Benzamide compounds and uses thereof

Abstract

The present application provides a new compound which effectively antagonizes P2X3 receptor, which is a compound shown in formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method thereof, and a use thereof in the preparation of a medicine

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry. Specifically, this invention relates to benzamide compounds, and more specifically, this invention relates to a benzamide compound, its preparation method, and its use in the preparation of drugs. Background Technology

[0002] P2X receptors are non-selective ATP-gated ion channel receptors, i.e., purinergic receptors, that bind to extracellular ATP, primarily derived from damaged or inflamed tissues. These receptors are widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems, and participate in various physiological processes, including regulation of heart rhythm and contractility, regulation of vascular tone, nociception (especially chronic pain), vas deferens contraction during ejaculation, bladder contraction during urination, platelet aggregation, macrophage activation, apoptosis, and neuron-glial interactions. The aforementioned P2X receptors include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7, and three heterologous receptors: P2X2 / 3, P2X4 / 6, and P2X1 / 5.

[0003] P2X3 is a subtype of the P2X receptor family that is selectively expressed in dorsal root ganglia of nerve endings, spinal cord, and brain neurons, specifically in small to medium diameter primary sensory neurons.

[0004] Numerous studies have shown that activation of P2X3 and P2X2 / 3 expressed in primary sensory neurons plays a crucial role in acute injury, hyperalgesia, and hypersensitivity responses in rodents. Many studies have demonstrated that upregulation of P2X3 receptor expression can lead to hyperalgesia and participate in pain signaling. P2X3 knockout mice exhibit reduced pain responses, and P2X3 receptor antagonists have shown a role in reducing nociception in pain and inflammatory pain models.

[0005] P2X3 is distributed in primary afferent nerves surrounding the airways and can regulate cough. Studies have shown that ATP released from damaged or inflamed airway tissue acts on P2X3 receptors in primary neurons, triggering depolarization and action potentials. These potentials transmit cough impulses, initiating coughing. P2X3 receptors play an important role in the cough reflex hypersensitivity response; by antagonizing P2X3 receptor binding, the cough reflex hypersensitivity response can be inhibited, thereby suppressing excessive coughing in patients with chronic cough. Furthermore, research has shown that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, or asthma; therefore, P2X3 antagonists also hold promise as new drugs for treating these diseases.

[0006] P2X3 has been reported to be involved in the afferent pathway controlling the bladder capacity reflex; P2X3 knockout mice exhibit significantly reduced urination frequency and significantly increased bladder capacity. Therefore, inhibiting the binding of P2X3 receptor antagonists to the P2X3 receptor could be effective in treating conditions involving urinary storage and voiding disorders, such as overactive bladder. Thus, P2X3 antagonists may be potential drugs for treating overactive bladder and related diseases.

[0007] P2X3 antagonists show great promise. Currently, commonly used cough medications such as gabapentin, morphine, and amitriptyline, or treatments using speech pathology, can improve coughs in many patients, but they are not suitable for all patients. Moreover, centrally acting drugs such as gabapentin may produce adverse side effects and are not suitable for long-term use. There is an urgent clinical need to develop long-term medications for chronic refractory coughs to provide doctors with treatment options. Therefore, the development of P2X3 antagonists is of great clinical significance. Summary of the Invention

[0008] The present invention aims to provide a P2X3 receptor antagonist that can be used to prepare drugs for treating cough, pain, respiratory diseases and genitourinary diseases.

[0009] In a first aspect, the present invention provides a compound, according to embodiments thereof, which is a compound of Formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug:

[0010]

[0011] in,

[0012] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0013] X is a halogen;

[0014] m is selected from the integers 1, 2, or 3;

[0015] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0016] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R aSubstituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0017] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0018] R 3 Independently selected from hydrogen, or, unsubstituted or substituted with 1-5 identical or different halogen atoms, C1-C4 alkyl groups;

[0019] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0020] R b and R c Independently selected from hydrogen or C1-C4 alkyl;

[0021] A is independently unsubstituted or replaced by R e The substituted 5 to 10-membered heteroaryl group, said to be R e In the substituted 5- to 10-membered heteroaryl groups, the R eThe substitution is one or more substitutions, wherein the R e Each substituent is independently selected from the following: halogen, unsubstituted or substituted C1-C3 alkyl group with 1-5 identical or different halogens, or unsubstituted or substituted -O-(C1-C3 alkyl group with 1-5 identical or different halogens; when there are multiple substituents, the substituents are identical or different.

[0022] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0023]

[0024] in,

[0025] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0026] X is a halogen;

[0027] m is selected from the integers 1, 2, or 3;

[0028] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0029] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl groups, each substitution independently refers to one or more of the following substituents: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c-COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0030] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0031] R 3 Independently selected from hydrogen, or, unsubstituted or substituted with 1-5 identical or different halogen atoms, C1-C4 alkyl groups;

[0032] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0033] R b and R c Independently selected from hydrogen or C1-C4 alkyl;

[0034] A independently is unsubstituted or R e The substituted 5 to 10-membered heteroaryl group, said to be R e In the substituted 5- to 10-membered heteroaryl groups, the R e The substitution is one or more substitutions, wherein the R e Each substituent is independently selected from the following: halogen, unsubstituted or substituted C1-C3 alkyl group with 1-5 identical or different halogens, or unsubstituted or substituted -O-(C1-C3 alkyl group with 1-5 identical or different halogens; when there are multiple substituents, the substituents are identical or different.

[0035] In a preferred embodiment of the present invention, when R 1 When the halogen is halogen, the halogen is F, Cl, Br, or I, preferably Cl.

[0036] In a preferred embodiment of the present invention, when R 1 When the C1-C4 alkyl group is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl or ethyl.

[0037] In a preferred embodiment of the present invention, when R 1When the C1-C4 alkyl group is substituted with 1-5 identical or different halogens, the C1-C4 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl or ethyl.

[0038] In a preferred embodiment of the present invention, when R 1 When the halogen is a C1-C4 alkyl group substituted with 1-5 identical or different halogens, the halogen is F, Cl, Br, I, preferably Cl or F.

[0039] In a preferred embodiment of the present invention, when X is a halogen, the halogen is either F or Cl.

[0040] In a preferred embodiment of the present invention, m is selected from integers 1, 2 or 3, preferably 1.

[0041] In a preferred embodiment of the present invention, when L is -(CH2) n When n is an integer, n is 0, 1 or 2, preferably n is 0 or 1.

[0042] In a preferred embodiment of the present invention, when R 2 For those not replaced or R a When the substituted C1-C6 alkyl group is used, the C1-C6 alkyl group is a C1-C4 alkyl group, preferably an sec-butyl group.

[0043] In a preferred embodiment of the present invention, when R 2 For not replaced or by R a When the substituted C1-C6 alkyl group is used, the C1-C6 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0044] In a preferred embodiment of the present invention, when R 2 For not replaced or by R a When the substituted C3-C7 cycloalkyl group is used, the C3-C7 alkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

[0045] In a preferred embodiment of the present invention, when R 2 For not replaced or by R a When a 4-7 membered heterocyclic alkyl group is substituted, the 4-7 membered heterocyclic alkyl group is a 4-membered, 5-membered, or 6-membered heterocyclic alkyl group.

[0046] In a preferred embodiment of the present invention, when R 2 For not replaced or by R a When the substituted 4-7 membered heterocyclic alkyl group is used, the heteroatom in the 4-7 membered heterocyclic alkyl group is one or more of N, S, O, and P, preferably one or more of N or O.

[0047] In a preferred embodiment of the present invention, when R 2 For not replaced or by R a When the substituted 4-7 membered heterocyclic alkyl group is used, the number of heteroatoms in the 4-7 membered heterocyclic alkyl group is 1 to 3, preferably 1 or 2.

[0048] In a preferred embodiment of the present invention, when R 2 For not replaced or by R a When the 4-7 membered heterocyclic alkyl group is substituted, the R a The number is 1 to 3, with 1 being preferred.

[0049] In a preferred embodiment of the present invention, R a It is a hydroxyl group.

[0050] In a preferred embodiment of the present invention, when R a When the halogen is halogen, the halogen is F, Cl, Br, or I, preferably F or Cl.

[0051] In a preferred embodiment of the present invention, when R a When the alkyl group is C1-C6, the C1-C6 alkyl group is C1-C3 alkyl group, preferably methyl.

[0052] In a preferred embodiment of the present invention, when R a When the alkyl group is a deuterated C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 deuterated alkyl group, preferably a C1-C3 deuterated alkyl group.

[0053] In a preferred embodiment of the present invention, when R a When the C1-C6 alkylene group is -(C1-C6 alkylene)-OH, the C1-C6 alkylene group is a C1-C4 alkylene group, preferably methylene, ethylene, n-propylene, or isopropylene, and more preferably methylene.

[0054] In a preferred embodiment of the present invention, R 3 It is hydrogen.

[0055] In a preferred embodiment of the present invention, when R 3 When the C1-C4 alkyl group is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, and preferably methyl.

[0056] In a preferred embodiment of the present invention, when A is R e When the substituted 5- to 10-membered heteroaryl group is used, the 5- to 10-membered heteroaryl group is a 6-membered heteroaryl group, preferably a pyrimidine or a pyridazine.

[0057] In a preferred embodiment of the present invention, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the R eThe substitution is a single substitution.

[0058] In a preferred embodiment of the present invention, when A is R e When the 5- to 10-membered heteroaryl group is replaced, the R e It is a C1-C3 alkyl group substituted with 1-5 identical or different halogens, preferably trifluoromethyl.

[0059] In a preferred embodiment of the present invention, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the R e It is an unsubstituted C1-C3 alkyl group, preferably methyl.

[0060] In a preferred embodiment of the present invention, -LR 2 Selected from

[0061] In a preferred embodiment of the present invention, -LR 2 for

[0062] In a preferred embodiment of the present invention, -LR 2 Selected from

[0063] In a preferred embodiment of the present invention, R 1 It can be methyl, ethyl, or Cl.

[0064] In a preferred embodiment of the present invention, -LR 2 Selected from

[0065] In a preferred embodiment of the present invention, -LR 2 Selected from

[0066] In a preferred embodiment of the present invention, R 3 It can be methyl or hydrogen.

[0067] In a preferred embodiment of the present invention, A is selected from...

[0068] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0069]

[0070] in,

[0071] R1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0072] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0073] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0074] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0075] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0076] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0077] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0078]

[0079] in,

[0080] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0081] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0082] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0083] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0084] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0085] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0086] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0087]

[0088] in,

[0089] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0090] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0091] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted aSubstituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0092] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0093] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0094] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0095] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0096]

[0097] in,

[0098] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0099] L stands for -(CH2) n- where n is selected from integers 0, 1, or 2;

[0100] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0101] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0102] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0103] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0104] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0105]

[0106] in,

[0107] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0108] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0109] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0110] Among them, those not replaced or by R aIn the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0111] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0112] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0113] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0114]

[0115] in,

[0116] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0117] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0118] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R aIn the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0119] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0120] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0121] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0122] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0123]

[0124] in,

[0125] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0126] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0127] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R aSubstituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0128] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0129] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0130] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0131] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0132]

[0133] in,

[0134] R 1 Selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0135] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0136] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0137] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R aIn the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0138] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0139] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0140] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0141]

[0142] in,

[0143] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0144] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0145] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b Rc -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0146] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0147] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0148] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0149] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0150]

[0151] in,

[0152] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0153] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0154] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted...a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0155] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0156] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0157] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0158] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0159]

[0160] in,

[0161] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0162] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0163] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0164] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0165] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0166] R b and Rc It is independently selected from hydrogen or C1-C4 alkyl.

[0167] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0168]

[0169] in,

[0170] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0171] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0172] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0173] Among them, those not replaced or by R aIn the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0174] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0175] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0176] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0177]

[0178] in,

[0179] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0180] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0181] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or R a Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R aIn the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxygenated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0182] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0183] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0184] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0185] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are:

[0186]

[0187] in,

[0188] R 1 Independently selected from halogens, C3-C6 cycloalkyl groups, or unsubstituted or C1-C4 alkyl groups substituted with 1-5 identical or different halogens;

[0189] L stands for -(CH2) n - where n is selected from integers 0, 1, or 2;

[0190] R 2 Independently selected from hydrogen, unsubstituted or R a Substituted C1-C6 alkyl, unsubstituted or R a Substituted C3-C7 cycloalkyl, unsubstituted or Ra Substituted 5-8 aryl groups, unsubstituted or R a Substituted 5-10 aryl groups, unsubstituted or R a Substituted 4-7 membered heterocyclic alkyl groups, unsubstituted or R a Substituted 6-12-membered heterobicycloalkyl groups; the R-substituted... a Substituted C1-C6 alkyl groups, the R-substituted a Substituted C3-C7 cycloalkyl groups, the R-substituted a The substituted 5-8 aryl group, the R- a The substituted 5-10 aryl group, the R-substituted a Substituted 4-7 membered heterocyclic alkyl groups, or those described above, are R a In the substituted 6-12 membered heterobicycloalkyl group, the R a The substitution is one or more substitutions, wherein the R a Each substituent is independently selected from the following: unsubstituted or substituted C1-C4 alkyl groups, halogens, -OH, -NR. b R c -COOR 4 Oxylated (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents may be the same or different;

[0191] Among them, those not replaced or by R a In the substituted 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 4-7 membered heterocyclic alkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; unsubstituted or R a In the substituted 6-12 membered heterobicycloalkyl groups, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0192] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0193] R b and R c It is independently selected from hydrogen or C1-C4 alkyl.

[0194] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are selected from any of the following compounds:

[0195]

[0196]

[0197] In a second aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the aforementioned compound, including its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients.

[0198] According to specific embodiments of the present invention, the pharmaceutical compositions of the present invention, comprising a therapeutically effective dose of the aforementioned compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable pharmaceutical carriers, diluents, or excipients, can be mixed to prepare a pharmaceutical formulation suitable for oral or parenteral administration. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation can be administered via any route, such as by infusion or bolus, or by absorption through the epithelium or mucous membranes (e.g., oral mucosa or rectum). Administration can be systemic or local. Examples of orally administered formulations include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The formulation can be prepared by methods known in the art and contains carriers, diluents, or excipients conventionally used in the field of pharmaceutical formulations.

[0199] In a third aspect, the present invention provides the use of the above-described compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the above-described pharmaceutical compositions, in the preparation of a medicament for treating diseases related to P2X3.

[0200] According to specific embodiments of the present invention, the use of the above-described compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the above-described pharmaceutical compositions in the preparation of a medicament for the treatment or prevention of pain. Such pain includes, for example, chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain.

[0201] According to specific embodiments of the present invention, the use of the above-described compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the above-described pharmaceutical compositions in the preparation of a medicament for the treatment or prevention of diseases of the urogenital system. These diseases include, for example, reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, and cystitis.

[0202] According to specific embodiments of the present invention, the use of the above-described compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the above-described pharmaceutical compositions in the preparation of a medicament for the treatment or prevention of respiratory diseases. These diseases include, for example, chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma and obstructive sleep apnea, chronic cough, refractory chronic cough, and acute cough.

[0203] Terms and Definitions

[0204] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0205] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0206] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0207] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0208] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0209] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. The term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces; when the solvent is water, it is a hydrate.

[0210] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; this modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0211] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0212] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0213] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds represent the absolute configuration of a stereocenter.

[0214] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0215] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0216] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), tritium ( 3 H), Iodine-125 125 I) or C-14 14C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0217] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0218] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0219] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0220] The term "C1-C6 alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2, 3 or 4 carbon atoms (“C1-C4 alkyl”), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0221] The term “C1-C3 alkoxy” should be understood as -O-(C1-C3 alkyl), where “C1-C3 alkyl” has the above definition.

[0222] The term “deuterated C1-C6 alkyl” should be understood as a C1-C6 alkyl in which one or more hydrogen atoms are replaced by deuterium, wherein “C1-C6 alkyl” has the above definition.

[0223] The term "C3-C7 cycloalkyl" should be understood as referring to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 7 carbon atoms, including fused or bridged polycyclic systems. Similarly, "C3-C6 cycloalkyl" should be understood as a saturated monovalent monocyclic or bicyclic hydrocarbon ring as defined above having 3 to 6 carbon atoms. Examples of such rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0224] The term "alkylene" should be understood as a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. Unless otherwise specified, the alkylene group contains 1-10 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in others, it contains 1-4 carbon atoms; and in still others, it contains 1-2 carbon atoms. Examples of such groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and so on.

[0225] The term "heterocyclic alkyl" should be understood to mean a saturated monovalent monocyclic hydrocarbon ring having a specified number of ring atoms, wherein one, two, or three ring atoms of the hydrocarbon ring are replaced by one, two, or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O)2, or N. "4- to 7-membered heterocyclic alkyl" should be understood to mean a saturated monovalent monocyclic "heterocyclic alkyl" ring as defined above, containing 4, 5, 6, or 7 ring atoms. Similarly, "4- to 6-membered heterocyclic alkyl" should be understood to mean a saturated monovalent monocyclic "heterocyclic alkyl" ring as defined above, containing 4, 5, or 6 ring atoms.

[0226] The term “6 to 12-membered heterocyclic alkyl” should be understood to mean a saturated monovalent bicyclic alkyl group in which two rings share one or two common ring atoms, wherein the bicyclic alkyl group contains 5, 6, 7, 8, 9 or 10 carbon atoms and one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O)2 or N, provided that the total number of ring atoms is not greater than 12.

