Benzofuran compounds and use thereof

Abstract

Disclosed in the present invention are benzofuran compounds and the use thereof. The compounds have TRPM3 antagonistic activity and can be applied to drugs for treating neuropathic pain or migraine.

Description

Benzofuran compounds and uses thereof

[0001] This application claims priority to the Chinese patent application No. 2024113498983, filed on September 26, 2024, and entitled "Benzofuran compounds and uses thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmacy, and relates to a class of benzofuran derivatives, a preparation method thereof, and an application thereof as a TRPM3 antagonist, in particular, a use thereof in a drug for treating neuropathic pain or migraine. BACKGROUND

[0003] Pain, as a warning signal of the body to potential harm or disease, can be acute, such as transient discomfort after trauma, or chronic, lasting for weeks, months or even longer, affecting the daily function and mental health of patients. Neuropathic pain refers to severe pain caused by damage or dysfunction of the nervous system, and its symptoms may include persistent burning, tingling or electric shock-like pain, which causes great physical and mental distress to patients. Migraine, as a special type of headache, is characterized by recurrent unilateral or bilateral pulsatile headache, often accompanied by nausea, vomiting, sensitivity to light and sound, and other symptoms, which seriously affects the work, study and social activities of patients. These diseases not only increase the medical burden of patients, but also may lead to long-term psychological problems such as anxiety and depression, further exacerbating the impact of the disease. Traditional treatment methods can relieve pain to some extent, but often have problems such as drug dependence and obvious side effects. Therefore, there is an urgent need for safe, effective and non-opioid therapeutic drugs to meet the huge demand.

[0004] TRPM3, as a member of the TRP channel family, is a non-selective cation channel with high permeability to calcium ions. It is widely expressed in nociceptive sensory neurons and plays a key role in the transmission of pain signals. Studies have shown that TRPM3 can be activated by various endogenous and exogenous ligands, and is involved in the occurrence of inflammatory and neuropathic pain. More importantly, TRPM3 antagonists have shown significant analgesic effects in animal models, not only effectively relieving thermal and mechanical pain, but also not adversely affecting body temperature, which is significantly different from traditional TRPV1 antagonists. Therefore, the development of TRPM3 target and its antagonists provides a new strategy for the treatment of pain, neuropathic pain and migraine, and is expected to become an important target for the next generation of analgesic drugs.

[0005] The present application relates to a class of compounds with TRPM3 antagonistic activity, which can be used for the treatment of neuropathic pain or migraine. SUMMARY

[0006] Technical problem solved: This invention provides a class of benzofuran derivatives that have TRPM3 antagonistic activity and can be used to prepare drugs for treating neuralgia or migraine.

[0007] Technical solution: A class of compounds as shown in Formula I, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof.

[0008] Among them, W1, W2 and W3 are each independently selected from -C(R9)-, -N-, -N(R8)-, -O- or -S-; W4 is selected from -C(R9)-, -N- or W4 is the key;

[0009] L is selected from -C(R) 10 R 11 )-、-N(R 12 -, -S-, or -O-;

[0010] R1, R2, R3, R4, R5, R6, R7, and R9 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, and C. 1-14 Alkyl, C 3-14 cycloalkyl, C 1-14 Alkyloxy, C 3-14 Cycloalkyloxy, 3 to 14-membered heterocyclic groups, C 5-14 aryl or 5 to 14-membered heteroaryl, wherein the above groups are optionally further surrounded by one or more radicals selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, C 1-14 Alkyl, C 3-14 Cycloalkyl, halogenated C 1-14 Alkyl, C 1-14 Alkyloxy, C 3-14 Cycloalkyloxy, 3 to 14-membered heterocyclic groups, C 5-14 Substituted by aryl or 5 to 14 heteroaryl groups;

[0011] X is selected from -NR 13 R 14 ;

[0012] R 10 and R 11 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, C 1-14 Alkyl, C 3-14 cycloalkyl, C 1-14 Alkyloxy, C 3-14 Cycloalkyloxy, 3 to 14-membered heterocyclic groups, C 5-14 aryl or 5 to 14-membered heteroaryl, or R 10 R11 and the directly attached carbon atoms form a carbonyl group, C 3-14 cycloalkyl or 3- to 14-membered heterocyclyl, wherein the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1-14 alkyl, C 3-14 cycloalkyl, halogen-substituted C 1-14 alkyl, C 1-14 alkyloxy, C 3-14 cycloalkyloxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl, wherein the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C

[0013] R8and R 12 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C 1-14 alkyl, C 3-14 cycloalkyl, C 1-14 alkyloxy, C 3-14 cycloalkyloxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl, wherein the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1-14 alkyl, C 3-14 cycloalkyl, halogen-substituted C 1-14 alkyl, C 1-14 alkyloxy, C 3-14 cycloalkyloxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl, wherein the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C

[0014] R 13 is selected from the group consisting of hydroxyl or R Y1 ;

[0015] R 14 is selected from the group consisting of R Y2 or -S(O)2R Y3 ; or R 13 , R 14 and the directly attached nitrogen atom form a saturated or unsaturated, 3- to 14-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S, wherein the 3- to 14-membered heterocyclic ring is optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1-14 alkyl, C 3-14 cycloalkyl, halogen-substituted C 1-14 alkyl, C 1-14 alkyloxy, C 3-14 cycloalkyloxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl, wherein the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C

[0016] R Y1 , R Y2 , R Y3 independently of one another in each case independently of one another selected from the group consisting of: hydrogen;

[0017] saturated or unsaturated, unsubstituted, mono- or polysubstituted C 1-6 alkyl;

[0018] saturated or unsaturated, unsubstituted, mono- or polysubstituted C 1-6 heteroalkyl;

[0019] saturated or unsaturated, unsubstituted, mono- or polysubstituted 3- to 14- membered cycloalkyl; wherein the 3- to 14- membered cycloalkyl is optionally connected by -C 1-6 alkylene- or -C 1-6 heteroalkylene- which in each case is saturated or unsaturated, unsubstituted, mono- or polysubstituted;

[0020] saturated or unsaturated, unsubstituted, mono- or polysubstituted 3- to 14- membered heterocycloalkyl; wherein the 3- to 14- membered heterocycloalkyl is optionally connected by -C 1-6 alkylene- or -C 1-6 heteroalkylene- which in each case is saturated or unsaturated, unsubstituted, mono- or polysubstituted;

[0021] unsubstituted, mono- or polysubstituted 6- to 14- membered aryl; wherein the 6- to 14- membered aryl is optionally connected by -C 1-6 alkylene- or -C 1-6 heteroalkylene- which in each case is saturated or unsaturated, unsubstituted, mono- or polysubstituted;

[0022] or unsubstituted, mono- or polysubstituted 5- to 14- membered heteroaryl; wherein the 5- to 14- membered heteroaryl is optionally connected by -C 1-6 alkylene- or -C 1-6 heteroalkylene- which in each case is saturated or unsaturated, unsubstituted, mono- or polysubstituted;

[0023] and wherein "mono- or polysubstituted" in each case independently denotes substitution by one or more substituents independently of one another selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CI, -CFCI2, -C 1-6 alkylene-CF3, -C 1-6 alkylene-CF2H, -C1-6 Alkylene -CFH2, -C 1-6 Alkylene -O-CF3, -C l-6 Alkylene -O-CF2H, -C 1-6 Alkylene -O-CFH2, -C 1-6 Alkylene-NH-C l-6 Alkylene-CF3, -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 Alkylene-CF3, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-C(=O)-C 1-6 Alkyl, -C(=O)OH, -C l-6 Alkylene -C(=O)-OH, -C(=O)-OC 1-6 Alkyl, -C l-6 Alkylene-C(=O)-OC 1-6 Alkyl group, -C(=O)OC 1-6 Alkylene -CF3, -C(=O)-NH2, -C 1-6 Alkylene -C(=O)-NH2, -C(=O)-NH(C 1-6 Alkyl), -C l-6 Alkylene-C(=O)-NH(C) 1-6 Alkyl), -C(=O)-N(C 1-6 Alkyl)2, -C l-6 Alkylene-C(=O)-N(C) 1-6 Alkyl)2, -C(=O)-NH(OH), -C l-6 Alkylene -C(=O)-NH(OH), -OH, -C l-6 Alkylenes -OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFC12, -OC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkylene-NH-C l-6 Alkyl, -OC 1-6 Alkylene-N(C) l-6 Alkyl)2、-OC(=O)-C 1-6 Alkyl, -C l-6 Alkylene-OC(=O)-C 1-6 Alkyl group, -OC (=O)-OC 1-6alkyl, -C l-6 alkylene-O-C(=O)-O-C 1-6 alkyl, -O-C(=O)-NH(C 1-6 alkyl), -C l-6 alkylene-O-C(=O)-NH(C 1-6 alkyl), -O-C(=O)-N(C 1-6 alkyl)2, -C l-6 alkylene-O-C(=O)-N(C 1-6 alkyl)2, -O-S(=O)2-NH2, -C 1-6 alkylene-O-S(=O)2-NH(C 1-6 alkyl), -C l-6 alkylene-O-S(=O)2-NH(C 1-6 alkyl), -O-S(=O)2-N(C l-6 alkyl)2, -C l-6 alkylene-O-S(=O)2-N(C l-6 alkyl)2, -NH2, -NO, -NO2, -C l-6 alkylene-NH2, -NH(C l-6 alkyl), -N(3- to 14-membered cycloalkyl)(C l-6 alkyl), -N(C l-6 alkyl)-C l-6 alkylene-OH, -N(H)-C 1-6 alkylene-OH, -C l-6 alkylene-NH(C l-6 alkyl), -N(C l-6 alkyl)2, -C l-6 alkylene-N(C l-6 alkyl)2, -NH-C(=O)-C 1-6 alkyl, -C l-6 alkylene-NH-C(=O)-C 1-6 alkyl, -NH-C(=O)-O-C 1-6 alkyl, -C l-6 alkylene-NH-C(=O)-O-C 1-6 alkyl, -NHC(=O)-NH2, -C l-6 alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 alkyl), -C l-6 alkylene-NH-C(=O)-NH(C l-6 alkyl), -NH-C(=O)-N(C 1-6 alkyl)2, -C l-6alkylene-NH-C(=O)-N(C 1-6 alkyl)2, -N(C l-6 alkyl)-C(=O)-C l-6 alkyl, -C l-6 alkylene-N(C l-6 alkyl)-C(=O)-C 1-6 alkyl, -N(C l-6 alkyl)-C(=O)-O-C 1-6 alkyl, -C l-6 alkylene-N(C l-6 alkyl)-C(=O)-O-C 1-6 alkyl, -N(C l-6 alkyl)-C(=O)-NH2, -C 1-6 alkylene-N(C 1-6 alkyl)-C(=O)-NH2, -N(C 1-6 alkyl)-C(=O)-NH(C 1-6 alkyl), -C 1-6 alkylene-N(C 1-6 alkyl)-C(=O)-NH(C 1-6 alkyl), -N(C 1-6 alkyl)-C(=O)-N(C 1-6 alkyl)2, -C 1-6 alkylene-N(C 1-6 alkyl)-C(=O)-N(C 1-6 alkyl)2, -NH-S(=O)2OH, -C 1-6 alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 alkyl, -C 1-6 alkylene-NH-S(=O)2-C 1-6 alkyl, -NH-S(=O)2-O-C 1-6 alkyl, -C 1-6 alkylene-NH-S(=O)-O-C 1-6 alkyl, -NH-S(=O)2-NH2, -C 1-6 alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 alkyl), -C 1-6 alkylene-NH-S(=O)2-NH(C 1-6 alkyl), -NH-S(=O)2N(C 1-6 alkyl)2, -C 1-6 alkylene-NH-S(=O)2N(C 1-6 alkyl)2, -N(C 1-6 alkyl)-S(=O)2-OH, -C1-6 Alkylene-N(C) 1-6 alkyl)-S(=O)2-OH, -N(C 1-6 alkyl)-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkylene-N(C) 1-6 alkyl)-S(=O)2-C 1-6 Alkyl, -N(C) 1-6 alkyl)-S(=O)2-OC 1-6 Alkyl, -C 1-6 Alkylene-N(C) 1-6 alkyl)-S(=O)2-OC 1-6 Alkyl, -N(C) 1-6 Alkyl)-S(=O)2-NH2、-C 1-6 Alkylene-N(C) 1-6 alkyl)-S(=O)2-NH2、-N(C 1-6 alkyl)-S(=O)2-NH(C 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)-S(=O)2-NH(C 1-6 alkyl), -N(C) 1-6 alkyl)-S(=O)2-N(C 1-6 Alkyl)2, -C 1-6 Alkylene-N(C) 1-6 alkyl)-S(=O)2-N(C 1-6 Alkyl groups: -2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 Alkyl, -C 1-6 Alkylene-SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, -S(=O)2-OH, -C 1-6 Alkylenes -S(=O)2-OH, -S(=O)2-OC 1-6 Alkyl, -C 1-6 Alkylene-S(=O)2-OC 1-6 Alkyl group, -S(=O)2-NH2, -C 1-6 Alkylene -S(=O)2-NH2, -S(=O)2-NH(C 1-6 Alkyl, -C 1-6Alkylene-S(=O)2-NH(C) 1-6 Alkyl), -S(=O)2-N(C 1-6 Alkyl)2, -C 1-6 Alkylene-S(=O)2-N(C) 1-6 Alkyl) 2, 3 to 14-membered cycloalkyl, -C 1-6 Alkylene (3- to 14-membered cycloalkyl), 3- to 14-membered heterocycloalkyl, -C 1-6 alkylene-(3 to 14-membered heterocyclic alkyl), -phenyl, -C 1-6 alkylene-phenyl, 5 to 14-membered heteroaryl, -C 1-6 Alkylene-(5 to 14-membered heteroaryl), -O-(3 to 14-membered cycloalkyl), -O-(3 to 14-membered heterocycloalkyl), -O-phenyl, -O-(5 to 14-membered heteroaryl), -C(=O)-(3 to 14-membered cycloalkyl), -C(=O)-(3 to 14-membered heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5 to 14-membered heteroaryl), -S(=O)2-(3 to 14-membered cycloalkyl), -S(=O)2-(3 to 14-membered heterocycloalkyl), -S(=O)2-phenyl or -S(=O)2-(5 to 14-membered heteroaryl).

