),7.00-7.03(m,1H),5.34(s,2 H),4.81-4.85(m,1H),4.07-4.08(m,1H),4.02-4.03(m,1H),2.71(d,J=4.4Hz,6H).

[0495] Example 14

[0496] (R)-N-(3-hydroxy-1-imino-1-(methoxyamino)propane-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-carboxamide

[0497] first step

[0498] (R)-N-(4-imino-9,9-dimethyl-8,8-diphenyl-2,7-dioxa-3-aza-8-sildecane-5-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-carboxamide

[0499] (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 12c (180 mg, 295.17 μmol) was dissolved in ethanol (3 mL), and potassium carbonate (122.39 mg, 885.52 μmol) and O-methylhydroxylamine hydrochloride (36.98 mg, 442.76 μmol) were added. The mixture was stirred at 90 °C for 1.5 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (R)-N-(4-imino-9,9-dimethyl-8,8-diphenyl-2,7-dioxa-3-aza-8-sildecane-5-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 14a (30 mg), yield: 15.47%.

[0500] MS m / z (ESI): 657.3 [M+1]

[0501] Step 2

[0502] (R)-N-(3-hydroxy-1-imino-1-(methoxyamino)propane-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-carboxamide

[0503] (R)-N-(4-imino-9,9-dimethyl-8,8-diphenyl-2,7-dioxa-3-aza-8-silyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 14a (30 mg, 45.67 μmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride (35.82 mg, 137.01 μmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (eluent: system B) to give (R)-N-(3-hydroxy-1-imino-1-(methoxyamino)propane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide 14 (3.9 mg), yield: 15.70%.

[0504] MS m / (ESI): 419.1 [M+1]

[0505] 1H NMR(400MHz,CD3OD)δ7.68(s,1H),7.38-7.43(m,2H),6.96-7.02(m,1H),5.34 (s,2H),4.74-4.76(m,1H),4.03-4.07(m,2H),3.87(s,3H),2.70-2.71(d,6H).

[0506] Example 15

[0507] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxamide

[0508] first step

[0509] 2-Chloro-5-(prop-1-yn-1-yl)pyridin-4-yl)tert-butyl carbamate

[0510] 2-Chloro-5-iodopyridin-4-yl)tert-butyl carbamate 15a (5.0 g, 14.10 mmol) was dissolved in tetrahydrofuran (50 mL), and triethylamine (4.3 g, 42.30 mmol), cuprous iodide (268 mg, 1.41 mmol), and palladium dichloride bis(triphenylphosphine) (989 mg, 1.41 mmol) were added. The mixture was stirred at 25 °C for 5 minutes under nitrogen protection, and then propyne (1.1 g, 28.20 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give 2-chloro-5-(propyne-1-yl)pyridin-4-yl)tert-butyl carbamate 15b (3.1 g), yield: 82.42%.

[0511] MS m / z(ESI): 267.1 [M+1]

[0512] Step 2

[0513] 6-Chloro-2-methyl-1H-pyrrolo[3,2-c]pyridine

[0514] 2-Chloro-5-(prop-1-yn-1-yl)pyridin-4-yl)tert-butyl carbamate 15b (3.4 g, 12.750 mmol) and tetrabutylammonium fluoride (7.1 g, 25.490 mmol) were dissolved in tetrahydrofuran (30 mL) solution and stirred at 70 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: C system) to give 6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridine 15c (1.8 g), yield: 84.75%.

[0515] MS m / z(ESI): 167.1 [M+1]

[0516] Step 3

[0517] 6-Chloro-2-methyl-1-p-toluenesulfonyl-1H-pyrrole

[0518] 6-Chloro-2-methyl-1H-pyrrolo[3,2-c]pyridine 15c (500 mg, 3.00 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydrogen (180 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, p-toluenesulfonyl chloride (687 mg, 3.60 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give 6-chloro-2-methyl-1-p-toluenesulfonyl-1H-pyrrole 15d (900 mg), yield: 93.48%.

[0519] MS m / z(ESI): 321.1 [M+1]

[0520] Step 4

[0521] 2-Methyl-5-(((2-methyl-1-p-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)oxy)methyl)thiazole

[0522] 6-Chloro-2-methyl-1-p-toluenesulfonyl-1H-pyrrole 15d (843 mg, 2.63 mmol) and 2-methylthiazolyl-5-yl)methanol 1a (340 mg, 2.63 mmol) were dissolved in tetrahydrofuran (4 mL), and 2-(di-tert-butylphosphine)-3,6-dimethoxy-2',4',6'triisopropylbiphenyl (127 mg, 0.263 mmol) and cesium carbonate (2.5 g, 7.89 mmol) were added. The mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give 2-methyl-5-(((2-methyl-1-p-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)oxy)methyl)thiazole 15e (900 mg), yield: 82.82%.

[0523] MS m / z(ESI): 414.2 [M+1]

[0524] Step 5

[0525] 2-Methyl-5-(((2-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)oxy)methyl)thiazole

[0526] 2-Methyl-5-(((2-methyl-1-p-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)oxy)methyl)thiazole 15e (500 mg, 1.210 mmol) was dissolved in water (5 mL), and sodium hydroxide (1.5 g, 36.270 mmol) was added. The mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: C system) to give 2-methyl-5-(((2-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)oxy)methyl)thiazole 15f (45 mg), yield: 14.35%.

[0527] MS m / z(ESI): 260.1 [M+1]

[0528] Step 6

[0529] 2-Methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid-4-nitrophenyl ester

[0530] 15f of 2-methyl-5-(((2-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)oxy)methyl)thiazole (125 mg, 0.482 mmol) and 15g of di(p-nitrophenyl) carbonate (190 mg, 0.626 mmol) were dissolved in acetonitrile (5 mL), and sodium carbonate (26 mg, 0.241 mmol) was added. The mixture was stirred at 110 °C for 12 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give 2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid-4-nitrophenyl ester 15h (100 mg), yield: 48.88%.

[0531] MS m / z(ESI): 425.35 [M+1]

[0532] Step 7

[0533] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxamide

[0534] The following substances were added: 2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid-4-nitrophenyl ester 15h (120 mg, 0.282 mmol), (S)-2-amino-3-((tert-butyldiphenylsilyl)oxy)propionamide 15i (193 mg, 0.565 mmol), N-methylimidazolium (69 mg, 0.848 mmol), and N,N-diisopropylethylamine (109 mg, 0.848 mmol). The solution was dissolved in tetrahydrofuran (5 mL) and stirred at 60 °C for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxamide 15j (90 mg), yield: 50.70%.

[0535] MS m / z(ESI): 628.5 [M+1]

[0536] Step 8

[0537] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxamide

[0538] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxamide 15j (100 mg, 0.159 mmol) was dissolved in tetrahydrofuran (5 mL), and a pyridine hydrogen fluoride solution (1 mL) was added. The mixture was stirred at 25 °C for 4 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added, and the solution was then dissolved in ethyl acetate. Extracted with ethyl acetate (50 mL × 3), the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was then preparatively separated by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-carboxamide 15 (6.8 mg), yield: 10.96%.

[0539] MS m / z(ESI): 390.2 [M+1]

[0540] 1 H NMR(400MHz, DMSO-d6)δ8.37(s,1H),8.24(d,J=8.0Hz,1H),7.70(s,1H),7.54(s,1H),7.20(s,1H),7.18(s,1H), 6.42(s,1H),5.54(s,2H),5.05(t,J=5.6Hz,1H),4.42-4.31(m,1H),3.84-3.64(m,2H),2.60(s,3H),2.46(s,3H).

[0541] Example 16

[0542] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2-methylthiazo-5-yl)ethyl)benzofuran-3-carboxamide

[0543] first step

[0544] 2-Methyl-5-vinylthiazole

[0545] 5-Bromo-2-methylthiazole 16a (2 g, 11.23 mmol) was dissolved in 1,4-dioxane (20 mL) and water (3 mL), and potassium carbonate (4.66 g, 33.70 mmol), potassium vinyltrifluoroborate (2.26 g, 16.85 mmol), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (732.09 mg, 1.12 mmol) were added. The mixture was stirred at 90 °C for 12 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and water (30 mL) was added. The mixture was extracted with ethyl acetate (25 mL × 3), washed with saturated sodium chloride aqueous solution (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 2-methyl-5-vinylthiazole 16b (1.2 g), yield: 85.33%.

[0546] MS m / z(ESI): 126.0 [M+1]

[0547] Step 2

[0548] Ethyl (E)-2-methyl-5-(2-(2-methylthiazo-5-yl)vinyl)benzofuran-3-carboxylate

[0549] Ethyl 5-bromo-2-methylbenzofuran-3-carboxylate 16c (50 mg, 176.61 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), and palladium acetate (3.96 mg, 17.66 μmol), 2-methyl-5-vinylthiazole 16b (33.16 mg, 264.91 μmol), triethylamine (53.61 mg, 529.82 μmol), and tris(m-tolyl)phosphine (10.75 mg, 35.32 μmol) were added. The mixture was stirred at 110 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 16d (15 mg) of ethyl (E)-2-methyl-5-(2-(2-methylthiazolyl-5-yl)vinyl)benzofuran-3-carboxylate, yield: 25.94%.

[0550] MS m / z(ESI): 328.4 [M+1]

[0551] Step 3

[0552] (E)-2-methyl-5-(2-(2-methylthiazo-5-yl)vinyl)benzofuran-3-carboxylic acid

[0553] Ethyl (E)-2-methyl-5-(2-(2-methylthiazol-5-yl)vinyl)benzofuran-3-carboxylic acid 16e (15 mg, 45.82 μmol) was dissolved in a mixture of methanol (1 mL) and water (0.3 mL), and lithium hydroxide (3.29 mg, 137.45 μmol) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, water (5 mL) was added, and the pH of the solution was adjusted to 4 with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (10 mL × 2), filtered, and concentrated under reduced pressure to obtain (E)-2-methyl-5-(2-(2-methylthiazol-5-yl)vinyl)benzofuran-3-carboxylic acid 16e (10 mg), yield: 72.91%. This product was used directly in the next reaction without purification.

[0554] MS m / z(ESI): 299.9 [M+1]

[0555] Step 4

[0556] (S,E)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2-methylthiazo-5-yl)vinyl)benzofuran-3-carboxamide

[0557] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (7.04 mg, 50.11 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), and (E)-2-methyl-5-(2-(2-methylthiazol-5-yl)vinyl)benzofuran-3-carboxylic acid 16e (10 mg, 33.41 μmol), N,N-diisopropylethylamine (12.95 mg, 100.22 μmol), 1-hydroxy-7-azobenzotriazole (4.55 mg, 33.41 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (19.05 mg, 50.11 μmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then separated by C18 reversed-phase column chromatography (eluent: system B) to give (S,E)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(2-(2-methylthiazolyl-5-yl)vinyl)benzofuran-3-carboxamide 16f (1.71 mg), yield: 13.28%.

[0558] MS m / z(ESI): 385.9 [M+1]

[0559] 1H NMR(500MHz,CD3OD)δ7.98(s,1H),7.62(s,1H),7.53-7.50(m,1H),7.48-7.44(m,1H),7.35(d,J =16.2Hz,1H),7.02(d,J=16.2Hz,1H),4.74-4.70(m,1H),4.00-3.94(m,2H),2.70-2.69(m,6H).

[0560] Step 5

[0561] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2-methylthiazo-5-yl)ethyl)benzofuran-3-carboxamide

[0562] (S,E)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(2-(2-methylthiazol-5-yl)vinyl)benzofuran-3-carboxamide 16f (30 mg, 77.83 μmol) was dissolved in methanol (1 mL), and palladium on carbon (216.04 mg, 233.50 μmol) was added. The mixture was stirred at 25 °C for 3 hours under a hydrogen atmosphere (15 psi). After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(2-(2-methylthiazol-5-yl)ethyl)benzofuran-3-carboxamide 16 (11 mg), yield: 36.48%.

[0563] MS m / z(ESI): 388.0 [M+1].

[0564] 1 H NMR (400MHz, CD3OD) δ7.65(d,J=1.2Hz,1H),7.50(s,1H),7.40(d,J=8.5Hz,1H),7.17(dd,J=1.7,8.5Hz,1H),4.6 8(t,J=4.8Hz,1H),3.95(dd,J=3.9,4.5Hz,2H),3.28-3.22(m,2H),3.13-3.07(m,2H),2.72(s,3H),2.69(s,3H).

[0565] Example 17

[0566] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(1-(2-methylthiazo-5-yl)cyclobutoxy)benzofuran-3-carboxamide

[0567] first step

[0568] 1-(2-methylthiazolyl-5-yl)cyclobutanol

[0569] 5-Bromo-2-methylthiazolium 16a (0.5 g, 2.81 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (269.82 mg, 4.21 mmol) was added at -78 °C. After stirring for 30 minutes, cyclobutanone 17a (393.65 mg, 5.62 mmol) was added dropwise, and the mixture was stirred at -78 °C to 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, saturated ammonium chloride (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 1-(2-methylthiazol-5-yl)cyclobutanol 17b (0.32 g), yield: 67.33%.

[0570] 1 H NMR (400MHz, CDCl3) δ7.51(s,1H),2.68(s,3H),2.49-2.42(m,4H),2.00-1.80(m,1H),1.76-1.71(m,2H).

[0571] Step 2

[0572] 2-Methyl-5-(1-(2-methylthiazolyl-5-yl)cyclobutoxy)benzofuran-3-carboxylic acid ethyl ester

[0573] Under nitrogen protection, ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (260.24 mg, 1.18 mmol) and 1-(2-methylthiazol-5-yl)cyclobutanol 17b (200 mg, 1.18 mmol) were dissolved in toluene (8 mL), and tributyl cyanomethylene phosphate (63.93 mg, 1.60 mmol) was added. The mixture was stirred at 110 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give ethyl 2-methyl-5-(1-(2-methylthiazol-5-yl)cyclobutoxy)benzofuran-3-carboxylate 17c (0.11 g), yield: 25.06%.

[0574] MS m / z(ESI): 372.0 [M+1]

[0575] Step 3

[0576] 2-Methyl-5-(1-(2-methylthiazo-5-yl)cyclobutoxy)benzofuran-3-carboxylic acid

[0577] Ethyl 2-methyl-5-(1-(2-methylthiazol-5-yl)cyclobutoxy)benzofuran-3-carboxylic acid 17c (110 mg, 296.14 μmol) was dissolved in a mixture of water (0.5 mL) and ethanol (2.0 mL), and sodium hydroxide (59.22 mg, 1.48 mmol) was added. The mixture was stirred at 90 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the pH of the solution was adjusted to 4 with 1 M hydrochloric acid, and the solution was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-methyl-5-(1-(2-methylthiazol-5-yl)cyclobutoxy)benzofuran-3-carboxylic acid 17d (80 mg), yield: 78.67%. This product was used directly in the next reaction without purification.

[0578] MS m / z(ESI): 344.0 [M+1]

[0579] Step 4

[0580] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(1-(2-methylthiazo-5-yl)cyclobutoxy)benzofuran-3-carboxamide

[0581] 2-Methyl-5-(1-(2-methylthiazol-5-yl)cyclobutoxy)benzofuran-3-carboxylic acid 17d (80 mg, 232.97 μmol) and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (36.02 mg, 256.26 μmol) were dissolved in N,N-dimethylformamide (1.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (97.44 mg, 256.26 μmol), 1-hydroxy-7-azobenzotriazole (31.71 mg, 232.97 μmol) and N,N-diisopropylethylamine (120.44 mg, 931.87 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(1-(2-methylthiazolyl-5-yl)cyclobutoxy)benzofuran-3-carboxamide 17 (26 mg), yield: 25.99%.

[0582] MS m / z(ESI): 430.0 [M+1]

[0583] 1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.53(s,1H),7.39-7.37(m,2H),7.26(s,1H),7.13-7.12(m,1H),6.74-6.71(m,1H), 4.48-4.45(m,1H),3.78-3.69(m,2H),2.72-2.67(m,4H),2.59(s,3H),2.54(s,3H),1.92-1.81(m,1H),1.78-1.76(m,1H).

[0584] Example 18

[0585] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2-methylthiazo-5-yl)ethyl)benzofuran-3-carboxamide

[0586] first step

[0587] ethyl 2-methyl-5-(2-(2-methylthiazo-5-yl)cyclopropyl)benzofuran-3-carboxylate

[0588] Ethyl (E)-2-methyl-5-(2-(2-methylthiazo-5-yl)vinyl)benzofuran-3-carboxylate 16d (60 mg, 183.26 μmol) and 8-(iodomethyl)-8,8'-spirobis[7,9-dioxa-8-silylbicyclo[4.3.0]non-1(6),2,4-triene]triethylammonium (133.98 mg, 274.90 μmol) were dissolved in dimethyl sulfoxide (6.0 mL), and 2,4,5,6-tetra(carbazole-9-yl)phenyl-1,3-dionitrile (28.92 mg, 36.65 μmol) were added. The mixture was purged with nitrogen three times under vacuum and reacted at 25 °C in a photocatalytic reactor for 12 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was poured into water (30 mL) and extracted with ethyl acetate (15 mL × 3). The organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: system A) to give ethyl 2-methyl-5-(2-(2-methylthiazolyl-5-yl)cyclopropyl)benzofuran-3-carboxylate 18a (9 mg), yield: 14.25%.

[0589] MS m / z(ESI): 342.1 [M+1]

[0590] Step 2

[0591] 2-Methyl-5-(2-(2-methylthiazo-5-yl)cyclopropyl)benzofuran-3-carboxylic acid

[0592] Ethyl 2-methyl-5-[2-(2-methylthiazol-5-yl)cyclopropyl]benzofuran-3-carboxylic acid 18a (62 mg, 181.59 μmol) was dissolved in a mixed solution of ethanol (0.6 mL), tetrahydrofuran (0.6 mL), and water (0.3 mL). Sodium hydroxide (36.32 mg, 907.96 μmol) was added, and the mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the solution was diluted with water (3.0 mL), and the pH of the solution was adjusted to 5 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (5.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-methyl-5-(2-(2-methylthiazol-5-yl)cyclopropyl)benzofuran-3-carboxylic acid 18b (30 mg), yield: 52.72%. This product was used directly in the next step of the reaction without purification.

[0593] MS m / z(ESI): 313.9 [M+1]

[0594] Step 3

[0595] N-((S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(2-(2-methylthiazo-5-yl)cyclopropyl)benzofuran-3-carboxamide

[0596] 2-Methyl-5-[2-(2-methylthiazol-5-yl)cyclopropyl]benzofuran-3-carboxylic acid 18b (30 mg, 95.73 μmol), N,N-diisopropylethylamine (61.86 mg, 478.67 μmol), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (20.19 mg, 143.60 μmol) were dissolved in N,N-dimethylformamide (1.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (54.60 mg, 143.60 μmol) and 1-hydroxy-7-azobenzotriazole (13.03 mg, 95.73 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and separated by C18 reversed-phase column (eluent: system B) to obtain N-((S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(2-(2-methylthiazolyl-5-yl)cyclopropyl)benzofuran-3-carboxamide 18 (2.06 mg), yield: 5.39%.

[0597] MS m / z(ESI): 400.5 [M+1].