[0227] The term "5-8 aryl" should be understood as a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 5-8 carbon atoms, exhibiting monovalent aromatic or partially aromatic properties, particularly a ring having 6 carbon atoms ("C6 aryl"), such as a phenyl group; when the 5-8 aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on its substitution site; for example, it can be ortho, para, or meta substituted.

[0228] The term "5-10 heteroaryl" should be understood as a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group having 5-10 ring atoms—particularly 5 or 6 carbon atoms—and comprising 1-5 heteroatoms independently selected from N, O, and S. Preferably, it comprises 1-3 monovalent monocyclic, bicyclic, or tricyclic aromatic ring groups—heteroatoms independently selected from N, O, and S, and in each case, these may be benzofused. In particular, the heteroaryl group is selected from thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or borazinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc.

[0229] The terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0230] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0231] Beneficial effects

[0232] According to embodiments of the present invention, the present invention has at least one of the following technical effects:

[0233] 1) It provides P2X3 antagonists with novel structures, excellent pharmacokinetic properties, and good efficacy or drug-likeness, which can be used to effectively treat P2X3-related diseases and symptoms;

[0234] 2) According to embodiments of the present invention, the compounds of the present invention have better pharmacokinetic properties compared with the positive control group compounds, especially compounds I-1, I-27, I-28, I-29, and I-30, which show significant improvement in pharmacokinetic properties;

[0235] 3) According to the embodiments of the present invention, compared with the positive control, the compounds of the present invention have less interference with the taste of rats, especially compounds I-1, I-27 and I-30, which have significantly less interference with the taste of rats than control compound 1;

[0236] 4) According to embodiments of the present invention, compared with the positive control, the compounds of the present invention significantly reduced the number of coughs and prolonged the cough latency in guinea pig cough models stimulated by citric acid / histamine and citric acid / ATP, demonstrating good antitussive effects.

[0237] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0238] Figure 1 The amount of water and quinine water consumed by rats in different administration groups after administration according to embodiments of the present invention.

[0239] Figure 2 The number of coughs in guinea pigs of different administration groups after administration according to embodiments of the present invention, following histamine / citric acid stimulation.

[0240] Figure 3 The number of coughs in guinea pigs of different administration groups after ATP / citric acid stimulation according to embodiments of the present invention. Detailed Implementation

[0241] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0242] Unless otherwise specified, the structures of the compounds in this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are in units of 10⁻¹⁰. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0243] The abbreviations of this invention are defined as follows:

[0244] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0245] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0246] T3P: Tricyclic propylphosphate anhydride, also known as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide or 1-propylphosphate anhydride.

[0247] TsCl: p-Toluenesulfonyl chloride

[0248] Et3N: Triethylamine

[0249] DMF: N,N-Dimethylformamide

[0250] LC-MS: Liquid chromatography-mass spectrometry

[0251] DCM: Dichloromethane

[0252] DMSO: Dimethyl sulfoxide

[0253] DMAP: 4-Dimethylaminopyridine

[0254] DIPEA: Also written as DIEA, diisopropylethylamine, i.e., N,N-diisopropylethylamine.

[0255] DIAD: Diisopropyl azodicarbonate

[0256] HEPES: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid

[0257] NIS: N-iodosuccinimide

[0258] PPh3: Triphenylphosphine

[0259] T3P: Tricyclic propylphosphate anhydride, also known as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide or 1-propylphosphate anhydride.

[0260] THF: Tetrahydrofuran

[0261] TLC: Thin-layer chromatography

[0262] IC 50 The half-maximum inhibitory concentration (MCI) is the concentration at which half of the maximum inhibitory effect is achieved.

[0263] Unless otherwise indicated, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 14.0.

[0264] Comparative Example 1: Comparative Compound 1 and its preparation

[0265]

[0266] The control compound 1 was synthesized with reference to patent application WO 2016 / 091776.

[0267] The term "compound 1" as used below refers to the compound described in Comparative Example 1.

[0268] Comparative Example 2: Comparative Compound 2 and its preparation

[0269]

[0270] The control compound 2 was synthesized with reference to patent application WO 2016 / 091776.

[0271] "Compound 2" as used below refers to the compound described in Comparative Example 2.

[0272] Example 1: Preparation of target compound I-1

[0273] 2-Fluoro-3-(5-methylthiazo-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (Target compound I-1)

[0274]

[0275] The synthetic route for target compound I-1 is shown below:

[0276]

[0277] Step 1: Synthesis of 3-bromo-2-fluoro-5-iodobenzoic acid

[0278]

[0279] 3-Bromo-2-fluorobenzoic acid (10 g, 45.7 mmol) was dissolved in concentrated sulfuric acid (40 mL), and NIS (10.27 g, 45.7 mmol) was added in portions at 0 °C. The mixture was stirred at room temperature for three hours. The solution was quenched with ice water (200 mL), filtered, and the filter cake was washed five times with water (200 mL) and dried under vacuum to obtain 3-bromo-2-fluoro-5-iodobenzoic acid, a white solid (10.9 g, yield 69.2%).

[0280] Step 2: Synthesis of 3-bromo-2-fluoro-5-hydroxybenzoic acid

[0281]

[0282] Cuprous oxide (0.656 g, 4.74 mmol) was added to a solution of 3-bromo-2-fluoro-5-iodobenzoic acid (10.9 g, 31.6 mmol) and sodium hydroxide (6.32 g, 158 mmol) in water (100 mL), and the mixture was reacted overnight at 100 °C. After cooling to room temperature, the mixture was filtered, and the pH of the filtrate was adjusted to 1 with 2 M hydrochloric acid solution. The filtrate was extracted with ethyl acetate (60 mL × 3), and the organic phase was concentrated to dryness to give 3-bromo-2-fluoro-5-hydroxybenzoic acid as a yellow solid (7.2 g, yield 96.8%).

[0283] Step 3: Synthesis of methyl 3-bromo-2-fluoro-5-hydroxybenzoate

[0284]

[0285] A methanol (120 mL) solution of 3-bromo-2-fluoro-5-hydroxybenzoic acid (7.2 g, 30.6 mmol) was added with thionyl chloride (10.9 g, 91.8 mmol), and the mixture was stirred at 55 °C for 16 hours. The solvent was then removed under reduced pressure, and the solution was concentrated to give a solid compound, methyl 3-bromo-2-fluoro-5-hydroxybenzoate (3.1 g, yield 40.8%), which was used in the next step without further purification.

[0286] Step 4: Synthesis of methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate

[0287]

[0288] Methyl 3-bromo-2-fluoro-5-hydroxybenzoate (3.1 g, 12.45 mmol), pinacol diboronate (3.48 g, 13.69 mmol), and potassium acetate (3.67 g, 37.3 mmol) were dissolved in 1,4-dioxane (50 mL), and the solution was degassed with a stream of nitrogen for 2 minutes. Pd(dppf)Cl2 (0.455 g, 0.622 mmol) was added, and the resulting solution was degassed with a stream of nitrogen for another 2 minutes. The reaction mixture was then stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate, a white solid (3.4 g, 92% yield).

[0289] Step 5: Synthesis of methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate

[0290]

[0291] At room temperature, methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (3.4 g, 11.48 mmol), 2-bromo-5-methylthiazole (2.453 g, 13.78 mmol), potassium carbonate (3.81 g, 27.6 mmol) in THF (30 mL) and water (10 mL) was added to Pd(dppf)Cl2 (1.260 g, 1.722 mmol). After three purgings under vacuum with nitrogen, the reaction was carried out at 90 °C for 16 h. The mixture was diluted with water (30 mL), extracted with ethyl acetate (40 mL × 3), concentrated to dryness, and the residue was purified by silica gel column chromatography to obtain methyl 2-fluoro-5-hydroxy-3-(5-methylthiazole-2-yl)benzoate as a yellow solid (1.41 g, yield 45.9%).

[0292] LC-MS, M / Z: 268.2 [M+H] +

[0293] Step 6: Synthesis of (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydrofuran-3-yl)oxy)benzoate

[0294]

[0295] Under nitrogen protection, cesium carbonate (2.58 g, 7.91 mmol) was added to a DMF (15 mL) solution of methyl 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)benzoate (1.41 g, 5.28 mmol) and (S)-tetrahydrofuran-3-yl-4-toluenesulfonate (1.53 g, 6.33 mmol), and the reaction was carried out at 90 °C for 18 h. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), concentrated to dryness, and the residue was purified by silica gel column chromatography to give (R)-2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydrofuran-3-yl)oxy)benzoate, a yellow solid (0.4 g, yield 22.5%).

[0296] LC-MS, M / Z: 338.4 [M+H] +

[0297] Step 7: Synthesis of (R)-2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydrofuran-3-yl)oxy)benzoic acid

[0298]

[0299] At room temperature, lithium hydroxide monohydrate (100 mg, 2.371 mmol) was added to a mixed solution of (R)-2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydrofuran-3-yl)oxy)benzoate (400 mg, 1.186 mmol) in THF (6 mL), water (2 mL), and MeOH (2 mL), and the mixture was stirred at room temperature for 3 hours. Subsequently, methanol and tetrahydrofuran were removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 4 with 2 M hydrochloric acid and then extracted with dichloromethane (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydrofuran-3-yl)oxy)benzoic acid as a white solid (300 mg, 78% yield).

[0300] LC-MS, M / Z: 324.3 [M+H] +

[0301] Step 8: Synthesis of 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-1)

[0302]

[0303] Under ice bath conditions, 1-propylphosphonic anhydride (0.59 g, 0.371 mmol) was added dropwise to a solution of (R)-2-fluoro-3-(5-methylthiazolyl)-5-((tetrahydrofuran-3-yl)oxy)benzoic acid (120 mg, 0.371 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (77 mg, 0.445 mmol), and N,N-diisopropylethylamine (240 mg, 1.856 mmol) in N,N-dimethylformamide (6 mL). 928 mmol (50% N,N-dimethylformamide solution), stirred overnight at room temperature, diluted with 20 mL of water, extracted with ethyl acetate (10 mL × 2), concentrated the organic phase to dryness, and purified the residue by silica gel column chromatography to give 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide, white solid (I-1) (40 mg, yield 21.7%).

[0304] 1H NMR (400MHz, CDCl3) δ8.93(d,2H),7.84(dd,1H),7.63-7.60(d,1H),7.49(dd,1H),7.09(dd,1H),5. 45-5.32(m,1H),5.05-4.95(m,1H),4.09-3.85(m,4H),2.57(d,3H),2.30-2.06(m,2H),1.73(d,3H).

[0305] LC-MS, M / Z: 497.2 [M+H] + .

[0306] Example 2: Preparation of target compound I-2

[0307] 2-Fluoro-5-(5-methylthiazo-2-yl)-3-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-2)

[0308]

[0309] The synthetic route for the target compound I-2 is shown below:

[0310]

[0311] Step 1: Synthesis of 5-bromo-2-fluoro-3-iodobenzonitrile

[0312]

[0313] At room temperature, 2,2,6,6-tetramethylpiperidine (8.86 mL, 52.5 mmol) was dissolved in THF (100 mL). Butyllithium (21.00 mL, 52.5 mmol, 2.5 M hexane solution) was slowly added dropwise at -20 °C over a period greater than 30 min. The mixture was stirred at -10 °C for 1 h. The mixture was then cooled to -70 °C, and diethylzinc (58.0 mL, 58.0 mmol, 1 M hexane solution) was added. The mixture was slowly heated to 0 °C and stirred for 2 h. The mixture was then cooled to -70 °C, and a solution of 5-bromo-2-fluorobenzonitrile (10 g, 50.0 mmol) in THF (50 mL) was added. The mixture was reacted at -70 °C for 0.5 h, then heated to -30 °C and stirred for 5 h. The reaction system was cooled again to -70°C, and a THF solution of iodine (44.4 g, 175 mmol) in 200 mL was added. The reaction was heated to room temperature and stirred overnight. The reaction was quenched by adding saturated sodium bisulfite solution (50 mL), filtered, and the filtrate was extracted with ethyl acetate (200 mL x 2). The organic phases were combined and washed separately with saturated sodium bisulfite solution (100 mL) and saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid was recrystallized from the ethyl acetate / petroleum ether system to give 5-bromo-2-fluoro-3-iodobenzonitrile, which was used directly in the next step.

[0314] Step 2: Synthesis of 5-bromo-2-fluoro-3-iodobenzoic acid

[0315]

[0316] The 5-bromo-2-fluoro-3-iodobenzonitrile obtained in the previous step was dissolved in concentrated sulfuric acid (30 mL) and reacted overnight at 120 °C. It was then diluted with ice water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain solid 5-bromo-2-fluoro-3-iodobenzoic acid (11.2 g, two-step yield 64.9%).

[0317] The subsequent synthesis method is described in Example 1.

[0318] 1 H NMR(400MHz, CDCl3)δ8.94(s,2H),7.91(dd,1H),7.78(dd,1H),7.48(d,1H),7.05(dd,1H),5.48- 5.27(m,1H),5.15-5.09(m,1H),4.09-3.92(m,4H),2.51(d,3H),2.33-2.18(m,2H),1.70(d,3H).

[0319] LC-MS, M / Z: 497.2 [M+H] +

[0320] Example 3: Preparation of target compound I-3

[0321] 4-Fluoro-3-(5-methylthiazo-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-3)

[0322]

[0323] The synthetic route for the target compound I-3 is shown below:

[0324]

[0325] The synthesis method is described in Example 1.

[0326] 1 H NMR (400MHz, CDCl3) δ8.91(d,2H),8.15(dd,1H),7.62-7.59(m,1H),7.55-7.46(m,1H),6.88(d,1H),5.39-5. 29(m,1H),5.09-5.04(m,1H),4.08-4.00(m,3H),3.93(td,1H),2.57(d,3H),2.32-2.16(m,2H),1.72(d,3H).

[0327] LC-MS, M / Z: 497.2 [M+H] + .

[0328] Example 4: Preparation of target compound I-4

[0329] 2-Fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-4)

[0330]

[0331] The synthetic route for the target compound I-4 is shown below:

[0332]

[0333] Step 1: Synthesis of cesium (4B) 2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate

[0334]

[0335] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)benzoate (4A) (0.20 g, 0.749 mmol) (synthesis reference Example 1) was added to DMSO (2 mL), along with cis-2,3-dimethylethylene oxide (170.1 mg, 2.38 mmol) and cesium carbonate (732.5 mg, 2.38 mmol). The mixture was heated to 100 °C and stirred overnight. After dilution with water (50 mL), the mixture was freeze-dried to give compound 2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (4B), a crude, off-white solid (1.3 g, 100% yield).

[0336] LC-MS, M / Z: 325.4 [M+H] + .

[0337] Step 2: Synthesis of 2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-4)

[0338]

[0339] Cesium 2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate crude product (4B) (1.3 g, 0.749 mmol) was added to 3 mL of N,N-dimethylformamide at room temperature, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (85.1 mg, 0.375 mmol), diisopropylethylamine (96.6 mg, 0.749 mmol), and dropwise 1-propylphosphonic anhydride (238.2 mg, 0.375 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. TLC showed the reaction of the starting material. After extraction, dilute with 5 mL of water, extract with ethyl acetate (10 mL × 2), concentrate the organic phase to dryness, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give 2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-4), an off-white solid (21 mg, yield 11.3%).

[0340] 1H NMR (400MHz, CDCl3) δ8.96(s,2H),7.90-7.88(m,1H),7.62(s,1H),7.56-7.53(m,1H),7.10-7.06(m,1H),5.41-5. 38(m,1H),4.43-4.40(m,1H),4.03-4.02(m,1H),2.58(d,3H),1.95-1.94(m,1H),1.74(d,2H),1.29-1.24(m,6H).

[0341] LC-MS, M / Z: 499.5 [M+H] + .

[0342] Example 5: Preparation of target compound I-5

[0343] 2-Fluoro-5-((cis-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-5)

[0344]

[0345] The synthetic route for the target compound I-5 is shown below:

[0346]

[0347] The synthesis method is described in Example 4.

[0348] 1 H NMR (400MHz, CDCl3) δ8.96(s,2H),7.90-7.88(m,1H),7.62(s,1H),7.56-7.53(m,1H),7.10-7.06(m,1H),5.41-5. 38(m,1H),4.43-4.40(m,1H),4.03-4.02(m,1H),2.58(d,3H),1.95-1.94(m,1H),1.74(d,2H),1.29-1.24(m,6H).

[0349] LC-MS, M / Z: 499.5 [M+H] + .

[0350] Example 6: Preparation of target compound I-6

[0351] 3-(5-chlorothiazolyl-2-yl)-2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-6)

[0352]

[0353] The synthetic route for the target compound I-6 is shown below:

[0354]

[0355] Step 1: Synthesis of methyl 3-(5-chlorothiazol-2-yl)-2-fluoro-5-hydroxybenzoate (6B)

[0356]

[0357] At room temperature, Pd(dppf)Cl2 (0.544 g, 0.743 mmol) was added to a mixed solution of methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (2.2 g, 7.43 mmol) (synthesis reference Example 1), 2-bromo-5-chlorothiazolium (1.475 g, 7.43 mmol), sodium carbonate (1.575 g, 14.86 mmol), 1,4-dioxane (40 mL), and water (10 mL). After three purgings under vacuum with nitrogen, the reaction was carried out at 90 °C for 18 h. Dilute with water (80 mL), extract with ethyl acetate (100 mL × 3), concentrate the organic phase to dryness, and purify the residue by silica gel column chromatography to obtain methyl 3-(5-chlorothiazol-2-yl)-2-fluoro-5-hydroxybenzoate (6B), a yellow solid (0.77 g, yield 36.0%).