[0024] Preferably, W1, W2, W3 and W4 are each independently selected from -C(R9)- or -N-, and one or two of W1, W2, W3 and W4 are -N-;

[0025] L is selected from -C(R) 10 R 11 )-、-N(R 12 - or -O-;

[0026] R1, R2, R3, R4, R5, R6, R7, and R9 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, and C. 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3- to 8-membered heterocyclic groups, C 5-8 Aryl or 5- to 8-membered heteroaryl;

[0027] The aforementioned groups may optionally be further surrounded by one or more radicals selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-8 Alkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3- to 8-membered heterocyclic groups, C 5-8 Substituted by aryl or 5 to 8-membered heteroaryl groups;

[0028] R 10 and R 11 each independently is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl, or R 10 , R 11 and the carbon atom directly attached thereto form a carbonyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl,

[0029] wherein the above groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, amino, C 1-8 alkyl, C 3-8 cycloalkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl;

[0030] R8and R 12 each independently is selected from hydrogen, deuterium, hydroxyl, amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl,

[0031] wherein the above groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, amino, C 1-8 alkyl, C 3-8 cycloalkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl;

[0032] R 13 is selected from hydroxyl or R Y1 ;

[0033] R 14 is selected from R Y2 or -S(O)2R Y3 ;

[0034] or R 13 , R 14 and the nitrogen atom directly attached thereto together form a saturated or unsaturated 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S, wherein said 3- to 8-membered heterocyclic ring is optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl.

[0035] Preferably, L is selected from -C(R 10 R 11 )-, -N(R 12 )- or -O-;

[0036] R1is selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, hydroxy, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, azepanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino or aminomethyl;

[0037] R2, R3, R4, R5, R6, R7and R9are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, hydroxy, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, piperazinyl, morpholinyl, azepanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino or aminomethyl,

[0038] the above groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, hydroxyl, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, aziridinyl, piperazinyl, morpholinyl, azinanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino, or aminomethyl;

[0039] R 10 , R 11 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, or R 10 , R 11 and the carbon atom directly attached thereto together form a carbonyl, cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl group;

[0040] R8, R 12 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, trideuteromethoxy, methoxyethyl, ethoxyethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, or dideuteromethyl;

[0041] R 13 is selected from the group consisting of hydroxyl or R Y1 ;

[0042] R 14 is selected from the group consisting of R Y2 or -S(O)2R Y3 ;

[0043] or R 13 , R 14together with the nitrogen atom directly attached thereto form a saturated or unsaturated 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S, wherein said 3- to 8-membered heterocyclic ring is optionally further substituted by one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, hydroxy, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, piperazinyl, morpholinyl, azepanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino or aminomethyl.

[0044] Preferably,

[0045] R1is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, trifluoromethyl, trideuteromethyl, difluoromethyl or dideuteromethyl;

[0046] R2, R3, R4, R5, R6, R7and R9are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, hydroxy, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, piperazinyl, morpholinyl, azepanyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl or dimethylamino;

[0047] R 10 , R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, trideuteromethoxy, trifluoromethyl, trideuteromethyl, or R 10 , R 11 and the carbon atoms directly attached thereto form a carbonyl group, a cyclopropyl group, a cyclobutyl group or an oxetanyl group;

[0048] R8, R 12 are each independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl or trideuteromethyl.

[0049] Preferably, R 13 is selected from R Y1 ;

[0050] R 14 is selected from R Y2 or -S(O)2R Y3 ;

[0051] or R13 R 14 Together with the nitrogen atom directly attached thereto, it forms a saturated or unsaturated 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, or S, wherein the 3- to 6-membered heterocycle is optionally further substituted by one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, azircyclohexyl, methoxy, trifluoromethoxy, trideuteroxy, hydroxymethyl, trifluoromethyl, trideutermethyl, dimethylamino, or aminomethyl.

[0052] Preferably, W4 is a bond, and W1, W2, W3 together with the two connected carbon atoms form a thiazole ring.

[0053] Preferably, X is selected from the following structures:

[0054] Preferably, the compound is selected from:

[0055] Compound S1, as shown above;

[0056] Compound S2, as shown above;

[0057] Compound S3, as shown above;

[0058] Compound S4, as shown above;

[0059] Compound S5, as shown above;

[0060] Compound S6, as shown above;

[0061] Compound S7, as shown above;

[0062] Compound S8, as shown above;

[0063] Compound S9, as shown above;

[0064] Compound S10, as shown above;

[0065] Compound S11, as shown above;

[0066] Compound S12, as shown above;

[0067] Compound S13, as shown above;

[0068] Compound S14, as shown above;

[0069] Compound S15, as shown above;

[0070] Compound S16, as shown above;

[0071] Compound S17, as shown above;

[0072] Compound S18, as shown above;

[0073] Compound S19, as shown above;

[0074] Compound S20, as shown above;

[0075] Compound S21, as shown above;

[0076] Compound S22, as shown above;

[0077] Compound S23, as shown above;

[0078] Compound S24, as shown above;

[0079] Compound S25, as shown above;

[0080] Compound S26, as shown above;

[0081] Compound S27, as shown above;

[0082] Compound S28, as shown above;

[0083] Compound S29, as shown above;

[0084] Compound S30, as shown above;

[0085] Compound S31, as shown above;

[0086] Compound S32, as shown above;

[0087] Compound S33, as shown above;

[0088] Compound S34, as shown above;

[0089] Compound S35, as shown above;

[0090] Compound S36, as shown above;

[0091] Compound S37, as shown above;

[0092] Compound S38, as shown above;

[0093] Compound S39, as shown above.

[0094] Compound S40, as shown above.

[0095] Compound S41, as shown above.

[0096] Compound S42, as shown above.

[0097] Compound S43, as shown above.

[0098] Compound S44, as shown above.

[0099] Compound S45, as shown above.

[0100] Compound S46, as shown above.

[0101] Compound S47, as shown above.

[0102] Compound S48, as shown above.

[0103] Compound S49, as shown above.

[0104] Compound S50, as shown above.

[0105] Compound S51, as shown above.

[0106] Compound S52, as described above.

[0107] Compound S53, as described above.

[0108] Compound S54, as described above.

[0109] Compound S55, as described above.

[0110] Compound S56, as described above.

[0111] Compound S57, as described above.

[0112] Compound S58, as described above.

[0113] Compound S59, as described above.

[0114] Compound S60, as described above.

[0115] Compound S61, as described above.

[0116] Compound S62, as described above.

[0117] Compound S63, as described above.

[0118] Compound S64, as described above.

[0119] Compound S65, as described above.

[0120] Compound S66, as described above.

[0121] Compound S67, as described above.

[0122] Compound S68, as described above.

[0123] Compound S69, as described above.

[0124] Compound S70, as described above.

[0125] Compound S71, as described above.

[0126] Compound S72, as described above.

[0127] Compound S73, as described above.

[0128] Compound S74, as described above.

[0129] Compound S75, as described above.

[0130] Compound S76, as described above.

[0131] Compound S77, as described above.

[0132] Compound S78, as described above.

[0133] Compound S79, as described above.

[0134] Compound S80, as described above.

[0135] Compound S81, as described above.

[0136] Compound S82, as described above.

[0137] Compound S83, as described above.

[0138] Compound S84, as described above.

[0139] Compound S85, as described above.

[0140] Compound S86, as described above.

[0141] Compound S87, as described above.

[0142] Compound S88, as described above.

[0143] Compound S89, as described above.

[0144] Compound S90, as described above.

[0145] Compound S91, as described above.

[0146] Compound S92, as described above.

[0147] Compound S93, as described above.

[0148] Compound S94, as described above.

[0149] Compound S95, as described above.

[0150] Compound S96, as described above.

[0151] Compound S97, as described above.

[0152] Compound S98, as described above.

[0153] Compound S99, as described above.

[0154] Compound S100, as described above.

[0155] Compound S101, as described above.

[0156] Compound S102, as described above.

[0157] Compound S103, as described above.

[0158] Compound S104, as described above.

[0159] Compound S105, as described above.

[0160] Compound S106, as described above.

[0161] Compound S107, as described above.

[0162] Compound S108, as described above.

[0163] Compound S109, as described above.

[0164] Compound S110, as described above.

[0165] Compound S111, as described above.

[0166] Compound S112, as described above.