[0598] 1H NMR (400MHz, CD3OD) δ7.5-7.7(m,2H),7.40(d,J=8.6Hz,1H),7.16(dd,J=1.7,8.5Hz,1H),4.69(t,J=4.8Hz,1H ),3.9-4.0(m,2H),2.70(s,3H),2.7-2.7(m,3H),2.4-2.5(m,2H),1.6-1.7(m,1H),1.48(td,J=5.5,9.0Hz,1H).

[0599] Example 19

[0600] (S)-3-hydroxy-2-(((2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-yl)methyl)amino)propionamide

[0601] first step

[0602] (2-Methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-yl)methanol

[0603] Under ice-water bath conditions, 2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid 19a (50 mg, 164.84 μmol, prepared according to patent WO2022112352) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (12.51 mg, 329.67 μmol) was added. The mixture was stirred at 25 °C for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate (1.0 g), the solid was filtered, and the filtrate was evaporated to dryness to obtain (2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-yl)methanol 19b (47 mg), yield: 98.54%. It was used directly for the next reaction without purification.

[0604] MS m / z(ESI): 290.0 [M+1]

[0605] Step 2

[0606] 2-Methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-carboxaldehyde

[0607] (2-Methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-yl)methanol 19b (47 mg, 162.43 μmol) was dissolved in tetrahydrofuran (2 mL), and manganese dioxide (282.43 mg, 3.25 mmol) was added. The mixture was stirred at 50 °C for 16 hours. The reaction was monitored by LCMS until completion. After the reaction was completed, the solid was filtered and concentrated under reduced pressure to obtain 2-methyl-5-((2-methylthiazol-5-yl)methoxy)benzofuran-3-carboxaldehyde 19c (6 mg), yield: 98.56%. This product was used directly for the next reaction without purification.

[0608] MS m / z(ESI): 288.0 [M+1]

[0609] Step 3

[0610] (S)-3-hydroxy-2-(((2-methyl-5-((2-methylthiazo-5-yl)methoxy)benzofuran-3-yl)methyl)amino)propionamide

[0611] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxaldehyde 19c (46 mg, 160.09 μmol) and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (33.76 mg, 240.14 μmol) were dissolved in a mixed solution of 1,2-dichloroethane (1.5 mL) and methanol (0.2 mL). Acetic acid (96.14 mg, 1.60 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. Then, sodium triacetoxyborohydride (339.30 mg, 1.60 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS until completion. After the reaction was completed, the mixture was quenched with water (2 mL) and extracted with dichloromethane (2 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was obtained by C 18 Preparative separation by reversed-phase column chromatography (eluent: system B) yielded (S)-3-hydroxy-2-(((2-methyl-5-((2-methylthiazolyl-5-yl)methoxy)benzofuran-3-yl)methyl)amino)propionamide 19 (2 mg), yield: 3.33%. MS m / z (ESI): 376.0 [M+1].

[0612] 1 H NMR(400MHz,CD3OD)δ7.68(s,1H),7.43-7.42(m,1H),7.37-7.35(m,1H),6.97-6.94( m,1H),5.33(s,2H),4.43-4.31(m,2H),4.01-3.92(m,3H),2.69(s,3H),2.51(s,3H).

[0613] Example 20

[0614] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(difluoro(2-methylthiazo-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide

[0615] first step

[0616] 5-(bromodifluoromethyl)-2-methylthiazole

[0617] At -78 °C, 1.0 g (5.62 mmol) of 5-bromo-2-methylthiazole 16a was dissolved in 20 mL of tetrahydrofuran solution, and 719.52 mg (12.23 mmol) of n-butyllithium was added. After stirring for 30 minutes under nitrogen protection at -78 °C, 3.54 g (16.85 mmol) of dibromodifluoromethane 20a was added dropwise to the reaction solution. The mixture was stirred at -78 °C to 25 °C for two hours. The reaction was monitored by LCMS until completion. After the reaction was completed, the mixture was quenched with 5 mL of water and extracted with ethyl acetate (5 mL × 2). The organic phases were combined and washed with saturated sodium chloride solution (5 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 0.44 g (5-(bromodifluoromethyl)-2-methylthiazole 20b), yield: 34.35%.

[0618] MS m / z(ESI): 227.8 [M+1]

[0619] Step 2

[0620] ethyl 5-(difluoro(2-methylthiazolyl-5-yl)methoxy)-2-methylbenzofuran-3-carboxylate

[0621] Ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (0.32 g, 1.45 mmol) was dissolved in tetrahydrofuran (7 mL) with stirring in an ice-water bath. Sodium hydroxide (63.93 mg, 1.60 mmol) was added, and the mixture was stirred at 0 °C for 30 minutes. Then, 5-(bromodifluoromethyl)-2-methylthiazolium 20b (0.43 g, 1.89 mmol) was added to the reaction solution. The mixture was stirred at room temperature for two hours. The reaction was monitored by LC-MS until completion. The reaction was quenched with water (0.5 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give ethyl 5-(difluoro(2-methylthiazol-5-yl)methoxy)-2-methylbenzofuran-3-carboxylate 20c (0.11 g), yield: 20.61%. MS m / z (ESI): 367.9 [M+1]

[0622] Step 3

[0623] 5-(difluoro(2-methylthiazo-5-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid

[0624] Ethyl 5-(difluoro(2-methylthiazol-5-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid 20c (55 mg, 149.71 μmol) was dissolved in a mixture of water (0.5 mL) and ethanol (1.0 mL), and sodium hydroxide (29.94 mg, 748.57 μmol) was added. The mixture was stirred at 90 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the pH of the solution was adjusted to 4 with 1 M hydrochloric acid, and the solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-(difluoro(2-methylthiazol-5-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid 20d (45 mg), yield: 88.58%. This product was used directly in the next reaction without purification.

[0625] MS m / z(ESI): 340.0 [M+1]

[0626] Step 4

[0627] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(difluoro(2-methylthiazo-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide

[0628] 20d (45 mg, 132.62 μmol) of 5-(difluoro(2-methylthiazol-5-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid and 1f (20.51 mg, 145.88 μmol) of (S)-2-amino-3-hydroxypropionamide hydrochloride were dissolved in 1.5 mL of N,N-dimethylformamide. Then, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (55.47 mg, 145.88 μmol), 1-hydroxy-7-azobenzotriazole (18.05 mg, 132.62 μmol), and N,N-diisopropylethylamine (51.42 mg, 397.86 μmol) were added, and the mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction solution was purified by C1 chromatography. 18 Reversed-phase column chromatography (eluent: system B) yielded (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(difluoro(2-methylthiazolyl-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide 20 (18 mg), yield: 31.90%.

[0629] MS m / z(ESI): 426.0 [M+1]

[0630] 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.76-7.74(m,1H),7.67-7.62(m,2H),7.49(s,1H) ),7.25-7.19(m,2H),4.49-4.44(m,1H),3.74-3.73(m,2H),2.72(s,3H),2.67(s,3H).

[0631] Example 21

[0632] (S)-N-(3-((1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)-2-methylbenzofuran-5-yl)-2-methylthiazolyl-5-carboxamide

[0633] first step

[0634] 5-((diphenylmethylene)amino)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[0635] Diphenylmethyleneimine 21a (140.83 mg, 777.06 μmol) and ethyl 5-bromo-2-methylbenzofuran-3-carboxylate 16c (0.2 g, 706.42 μmol) were dissolved in dioxane (1 mL). [9,9-dimethyl-4,5-bis(diphenylphospho)oxanthracene][2-amino-1,1-diphenyl]palladium(II)methanesulfonate dichloromethyl adduct (66.99 mg, 70.64 μmol) and cesium carbonate (690.50 mg, 2.12 mmol) were added, and the mixture was stirred at 100 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, water (5 mL) was added at 0 °C, and the mixture was extracted with dichloromethane (5 mL × 3). The organic layers were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: system A) to give compound 5-((diphenylmethylene)amino)-2-methylbenzofuran-3-carboxylic acid ethyl ester 21b (0.12 g), yield: 44.30%.

[0636] MS m / z(ESI): 384.2 [M+1]

[0637] Step 2

[0638] ethyl 5-amino-2-methylbenzofuran-3-carboxylate

[0639] Ethyl 5-((diphenylmethylene)amino)-2-methylbenzofuran-3-carboxylate 21b (100 mg, 260.80 μmol) was dissolved in tetrahydrofuran (2 mL), and hydrochloric acid (190.18 mg, 5.22 mmol) was added. The mixture was stirred at 20 °C for 16 hours, and the reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with water (2 mL), extracted with dichloromethane (10 mL × 3), and the aqueous phase was lyophilized to obtain ethyl 5-amino-2-methylbenzofuran-3-carboxylate 21c (40 mg), yield: 69.96%. It was directly used for the next reaction without purification.

[0640] MS m / z(ESI): 220.0 [M+1]

[0641] Step 3

[0642] ethyl 2-methyl-5-(2-methylthiazolyl-5-carbamate)benzofuran-3-carboxylate

[0643] Ethyl 5-amino-2-methylbenzofuran-3-carboxylate 21c (40 mg, 182.45 μmol) and 2-methylthiazolium-5-carboxylic acid 21d (39.18 mg, 273.68 μmol) were dissolved in N,N-dimethylformamide (1 mL), and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (104.06 mg, 273.68 μmol) and N,N-diisopropylethylamine (117.90 mg, 912 μmol) were added. The mixture was stirred at 20°C for 16 hours with 0.26 μmol of ethyl acetate (10 mL × 3) and the reaction was monitored by LC-MS. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give compound 2-methyl-5-(2-methylthiazolyl-5-carboxamido)benzofuran-3-carboxylic acid ethyl ester 21e (40 mg), yield: 63.66%.

[0644] MS m / z(ESI): 345.0 [M+1]

[0645] 1 H NMR (400MHz, CDCl3) δ8.71(d,J=8.6Hz,1H),8.25(s,1H),8.12(s,1H),7.66(dd,J=2.2,9.1Hz, 1H),7.38(d,J=8.8Hz,1H),4.41(d,J=7.2Hz,2H),2.76(d,J=2.3Hz,6H),1.44(t,J=7.1Hz,3H).

[0646] Step 4

[0647] 2-Methyl-5-(2-methylthiazo-5-carbamate)benzofuran-3-carboxylic acid

[0648] Ethyl 2-methyl-5-(2-methylthiazol-5-carboxamido)benzofuran-3-carboxylic acid 21e (30 mg, 87.11 μmol) was dissolved in a mixture of water (0.2 mL) and ethanol (1 mL), and sodium hydroxide (17.42 mg, 435.56 μmol) was added. The mixture was stirred at 90 °C for 2 hours. The reaction was monitored by LC-MS. The pH of the solution was adjusted to 5 with 1 M hydrochloric acid, and the mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3). The extract was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-5-(2-methylthiazol-5-carboxamido)benzofuran-3-carboxylic acid 21f (25 mg), yield: 90.72%. This product was used directly in the next step of the reaction without purification.

[0649] MS m / z(ESI): 316.9 [M+1]

[0650] Step 5

[0651] (S)-N-(3-((1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)-2-methylbenzofuran-5-yl)-2-methylthiazolyl-5-carboxamide

[0652] Dissolve (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (16.66 mg, 118.55 μmol) and 2-methyl-5-(2-methylthiazol-5-carboxamido)benzofuran-3-carboxylic acid 21f (25 mg, 79.03 μmol) in N,N-dimethylformamide (1 mL), then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (45.07 mg, 118.55 μmol) and 1-hydroxy-7-azobenzotriazole (10.76 mg). The mixture was prepared by stirring N,N-diisopropylethylamine (79.03 μmol) at 20 °C for 16 hours, with the reaction monitored by LCMS. The mixture was then filtered, concentrated under reduced pressure, and the residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give (S)-N-(3-((1-amino-3-hydroxy-1-oxopropane-2-yl)carbamoyl)-2-methylbenzofuran-5-yl)-2-methylthiazolyl-5-carboxamide 21 (11.33 mg), yield: 35.62%.

[0653] MS m / z(ESI): 403.0 [M+1]

[0654] 1 H NMR(500MHz,CD3OD)δ8.35(s,1H),8.01(d,J=1.7Hz,1H),7.66-7.57(m,1H),7.48(d ,J=8.9Hz,1H),4.69(t,J=5.0Hz,1H),3.99-3.91(m,2H),2.76(s,3H),2.70(s,3H).

[0655] Example 22

[0656] N-[(1S)-2-amino-1-(hydroxymethyl)-2-oxoethyl]-2-methyl-5-[dideuter-(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxamide

[0657] first step

[0658] Dideuterium-(2-methylthiazolyl-5-yl)methanol

[0659] 2-Methylthiazol-5-carboxylic acid 21d (1 g, 6.99 mmol) was dissolved in tetrahydrofuran (10 mL), and deuterated lithium aluminum hydride (450 mg, 9.78 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then at 20 °C for 12 h. The reaction was monitored by TLC. After the reaction was completed, sodium sulfate decahydrate (5.4 g) was added to quench the reaction. The mixture was filtered, extracted with ethyl acetate (200 mL × 3), and the organic phases were combined and concentrated under reduced pressure to give dideuterium-(2-methylthiazol-5-yl)methanol 22a (1.1 g). This unpurified product was directly used in the next step of the reaction.

[0660] Step 2

[0661] 5-[chloro(dideuterium)methyl]-2-methylthiazole

[0662] Dissolve 1.1 g (8.38 mmol) of dideuterium-(2-methylthiazol-5-yl)methanol 22a in 10 mL of dichloromethane, add 2 g (16.8 mmol) of thionyl chloride at 0 °C, and stir at 25 °C for 2 hours. Monitor the reaction by LCMS. After the reaction is complete, concentrate under reduced pressure to obtain 1.2 g (5-chloro(dideuterium)methyl)-2-methylthiazol 22b), which is used directly in the next reaction without purification.

[0663] MS m / z (ESI): 147.8 [M+1]

[0664] Step 3

[0665] 2-Methyl-5-[dideuter-(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxylic acid ethyl ester

[0666] Ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (1.62 g, 7.35 mmol) and 5-[chloro(dideuterium)methyl]-2-methylthiazole 22b (1.1 g, 7.35 mmol) were dissolved in N,N-dimethylformamide (150 mL), and cesium carbonate (7.19 g, 22.0 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was filtered, diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 22c (1.3 g) of ethyl 2-methyl-5-[dideuterium-(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxylate, yield: 24.54%. MS m / z (ESI): 334.4 [M+1]

[0667] Step 4

[0668] 2-Methyl-5-[dideuter-(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxylic acid

[0669] Ethyl 2-methyl-5-[dideuterium-(2-methylthiazolium-5-yl)methoxy]benzofuran-3-carboxylic acid 22c (0.3 g, 0.90 mmol) was dissolved in a mixture of ethanol (5 mL) and water (1 mL), and sodium hydroxide (180 mg, 4.5 mmol) was added. The mixture was stirred at 90 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the solution was concentrated under reduced pressure and diluted with water (20 mL). The pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-5-[dideuterium-(2-methylthiazolium-5-yl)methoxy]benzofuran-3-carboxylic acid 22d (0.25 g), which was directly used in the next reaction without purification.

[0670] MS m / z(ESI): 306.0 [M+1]

[0671] Step 5

[0672] N-[(1S)-2-amino-1-(hydroxymethyl)-2-oxoethyl]-2-methyl-5-[dideuter-(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxamide

[0673] 2-Methyl-5-[(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxylic acid 22d (0.2 g, 0.66 mmol) and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (138 mg, 0.98 mmol) were dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxy-7-azabenzotriazole (89.2 g, 0.66 mmol), N,N-diisopropylethylamine (423 g, 3.27 mmol) and 2-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (374 mg, 0.98 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and separated by C18 reversed-phase column (eluent: system B) to give N-[(1S)-2-amino-1-(hydroxymethyl)-2-oxoethyl]-2-methyl-5-[dideuter-(2-methylthiazolyl-5-yl)methoxy]benzofuran-3-carboxamide 22 (66.9 mg), yield: 26.09%.

[0674] MS m / z(ESI): 392.1 [M+1]

[0675] 1 H NMR(400MHz, DMSO-d6)δ7.72(s,1H),7.63(d,J=8.0Hz,1H),7.45-7.53(m,2H),7.40(d,J=2.8Hz,1H),7.21 (s,1H),6.98(dd,J=8.8,2.4Hz,1H),4.43-4.53(m,1H),3.75(dd,J=5.2,2.0Hz,2H),2.63(d,J=2.0Hz,6H).

[0676] Example 23

[0677] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxamide

[0678] first step

[0679] 2-Methyl-5-(((2-methylthiazolyl-5-yl)methyl)amino)benzofuran-3-carboxylic acid ethyl ester

[0680] 5-(chloromethyl)-2-methylthiazolium 1b (32.32 mg, 218.94 μmol) and ethyl 5-amino-2-methylbenzofuran-3-carboxylate 21c (40 mg, 182.45 μmol) were dissolved in N,N-dimethylformamide (1 mL), and cesium carbonate (178.34 mg, 547.36 μmol) was added. The mixture was stirred at 40 °C for 5 hours. The reaction was monitored by LCMS. After the reaction was completed, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give ethyl 2-methyl-5-(((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylate 23a (20 mg), yield: 33.18%.

[0681] MS m / z(ESI): 331.0 [M+1]

[0682] Step 2

[0683] 2-Methyl-5-(((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxylic acid

[0684] Ethyl 2-methyl-5-((((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylic acid 23a (20 mg, 60.53 μmol) was dissolved in a mixture of water (0.1 mL) and ethanol (0.5 mL), and sodium hydroxide (12.11 mg, 302.66 μmol) was added. The mixture was stirred at 90 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the pH of the solution was adjusted to 5 with 1 M hydrochloric acid, and the solution was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-methyl-5-(((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylic acid 23b (18 mg), yield: 98.35%. This product was used directly in the next reaction without purification.

[0685] MS m / z(ESI): 302.9 [M+1]

[0686] Step 3

[0687] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxamide

[0688] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (10.46 mg, 74.42 μmol), 2-methyl-5-(((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylic acid 23b (15 mg, 49.61 μmol) were dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (28.30 mg, 74.42 μmol), 1-hydroxy-7-azabenzotriazole (6.75 mg, 49.61 μmol), and N,N-diisopropylethylamine (19.24 mg, 148.84 μmol) were added. The mixture was stirred at 20 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(((2-methylthiazolyl-5-yl)methyl)amino)benzofuran-3-carboxamide 23 (5.46 mg), yield: 28.33%.

[0689] MS m / z(ESI): 411.1 [M+23]

[0690] 1 H NMR (400MHz, CD3OD) δ7.74-7.01(m,3H),6.85-6.59(m,1H),4.57-4.45(m,3H),4.02-3.83(m,2H),2.63(s,6H).

[0691] Example 24

[0692] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(methyl((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxamide

[0693] first step

[0694] 2-Methyl-5-(methyl((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxylic acid ethyl ester

[0695] Ethyl 2-methyl-5-[(2-methylthiazol-5-yl)methylamino]benzofuran-3-carboxylate 23a (100 mg, 302.66 μmol) was dissolved in tetrahydrofuran (1 mL), and potassium carbonate (125.49 mg, 907.99 μmol) and iodomethane (128.88 mg, 907.99 μmol) were added. The mixture was stirred at 20 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to obtain ethyl 2-methyl-5-(methyl((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylate 24a (40 mg), yield: 38.37%.