[0358] LC-MS, M / Z: 288.1 [M+H] +

[0359] Step 1: Synthesis of cesium (6C) 3-(5-chlorothiazol-2-yl)-2-fluoro-5-((trans-3-hydroxybutane-2-yl)oxy)benzoate

[0360]

[0361] Methyl 2-fluoro-5-hydroxy-3-(5-chlorothiazol-2-yl)benzoate (6B) (0.22 g, 0.749 mmol) was added to DMSO (2 mL), along with cis-2,3-dimethyl ethylene oxide (170.1 mg, 2.38 mmol) and cesium carbonate (732.5 mg, 2.38 mmol). The mixture was heated to 100 °C and stirred overnight. After dilution with water (50 mL), the mixture was freeze-dried to give compound 3-(5-chlorothiazol-2-yl)-2-fluoro-5-((trans-3-hydroxybutan-2-yl)oxy)benzoate (6C), a grayish-white crude solid (1.4 g, crude).

[0362] LC-MS, M / Z: 345.8 [M+H-Cs] + .

[0363] Step 2: Synthesis of 3-(5-chlorothiazol-2-yl)-2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-6)

[0364]

[0365] Cesium 3-(5-chlorothiazol-2-yl)-2-fluoro-5-((trans-3-hydroxybutan-2-yl)oxy)benzoate crude product (6C) (1.4 g, 0.749 mmol) was added to 3 mL of N,N-dimethylformamide at room temperature, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (85.1 mg, 0.375 mmol), diisopropylethylamine (96.6 mg, 0.749 mmol), and dropwise 1-propylphosphonic anhydride (238.2 mg, 0.375 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. TLC (PE:EA = 2:1) was performed. After the reactants had reacted completely, 5 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give 3-(5-chlorothiazol-2-yl)-2-fluoro-5-((trans-3-hydroxybut-2-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-6), an off-white solid (33 mg, yield 8.5%).

[0366] 1 H NMR(400MHz,MeOD)δ9.04(s,2H),7.92-7.89(m,1H),7.87-7.86(m,1H),7.30-7.28(m,1H) ,5.37-5.34(m,1H),4.35-4.33(m,1H),3.87-3.84(m,1H),1.68(d,3H),1.30-1.26(m,6H).

[0367] LC-MS, M / Z: 519.9 [M+H] +

[0368] Example 7: Preparation of target compound I-7

[0369] 3-(5-chlorothiazo-2-yl)-2-fluoro-5-((cis-3-hydroxybut-2-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-7)

[0370]

[0371] The synthetic route for the target compound I-7 is shown below:

[0372]

[0373] The synthesis method is described in Example 6.

[0374] 1 H NMR(400MHz,MeOD)δ9.04(s,2H),7.92-7.89(m,1H),7.87-7.86(m,1H),7.30-7.28(m,1H) ,5.37-5.34(m,1H),4.35-4.33(m,1H),3.87-3.84(m,1H),1.68(d,3H),1.30-1.26(m,6H).

[0375] LC-MS, M / Z: 519.9 [M+H] + .

[0376] Example 8: Preparation of target compound I-8

[0377] 3-(5-chlorothiazo-2-yl)-2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-8)

[0378]

[0379] The synthetic route for I-8 is shown below:

[0380]

[0381] Step 1: Synthesis of (R)-3-(5-chlorothiazolyl-2-yl)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzoate (8C)

[0382]

[0383] Cesium carbonate (340 mg, 1.043 mmol) was added to a 4 mL solution of methyl 3-(5-chlorothiazol-2-yl)-2-fluoro-5-hydroxybenzoate (8A) (200 mg, 0.695 mmol) (synthesis reference Example 6) in N,N-dimethylformamide and stirred at room temperature for 10 min. Add (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate (8B) (202 mg, 0.834 mmol), and react under nitrogen protection at 90 °C for 3 h. Cool to room temperature, quench with water (50 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give (R)-3-(5-chlorothiazol-2-yl)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzoate (8C), white solid (140 mg, yield 56.3%).

[0384] LC-MS, M / Z: 358.1 [M+H] + .

[0385] Step 2: Synthesis of (R)-3-(5-chlorothiazol-2-yl)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzoic acid (8D)

[0386]

[0387] Methyl (R)-3-(5-chlorothiazol-2-yl)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzoate (8C) (140 mg, 0.391 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), followed by the addition of lithium hydroxide monohydrate (65.7 mg, 1.565 mmol) and water (2 mL). The reaction mixture was stirred at room temperature for 18 h. The pH of the reaction solution was adjusted to <2 with 2N dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain crude (R)-3-(5-chlorothiazol-2-yl)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzoic acid (8D) (135 mg, 100% yield), which was directly added to the next reaction step.

[0388] LC-MS, M / Z: 344.1 [M+H] + .

[0389] Step 3: Synthesis of 3-(5-chlorothiazo-2-yl)-2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-8)

[0390]

[0391] Add (R)-3-(5-chlorothiazol-2-yl)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzoic acid (8D) (135 mg, 0.393 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (8E) (89 mg, 0.393 mmol), N,N-diisopropylethylamine (254 mg, 1.964 mmol), and N,N-dimethylformamide (4 mL) to the reaction flask in sequence. Cool to approximately 0 °C, and then add 1-propylphosphonic anhydride (50% N,N-dimethylformamide solution) dropwise. 625 mg, 0.982 mmol), after addition, the mixture was allowed to return to room temperature for 3 h, then quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel plate separation (petroleum ether: ethyl acetate (V / V) = 1:1) to give 3-(5-chlorothiazol-2-yl)-2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-8), white solid (6.8 mg, yield 3.4%).

[0392] 1 H NMR(400MHz,DMSO-d6)δ9.25-9.24(d,1H),9.12(s,2H),8.12-8.11(d,1H),7.73-7.71(m,1H),7.30-7.28(m,1H), 5.29-5.26(m,1H),5.19-5.16(m,1H),3.90-3.77(m,4H),2.26-2.21(m,1H),2.02-1.97(m,1H),1.58-1.56(d,3H).

[0393] LC-MS, M / Z: 517.1 [M+H] + .

[0394] Example 9: Preparation of target compound I-9

[0395] 2-Fluoro-5-(((S)-4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (Target compound I-9)

[0396]

[0397] The synthetic route for the target compound I-9 is shown below:

[0398]

[0399] Step 1: Synthesis of (S)-(4-methylmorpholino-3-yl)-4-methylbenzenesulfonate methyl ester (9B)

[0400]

[0401] (R)-(4-methylmorpholin-3-yl)methanol (9A) (1.31 g, 10.0 mmol) was added to dichloromethane (20 mL), followed by triethylamine (2.01 g, 20 mmol) and 4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (2.10 g, 11.0 mmol) was added. The mixture was stirred overnight at room temperature. The solution was diluted with dichloromethane (50 mL), concentrated with silica gel (50 mL), and the residue was purified by silica gel column chromatography (ethyl acetate:methanol:ammonia (V / V) = 10:1:0.03) to give crude (S)-(4-methylmorpholin-3-yl)4-methylbenzenesulfonate (9B), in oil form (0.6 g, yield 21.1%).

[0402] Step 2: Synthesis of methyl (S)-2-fluoro-5-((4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazo-2-yl)benzoate (9C)

[0403]

[0404] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.20 g, 0.749 mmol) (synthesis reference Example 1) was added to DMF (2 mL), followed by the addition of cesium carbonate (0.37 g, 1.124 mmol). The mixture was heated to 50 °C and stirred for 0.5 h. Then, crude (S)-(4-methylmorpholino-3-yl)4-methylbenzenesulfonate (9B) (0.33 g, 1.124 mmol) was added, and the mixture was heated to 90 °C and stirred overnight. Cool to room temperature, dilute with distilled water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain crude (S)-2-fluoro-5-((4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazolyl-2-yl)benzoate (9C), in oil form (90 mg, yield 21.0%).

[0405] LC-MS, M / Z: 381.4 [M+H] + .

[0406] Step 3: Synthesis of (S)-2-fluoro-5-((4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazo-2-yl)benzoate lithium (9D)

[0407]

[0408] At room temperature, crude methyl (S)-2-fluoro-5-((4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazol-2-yl)benzoate (9C) (90 mg, 0.237 mmol) was added to 0.5 mL of tetrahydrofuran solution, followed by 0.2 mL of water and lithium hydroxide (56.8 mg, 2.37 mmol). The mixture was reacted overnight at room temperature, concentrated to dryness, and the residue was added to water (10 mL) and freeze-dried to give lithium (S)-2-fluoro-5-((4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazol-2-yl)benzoate (9D) (150 mg, 100% yield).

[0409] LC-MS, M / Z: 367.4 [M+2H-Li] + .

[0410] Step 4: Synthesis of 2-fluoro-5-(((S)-4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-9)

[0411]

[0412] At room temperature, crude lithium (S)-2-fluoro-5-((4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazo-2-yl)benzoate (9D) (150 mg, 0.237 mmol) was added to 3 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (53.9 mg, 0.237 mmol), diisopropylethylamine (106 mg, 0.811 mmol), and dropwise 1-propylphosphonic anhydride (104.6 mg, 0.411 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. The solution was then diluted with 5 mL of water. Extracted with ethyl acetate (10 mL × 2), the organic phase was concentrated to dryness, and the residue was isolated by silica gel plate (ethyl acetate:methanol:ammonia water V / V = 10:1:0.02) to obtain 2-fluoro-5-(((S)-4-methylmorpholin-3-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-9), a grayish solid (3.6 mg, yield 2.8%).

[0413] 1H NMR(400MHz,DMSO-d6)δ9.13(s,2H),8.34(s,2H),7.76-7.74(m,1H),7.25-7.23(m,1H),5.29-5.26(m,1H),4.21-4.17(m,1H),4.0 1-3.97(m,1H),3.86-3.83(m,2H),3.63-3.56(m,2H),2.69-2.66(m,2H),2.63-2.59(s,3H),2.44(s,3H),1.87(s,1H),1.57(d,3H).

[0414] LC-MS, M / Z: 540.6 [M+H] + .

[0415] Example 10: Preparation of target compound I-10

[0416] 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-10)

[0417]

[0418] The synthetic route for the target compound I-10 is shown below:

[0419]

[0420] Step 1: Synthesis of (S)-(tetrahydrofuran-2-yl)-4-methylbenzenesulfonate (10B)

[0421]

[0422] (S)-(tetrahydrofuran-2-yl)methanol (10A) (1.02 g, 10.0 mmol) was added to dichloromethane (20 mL), followed by triethylamine (2.01 g, 20 mmol) and 4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (2.10 g, 11.0 mmol) was added. The mixture was stirred overnight at room temperature. The solution was diluted with dichloromethane (50 mL), concentrated with silica gel (50 mL), and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to give compound (S)-(tetrahydrofuran-2-yl)4-methylbenzenesulfonate (10B), a white solid (1.31 g, yield 50.8%).

[0423] Step 2: Synthesis of (S)-2-fluoro-3-(5-methylthiazolyl)-5-((tetrahydrofuran-2-yl)methoxy)benzoate (10C)

[0424]

[0425] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.20 g, 0.749 mmol) (synthesis reference Example 1) was added to DMF (2 mL), followed by the addition of cesium carbonate (0.37 g, 1.124 mmol). The mixture was heated to 50 °C and stirred for 0.5 h. Then, methyl (S)-(tetrahydrofuran-2-yl)4-methylbenzenesulfonate (10B) (0.29 g, 1.124 mmol) was added, and the mixture was heated to 90 °C and stirred overnight. Cool to room temperature, dilute with distilled water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the liquid and dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give compound (S)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydrofuran-2-yl)methoxy)benzoate (10C), oil (70 mg, yield 26.6%).

[0426] LC-MS, M / Z: 352.4 [M+H] + .

[0427] Step 3: Synthesis of (S)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydrofuran-2-yl)methoxy)lithium benzoate (10D)

[0428]

[0429] At room temperature, methyl (S)-2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydrofuran-2-yl)methoxy)benzoate (10C) (70 mg, 0.199 mmol) was added to 0.5 mL of tetrahydrofuran solution, followed by 0.2 mL of water and lithium hydroxide (47.8 mg, 1.99 mmol). The mixture was reacted overnight at room temperature, concentrated to dryness, and the residue was added to water (10 mL) and freeze-dried to give lithium (S)-2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydrofuran-2-yl)methoxy)benzoate (10D) (110.1 mg, 100% yield).

[0430] LC-MS, M / Z: 337.3 [M+H-Li] + .

[0431] Step 4: 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-10)

[0432]

[0433] At room temperature, (S)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydrofuran-2-yl)methoxy)lithium benzoate (10D) (110.1 mg, 0.199 mmol) was added to 3 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (45.3 mg, 0.199 mmol), diisopropylethylamine (77 mg, 0.597 mmol), and dropwise 1-propylphosphonic anhydride (190 mg, 0.299 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. TLC (PE:EA = 2:1) showed the starting material... After the reaction was complete, 5 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((S)-tetrahydrofuran-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-10), an off-white solid (16 mg, yield 15.8%).

[0434] 1 H NMR(400MHz,DMSO-d6)δ9.19(d,1H),9.10(s,2H),7.74-7.72(m,2H),7.22-7.20(m,1H),5.27-5.24(m,1H),4.16-3.96(m,3H), 3.77-3.74(m,1H),3.69-3.63(m,1H),2.51-2.48(m,3H),2.00-1.97(m,1H),1.96-1.88(m,2H),1.86-1.72(m,1H),1.55(d,3H).

[0435] LC-MS, M / Z: 511.5 [M+H] + .

[0436] Example 11: Preparation of target compound I-11

[0437] 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-tetrahydrofuran-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (Target compound I-11)

[0438]

[0439] The synthetic route for the target compound I-11 is shown below:

[0440]

[0441] The synthesis method is described in Example 10.

[0442] 1 H NMR(400MHz,DMSO-d6)δ9.19(d,1H),9.10(s,2H),7.74-7.72(m,2H),7.22-7.20(m,1H),5.27-5.24(m,1H),4.16-3.96(m,3H), 3.77-3.74(m,1H),3.69-3.63(m,1H),2.51-2.48(m,3H),2.00-1.97(m,1H),1.96-1.88(m,2H),1.86-1.72(m,1H),1.55(d,3H).

[0443] LC-MS, M / Z: 511.5 [M+H] + .

[0444] Example 12: Preparation of target compound I-12

[0445] 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-tetrahydrofuran-3-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-12)

[0446]

[0447] The synthetic route for the target compound I-12 is shown below:

[0448]

[0449] The synthesis method is described in Example 10.

[0450] 1H NMR (400MHz, DMSO-d6) δ9.20-9.18(m,1H),9.10(s,2H),7.74-7.72(m,2H),7.22-7.20(m,1H),5.29-5.22(m,1H),4.02-3.95(m,2H),3.78-3 .74(m,2H),3.65-3.63(m,1H),3.55-3.52(m,1H),2.64-2.52(m,1H), 2.51-2.48(m,3H),2.01-1.98(m,1H),1.71-1.66(m,1H),1.59(d,3H).

[0451] LC-MS, M / Z: 511.5 [M+H] + .

[0452] Example 13: Preparation of target compound I-13

[0453] 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((S)-tetrahydrofuran-3-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-13)

[0454]

[0455] The synthetic route for the target compound I-13 is shown below:

[0456]

[0457] The synthesis method is described in Example 10.

[0458] 1 H NMR (400MHz, DMSO-d6) δ9.20-9.18(m,1H),9.10(s,2H),7.74-7.72(m,2H),7.22-7.20(m,1H),5.29-5.22(m,1H),4.02-3.95(m,2H),3.78-3 .74(m,2H),3.65-3.63(m,1H),3.55-3.52(m,1H),2.64-2.52(m,1H), 2.51-2.48(m,3H),2.01-1.98(m,1H),1.71-1.66(m,1H),1.59(d,3H).

[0459] LC-MS, M / Z: 511.5 [M+H] + .

[0460] Example 14: Preparation of target compound I-14

[0461] (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetane-3-yloxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-14)

[0462]

[0463] The synthetic route for the target compound I-14 is shown below:

[0464]

[0465] Step 1: Synthesis of 4-methylbenzenesulfonic acid oxetane-3-yl ester (14B)

[0466]

[0467] Oxycyclobutane-3-ol (14A) (740 mg, 10.0 mmol) was added to dichloromethane (20 mL), followed by triethylamine (2.01 g, 20 mmol) and 4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (2.10 g, 11.0 mmol) was added. The mixture was stirred overnight at room temperature. The solution was diluted with dichloromethane (50 mL), concentrated with silica gel (50 mL), and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give compound oxycyclobutane-3-yl ester of 4-methylbenzenesulfonate (14B), a white solid (1.40 g, yield 61%).