[0167] Compound S113, as described above.

[0168] Compound S114, as described above.

[0169] Compound S115, as described above.

[0170] Compound S116, as described above.

[0171] Compound S117, as described above.

[0172] Compound S118, as described above.

[0173] Compound S119, as described above.

[0174] Compound S120, as described above.

[0175] Compound S121, as described above.

[0176] Compound S122, as described above.

[0177] Compound S123, as described above.

[0178] Compound S124, as described above.

[0179] Compound S125, as described above.

[0180] Compound S126, as described above.

[0181] Compound S127, as described above.

[0182] Compound S128, as described above.

[0183] Compound S129, as described above.

[0184] Compound S130, as described above.

[0185] Compound S131, as described above.

[0186] Compound S132, as described above.

[0187] Compound S133, as described above.

[0188] Compound S134, as described above.

[0189] Compound S135, as described above.

[0190] Compound S136, as described above.

[0191] Compound S137, as described above.

[0192] Compound S138, as described above.

[0193] Compound S139, as described above.

[0194] Compound S140, as described above.

[0195] Compound S141, as described above.

[0196] Compound S142, as described above.

[0197] Compound S143, as described above.

[0198] Compound S144, as described above.

[0199] Compound S145, as described above.

[0200] Compound S146, as described above.

[0201] Compound S147, as shown above.

[0202] The present application provides a kind of compound shown in formula I, or its pharmaceutically acceptable salt, deuterium compound, solvate, racemic mixture, enantiomer, diastereoisomer and tautomer, in the application of treating pain drug.

[0203] The present application provides a kind of compound shown in formula I, or its pharmaceutically acceptable salt, deuterium compound, solvate, racemic mixture, enantiomer, diastereoisomer and tautomer, in the application of treating neuropathic pain drug.

[0204] The present application provides a kind of compound shown in formula I, or its pharmaceutically acceptable salt, deuterium compound, solvate, racemic mixture, enantiomer, diastereoisomer and tautomer, in the application of treating migraine drug.

[0205] The present application provides a kind of pharmaceutical composition, comprising compound shown in formula I or its pharmaceutically acceptable salt, deuterium compound, solvate, racemic mixture, enantiomer, diastereoisomer, tautomer and pharmaceutically acceptable carrier. Beneficial effects:

[0206] The benzofuran derivative compound described in the application has the characteristics of TRPM3 antagonistic activity, and can be used for preparing a drug for treating neuropathic pain or migraine. DETAILED DESCRIPTION

[0207] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative efforts belong to the scope of protection of the present application.

[0208] "Substituted" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, which can be determined (by experiment or theory) by those skilled in the art without excessive efforts. For example, free amino or hydroxyl groups combined with carbon atoms having unsaturated bonds (such as alkenes) can be unstable.

[0209] Example 1: synthesis of compound S1

[0210] Synthesis of intermediate B1 in step 1

[0211] NMP (10 ml), dimethyl glycine (100 mg, 0.9 mmol, 0.3 eq), cesium carbonate (1.98 g, 6.0 mmol, 2.0 eq), a2 (940 mg. 4.5 mmol, 1.5 eq), A1 (660 mg, 3.0 mmol, 1.0 eq), CuI (600 mg, 3.15, 1.05 eq), nitrogen replacement 3 times, then heated to 120 °C overnight, TLC (PE / EA = 10 / 1), raw material disappeared, the reaction was complete, 20 ml water was added, washed with saturated NaCl, dried with anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed (petroleum ether: ethyl acetate = 10:1), and white solid B1 450 mg was obtained in a yield of 43.22%. ESI-MS: 348.3 [M+H]+

[0212] Synthesis of intermediate C1 in step 2

[0213] B1 (450 mg, 1.29 mmol, 1.0 eq), NaOH (460 mg, 11.6 mmol, 9.0 eq), 5 ml of methanol, 2 ml of water were added, and refluxed overnight. After completion, the PH was adjusted to 5 to 6, and C1 400 mg was precipitated and filtered in a yield of 97.20%. ESI-MS: 320.6 [M+H]+

[0214] Step 3

[0215] C1 (400 mg, 1.25 mmol, 1.0 eq), D1 (200 mg, 1.42 mmol, 1.15 eq), TEA (400 mg, 3.96 mmol, 3.0 eq), HATU (720 mg, 1.89 mmol, 1.5 eq) were sequentially added to 5 ml of dichloromethane and stirred at room temperature. TLC (DCM / MeOH = 10 / 1) was used to monitor the disappearance of the raw material until the reaction was complete. Water 60 ml was added to precipitate the crude product, and EA 10 ml was added to hot slurry to obtain white solid S1 350 mg in a yield of 69.13%. ESI-MS: 406.3 [M+H]+

[0216] 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 3.4 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.75 - 7.59 (m, 4H), 7.59 - 7.55 (m, 1H), 7.48 (s, 1H), 7.25 - 7.01 (m, 2H), 6.90 (d, J = 7.7 Hz, 1H), 5.15 (d, J = 135.3 Hz, 1H), 4.45 (q, J = 5.0 Hz, 1H), 3.71 (d, J = 4.9 Hz, 2H), 2.70 (s, 3H).

[0217] Example 2: Synthesis of compound S2

[0218] Synthesis of intermediate B2 in step 1

[0219] Pyridine (5 ml), cesium carbonate (148 mg, 2.72 mmol, 2.0 eq), a2 (426 mg, 2.04 mmol, 1.5 eq), A1 (300 mg, 1.36 mmol, 1 eq), CuI (47.5 mg, 1.49 mmol, 1.1 eq), nitrogen replacement 3 times, then heated to 120 °C overnight, TLC (PE / EA = 5 / 1), raw material disappeared, the reaction was complete, 20 ml water was added, washed with saturated NaCl, dried with anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed (petroleum ether: ethyl acetate = 5:1), and white solid B2 300 mg was obtained in a yield of 46.32% ESI-MS: 348.3 [M+H]+;

[0220] Synthesis of intermediate C2 in step 2

[0221] B1 (300 mg, 0.86 mmol, 1 eq), NaOH (138 mg, 3.45 mmol, 4 eq), 5 ml of methanol, 2 ml of water were added, and refluxed overnight. After completion, the PH was adjusted to 5 to 6, and C2 300 mg was precipitated and filtered in a yield of 97.20% ESI-MS: 320.6 [M+H]+;

[0222] Step 3

[0223] C1 (300 mg, 0.94 mmol, 1 eq), D1 (172 mg, 1.22 mmol, 1.3 eq), DIPEA (606 mg, 4.7 mmol, 5 eq), HATU (535.8 mg, 1.44 mmol, 1.5 eq) were added successively into DMF 4.5 ml, stirred at room temperature, TLC (DCM / MeOH = 10 / 1) was used to monitor the reaction until the starting material was consumed. Water 10 ml was added to precipitate the crude product, which was filtered and dried to give S2 80 mg as a white solid; ESI-MS: 406.3 [M+H]+

[0224] 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 1.0 Hz, 1H), 8.57 (d, J = 5.9 Hz, 1H), 8.05 (dd, J = 5.9, 1.0 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.76 - 7.56 (m, 2H), 7.53 (d, J = 2.5 Hz, 1H), 7.18 - 7.06 (m, 2H), 4.43 (t, J = 5.2 Hz, 1H), 3.70 (d, J = 5.2 Hz, 2H), 3.58 (s, 4H), 2.69 (s, 3H).

[0225] Example 3: Synthesis of compound S3

[0226] Synthesis of intermediate B3 in step 1

[0227] Pyridine 10 ml, A1 (220 mg, 1.0 mmol, 1.0 eq), a3 (330 mg, 1.5 mmol, 1.5 eq), CuI (210 mg, 1.1 mmol, 1.1 eq), cesium carbonate (650 mg, 2.0 mmol, 2.0 eq) were added successively, replaced with nitrogen for 3 times, then heated to 120 °C and reacted overnight. TLC (PE / EA = 5 / 1) was used to monitor the reaction until the starting material was consumed. After the reaction was completed, it was concentrated to dryness and directly used in the next step without treatment

[0228] Synthesis of intermediate C3 in step 2

[0229] Methanol 10 ml, B3 crude product (theoretical), NaOH (160 mg, 4.0 mmol, 4.0 eq), water 1 ml were added into a 50 ml reaction bottle, and reacted at 50 °C overnight. TLC (PE / EA = 5 / 1, DCM / MeOH = 40 / 1) was used to monitor the reaction until the starting material was consumed. The PH was adjusted to 5-6, and the solid was precipitated and filtered to give C3 260 mg; ESI-MS: 334.6 [M+H]+

[0230] Step 3

[0231] Into a 25ml reaction flask, add DMF 5ml, C3(260mg, 0.78mmol, 1.0eq), D2(155mg, 1.1mmol, 1.3eq), DIPEA(560mg, 4.3mmol, 5.0eq), HATU(500mg 1.29mmol, 1.5eq) in turn, stir at room temperature for half an hour, monitor the reaction by TLC(DCM / MeOH=40 / 1), add water 50ml slowly dropwise, solid precipitates, filter the filter cake, wash the filter cake with a large amount of water, collect the filter cake, and collect S3 130mg, yield 39.73%; ESI-MS: 418.42[M+H]+

[0232] Example 4: Synthesis of compound S4

[0233] Synthesis of intermediate B4 in step 1

[0234] Add A1(160mg, 0.725mmol, 1.0eq) to a 25ml single-necked flask, then add 16.5ml of pyridine, stir uniformly, and then add a4(250mg, 1.03mmol, 1.5eq), Cs2CO3(488.4mg, 1.5mmol, 2.0eq), CuI(156.27mg, 0.82mmol, 1.1eq) in turn, then stir uniformly, and then heat to 130℃ overnight, the reaction liquid turns black, TLC and LCMS detection(tlc=PE:EA=5:1), LCMS corrects column purification(PE:EA=100:~5:1), and gets 220mg of white solid B3, yield 40.8%; ESI-MS: 362.3[M+H]+

[0235] Synthesis of intermediate C4 in step 2

[0236] Add B4(220mg, 0.61mmo, 1eq) to 2ml of methanol, stir uniformly, then add NaOH(98mg, 2.45mmol, 4eq), TLC(DCM:MeOH=10;1), after the reaction is complete, spin dry the solvent, and column purification(DCM:MeOH=100~5:1), get white solid 90mg C4, yield 45%; ESI-MS: 334.6[M+H]+;

[0237] Step 3

[0238] D1 (50 mg, 0.36 mmol, 1.3 eq) was stirred in 4.5 ml DMF, 90 mg C4 was added and stirred until dissolved. DIPEA (174 mg, 0.15 mmol, 5 eq) was added and stirred until dissolved. HATU (154 mg, 0.41 mmol, 1.5 eq) was added and stirred until dissolved. The reaction was allowed to react at room temperature for 30 minutes. TLC and LCMS were used to monitor the reaction. TLC (DCM:MeOH = 10:1) and LCMS showed that the reaction was complete. 10 volumes of water (45 ml) were added and a large amount of solid precipitated. The solid was then filtered and dried. The solid was ESI-MS: 420.4 [M+H]+

[0239] 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.6 Hz, 1H), 7.74 - 7.59 (m, 3H), 7.56 - 7.42 (m, 2H), 7.09 (dd, J = 8.9, 2.5 Hz, 1H), 6.84 (dd, J = 7.6, 1.1 Hz, 1H), 4.44 (t, J = 5.2 Hz, 1H), 3.70 (d, J = 5.2 Hz, 2H), 3.59 (s, 6H), 2.69 (s, 6H).