[0696] MS m / z (ESI): 345.1 [M+1]

[0697] Step 2

[0698] 2-Methyl-5-(methyl((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxylic acid

[0699] Ethyl 2-methyl-5-(methyl((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylic acid 24a (40 mg, 116.13 μmol) was dissolved in a mixture of water (0.1 mL) and ethanol (0.5 mL), and sodium hydroxide (23.23 mg, 580.67 μmol) was added. The mixture was stirred at 90 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH of the solution was adjusted to 5 with 1 M hydrochloric acid, and the mixture was extracted with dichloromethane (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-methyl-5-(methyl((2-methylthiazol-5-yl)methyl)amino)benzofuran-3-carboxylic acid 24b (35 mg), yield: 95.26%. This product was used directly in the next step of the reaction without purification.

[0700] MS m / z(ESI): 316.9 [M+1]

[0701] Step 3

[0702] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(methyl((2-methylthiazo-5-yl)methyl)amino)benzofuran-3-carboxamide

[0703] Add 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (54.08 mg, 142.24 μmol) and 1-hydroxy-7-azabenzotriazole (12.91 mg) to a solution of ((S)-2-amino-3-hydroxypropionamide hydrochloride 1f (19.99 mg, 142.24 μmol), 2-methyl-5-(methyl((2-methylthiazolyl-5-yl)methyl)amino)benzofuran-3-carboxylic acid 24b (30 mg, 94.82 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 20 °C for 16 hours with N,N-diisopropylethylamine (94.82 μmol) and N,N-diisopropylethylamine (36.77 mg, 284.47 μmol). The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(methyl((2-methylthiazolyl-5-yl)methyl)amino)benzofuran-3-carboxamide 24 (18.52 mg), yield: 35.62%.

[0704] MS m / z(ESI): 403.2 [M+1]

[0705] 1 H NMR(400MHz,DMSO-d6)δ7.68-7.31(m,3H),7.30-7.06(m,2H),7.03-6.83(m,1H),5.03(s,1H),4 .73(s,2H),4.46(dd,J=2.0,3.8Hz,1H),3.73(d,J=4.8Hz,2H),2.87(s,3H),2.69-2.53(m,6H).

[0706] Example 25

[0707] (S)-N-(3-((1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)-2-methylbenzofuran-5-yl)-N,2-dimethylthiazolyl-5-carboxamide

[0708] first step

[0709] Ethyl 5-(N,2-dimethylthiazolyl-5-carbamate)-2-methylbenzofuran-3-carboxylate

[0710] Ethyl 2-methyl-5-(2-methylthiazol-5-carboxamido)benzofuran-3-carboxylate 21e (60 mg, 174.22 μmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydrogen (20.90 mg, 522.67 μmol) and methyl iodine (123.65 mg, 871.12 μmol) were added. The mixture was stirred at 20 °C for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give ethyl 5-(N,2-dimethylthiazol-5-carboxamido)-2-methylbenzofuran-3-carboxylate 25a (20 mg), yield: 32.03%.

[0711] MS m / z(ESI): 359.0 [M+1]

[0712] Step 2

[0713] 5-(N,2-Dimethylthiazolyl-5-carbamate)-2-methylbenzofuran-3-carboxylic acid

[0714] Ethyl 5-(N,2-dimethylthiazol-5-carboxamido)-2-methylbenzofuran-3-carboxylic acid 25a (20 mg, 55.80 μmol) was dissolved in a mixture of water (0.1 mL) and ethanol (0.5 mL), and sodium hydroxide (11.16 mg, 279.01 μmol) was added. The mixture was stirred at 90 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the pH of the solution was adjusted to 5 with 1 M hydrochloric acid, extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(N,2-dimethylthiazol-5-carboxamido)-2-methylbenzofuran-3-carboxylic acid 25b (15 mg), yield: 81.37%. This product was used directly in the next reaction without purification.

[0715] MS m / z(ESI): 331.0 [M+1]

[0716] Step 3

[0717] (S)-N-(3-((1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)-2-methylbenzofuran-5-yl)-N,2-dimethylthiazolyl-5-carboxamide

[0718] Dissolve (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (6.38 mg, 45.41 μmol), 5-(N,2-dimethylthiazol-5-carboxamido)-2-methylbenzofuran-3-carboxylic acid 25b (10 mg, 30.27 μmol) in N,N-dimethylformamide (1 mL) solution, then add 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (17.26 mg, 45.41 μmol), 1-hydroxy-7-azabenzotriazole (4.12 mg, 4.12 μmol) The mixture was prepared by stirring at 20°C for 16 hours with N,N-diisopropylethylamine (11.74 mg, 90.81 μmol) and 30.27 μmol (mg). The reaction was monitored by LCMS. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was then separated by C18 reversed-phase column chromatography (eluent: system B) to give (S)-N-(3-((1-amino-3-hydroxy-1-oxopropane-2-yl)carbamoyl)-2-methylbenzofuran-5-yl)-N,2-dimethylthiazolyl-5-carboxamide 25 (1.28 mg), yield: 10.15%.

[0719] MS m / z(ESI): 417.2 [M+1]

[0720] 1 H NMR (400MHz, CD3OD) δ7.82(d,J=1.8Hz,1H),7.60(d,J=8.6Hz,1H),7.37(s,1H),7.26(dd,J=2. 0,8.6Hz,1H),4.68-4.66(m,1H),3.93(d,J=5.1Hz,2H),3.47(s,3H),2.75(s,3H),2.50(s,3H).

[0721] Example 26

[0722] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-(2-methylthiazo-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxamide

[0723] first step

[0724] 4-(2-methylthiazolyl-5-yl)tetrahydro-2H-pyran-4-ol

[0725] 5-Bromo-2-methylthiazol 16a (500 mg, 2.81 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium solution (2.5 M, 3.37 mmol, 1.35 mL) was added. The mixture was stirred at -78 °C for 1 hour under nitrogen protection. Then, tetrahydro-4H-pyran-4-one 26a (422 mg, 4.21 mmol) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, saturated ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 4-(2-methylthiazol-5-yl)tetrahydro-2H-pyran-4-ol 26b (400 mg), yield: 71.48%. MS m / z(ESI): 200.1 [M+1]

[0726] Step 2

[0727] 2-Methyl-5-((4-(2-methylthiazo-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxylic acid ethyl ester

[0728] 4-(2-methylthiazolyl-5-yl)tetrahydro-2H-pyran-4-ol 26b (244 mg, 1.23 mmol) was dissolved in toluene (6 mL), and ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (180 mg, 0.817 mmol) and tributylphosphine (248 mg, 1.23 mmol) were added dropwise to the reaction solution under nitrogen protection. The mixture was stirred at 115 °C for 18 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 26c (100mg) of ethyl 2-methyl-5-((4-(2-methylthiazolyl-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxylate, yield: 30.47%.

[0729] MS m / z (ESI): 402.7 [M+1]

[0730] Step 3

[0731] 2-Methyl-5-((4-(2-methylthiazo-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxylic acid

[0732] Ethyl 2-methyl-5-((4-(2-methylthiazol-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxylic acid 26c (100 mg, 0.249 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and an aqueous solution of sodium hydroxide (40 mg, 0.996 mmol) (1 mL) was added. The mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a pale yellow solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to obtain 2-methyl-5-((4-(2-methylthiazol-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxylic acid 26d (90 mg), which was directly used in the next reaction without purification.

[0733] MS m / z(ESI): 374.0 [M+1]

[0734] Step 4

[0735] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-(2-methylthiazo-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxamide

[0736] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (68 mg, 0.482 mmol) was dissolved in N,N-dimethylformamide (3 mL) and added to N,N-diisopropylethylamine (156 mg, 1.21 mmol). The reaction solution was stirred at 25 °C for 5 minutes. 2-methyl-5-((4-(2-methylthiazolyl-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxylic acid 26d (90 mg, 0.241 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (183 mg, 0.482 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D). The obtained sample was further separated by HPLC (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((4-(2-methylthiazolyl-5-yl)tetrahydro-2H-pyran-4-yl)oxy)benzofuran-3-carboxamide 26 (50.9 mg), yield: 45.96%.

[0737] MS m / z(ESI): 460.3 [M+1]

[0738] 1 H NMR (400MHz, DMSO-d6) δ7.54-7.45(m,3H),7.36(d,J=8.8Hz,1H),7.25-7.19(m,2H),6.59(dd,J=8.8,2.4Hz,1H),5.00(t,J=5.6Hz,1H),4. 48-4.41(m,1H),3.90-3.82(m,2H),3.78-3.67(m,2H),3.66-3.58(m, 2H),2.62(s,3H),2.62(s,3H),2.33-2.24(m,2H),2.23-2.14(m,2H).

[0739] Example 27

[0740] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((3-(2-methylthiazo-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxamide

[0741] first step

[0742] 3-(2-methylthiazolyl-5-yl)oxecyclobut-3-ol

[0743] 5-Bromo-2-methylthiazolium 16a (1 g, 5.62 mmol) was dissolved in tetrahydrofuran (15 mL), and n-butyllithium solution (2.5 M, 6.74 mmol, 2.70 mL) was added. The mixture was stirred at -78 °C for 1 hour under nitrogen protection. Then, oxetane-3-one 27a (607.10 mg, 8.42 mmol) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, saturated ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 3-(2-methylthiazol-5-yl)oxetane-3-ol 27b (800 mg), yield: 83.19%.

[0744] MS m / z(ESI): 172.1 [M+1]

[0745] Step 2

[0746] 2-Methyl-5-((3-(2-methylthiazo-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxylic acid ethyl ester

[0747] 3-(2-methylthiazolyl-5-yl)oxetane-3-ol 27b (349.86 mg, 2.04 mmol) was dissolved in toluene (7 mL), and ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (300 mg, 1.36 mmol) and tributylphosphine (551.22 mg, 2.72 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (687.43 mg, 2.72 mmol) was dissolved in toluene (3 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at 115 °C for 18 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 27c (130mg) of ethyl 2-methyl-5-((3-(2-methylthiazolyl-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxylate, yield: 25.56%.

[0748] MS m / z(ESI): 374.2 [M+1]

[0749] Step 3

[0750] 2-Methyl-5-((3-(2-methylthiazo-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxylic acid

[0751] Ethyl 2-methyl-5-((3-(2-methylthiazol-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxylic acid 27c (130 mg, 0.348 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and a solution of sodium hydroxide (56 mg, 1.392 mmol) in water (1 mL) was added. The mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to obtain 2-methyl-5-((3-(2-methylthiazol-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxylic acid 27d (100 mg), which was directly used for the next reaction. MS m / z (ESI): 346.1 [M+1]

[0752] Step 4

[0753] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((3-(2-methylthiazo-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxamide

[0754] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (82 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (187 mg, 1.45 mmol) was added. The reaction solution was stirred at 25 °C for 5 minutes. 2-methyl-5-((3-(2-methylthiazolyl)oxetane-3-yl)oxy)benzofuran-3-carboxylic acid 27d (100 mg, 0.29 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (220 mg, 0.58 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D). The obtained sample was further separated by HPLC (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((3-(2-methylthiazolyl-5-yl)oxetane-3-yl)oxy)benzofuran-3-carboxamide 27 (26.4 mg), yield: 21.13%.

[0755] MS m / z(ESI): 432.2 [M+1]

[0756] 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.53(s,1H),7.49-7.43(m,2H),7.26(s,1H),6.97(d,J=2.8Hz,1H),6.7 2(dd,J=8.8,2.4Hz,1H),5.11-5.02(m,5H),4.51-4.45(m,1H),3.80-3.69(m,2H),2.61(s,3H),2.57(s,3H).

[0757] Example 28

[0758] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxamide

[0759] first step

[0760] 2-Iodo-4-trifluoromethoxyphenol

[0761] 4-Trifluoromethoxyphenol 28a (5 g, 28.07 mmol) was dissolved in acetonitrile (40 mL), and p-toluenesulfonic acid hydrate (5.34 g, 28.07 mmol) was added. The mixture was stirred at 25 °C for 10 minutes, and then N-iodosuccinimide (6.32 g, 28.07 mmol) was added at 25 °C. The mixture was stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 2-iodo-4-trifluoromethoxyphenol 28b (2.88 g), yield: 33.75%.

[0762] MS m / z(ESI): 302.92 [M-1]

[0763] Step 2

[0764] 2-Methyl-5-(trifluoromethoxy)benzofuran-3-carboxylic acid methyl ester

[0765] 2-Iodo-4-trifluoromethoxyphenol 28b (1 g, 3.29 mmol), triethylamine (665.71 mg, 6.58 mmol), and chloro(crotonyl)(tri-tert-butylphosphine)palladium(II) (168.11 mg, 328.94 μmol) were dissolved in 10 mL of acetonitrile. Methyl butyronitrile 28c (484.04 mg, 4.93 mmol) was added under nitrogen protection, and the mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system C) to give methyl 2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxylate 28d (400 mg), yield: 44.35%.

[0766] 1 H NMR (400MHz, CDCl3) δ7.81-7.80(m,1H),7.41(d,J=8.8Hz,1H),7.16-7.13(m,1H),3.96(s,3H),2.78(s,3H).

[0767] Step 3

[0768] 2-Methyl-5-(trifluoromethoxy)benzofuran-3-carboxylic acid

[0769] 250 mg (911.77 μmol) of methyl 2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxylic acid 28e was dissolved in 10 mL of a mixed solution (tetrahydrofuran:methanol:water = 2:2:1). Sodium hydroxide (109.40 mg, 2.74 mmol) was added at 25 °C, and the mixture was stirred at 70 °C for 4 hours. After the reaction was complete, the solution was concentrated under reduced pressure. The pH of the aqueous phase was then adjusted to 5 with 2N hydrochloric acid. The solid was filtered under reduced pressure and washed with water. The solution was then concentrated under reduced pressure to obtain 210 mg (2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxylic acid 28e), yield: 88.53%.

[0770] MS m / z(ESI): 259.02 [M-1]

[0771] Step 4

[0772] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxamide

[0773] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (40 mg, 0.284 mmol) and N,N-diisopropylethylamine (124 mg, 0.961 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at 25 °C for 5 minutes. 2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxylic acid 28e (50 mg, 0.192 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (146 mg, 0.384 mmol) were added to the reaction solution and stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D). The sample was further separated by HPLC (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(trifluoromethoxy)benzofuran-3-carboxamide 28 (26.2 mg), yield: 39.73%.

[0774] MS m / z(ESI): 347.0 [M+1]

[0775] 1H NMR(400MHz,DMSO-d6)δ7.80(d,J=8.0Hz,1H),7.75-7.69(m,2H),7.48(s,1H),7.35-7.29(m,1H),7 .18(s,1H),5.00(t,J=5.6Hz,1H),4.48(dt,J=8.0,5.2Hz,1H),3.75(t,J=5.4Hz,2H),2.69(s,3H).

[0776] Example 29

[0777] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxamide

[0778] first step

[0779] ethyl 2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxylate

[0780] To a 15 mL toluene solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (750.0 mg, 3.41 mmol), 2-fluoropyridine (1.3 g, 13.62 mmol), trimethyl(pentafluoroethyl)silane 29a (2.6 g, 13.62 mmol), tetramethylammonium fluoride (1.6 g, 17.03 mmol), and selective fluorine (4 g, 6.81 mmol) were added, and the mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system C) to give ethyl 2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxylate 29b (100 mg), yield: 8.68%.

[0781] MS m / z(ESI): 339.4 [M+1]

[0782] Step 2

[0783] 2-Methyl-5-(pentafluoroethoxy)benzofuran-3-carboxylic acid

[0784] To a methanol (2 mL) solution of ethyl 2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxylic acid 29b (100 mg, 0.3 mmol), 2 mL of tetrahydrofuran and 1 mL of an aqueous solution of sodium hydroxide (47.3 mg, 1.2 mmol) were added, and the mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with 2N hydrochloric acid, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give 2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxylic acid 29c (60 mg), yield: 54.52%. MS m / z (ESI): 311.4 [M+1]

[0785] Step 3

[0786] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxamide

[0787] To a solution of 2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxylic acid 29c (60 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (150 mg, 1.16 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (147.1 mg, 0.39 mmol), and (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (81.5 mg, 0.58 mmol) were added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system D). The obtained sample was further separated by HPLC (eluent: system B) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(pentafluoroethoxy)benzofuran-3-carboxamide 29 (8.1 mg), yield: 10.57%.

[0788] MS m / z(ESI): 397.1 [M+1]

[0789] 1H NMR(400MHz,DMSO-d6)δ7.81(d,J=8.0Hz,1H),7.73-7.71(m,2H),7.49(s,1H),7.30(dd,J=8.8,2.4 Hz,1H),7.19(s,1H),4.99(t,J=5.6Hz,1H),4.50-4.46(m,1H),3.75(t,J=5.6Hz,2H),2.70(s,3H).

[0790] Example 30

[0791] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-(2-methylthiazo-5-yl)cyclopentyl)oxy)benzofuran-3-carboxamide

[0792] first step

[0793] 1-(2-methylthiazolyl-5-yl)-1-cyclopentanol

[0794] 5-Bromo-2-methylthiazolium 16a (1 g, 5.62 mmol) was dissolved in tetrahydrofuran (15 mL), and 2.5 M n-butyllithium solution (6.74 mmol, 2.70 mL) was added. The mixture was stirred at -78 °C for 1 hour under nitrogen protection. Then, cyclopentanone 30a (709 mg, 8.42 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, saturated ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 1-(2-methylthiazol-5-yl)-1-cyclopentanol 30b (700 mg), yield: 68.01%.

[0795] MS m / z (ESI): 184.5 [M+1]

[0796] Step 2

[0797] 2-Methyl-5-((1-(2-methylthiazo-5-yl)cyclopentyl)oxy)benzofuran-3-carboxylic acid ethyl ester

[0798] 1-(2-methylthiazol-5-yl)-1-cyclopentanol 30b (250 mg, 1.36 mmol) was dissolved in toluene (7 mL), and ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (200 mg, 0.908 mmol) and tributylphosphine (367 mg, 1.82 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (458 mg, 1.82 mmol) was dissolved in toluene (3 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at 115 °C for 18 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give ethyl 2-methyl-5-((1-(2-methylthiazol-5-yl)cyclopentyl)oxy)benzofuran-3-carboxylate 30c (100 mg), yield: 28.56%.

[0799] MS m / z(ESI): 386.2 [M+1]

[0800] Step 3

[0801] 2-Methyl-5-((1-(2-methylthiazo-5-yl)cyclopentyl)oxy)benzofuran-3-carboxylic acid

[0802] Ethyl 2-methyl-5-((1-(2-methylthiazol-5-yl)cyclopentyl)oxy)benzofuran-3-carboxylic acid 30c (100 mg, 0.259 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Sodium hydroxide (42 mg, 1.04 mmol) dissolved in water (1 mL) was added, and the mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to obtain 2-methyl-5-((1-(2-methylthiazol-5-yl)cyclopentyl)oxy)benzofuran-3-carboxylic acid 30d (80 mg), which was directly used in the next reaction without purification.