[0468] Step 2: Synthesis of methyl 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetane-3-yloxy)benzoate (14C)

[0469]

[0470] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.20 g, 0.749 mmol) (synthesis reference Example 1) was added to DMF (2 mL), followed by the addition of cesium carbonate (0.37 g, 1.124 mmol). The mixture was heated to 50 °C and stirred for 0.5 h. Then, 4-methylbenzenesulfonate oxetane-3-yl ester (14B) (0.26 g, 1.124 mmol) was added, and the mixture was heated to 90 °C and stirred overnight. Cool to room temperature, dilute with distilled water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the liquid and dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give methyl 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetanebut-3-yloxy)benzoate (14C), oil (80 mg, yield 33.1%).

[0471] LC-MS, M / Z: 324.3 [M+H] + .

[0472] Step 3: Synthesis of lithium 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetane-3-yloxy)benzoate (14D)

[0473]

[0474] Methyl 2-fluoro-3-(5-methylthiazol-2-yl)-5-(oxetane-3-yloxy)benzoate (14C) (80 mg, 0.248 mmol) was added to 0.5 mL of tetrahydrofuran solution at room temperature, followed by 0.2 mL of water and lithium hydroxide monohydrate (59.4 mg, 2.48 mmol). The reaction was carried out overnight at room temperature, concentrated to dryness, and the residue was added to water (10 mL) and freeze-dried to give crude 2-fluoro-3-(5-methylthiazol-2-yl)-5-(oxetane-3-yloxy)benzoate (14D) (138.1 mg, 100% yield).

[0475] LC-MS, M / Z: 309.3 [M+H-Li] + .

[0476] Step 4: Synthesis of (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetane-3-yloxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-14)

[0477]

[0478] At room temperature, crude lithium 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetanebut-3-yloxy)benzoate (14D) (138.1 mg, 0.248 mmol) was added to 3 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (59.2 mg, 0.248 mmol), diisopropylethylamine (96 mg, 0.744 mmol), and dropwise 1-propylphosphonic anhydride (237 mg, 0.372 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. TLC (PE:EA = 1:1) was then performed. After the reactants had reacted completely, 5 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(oxetanebut-3-yloxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-14), an off-white solid (27 mg, yield 22.5%).

[0479] 1 H NMR(400MHz,DMSO-d6)δ9.23(d,1H),9.12(s,2H),7.44(d,1H),7.56(q,1H),7.11(q,1H),5.44-5.3 9(m,1H),5.29-5.26(m,1H),4.95-4.92(m,2H),4.58-4.55(m,2H),2.53-2.49(s,3H),1.56(s,3H).

[0480] LC-MS, M / Z: 483.5 [M+H] + .

[0481] Example 15: Preparation of target compound I-15

[0482] (R)-5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-15)

[0483]

[0484] The synthetic route for the target compound I-15 is shown below:

[0485]

[0486] Step 1: Synthesis of cyclopropyl methyl 4-methylbenzenesulfonate (15B)

[0487]

[0488] Cyclopropylmethanol (15A) (720 mg, 10.0 mmol) was added to dichloromethane (20 mL), followed by triethylamine (2.01 g, 20 mmol) and 4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (2.10 g, 11.0 mmol) was added. The mixture was stirred overnight at room temperature. The solution was diluted with dichloromethane (50 mL), concentrated with silica gel (50 mL), and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give compound cyclopropylmethyl 4-methylbenzenesulfonic acid (15B), a white solid (1.65 g, 73% yield).

[0489] Step 2: Synthesis of methyl 5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (15C)

[0490]

[0491] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.20 g, 0.749 mmol) (synthesis reference Example 1) was added to DMF (2 mL), followed by the addition of cesium carbonate (0.37 g, 1.124 mmol). The mixture was heated to 50 °C and stirred for 0.5 h. Then, cyclopropyl methyl 4-methylbenzenesulfonate (15B) (0.25 g, 1.124 mmol) was added, and the mixture was heated to 90 °C and stirred overnight. Cool to room temperature, dilute with distilled water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give compound methyl 5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (15C), oil (65 mg, yield 27.0%).

[0492] LC-MS, M / Z: 322.4 [M+H] + .

[0493] Step 3: Synthesis of lithium 5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (15D)

[0494]

[0495] Methyl 5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoate (15C) (65 mg, 0.202 mmol) was added to 0.5 mL of tetrahydrofuran solution at room temperature, followed by 0.2 mL of water and lithium hydroxide (48.5 mg, 2.02 mmol). The reaction was carried out overnight at room temperature, concentrated to dryness, and the residue was added to water (10 mL) and freeze-dried to give lithium 5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoate (15D) (103.3 mg, 100% yield).

[0496] LC-MS, M / Z: 307.3 [M+H-Li] + .

[0497] Step 4: Synthesis of (R)-5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-15)

[0498]

[0499] At room temperature, crude lithium 5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (15D) (103.3 mg, 0.202 mmol) was added to 3 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (58.8 mg, 0.202 mmol), diisopropylethylamine (78 mg, 0.606 mmol), and dropwise 1-propylphosphonic anhydride (192 mg, 0.303 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. TLC (PE:EA = 1:1) was then performed. After the reactants had reacted completely, 5 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give (R)-5-(cyclopropylmethoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-15), an off-white solid (19 mg, yield 19.6%).

[0500] 1H NMR(400MHz, CDCl3)δ8.88(s,2H),7.87(d,1H),7.54(s,1H),7.45(d,1H),7.02-6.93(m,1H),5.33-5.30 (m,1H),3.80(d,2H),2.50(s,3H),1.65(d,3H),1.12-1.06(m,1H),0.60-0.55(m,2H),0.29-026(m,2H).

[0501] LC-MS, M / Z: 481.5 [M+H] + .

[0502] Example 16: Preparation of target compound I-16

[0503] (R)-2-fluoro-5-((1-methylpiperidin-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-16)

[0504]

[0505] The synthetic route for the target compound I-16 is shown below:

[0506]

[0507] Step 1: Synthesis of tert-butyl 4-[(4-methylphenyl)sulfonyl]-1-piperidinecarboxylate (16B)

[0508]

[0509] N-Boc-4-hydroxypiperidine (16A) (2.0 g, 9.94 mmol) was added to dichloromethane (20 mL), followed by triethylamine (2.01 g, 19.87 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (2.84 g, 14.91 mmol) was added. The mixture was stirred overnight at room temperature. The solution was diluted with ethyl acetate (50 mL), concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to give tert-butyl 4-[(4-methylphenyl)sulfonyl]-1-piperidinecarboxylate (16B), a white solid (2.3 g, yield 65.1%).

[0510] Step 2: Synthesis of methyl 2-fluoro-5-((1-piperidinylcarboxylate-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (16C)

[0511]

[0512] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.50 g, 1.871 mmol) (synthesis reference Example 1) was added to DMF (25 mL), along with cesium carbonate (1.83 g, 5.61 mmol) and tert-butyl 4-[(4-methylphenyl)sulfonyl]-1-piperidinecarboxylate (16B) (0.67 g, 1.871 mmol). The mixture was heated to 80 °C and stirred overnight. Cool to room temperature, dilute with distilled water (50 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give methyl 2-fluoro-5-((1-piperidinic acid tert-butyl-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (16C), white solid (0.4 g, yield 39.6%).

[0513] LC-MS, M / Z: 451.5 [M+H] + .

[0514] Step 3: Synthesis of lithium 2-fluoro-5-((1-piperidinylcarboxylate-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (16D)

[0515]

[0516] Methyl 2-fluoro-5-((1-piperidinylcarboxylate-4-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (16C) (0.4 g, 0.888 mmol) was added to 10 mL of tetrahydrofuran solution at room temperature, followed by 2.5 mL of water and 2.5 mL of methanol, and lithium hydroxide (0.11 g, 4.44 mmol). The reaction was carried out overnight at room temperature, concentrated to dryness, and the residue was added to water (10 mL) and freeze-dried to give lithium 2-fluoro-5-((1-piperidinylcarboxylate-4-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (16D) (0.38 g, 98% yield).

[0517] LC-MS, M / Z: 436.5 [M+H-Li] + .

[0518] Step 4: Synthesis of (R)-2-fluoro-5-((1-piperidinylcarboxylate-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (16E)

[0519]

[0520] At room temperature, 2-fluoro-5-((1-piperidinylcarbamate-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate lithium (16D) (0.38 g, 0.871 mmol) was added to 10 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (0.20 g, 1.045 mmol), diisopropylethylamine (0.34 g, 2.61 mmol), and dropwise 1-propylphosphonic anhydride (0.83 g, 2.61 mmol, 50% N,N-dimethylformamide solution). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection, and then diluted with 10 mL of water. Extracted with ethyl acetate (10 mL × 2), the organic phase was concentrated to dryness, and the residue was isolated by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain (R)-2-fluoro-5-((1-piperidinic acid tert-butyl-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (16E), a white solid (160 mg, yield 30.1%).

[0521] LC-MS, M / Z: 610.6 [M+H] + .

[0522] Step 5: Synthesis of (R)-2-fluoro-5-((1-piperidin-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (16F)

[0523]

[0524] At room temperature, (R)-2-fluoro-5-((1-piperidin-4-yl)oxy)-3-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (16E) (160 mg, 0.262 mmol) was added to 2 mL of methanol, followed by the addition of 4 M dioxane hydrochloride solution (2.0 g, 8.0 mmol). After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated and lyophilized to give (R)-2-fluoro-5-((1-piperidin-4-yl)oxy)-3-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (16F), a white solid (50 mg, yield 37.4%).

[0525] LC-MS, M / Z: 510.5 [M+H] + .

[0526] Step 6: Synthesis of (R)-2-fluoro-5-((1-methylpiperidin-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-16)

[0527]

[0528] At room temperature, (R)-2-fluoro-5-((1-piperidin-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (16F) (50 mg, 0.098 mmol) was added to 2 mL of methanol, followed by paraformaldehyde (15 mg, 0.491 mmol), sodium cyanoborohydride (31 mg, 0.491 mmol), and glacial acetic acid (0.59 mg, 0.01 mmol). After the addition was complete, the mixture was placed under nitrogen protection in a chamber. The mixture was stirred at room temperature overnight. After concentration, the reaction solution was diluted with saturated sodium bicarbonate solution (10 mL). It was extracted with dichloromethane (5 mL × 3). The organic phase was concentrated to dryness. The residue was isolated by using a large silica gel plate (dichloromethane:methanol (V / V) = 10:1) to obtain (R)-2-fluoro-5-((1-methylpiperidin-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-16), a white solid (30 mg, yield 58.0%).

[0529] 1 H NMR(400MHz,DMSO-d6)δ9.27(d,1H),9.11(s,2H),7.74(m,2H),7.25(s,1H),5.25(s,1H),4.59(s ,1H),2.87(s,2H),2.51(s,3H),2.48(s,3H),2.39(s,2H),2.01(s,2H),1.79(s,2H),1.55(d,3H).

[0530] LC-MS, M / Z: 524.6 [M+H] + .

[0531] Example 17: Preparation of target compound I-17

[0532] Synthesis of (R)-2-fluoro-5-((1-piperidin-4-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-17)

[0533]

[0534] The synthetic route for the target compound I-17 is shown below:

[0535]

[0536] The synthesis of target compound I-17 was performed following the synthesis steps of 16F in Example 16 above (56 mg, yield 39.8%).

[0537] 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),9.11(s,2H),8.91(s,2H),7.79(s,1H),7.72(s,1H),7.29(s,1H),5 .26(s,1H),4.76(s,1H),3.22(s,2H),3.06(s,2H),2.51(s,3H),2.07(s,2H),1.84(s,2H),1.55(d,3H).

[0538] LC-MS, M / Z: 510.5 [M+H] + .

[0539] Example 18: Preparation of I-18

[0540] 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-morpholino-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide hydrochloride (I-18)

[0541]

[0542] The synthetic route for I-18 is shown below:

[0543]

[0544] Step 1: Synthesis of (R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (18C)

[0545]

[0546] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)benzoate (18A) (500 mg, 1.871 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), and cesium carbonate (914 mg, 2.81 mmol) was added. The mixture was stirred at room temperature for 10 min, and then (R)-2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (1042 mg, 2.81 mmol) was added. The mixture was purged with nitrogen three times, and the temperature was raised to 90 °C for 4 h under nitrogen protection. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give crude (R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazol-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (18C) (873 mg, 100% yield).

[0547] LC-MS, M / Z: 467.4 [M+H] + .

[0548] Step 2: Synthesis of (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate lithium (18D)

[0549]

[0550] In the previous step, crude product (R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazolyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (18C) (873 mg, 1.871 mmol) was added to a methanol (10 mL) and tetrahydrofuran (10 mL) solution, followed by the addition of lithium hydroxide monohydrate (314 mg, 7.49 mmol) and water (5 mL). The reaction was carried out at room temperature for 24 h. The reaction solution was lyophilized, and the crude product was directly fed into the next reaction step.

[0551] LC-MS, M / Z: 453.3 [M+2H-Li] + .

[0552] Step 3: Synthesis of tert-butyl(R)-2-((4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid ester (18F)

[0553]

[0554] The crude product (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)lithium benzoate (18D) (847 mg, 1.872 mmol) from the previous step was dissolved in N,N-dimethylformamide (10 mL). In the reaction flask, (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (469 mg, 2.059 mmol) and N,N-diisopropylethylamine (726 mg, 5.62 mmol) were added sequentially. The reaction solution was cooled to about 0 °C, and 1-propylphosphonic anhydride (3.573 g, 5.62 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 20 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give tert-butyl(R)-2-((4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid ester (18F), a white solid (530 mg, yield 45.3%).

[0555] LC-MS, M / Z: 626.2 [M+H] + .

[0556] Step 4: Synthesis of 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-morpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide hydrochloride (I-18)

[0557]

[0558] Tert-butyl(R)-2-((4-fluoro-3-(5-methylthiazol-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid ester (18F) (450 mg, 0.719 mmol) was dissolved in methanol (2 mL), and a dioxane solution of hydrogen chloride (4 M, 2 mL, 8 mmol) was added. The mixture was stirred at room temperature for 18 h. The reaction solution was concentrated to give 2-fluoro-3-(5-methylthiazol-2-yl)-5-(((R)-morpholine-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide hydrochloride (I-18), a yellow solid (400 mg, 99% yield).

[0559] 1H NMR (400MHz, DMSO-d6): δ9.44-9.32(m,2H),9.25-9.23(d,1H),9.10(s,2H),7.76-7.71(m,2H),7.24-7.22(m,1H),5.29- 5.22(m,1H),4.18-3.96(m,5H),3.81-3.75(m,1H),3.20-3.16(d,1H),2.98-2.92(m,2H),2.51(s,3H),1.55-1.53(d,3H).

[0560] LC-MS, M / Z: 526.4 [M+H] + .

[0561] Example 19: Preparation of I-19

[0562] 2-Fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-19)

[0563]

[0564] The synthetic route for I-19 is shown below:

[0565]

[0566] Synthesis of 2-fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-19)

[0567]

[0568] In a sealed tube, 2-fluoro-3-(5-methylthiazolyl)-5-(((R)-morpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide hydrochloride (synthesis reference Example 18) (1.26 g, 2.398 mmol) was dissolved in dry methanol (10 mL), and paraformaldehyde (1.079 g, 11.99 mmol) and acetic acid (0.144 g, 2.398 mmol) were added sequentially. The mixture was stirred at room temperature for 10 min, and then sodium cyanoborohydride (0.753 g, 11.99 mmol) was added. The reaction was continued at room temperature for 20 h. The reaction solution was quenched with saturated sodium bicarbonate (50 mL), extracted with dichloromethane (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel plate (dichloromethane:methanol (V / V) = 50:1) to give 2-fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-19), a white solid (598.5 mg, yield 46.3%).

[0569] 1 H NMR(400MHz,DMSO-d6)δ9.21-9.19(d,1H),9.11(s,2H),7.74-7.72(m,2H),7.23-7.21(m,1H),5.27-5.24(m,1H),4.06-4.05(d,2H),3 .82-3.79(m,2H),3.55(t,1H),2.84-2.81(m,1H),2.67-2.64(m,1H),2.51(s,3H),2.23(s,3H),2.08-1.99(m,2H),1.56-1.54(d,3H).

[0570] LC-MS, M / Z: 540.4 [M+H] + .

[0571] Example 20: Preparation of compound I-20

[0572] 2-Fluoro-5-(((R)-4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-20)

[0573]

[0574] The synthetic route for I-20 is shown below:

[0575]

[0576] Step 1: Synthesis of (R)-2-fluoro-3-(5-methylthiazolyl)-5-(morpholin-2-ylmethoxy)benzoate methyl hydrochloride (20B)

[0577]

[0578] Add 5 mL (20 mmol) of 4 M hydrogen chloride in 1,4-dioxane solution to (R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (20A) (0.5 g, 1.072 mmol), stir the reaction mixture at room temperature for 30 min, concentrate the reaction solution, and directly feed the crude product into the next reaction step.