[0240] Example 5: Synthesis of compound S5

[0241] Synthesis of intermediate B5 in step 1

[0242] A1 (300 mg, 1.36 mmol, 1 eq) was added to a single-neck flask, then pyridine (5 ml) was added and stirred until dissolved. a5 (426 mg, 2.04 mmol, 1.5 eq), Cs2CO3 (148 mg, 2.72 mmol, 2.0 eq), CuI (47.5 mg, 1.49 mmol, 1.1 eq) were added in turn and stirred until dissolved. The temperature was then increased to 130°C and the reaction was allowed to react overnight. TLC and LCMS were used to monitor the reaction (TLC = PE:EA = 5:1). The product was purified by column chromatography (PE:EA = 20:1 - 5:1) to obtain white solid B5 (300 mg, containing solvent)

[0243] Synthesis of intermediate C5 in step 2

[0244] B5 (300 mg, 0.86 mmol, 1 eq) was added to a 10 ml single-neck flask, then 5 ml of methanol was added and stirred until dissolved. NaOH (138 mg, 3.45 mmol, 4 eq) was added and stirred until dissolved. The reaction was monitored by TLC (TLC (DCM:MeOH = 10:1). After the reaction was complete, EA was added to dilute the solution. The pH was adjusted to 5 with 1M hydrochloric acid and a large amount of solid precipitated. The solid was then filtered and dried to obtain white solid C5 (300 mg, crude).

[0245] Step 3

[0246] C5 (300 mg, 0.94 mmol, 1 eq) was added into DMF (4.5 ml) and stirred uniformly, D1 (172 mg, 1.22 mmol, 1.3 eq) was added into the reaction, the reaction was not dissolved, and was stirred uniformly. DIPEA (606 mg, 4.7 mmol, 5 eq) was added into the reaction, and then HATU (535.8 mg, 1.44 mmol, 1.5 eq) was added into the reaction solution. The reaction was dissolved, and was reacted at room temperature for 30 minutes. TLC and LCMS monitoring, TLC (DCM:MeOH = 10:1) LCMS was correct. After the reaction was completed, 10 volumes of water were added, and a large amount of solid was precipitated. Then, the solid was filtered, and was dried to obtain 160 mg of S5; ESI-MS: 406.3 [M+H]+.

[0247] 1H NMR (400 MHz, DMSO-d6) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.43 (dd, J = 8.4, 1.7 Hz, 1H), 7.77 (dd, J = 8.2, 1.3 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.42 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 7.6, 1.2 Hz, 1H), 6.98 (dd, J = 8.9, 2.5 Hz, 1H), 4.42 (t, J = 5.1 Hz, 1H), 3.69 (d, J = 5.2 Hz, 2H), 3.59 (s, 4H), 2.68 (s, 3H).

[0248] Example 6: Synthesis of compound S6

[0249] Referring to the synthesis method of S1 to S5, compound S6 was synthesized by using the corresponding raw materials.

[0250] ESI-MS: 412.3 [M+H]+

[0251] 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.81 (d, J = 8 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.49 (m, 2H), 7.07 (d, J = 8 Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 4.38 (t, J = 5 Hz, 1H), 3.64 (m, 2H), 3.51 (m, 4H), 2.63 (s, 3H).

[0252] Example 7: Synthesis of compound S7

[0253] Compound S7was synthesized according to the synthetic method of S1-S5 using the corresponding starting materials.

[0254] ESI-MS: 404.3 [M+H]+

[0255] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.64 (ddd, J = 8.5, 1.8, 0.9 Hz, 1H), 7.83 (s, 1H), 7.78 (dt, J = 8.5, 1.0 Hz, 1H), 7.70 - 7.54 (m, 4H), 7.28 (s, 1H), 7.12 (dd, J = 8.9, 2.5 Hz, 1H), 7.04 (s, 1H), 6.89 (dd, J = 7.8, 1.0 Hz, 1H), 2.68 (s, 3H), 1.49 (s, 6H).

[0256] Example 8: Synthesis of compound S8

[0257] Compound S8was synthesized according to the synthetic method of S1-S5 using the corresponding starting materials.

[0258] ESI-MS: 416.1 [M+H]+

[0259] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.60 (dd, J = 8.7, 1.9 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.69 - 7.57 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 8.8, 2.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.74 (d, J = 13.2 Hz, 1H), 2.86 (d, J = 27.1 Hz, 2H), 2.61 (s, 3H), 2.25 (s, 3H), 2.14 - 1.95 (m, 2H), 1.79 (d, J = 12.5 Hz, 2H), 1.57 (q, J = 11.2 Hz, 2H).

[0260] Example 9: Synthesis of compound S9

[0261] Compound S9was synthesized according to the synthetic method of S1-S5 using the corresponding starting materials.

[0262] ESI-MS: 403.2 [M+H]+

[0263] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.62 (dd, J = 8.4, 1.8 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.70 - 7.56 (m, 3H), 7.42 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.8, 2.5 Hz, 1H), 6.90 (dd, J = 7.8, 1.0 Hz, 1H), 4.82 (t, J = 5.7 Hz, 1H), 3.61 (d, J = 5.7 Hz, 2H), 2.62 (s, 3H), 2.23 (dt, J = 12.6, 9.6 Hz, 2H), 2.13 - 2.03 (m, 2H), 1.86 - 1.64 (m, 2H).

[0264] Example 10: Synthesis of compound S10

[0265] Synthesis of intermediate A10 in Step 1

[0266] Intermediate A10 was synthesized according to the synthetic method of S1 to S5 using the corresponding starting materials.

[0267] Synthesis of final product S10 in Step 2

[0268] Intermediate A10 (50 mg, 0.1 mmol) was dissolved in 2M HC1 in EA (5 mL), stirred at room temperature overnight, TLC detected the reaction, after the reaction was completed. The solvent was rotary evaporated, EA (5 mL) was added and stirred for 10 min, filtered, and the filter cake was obtained to give the hydrochloride salt of compound S10 as a solid 30 mg, yield 78%

[0269] ESI-MS: 424.4 [M+H]+

[0270] 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.91 (s, 1H), 9.15 (dd, J = 4.6, 1.6 Hz, 1H), 8.94 (d, J = 8.6 Hz, 1H), 8.63 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.82 (ddd, J = 8.3, 6.0, 1.6 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 8.8, 2.5 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.10 - 5.00 (m, 1H), 3.79 (dd, J = 39.6, 12.5 Hz, 5H), 2.68 (s, 3H).

[0271] Example 11: Synthesis of compound S16

[0272] Compound S16 was synthesized according to the synthetic method of S10 using the corresponding starting materials.

[0273] ESI-MS: 430.4 [M+H]+

[0274] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.88 (dd, J = 8.1, 0.8 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.9, 2.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.56 (dt, J = 16.4, 8.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.02 - 2.92 (m, 2H), 2.81 (dd, J = 11.5, 8.1 Hz, 2H), 2.63 (s, 3H).

[0275] Example 12: Synthesis of compound S30

[0276] Compound S30 was synthesized according to the synthetic method of S1 to S5 using the corresponding starting materials.

[0277] ESI-MS: 436.2 [M+H]+

[0278] 1H NMR (400 MHz, DMSO) δ 8.91 (dd, J = 4.1, 1.7 Hz, 1H), 8.44 (dd, J = 8.5, 1.7 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.45 - 7.42 (m, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 8.9, 2.6 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.44 - 4.39 (m, 1H), 3.96 (s, 3H), 3.69 (t, J = 5.4 Hz, 2H), 2.67 (s, 3H).

[0279] Example 13: Synthesis of compound S33

[0280] Compound S33 was synthesized according to the synthetic method of S1 to S5 using the corresponding starting materials.

[0281] ESI-MS: 409.14 [M+H]+

[0282] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J = 8.9, 2.6 Hz, 1H), 6.93 (dd, J = 8.4, 7.3 Hz, 1H), 6.57 (d, J = 7.3 Hz, 1H), 4.97 (t, J = 5.6 Hz, 1H), 4.46 - 4.41 (m, 1H), 4.15 (s, 3H), 3.70 (t, J = 5.4 Hz, 2H), 2.67 (s, 3H), 2.18 (t, J = 7.3 Hz, 1H).

[0283] Example 14: Synthesis of compound S37

[0284] Compound S37 was synthesized according to the synthetic method of S10 using the corresponding starting materials.

[0285] ESI-MS: 426.7 [M+H]+

[0286] 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.40 - 7.25 (m, 2H), 7.13 (dd, J = 8.9, 2.5 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 5.05 (q, J = 10.3, 9.9 Hz, 1H), 4.05 (s, 3H), 3.85 (d, J = 12.6 Hz, 4H), 3.46 (d, J = 21.4 Hz, 1H), 2.67 (s, 3H).

[0287] Example 15: Synthesis of compound S38

[0288] Compound S38 was synthesized according to the synthetic method of S1 to S5 using the corresponding starting materials.

[0289] ESI-MS: 408.8 [M+H]+

[0290] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.65 (dd, J = 20.6, 8.4 Hz, 2H), 7.54 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.32 (dt, J = 15.8, 8.3 Hz, 2H), 7.20 - 7.04 (m, 2H), 6.44 (d, J = 7.3 Hz, 1H), 4.97 (t, J = 5.7 Hz, 1H), 4.43 (dt, J = 7.9, 5.1 Hz, 1H), 4.05 (s, 3H), 3.70 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0291] Example 16: Synthesis of compound S39

[0292] Compound S39 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0293] ESI-MS: 405.1 [M+H]+

[0294] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 - 8.60 (m, 1H), 8.39 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 - 7.56 (m, 3H), 7.53 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.8, 2.5 Hz, 1H), 6.87 (dd, J = 7.7, 1.0 Hz, 1H), 5.15 (t, J = 5.8 Hz, 1H), 4.61 (d, J = 6.5 Hz, 2H), 4.50 (d, J = 6.4 Hz, 2H), 3.73 (d, J = 5.8 Hz, 2H), 2.65 (s, 3H).

[0295] Example 17: Synthesis of compound S40

[0296] Compound S40 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0297] ESI-MS: 409.1 [M+H]+

[0298] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.14 (s, 1H), 7.08 (dd, J = 8.9, 2.6 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.43 (dt, J = 8.0, 5.1 Hz, 1H), 4.19 (s, 3H), 3.70 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0299] Example 18: Synthesis of compound S41

[0300] Compound S41 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0301] ESI-MS: 423.2 [M+H]+

[0302] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.14 (s, 1H), 7.08 (dd, J = 8.9, 2.6 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.43 (dt, J = 8.0, 5.1 Hz, 1H), 4.19 (s, 3H), 3.70 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0303] Example 19: Synthesis of compound S42

[0304] Compound S42 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0305] ESI-MS: 407.2 [M+H]+

[0306] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.27 (s, 1H), 7.14 - 6.98 (m, 3H), 6.73 (d, J = 7.6 Hz, 1H), 4.20 (s, 3H), 2.67 (s, 3H), 1.49 (s, 6H).

[0307] Example 20: Synthesis of compound S43

[0308] Compound S43 was synthesized according to the synthetic method of S10, using the corresponding starting materials.