[0803] MS m / z(ESI): 358.6 [M+1]

[0804] Step 4

[0805] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-(2-methylthiazo-5-yl)cyclopentyl)oxy)benzofuran-3-carboxamide

[0806] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (47 mg, 0.448 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (145 mg, 1.12 mmol) was added. The mixture was stirred at 25 °C for 5 minutes. 2-methyl-5-((1-(2-methylthiazol-5-yl)cyclopentyl)oxy)benzofuran-3-carboxylic acid 30d (80 mg, 0.224 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (170 mg, 0.448 mmol) were added to the reaction solution and stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was complete, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D) and further purified by preparative separation (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((1-(2-methylthiazolyl-5-yl)cyclopentyl)oxy)benzofuran-3-carboxamide 30 (21.45 mg), yield: 21.61%. MS m / z (ESI): 444.2 [M+1]

[0807] 1 H NMR (400MHz, DMSO-d6) δ7.54(s,1H),7.50-7.42(m,2H),7.37(d,J=8.8Hz,1H),7.24-7.17(m,2H),6.62(dd,J=8.8,2.4Hz,1H),5.00(t,J=5.2Hz, 1H),4.51-4.38(m,1H),3.78-3.66(m,2H),2.62(s,3H),2.60(s,3H),2.3 9-2.30(m,2H),2.17-2.07(m,2H),1.95-1.82(m,2H),1.81-1.70(m,2H).

[0808] Example 31

[0809] (R)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0810] first step

[0811] (R)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0812] To a solution of 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (105.82 mg, 0.82 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (124.52 mg, 0.33 mmol) and (2R)-2-amino-3-hydroxypropionamide hydrochloride 31a (17.05 mg, 0.16 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: system C) and further separated by preparative separation (eluent: system B) to give (R)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 31 (9.01 mg), yield: 15.60%.

[0813] MS m / z(ESI): 392.2 [M+1]

[0814] 1 H NMR (400MHz, DMSO-d6) δ7.73(s,1H),7.62(d,J=8.0Hz,1H),7.49(d,J=9.0Hz,2H),7.42(d,J=2.4Hz,1H),7.21(s,1H) ,6.98(dd,J=9.2,2.8Hz,1H),5.04(t,J=5.6Hz,1H),4.55-4.45(m,1H),3.80-3.72(m,2H),2.64(s,1H),2.63(s,1H).

[0815] Example 32

[0816] (S)-N-(1-amino-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0817] first step

[0818] (S)-N-(1-amino-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0819] (S)-2-aminopropionamide hydrochloride 32a (41 mg, 0.328 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (106 mg, 0.819 mmol) was added. The reaction solution was stirred at 25 °C for 5 minutes. 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.164 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (125 mg, 0.328 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D). Further preparative separation (eluent: system B) yielded (S)-N-(1-amino-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 32 (40.74 mg), yield: 66.27%.

[0820] MS m / z(ESI): 376.2 [M+1]

[0821] 1 H NMR (400MHz, DMSO-d6) δ7.86(d,J=7.6Hz,1H),7.72(s,1H),7.56-7.43(m,2H),7.36(d,J=2.4Hz,1H),7. 11(s,1H),6.96(dd,J=8.8,2.8Hz,1H),4.56-4.43(m,1H),2.63(d,J=5.6Hz,6H),1.37(d,J=7.2Hz,3H).

[0822] Example 33

[0823] N-((2S,3R)-1-amino-3-hydroxy-1-oxobut-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0824] first step

[0825] N-((2S,3R)-1-amino-3-hydroxy-1-oxobut-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0826] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.174 mmol), diisopropylethylamine (106 mg, 0.819 mmol) and tetramethylurea hexafluorophosphate (124 mg, 0.328 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at 25 °C for 5 minutes. (2S,3R)-2-amino-3-hydroxybutyramide hydrochloride 33a (30 mg, 0.197 mmol) was added to the reaction solution and stirred at 25 °C for 20 minutes. After the reaction was monitored by LC-MS, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D), and further purified by preparative separation (eluent: system B) to obtain N-((2S,3R)-1-amino-3-hydroxy-1-oxobut-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 33 (41.72 mg), yield: 62.81%.

[0827] MS m / z(ESI): 406.2 [M+1]

[0828] 1 H NMR (400MHz, DMSO-d6) δ7.72(s,1H),7.52-7.42(m,3H),7.37(d,J=8.7Hz,1H),7.20-7.15(m,1H),6.99(dd,J=8.9,2.6Hz,1 H),5.08(d,J=5.7Hz,1H),4.39(dd,J=8.7,3.4Hz,1H),4.18-4.10(m,1H),2.65(s,3H),2.63(s,3H),1.15(d,J=6.4Hz,3H).

[0829] Example 34

[0830] 2-Methyl-N-(1-methylpiperidin-4-yl)-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0831] first step

[0832] 2-Methyl-N-(1-methylpiperidin-4-yl)-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0833] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 163.75 μmol), 1-methyl-4-aminopiperidine hydrochloride 34a (22.44 mg, 196.50 μmol) and N,N-diisopropylethylamine (42.33 mg, 327.50 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then tetramethylurea hexafluorophosphate (74.71 mg, 196.50 μmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (eluent: system B) to give 2-methyl-N-(1-methylpiperidin-4-yl)-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 34 (18.71 mg), yield: 28.46%.

[0834] MS m / z(ESI): 402.3 [M+1]

[0835] 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=7.8Hz,1H),7.68(s,1H),7.45(d,J=8.8Hz,1H),7.21(d,J=2.8Hz,1H),6.94(dd,J=8.8,2.8Hz,1H), 3.76-3.72(m,1H),2.80-2.70(m,2H),2.63(s,3H),2.56(s,3H),2.16(s,3H),2.01-1.94(m,2H),1.83-1.79(m,2H),1.65-1.56(m,2H).

[0836] Example 35

[0837] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0838] first step

[0839] 5-(benzyloxy)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[0840] Potassium carbonate (1.23 g, 9.08 mmol) and potassium iodide (75.3 mg, 0.454 mmol) were added to a solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (1 g, 4.54 mmol) in N,N-dimethylformyl (15 mL), followed by benzyl chloride (1.15 g, 9.08 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give ethyl 5-(benzyloxy)-2-methylbenzofuran-3-carboxylate 35a (1.09 g), yield: 77.35%.

[0841] MS m / z(ESI): 311.2 [M+1]

[0842] Step 2

[0843] 5-(benzyloxy)-2-methylbenzofuran-3-carboxylic acid

[0844] Ethyl 5-benzyloxy-2-methyl-benzofuran-3-carboxylic acid 35a (1.09 g, 3.51 mmol) was dissolved in 25 mL of a mixed solution (tetrahydrofuran:methanol:water = 2:2:1), and sodium hydroxide (561.92 mg, 14.05 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After the reaction was completed, the solution was concentrated under reduced pressure, and the pH was adjusted to 5 by adding dilute hydrochloric acid dropwise. The solution was then filtered and washed with water. The solid was dried under reduced pressure to give 5-benzyloxy-2-methyl-benzofuran-3-carboxylic acid 35b (950 mg), yield: 95.82%.

[0845] MS m / z(ESI): 281.1 [M-1]

[0846] Step 3

[0847] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(benzyloxy)-2-methylbenzofuran-3-carboxamide

[0848] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (239.02 mg, 1.70 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (646.53 mg, 1.70 mmol) were dissolved in N,N-dimethylformamide (8 mL), and 5-benzyloxy-2-methyl-benzofuran-3-carboxylic acid 35b (400 mg, 1.42 mmol) and N,N-diisopropylethylamine (732.54 mg, 5.67 mmol) were added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system D) to obtain (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(benzyloxy)-2-methylbenzofuran-3-carboxamide 35c (520 mg), yield: 99.62%.

[0849] MS m / z(ESI): 369.2 [M+1]

[0850] Step 4

[0851] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-5-(benzyloxy)-2-methylbenzofuran-3-carboxamide

[0852] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(benzyloxy)-2-methylbenzofuran-3-carboxamide 35c (520 mg, 1.41 mmol) and imidazole (192.19 mg, 2.82 mmol) were dissolved in tetrahydrofuran (10 mL). Tert-butyldiphenylchlorosilane (465.58 mg, 1.69 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-5-(benzyloxy)-2-methylbenzofuran-3-carboxamide 35d (730 mg), yield: 85.23%. MS m / z (ESI): 607.5 [M+1]

[0853] Step 5

[0854] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide

[0855] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-(benzyloxy)-2-methylbenzofuran-3-carboxamide 35d (730 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL), and then 10% palladium on carbon (64.02 mg, 601.53 μmol) was added. The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system D) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (268 mg), yield: 43.12%.

[0856] MS m / z (ESI): 517.4 [M+1]

[0857] Step 6

[0858] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0859] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (50 mg, 96.78 μmol), (4-methylthiazolyl-5-yl)methane-d2-ol 35f (19.04 mg, 145.16 μmol), and tributylphosphine (39.16 mg, 193.55 μmol) were dissolved in tetrahydrofuran (2 mL). Azodicarbonyl dipiperidine (48.84 mg, 193.55 μmol) was added under nitrogen protection, and the mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give 35 g (55 mg) of (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide, yield: 90.23%.

[0860] MS m / z (ESI): 630.4 [M+1]

[0861] Step 7

[0862] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0863] 35 g (55 mg, 87.32 μmol) of (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide was dissolved in tetrahydrofuran (3 mL), and then tetrabutylammonium fluoride (68.50 mg, 261.97 μmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 35 (15.33 mg), yield: 44.85%.

[0864] MS m / z(ESI): 392.2 [M+1]

[0865] 1 H NMR(400MHz, DMSO-d6)δ8.98(s,1H),7.62(d,J=8.0Hz,1H),7.54-7.34(m,3H),7.18(s,1H),6.98(dd,J=8.8,2.8H z,1H),5.01(t,J=5.6Hz,1H),4.48(dt,J=8.0,5.2Hz,1H),3.75(td,J=5.4,2.0Hz,2H),2.64(s,3H),2.42(s,3H).

[0866] Example 36

[0867] N-(3,3-difluoropiperidin-4-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0868] first step

[0869] 3,3-Difluoro-4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carbamate)piperidine-1-carboxylic acid tert-butyl ester

[0870] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.164 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 4-amino-3,3-difluoropiperidine-1-carboxylic acid tert-butyl hydrochloride 36a (77 mg, 0.328 mmol), N,N-diisopropylethylamine (63 mg, 0.491 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (125 mg, 0.328 mmol) were added. The mixture was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 3,3-difluoro-4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)piperidine-1-carboxylic acid tert-butyl ester 36b (80 mg), yield: 93.31%.

[0871] MS m / z(ESI): 524.8 [M+1]

[0872] Step 2

[0873] N-(3,3-difluoropiperidin-4-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0874] 3,3-Difluoro-4-(2-methyl-5-((2-methylthiazol-5-yl)methoxy-d2)benzofuran-3-carboxamido)piperidin-1-carboxylic acid tert-butyl ester 36b (80 mg, 0.153 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (eluent: system B) to give N-(3,3-difluoropiperidin-4-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy-d2)benzofuran-3-carboxamide 36 (50.80 mg), yield: 78.51%.

[0875] MS m / z(ESI): 424.2 [M+1]

[0876] 1H NMR (400MHz, DMSO-d6) δ8.21(d,J=8.8Hz,1H),7.69(s,1H),7.47(d,J=8.8Hz,1H),7.21(d,J=2.4Hz,1H),6.96(dd,J=8.8,2.4Hz ,1H),4.58-4.41(m,1H),3.20-3.11(m,1H),2.98-2.81(m,2H),2.64(s,4H),2.58(s,3H),2.54-2.52(m,1H),1.86-1.67(m,2H).

[0877] Example 37

[0878] N-(4,4-Difluoropyrrolidone-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0879] first step

[0880] 3,3-Difluoro-4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carbamate)pyrrolidine-1-carboxylic acid tert-butyl ester

[0881] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (85 mg, 278.37 μmol) and N,N-diisopropylethylamine (179.89 mg, 1.39 mmol) were dissolved in dichloromethane (3 mL), and 4-amino-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl hydrochloride 37a (74.24 mg, 334.05 μmol) and 2-(7-azobenzotriazole)-N,N N',N'-Tetramethylurea hexafluorophosphate (211.69 mg, 556.75 μmol) was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system D) to give 3,3-difluoro-4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester 37b (122 mg), yield: 86.01%.

[0882] MS m / z (ESI): 510.2 [M+1]

[0883] Step 2

[0884] N-(4,4-Difluoropyrrolidone-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0885] To 2 mL of dichloromethane containing 122 mg (239.42 μmol) of tert-butyl 3,3-difluoro-4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)pyrrolidine-1-carboxylate 37b, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25 °C for 30 min. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by HPLC (eluent: system B) to give N-(4,4-difluoropyrrolidine-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 37 (78.54 mg), yield: 80.12%.

[0886] MS m / z(ESI): 410.2 [M+1]

[0887] 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=8.4Hz,1H),7.69(s,1H),7.49(d,J=9.2Hz,1H),7.24(d,J=2.4Hz,1H),6.99(dd,J=8 .8,2.4Hz,1H),4.77-4.64(m,1H),3.46-3.29(m,3H),3.22-3.05(m,1H),3.04-2.91(m,1H),2.64(s,3H),2.60(s,3H).

[0888] Example 38

[0889] N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0890] first step

[0891] N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0892] To a solution of 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (105.82 mg, 0.818 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (93.39 mg, 0.246 mmol), and 3-aminopyrrolidine-2-one hydrochloride 38a (44.73 mg, 0.327 mmol) were added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was preparatively separated by HPLC (eluent: system B) to give N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 38 (27 mg), yield: 42.56%. MS m / z (ESI): 419.2 [M+1]

[0893] 1 H NMR (400MHz, DMSO-d6) δ7.69 (s, 1H), 7.48-7.38 (m, 2H), 7.24 (d, J = 2.6Hz, 1H), 6.95 (dd, J = 8.8, 2.4Hz, 1 H),4.91(s,1H),3.74-3.59(m,6H),2.63(s,3H),2.60(s,3H),2.18(d,J=13.6Hz,2H),1.71-1.55(m,2H).

[0894] Example 39

[0895] N-(3-carbamoyloxetane-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0896] first step

[0897] 3-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carbamate)oxetane-3-carboxylic acid methyl ester

[0898] Add 3-aminooxetane-3-carboxylic acid methyl hydrochloride 39a (64.42 mg, 491.25 μmol) and N,N-diisopropylethylamine (211.63 mg, 1.64 mmol) to a solution of 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (100 mg, 327.50 μmol) and (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (149.43 mg, 393.00 μmol) in N,N-dimethylformamide (5 mL). After the reaction was completed by stirring at 25°C for 1 hour, the mixture was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (eluent: system D) to give methyl 3-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)oxetane-3-carboxylate 39b (85 mg), yield: 62.02%.

[0899] MS m / z(ESI): 419.7 [M+1]

[0900] Step 2

[0901] N-(3-carbamoyloxetane-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0902] 3-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)oxetane-3-carboxylate methyl ester 39b (85 mg, 203.13 μmol) was dissolved in 7M ammonia-methanol solution (2 mL), and stirred at 70 °C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by HPLC (eluent: system B) to obtain N-(3-carbamoyloxetane-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 39 (43.13 mg), yield: 52.28%.

[0903] MS m / z(ESI): 404.2 [M+1]

[0904] 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.71(s,1H),7.52-7.44(m,2H),7.22(d,J=8.8Hz,2H),6.9 9(dd,J=9.2,2.8Hz,1H),4.88(d,J=6.4Hz,2H),4.69(d,J=6.4Hz,2H),2.67(s,3H),2.64(s,3H).

[0905] Example 40

[0906] N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0907] first step

[0908] N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0909] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (60 mg, 0.197 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then (1-aminocyclopropyl)methanol 40a (34 mg, 0.393 mmol), N,N-diisopropylethylamine (76 mg, 0.590 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (149 mg, 0.393 mmol) were added. The mixture was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D), and further purified by HPLC (eluent: system B) to obtain N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 40 (52.75 mg), yield: 71.69%.

[0910] MS m / z (ESI): 375.2 [M+1]

[0911] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.70(s,1H),7.44(d,J=8.8Hz,1H),7.27(d,J=2.8Hz,1H),6. 94(dd,J=8.8,2.8Hz,1H),4.74(s,1H),3.57(s,2H),2.64(s,3H),2.57(s,3H),0.88-0.69(m,4H).

[0912] Example 41

[0913] N-(3-(hydroxymethyl)oxetane-3-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0914] first step

[0915] N-(3-(hydroxymethyl)oxetane-3-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0916] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.164 mmol) and (3-aminooxetane-3-yl)methanol hydrochloride 41a (33.77 mg, 0.328 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (63.49 mg, 0.491 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (124.52 mg, 0.328 mmol) were added to the reaction solution and stirred at 25 °C for 20 minutes. After the reaction was monitored by LC-MS, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D), and further purified by HPLC (eluent: system B) to obtain N-(3-(hydroxymethyl)oxetane-3-yl)-2-methyl-5-((2-methylthiazolyl)methoxy-d2)benzofuran-3-carboxamide 41 (14.94 mg), yield: 23.37%.

[0917] MS m / z(ESI): 391.2 [M+1].

[0918] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.70(s,1H),7.47(d,J=8.9Hz,1H),7.33(d,J=2.6Hz,1H),6.96(dd,J=8.9,2.6Hz,1 H), 5.20 (t, J = 5.8Hz, 1H), 4.69 (d, J = 6.5Hz, 2H), 4.56 (d, J = 6.5Hz, 2H), 3.79 (d, J = 5.8Hz, 2H), 2.64 (s, 3H), 2.61 (s, 3H).

[0919] Example 42

[0920] N-(1,3-Dihydroxy-2-methylpropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0921] first step

[0922] N-(1,3-Dihydroxy-2-methylpropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0923] To a solution of 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.163 mmol) in N,N-dimethylformamide (1.98 mL), N,N-diisopropylethylamine (84.65 mg, 0.655 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (93.39 mg, 0.245 mmol) and 2-amino-2-methyl-1,3-propanediol hydrochloride 42a (34.43 mg, 0.327 mmol) were added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system D) and preparative chromatography (eluent: system B) to give N-(1,3-dihydroxy-2-methylpropyl-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 42 (11.71 mg), yield: 18.22%.

[0924] MS m / z(ESI): 393.2 [M+1]

[0925] 1 H NMR (400MHz, DMSO-d6) δ7.71(s,1H),7.47(d,J=8.8Hz,1H),7.30(d,J=2.4Hz,1H),7.05(s,1H),6. 95(dd,J=8.8,2.4Hz,1H),5.01(s,2H),3.67-3.55(m,4H),2.64(s,3H),2.60(s,3H),1.33(s,3H).

[0926] Example 43

[0927] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0928] first step

[0929] (1-Methyl-1H-pyrazole-5-yl)methane-d2-ol

[0930] 1-Methyl-1H-pyrazole-5-carboxylate 43a (500 mg, 3.57 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium deuterated aluminum hydride (224.66 mg, 5.35 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the solution was concentrated under reduced pressure to give (1-methyl-1H-pyrazole-5-yl)methane-d2-ol 43b (350 mg), yield: 85.94%.

[0931] MS m / z(ESI): 115.10 [M+1]

[0932] Step 2

[0933] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0934] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (60 mg, 116.13 μmol), (1-methyl-1H-pyrazol-5-yl)methane-d2-ol 43b (15.91 mg, 139.36 μmol) and tributylphosphine (46.99 mg, 232.26 μmol) were dissolved in tetrahydrofuran (2 mL), and azodicarbonyl dipiperidine (58.60 mg, 232.26 μmol) was added under nitrogen protection. The mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy-d2)benzofuran-3-carboxamide 43c (70 mg), yield: 98.37%.