[0579] Step 2: Synthesis of (R)-2-fluoro-5-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)benzoate (20C)

[0580]

[0581] The crude product (R)-2-fluoro-3-(5-methylthiazolyl)-5-(morpholin-2-ylmethoxy)benzoate hydrochloride (20B) from the previous step was dissolved in dry acetonitrile (10 mL), and then triethylamine (0.325 g, 3.22 mmol), potassium carbonate (0.222 g, 1.608 mmol), and deuterated iodomethane (0.155 g, 1.072 mmol) were added sequentially. The reaction was carried out at room temperature for 20 h after the addition was complete. Add water (50 mL), extract with dichloromethane (30 mL × 3), combine the organic phases, dry to anhydrous sodium sulfate, concentrate, and separate the residue by column chromatography (dichloromethane:methanol (V / V) = 100:1) to give (R)-2-fluoro-5-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazol-2-yl)benzoate (20C), a pale yellow oil (300 mg, yield: 73.0%).

[0582] LC-MS, M / Z: 384.2 [M+H] + .

[0583] Step 3: Synthesis of (R)-2-fluoro-5-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)lithium benzoate (20D)

[0584]

[0585] Methyl (R)-2-fluoro-5-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)benzoate (20C) (300 mg, 0.782 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), followed by the addition of lithium hydroxide monohydrate (131 mg, 3.13 mmol) and water (2 mL). The reaction mixture was then reacted at room temperature for 4 h. The reaction solution was lyophilized, and the crude product was directly fed into the next reaction step.

[0586] LC-MS, M / Z: 370.2 [M+2H-Li] + .

[0587] Step 4: Synthesis of 2-fluoro-5-(((R)-4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-20)

[0588]

[0589] The crude product from the previous step, (R)-2-fluoro-5-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)lithium benzoate (20D) (289 mg, 0.782 mmol), was dissolved in dry N,N-dimethylformamide (5 mL). Then, (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (196 mg, 0.861 mmol) and N,N-diisopropylethylamine (303 mg, 2.347 mmol) were added sequentially. The mixture was cooled to 0-5 °C, and 1-propylphosphonic anhydride (1.493 g, 2.347 mmol, 50% N,N-dimethylformamide solution) was added dropwise. The mixture was reacted at room temperature for 4 h. The reaction mixture was quenched with water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel plate (dichloromethane:methanol (V / V) = 20:1, +NH3) to give 2-fluoro-5-(((R)-4-(methyl-d3)morpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-20), a white solid (25 mg, yield 5.9%).

[0590] 1H NMR (400MHz, DMSO-d6): δ9.19-9.17(d,1H),9.09(s,2H),7.72-7.70(m,2H),7.22-7.20(m,1H),5.28-5.21(m,1H),4.04-4.03(d,2 H),3.79-3.75(m,2H),3.54-3.48(m,1H),2.76-2.74(d,1H),2.59-2.56(d,1H),2.50(s,3H),2.02-1.89(m,2H),1.54-1.52(d,3H).

[0591] LC-MS, M / Z: 543.4 [M+H] + .

[0592] Example 21: Preparation of compound I-21

[0593] (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-21)

[0594]

[0595] The synthetic route for I-21 is shown below:

[0596]

[0597] 2-Fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (21C)

[0598]

[0599] (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (21F)

[0600]

[0601] Prepared according to the method of patent WO 2016 / 091776.

[0602] Step 1: Synthesis of methyl (tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonate (21B)

[0603]

[0604] (Tetrahydro-2H-pyran-4-yl)methanol (21A) (2 g, 17.22 mmol), triethylamine (3.48 g, 34.4 mmol), and 4-dimethylaminopyridine (0.421 g, 3.44 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature, and p-toluenesulfonyl chloride (3.94 g, 20.66 mmol) was added in portions. After the addition was complete, the reaction was continued at room temperature for 20 h. The reaction was quenched with water (30 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to give methyl (tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonate (21B), a white solid (4.5 g, 97% yield).

[0605] Step 2: Synthesis of methyl 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (21D)

[0606]

[0607] Cesium carbonate (366 mg, 1.122 mmol) was added to a solution of methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (21C) (200 mg, 0.748 mmol) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 30 min. Methyl (tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonate (21B) (303 mg, 1.122 mmol) was added, and the reaction was carried out under nitrogen protection at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give methyl 2-fluoro-3-(5-methylthiazolyl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (21D), a white solid (90 mg, yield 32.9%).

[0608] LC-MS, M / Z: 366.2 [M+H] + .

[0609] Step 3: Synthesis of 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoic acid (21E)

[0610]

[0611] Methyl 2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (21D) (90 mg, 0.246 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), followed by the addition of lithium hydroxide monohydrate (41.3 mg, 0.985 mmol) and water (2 mL). The reaction was continued with stirring at room temperature for 20 h. Subsequently, methanol and tetrahydrofuran were removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 4 with 2 M hydrochloric acid and then extracted with dichloromethane (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-fluoro-3-(5-methylthiazol-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoic acid (21E) (87 mg, crude product), which was directly added to the next reaction.

[0612] LC-MS, M / Z: 352.3 [M+H] + .

[0613] Step 4: Synthesis of (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-21)

[0614]

[0615] Add 2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoic acid (21E) (87 mg, 0.248 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (21F) (67.6 mg, 0.297 mmol), N,N-diisopropylethylamine (96 mg, 0.743 mmol), and N,N-dimethylformamide (5 mL) to the reaction flask in sequence. Cool to approximately 0 °C, and then add 1-propylphosphonic anhydride (473 mg, 0.743 mmol) dropwise. Add 50% N,N-dimethylformamide solution, restore to room temperature for 2 hours, quench with water (50 mL), extract with ethyl acetate (30 mL × 3), combine organic phases, dry with anhydrous sodium sulfate, concentrate, and separate and purify the residue with silica gel (petroleum ether: ethyl acetate (V / V) = 1:1) to give (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-21), white solid (59.2 mg, yield 45.6%).

[0616] 1H NMR(400MHz,DMSO-d6)δ9.20-9.18(d,1H),9.10(s,2H),7.74-7.71(m,2H),7.21-7.19(dd,1H),5.29-5.22(m,1H),3.91-3.8 4(m,4H),3.35-3.31(m,2H),2.52-2.51(d,3H),2.05-1.94(m,1H),1.69-1.65(dd,2H),1.56-1.54(d,3H),1.39-1.28(m,2H).

[0617] LC-MS, M / Z: 525.2 [M+H] + .

[0618] Example 22: Preparation of compound I-22

[0619] 3-(5-Ethiazole-2-yl)-2-fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-22)

[0620]

[0621] The synthetic route for the target compound I-22 is shown below:

[0622]

[0623] Step 1: Synthesis of methyl 3-(5-ethylthiazolyl)-2-fluoro-5-hydroxybenzoate (22B)

[0624]

[0625] 2-Bromo-5-ethylthiazole (22A) (1.04 g, 5.40 mmol) and methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (1.60 g, 5.40 mmol) (synthesis reference Example 1) were added to 1,4-dioxane (10 mL) and water (2.5 mL), followed by the addition of sodium carbonate (2.01 g, 19.87 mmol), and the mixture was purged with nitrogen three times. Then, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (395 mg, 0.54 mmol) was added, and the mixture was purged with nitrogen three times again. The mixture was then stirred at 80 °C overnight. Dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), concentrate the organic phase, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to give methyl 3-(5-ethylthiazol-2-yl)-2-fluoro-5-hydroxybenzoate (22B), a white solid (0.8 g, yield 52.6%).

[0626] Step 2: Synthesis of (R)-2-((3-(5-ethylthiazolyl-2-yl)-4-fluoro-5-(methoxycarbonyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (22C)

[0627]

[0628] Compound methyl 3-(5-ethylthiazol-2-yl)-2-fluoro-5-hydroxybenzoate (22B) (0.80 g, 2.84 mmol) and (R)-2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (1.06 g, 2.84 mmol) (synthetic method according to patent WO2016 / 091776) were added to DMF (10 mL), cesium carbonate (2.78 g, 8.53 mmol) was added, the mixture was heated to 80 °C, and stirred overnight. Cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the liquid and dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give (R)-2-((3-(5-ethylthiazol-2-yl)-4-fluoro-5-(methoxycarbonyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (22C), white solid (0.75 g, yield 54.9%).

[0629] LC-MS, M / Z (ESI): 481.5 [M+H] + .

[0630] Step 3: Synthesis of lithium (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-3-(5-ethylthiazolyl)-2-fluorobenzoate (22D)

[0631]

[0632] At room temperature, (R)-2-((3-(5-ethylthiazol-2-yl)-4-fluoro-5-(methoxycarbonyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (22C) (0.75 g, 1.56 mmol) was added to 8 mL of tetrahydrofuran solution, followed by 2 mL of water and lithium hydroxide (0.15 g, 6.24 mmol). The reaction was carried out overnight at room temperature, concentrated to dryness, and the residue was added to water (10 mL) and freeze-dried to give (R)-5-((4-(tert-butoxycarbonyl)morpholine-2-yl)methoxy)-3-(5-ethylthiazol-2-yl)-2-fluorobenzoate lithium (22D) (0.72 g, 99% yield).

[0633] LC-MS, M / Z (ESI): 467.5 [M+2H-Li] + .

[0634] Step 4: Synthesis of (R)-2-((3-(5-ethylthiazolyl-2-yl)-4-fluoro-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (22E)

[0635]

[0636] At room temperature, lithium (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-3-(5-ethylthiazo-2-yl)-2-fluorobenzoate (22D) (0.60 g, 1.286 mmol) was added to 10 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (0.35 g, 1.543 mmol) (synthetic method according to patent WO2016 / 091776), N,N-diisopropylethylamine (0.499 g, 3.86 mmol), and dropwise a 50% solution of 1-propylphosphonic anhydride in N,N-dimethylformamide (2.455 g, 3.86 mmol). After the addition was complete, the mixture was kept at room temperature under nitrogen protection. Stir overnight, dilute with 10 mL of water, extract with ethyl acetate (10 mL × 2), concentrate the organic phase to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give (R)-2-((3-(5-ethylthiazol-2-yl)-4-fluoro-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (22E), white solid (0.50 g, yield 60.8%).

[0637] LC-MS, M / Z (ESI): 640.7 [M+H] + .

[0638] Step 5: Synthesis of 3-(5-ethylthiazolyl)-2-fluoro-5-(((R)-morpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (22F)

[0639]

[0640] At room temperature, (R)-2-((3-(5-ethylthiazol-2-yl)-4-fluoro-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (22E) (0.5 g, 0.782 mmol) was added to 5 mL of methanol, followed by 2.0 mL (8.0 mmol) of 4 M hydrogen chloride solution of 1,4-dioxane. After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated and lyophilized to give 3-(5-ethylthiazol-2-yl)-2-fluoro-5-(((R)-morpholine-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (22F), a white solid (0.2 g, yield 47.4%).

[0641] LC-MS, M / Z (ESI): 540.6 [M+H] + .

[0642] Step 6: Synthesis of 3-(5-ethylthiazolyl)-2-fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-22)

[0643]

[0644] At room temperature, 3-(5-ethylthiazolyl)-2-fluoro-5-(((R)-morpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (22F) (0.2 g, 0.371 mmol) was added to 10 mL of methanol, followed by paraformaldehyde (56 mg, 1.853 mmol), sodium cyanoborohydride (116 mg, 1.853 mmol), and glacial acetic acid (2.23 mg, 0.037 mmol). The mixture was then added under nitrogen protection. The mixture was stirred overnight at room temperature. The reaction solution was concentrated and diluted with saturated sodium bicarbonate solution (10 mL). It was extracted with dichloromethane (5 mL × 3). The organic phase was concentrated to dryness. The residue was purified by silica gel agar (dichloromethane:methanol V / V = 10:1) to obtain 3-(5-ethylthiazol-2-yl)-2-fluoro-5-(((R)-4-methylmorpholino-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-22), a white solid (26 mg, yield 12.6%).

[0645] 1 H NMR(400MHz,DMSO-d6)δ9.23(d,1H),9.11(s,2H),7.79–7.75(m,2H),7.24–7.22(m,1H),5.30–5.23(m,1H),4.20–4.13(m,3H),4.07–4.03 (m,1H),3.87–3.80(m,1H),3.51(d,1H),3.07–3.02(m,2H),2.98–2.88(m,2H),2.80(s,3H),2.01–1.93(m,1H),1.56(d,3H),1.29(t,3H).

[0646] LC-MS, M / Z: 554.6 [M+H] + .

[0647] Example 23: Preparation of compound I-23

[0648] 2-Chloro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (Target compound I-23)

[0649]

[0650] The synthetic route for the target compound I-23 is shown below:

[0651]

[0652] Step 1: Synthesis of methyl 2-chloro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (23B)

[0653]

[0654] Methyl 3-bromo-2-chloro-5-hydroxybenzoate (23A) (1.0 g, 3.77 mmol), pinacol diboronate (1.052 g, 4.14 mmol), and potassium acetate (1.019 g, 11.30 mmol) were dissolved in 1,4-dioxane (10 mL), and the solution was degassed with a stream of nitrogen for 2 min. Palladium dichloride (0.138 g, 0.188 mmol) was added, and the resulting solution was degassed with a stream of nitrogen for another 2 min. The reaction mixture was then stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl 2-chloro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate, a white solid (0.69 g, 60.0% yield).

[0655] Step 2: Synthesis of methyl 2-chloro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (23C)

[0656]

[0657] 2-Bromo-5-methylthiazole (0.43 g, 2.43 mmol), methyl 2-chloro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (23B) (0.69 g, 2.21 mmol) were added to 1,4-dioxane (5 mL) and water (1.5 mL), followed by the addition of sodium carbonate (0.468 g, 4.42 mmol). The mixture was purged with nitrogen three times, and then [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (162 mg, 0.22 mmol) was added. The mixture was then purged with nitrogen three times again and stirred at 80 °C overnight. Dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), concentrate the organic phase, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to give methyl 2-chloro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (23C), a white solid (0.38 g, yield 60.7%).

[0658] Step 3: Synthesis of (R)-2-((4-chloro-3-(methoxycarbonyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23D)

[0659]

[0660] 2-chloro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate methyl ester (0.38 g, 1.34 mmol) and (R)-2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23C) (0.55 g, 1.47 mmol) (synthetic method according to patent WO2016 / 091776) were added to DMF (5 mL), cesium carbonate (1.31 g, 4.02 mmol) was added, the mixture was heated to 80 °C, and stirred overnight. Cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to give (R)-2-((4-chloro-3-(methoxycarbonyl)-5-(5-methylthiazolyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23D), a colorless oily liquid (0.42 g, yield 64.9%).

[0661] LC-MS, M / Z (ESI): 483.1 [M+H] + .

[0662] Step 4: Synthesis of (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-chloro-3-(5-methylthiazol-2-yl)benzoic acid (23E)

[0663]

[0664] At room temperature, (R)-2-(((4-chloro-3-(methoxycarbonyl)-5-(5-methylthiazol-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23D) (0.42 g, 0.87 mmol) was added to 5 mL of tetrahydrofuran solution, followed by 1 mL of water and sodium hydroxide (0.07 g, 1.74 mmol). The mixture was heated to 60 °C and stirred for 2 hours. The mixture was concentrated to dryness, and the residue was added to water (10 mL). The pH was adjusted to 6 by adding 1 M hydrochloric acid. The mixture was extracted with dichloromethane (20 mL × 3), concentrated to dryness, and freeze-dried to give (R)-5-((4-(tert-butoxycarbonyl)morpholine-2-yl)methoxy)-2-chloro-3-(5-methylthiazol-2-yl)benzoic acid (23E) (0.4 g, 98% yield).

[0665] LC-MS, M / Z (ESI): 469.1 [M+H] + .

[0666] Step 5: Synthesis of (R)-2-((4-chloro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23F)

[0667]

[0668] At room temperature, (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-chloro-3-(5-methylthiazolyl-2-yl)benzoic acid (23E) (0.3 g, 0.64 mmol) was added to 5 mL of N,N-dimethylformamide, followed by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (0.18 g, 0.77 mmol) (synthetic method according to patent WO2016 / 091776), N,N-diisopropylethylamine (0.25 g, 1.91 mmol), and dropwise a 50% solution of 1-propylphosphonic anhydride in N,N-dimethylformamide (1.22 g, 1.91 mmol). After the addition was complete, the mixture was stirred at room temperature under nitrogen protection. At night, dilute with 10 mL of water, extract with ethyl acetate (10 mL × 2), concentrate the organic phase to dryness, and purify the residue by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give (R)-2-((4-chloro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23F), white solid (0.25 g, yield 62.0%).

[0669] LC-MS, M / Z (ESI): 642.2 [M+H] + .

[0670] Step 6: Synthesis of 2-chloro-3-(5-methylthiazolyl-2-yl)-5-(((R)-morpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (23G)

[0671]

[0672] At room temperature, (R)-2-((4-chloro-3-(5-methylthiazol-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (23F) (0.25 g, 0.39 mmol) was added to 5 mL of methanol, followed by 1.0 mL (4.0 mmol) of 4M hydrogen chloride in 1,4-dioxane. After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated and lyophilized to give 2-chloro-3-(5-methylthiazol-2-yl)-5-(((R)-morpholine-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (23G), a white solid (0.07 g, yield 33.1%).

[0673] LC-MS, M / Z (ESI): 542.1 [M+H] + .