[0309] ESI-MS: 427.2 [M+H]+

[0310] 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.7 Hz, 1H), 8.10 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.9, 2.6 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.55 (dt, J = 16.4, 8.1 Hz, 1H), 4.17 (s, 3H), 3.29 - 3.17 (m, 2H), 3.03 - 2.90 (m, 1H), 2.80 (dd, J = 11.8, 8.1 Hz, 1H), 2.62 (s, 3H).

[0311] Example 21: Synthesis of compound S44

[0312] Compound S44 was synthesized according to the synthetic method of S1 to S5, using the corresponding starting materials.

[0313] ESI-MS: 431.1 [M+H]+

[0314] 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J = 4.3, 1.7 Hz, 1H), 8.87 (dd, J = 8.5, 1.7 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 8.5, 4.3 Hz, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.26 (dd, J = 8.8, 2.5 Hz, 1H), 7.14 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.45 (dt, J = 8.0, 5.2 Hz, 1H), 3.70 (t, J = 5.4 Hz, 2H), 2.70 (s, 3H).

[0315] Example 22: Synthesis of compound S45

[0316] Compound S45 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0317] ESI-MS: 445.1 [M+H]+

[0318] 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J = 4.3, 1.7 Hz, 1H), 8.87 (dd, J = 8.5, 1.7 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 8.5, 4.3 Hz, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.26 (dd, J = 8.8, 2.5 Hz, 1H), 7.14 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.45 (dt, J = 8.0, 5.2 Hz, 1H), 3.70 (t, J = 5.4 Hz, 2H), 2.70 (s, 3H).

[0319] Example 23: Synthesis of compound S46

[0320] Compound S46 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0321] ESI-MS: 429.2 [M+H]+

[0322] 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J = 4.3, 1.7 Hz, 1H), 8.87 (dd, J = 8.5, 1.7 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.81 (dd, J = 8.5, 4.3 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.34 - 7.22 (m, 2H), 7.05 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 2.69 (s, 3H), 1.50 (s, 6H).

[0323] Example 24: Synthesis of compound S47

[0324] Compound S47 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0325] ESI-MS: 423.2 [M+H]+

[0326] 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.24 (d, J = 6.7 Hz, 2H), 7.18 - 7.12 (m, 1H), 7.06 (dd, J = 8.8, 2.5 Hz, 1H), 6.31 (dd, J = 6.6, 1.7 Hz, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.43 (dt, J = 8.0, 5.1 Hz, 1H), 3.96 (s, 3H), 3.71 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0327] Example 25: Synthesis of compound S48

[0328] Compound S48 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0329] ESI-MS: 436.2 [M+H]+

[0330] 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.29 - 7.20 (m, 2H), 7.12 (s, 1H), 7.07 (dd, J = 8.9, 2.5 Hz, 1H), 6.34 (dd, J = 6.7, 1.5 Hz, 1H), 5.00 (d, J = 5.7 Hz, 1H), 4.32 (dd, J = 8.7, 3.6 Hz, 1H), 4.09 (td, J = 6.1, 3.6 Hz, 1H), 3.96 (s, 3H), 2.70 (s, 3H), 2.51 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0331] Example 26: Synthesis of compound S49

[0332] Compound S49 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0333] ESI-MS: 408.2 [M+H]+

[0334] 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.29 - 7.20 (m, 2H), 7.12 (s, 1H), 7.07 (dd, J = 8.9, 2.5 Hz, 1H), 6.34 (dd, J = 6.7, 1.5 Hz, 1H), 5.00 (d, J = 5.7 Hz, 1H), 4.32 (dd, J = 8.7, 3.6 Hz, 1H), 4.09 (td, J = 6.1, 3.6 Hz, 1H), 3.96 (s, 3H), 2.70 (s, 3H), 2.51 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0335] Example 27: Synthesis of compound S50

[0336] Compound S50 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0337] ESI-MS: 422.2 [M+H]+

[0338] 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.9 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.33 (dd, J = 7.9, 0.9 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 7.11 (s, 1H), 6.99 - 6.90 (m, 2H), 6.60 (dd, J = 7.6, 1.0 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 4.99 (d, J = 5.6 Hz, 1H), 4.31 (dd, J = 8.7, 3.6 Hz, 1H), 4.08 (td, J = 6.1, 3.7 Hz, 1H), 3.91 (s, 3H), 2.68 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0339] Example 28: Synthesis of compound S51

[0340] Compound S51 was synthesized according to the synthetic method of S1 to S5, using the corresponding raw materials.

[0341] ESI-MS: 404.2 [M+H]+

[0342] 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.40 - 7.26 (m, 3H), 7.01 - 6.89 (m, 2H), 6.58 (dd, J = 7.6, 0.9 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 4.52 (dt, J = 10.5, 8.6 Hz, 1H), 3.91 (s, 3H), 3.21 (dd, J = 9.4, 4.3 Hz, 2H), 2.35 (ddd, J = 12.6, 8.4, 4.4 Hz, 1H), 2.02 - 1.93 (m, 1H), 1.24 (s, 3H).

[0343] Example 29: Synthesis of compound S52

[0344] Compound S52 was synthesized according to the synthetic method of S1 to S5, using the corresponding raw materials.

[0345] ESI-MS: 406.2 [M+H]+

[0346] 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 7.9, 1.0 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.05 (s, 1H), 6.98 - 6.90 (m, 2H), 6.59 (dd, J = 7.7, 0.9 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 3.92 (s, 3H), 2.65 (s, 3H), 1.48 (s, 6H).

[0347] Example 30: Synthesis of compound S53

[0348] Compound S53 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0349] ESI-MS: 421.1 [M+H]+

[0350] 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.54 (s, 2H), 7.47 - 7.41 (m, 3H), 7.33 (dd, J = 7.9, 0.9 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.59 (dd, J = 7.7, 0.9 Hz, 1H), 6.46 (d, J = 3.1 Hz, 1H), 4.92 (d, J = 7.6 Hz, 1H), 3.91 (s, 3H), 2.70 (s, 3H).

[0351] Example 31: Synthesis of compound S54

[0352] Compound S54 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0353] ESI-MS: 409.2 [M+H]+

[0354] 1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 8.9 Hz, 1H), 7.34 (dd, J = 7.9, 0.9 Hz, 1H), 7.29 (dd, J = 5.8, 2.8 Hz, 2H), 7.04 (s, 1H), 6.99 - 6.91 (m, 2H), 6.59 (dd, J = 7.6, 0.9 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 4.86 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.58 (dd, J = 10.7, 5.6 Hz, 2H), 3.50 (dd, J = 10.7, 5.8 Hz, 2H), 2.61 (s, 3H), 1.25 (s, 3H).

[0355] Example 32: Synthesis of compound S55

[0356] Compound S55 was synthesized according to the synthetic route of S10, using the corresponding starting materials.

[0357] ESI-MS: 426.2 [M+H]+

[0358] 1H NMR (400 MHz, DMSO-d6) δ 9.97 (d, J = 75.9 Hz, 2H), 8.55 (dd, J = 12.5, 8.2 Hz, 1H), 7.63 - 7.49 (m, 1H), 7.45 - 7.26 (m, 2H), 7.06 - 6.87 (m, 2H), 6.80 - 6.68 (m, 1H), 6.60 (dd, J = 11.8, 7.6 Hz, 1H), 5.06 (dd, J = 15.9, 8.7 Hz, 1H), 3.93 - 3.80 (m, 3H), 3.76 (t, J = 11.7 Hz, 2H), 2.64 (q, J = 3.1, 2.2 Hz, 3H).

[0359] Example 33: Synthesis of compound S56

[0360] Compound S56 was synthesized according to the synthetic route of S1 to S5, using the corresponding starting materials.

[0361] ESI-MS: 410.1 [M+H]+

[0362] 1H NMR (400 MHz, DMSO-d6) δ 7.75 - 7.63 (m, 3H), 7.60 (d, J = 2.5 Hz, 1H), 7.44 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.9, 2.5 Hz, 1H), 7.13 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.95 (t, J = 5.6 Hz, 1H), 4.45 (s, 3H), 3.70 (t, J = 5.5 Hz, 2H), 2.69 (s, 3H).

[0363] Example 34: Synthesis of compound S57

[0364] Compound S57 was synthesized according to the synthetic method of S1-S5, using the corresponding raw materials.

[0365] ESI-MS: 423.2 [M+H]+

[0366] 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.40 (s, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.8, 2.5 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.80 (d, J = 7.7 Hz, 1H), 4.98 (d, J = 5.6 Hz, 1H), 4.44 (s, 3H), 4.33 (dd, J = 8.7, 3.6 Hz, 1H), 4.08 (td, J = 6.1, 3.7 Hz, 1H), 2.70 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0367] Example 35: Synthesis of compound S58

[0368] Compound S58 was synthesized according to the synthetic method of S1-S5, using the corresponding raw materials.

[0369] ESI-MS: 406.1 [M+H]+

[0370] 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.8, 2.5 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 4.54 (dt, J = 10.6, 8.6 Hz, 1H), 4.45 (s, 3H), 3.21 (dd, J = 9.5, 4.2 Hz, 2H), 2.66 (s, 3H), 2.35 (ddt, J = 12.6, 8.3, 4.1 Hz, 1H), 1.98 (dq, J = 11.8, 9.4 Hz, 1H).

[0371] Example 36: Synthesis of compound S59

[0372] Compound S59 was synthesized according to the synthetic route of S10, using the corresponding starting materials.

[0373] ESI-MS: 428.2 [M+H]+

[0374] 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 2H), 8.58 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 18.8, 8.6 Hz, 2H), 7.48 (d, J = 2.5 Hz, 1H), 7.32 - 7.18 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 5.05 (q, J = 10.3 Hz, 1H), 4.44 (s, 3H), 3.92 - 3.67 (m, 3H), 3.50 - 3.42 (m, 1H), 2.67 (s, 3H).

[0375] Example 37: Synthesis of compound S60

[0376] Compound S60 was synthesized according to the synthetic route of S1 to S5, using the corresponding starting materials.

[0377] ESI-MS: 409.1 [M+H]+

[0378] 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.49 - 7.39 (m, 3H), 7.15 - 7.08 (m, 2H), 7.03 (dd, J = 8.9, 2.6 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.43 (dt, J = 8.0, 5.1 Hz, 1H), 3.95 (s, 3H), 3.70 (t, J = 5.1 Hz, 2H), 2.67 (s, 3H).

[0379] Example 38: Synthesis of compound S61

[0380] Compound S61 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0381] ESI-MS: 423.2 [M+H]+

[0382] 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.49 - 7.39 (m, 3H), 7.15 - 7.08 (m, 2H), 7.03 (dd, J = 8.9, 2.6 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.43 (dt, J = 8.0, 5.1 Hz, 1H), 3.95 (s, 3H), 3.70 (t, J = 5.1 Hz, 2H), 2.67 (s, 3H).

[0383] Example 39: Synthesis of compound S62

[0384] Compound S62 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0385] ESI-MS: 405.2 [M+H]+

[0386] 1H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.12 (m, 2H), 7.84 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.11 (t, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.9, 2.6 Hz, 1H), 6.66 (dd, J = 7.9, 0.8 Hz, 1H), 4.53 (dt, J = 10.6, 8.6 Hz, 1H), 3.95 (s, 3H), 3.21 (dd, J = 9.4, 4.2 Hz, 2H), 2.64 (s, 3H), 2.34 (ddt, J = 12.5, 8.5, 4.1 Hz, 1H), 1.97 (dq, J = 11.8, 9.4 Hz, 1H).