[0935] MS m / z(ESI): 611.32 [M-1]

[0936] Step 3

[0937] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy-d2)benzofuran-3-carboxamide

[0938] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy-d2)benzofuran-3-carboxamide 43c (70 mg, 114.23 μmol) was dissolved in tetrahydrofuran (2 mL), and then 1 M tetrabutylammonium fluoride tetrahydrofuran solution (89.60 mg, 342.70 μmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy-d2)benzofuran-3-carboxamide 43 (14.5 mg), yield: 33.90%.

[0939] MS m / z (ESI): 375.2 [M+1]

[0940] 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=8.0Hz,1H),7.54-7.41(m,3H),7.36(d,J=2.0Hz,1H),7.19(s,1H),7.01-7. 00(m,1H),6.40(d,J=2.0Hz,1H),5.03(s,1H),4.51-4.46(m,1H),3.85(s,3H),3.80-3.70(m,2H),2.64(s,3H).

[0941] Example 44

[0942] N-(3,3-Difluoropiperidin-4-yl)-6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole-1-carboxamide

[0943] first step

[0944] 6-((2-Fluorobenzyl)oxy)-2-methyl-1H-indole

[0945] A mixture of 2-methyl-1H-indole-6-ol 44a (1000 mg, 6.79 mmol) and potassium carbonate (1.88 g, 13.59 mmol) was stirred in acetonitrile (40 mL) for 10 min. 1-(bromomethyl)-2-fluorobenzene 44b (1.41 g, 7.47 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 16 h. The reaction was monitored by LCMS. After the reaction was complete, 10 mL of water was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole 44c (1 g), yield: 57.65%.

[0946] MS m / z(ESI): 255.9 [M+1].

[0947] Step 2

[0948] 3,3-Difluoro-4-(6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole-1-carbamate)piperidine-1-carboxylic acid tert-butyl ester

[0949] To a solution of tert-butyl 4-amino-3,3-difluoropiperidin-1-carboxylate hydrochloride 36a (200 mg, 846.53 μmol) in dichloromethane (10 mL), bis(trichloromethyl) carbonate (87.92 mg, 296.29 μmol) was added, and the mixture was stirred for 30 minutes. Then, triethylamine (34.26 mg, 338.61 μmol) was added, and the mixture was stirred at 25 °C for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was reserved for later use. Sodium hydroxide (73.33 mg, 1.83 mmol) was added to a solution of 6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole 44c (195 mg, 763.85 μmol) in tetrahydrofuran (8 mL), and the mixture was stirred at 25 °C for 1 hour. The residue was then added to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, 10 mL of water was added to quench the reaction mixture, followed by extraction with ethyl acetate (30 mL × 3). The combined organic layers were washed with 40 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 44d (100 mg) of tert-butyl 3,3-difluoro-4-(6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole-1-carboxamido)piperidine-1-carboxylic acid, yield: 25.30%. MS m / z (ESI): 518.2 [M+1].

[0950] Step 3

[0951] N-(3,3-Difluoropiperidin-4-yl)-6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole-1-carboxamide

[0952] A solution of tert-butyl 3,3-difluoro-4-(6-((2-fluorobenzyl)oxy)-2-methyl-1H-indole-1-carboxamido)piperidin-1-carboxylate 44d (50 mg, 96.61 μmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (0.4 mL), and the mixture was stirred at 25 °C for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give N-(3,3-difluoro-4-piperidinyl)-6-((2-fluorophenyl)methoxy)-2-methyl-indole-1-carboxamide 44 (4.75 mg), yield: 11.78%.

[0953] MS m / z(ESI): 418.2 [M+1].

[0954] 1 H NMR (400MHz, CD3OD) δ7.53(t,J=7.0Hz,1H),7.41-7.30(m,3H),7.21-7.16(m,1H),7.16-7.09(m,1H),6.83(dd,J= 2.1,8.5Hz,1H),6.26(s,1H),5.19-5.07(m,2H),4.54-4.37(m,1H),3.29-3.22(m,1H),3.12-2.88(m,2H),2.77(br t,J=12.2Hz,1H),2.49(s,3H),2.09-1.77(m,2H).

[0955] Example 45

[0956] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,4-dimethylthiazo-5-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[0957] first step

[0958] methyl 2,4-dimethylthiazole-5-carboxylate

[0959] At 0 °C, thionyl chloride (5.90 g, 3.62 mL) was added to a methanol solution of 2,4-dimethylthiazol-5-carboxylic acid 45a (3 g, 19.09 mmol), and the mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system C) to give methyl 2,4-dimethylthiazol-5-carboxylic acid 45b (2.0 g), yield: 61.21%.

[0960] MS m / z(ESI): 172.0 [M+1]

[0961] Step 2

[0962] (2,4-Dimethylthiazo-5-yl)methane-d2-ol

[0963] To a tetrahydrofuran solution of methyl 2,4-dimethylthiazol-5-carboxylate 45b (500 mg, 2.92 mmol), lithium deuterated aluminum hydroxide (183.98 mg, 4.38 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, water was slowly added to the reaction solution, followed by a 15% sodium hydroxide aqueous solution. The mixture was stirred for 10 minutes, filtered, and the solid was washed with dichloromethane. The filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D) to give (2,4-dimethylthiazol-5-yl)methane-d2-ol 45c (280 mg), yield: 66.03%.

[0964] MS m / z (ESI): 146.4 [M+1]

[0965] Step 3

[0966] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-5-((2,4-dimethylthiazo-5-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[0967] To a tetrahydrofuran solution of tributylphosphine (125.31 mg, 619.36 μmol), (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (80 mg, 154.84 μmol), (2,4-dimethylthiazolyl-5-yl)methane-d2-ol 45c (36.57 mg, 278.71 μmol), and azodicarbonylpiperidine (156.27 mg, 619.36 μmol) were added, and the reaction was carried out under nitrogen protection with stirring at 50 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-((2,4-dimethylthiazolyl-5-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 45d (50 mg), yield: 51.27%.

[0968] MS m / z (ESI): 644.2 [M+1]

[0969] Step 4

[0970] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,4-dimethylthiazo-5-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[0971] A 1M tetrabutylammonium fluoride tetrahydrofuran solution (40.61 mg, 155.31 μmol) was added to a tetrahydrofuran solution of (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-((2,4-dimethylthiazolyl-5-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 45d (50 mg, 77.66 μmol), and stirred at 25°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2,4-dimethylthiazolyl-5-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 45 (22.52 mg), yield: 71.52%.

[0972] MS m / z(ESI): 406.4 [M+1]

[0973] 1H NMR(400MHz, DMSO-d6)δ7.61(d,J=8.0Hz,1H),7.51-7.44(m,2H),7.40(d,J=2.4Hz,1H),7.18(s,1H),6.96(dd ,J=8.8,2.4Hz,1H),4.98(s,1H),4.52-4.45(m,1H),3.79-3.73(m,2H),2.65(s,3H),2.58(s,3H),2.33(s,3H).

[0974] Example 46

[0975] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(phenylmethoxy-d2)benzofuran-3-carboxamide

[0976] first step

[0977] Benzyl-d2-ol

[0978] At 0°C, lithium aluminum hydride (181.2 mg, 4.77 mmol) was added to a solution of methyl benzoate 46a (500 mg, 3.67 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at 25°C for 3 hours. After the reaction was complete, water was slowly added to the reaction solution, followed by a 15% sodium hydroxide aqueous solution, and the mixture was stirred for 10 minutes. The residue was purified by silica gel column chromatography (eluent: system C) to give phenylmethane-d2-ol 46b (360 mg), yield: 88.99%.

[0979] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.27(m,4H),7.26-7.20(m,1H),5.12(s,1H).

[0980] Step 2

[0981] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-5-(phenylmethoxy-d2)benzofuran-3-carboxamide

[0982] To a solution of (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (80 mg, 0.15 mmol) in tetrahydrofuran (2 mL), phenylmethane-d2-ol 46b (25.6 mg, 0.23 mmol), azodicarbonyl dipiperidine (156.27 mg, 0.62 mmol), and tributylphosphine (125.31 mg, 0.62 mmol) were added, and the mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-(phenylmethoxy-d2)benzofuran-3-carboxamide 46c (50 mg), yield: 53.04%.

[0983] MS m / z(ESI): 609.4 [M+1]

[0984] Step 3

[0985] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(phenylmethoxy-d2)benzofuran-3-carboxamide

[0986] Tetrabutylammonium fluoride (38.65 mg, 0.15 mmol) was added to a tetrahydrofuran (3 mL) solution of (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-(phenylmethoxy-d2)benzofuran-3-carboxamide 46c (45 mg, 0.07 mmol) and stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then separated by HPLC (eluent: system B) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-5-(phenylmethoxy-d2)benzofuran-3-carboxamide 46 (11.77 mg), yield: 42.99%.

[0987] MS m / z(ESI): 371.2 [M+1]

[0988] 1H NMR(400MHz, DMSO-d6)δ7.61(d,J=8.0Hz,1H),7.52-7.46(m,4H),7.44-7.38(m,3H),7.37-7.31(m,1H),7.20( s,1H),6.98(dd,J=8.9,2.6Hz,1H),5.03(t,J=5.6Hz,1H),4.54-4.44(m,1H),3.82-3.72(m,2H),2.65(s,3H).

[0989] Example 47

[0990] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-chloro-6-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[0991] first step

[0992] (2-Chloro-6-fluorophenyl)methane-d2-ol

[0993] Methyl 2-chloro-6-fluorobenzoate 47a (600 mg, 3.18 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum deuterated hydride (134 mg, 3.18 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, water, 15% sodium hydroxide solution, and water were slowly added sequentially while stirring the reaction mixture. The mixture was stirred for 10 minutes, then filtered. The solid was washed with dichloromethane, and the filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D) to give (2-chloro-6-fluorophenyl)methane-d2-ol 47b (400 mg), yield: 77.33%.

[0994] MS m / z (ESI): 163.4 [M+1]

[0995] Step 2

[0996] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-5-((2-chloro-6-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[0997] (2-chloro-6-fluorophenyl)methane-d2-ol 47b (38 mg, 0.232 mmol) was dissolved in tetrahydrofuran (5 mL), and (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (80 mg, 0.155 mmol) and tributylphosphine (125 mg, 0.619 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (156 mg, 0.619 mmol) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at 65 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-((2-chloro-6-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 47c (70 mg), yield: 68.37%.

[0998] MS m / z(ESI): 661.3 [M+1]

[0999] Step 3

[1000] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-chloro-6-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1001] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-((2-chloro-6-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 47c (70 mg, 0.106 mmol) was dissolved in tetrahydrofuran (3 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was concentrated and diluted with water. The organic layers were extracted with ethyl acetate and washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-chloro-6-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 47 (16.25 mg), yield: 36.30%.

[1002] MS m / z(ESI): 423.2 [M+1]

[1003] 1H NMR (400MHz, DMSO-d6) δ7.67 (d, J = 8.0Hz, 1H), 7.58-7.41 (m, 5H), 7.36-7.29 (m, 1H), 7.18 (s, 1H), 7. 00(dd,J=9.2,2.8Hz,1H),5.01(t,J=6.0Hz,1H),4.53-4.45(m,1H),3.82-3.70(m,2H),2.66(s,3H).

[1004] Example 48

[1005] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1006] first step

[1007] (2-Fluorophenyl)methane-d2-ol

[1008] 2-Fluorobenzoate 48a (500 mg, 3.24 mmol) was dissolved in tetrahydrofuran (10 mL), and deuterated lithium aluminum hydride (204.26 mg, 4.87 mmol) was added at 0 °C. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate solution, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system C) to give (2-fluorophenyl)methane-d2-ol 48b (370 mg), yield: 89.01%.

[1009] MS m / z(ESI): 129.2 [M+1]

[1010] Step 2

[1011] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1012] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (50 mg, 96.78 μmol), (2-fluorophenyl)methane-d2-ol 48b (14.88 mg, 116.13 μmol) and tributylphosphine (39.16 mg, 193.55 μmol) were dissolved in tetrahydrofuran (2 mL), and azodicarbonylpiperidine (48.84 mg, 193.55 μmol) was added under nitrogen protection. The mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to obtain (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 48c (55 mg), yield: 90.67%.

[1013] MS m / z(ESI): 625.30 [M⁻¹]

[1014] Step 3: (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1015] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 48c (55 mg, 87.75 μmol) was dissolved in tetrahydrofuran (2 mL), and then 1 M tetrabutylammonium fluoride tetrahydrofuran solution (68.83 mg, 263.25 μmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 48 (9.46 mg), yield: 27.76%.

[1016] MS m / z(ESI): 389.3 [M+1]

[1017] 1H NMR (400MHz, DMSO-d6) δ7.74-7.51(m,2H),7.50-7.39(m,4H),7.36-7.14(m,3H),6.98(dd,J=9. 2,2.8Hz,1H),5.02(d,J=5.4Hz,1H),4.48(d,J=6.8Hz,1H),3.74(d,J=5.6Hz,2H),2.64(s,3H).

[1018] Example 49

[1019] N-(3-carbamoyltetrahydrofuran-3-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1020] first step

[1021] 3-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carbamate)tetrahydrofuran-3-carboxylic acid methyl ester

[1022] Add 3-aminotetrahydrofuran-3-carboxylic acid methyl hydrochloride 49a (89.22 mg, 491.25 μmol) and N,N- to a solution of 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (100 mg, 327.50 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (149.43 mg, 3.00 μmol) in N,N-dimethylformamide to a solution (5 mL). Diisopropylethylamine (211.63 mg, 1.64 mmol) was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (eluent: system D) to give methyl 3-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)tetrahydrofuran-3-carboxylate 49b (61 mg), yield: 56.48%.

[1023] MS m / z(ESI): 433.3 [M+1]

[1024] Step 2

[1025] N-(3-carbamoyltetrahydrofuran-3-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1026] 61 mg (141.05 μmol) of methyl 3-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamidyl)tetrahydrofuran-3-carboxylate 49b was dissolved in 20 mL of 7 M ammonia-methanol solution and stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by HPLC (eluent: system B) to give N-(3-carbamoyltetrahydrofuran-3-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 49 (22.19 mg), yield: 37.69%.

[1027] MS m / z(ESI): 417.9 [M+1]

[1028] 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.70(s,1H),7.48(d,J=8.8Hz,1H),7.32(d,J=2.4Hz,1H),7.13-7.05(m,2H),6.98(dd ,J=9.2,2.8Hz,1H),4.19(d,J=9.2Hz,1H),3.95(d,J=9.6Hz,1H),3.89-3.84(m,2H),2.65-2.61(m,6H),2.39-2.33(m,2H).

[1029] Example 50

[1030] N-(4-carbamoyltetrahydro-2H-pyran-4-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1031] first step

[1032] 4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carbamate)tetrahydro-2H-pyran-4-carboxylic acid methyl ester

[1033] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (80 mg, 0.262 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 4-aminotetrahydro-2H-pyran-4-carboxylic acid methyl ester hydrochloride 50a (63 mg, 0.393 mmol), N,N-diisopropylethylamine (102 mg, 0.786 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (149 mg, 0.393 mmol) were added. The mixture was stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system D) to give methyl 4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylate 50b (90 mg), yield: 76.73%.

[1034] MS m / z(ESI): 447.2 [M+1]

[1035] Step 2

[1036] 4-(2-Methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carbamate)tetrahydro-2H-pyran-4-carboxylic acid

[1037] 4-(2-methyl-5-((2-methylthiazol-5-yl)methoxy-d2)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylic acid methyl ester 50b (80 mg, 0.179 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Sodium hydroxide (29 mg, 0.717 mmol) dissolved in water (1 mL) was added, and the mixture was stirred at 50 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to obtain 4-(2-methyl-5-((2-methylthiazol-5-yl)methoxy-d2)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylic acid 50c (70 mg). This unpurified product was directly used in the next reaction, with a yield of 90.34%.

[1038] MS m / z(ESI): 433.3 [M+1]

[1039] Step 3

[1040] N-(4-carbamoyltetrahydro-2H-pyran-4-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1041] 50c (70 mg, 0.162 mmol) of 4-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylic acid was dissolved in N,N-dimethylformamide (3 mL), and ammonium chloride (35 mg, 0.647 mmol), N,N-diisopropylethylamine (84 mg, 0.647 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (123 mg, 0.324 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was complete, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system B) to give N-(4-carbamoyltetrahydro-2H-pyran-4-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 50 (62.10 mg), yield: 36.30%. MS m / z (ESI): 432.2 [M+1]

[1042] 1 H NMR (400MHz, DMSO-d6) δ7.81(s,1H),7.69(s,1H),7.49(d,J=8.8Hz,1H),7.29(d,J=2.8Hz,1H),7.0 7-6.91(m,3H),3.82-3.72(m,2H),3.69-3.59(m,2H),2.64(s,3H),2.64(s,3H),2.14-1.96(m,4H).

[1043] Example 51

[1044] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)-N-(2-oxopyrrolidine-3-yl)benzofuran-3-carboxamide

[1045] first step

[1046] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)-N-(2-oxopyrrolidine-3-yl)benzofuran-3-carboxamide

[1047] To a solution of 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 0.163 mmol) in N,N-dimethylformamide (1.98 mL), N,N-diisopropylethylamine (84.65 mg, 0.655 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (93.39 mg, 0.245 mmol) and 3-aminopyrrolidone-2-one hydrochloride 51a (34.43 mg, 0.327 mmol) were added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by HPLC (eluent: system B) to give 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)-N-(2-oxopyrrolidine-3-yl)benzofuran-3-carboxamide 51 (27.0 mg), yield: 42.56%.

[1048] MS m / z(ESI): 388.2 [M+1]

[1049] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=8.5Hz,1H),7.89(s,1H),7.72(s,1H),7.47(d,J=8.9Hz,1H),7.38(d,J=2.5Hz,1H), 7.02-6.92(m,1H),4.67-4.55(m,1H),3.30-3.19(m,2H),2.63(d,J=7.9Hz,6H),2.45-2.35(m,1H),2.11-1.96(m,1H).

[1050] Example 52

[1051] N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1052] first step

[1053] N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1054] 2-Methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (50 mg, 163.75 μmol), 2-amino-2-methylpropionamide hydrochloride 52a (20.07 mg, 196.50 μmol) and N,N-diisopropylethylamine (42.33 mg, 327.50 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (74.71 mg, 196.50 μmol) were added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by HPLC (eluent: system B) to give N-(1-amino-2-methyl-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamide 52 (56.1 mg), yield: 87.97%. MS m / z (ESI): 390.0 [M+1]

[1055] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=8.5Hz,1H),7.89(s,1H),7.72(s,1H),7.47(d,J=8.9Hz,1H),7.38(d,J=2.5Hz,1H), 7.02-6.92(m,1H),4.67-4.55(m,1H),3.30-3.19(m,2H),2.63(d,J=7.9Hz,6H),2.45-2.35(m,1H),2.11-1.96(m,1H).

[1056] Example 53

[1057] (S)-3-hydroxy-2-(8-((2-methylthiazo-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionamide

[1058] first step

[1059] Methyl (S)-3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropionate

[1060] Imidazole (736.87 mg, 10.82 mmol) and tert-butyldiphenylchlorosilane (2.52 g, 9.16 mmol) were added to a dichloromethane solution of (S)-2,3-dihydroxypropionate 53a (1 g, 8.33 mmol) in an ice bath (12 mL). The mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give (S)-3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropionate methyl ester 53b (2.5 g), yield: 83.75%.