[0674] Step 7: Synthesis of 2-chloro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-23)

[0675]

[0676] At room temperature, 2-chloro-3-(5-methylthiazolyl-2-yl)-5-(((R)-morpholin-2-yl)methoxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (23g) (0.07g, 0.13mmol) was added to 5mL of methanol, followed by the addition of paraformaldehyde (19mg, 0.65mmol), sodium cyanoborohydride (41mg, 0.65mmol), and glacial acetic acid (0.77mg, 0.01mmol). After the addition was complete, the mixture was stirred at room temperature under nitrogen protection. After stirring overnight, the reaction solution was concentrated and diluted with saturated sodium bicarbonate solution (10 mL). It was extracted with dichloromethane (5 mL × 3), the organic phase was concentrated to dryness, and the residue was isolated by using a large silica gel plate (dichloromethane:methanol V / V = 10:1) to obtain 2-chloro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-23), a white solid (12 mg, yield 16.6%).

[0677] 1 H NMR(400MHz,DMSO-d6)δ9.20(d,1H),9.10(s,2H),7.70(d,1H),7.66(d,1H),7.20(d,1H),5.26–5.15(m,1H),4.05(d,1H),3.88–3.6 4(m,2H),3.62–3.43(m,1H),2.74(d,1H),2.57(d,1H),2.50(s,3H),2.17(s,3H),2.02–1.92(m,2H),1.91–1.83(m,1H),1.52(d,3H).

[0678] LC-MS, M / Z: 556.1 [M+H] + .

[0679] Example 24: Preparation of compound I-24

[0680] (R)-2-fluoro-5-((4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)benzamide (target compound I-24)

[0681]

[0682] The synthetic route for the target compound I-24 is shown below:

[0683]

[0684] Step 1: Synthesis of (R)-2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[0685]

[0686] (R)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (10.0 g, 46.0 mmol), 4-dimethylaminopyridine (1.125 g, 9.21 mmol), and triethylamine (9.32 g, 92.0 mmol) were added to anhydrous dichloromethane (100 mL), followed by the addition of p-toluenesulfonyl chloride (9.65 g, 50.6 mmol) at room temperature. The reaction was carried out for 15 h at room temperature. The reaction mixture was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 3:1) to ensure complete reaction. Water (100 mL) and DCM (300 mL) were added to the reaction mixture, and the aqueous phase was extracted with DCM (100 mL × 3). The combined extracts were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-1:1) to obtain compound (R)-2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (12.0 g, yield 70.2%).

[0687] Step 2: Synthesis of tert-butyl(R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[0688]

[0689] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.60 g, 2.245 mmol) and cesium carbonate (1.46 g, 4.49 mmol) were added to DMF (10 mL), followed by (R)-2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (1.00 g, 2.69 mmol). The reaction mixture was reacted at 100 °C for 15 h. TLC (petroleum ether:ethyl acetate (V / V) = 1:1) was used to monitor that most of the starting materials had reacted completely. Water (100 mL) and EA (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with EA (100 mL × 3). The combined extracts were washed with saturated brine (100 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:1-1:100) to obtain the compound tert-butyl(R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.60 g, yield 57.3%).

[0690] Step 3: Synthesis of (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoic acid (4)

[0691]

[0692] The synthesis of tert-butyl(R)-2-((4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazolyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.60 g, 1.286 mmol) was carried out in methanol (10 mL), THF (2 mL), and water (2 mL), and LiOH was added at room temperature. . H2O (0.123 g, 5.14 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 15 hours. The reaction of the starting materials was monitored by TLC (petroleum ether: ethyl acetate (V / V) = 1:1) to ensure complete reaction. The reaction solution was evaporated to dryness, and water (50 mL) and EA (100 mL) were added to the crude product. The pH was then adjusted to 5 with 1 N hydrochloric acid, and the product was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoic acid (0.50 g, yield 86.0%).

[0693] Step 4: Synthesis of (R)-2-((4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((2-(trifluoromethyl)pyrimidin-5-yl)methyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[0694]

[0695] (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoic acid (0.15 g, 0.331 mmol), T3P (0.316 g, 0.497 mmol, 50% in DMF), and DIPEA (0.171 g, 1.326 mmol) were added to DMF (5 mL), and the mixture was stirred at room temperature for 0.5 h. Then, (2-(trifluoromethyl)pyrimidin-5-yl)methylamine (0.088 g, 0.497 mmol) was added, and the mixture was reacted at room temperature for 15 h. The reaction of the starting materials was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure complete reaction. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:1-1:100) to obtain compound (R)-2-((4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((2-(trifluoromethyl)pyrimidin-5-yl)methyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.10 g, yield 49.3%).

[0696] Step 5: Synthesis of (R)-2-fluoro-3-(5-methylthiazolyl-2-yl)-5-(morpholin-2-ylmethoxy)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)benzamide (7)

[0697]

[0698] (R)-2-((4-fluoro-3-(5-methylthiazol-2-yl)-5-(((2-(trifluoromethyl)pyrimidin-5-yl)methyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.10 g, 0.164 mmol) was added to DCM (2 mL), followed by HCl / Dioxane (5 mL, 3 mol / L). The reaction was carried out at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the starting material was fully reacted. The reaction solution was evaporated to dryness to give compound (R)-2-fluoro-3-(5-methylthiazol-2-yl)-5-(morpholine-2-ylmethoxy)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)benzamide (0.05 g, yield 59.8%).

[0699] Step 6: Synthesis of (R)-2-fluoro-5-((4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazolyl-2-yl)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)benzamide (I-24)

[0700]

[0701] (R)-2-fluoro-3-(5-methylthiazolyl)-5-(morpholin-2-ylmethoxy)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)benzamide (7) (0.05 g, 0.098 mmol), paraformaldehyde (0.015 g, 0.489 mmol), and NaBH3CN (0.031 g, 0.489 mmol) were added to MeOH (5 mL), followed by acetic acid (0.2 mL). The reaction was carried out at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the reaction was complete. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with saturated brine (50 mL x 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by Pre-TLC (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain a white solid (R)-2-fluoro-5-((4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)benzamide (target compound I-24) (10 mg, yield 19.47%).

[0702] 1 H NMR (400MHz, DMSO) δ9.19(s,1H),9.04(s,2H),7.72(s,2H),7.27(s,1H),4.61(d,J=4.4Hz,2H),4.04(d,J=4.0Hz,2H),3.78(d,J=9.0Hz ,2H),3.53(d,J=10.8Hz,1H),2.75(d,J=10.8Hz,1H),2.57(d,J=10.8Hz,1H),2.51(s,3H),2.17(s,3H),1.93(dd,J=29.8,10.0Hz,2H).

[0703] LC-MS, M / Z: 526.2 [M+H] + .

[0704] Example 25: Preparation of compound I-25

[0705] 2-Fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-3-(5-methylthiazo-2-yl)-N-((R)-1-(6-(trifluoromethyl)pyridazin-3-yl)ethyl)benzamide (Target compound I-25)

[0706]

[0707] The synthesis method is described in Example 19.

[0708] LC-MS, M / Z: 540.1 [M+H] + .

[0709] Example 26: Preparation of compound I-26

[0710] 2-Fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)-3-(5-methylthiazolyl-2-yl)benzamide (Target compound I-26)

[0711]

[0712] The synthetic route for I-26 is shown below:

[0713]

[0714] Step 1: Synthesis of (S)-2-methyl-N-((2-methylpyrimidin-5-yl)methylene)propane-2-sulfinamide

[0715]

[0716] 2-Methylpyrimidine-5-carboxaldehyde (1.0 g, 8.19 mmol) and cesium carbonate (3.20 g, 9.83 mmol) were added to anhydrous dichloromethane (20 mL), followed by the addition of (S)-2-methylpropane-2-sulfinamide (1.19 g, 9.83 mmol) at room temperature. The reaction was allowed to proceed for 15 h at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 2:1) to ensure complete reaction. Water (100 mL) and DCM (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with DCM (100 mL x 3). The combined extracts were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-1:1) to obtain compound (S)-2-methyl-N-((2-methylpyrimidin-5-yl)methylene)propane-2-sulfinamide (1.2 g, yield 65.0%).

[0717] Step 2: Synthesis of (S)-2-methyl-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)propane-2-sulfinamide

[0718]

[0719] (S)-2-methyl-N-((2-methylpyrimidin-5-yl)methylene)propane-2-sulfinamide (1.20 g, 5.33 mmol) was added to anhydrous THF (20 mL), and methyl magnesium chloride (10.6 mL, 32 mmol, 3 mol / L) was added dropwise at -10 °C. The reaction was carried out at 0 °C for 3 h. TLC (petroleum ether:ethyl acetate (V / V) = 2:1) was used to monitor that most of the starting materials had reacted completely. Water (100 mL) and EA (100 mL) were added to the reaction solution, and the aqueous phase was extracted with EA (100 mL × 3). The combined extracts were washed with saturated brine (100 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:1-1:100) to obtain compound (S)-2-methyl-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)propane-2-sulfinamide (0.60 g, yield 46.7%).

[0720] Step 3: Synthesis of (R)-1-(2-methylpyrimidin-5-yl)ethyl-1-amine

[0721]

[0722] (S)-2-methyl-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)propane-2-sulfinamide (0.60 g, 2.486 mmol) was added to EA (5 mL), followed by HCl / Dioxane (15 mL, 3 mol / L). The reaction was carried out at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the starting material was fully reacted. The reaction solution was evaporated to dryness to give compound (R)-1-(2-methylpyrimidin-5-yl)ethyl-1-amine (0.7 g, yield 61.6%).

[0723] Step 4: Synthesis of (R)-2-((4-fluoro-3-(((R)-1-(2-methylpyrimidin-5-yl)ethyl)carbamoyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[0724]

[0725] (R)-5-((4-(tert-butoxycarbonyl)morpholin-2-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoic acid (HW091050-IN-04) (0.20 g, 0.442 mmol), T3P (0.42 g, 0.663 mmol, 50% in DMF) and DIPEA (0.23 g, 1.768 mmol) were added to DMF (5 mL), and the mixture was stirred at room temperature for 0.5 h. Then (R)-1-(2-methylpyrimidin-5-yl)ethyl-1-amine (HW091050-IN-03) (0.091 g, 0.663 mmol) was added, and the mixture was reacted at room temperature for 15 h. The reaction of the starting materials was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure complete reaction. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 30:1-1:100) to obtain compound (R)-2-((4-fluoro-3-(((R)-1-(2-methylpyrimidin-5-yl)ethyl)carbamoyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.20 g, yield 79.0%).

[0726] Step 5: Synthesis of 2-fluoro-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)-3-(5-methylthiazolyl)-5-(((R)-morpholin-2-yl)methoxy)benzamide

[0727]

[0728] (R)-2-((4-fluoro-3-((((R)-1-(2-methylpyrimidin-5-yl)ethyl)carbamoyl)-5-(5-methylthiazolyl-2-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.20 g, 0.350 mmol) was added to DCM (2 mL), followed by HCl / Dioxane (5 mL, 3 mol / L). The reaction was carried out at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the reaction was complete. The reaction solution was evaporated to dryness to give compound 2-fluoro-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)-3-(5-methylthiazolyl)-5-(((R)-morpholine-2-yl)methoxy)benzamide (0.10 g, yield 60.6%).

[0729] Step 6: Synthesis of 2-fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)-3-(5-methylthiazolyl-2-yl)benzamide (I-26)

[0730]

[0731] 2-Fluoro-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)-3-(5-methylthiazolyl)-5-(((R)-morpholin-2-yl)methoxy)benzamide (0.10 g, 0.212 mmol), paraformaldehyde (0.032 g, 1.060 mmol), and NaBH3CN (0.067 g, 1.060 mmol) were added to MeOH (5 mL), followed by acetic acid (0.2 mL). The reaction was carried out at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the starting material was fully reacted. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated and purified by Pre-TLC (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain a white solid 2-fluoro-5-(((R)-4-methylmorpholin-2-yl)methoxy)-N-((R)-1-(2-methylpyrimidin-5-yl)ethyl)-3-(5-methylthiazolyl-2-yl)benzamide (I-26) (16 mg, yield 15.54%).

[0732] 1 H NMR(400MHz,DMSO)δ9.07(d,J=7.6Hz,1H),8.70(s,2H),7.71(t,J=4.0Hz,2H),7.15 (dd,J=5.0,3.2Hz,1H),5.13–5.08(m,1H),4.04(d,J=5.0Hz,2H),3.81–3.75(m,2H), 3.58–3.46(m,2H),2.75(d,J=11.0Hz,1H),2.59(s,3H),2.51(d,J=0.6Hz,3H),2.17 (s,3H),1.99(dd,J=11.0,8.0Hz,1H),1.88(t,J=10.6Hz,1H),1.48(d,J=7.0Hz,3H).

[0733] LC-MS, M / Z: 486.1 [M+H] + .

[0734] Example 27: Preparation of compound I-27

[0735] 2-Fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-27)

[0736]

[0737] The synthetic route for I-27 is shown below:

[0738]

[0739] Step 1: Synthesis of (4R,5R)-4,5-dimethyl-1,3,2-dioxathiacyclopentane-2-oxide (27B)

[0740]

[0741] (2R,3R)-(-)-2,3-butanediol (2 g, 22.19 mmol) and pyridine (3.86 g, 48.8 mmol) were dissolved in dry tetrahydrofuran (20 mL). The reaction temperature was adjusted to 0-5 °C, and thionyl chloride (2.9 g, 24.41 mmol) was slowly added. The mixture was heated to room temperature and stirred for 16 h. The reaction was quenched with water (30 mL), and 20 mL of ethyl acetate was added. The mixture was separated, and the organic phase was washed with saturated ammonium chloride (20 mL) and saturated sodium chloride aqueous solution (20 mL). The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless liquid (4R,5R)-4,5-dimethyl-1,3,2-dioxathiacyclopentane-2-oxide (27B) (2.4 g, 79% yield).

[0742] 1 H NMR (400MHz, Chloroform-d) δ4.63 (dq, J=9.0, 6.1Hz, 1H), 4.07 (dq, J=9.0, 6.1Hz, 1H), 1.52 (d, J=6.2Hz, 3H), 1.43 (d, J=6.1Hz, 3H).

[0743] Step 2: Synthesis of methyl 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (27D)

[0744]

[0745] Under nitrogen protection, cesium carbonate (1.22 g, 3.74 mmol) was added to a solution of methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (500 mg, 1.871 mmol) (synthesis reference Example 1) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 30 min. Then, (4R,5R)-4,5-dimethyl-1,3,2-dioxathiacyclopentane-2-oxide (27B) (382 mg, 2.81 mmol) was added, and the mixture was heated to 80 °C and reacted for 16 h, followed by cooling to room temperature. The reaction solution was concentrated to dryness under reduced pressure, and chloroform (20 mL) and 4M sulfuric acid solution (20 mL) were added. The mixture was stirred at 70 °C for 5 h, separated, and the pH of the aqueous phase was adjusted to 7-8 with sodium bicarbonate. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give a white solid methyl 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (27D) (380 mg, yield 60%).

[0746] LC-MS, M / Z: 340.1 [M+H] + .

[0747] Step 3: Synthesis of 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (27E)

[0748]

[0749] Methyl 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (27D) (200 mg, 0.589 mmol) was dissolved in methanol (4 mL), followed by the addition of lithium hydroxide monohydrate (70.7 mg, 1.765 mmol) and water (0.4 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to dryness, and water (5 mL) was added. The pH was adjusted to 2-3 with 1 M hydrochloric acid solution. The aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a white solid 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (27E) (190 mg, 99% yield).

[0750] LC-MS, M / Z: 326.1 [M+H] + .

[0751] Step 4: 2-Fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-27)

[0752]

[0753] Under nitrogen protection, 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoic acid (27E) (190 mg, 0.584 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (160 mg, 0.701 mmol), N,N-diisopropylethylamine (226 mg, 1.752 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to the reaction flask. The mixture was cooled to approximately 0 °C, and a 50% solution of 1-propylphosphonic anhydride in N,N-dimethylformamide (557 mg, 0.876 mmol) was added dropwise. After adding mmol), the mixture was allowed to return to room temperature for 16 h. The reaction was quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel (petroleum ether: ethyl acetate (V / V) = 1:1) to give a white solid 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-27) (110 mg, yield 37.8%).

[0754] 1 H NMR(400MHz,Chloroform-d)δ8.94(s,2H),7.86(dd,J=5.9,3.3Hz,1H),7.63–7.58(m,1H) ,7.50(dd,J=5.8,3.4Hz,1H),7.10(dd,J=12.3,6.5Hz,1H),5.38(ddd,J=7.7,4.4,1.5Hz,1 H),4.40(qd,J=6.3,3.3Hz,1H),4.01(ddd,J=6.5,4.8,3.3Hz,1H),2.56(d,J=1.2Hz,3H), 2.07(d,J=4.9Hz,1H), 1.72(d,J=7.1Hz,3H), 1.26(d,J=6.3Hz,3H), 1.23(d,J=6.5Hz,3H).

[0755] LC-MS, M / Z: 499.1 [M+H] + .

[0756] Example 28: Preparation of compound I-28

[0757] 2-Fluoro-5-(((2S,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-28)

[0758]

[0759] The synthetic route for I-28 is shown below:

[0760]

[0761] Step 1: (2S,3S)-3-(4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)but-2-benzoate (28A)

[0762]

[0763] Under nitrogen protection, 2-fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-27) (60 mg, 0.12 mmol), triphenylphosphine (95 mg, 0.361 mmol), benzoic acid (22.1 mg, 0.181 mmol), and dry tetrahydrofuran (2 mL) were added to the reaction flask. The temperature of the reaction solution was adjusted to 0- Azodiisopropyl ester (73.0 mg, 0.361 mmol) was slowly added at 5 °C, and the mixture was heated to room temperature and reacted for 16 h. The reaction solution was directly concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give a white solid (2S,3S)-3-(4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)but-2-benzoate (28A) (60 mg, yield 83%).