[0387] Example 40: Synthesis of compound S63

[0388] Compound S63 was synthesized according to the synthetic method of S10 using the corresponding starting materials.

[0389] ESI-MS: 427.2 [M+H]+

[0390] 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 2H), 9.31 (s, 1H), 8.67 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.19 (dd, J = 8.9, 2.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.05 (q, J = 9.7 Hz, 1H), 4.16 (s, 3H), 3.87 - 3.70 (m, 4H), 2.68 (s, 3H).

[0391] Example 41: Synthesis of compound S64

[0392] Compound S64 was synthesized according to the synthetic method of S1 to S5 using the corresponding starting materials.

[0393] ESI-MS: 375.4 [M+H]+

[0394] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.70 (d, J = 6.7 Hz, 1H), 8.62 (dd, J = 8.6, 1.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 6.94 - 6.89 (m, 1H), 5.00 (h, J = 6.9 Hz, 1H), 4.73 (t, J = 6.9 Hz, 2H), 4.57 (t, J = 6.5 Hz, 2H), 2.66 (s, 3H).

[0395] Example 42: Synthesis of compound S65

[0396] Compound S65 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0397] ESI-MS: 412.4 [M+H]+

[0398] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.14 (d, J = 4.9 Hz, 1H), 7.10 (dd, J = 8.8, 2.5 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H), 4.97 (t, J = 5.7 Hz, 1H), 4.43 (dt, J = 7.9, 5.1 Hz, 1H), 3.70 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0399] Example 43: Synthesis of compound S66

[0400] Compound S66 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0401] ESI-MS: 427.4 [M+H]+

[0402] 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 0.9 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.25 (ddd, J = 9.3, 1.9, 1.0 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), 7.13 (s, 1H), 6.24 (dd, J = 10.9, 1.9 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.46 - 4.42 (m, 1H), 4.00 (s, 3H), 3.71 (t, J = 5.4 Hz, 2H), 2.69 (s, 3H).

[0403] Example 44: Synthesis of compound S67

[0404] Compound S67 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0405] ESI-MS: 441.4 [M+H]+

[0406] 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 0.9 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.25 (ddd, J = 9.3, 1.9, 1.0 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), 7.13 (s, 1H), 6.24 (dd, J = 10.9, 1.9 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.46 - 4.42 (m, 1H), 4.00 (s, 3H), 3.71 (t, J = 5.4 Hz, 2H), 2.69 (s, 3H).

[0407] Example 45: Synthesis of compound S68

[0408] Compound S68 was synthesized according to the synthetic method of S10, using the corresponding starting materials.

[0409] ESI-MS: 445.4 [M+H]+

[0410] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 0.6 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 0.6 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.01 (dd, J = 8.4, 1.9 Hz, 1H), 5.14 (tddd, J = 20.9, 9.2, 4.1, 2.2 Hz, 1H), 3.93 (s, 2H), 3.66 (tt, J = 6.6, 3.3 Hz, 1H), 3.62 - 3.39 (m, 2H), 3.11 - 3.01 (m, 1H), 2.99 - 2.89 (m, 1H).

[0411] Example 46: Synthesis of compound S69

[0412] Compound S69 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0413] ESI-MS: 409.4 [M+H]+

[0414] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J = 8.9, 2.5 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.97 (t, J = 5.6 Hz, 1H), 4.41 (dt, J = 8.0, 5.1 Hz, 1H), 3.85 (s, 3H), 3.69 (t, J = 5.4 Hz, 2H), 2.67 (s, 3H).

[0415] Example 47: Synthesis of compound S70

[0416] Compound S70 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0417] ESI-MS: 423.4 [M+H]+

[0418] 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 2.5 Hz, 1H), 6.98 (dd, J = 8.8, 2.5 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.43 (ddt, J = 10.2, 7.9, 5.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 2.67 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[0419] Example 48: Synthesis of compound S71

[0420] Compound S71 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0421] ESI-MS: 412.4 [M+H]+

[0422] 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 2.5 Hz, 1H), 6.98 (dd, J = 8.8, 2.5 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.43 (ddt, J = 10.2, 7.9, 5.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 2.67 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[0423] Example 49: Synthesis of compound S72

[0424] Compound S72 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0425] ESI-MS: 423.4 [M+H]+

[0426] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2.5 Hz, 2H), 7.38 - 7.31 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H), 6.73 (dd, J = 7.8, 0.9 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 4.30 (dd, J = 8.7, 3.5 Hz, 1H), 4.08 (td, J = 6.0, 3.5 Hz, 1H), 3.85 (s, 3H), 2.68 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H).

[0427] Example 50: Synthesis of compound S73

[0428] Compound S73 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0429] ESI-MS: 437.5 [M+H]+

[0430] 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 6.3, 1.7 Hz, 3H), 7.39 - 7.34 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 6.98 (dd, J = 8.9, 2.5 Hz, 1H), 6.70 (dd, J = 7.9, 0.9 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 4.28 (d, J = 7.4 Hz, 2H), 4.08 (td, J = 6.0, 3.5 Hz, 1H), 2.68 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H).

[0431] Example 51: Synthesis of compound S74

[0432] Compound S74 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0433] ESI-MS: 408.4 [M+H]+

[0434] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.45 (s, 1H), 8.13 (d, J = 0.9 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.16 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 4.97 (t, J = 5.6 Hz, 1H), 4.48 - 4.44 (m, 1H), 3.98 (s, 3H), 3.72 (t, J = 5.5 Hz, 2H), 2.66 (s, 3H).

[0435] Example 52: Synthesis of compound S75

[0436] Compound S75 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0437] ESI-MS: 422.5 [M+H]+

[0438] 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 1.0 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 5.9 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 4.35 (dd, J = 8.6, 3.5 Hz, 1H), 4.11 (td, J = 6.0, 3.4 Hz, 1H), 3.98 (s, 3H), 2.67 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H).

[0439] Example 53: Synthesis of compound S76

[0440] Compound S76 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0441] ESI-MS: 404.4 [M+H]+

[0442] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 0.9 Hz, 1H), 7.84 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.94 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 4.55 (dt, J = 10.5, 8.6 Hz, 1H), 3.98 (s, 3H), 3.22 (dd, J = 9.3, 4.3 Hz, 2H), 2.63 (s, 3H), 2.38 (tt, J = 8.5, 4.4 Hz, 1H), 2.03 - 1.96 (m, 1H).

[0443] Example 54: Synthesis of compound S77

[0444] Compound S77 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0445] ESI-MS: 405.4 [M+H]+

[0446] 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 1.0 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 5.9 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 4.35 (dd, J = 8.6, 3.5 Hz, 1H), 4.11 (td, J = 6.0, 3.4 Hz, 1H), 3.98 (s, 3H), 2.67 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H).

[0447] Example 55: Synthesis of compound S78

[0448] Compound S78 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0449] ESI-MS: 413.5 [M+H]+

[0450] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.87 (dd, J = 8.1, 0.8 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 2H), 7.40 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 5.32 (t, J = 4.8 Hz, 2H), 4.94 (s, 1H), 2.72 (s, 3H).

[0451] Example 56: Synthesis of compound S79

[0452] Compound S79 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0453] ESI-MS: 425.5 [M+H]+

[0454] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.87 (dd, J = 8.1, 0.8 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 2H), 7.40 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 5.32 (t, J = 4.8 Hz, 2H), 4.94 (s, 1H), 2.72 (s, 3H).

[0455] Example 57: Synthesis of compound S80

[0456] Compound S80 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0457] ESI-MS: 410.5 [M+H]+

[0458] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.86 (dd, J = 8.1, 0.8 Hz, 1H), 7.82 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.12 (dd, J = 8.8, 2.5 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 2.67 (s, 3H), 1.49 (s, 6H).

[0459] Example 58: Synthesis of compound S81

[0460] Following the procedure for the synthesis of S1 to S5, compound S81 was synthesized using the corresponding starting materials.

[0461] ESI-MS: 408.4 [M+H]+

[0462] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.88 - 7.83 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 8.8, 2.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.57 - 4.50 (m, 1H), 3.23 - 3.19 (m, 2H), 2.66 (s, 3H), 2.36 - 2.31 (m, 1H), 2.01 - 1.95 (m, 1H).

[0463] Example 59: Synthesis of compound S82

[0464] Following the procedure for the synthesis of S1 to S5, compound S82 was synthesized using the corresponding starting materials.

[0465] ESI-MS: 452.5 [M+H]+

[0466] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.89 (dd, J = 8.2, 0.8 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 8.9, 2.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 3.68 - 3.62 (m, 2H), 3.45 (d, J = 10.6 Hz, 2H), 2.67 (s, 3H), 2.02 - 1.94 (m, 4H).

[0467] Example 60: Synthesis of compound S83

[0468] Compound S83 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0469] ESI-MS: 426.5 [M+H]+

[0470] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.89 (dd, J = 8.2, 0.8 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 8.9, 2.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 3.68 - 3.62 (m, 2H), 3.45 (d, J = 10.6 Hz, 2H), 2.67 (s, 3H), 2.02 - 1.94 (m, 4H).

[0471] Example 61: Synthesis of compound S84

[0472] Compound S84 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0473] ESI-MS: 403.16 [M+H]+

[0474] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 (ddd, J = 8.5, 1.8, 0.9 Hz, 1H), 8.02 (t, J = 5.9 Hz, 1H), 7.79 (dt, J = 8.5, 1.0 Hz, 1H), 7.71 - 7.56 (m, 3H), 7.41 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 6.92 (dd, J = 7.7, 1.0 Hz, 1H), 3.92 (p, J = 6.3 Hz, 1H), 3.67 (dt, J = 8.0, 6.5 Hz, 1H), 3.59 - 3.52 (m, 1H), 3.28 (td, J = 5.9, 3.9 Hz, 3H), 2.63 (s, 3H), 1.87 - 1.79 (m, 1H), 1.80 - 1.70 (m, 2H), 1.57 - 1.46 (m, 1H).

[0475] Example 62: Synthesis of compound S85

[0476] Compound S85 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0477] ESI-MS: 403.16 [M+H]+

[0478] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 (ddd, J = 8.5, 1.8, 0.8 Hz, 1H), 8.02 (t, J = 5.9 Hz, 1H), 7.79 (dt, J = 8.6, 1.0 Hz, 1H), 7.70 - 7.57 (m, 3H), 7.41 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.8, 2.5 Hz, 1H), 6.92 (dd, J = 7.7, 1.0 Hz, 1H), 3.92 (p, J = 6.3 Hz, 1H), 3.67 (dt, J = 8.1, 6.5 Hz, 1H), 3.55 (dt, J = 8.1, 6.8 Hz, 1H), 3.30 - 3.23 (m, 3H), 2.63 (s, 3H), 1.84 (dd, J = 10.4, 4.0 Hz, 1H), 1.80 - 1.72 (m, 2H), 1.56 - 1.46 (m, 1H).