[1061] 1 H NMR (400MHz, CDCl3) δ7.70-7.61(m,4H),7.50-7.36(m,6H),4.26(t,J=2.9Hz,1H),4.03-3.90(m,2H),3.80(s,3H),1.05(s,9H)

[1062] Step 2

[1063] Methyl (R)-2-bromo-3-((tert-butyldiphenylsilyl)oxy)propionate

[1064] Under a nitrogen atmosphere, methyl (S)-3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropionate 53b (234 mg, 652.72 μmol) and triphenylphosphine (273.92 mg, 1.04 mL) were dissolved in 10 mL of dichloromethane. After cooling, carbon tetrabromide (346.33 mg, 1.04 mmol) was added. The reaction solution was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sulfuric acid, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: C system) to give methyl (R)-2-bromo-3-((tert-butyldiphenylsilyl)oxy)propionate 53c (32 mg), yield: 11.63%.

[1065] MS m / z(ESI): 421.0 [M+1]

[1066] Step 3

[1067] O-(4-bromophenyl)hydroxylamine

[1068] Potassium tert-butoxide (324.30 mg, 2.89 mL) was added to a 5 mL methanol solution of bromophenol 53d (500 mg, 2.89 mL), and the mixture was stirred at room temperature for 10 minutes. The solution was then concentrated under reduced pressure. The residue was dissolved in dichloromethane at 0 °C, and 2,4,6-trimethylbenzenesulfonic acid amino (622.14 mg, 2.89 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give O-(4-bromophenyl)hydroxylamine 53e (540 mg), yield: 99.38%.

[1069] MS m / z (ESI): 187.9 [M+1]

[1070] Step 4

[1071] 8-Bromo-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylic acid tert-butyl ester

[1072] O-(4-bromophenyl)hydroxylamine 53e (540 mg, 2.87 mL) was dissolved in 5 mL of acetic acid and 0.5 mL of sulfuric acid. Tert-butyl 4-oxopiperidinium-1-carboxylate 53f (858.36 mg, 4.31 mL) was added in portions. The mixture was stirred at room temperature for 10 minutes, then heated to 120 °C and stirred for 3 hours. After the reaction was complete, the reaction was quenched with sodium hydroxide, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in water (6 mL) and isopropanol (5 mL). In this reaction, potassium carbonate (793.85 mg, 5.74 mL) and tert-butyl carbonate (752.17 mg, 3.45 mL) were added to the above mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: C system) to give 53 g (500 mg) of tert-butyl 8-bromo-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylate, yield: 49.43%.

[1073] MS m / z(ESI): 352.1 [M+1]

[1074] Step 5

[1075] 8-((2-methylthiazolyl-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylic acid tert-butyl ester

[1076] To a solution of 53 g (300 mg, 851.73 μmol) of 8-bromo-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylic acid tert-butyl ester in dioxane (3 mL), (2-methylthiazolyl-5-yl)methanol 1a (132.03 mg, 1.02 mmol), cesium carbonate (555.02 mg, 1.70 mmol), tris(dibenzylacetone)palladium (77.99 mg, 85.17 μmol), and 2-(di-tert-butylphosphine)-3,6- Dimethoxy-2'-4'-6'tri-1-propyl-1,1'-bisphenyl (123.85 mg, 255.52 μmol) was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl 8-((2-methylthiazolyl-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylic acid 53 h (138 mg), yield: 40.46%.

[1077] MS m / z(ESI): 401.1 [M+1]

[1078] Step 6

[1079] 8-((2-methylthiazolyl-5-yl)methoxy)-1,2,3,4-tetrahydrobenzofurano[3,2-c]pyridine

[1080] 3 mL of hydrochloric acid was added to 2 mL of dichloromethane containing 53 h (300 mg, 749.08 μmol) of 8-((2-methylthiazol-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylic acid tert-butyl ester 53 h. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 53 i (180 mg) of 8-((2-methylthiazol-5-yl)methoxy)-1,2,3,4-tetrahydrobenzofurano[3,2-c]pyridine 53 i, yield: 80%. MS m / z (ESI): 301.1 [M+1]

[1081] Step 7

[1082] Methyl (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazo-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionate

[1083] 8-((2-methylthiazolyl-5-yl)methoxy)-1,2,3,4-tetrahydrobenzofurano[3,2-c]pyridine 53i (120 mg, 399.50 μmol), (R)-2-bromo-3-((tert-butyldiphenylsilyl)oxy)propionate methyl ester 53c (420.87 mg, 998.75 μmol), and potassium carbonate (143.55 mg, 1.04 mmol) were dissolved in 5 mL of acetonitrile. The mixture was heated at 80°C for 16 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system D) to give 53j (80mg) of methyl (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazolyl-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionate, yield: 31.24%.

[1084] MS m / z (ESI): 641.2 [M+1]

[1085] Step 8

[1086] (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazo-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionic acid

[1087] To 2 mL of dichloroethane containing methyl (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-(((2-methylthiazol-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionate 53k (75 mg, 117.03 μmol), trimethyltin hydroxide (253.94 mg, 1.40 mL) was added. The reaction was carried out at 80 °C for 16 hours. After the reaction was completed, the aqueous solution was adjusted to acidity, extracted with ethyl acetate, and concentrated under reduced pressure to obtain (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazol-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionate 53k (60 mg), yield: 81.79%.

[1088] MS m / z(ESI): 627.2 [M+1]

[1089] Step 9

[1090] (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazo-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionamide

[1091] Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (66.72 mg, 175.48 μmol) and N,N-diisocyanate to a solution of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazolyl-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionic acid at 53 kJ (55 mg, 87 μmol) in N,N-dimethylformamide. Propylethylamine (56.70 mg, 438.71 μmol) was reacted at room temperature for half an hour. After the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system D) to give (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-((2-methylthiazol-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionamide 53 l (45 mg), yield: 81.95%. MS m / z (ESI): 626.2 [M+1]

[1092] Step 10

[1093] (S)-3-hydroxy-2-(8-((2-methylthiazo-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionamide

[1094] (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(8-(((2-methylthiazolyl-5-yl)methoxy)-3,4-dihydrobenzofuran[3,2-c]pyridin-2(1H)-yl)propionamide 53L (40 mg, 63 μmol) and tetrabutylammonium fluoride (50.13 mg, 191.74 μmol) were dissolved in 3 mL of tetrahydrofuran and stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was poured into… The extract was obtained in water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give (S)-3-hydroxy-2-(8-(((2-methylthiazolyl-5-yl)methoxy)-3,4-dihydrobenzofurano[3,2-c]pyridin-2(1H)-yl)propionamide 53 (9.37 mg), yield: 37.84%.

[1095] MS m / z(ESI): 388.2 [M+1]

[1096] 1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.41-7.33(m,2H),7.13-7.07(m,2H),6.87-6.83(m,1H),5.31(s,2H ),4.67(s,1H),3.88-3.83(m,2H),3.76-3.60(m,3H),3.05-2.97(m,2H),2.82-2.77(m,2H),2.64(s,3H).

[1097] Example 54

[1098] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxamide

[1099] first step

[1100] (2-(trifluoromethyl)pyridin-3-yl)methane-d2-ol

[1101] 500 mg (2.44 mmol) of methyl 2-trifluoromethylnicotinate 54a was dissolved in 10 mL of tetrahydrofuran. Lithium aluminum deuterate (154 mg, 3.66 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, water, 15% sodium hydroxide solution, and water were slowly added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was then filtered, and the solid was washed with dichloromethane. The filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give (2-(trifluoromethyl)pyridin-3-yl)methane-d2-ol 54b (250 mg), yield: 57.26%. MS m / z (ESI): 180.1 [M+1]

[1102] Step 2

[1103] 2-Methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxylic acid ethyl ester

[1104] (2-(trifluoromethyl)pyridin-3-yl)methane-d2-ol 54b (98 mg, 0.545 mmol) was dissolved in tetrahydrofuran (5 mL), and ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (100 mg, 0.454 mmol) and tributylphosphine (184 mg, 0.908 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (229 mg, 0.908 mmol) dissolved in tetrahydrofuran (3 mL) was slowly added dropwise to the reaction solution. The mixture was stirred at 65 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give ethyl 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxylate 54c (110 mg), yield: 63.52%.

[1105] MS m / z(ESI): 382.2 [M+1]

[1106] Step 3

[1107] 2-Methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxylic acid

[1108] Ethyl 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxylic acid 54c (110 mg, 0.288 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Sodium hydroxide (46 mg, 1.15 mmol) dissolved in water (1 mL) was added, and the mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a pale yellow solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to give 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxylic acid 54d (90 mg), yield: 88.31%.

[1109] MS m / z(ESI): 354.4 [M+1]

[1110] Step 4

[1111] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxamide

[1112] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (54 mg, 0.382 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (165 mg, 1.27 mmol) was added. The mixture was stirred at 25 °C for 5 minutes. 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxylic acid 54d (90 mg, 0.255 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (194 mg, 0.510 mmol) were added to the reaction solution and stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy-d2)benzofuran-3-carboxamide 54 (65.77 mg), yield: 52.88%.

[1113] MS m / z(ESI): 440.2 [M+1]

[1114] 1 H NMR (400MHz, DMSO-d6) δ8.75(dd,J=4.8,1.6Hz,1H),8.28(dd,J=7.6,1.2Hz,1H),7.79(dd,J=8.0,4.8Hz,1H),7.63(d,J=8.0Hz,1H),7.51(d,J=8.8Hz, 1H),7.47(s,1H),7.44(d,J=2.4Hz,1H),7.17(s,1H),7.00(dd,J=8.8,2.8H z,1H),4.96(s,1H),4.54-4.44(m,1H),3.75(d,J=5.2Hz,2H),2.66(s,3H).

[1115] Example 55

[1116] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxamide

[1117] first step

[1118] (tetrahydro-2H-pyran-4-yl)methane-d2-ol

[1119] Methyl tetrahydro-2H-pyran-4-carboxylate 55a (500 mg, 3.47 mmol) was dissolved in tetrahydrofuran (10 mL). Lithium aluminum deuterate (218 mg, 5.20 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, water, 15% sodium hydroxide solution, and water were added slowly in sequence, and the mixture was stirred for 10 minutes. The mixture was filtered, and the solid was washed with dichloromethane. The filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give (tetrahydro-2H-pyran-4-yl)methane-d2-ol 55b (300 mg), yield: 73.20%.

[1120] 1 H NMR (400MHz, CDCl3) δ4.08-3.95(m,2H),3.42(td,J=11.6,2.0Hz,2H),1.83-1.60(m,3H),1.41-1.28(m,2H).

[1121] Step 2

[1122] 2-Methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxylic acid ethyl ester

[1123] (Tetrahydro-2H-pyran-4-yl)methane-d2-ol 55b (64 mg, 0.545 mmol) was dissolved in tetrahydrofuran (5 mL), and ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (100 mg, 0.454 mmol) and tributylphosphine (184 mg, 0.908 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (229 mg, 0.908 mmol) dissolved in tetrahydrofuran (3 mL) was slowly added dropwise to the reaction solution. The mixture was stirred at 65 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give ethyl 2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxylate 55c (70 mg), yield: 48.12%.

[1124] MS m / z(ESI): 321.2 [M+1]

[1125] Step 3

[1126] 2-Methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxylic acid

[1127] Ethyl 2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxylic acid 55c (70 mg, 0.218 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Sodium hydroxide (35 mg, 0.874 mmol) dissolved in water (1 mL) was added, and the mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to weakly acidic with saturated citric acid aqueous solution, and a solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to obtain 2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxylic acid 55d (60 mg), yield: 93.94%.

[1128] MS m / z(ESI): 293.3 [M+1]

[1129] Step 4

[1130] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxamide

[1131] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (43 mg, 0.308 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (133 mg, 1.03 mmol) was added. The mixture was stirred at 25 °C for 5 minutes. 2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxylic acid 55d (60 mg, 0.205 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (156 mg, 0.411 mmol) were added to the reaction solution and stirred at 25 °C for 20 minutes. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy-d2)benzofuran-3-carboxamide 55 (45.38 mg), yield: 58.43%.

[1132] MS m / z(ESI): 379.2 [M+1]

[1133] 1H NMR (400MHz, DMSO-d6) δ7.60(d,J=8.0Hz,1H),7.51-7.42(m,2H),7.31(d,J=2.4Hz,1H),7.18(s,1H),6.91(dd,J=8.8,2.8Hz,1H),4.99(t,J=5.6Hz,1 H),4.54-4.42(m,1H),3.93-3.84(m,2H),3.81-3.68(m,2H),3.39-3.32(m, 2H),2.64(s,3H),2.11-1.97(m,1H),1.78-1.63(m,2H),1.43-1.26(m,2H).

[1134] Example 56

[1135] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2-methylthiazo-5-yl)methyl)thio)benzofuran-3-carboxamide

[1136] first step

[1137] 2-Methyl-5-(((2-methylthiazo-5-yl)methyl)thio)benzofuran-3-carboxylic acid ethyl ester

[1138] Under nitrogen protection, potassium carbonate (61.99 mg, 448.5 μmol), ethyl 5-bromo-2-methyl-benzofuran-3-carboxylate 16c (137.57 mg, 485.90 μmol), tris(dibenzylpyrone)palladium (34.23 mg, 37.38 μmol), and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (35.64 mg, 74.75 μmol) were added to a solution of S-((2-methylthiazolyl-5-yl)methyl)ethyl sulfate 56a (70 mg, 373.77 μmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL), and the mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (elution: system A) to give 56b (55 mg) of ethyl 2-methyl-5-(((2-methylthiazolyl-5-yl)methyl)thio)benzofuran-3-carboxylate, yield: 42.35%.

[1139] MS m / z(ESI): 348.0 [M+1].

[1140] Step 2

[1141] 2-Methyl-5-(((2-methylthiazo-5-yl)methyl)thio)benzofuran-3-carboxylic acid

[1142] Ethyl 2-methyl-5-(((2-methylthiazol-5-yl)methyl)thio)benzofuran-3-carboxylic acid 56b (45 mg, 129.51 μmol) was dissolved in ethanol (1.2 mL) and water (0.3 mL), and sodium hydroxide (25.90 mg, 647.57 μmol) was added. The mixture was stirred at 70 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with 1 N hydrochloric acid, diluted with water (15 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-5-[(2-methylthiazol-5-yl)methylthio]benzofuran-3-carboxylic acid 56c (40 mg), yield: 96.70%.

[1143] MS m / z(ESI): 320.0 [M+1].

[1144] Step 3

[1145] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(((2-methylthiazo-5-yl)methyl)thio)benzofuran-3-carboxamide

[1146] To a solution of 2-methyl-5-[(2-methylthiazolyl-5-yl)methylthioalkyl]benzofuran-3-carboxylic acid 56c (30 mg, 93.93 μmol) in N,N-dimethylformamide (1.5 mL), (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (19.80 mg, 140.89 μmol), N-ethyl-N-isopropylpropyl-2-amine (36.42 mg, 281.78 μmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (42.86 mg, 112.71 μmol) and 1-hydroxy-7-azabenzotriazole (12.78 mg, 93.93 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, water (10 mL) was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was preparatively separated by a C18 reversed-phase column (elution: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(((2-methylthiazolyl-5-yl)methyl)thio)benzofuran-3-carboxamide 56 (20.9 mg), yield: 54.88%.

[1147] MS m / z(ESI): 406.2 [M+1].

[1148] 1 H NMR (400MHz, CD3OD) δ7.88 (d, J=1.7Hz, 1H), 7.45-7.41 (m, 1H), 7.39 (s, 1H), 7.33 (dd, J=1.8, 8.6Hz,1H),4.68(t,J=4.9Hz,1H),4.37(s,2H),3.99-3.91(m,2H),2.70(s,3H),2.67(s,3H).

[1149] Example 57

[1150] (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1151] first step

[1152] (S)-2-amino-3-hydroxy-2-methylpropionate

[1153] (S)-2-amino-3-hydroxy-2-methylpropionic acid 57a (100 mg, 839.50 μmol) was dissolved in 5 mL of methanol, and thionyl chloride (644.20 mg, 5.41 mmol) was slowly added. The mixture was stirred at 75 °C for 6 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give methyl (S)-2-amino-3-hydroxy-2-methylpropionic acid 57b (100 mg), yield: 89%. This methyl ester was used directly in the next reaction without purification. MS m / z (ESI): 134.1 [M+1]

[1154] Step 2

[1155] Methyl (S)-3-hydroxy-2-methyl-2-(2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carbamoyl)propionate

[1156] Methyl (S)-2-amino-3-hydroxy-2-methylpropionate 57b (100 mg, 751.06 μmol) and 2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxylic acid 22d (114.67 mg, 375.53 μmol) were dissolved in 5 mL In N,N-dimethylformamide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (571.15 mg, 1.50 mmol) and N,N-diisopropylethylamine (485.34 mg, 3.76 mmol) were added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system B) to give methyl (S)-3-hydroxy-2-methyl-2-(2-methyl-5-((2-methylthiazolyl-5-yl)methoxy-d2)benzofuran-3-carboxamido)propionate 57c (120 mg), yield: 38.00%.

[1157] MS m / z(ESI): 421.1 [M+1]

[1158] Step 3

[1159] (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazo-5-yl)methoxy-d2)benzofuran-3-carboxamide

[1160] Methyl (S)-3-hydroxy-2-methyl-2-(2-methyl-5-((2-methylthiazol-5-yl)methoxy-d2)benzofuran-3-carboxamido)propionate 57c was dissolved in 5 mL of ammonia-methanol solution and stirred at 70 °C for 48 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-5-((2-methylthiazol-5-yl)methoxy-d2)benzofuran-3-carboxamide 57 (15.95 mg), yield: 15.04%.

[1161] MS m / z(ESI): 406.2 [M+1]

[1162] 1 H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.63(s,1H),7.51-7.43(m,3H),7.31(s,1H),6.98(dd,J=8.8,2 .4Hz,1H),5.17-5.09(m,1H),4.02-3.93(m,1H),3.82-3.73(m,1H),2.68-2.62(m,6H),1.54(s,3H).

[1163] Example 58

[1164] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-6-(benzyloxy)-2-methyl-1H-indole-1-carboxamide

[1165] first step

[1166] 6-(benzyloxy)-2-methyl-1H-indole

[1167] 2-Methyl-1H-indole-6-ol 44a (1.0 g, 6.79 mmol) was dissolved in N,N-dimethylformamide (20 mL), and benzyl bromide 58a (1.51 g, 8.83 mmol) and potassium carbonate (2.82 g, 20.38 mmol) were added. The mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 6-(benzyloxy)-2-methyl-1H-indole 58b (880 mg), yield: 54.58%.

[1168] MS m / z(ESI): 238.2 [M+1].

[1169] Step 2

[1170] 6-(benzyloxy)-2-methyl-1H-indole-1-carboxylic acid-4-nitrophenyl ester

[1171] 6-(benzyloxy)-2-methyl-1H-indole 58b (700 mg, 2.95 mmol) was dissolved in acetonitrile (20 mL), and sodium carbonate (156 mg, 1.47 mmol) and di(p-nitrobenzene) carbonate (15 g, 1.35 g, 4.42 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give 6-(benzyloxy)-2-methyl-1H-indole-1-carboxylic acid-4-nitrophenyl ester 58c (800 mg), yield: 67.39%.