[0764] LC-MS, M / Z: 603.2 [M+H] + .

[0765] Step 2: Synthesis of 2-fluoro-5-(((2S,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-28)

[0766]

[0767] (2S,3S)-3-(4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)but-2-benzoate (28A) (60 mg, 0.1 mmol) was dissolved in methanol (4 mL), followed by the addition of lithium hydroxide monohydrate (20 mg, 0.5 mmol) and water (0.4 mL). The reaction was continued with stirring at room temperature for 16 h. The reaction solution was concentrated to dryness, and water (5 mL) was added. The aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel to give a white solid 2-fluoro-5-(((2S,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-28) (190 mg, yield 71%).

[0768] 1 H NMR(400MHz,Chloroform-d)δ8.95(s,2H),7.88(dd,J=5.9,3.3Hz,1H),7.61(dd,J=2.5, 1.3Hz, 1H), 7.52 (dd, J=5.8, 3.3Hz, 1H), 7.09 (dd, J=12.3, 6.4Hz, 1H), 5.38 (td, J=9.1, 8. 5,2.9Hz,1H),4.24(p,J=6.2Hz,1H),3.85(td,J=6.4,3.2Hz,1H),2.57(d,J=1.1Hz,3H),2 .42(d,J=3.8Hz,1H),1.73(d,J=7.1Hz,3H),1.26(d,J=6.3Hz,3H),1.24(d,J=6.6Hz,3H).

[0769] LC-MS, M / Z: 499.1 [M+H] + .

[0770] Example 29: Preparation of compound I-29

[0771] 2-Fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-29)

[0772]

[0773] The synthetic route for I-29 is shown below:

[0774]

[0775] Step 1: Synthesis of (4S,5S)-4,5-dimethyl-1,3,2-dioxathiacyclopentane-2-oxide (29B)

[0776]

[0777] (2S,3S)-(-)-2,3-butanediol (1 g, 11.10 mmol) and pyridine (1.93 g, 24.41 mmol) were dissolved in dry tetrahydrofuran (10 mL). The reaction temperature was adjusted to 0-5 °C, and thionyl chloride (1.45 g, 12.21 mmol) was slowly added. The mixture was stirred at room temperature for 16 h, and the reaction was quenched with water (15 mL). 10 mL of ethyl acetate was added, and the mixture was separated. The organic phase was washed with saturated ammonium chloride (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless liquid (4S,5S)-4,5-dimethyl-1,3,2-dioxathiacyclopentane-2-oxide (29B) (0.8 g, yield 53%).

[0778] Step 2: Synthesis of methyl 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (29D)

[0779]

[0780] Under nitrogen protection, cesium carbonate (1.22 g, 3.74 mmol) was added to a solution of methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (500 mg, 1.871 mmol) (synthesis reference Example 1) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 30 min. Then, (4S,5S)-4,5-dimethyl-1,3,2-dioxathiacyclopentane-2-oxide (29B) (382 mg, 2.81 mmol) was added, and the mixture was heated to 80 °C and reacted for 16 h, followed by cooling to room temperature. The reaction solution was concentrated to dryness under reduced pressure, and chloroform (20 mL) and 4M sulfuric acid solution (20 mL) were added. The mixture was stirred at 70 °C for 5 h, separated, and the pH of the aqueous phase was adjusted to 7-8 with sodium bicarbonate. It was extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give a white solid methyl 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (29D) (400 mg, yield 63%).

[0781] LC-MS, M / Z: 340.1 [M+H] + .

[0782] Step 3: Synthesis of 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (29E)

[0783]

[0784] Methyl 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (29D) (400 mg, 1.18 mmol) was dissolved in methanol (8 mL), followed by the addition of lithium hydroxide monohydrate (141 mg, 3.54 mmol) and water (0.8 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to dryness, and water (10 mL) was added. The pH was adjusted to 2-3 with 1 M hydrochloric acid solution. The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a white solid of 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (29E) (356 mg, 93% yield).

[0785] LC-MS, M / Z: 326.1 [M+H] + .

[0786] Step 4: 2-Fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-29)

[0787]

[0788] Under nitrogen protection, 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoic acid (29E) (356 mg, 1.09 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (272 mg, 1.42 mmol), N,N-diisopropylethylamine (424 mg, 3.82 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to the reaction flask. The mixture was cooled to approximately 0 °C, and a 50% solution of 1-propylphosphonic anhydride in N,N-dimethylformamide (1.04 g, 1.64 mL) was added dropwise. After adding ol), the reaction was brought back to room temperature and reacted for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel (petroleum ether: ethyl acetate (V / V) = 1:1) to give a white solid 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-29) (190 mg, yield 34.8%).

[0789] 1 H NMR(400MHz,Chloroform-d)δ8.94(s,2H),7.86(dd,J=5.9,3.3Hz,1H),7.63–7.58(m,1H) ,7.50(dd,J=5.8,3.4Hz,1H),7.10(dd,J=12.3,6.5Hz,1H),5.38(ddd,J=7.7,4.4,1.5Hz,1 H),4.40(qd,J=6.3,3.3Hz,1H),4.01(ddd,J=6.5,4.8,3.3Hz,1H),2.56(d,J=1.2Hz,3H), 2.07(d,J=4.9Hz,1H), 1.72(d,J=7.1Hz,3H), 1.26(d,J=6.3Hz,3H), 1.23(d,J=6.5Hz,3H).

[0790] LC-MS, M / Z: 499.1 [M+H] + .

[0791] Example 30: Preparation of compound I-30

[0792] 2-Fluoro-5-(((2R,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-30)

[0793]

[0794] The synthetic route for I-30 is shown below:

[0795]

[0796] Step 1: (2R,3R)-3-(4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)but-2-benzoate (30A)

[0797]

[0798] Under nitrogen protection, 2-fluoro-5-(((2R,3S)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-29) (80 mg, 0.16 mmol), triphenylphosphine (126 mg, 0.481 mmol), benzoic acid (29.4 mg, 0.241 mmol), and dry tetrahydrofuran (2 mL) were added to the reaction flask. The temperature of the reaction solution was adjusted to 0- Azodiisopropyl ester (97.0 mg, 0.481 mmol) was slowly added at 5 °C, and the mixture was heated to room temperature and reacted for 16 h. The reaction solution was directly concentrated to dryness, and the residue was purified by silica gel plate (petroleum ether: ethyl acetate (V / V) = 2:1) to give a white solid (2R,3R)-3-(4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)but-2-benzoate (30A) (90 mg, yield 93%).

[0799] LC-MS, M / Z: 603.2 [M+H] + .

[0800] Step 2: Synthesis of 2-fluoro-5-(((2R,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-30)

[0801]

[0802] (2R,3R)-3-(4-fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)phenoxy)but-2-benzoate (30A) (60 mg, 0.1 mmol) was dissolved in methanol (4 mL), followed by the addition of lithium hydroxide monohydrate (20 mg, 0.5 mmol) and water (0.4 mL). The reaction was continued with stirring at room temperature for 16 h. The reaction solution was concentrated to dryness, and water (5 mL) was added. The aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel to give a white solid 2-fluoro-5-(((2R,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-30) (39 mg, yield 79%).

[0803] 1 H NMR(400MHz,Chloroform-d)δ8.95(s,2H),7.88(dd,J=5.9,3.3Hz,1H),7.61(dd,J=2.5, 1.3Hz, 1H), 7.52 (dd, J=5.8, 3.3Hz, 1H), 7.09 (dd, J=12.3, 6.4Hz, 1H), 5.38 (td, J=9.1, 8. 5,2.9Hz,1H),4.24(p,J=6.2Hz,1H),3.85(td,J=6.4,3.2Hz,1H),2.57(d,J=1.1Hz,3H),2 .42(d,J=3.8Hz,1H),1.73(d,J=7.1Hz,3H),1.26(d,J=6.3Hz,3H),1.24(d,J=6.6Hz,3H).

[0804] LC-MS, M / Z: 499.1 [M+H] + .

[0805] Example 31: Preparation of compound I-31

[0806] (R)-2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-31)

[0807]

[0808] The synthetic route for compound I-31 is shown below:

[0809]

[0810] Step 1: Synthesis of 2-hydroxy-2-methylpropyl-4-methylbenzenesulfonate (31B)

[0811]

[0812] 2-Methylpropane-1,2-diol (31B-1) (2.0 g, 22.19 mmol), 4-dimethylaminopyridine (0.271 g, 2.22 mmol), and triethylamine (4.49 g, 44.40 mmol) were added to anhydrous dichloromethane (40 mL), followed by the addition of p-toluenesulfonyl chloride (4.65 g, 24.21 mmol) at room temperature. The reaction was carried out for 15 h at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 3:1) to ensure the starting material was fully reacted. Water (100 mL) and DCM (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with DCM (100 mL × 3). The combined extracts were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-1:1) to give compound 2-hydroxy-2-methylpropyl-4-methylbenzenesulfonate (31B) (4.5 g, yield 83%).

[0813] Step 2: Synthesis of methyl 2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazolyl-2-yl)benzoate (31C)

[0814]

[0815] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (31A) (synthesis reference Example 1) (0.2 g, 0.748 mmol) and cesium carbonate (0.366 g, 1.122 mmol) were added to DMF (4 mL), followed by 2-hydroxy-2-methylpropyl-4-methylbenzenesulfonate (31B) (0.219 g, 0.898 mmol). The reaction mixture was reacted at 110 °C for 36 h. TLC (petroleum ether:ethyl acetate (V / V) = 1:1) was used to monitor that most of the starting materials had reacted completely. Water (100 mL) and EA (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with EA (100 mL × 3). The combined extracts were washed with saturated brine (100 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:1-1:100) to give methyl 2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazolyl-2-yl)benzoate (31C) (0.1 g, yield 39%).

[0816] Step 3: Synthesis of 2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazol-2-yl)benzoic acid (31D)

[0817]

[0818] Methyl 2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazolyl-2-yl)benzoate (31C) (0.1 g, 0.295 mmol) was added to methanol (3 mL) and water (0.5 mL), followed by the addition of lithium hydroxide monohydrate (0.049 g, 1.179 mmol) at room temperature. The reaction mixture was allowed to react for 15 hours at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure complete reaction of the starting materials. The reaction solution was concentrated to dryness under reduced pressure. Water (50 mL) and EA (100 mL) were added to the crude product. The pH was then adjusted to 7 with 1 N hydrochloric acid, and the product was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried with sodium sulfate, and concentrated to obtain 2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazol-2-yl)benzoic acid (31D) (50 mg, yield 52.2%).

[0819] Step 4: Synthesis of (R)-2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-31)

[0820]

[0821] 2-Fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazol-2-yl)benzoic acid (31D) (0.05 g, 0.154 mmol), a 50% solution of 1-propylphosphonic anhydride in N,N-dimethylformamide (0.147 g, 0.231 mmol), and DIPEA (0.079 g, 0.615 mmol) were added to DMF (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine hydrochloride (31E) (0.035 g, 0.184 mmol) was added, and the mixture was reacted at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the starting material was completely reacted. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then separated and purified by passing it through a silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain a white solid (R)-2-fluoro-5-(2-hydroxy-2-methylpropoxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-31) (7 mg, yield 9%).

[0822] 1 H NMR(400MHz,DMSO)δ9.20(d,J=7.0Hz,1H),9.11(s,2H),7.78–7.69(m,2H),7.22–7.19(m,1 H), 5.27 (m, 1H), 4.64 (s, 1H), 3.78 (s, 2H), 2.51 (s, 3H), 1.55 (d, J = 7.0Hz, 3H), 1.19 (s, 6H).

[0823] LC-MS, M / Z: 499.10 [M+H] + .

[0824] Example 32: Preparation of compound I-32

[0825] (R)-2-fluoro-5-((1-hydroxycyclopropyl)methoxy)-3-(5-methylthiazolyl-2-yl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (Compound I-32)

[0826]

[0827] The method for synthesizing compound I-32 is described in Example 31.

[0828] LC-MS, M / Z: 497.1 [M+H]+ .

[0829] Example 33: Preparation of compound I-33

[0830] (R)-2-fluoro-5-(1-(hydroxymethyl)cyclopropoxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-33)

[0831]

[0832] The method for synthesizing compound I-33 is described in Example 31.

[0833] LC-MS, M / Z: 497.1 [M+H] + .

[0834] Example 34: Preparation of target compound I-34

[0835] (R)-2-fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-34)

[0836]

[0837] The synthetic route for compound I-34 is shown below:

[0838]

[0839] Step 1: Synthesis of methyl 5-((1-(tert-butoxy)-2-methyl-1-oxopropyl-2-yl)oxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate

[0840]

[0841] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.30 g, 1.122 mmol) and cesium carbonate (0.73 g, 2.245 mmol) were added to anhydrous DMF (5 mL), followed by the addition of tert-butyl 2-bromo-2-methylpropionate (0.38 g, 1.684 mmol) at room temperature. The reaction was carried out for 15 h at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 2:1) to ensure the starting material was fully reacted. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-1:1) to obtain compound methyl 5-((1-(tert-butoxy)-2-methyl-1-oxopropyl-2-yl)oxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (0.3 g, yield 65.3%).

[0842] Step 2: Synthesis of 2-(4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazol-2-yl)phenoxy)-2-methylpropionic acid

[0843]

[0844] Methyl 5-((1-(tert-butoxy)-2-methyl-1-oxopropyl-2-yl)oxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (0.3 g, 0.733 mmol) was added to anhydrous DCM (5 mL), and the reaction mixture was reacted dropwise with CF3COOH (1.0 mL) at 0 °C for 15 h. TLC (petroleum ether:ethyl acetate (V / V) = 2:1) was used to monitor that most of the starting materials had reacted completely. Water (100 mL) and DCM (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with DCM (100 mL x 3). The combined extracts were washed with saturated brine (100 mL x 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:1-1:100) to obtain compound 2-(4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazol-2-yl)phenoxy)-2-methylpropionic acid (3) (0.25 g, yield 97.0%).

[0845] Step 3: Synthesis of methyl 2-fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate

[0846]

[0847] 0.25 g (0.707 mmol) of 2-(4-fluoro-3-(methoxycarbonyl)-5-(5-methylthiazol-2-yl)phenoxy)-2-methylpropionic acid was added to anhydrous THF (5 mL), followed by BH3 / THF (2.1 mL, 2.212 mol, 1 mol / L). The reaction was carried out at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure the starting material was fully reacted. The reaction solution was evaporated to dryness to give methyl 2-fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (0.08 g, yield 33.3%).

[0848] Step 4: Synthesis of 2-fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid

[0849]

[0850] Methyl 2-fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (0.08 g, 0.236 mmol) was added to MeOH (4 mL), H₂O (0.5 mL), and THF (0.5 mL), and LiOH was added at room temperature. . H2O (0.023 g, 0.943 mmol), reacted at room temperature for 15 h. TLC (petroleum ether: ethyl acetate (V / V) = 1:1) was used to monitor the reaction of the starting materials until complete. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to give compound 2-fluoro-5-((1-hydroxy-2-methylpropyl-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (5) (0.06 g, yield 78.0%).

[0851] Step 5: Synthesis of (R)-2-fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl))pyrimidin-5-yl)ethyl)benzamide (I-34)

[0852]

[0853] 2-Fluoro-5-((1-hydroxy-2-methylprop-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (5) (0.06 g, 0.184 mmol), T3P (0.21 g, 0.277 mmol, 50% in DMF) and DIPEA (0.095 g, 0.738 mmol) were added to DMF (6 mL), and the mixture was stirred at room temperature for 0.5 h. Then (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl-1-amine (0.042 g, 0.221 mmol) was added, and the mixture was reacted at room temperature for 15 h. The reaction of the starting materials was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure complete reaction. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated and purified by Pre-TLC (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain a white solid (R)-2-fluoro-5-((1-hydroxy-2-methylpropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl))pyrimidin-5-yl)ethyl)benzamide (I-34) (2.5 mg, yield 2.72%).

[0854] 1 H NMR(400MHz,DMSO)δ9.19(d,J=6.8Hz,1H),9.09(s,2H),7.89–7.83(m,1H),7.71(s,1H),7.25(s,1H),5 .51(d,J=12.4Hz,1H),5.34–5.18(m,2H),4.99(s,1H),2.51(s,3H),1.55(d,J=7.0Hz,3H),1.20(s,6H).

[0855] LC-MS, M / Z: 499.1 [M+H] + .

[0856] Example 35: Preparation of target compound I-35

[0857] 2-Fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-35)

[0858]

[0859] The synthetic route for compound I-35 is shown below:

[0860]

[0861] Step 1: Synthesis of methyl 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate

[0862]

[0863] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazolyl-2-yl)benzoate (0.15 g, 0.561 mmol) and cesium carbonate (0.366 g, 1.122 mmol) were added to anhydrous DMF (2 mL), followed by the addition of 2-bromoprop-1-ol (0.12 g, 0.842 mmol) at room temperature. The reaction was carried out at 110 °C for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 2:1) to ensure the starting material was fully reacted. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1-1:1) to obtain methyl 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (0.15 g, yield 82%).