[0479] Example 63: Synthesis of compound S86

[0480] Compound S86 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0481] ESI-MS: 402.17 [M+H]+

[0482] 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.15 (d, J = 4.6 Hz, 1H), 8.95 (d, J = 8.6 Hz, 2H), 8.23 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 8.8, 2.5 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 4.24 - 4.12 (m, 2H), 2.94 (s, 1H), 2.66 (s, 3H), 1.76 - 1.51 (m, 3H), 1.24 (d, J = 4.1 Hz, 1H).

[0483] Example 64: Synthesis of compound S87

[0484] Compound S87 was synthesized according to the synthetic method of S1 to S5, using the corresponding starting materials.

[0485] ESI-MS: 407-13 [M+H]+

[0486] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.5, 1.3 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.62 (dd, J = 14.3, 8.4 Hz, 2H), 7.52 - 7.36 (m, 2H), 7.25 (dd, J = 7.7, 1.3 Hz, 1H), 7.12 (s, 1H), 7.05 (dd, J = 8.8, 2.5 Hz, 1H), 4.95 (t, J = 5.6 Hz, 1H), 4.42 (dt, J = 7.9, 5.1 Hz, 1H), 3.69 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0487] Example 65: Synthesis of compound S88

[0488] Compound S88 was synthesized according to the synthetic method of S1 to S5, using the corresponding starting materials.

[0489] ESI-MS: 423.16 [M+H]+

[0490] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.12 (s, 1H), 7.01 (dd, J = 8.9, 2.5 Hz, 1H), 6.93 (dd, J = 8.3, 7.3 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 4.31 (dd, J = 8.7, 3.5 Hz, 1H), 4.15 (s, 3H), 4.09 (td, J = 6.0, 3.5 Hz, 1H), 2.68 (s, 3H), 1.25 (d, J = 9.3 Hz, 2H), 1.07 (d, J = 6.3 Hz, 3H).

[0491] Example 66: Synthesis of compound S89

[0492] Compound S89 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0493] ESI-MS: 405.15 [M+H]+

[0494] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.01 (dd, J = 8.9, 2.5 Hz, 1H), 6.93 (dd, J = 8.3, 7.3 Hz, 1H), 6.56 (dd, J = 7.4, 0.8 Hz, 1H), 4.54 (dt, J = 10.6, 8.6 Hz, 1H), 4.15 (s, 3H), 3.20 (dd, J = 9.4, 4.2 Hz, 2H), 2.64 (s, 3H), 2.35 (dd, J = 8.2, 4.1 Hz, 1H), 1.98 (dd, J = 11.9, 10.3 Hz, 1H), 1.31 - 1.21 (m, 3H).

[0495] Example 67: Synthesis of compound S90

[0496] Compound S90 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0497] ESI-MS: 424.13 [M+H]+

[0498] 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.69 (dd, J = 8.1, 0.9 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.10 - 7.02 (m, 2H), 6.88 (dd, J = 8.1, 0.9 Hz, 1H), 2.79 (s, 3H), 2.67 (s, 3H), 1.49 (s, 6H).

[0499] Example 68: Synthesis of compound S91

[0500] Following the procedure for the synthesis of S1 to S5, compound S91 was synthesized using the corresponding starting materials.

[0501] ESI-MS: 427.12 [M+H]+

[0502] 1H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 8.2, 0.9 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.89 (dd, J = 8.0, 0.9 Hz, 1H), 4.85 (t, J = 5.7 Hz, 2H), 3.59 (dd, J = 10.7, 5.6 Hz, 2H), 3.50 (dd, J = 10.6, 5.7 Hz, 2H), 2.79 (s, 3H), 2.63 (s, 3H), 1.25 (s, 3H).

[0503] Example 69: Synthesis of compound S92

[0504] Following the procedure for the synthesis of S1 to S5, compound S92 was synthesized using the corresponding starting materials.

[0505] ESI-MS: 438.10 [M+H]+

[0506] 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 7.7 Hz, 1H), 7.70 (dd, J = 8.1, 0.9 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 5.1, 2.0 Hz, 2H), 7.46 (s, 1H), 7.45 - 7.41 (m, 2H), 7.10 (dd, J = 8.9, 2.5 Hz, 1H), 6.89 (dd, J = 8.0, 0.9 Hz, 1H), 5.76 (s, 1H), 4.93 (d, J = 7.6 Hz, 1H), 2.79 (s, 3H), 2.71 (s, 3H).

[0507] Example 70: Synthesis of compound S93

[0508] Following the procedure for the synthesis of S1 to S5, compound S93 was synthesized using the corresponding starting materials.

[0509] ESI-MS: 466.14 [M+H]+

[0510] 1 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.71 (dd, J = 8.1, 0.9 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.8, 2.6 Hz, 1H), 7.01 (s, 1H), 6.96 (dd, J = 8.1, 0.9 Hz, 1H), 6.91 (s, 1H), 3.70 - 3.63 (m, 2H), 3.44 (d, J = 9.8 Hz, 2H), 2.78 (s, 3H), 2.67 (s, 3H), 1.96 - 1.88 (m, 2H), 1.25 (d, J = 9.2 Hz, 2H).

[0511] Example 71: Synthesis of compound S94

[0512] Following the procedure for the synthesis of S1 to S5, compound S94 was synthesized using the corresponding starting materials.

[0513] ESI-MS: 409.8 [M+H]+

[0514] 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 0.9 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.12 - 7.04 (m, 2H), 6.46 (dd, J = 7.3, 0.9 Hz, 1H), 4.88 (t, J = 5.7 Hz, 2H), 4.05 (s, 3H), 3.60 (dd, J = 10.7, 5.6 Hz, 2H), 3.53 - 3.49 (m, 2H), 2.64 (s, 3H), 1.26 (s, 3H).

[0515] Example 72: Synthesis of compound S95

[0516] Compound S95 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0517] ESI-MS: 439.8 [M+H]+

[0518] 1H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 18.4, 8.3 Hz, 3H), 7.58 - 7.52 (m, 2H), 7.44 (d, J = 7.7 Hz, 3H), 7.26 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.92 (d, J = 7.6 Hz, 1H), 2.70 (s, 3H), 2.60 (s, 3H).

[0519] Example 73: Synthesis of compound S96

[0520] Compound S96 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0521] ESI-MS: 435.8 [M+H]+

[0522] 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 7.6 Hz, 1H), 7.62 - 7.50 (m, 3H), 7.50 - 7.31 (m, 4H), 7.20 (t, J = 8.0 Hz, 1H), 6.98 (dd, J = 9.0, 2.6 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 4.91 (d, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.70 (s, 3H), 2.55 (s, 3H).

[0523] Example 74: Synthesis of compound S97

[0524] Following the method of synthesis of S1 to S5, compound S97 was synthesized using the corresponding starting materials.

[0525] ESI-MS: 418.8 [M+H]+

[0526] 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 6.93 (dd, J = 8.8, 2.6 Hz, 1H), 6.67 (dd, J = 7.8, 0.9 Hz, 1H), 4.52 (dt, J = 10.5, 8.6 Hz, 1H), 3.75 (s, 3H), 3.62 (tt, J = 6.6, 3.3 Hz, 1H), 3.23 - 3.11 (m, 3H), 2.63 (s, 3H).

[0527] Example 75: Synthesis of compound S98

[0528] Following the method of synthesis of S1 to S5, compound S98 was synthesized using the corresponding starting materials.

[0529] ESI-MS: 436.8 [M+H]+

[0530] 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.9 Hz, 1H), 7.42 - 7.27 (m, 4H), 7.14 (dd, J = 16.7, 8.7 Hz, 2H), 6.93 (dd, J = 8.9, 2.5 Hz, 1H), 6.70 (dd, J = 7.9, 0.9 Hz, 1H), 5.00 (d, J = 5.5 Hz, 1H), 4.29 (dd, J = 8.7, 3.5 Hz, 1H), 4.11 - 4.04 (m, 1H), 3.75 (s, 3H), 2.67 (s, 3H), 2.49 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H).

[0531] Example 76: Synthesis of compound S99

[0532] Following the method of synthesis of S1 to S5, compound S99 was synthesized using the corresponding starting materials.

[0533] ESI-MS: 421.8 [M+H]+

[0534] 1H NMR (400 MHz, DMSO-d6) d 8.15 (d, J = 8.6 Hz, 1H), 7.83 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 6.93 (dd, J = 8.9, 2.5 Hz, 1H), 6.67 (dd, J = 7.9, 0.9 Hz, 1H), 4.52 (dt, J = 10.5, 8.6 Hz, 1H), 3.23 - 3.15 (m, 3H), 2.63 (s, 3H), 2.38 - 2.29 (m, 1H).

[0535] Example 77: Synthesis of compound S100

[0536] Compound S100 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0537] ESI-MS: 439.8 [M+H]+

[0538] 1H NMR (400 MHz, DMSO-d6) d 7.53 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 7.35 - 7.27 (m, 3H), 7.13 (dd, J = 15.3, 7.3 Hz, 2H), 6.92 (dd, J = 8.9, 2.5 Hz, 1H), 6.69 (dd, J = 7.9, 0.9 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 4.29 (dd, J = 8.7, 3.5 Hz, 1H), 4.08 (td, J = 6.1, 3.6 Hz, 1H), 2.67 (s, 3H), 2.49 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H).

[0539] Example 78: Synthesis of compound S101

[0540] Compound S101 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0541] ESI-MS: 425.8 [M+H]+

[0542] 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 8.1, 0.9 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.92 (dd, J = 8.9, 2.6 Hz, 1H), 6.67 (dd, J = 7.8, 0.9 Hz, 1H), 4.97 (t, J = 5.6 Hz, 1H), 4.41 (dt, J = 7.9, 5.1 Hz, 1H), 3.69 (t, J = 5.4 Hz, 2H), 2.66 (s, 3H).

[0543] Example 79: Synthesis of compound S102

[0544] Compound S102 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0545] ESI-MS: 422.8 [M+H]+

[0546] 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18 - 7.08 (m, 2H), 6.92 (dd, J = 8.9, 2.6 Hz, 1H), 6.68 (dd, J = 7.9, 0.9 Hz, 1H), 4.97 (t, J = 5.6 Hz, 1H), 4.41 (dt, J = 7.9, 5.0 Hz, 1H), 3.75 (s, 3H), 3.69 (t, J = 5.4 Hz, 2H), 2.66 (s, 3H).

[0547] Example 80: Synthesis of compound S103

[0548] Compound S103 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0549] ESI-MS: 405.1 [M+H]+

[0550] 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 0.9 Hz, 2H), 7.62 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.10 (dd, J = 8.8, 2.5 Hz, 1H), 6.43 (dd, J = 7.3, 0.9 Hz, 1H), 4.54 (dt, J = 10.5, 8.6 Hz, 1H), 4.05 (s, 3H), 3.20 (dd, J = 9.4, 4.2 Hz, 2H), 2.66 (s, 3H), 2.37 - 2.31 (m, 1H), 2.03 - 1.92 (m, 1H).

[0551] Example 81: Synthesis of compound S104

[0552] Compound S104 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0553] ESI-MS: 402.1 [M+H]+

[0554] 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 0.9 Hz, 2H), 7.62 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.10 (dd, J = 8.8, 2.5 Hz, 1H), 6.43 (dd, J = 7.3, 0.9 Hz, 1H), 4.54 (dt, J = 10.5, 8.6 Hz, 1H), 4.05 (s, 3H), 3.20 (dd, J = 9.4, 4.2 Hz, 2H), 2.66 (s, 3H), 2.37 - 2.31 (m, 1H), 2.03 - 1.92 (m, 1H).