[1172] MS m / z(ESI): 403.3 [M+1]

[1173] Step 3

[1174] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-6-(benzyloxy)-2-methyl-1H-indole-1-carboxamide

[1175] 58c of 6-(benzyloxy)-2-methyl-1H-indole-1-carboxylic acid-4-nitrophenyl ester (700 mg, 1.74 mmol) was dissolved in tetrahydrofuran (15 mL), and N-methylimidazolium (714 mg, 8.70 mmol), N,N-diisopropylethylamine (1.12 g, 8.70 mmol) and (S)-2-amino-3-((tert-butyldiphenylsilyl)oxy)propionamide 15i (1.79 g, 5.22 mmol) were added. The reaction mixture was stirred at 60 °C for 18 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-6-(benzyloxy)-2-methyl-1H-indole-1-carboxamide 58d (800 mg), yield: 75.91%.

[1176] MS m / z (ESI): 606.5 [M+1]

[1177] Step 4

[1178] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-6-(benzyloxy)-2-methyl-1H-indole-1-carboxamide

[1179] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-6-(benzyloxy)-2-methyl-1H-indole-1-carboxamide 58d (50 mg, 0.083 mmol) was dissolved in tetrahydrofuran (2.5 mL), and 65% hydrofluoric acid pyridine solution (570 mg, 5.75 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-6-(benzyloxy)-2-methyl-1H-indole-1-carboxamide 58 (2.93 mg), yield: 9.66%.

[1180] MS m / z(ESI): 368.2 [M+1]

[1181] 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=8.0Hz,1H),7.78(d,J=2.0Hz,1H),7.58-7.48(m,2H),7.47-7.41(m,1H),7.38-7.29(m,2H),7.24(s,1H ),6.79(dd,J=8.4,2.0Hz,1H),6.30(s,1H),5.21-5.12(m,2H),5.05(t,J=5.6Hz,1H),4.47-4.38(m,1H),3.86-3.69(m,2H),2.47(s,3H).

[1182] Example 59

[1183] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1184] first step

[1185] (2-Methoxypyridin-3-yl)methane-d2-ol

[1186] Lithium aluminum deuteride (502 mg, 11.960 mmol) was dissolved in 5 mL of tetrahydrofuran solution. Methyl 2-methoxynicotinic acid ester 59a (1.0 g, 5.980 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 2 mL of water and 0.5 mL of 15% sodium hydroxide solution were added. The mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give (2-methoxypyridin-3-yl)methane-d2-ol 59b (792 mg), yield: 93.79%. MS m / z (ESI): 142.0 [M+1]

[1187] Step 2

[1188] 5-((2-methoxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[1189] Ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (100 mg, 0.454 mmol) was dissolved in tetrahydrofuran (5 mL). (2-methoxypyridin-3-yl)methane-d2-ol 59b (77 mg, 0.544 mmol) and tributylphosphine (184 mg, 0.908 mmol) were added. Under nitrogen protection, azodicarbonylpiperidine (229 mg, 0.908 mmol) dissolved in tetrahydrofuran (3 mL) was slowly added dropwise to the reaction mixture. The mixture was stirred at 60 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give ethyl 5-((2-methoxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylate 59c (150 mg), yield: 96.20%.

[1190] MS m / z(ESI): 344.3 [M+1]

[1191] Step 3

[1192] 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[1193] Ethyl 5-((2-methoxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylate 59c (500 mg, 1.460 mmol) was dissolved in 4M 1,4-dioxane hydrochloric acid solution (5 mL). The solution was stirred at 90 °C for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain ethyl 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylate 59d (200 mg). This ethyl 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylate 59d was directly used in the next reaction without purification. The yield was 41.70%.

[1194] MS m / z(ESI): 330.3 [M+1]

[1195] Step 4

[1196] 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylic acid

[1197] Ethyl 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylic acid 59d (150 mg, 0.455 mmol) was dissolved in tetrahydrofuran (4 mL) and methanol (4 mL), and an aqueous solution of sodium hydroxide (36.43 mg, 0.911 mmol) (2 mL) was added. The mixture was stirred at 65 °C for 4 hours. After the reaction was completed, the pH was adjusted to weakly acidic with 1 N hydrochloric acid solution, and a solid precipitated. The solid was filtered under reduced pressure, washed several times with water, and dried to obtain 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylic acid 59e (80 mg), yield: 58.30%.

[1198] MS m / z(ESI): 302.1 [M+1]

[1199] Step 5

[1200] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1201] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (35 mg, 0.248 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (107 mg, 0.829 mmol) was added. 5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxylic acid 59e (50 mg, 0.166 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (50.48 mg, 0.133 mmol), stirred at 25 °C for 20 minutes, after the reaction was completed, added aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 3), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-hydroxypyridin-3-yl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 59 (2.14 mg), yield: 3.33%.

[1202] MS m / z(ESI): 388.2 [M+1]

[1203] 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),7.66-7.55(m,2H),7.52-7.44(m,2H),7.39(q,J=2.9Hz,2H),7.17(s,1H),6.96(dd,J=8.9 ,2.6Hz,1H),6.23(t,J=6.6Hz,1H),5.03(t,J=5.7Hz,1H),4.48(dt,J=7.9,5.0Hz,1H),3.76(td,J=5.4,1.8Hz,2H),2.65(s,3H).

[1204] Example 60

[1205] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-(((2-methylthiazo-5-yl)methyl)thio)-1H-indole-1-carboxamide

[1206] first step

[1207] 2-Methyl-5-(((2-methyl-1H-indol-6-yl)thio)methyl)thiazole

[1208] Under a nitrogen atmosphere, 6-bromo-2-methyl-1H-indole 60a (100.95 mg, 480.56 μmol), potassium carbonate (53.13 mg, 384.45 μmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (30.55 mg, 64.07 μmol), and tris(dibenzylideneacetone)dipalladium (29.34 mg, 32.04 μmol) were added to a solution of S-((2-methylthiazolyl-5-yl)methyl)ethyl sulfate 56a (60 mg, 320.37 μmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL), and the mixture was stirred at 100 °C for 16 hours. After the reaction was completed, water (10 mL) was added at 25 °C to quench the reaction, then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (elution: system A) to give 2-methyl-5-(((2-methyl-1H-indol-6-yl)thio)methyl)thiazole 60b (24 mg), yield: 27.30%.

[1209] MS m / z(ESI): 275.0 [M+1].

[1210] Step 2

[1211] 2-Methyl-6-(((2-methylthiazo-5-yl)methyl)thio)-1H-indole-1-carboxylic acid p-nitrobenzene ester

[1212] At 0 °C and under a nitrogen atmosphere, 60% sodium hydride (10.49 mg, 262.39 μmol) was added to a solution of 2-methyl-5-(((2-methyl-1H-indol-6-yl)thio)methyl)thiazole 60b (24 mg, 87.46 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 20 °C for 20 minutes, and then di(p-nitrobenzene) carbonate 60c (47.89 mg, 157.43 μmol) was added. The mixture was stirred at 20 °C for 16 hours. After the reaction was completed, water (10 mL) was added to quench the reaction mixture, then diluted with ethyl acetate (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (elution: system A) to give 60d (20 mg) of 2-methyl-6-(((2-methylthiazolyl-5-yl)methyl)thio)-1H-indole-1-carboxylic acid p-nitrobenzene ester, yield: 52.03%.

[1213] MS m / z(ESI): 440.0 [M+1].

[1214] Step 3

[1215] (S)-N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-6-(((2-methylthiazo-5-yl)methyl)thio)-1H-indole-1-carboxamide

[1216] To a tetrahydrofuran (0.8 mL) solution of 2-methyl-6-(((2-methylthiazolyl-5-yl)methyl)thio)-1H-indole-1-carboxylic acid p-nitrobenzene 60d (20 mg, 45.51 μmol), (S)-2-amino-3-(tert-butyl(dimethyl)silyl)oxy-propionamide 60e (19.87 mg, 91.01 μmol), 1-methyl-1H-imidazolium (11.21 mg, 136.52 μmol), and N-ethyl-N-isopropylpropane-2-amine (17.64 mg, 136.52 μmol) were added, and the mixture was stirred at 70 °C for 16 hours. After the reaction was completed, water (10 mL) was added to quench the reaction mixture, and then it was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (elution: system A) to give (S)-N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-6-(((2-methylthiazolyl-5-yl)methyl)thio)-1H-indole-1-carboxamide 60f (18 mg), yield: 76.25%.

[1217] MS m / z(ESI): 519.2 [M+1].

[1218] Step 4

[1219] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-(((2-methylthiazo-5-yl)methyl)thio)-1H-indole-1-carboxamide

[1220] Add 2,2,2-trifluoroacetic acid (153.50 mg, 1.35 mmol) to a solution of (S)-N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-6-(((2-methylthiazolyl-5-yl)methyl)thio)-1H-indole-1-carboxamide 60f (15 mg, 28.91 μmol) in dichloromethane (0.5 mL) and stir at 20 °C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (elution: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-(((2-methylthiazolyl-5-yl)methyl)thio)-1H-indole-1-carboxamide 60 (3.8 mg), yield: 32.49%.

[1221] MS m / z(ESI): 405.1 [M+1].

[1222] 1H NMR (400MHz, CD3OD) δ7.98(s,1H),7.36(d,J=8.1Hz,1H),7.32(s,1H),7.12(dd,J=1.4,8.1Hz, 1H),6.33(s,1H),4.63-4.57(m,1H),4.34(s,2H),4.01-3.91(m,2H),2.63(s,3H),2.56(s,3H).

[1223] Example 61

[1224] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(1-(2-methylthiazo-5-yl)cyclopropoxy)benzofuran-3-carboxamide

[1225] first step

[1226] 1-(2-methylthiazolyl-5-yl)cyclopropane-1-ol

[1227] Under nitrogen protection, methyl 2-methylthiazol-5-carboxylate 61a (1 g, 6.36 mmol) was dissolved in tetrahydrofuran (20 mL), and tetraisopropoxytitanium (361.62 mg, 1.27 mmol) was added dropwise at 0 °C, with stirring for 10 min. Ethyl magnesium bromide diethyl ether solution (1.91 g, 14.31 mmol) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS. After the reaction was complete, saturated ammonium chloride (20 mL) and water (5 mL) were added, followed by extraction with ethyl acetate (20 mL × 3). The organic layer was washed with saturated sodium chloride solution (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(2-methylthiazol-5-yl)cycloprop-1-ol 61b (500 mg), yield: 34.94%.

[1228] MS m / z (ESI): 156.1 [M+1].

[1229] Step 2

[1230] 2-Methyl-5-(1-(2-methylthiazo-5-yl)cyclopropoxy)benzofuran-3-carboxylic acid ethyl ester

[1231] 1-(2-methylthiazolyl-5-yl)cyclopropane-1-ol 61b (150 mg, 966.39 μmol), ethyl 5-bromo-2-methylbenzofuran-3-carboxylate 16c (410.40 mg, 1.45 mmol), and 9-(dicyclohexyl(2,4,6-tris(prop-2-yl)-3-(prop-2-yloxy)-(1,1-biphenyl)-2-yl)phosphoryl)-9- (Methanesulfonyloxy)-8-methyl-8-aza-9-palladium tricyclo[8.4.0.02,7]tetradec-1(10),2,4,6,11,13-hexane-8-onium-9,9-dichloride (71.01 mg, 77.31 μmol) and potassium phosphate (615.40 mg, 2.90 mmol) were dissolved in toluene (5 mL) and stirred at 100 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 61c (110 mg) of ethyl 2-methyl-5-(1-(2-methylthiazolyl-5-yl)cyclopropoxy)benzofuran-3-carboxylate, yield: 17.52%. MS m / z (ESI): 358.1 [M+1].

[1232] Step 3

[1233] 2-Methyl-5-(1-(2-methylthiazo-5-yl)cyclopropoxy)benzofuran-3-carboxylic acid

[1234] Ethyl 2-methyl-5-(1-(2-methylthiazol-5-yl)cyclopropoxy)benzofuran-3-carboxylic acid 61c (70 mg, 195.85 μmol) was dissolved in 2.3 mL of a mixed solution (tetrahydrofuran:ethanol:water = 1:1:0.3), and lithium hydroxide monohydrate (32.87 mg, 783.39 μmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, water (10 mL) was added, and the pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-methyl-5-(1-(2-methylthiazol-5-yl)cyclopropoxy)benzofuran-3-carboxylic acid 61d (20 mg), yield: 15.50%.

[1235] MS m / z(ESI): 330.1 [M+1].

[1236] Step 4: (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(1-(2-methylthiazolyl-5-yl)cyclopropoxy)benzofuran-3-carboxamide

[1237] 2-Methyl-5-(1-(2-methylthiazol-5-yl)cyclopropoxy)benzofuran-3-carboxylic acid 61d (18 mg, 54.65 μmol) and (S)-2-amino-3-hydroxypropamide hydrochloride 1f (9.22 mg, 65.58 μmol) were dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (24.94 mg, 65.58 μmol), 1-hydroxy-7-azobenzotriazole (7.44 mg, 54.65 μmol) and N,N-diisopropylethylamine (21.19 mg, 163.95 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-(1-(2-methylthiazolyl-5-yl)cyclopropoxy)benzofuran-3-carboxamide 61 (4.59 mg), yield: 21.80%.

[1238] MS m / z(ESI): 416.1 [M+1].

[1239] 1 H NMR (400MHz, CD3OD) δ8.36-8.29(m,1H),7.84(s,1H),7.43(d,J=8.9Hz,1H),7.26(d,J=10.1H z,1H),4.72-4.69(m,1H),3.96(d,J=4.3Hz,2H),2.68(d,J=4.3Hz,6H),1.54(d,J=6.8Hz,4H).

[1240] Example 62

[1241] 5-((2-fluorophenyl)methoxy-d2)-N-(3-hydroxy-1-(hydroxyamino)-1-iminopropyl-2-yl)-2-methylbenzofuran-3-carboxamide

[1242] first step

[1243] 1-(chloromethyl-d2)-2-fluorobenzene

[1244] (2-fluorophenyl)methane-d2-ol 48b (900 mg, 7.02 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (1.67 g, 14.05 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC. After the reaction was completed, the solution was concentrated under reduced pressure to give 1-(chloromethyl-d2)-2-fluorobenzene 62a (830 mg), yield: 80.62%. This product was used directly in the next step without purification.

[1245] Step 2

[1246] (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-5-hydroxy-2-methylbenzofuran-3-carboxamide

[1247] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 35e (3.3 g, 6.39 mmol) was dissolved in tetrahydrofuran (30 mL), and triethylamine (2.59 g, 25.55 mmol) and trifluoroacetic anhydride (3.35 g, 15.97 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, 30 mL of water was added, and the pH of the solution was adjusted to 8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 62b (2.9 g), yield: 91.05%.

[1248] MS m / z(ESI): 499.1 [M+1].

[1249] Step 3

[1250] N-(1-Cyano-2-hydroxyethyl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide

[1251] (R)-N-(2-((tert-butyldiphenylsilyl)oxy)-1-cyanoethyl)-5-hydroxy-2-methylbenzofuran-3-carboxamide 62b (1 g, 2.01 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.96 g, 6.02 mmol) and 1-(chloromethyl-d2)-2-fluorobenzene 62a (293.97 mg, 2.01 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give N-(1-cyano-2-hydroxyethyl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 62c (170 mg), yield: 22.89%.

[1252] MS m / z(ESI): 371.0 [M+1].

[1253] Step 4

[1254] 5-((2-fluorophenyl)methoxy-d2)-N-(3-hydroxy-1-(hydroxyamino)-1-iminopropyl-2-yl)-2-methylbenzofuran-3-carboxamide

[1255] N-(1-cyano-2-hydroxyethyl)-5-((2-fluorophenyl)methoxy-d2)-2-methylbenzofuran-3-carboxamide 62c (30 mg, 81.00 μmol) was dissolved in ethanol (1 mL), and potassium carbonate (33.58 mg, 243.00 μmol) and hydroxylamine hydrochloride (11.26 mg, 162.00 μmol) were added. The mixture was stirred at 90 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give 5-((2-fluorophenyl)methoxy-d2)-N-(3-hydroxy-1-(hydroxyamino)-1-iminopropyl-2-yl)-2-methylbenzofuran-3-carboxamide 62 (10 mg), yield: 30.60%. MS m / z (ESI): 404.1 [M+1].

[1256] 1H NMR(400MHz,CD3OD)δ7.59-7.50(m,1H),7.40(s,2H),7.39-7.33(m,1H),7.23-7.18(m,1H),7.1 7-7.11(m,1H),7.06-6.98(m,1H),4.79(t,J=4.7Hz,1H),4.06-3.93(m,2H),2.72-2.65(m,3H).

[1257] Example 63

[1258] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-(1,1-difluoro-2-(2-methylthiazo-5-yl)ethyl)-2-methylbenzofuran-3-carboxamide

[1259] first step

[1260] (E)-5-(2-ethoxyvinyl)-2-methylthiazole

[1261] 5-Bromo-2-methylthiazole 16a (5.0 g, 28.080 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronyl 63a (6 g, 33.700 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.0 g, 2.81 mmol), and sodium carbonate (8.9 g, 84.250 mmol) were dissolved in 1 mL of water and 10 mL of 1,4-dioxane. The mixture was stirred at 90 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give (E)-5-(2-ethoxyvinyl)-2-methylthiazole 63b (2.9 g), yield: 60.81%.

[1262] MS m / z(ESI): 170.5 [M+1].

[1263] Step 2

[1264] (Z)-5-(1-ethoxy-2-(2-methylthiazo-5-yl)vinyl)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[1265] (E)-5-(2-ethoxyvinyl)-2-methylthiazole 63b (2.0 g, 11.820 mmol), ethyl 5-bromo-2-methylbenzofuran-3-carboxylate 16c (4.3 g, 15.360 mmol), sodium bicarbonate (2.9 g, 35.450 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene (683 mg, 1.180 mmol), and allyl(chloro)palladium (216 mg, 0.590 mmol) were dissolved in 20 mL of N,N-dimethylformamide and stirred at 150 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 63c (1.5 g) of (Z)-5-(1-ethoxy-2-(2-methylthiazolyl-5-yl)vinyl)-2-methylbenzofuran-3-carboxylic acid ethyl ester, yield: 34.1%.

[1266] MS m / z(ESI): 372.2 [M+1].

[1267] Step 3

[1268] ethyl 2-methyl-5-(2-(2-methylthiazo-5-yl)acetyl)benzofuran-3-carboxylate

[1269] (Z)-5-(1-ethoxy-2-(2-methylthiazol-5-yl)vinyl)-2-methylbenzofuran-3-carboxylate 63c (2.2 g, 5.92 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added. The mixture was stirred at 25 °C for 5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-methyl-5-(2-(2-methylthiazol-5-yl)acetyl)benzofuran-3-carboxylate 63d (1.5 g), yield: 73.75%.

[1270] MS m / z(ESI): 344.2 [M+1].