[0864] Step 2: Synthesis of 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid

[0865]

[0866] Methyl 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)benzoate (0.15 g, 0.461 mmol) was added to MeOH (4 mL), H₂O (0.5 mL), and THF (0.5 mL), and LiOH was added at room temperature. . The reaction mixture was prepared by reacting H₂O (0.044 g, 1.844 mmol) at room temperature for 15 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure complete reaction. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (0.10 g, yield 69.7%).

[0867] Step 3: Synthesis of 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-)yl)ethyl)benzamide (I-35)

[0868]

[0869] 2-Fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (0.10 g, 0.321 mmol), T3P (0.366 g, 0.482 mmol, 50% in DMF) and DIPEA (0.166 g, 1.285 mmol) were added to DMF (5 mL), and the mixture was stirred at room temperature for 0.5 h. Then (R)-1-(5-(trifluoromethyl)pyrimidin-2-yl)ethyl-1-amine (0.061 g, 0.321 mmol) was added, and the mixture was reacted at room temperature for 15 h. The reaction of the starting materials was monitored by TLC (petroleum ether:ethyl acetate (V / V) = 1:1) to ensure complete reaction. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with saturated brine (50 mL × 3), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated and purified by Pre-TLC (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain a white solid 2-fluoro-5-((1-hydroxypropyl-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-)yl)ethyl)benzamide (I-35) (6.0 mg, yield 3.86%).

[0870] 1 H NMR (400MHz, DMSO) δ9.20(d,J=7.0Hz,1H),9.09(d,J=6.8Hz,2H),7.74(d,J=5.4Hz,1H),7.71(s,1H),7.21–7.17(m,1H),5.26 (d,J=7.0Hz,1H),4.90(s,1H),3.94(s,1H),3.87(d,J=5.2Hz,2H),2.51(s,3H),1.55(d,J=7.0Hz,3H),1.14(d,J=6.2Hz,3H).

[0871] LC-MS, M / Z: 485.1 [M+H] + .

[0872] Example 36: Preparation of target compound I-36

[0873] 2-Fluoro-5-(2-hydroxypropoxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-36)

[0874]

[0875] The method for synthesizing compound I-36 is described in Example 35.

[0876] LC-MS, M / Z: 485.1 [M+H] + .

[0877] Example 37: Preparation of target compound I-37

[0878] 2-Fluoro-5-(((3R,5R)-5-hydroxytetrahydrofuran-3-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-37) and 2-Fluoro-5-(((3R,5S)-5-hydroxytetrahydrofuran-3-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-38)

[0879]

[0880] The synthetic routes for compounds I-37 and I-38 are shown below:

[0881]

[0882] 2-Fluoro-3-(5-methylthiazolyl-2-yl)-5-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-1) (1.5 g, 3 mmol) and ferric chloride (0.245 g, 1.5 mmol) were placed in a round-bottom flask. Pyridine (15 mL) was added under nitrogen protection, followed by the slow addition of tert-butyl hydroperoxide (1.56 g, 12.1 mmol, 70% aqueous solution). The reaction was stirred at room temperature for 48 hours. A saturated sodium EDTA solution (100 mL) was added and stirred for 10 min. 100 mL of brine was added, and the aqueous phase was extracted with DCM. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative chromatography to give pale yellow solids 2-fluoro-5-(((3R,5R)-5-hydroxytetrahydrofuran-3-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-37) and 2-fluoro-5-(((3R,5S)-5-hydroxytetrahydrofuran-3-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-38) (2 mg, yield 0.13%).

[0883] 1 H NMR(400MHz, DMSO-d6)δ9.20(d,J=7.0Hz,1H),9.13–9.07(m,2H),7.90–7.66(m,2H),7.21(dd,J=5.0,3.4Hz,1H),6.47(d,J=4.5Hz,1H) ,5.40–5.10(m,2H),4.73(d,J=4.7Hz,1H),4.09–3.65(m,2H),2.51(s,3H),2.41–2.29(m,1H),2.07–1.87(m,1H),1.54(t,J=6.3Hz,3H).

[0884] LC-MS, M / Z: 513.1 [M+H] + .

[0885] Example 38: Preparation of target compound I-39

[0886] 2-Fluoro-3-(5-methylthiazo-2-yl)-5-(((S)-3-oxobutan-2-yl)oxy)-N-((R)-1-(2-(trifluoromethyl))pyrimidin-5-yl)ethyl)benzamide (Target compound I-39)

[0887]

[0888] The synthetic route for compound I-39 is shown below:

[0889]

[0890] 2-Fluoro-5-(((2S,3R)-3-hydroxybut-2-yl)oxy)-3-(5-methylthiazolyl-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-27) (200 mg, 0.4 mmol) was placed in a round-bottom flask under nitrogen protection, and Dess-Martin reagent (340 mg, 0.8 mmol) and DCM (5 ml) were added. The mixture was stirred at room temperature for 3 hours, and the reaction was analyzed by TLC. After the starting material had completely reacted, ethyl acetate (5 ml) was added for dilution, followed by the addition of water (5 ml). The organic phase was extracted and collected, then dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-5:1). The white solid 2-fluoro-3-(5-methylthiazo-2-yl)-5-(((S)-3-oxobutane-2-yl)oxy)-N-((R)-1-(2-(trifluoromethyl))pyrimidin-5-yl)ethyl)benzamide (I-39) (120 mg, yield 60%) was obtained.

[0891] 1H NMR(400MHz, CDCl3)δ8.87(s,2H),7.84–7.71(m,1H),7.53(s,1H),7.45–7.36(m,1H),7.03(dd,J=11.9,6.5Hz,1 H),5.75–5.13(m,1H),4.67(q,J=6.8Hz,1H),2.49(s,3H),2.15(s,3H),1.81–1.57(m,3H),1.44(d,J=6.8Hz,3H).

[0892] LC-MS, M / Z (ESI): 497.5 [M+H]+

[0893] Example 39: Preparation of target compound I-40

[0894] (R)-5-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (target compound I-40)

[0895]

[0896] The synthetic route for compound I-40 is shown below:

[0897]

[0898] Step 1: Synthesis of methyl 5-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)benzoate (3)

[0899]

[0900] Methyl 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)benzoate (1) (100 mg, 0.374 mmol) was added to a round-bottom flask, along with triphenylphosphine (294 mg, 1.12 mmol) and the compound (64.1 mg, 0.56 mmol). Under nitrogen protection, DIAD (227 mg, 1.12 mmol) and THF (2 ml) were added. The reaction was carried out at room temperature for 16 hours, and the reaction was detected by TLC. After the starting material was completely consumed, the reaction was quenched with water, diluted with ethyl acetate (5 ml), and the organic phase was extracted and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-5:1). A colorless oily liquid, methyl 5-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoate (120 mg, 88% yield), was obtained.

[0901] Step 2: Synthesis of 5-((2-oxazolylcyclo[2.1.1]hexyl-1-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoic acid

[0902]

[0903] Methyl 5-((2-oxabicyclo[2.1.1]hexyl-1-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoate (3) (140 mg, 0.385 mmol) and lithium hydroxide monohydrate (64.6 mg, 1.54 mmol) were placed in a round-bottom flask, and methanol (3 ml) and water (0.3 ml) were added. The mixture was stirred at room temperature for 3 hours and the reaction was detected by TLC. After the reactants had completely reacted, the methanol was removed, and the mixture was placed at 0 °C. 4 M hydrochloric acid was slowly added dropwise to adjust the pH to 3, resulting in the precipitation of a large amount of white solid. The mixture was stirred for 30 minutes, and the solid was collected by filtration and dried in a vacuum drying oven. The white solid 5-((2-oxabicyclo[2.1.1]hexyl-1-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoic acid (4) (92 mg, yield 68.1%) was obtained.

[0904] Step 3: Synthesis of (R)-5-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

[0905]

[0906] 5-((2-oxazolylcyclo[2.1.1]hexyl-1-yl)methoxy)-2-fluoro-3-(5-methylthiazol-2-yl)benzoic acid (4) (92 mg, 0.263 mmol) was placed in a round-bottom flask, and HOBT (42.7 mg, 0.316 mmol), EDCI (60.6 mg, 0.316 mmol), and the compound (76 mg, 118 mmol) were added. DMF (3 ml) was added, and DIPEA (102 mg, 0.79 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was transferred to room temperature and reacted overnight. The reaction was detected by TLC, and after the starting material was completely consumed, ethyl acetate (5 ml) was added for dilution, followed by the addition of saturated sodium bicarbonate (5 ml). The organic phase was extracted and collected. The mixture was washed once with saturated sodium bicarbonate solution, twice with dilute hydrochloric acid solution, and once with saturated sodium chloride solution. The organic phase was collected and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography (100% ethyl acetate). The pale yellow solid (R)-5-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-2-fluoro-3-(5-methylthiazolyl-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (70 mg, yield 50.7%) was obtained.

[0907] 1H NMR(400MHz, DMSO-d6)δ9.19(d,J=7.1Hz,1H),9.10(s,2H),7.77–7.73(m,1H),7.72–7.69(m,1H),7.25–7.21(m,1H),5.29–5.22(m,1H) ),4.30(s,2H),3.69(s,2H),2.92(t,J=3.1Hz,1H),2.51(s,3H),1.85–1.81(m,2H),1.54(d,J=7.1Hz,3H),1.43(dd,J=4.4,1.6Hz,2H).

[0908] LC-MS, M / Z (ESI): 523.5 [M+H] + .

[0909] Test Example 1: FLIPR method for determining the antagonistic activity of hP2X3 antagonists against hP2X3

[0910] The antagonistic activity of human P2X3 receptor (hP2X3) antagonists against hP2X3 was evaluated using the FLIPR Calcium4Assay Kit (Molecular Devices, R8141) and the FLIPR TETRA instrument (MolecularDevices, 0296) to detect calcium flow signals. Twenty-four hours before the experiment, human cells stably transfected with the hP2X3 receptor were cultured at a rate of 2 × 10⁻⁶ cells / year. 5 Cells were seeded at a density of 50 μL / mL in 384-well plates and incubated at 37°C for 16–24 h in a 5% CO2 incubator. 500 nmol of the desired concentration of the test compound was prepared using DMSO stock solution (20–50 mM DMSO), and added to each well of the 384-well plate. 30 μL of FLIPR Assay buffer (containing 1.26 mM Ca) was then added to the top of each well. 2+ Mix 1×HBSS + 2mM CaCl2 + 20mM HEPES, shake for 20-40 min to mix. Prepare 3 times the required concentration of agonist (α,β-meATP) using FLIPR Assay buffer (final concentration required 400 nM), and add 45 μL of agonist to each well of another 384-well plate. Take the cell culture plate from the previous day, aspirate the cell supernatant, and add 30 μL of Dye to each well. The cells were incubated for 1 hour using a Calcium 4 Assay Kit (diluted with FLIPR buffer). 15 μL of the compound was added to each well (using a FLIPR instrument). After 15 minutes, 22.5 μL of the agonist was added to each well, and the fluorescence signal was detected (excitation wavelength 470 nm-495 nm, emission wavelength 515 nm-575 nm). The difference between the peak and trough values ​​was used as the baseline data. The highest concentration of the positive control was taken as the 100% inhibition rate, and DMSO data as the 0% inhibition rate. The inhibition effect curve of the compound was fitted using GraphpadPrism 6 software, and the IC50 was calculated. 50 value.

[0911] Table 1 shows the antagonistic activity of the tested compounds against hP2X3.

[0912]

[0913]

[0914] The experimental results show that compounds I-1, I-4, I-5, I-14, I-27, I-28, I-29, and I-30 of this application exhibit better activity in inhibiting the hP2X3 receptor than control compound 1.

[0915] Test Example 2: Pharmacokinetic Tests in Rats and Mice

[0916] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Three rats were administered 10 mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, and plasma was collected and stored at -20°C. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4°C, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0917] Pharmacokinetic studies were conducted in mice using male ICR mice (20-25g, fasted overnight). Three mice were administered 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0918] Table 2. Rat pharmacokinetics of the tested compounds

[0919]

[0920]

[0921] The experimental results show that, in a rat model, the pharmacokinetic properties of compound I-1 of the present invention are improved compared with those of control compound 1.

[0922] Table 3. Pharmacokinetics of the tested compounds in mice.

[0923]

[0924] Mouse studies showed that the pharmacokinetic properties of compounds I-1, I-27, I-28, I-29, and I-30 of the present invention were significantly improved compared with control compounds 1 and 2.

[0925] Test Example 3: Taste Test in Rats

[0926] After 3 days of overnight water deprivation training, SD rats were administered the drug. Half an hour after administration, each animal was given one bottle of water and one bottle of 0.3 mM quinine aqueous solution. The water bottles were removed 15 minutes after water administration. The amount of water and 0.3 mM quinine ingested by the rats were measured. The effect of the compound on the taste of SD rats was evaluated based on the difference between the amount of water and quinine ingested.

[0927] Table 4 shows the water / water-quinine uptake multiples in animals treated with the corresponding compounds.

[0928] compound Water / Quinine Water solvent 34.7 Control compound 1 30 mg / kg ip 11.4 I-1 30mg / kg ip 18.2 I-27 30mg / kg ip 29.4 I-28 30mg / kg ip 15.4 I-29 30mg / kg ip 12.0 I-30 30mg / kg ip 22.9

[0929] The experimental results show that, compared with the positive control, the compounds of the present invention have less interference with the taste perception of rats, especially compounds I-1, I-27, and I-30, which have significantly less interference with the taste perception of rats than the control compound 1. Figure 1 ).

[0930] Test Example 4: Histamine / Citrate Cough Efficacy Test in Guinea Pigs

[0931] Before being introduced into the group, the animals were acclimatized for 3-7 days. Once they reached the target weight (300-400g), they were numbered and randomly grouped.

[0932] The compound or excipient was administered to guinea pigs via nasal drops 0.25–24 hours prior to the start of cough assessment. The dosage range of the test substance was 0.17 mg / kg–1.5 mg / kg. During cough assessment, after the animals were acclimatized in a whole-body volumetric scanning chamber, they underwent histamine nebulization, followed by citric acid nebulization. The number of coughs and the cough latency were recorded for 22 minutes from the start of histamine nebulization until the end of the observation period.

[0933] The experimental data were analyzed and compared using one-way ANOVA. A p-value < 0.05 was considered statistically significant. Pairwise comparisons were performed using the t-test method.

[0934] Table 5. Number of coughs in guinea pigs after administration of the corresponding compounds, stimulated by histamine / citric acid.

[0935]

[0936]

[0937] Data show that, compared with the positive control, the compound of this invention significantly reduced the number of coughs and prolonged the cough latency in a citric acid / histamine-stimulated guinea pig cough model, demonstrating a good antitussive effect. Figure 2 ).

[0938] Test Example 5: Guinea Pig ATP / Citrate Cough Efficacy Test

[0939] Before enrollment, animals were acclimatized for 3-7 days until they reached the target weight (300-400g), at which point they were numbered and randomly grouped. The compound or excipient was administered to guinea pigs via nasal drops 0.25–24 hours before the cough assessment. The dosage range of the test substance was 0.17 mg / kg–1.5 mg / kg. During the cough assessment, after acclimatization in a whole-body volume scanning chamber, animals underwent ATP nebulization, followed by citric acid nebulization after a few minutes. The number of coughs and the cough latency were recorded within 15 minutes of the start of citric acid nebulization.

[0940] One-way ANOVA was used to analyze and compare the data of each group. A p-value < 0.05 was considered statistically significant. The t-test was used to compare differences between pairs of data.

[0941] Table 6. Number of coughs in guinea pigs after administration of the corresponding compounds, stimulated by ATP / citric acid.

[0942] compound Average number of coughs within 15 minutes Cough suppression rate vs. solvent (%) solvent 19.8 Reference compound 1 8.1 59.1 I-1 6.5 67.2 I-27 6.3 68.2 I-30 7.1 64.1

[0943] Data showed that, compared with the positive control, the compound of this invention significantly reduced the number of coughs and prolonged the cough latency in a citric acid / ATP-stimulated guinea pig cough model, demonstrating a good antitussive effect. Figure 3 ).

[0944] Test Example 4: Canine Pharmacokinetics Study

[0945] Canine pharmacokinetic studies were conducted using male beagle dogs, weighing 8-10 kg, which were fasted overnight. Three beagle dogs were administered 5 mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours post-administration. Three other beagle dogs were administered 1 mg / kg intravenously, with blood samples collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours post-administration. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, and plasma was collected and stored at -20°C. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4°C for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0946] Table 4. Canine pharmacokinetics of the tested compounds

[0947]

[0948] The experimental results show that compounds I-29 and I-30 of the present invention have low clearance rates after intravenous injection, high exposure rates after oral and intravenous administration, and long half-lives. Compared with the control compounds, I-29 and I-30 exhibit better pharmacokinetic characteristics and better drug-like properties.

Claims

1. A compound, and its pharmaceutically acceptable salt, characterized in that, The compound is selected from any of the following compounds: 。 2. A pharmaceutical composition, characterized in that, It comprises the compound as claimed in claim 1, its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

3. Use of the compound of claim 1, its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating and antagonizing P2X3-related diseases, wherein the P2X3-related diseases are refractory chronic cough and acute cough.

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