[1271] Step 4

[1272] 2-Methyl-5-(2-((2-methylthiazolyl-5-yl)methyl)-1,3-dithiocyclopentan-2-yl)benzofuran-3-carboxylic acid ethyl ester

[1273] Ethyl 2-methyl-5-(2-(2-methylthiazolyl-5-yl)acetyl)benzofuran-3-carboxylate 63d (150 mg, 0.436 mmol), boron trifluoride ether (62 mg, 0.436 mmol), and 1,2-ethylenedithiol 63e (205 mg, 2.180 mmol) were dissolved in 5 mL of toluene, p-toluenesulfonic acid (15 mg, 0.087 mmol), and the mixture was heated to reflux overnight. After the reaction was complete, 20 mL of saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate (20 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 63 f (80 mg) of ethyl 2-methyl-5-(2-((2-methylthiazol-5-yl)methyl)-1,3-dithiocyclopentan-2-yl)benzofuran-3-carboxylate, yield: 43.7%. MS m / z (ESI): 420.2 [M+1].

[1274] Step 5

[1275] ethyl 5-(1,1-difluoro-2-(2-methylthiazolyl-5-yl)ethyl)-2-methylbenzofuran-3-carboxylate

[1276] N-iodosuccinimide (21 mg, 0.095 mmol) was dissolved in 3 mL of dichloromethane. 1 mL of pyridine hydrogen fluoride was added at -78 °C. Then, ethyl 2-methyl-5-(2-((2-methylthiazolyl-5-yl)methyl)-1,3-dithiocyclopentan-2-yl)benzofuran-3-carboxylate 63f (20 mg, 0.047 mmol) was dissolved in 2 mL of dichloromethane and slowly added to the reaction solution. The mixture was stirred at -78 °C for 2 hours. After the reaction was completed, the mixture was extracted with dichloromethane (10 × 3 mL), the combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 63 g (30 mg) of ethyl 5-(1,1-difluoro-2-(2-methylthiazolyl-5-yl)ethyl)-2-methylbenzofuran-3-carboxylate, yield: 100%. It was carried out directly in the next step of the reaction without purification.

[1277] MS m / z(ESI): 366.2 [M+1].

[1278] Step 6

[1279] 5-(1,1-Difluoro-2-(2-methylthiazo-5-yl)ethyl)-2-methylbenzofuran-3-carboxylic acid

[1280] 63 g (17 mg, 0.046 mmol) of ethyl 5-(1,1-difluoro-2-(2-methylthiazol-5-yl)ethyl)-2-methylbenzofuran-3-carboxylic acid was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Then, a solution of sodium hydroxide (6 mg, 0.140 mmol) dissolved in water (1 mL) was added. The mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure, and 1 N dilute hydrochloric acid was added to adjust the pH to 7. The solution was then concentrated under reduced pressure again to obtain 63 h (14 mg) of 5-(1,1-difluoro-2-(2-methylthiazol-5-yl)ethyl)-2-methylbenzofuran-3-carboxylic acid, with a yield of 90%. This product was used directly for the next reaction without purification.

[1281] MS m / z(ESI): 338.1 [M+1].

[1282] Step 7 (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(1,1-difluoro-2-(2-methylthiazolyl-5-yl)ethyl)-2-methylbenzofuran-3-carboxamide

[1283] (S)-2-amino-3-hydroxypropionamide hydrochloride 1f (9 mg, 0.065 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (28 mg, 0.219 mmol) was added. The mixture was stirred at 25 °C for 5 minutes. Then, 5-(1,1-difluoro-2-(2-methylthiazolyl-5-yl)ethyl)-2-methylbenzofuran-3-carboxylic acid 63h (14 mg, 0.044 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (25 mg, 0.065 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 20 minutes. After the reaction was complete, an aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(1,1-difluoro-2-(2-methylthiazolyl-5-yl)ethyl)-2-methylbenzofuran-3-carboxamide 63 (4.56 mg), yield: 24.51%.

[1284] MS m / z(ESI): 424.2 [M+1].

[1285] 1H NMR (400MHz, DMSO-d6) δ7.96(d,J=1.8Hz,1H),7.79(d,J=8.0Hz,1H),7.68(d,J=8.6Hz,1H),7.53-7.47(m,2H),7.42(s,1 H),7.19(s,1H),4.99(s,1H),4.54-4.44(m,1H),3.91(t,J=16.4Hz,2H),3.75(d,J=5.2Hz,2H),2.69(s,3H),2.57(s,3H).

[1286] Example 64

[1287] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)-1H-indole-1-carboxamide

[1288] first step

[1289] 6-Bromo-2-methyl-1-toluenesulfonyl-1H-indole

[1290] 6-Bromo-2-methyl-1H-indole 64a (1.5 g, 7.14 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium hydride (1.14 g, 28.56 mmol) of 60% purity was added. The mixture was stirred at 25 °C for 0.5 h. Then, p-toluenesulfonyl chloride (2.04 g, 10.71 mmol) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at 25 °C for 2 h. The reaction was monitored by LC-MS. After the reaction was completed, an aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give 6-bromo-2-methyl-1-toluenesulfonyl-1H-indole 64b (2.1 g), yield: 80.74%.

[1291] 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),7.76-7.59(m,2H),7.39-7.32(m,1H),7.28-7.25(m,3H),6.32(s,1H),2.58(s,3H),2.39(s,3H).

[1292] Step 2

[1293] 2-Methyl-5-(((2-methyl-1-p-toluenesulfonyl-1H-indol-6-yl)oxy)methyl)thiazole

[1294] 6-Bromo-2-methyl-1-toluenesulfonyl-1H-indole 64b (2.1 g, 5.77 mmol), (2-methylthiazolyl-5-yl)methanol 1a (894 mg, 6.92 mmol) and cesium carbonate (3.76 g, 11.53 mmol) were dissolved in 1,4-dioxane (10 mL), and tris(dibenzylacetone)palladium (528 mg, 0.577 mmol) and 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-bisphenyl (838 mg, 1.73 mmol) were added. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give 2-methyl-5-(((2-methyl-1-p-toluenesulfonyl-1H-indol-6-yl)oxy)methyl)thiazole 64c (1 g), yield: 42.05%. MS m / z (ESI): 413.2 [M+1]

[1295] Step 3

[1296] 2-Methyl-5-(((2-methyl-1H-indol-6-yl)oxy)methyl)thiazole

[1297] 2-Methyl-5-(((2-methyl-1-p-toluenesulfonyl-1H-indol-6-yl)oxy)methyl)thiazole 64c (1 g, 2.42 mmol) was dissolved in ethanol (48 mL), and sodium hydroxide (2.91 g, 72.72 mmol) dissolved in water (24 mL) was added. The mixture was stirred at 90 °C for 24 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure and extracted with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (eluent: C system) to give 2-methyl-5-(((2-methyl-1H-indol-6-yl)oxy)methyl)thiazole 64d (330 mg), yield: 52.70%.

[1298] MS m / z(ESI): 259.1 [M+1]

[1299] Step 4

[1300] 2-Methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-1-carboxylic acid p-nitrobenzene ester

[1301] 2-Methyl-5-((((2-methyl-1H-indol-6-yl)oxy)methyl)thiazole 64d (210 mg, 0.813 mmol) was dissolved in acetonitrile (8 mL), and sodium carbonate (43 mg, 0.406 mmol) and di(p-nitrobenzene) carbonate (15 g, 321 mg, 1.06 mmol) were added. The mixture was stirred at 110 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give 2-methyl-6-((2-methylthiazol-5-yl)methoxy)-1H-indol-1-carboxylic acid p-nitrobenzene 64e (160 mg), yield: 46.48%.

[1302] MS m / z(ESI): 424.2 [M+1]

[1303] Step 5

[1304] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-1-carboxamide

[1305] 2-Methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-1-carboxylic acid p-nitrobenzene 64e (160 mg, 0.378 mmol) was dissolved in tetrahydrofuran (4 mL), and N-methylimidazolium (93 mg, 1.13 mmol) and (S)-2-amino-3-((tert-butyldiphenylsilyl)oxy)propionamide 15i (259 mg, 0.756 mmol) were added. The mixture was stirred at 40 °C for 36 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: C system) to give (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-1-carboxamide 64f (100 mg), yield: 42.22%.

[1306] MS m / z (ESI): 627.4 [M+1]

[1307] Step 6

[1308] (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-methylthiazo-5-yl)methoxy)-1H-indole-1-carboxamide

[1309] (S)-N-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-1-carboxamide 64f (45 mg, 0.072 mmol) was dissolved in tetrahydrofuran (3 mL), and 2.88 mL of 65% pure pyridine hydrofluoric acid solution (3.28 g, 21.54 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by HPLC (eluent: system B) to give (S)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-methylthiazolyl-5-yl)methoxy)-1H-indole-1-carboxamide 64 (9.03 mg), yield: 32.38%.

[1310] MS m / z(ESI): 389.2 [M+1]

[1311] 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=8.4Hz,1H),7.73-7.66(m,2H),7.54(s,1H),7.34(d,J=8.4Hz,1H),7.25(s,1H),6.79(dd ,J=8.4,2.4Hz,1H),6.28(s,1H),5.30(s,2H),5.06(s,1H),4.49-4.36(m,1H),3.86-3.70(m,2H),2.63(s,3H),2.47(s,3H).

[1312] Example 65

[1313] (S)-N-(1-amino-3-hydroxy-1-thionopropyl-2-yl)-5-((2-fluorobenzyl)oxy)-2-methylbenzofuran-3-carboxamide

[1314] first step

[1315] 5-((2-fluorobenzyl)oxy)-2-methylbenzofuran-3-carboxylic acid ethyl ester

[1316] Ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 2c (1 g, 4.54 mmol) was dissolved in acetonitrile (20 mL), and potassium carbonate (1.88 g, 13.62 mmol), 1-(bromomethyl)-2-fluorobenzene 65a (1.12 g, 5.90 mmol), and potassium iodide (75 mg, 0.454 mmol) were added. The mixture was stirred at 90 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system D) to give ethyl 5-((2-fluorobenzyl)oxy)-2-methylbenzofuran-3-carboxylate 65b (1.3 g), yield: 87.19%.

[1317] MS m / z(ESI): 329.2 [M+1].

[1318] Step 2

[1319] 5-((2-fluorobenzyl)oxy)-2-methylbenzofuran-3-carboxylic acid

[1320] Ethyl 5-((2-fluorobenzyl)oxy)-2-methylbenzofuran-3-carboxylic acid 65b (1 g, 3.05 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (6 mL), followed by the addition of an aqueous solution of sodium hydroxide (487 mg, 12.18 mmol) (3 mL). The reaction mixture was stirred at 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the solution was concentrated under reduced pressure, and the pH was adjusted to weakly acidic by adding saturated citric acid aqueous solution. A solid precipitated out, was filtered under reduced pressure, washed several times with water, and dried to obtain 5-((2-fluorobenzyl)oxy)-2-methylbenzofuran-3-carboxylic acid 65c (900 mg), yield: 98.41%.

[1321] MS m / z(ESI): 301.1 [M+1].

[1322] Step 3

[1323] N-(tert-Butoxycarbonyl)-O-(tert-Butyldiphenylsilyl)-L-Serine methyl ester

[1324] (tert-Butoxycarbonyl)-L-serine methyl ester 65d (3 g, 13.68 mmol) was dissolved in tetrahydrofuran (60 mL), and imidazole (2.33 g, 34.21 mmol), tert-butyldiphenylchlorosilane (4.89 g, 17.79 mmol), and 4-dimethylaminopyridine (134 mg, 1.09 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, water (30 mL) was added, and ethyl acetate was added for extraction (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (eluent: C system) to give N-(tert-Butoxycarbonyl)-O-(tert-Butyldiphenylsilyl)-L-serine methyl ester 65e (8.1 g), yield: 97.01%.

[1325] MS m / z(ESI): 458.4 [M+1]

[1326] Step 4

[1327] (S)-(1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-oxopropane-2-yl)tert-butyl carbamate

[1328] N-(tert-Butoxycarbonyl)-O-(tert-Butyldiphenylsilyl)-L-serine methyl ester 65e (4 g, 8.74 mmol) was added to 50 mL of 7.0 M ammonia-methanol solution and stirred at 25 °C for 36 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure and extracted with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by column chromato...

Claims

1. A compound of Formula (I) or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: ###0001### (I) ​ wherein: X is selected from NH, O, S or Se; L is selected from H, D, halogen, haloalkyl or ring A; ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further substituted with one or more R0; T is selected from -NR x -, -CR x R y -, -O- or -S-, T is preferably -O-; U is selected from -NR z R w or -OR z , U is preferably -NR z R w ; R0, R1, R2, R3, R4, R5, R6, R x , R y each independently is selected from a hydrogen atom, deuterium, a halogen, an amino group, a hydroxyl group, a cyano group, an amido group, an alkoxy group, a thiol group, an alkyl group, or a haloalkyl group; or, R1and R2together form =0, =S, =NR a , R3and R4together form =0, =S, =NR a ; or, R1and R2, R2and R x , R z and R5each optionally taken together with the atoms to which they are attached form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, said 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl optionally further substituted with one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amido, or =0; R z , R w each independently is selected from a hydrogen atom, an amino group, a hydroxyl group, a cyano group, an amido group, an alkoxy group, an alkyl group, a cycloalkyl group, or a heterocyclyl group, wherein the amido group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group is optionally further substituted by one or more R 01 ; R 01 the same or different, each independently selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, carbonylalkyl, amido-substituted alkyl, thioamido-substituted alkyl, thioamido, amido, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, =0, =S, -C(=NR a )NR b R c , -C(=NR a )R b , -C(=NR a )NR b OR c , -S(=NR a )(O)R b , -S(=NR a )NR b R c , -S(=NR a )R b , -P(O)R a R b , -S(=NR a )(O)NR b R c or -OR a ; s is 0, 1, 2 or 3; when L is selected from ring A, X is selected from O or S, T is selected from -O- and R3and R4together form =O, at least one of the following conditions needs to be fulfilled, provided that, (1) R1and R2are each independently selected from deuterium, halogen, amino, hydroxyl, cyano, amido, alkoxy, thiol, or, R1and R2together form =0, =S, =NR a or, R1and R2together with the atoms to which they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, said 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl optionally further substituted with one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amido, or =0; (2) R 01 selected from -C(=NR a )R b R c , thioamido substituted alkyl, thioamido, -C(=NR a )R b , -C(=NR a )NR b OR c , -S(=NR a )(O)R b , -S(=NR a )NR b R c , -S(=NR a )R b , -P(O)R a R b or -S(=NR a )(O)NR b R c ; (3) R z and any two of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R R a , R b , R c each independently is selected from a hydrogen atom, a cyano group, a hydroxyl group, an amino group, an alkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from an alkyl group, a halo group, a nitro group, a cyano group, an amino group, a carboxyl group, a hydroxyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, or a =0 substituent; or R a , R b , R c any two of which are joined to form a saturated or unsaturated heterocyclic ring, which is further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, amino, carboxyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or =0.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of general formula (II), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: wherein: n is 0, 1, 2 or 3; R0, R1, R2, R3, R4, R5, R6, s, U, ring A and T are defined as in claim 1.

3. The compound according to claim 2, which is a compound according to general formula (III) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof: ###0002### (III) ​ wherein: R0, R3, R4, U, ring A and n are defined as in claim 2.

4. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of general formula (IV), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: wherein: R0, R z , R w , ring A and n are as defined in claim 2.

5. A compound of Formula (I-A) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof: ###00017### (I-A). wherein: ring B is selected from a fused ring, said fused ring is optionally further substituted with one or more R0; X is selected from NH, O, S or Se; R0, R1, R2, R3, R4are each independently selected from a hydrogen atom, deuterium, halogen, amino, hydroxyl, cyano, amido, alkoxy, thiol, alkyl or haloalkyl; or R2and R3together form =O; U is selected from -NR x R y or -OR x , U is preferably -NR x R y ; R x , R y each independently is selected from a hydrogen atom, an amino group, a hydroxyl group, a cyano group, an amido group, an alkoxy group, an alkyl group, a cycloalkyl group, or a heterocyclyl group, wherein the amido group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group is optionally further substituted by one or more R 01 groups; R 01 the same or different, each independently selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, carbonylalkyl, amido-substituted alkyl, thioamido-substituted alkyl, thioamido, amido, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, =0; n is 0, 1, 2 or 3.

6. A compound of Formula (I-B) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof: wherein: ring A is selected from cycloalkyl, heterocycloalkyl, fused ring, aryl or heteroaryl, said cycloalkyl, heterocycloalkyl, fused ring, aryl, heteroaryl are optionally further substituted with one or more R0; Ring B is selected from the following groups: Q is selected from nothing or -CR1R2-; T is selected from the group consisting of nothing, -NR x -, -CR x R y -, -O- or -S-, T is preferably -O-; U is selected from -NR z R w or -OR z , U is preferably -NR z R w ; R0, R1, R2, R3, R4, R5, R x , R y , R z , R w each independently is selected from the group consisting of a hydrogen atom, deuterium, a halogen, an amino group, a hydroxyl group, a cyano group, an amido group, an alkoxy group, a thiohydroxy group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an amido-substituted alkyl group, a thioamido-substituted alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, wherein said hydroxyalkyl group, amido-substituted alkyl group, thioamido-substituted alkyl group, amido group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group is optionally further substituted with one or more R 01 ; or R1and R2together form =0, =S or =NR a or R3and R4together form =0, =S or =NR a ; or, R1and R2, R2and R x , R z and R5each optionally taken together with the atoms to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, each of which is optionally further substituted with one or more substituents selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, amido, or =0; R 01 the same or different, each independently selected from deuterium, hydroxyl, amino, halogen, nitro, cyano, alkyl, carbonylalkyl, amido-substituted alkyl, thioamido-substituted alkyl, thioamido, amido, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, =0, =S, -C(=NR a )NR b R c , -C(=NR a )R b , -C(=NR a )NR b OR c , -S(=NR a )(O)R b , -S(=NR a )NR b R c , -S(=NR a )R b , -P(O)R a R b , -S(=NR a )(O)NR b R c , -OR a ; R a , R b , R c each independently is selected from a hydrogen atom, a cyano group, a hydroxyl group, an amino group, an alkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from an alkyl group, a halo group, a nitro group, a cyano group, an amino group, a carboxyl group, a hydroxyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, or =0; or R a , R b , R c any two of which are joined to form a saturated or unsaturated heterocyclic ring, which is further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, amino, carboxyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or =0 substituents; n is 0, 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5.

7. The compound according to claim 6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (II-B): wherein: R' is selected from a hydrogen atom, deuterium, halogen, amino, hydroxyl, cyano, amido, alkoxy, thiol, alkyl, haloalkyl, cycloalkyl, heterocyclyl; R0, R1, R2, R3, R4, R5, ring A, T, U, n, m are defined as in claim 6.

8. The compound according to any one of claims 1 to 4, 6, 7, wherein ring A is selected from the following groups: ###00003### or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof. ​ 9. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5-6 membered aryl or a 5-6 membered heteroaryl.

10. The compound according to any one of claims 1 to 9, or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a thiazole ring or a pyridine ring.

11. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein R0is selected from halogen, alkyl or haloalkyl.

12. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is of the following structural formula:

13. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

14. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a TRPM3 antagonist.

15. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the prevention and / or treatment of a disease mediated by TRPM3, wherein preferably the disease mediated by TRPM3 is pain or a pain-related condition.

16. Use according to claim 15, wherein the pain or pain-related condition mediated by TRPM3 is selected from acute pain, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, idiopathic pain or migraine.

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