[0555] Example 82: Synthesis of compound S105

[0556] Compound S105 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0557] ESI-MS: 422.9 [M+H]+

[0558] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.38 - 7.23 (m, 2H), 7.18 - 7.04 (m, 2H), 6.46 (d, J = 7.3 Hz, 1H), 5.00 (d, J = 5.7 Hz, 1H), 4.32 (dd, J = 8.7, 3.5 Hz, 1H), 4.08 (td, J = 6.0, 3.5 Hz, 1H), 2.70 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0559] Example 83: Synthesis of compound S106

[0560] Compound S106 was synthesized according to the synthetic procedure of S10 using the corresponding starting materials.

[0561] ESI-MS: 390.9 [M+H]+

[0562] 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 6.5 Hz, 1H), 7.84 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.10 (dd, J = 8.8, 2.5 Hz, 1H), 6.46 (d, J = 7.3 Hz, 1H), 4.53 (q, J = 6.1 Hz, 1H), 4.05 (s, 3H), 3.43 - 3.29 (m, 3H), 3.19 (qt, J = 7.4, 5.3, 4.5 Hz, 2H), 2.67 (s, 3H), 2.18 (dt, J = 14.8, 7.2 Hz, 1H), 1.99 (dq, J = 13.2, 6.5 Hz, 1H).

[0563] Example 84: Synthesis of compound S107

[0564] Compound S107 was synthesized according to the synthetic procedure of S10 using the corresponding starting materials.

[0565] ESI-MS: 390.9 [M+H]+

[0566] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 6.4 Hz, 1H), 7.84 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.40 - 7.22 (m, 2H), 7.10 (dd, J = 8.8, 2.5 Hz, 1H), 6.46 (d, J = 7.3 Hz, 1H), 4.52 (q, J = 5.8 Hz, 1H), 4.05 (s, 3H), 3.37 (s, 2H), 3.34 - 3.28 (m, 1H), 3.20 (ddt, J = 16.9, 11.4, 5.3 Hz, 2H), 2.66 (s, 3H), 2.19 (dq, J = 14.8, 7.4 Hz, 1H), 1.99 (dq, J = 13.2, 6.4 Hz, 1H).

[0567] Example 85: Synthesis of compound S108

[0568] Compound S108 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0569] ESI-MS: 406.9 [M+H]+

[0570] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 6.7 Hz, 2H), 7.62 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.38 - 7.23 (m, 3H), 7.10 (dd, J = 8.9, 2.5 Hz, 1H), 7.05 (s, 1H), 6.45 (d, J = 7.3 Hz, 1H), 4.05 (s, 3H), 2.67 (s, 3H), 1.49 (s, 6H).

[0571] Example 86: Synthesis of compound S109

[0572] Compound S109 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0573] ESI-MS: 417.1 [M+H]+

[0574] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.60 (ddd, J = 8.5, 1.8, 0.8 Hz, 1H), 7.99 (t, J = 5.9 Hz, 1H), 7.80 (dt, J = 8.4, 1.0 Hz, 1H), 7.72 - 7.53 (m, 3H), 7.39 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 6.95 (dd, J = 7.7, 1.0 Hz, 1H), 3.80 (ddd, J = 11.5, 4.4, 2.0 Hz, 2H), 3.20 (td, J = 11.7, 2.1 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 2.63 (s, 3H), 1.72 (ddt, J = 11.2, 7.8, 4.0 Hz, 1H), 1.51 (ddd, J = 12.6, 4.2, 2.0 Hz, 2H), 1.21 - 1.07 (m, 2H).

[0575] Example 87: Synthesis of compound S110

[0576] Compound S110 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0577] ESI-MS: 417.1 [M+H]+

[0578] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.60 (ddd, J = 8.5, 1.8, 0.8 Hz, 1H), 7.99 (t, J = 5.9 Hz, 1H), 7.80 (dt, J = 8.4, 1.0 Hz, 1H), 7.72 - 7.53 (m, 3H), 7.39 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 6.95 (dd, J = 7.7, 1.0 Hz, 1H), 3.80 (ddd, J = 11.5, 4.4, 2.0 Hz, 2H), 3.20 (td, J = 11.7, 2.1 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 2.63 (s, 3H), 1.72 (ddt, J = 11.2, 7.8, 4.0 Hz, 1H), 1.51 (ddd, J = 12.6, 4.2, 2.0 Hz, 2H), 1.21 - 1.07 (m, 2H).

[0579] Example 88: Synthesis of compound S111

[0580] Compound S111 was synthesized according to the synthetic method of S10 using corresponding starting materials.

[0581] ESI-MS: 388.2 [M+H]+

[0582] 1H NMR (400 MHz, DMSO) δ 9.45 (d, J = 67.9 Hz, 2H), 9.25 (d, J = 3.4 Hz, 1H), 9.16 (d, J = 8.1 Hz, 1H), 8.47 (d, J = 6.5 Hz, 1H), 8.03 - 7.86 (m, 3H), 7.70 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.7, 2.0 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 5.4 Hz, 1H), 3.41 - 3.26 (m, 3H), 3.20 (s, 2H), 2.69 (s, 3H), 2.19 (dd, J = 13.1, 6.8 Hz, 1H), 1.99 (d, J = 6.1 Hz, 1H).

[0583] Example 89: Synthesis of compound S112

[0584] Compound S112 was synthesized according to the synthetic method of S10 using the corresponding starting materials.

[0585] ESI-MS: 388.2 [M+H]+

[0586] 1H NMR (400 MHz, DMSO) δ 9.45 (d, J = 67.9 Hz, 2H), 9.25 (d, J = 3.4 Hz, 1H), 9.16 (d, J = 8.1 Hz, 1H), 8.47 (d, J = 6.5 Hz, 1H), 8.03 - 7.86 (m, 3H), 7.70 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.7, 2.0 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 5.4 Hz, 1H), 3.41 - 3.26 (m, 3H), 3.20 (s, 2H), 2.69 (s, 3H), 2.19 (dd, J = 13.1, 6.8 Hz, 1H), 1.99 (d, J = 6.1 Hz, 1H).

[0587] Example 90: Synthesis of compound S113

[0588] Compound S113 was synthesized according to the synthetic method of S1 to S5 using the corresponding starting materials.

[0589] ESI-MS: 450.2 [M+H]+

[0590] 1H NMR (400 MHz, DMSO) δ 8.91 (dd, J = 4.1, 1.7 Hz, 1H), 8.42 (dd, J = 8.5, 1.7 Hz, 1H), 7.59 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.39 (dd, J = 12.5, 7.8 Hz, 3H), 7.14 (d, J = 8.7 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.9, 2.5 Hz, 1H), 4.99 (d, J = 5.6 Hz, 1H), 4.31 - 4.27 (m, 1H), 4.06 (s, 1H), 3.96 (s, 3H), 2.67 (s, 4H), 1.05 (d, J = 6.3 Hz, 3H).

[0591] Example 91: Synthesis of compound S114

[0592] Compound S114 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0593] ESI-MS: 426.2 [M+H]+

[0594] 1H NMR (400 MHz, DMSO) δ 7.78 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 2.3 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J = 8.8, 2.5 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.45 - 4.40 (m, 1H), 3.70 (t, J = 5.4 Hz, 2H), 2.78 (s, 3H), 2.67 (s, 3H).

[0595] Example 92: Synthesis of compound S115

[0596] Compound S115 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0597] ESI-MS: 426.2

[0598] 1H NMR (400 MHz, DMSO) d 7.68 (t, J = 6.8 Hz, 2H), 7.62 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.44 (t, J = 8.1 Hz, 2H), 7.08 (dd, J = 8.8, 2.5 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.43 (dd, J = 13.2, 5.2 Hz, 2H), 3.70 (t, J = 5.4 Hz, 2H), 2.79 (s, 3H), 2.68 (s, 3H).

[0599] Example 93: Synthesis of compound S116

[0600] Compound S116 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0601] ESI-MS: 440.2 [M+H]+

[0602] 1H NMR (400 MHz, DMSO) d 7.70 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.40 (s, 1H), 7.12 (s, 1H), 7.09 (dd, J = 8.9, 2.5 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 4.99 (d, J = 5.7 Hz, 1H), 4.31 (dd, J = 8.7, 3.6 Hz, 1H), 4.10 - 4.06 (m, 1H), 2.79 (s, 3H), 2.69 (s, 3H), 1.07 (d, J = 6.3 Hz, 3H).

[0603] Example 94: Synthesis of compound S117

[0604] Compound S117 was synthesized according to the synthetic method of S10 using corresponding starting materials.

[0605] ESI-MS: 444.2 [M+H]+

[0606] 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.8, 2.6 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 4.56 (s, 1H), 3.23 (d, J = 12.3 Hz, 2H), 2.95 (d, J = 17.9 Hz, 2H), 2.79 (s, 3H), 2.63 (s, 3H).

[0607] Example 95: Synthesis of compound S118

[0608] Compound S118 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0609] ESI-MS: 426.5 [M+H]+

[0610] 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 7.94 - 7.91 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.13 (s, 1H), 7.03 - 6.98 (m, 2H), 4.96 (t, J = 5.6 Hz, 1H), 4.43 (s, 1H), 3.69 (s, 1H), 2.67 (s, 3H), 1.47 (s, 3H).

[0611] Example 96: Synthesis of compound S119

[0612] Compound S119 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0613] ESI-MS: 423.4 [M+H]+

[0614] 1H NMR (400 MHz, DMSO) δ 8.17 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 6.38 (dd, J = 8.3, 2.8 Hz, 1H), 4.54 (q, J = 8.9 Hz, 1H), 4.18 (d, J = 1.2 Hz, 3H), 3.21 (dd, J = 9.4, 4.2 Hz, 2H), 2.65 (s, 3H), 2.40 - 2.28 (m, 2H), 1.98 (p, J = 9.7 Hz, 2H).

[0615] Example 97: Synthesis of compound S120

[0616] Compound S120 was synthesized according to the synthetic method of S10 using corresponding starting materials.

[0617] ESI-MS: 445.4 [M+H]+

[0618] 1H NMR (400 MHz, DMSO) δ 8.47 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.44 (dd, J = 8.4, 2.8 Hz, 1H), 4.99 (s, 1H), 4.18 (d, J = 1.1 Hz, 3H), 3.72 (d, J = 26.2 Hz, 3H), 2.62 (s, 3H), 1.24 (s, 2H).

[0619] Example 98: Synthesis of compound S121

[0620] Compound S121 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0621] ESI-MS: 407.2 [M+H]+

[0622] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.65 - 8.59 (m, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 - 7.57 (m, 3H), 7.44 (d, J = 2.5 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.90 (dd, J = 7.7, 1.0 Hz, 1H), 4.84 (t, J = 5.7 Hz, 2H), 3.58 (dd, J = 10.7, 5.6 Hz, 2H), 3.50 (dd, J = 10.7, 5.8 Hz, 2H), 2.63 (s, 3H), 1.25 (s, 3H).

[0623] Example 99: Synthesis of compound S122

[0624] Compound S122 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0625] ESI-MS: 420.2 [M+H]+

[0626] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.65 - 8.59 (m, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 - 7.57 (m, 3H), 7.44 (d, J = 2.5 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.90 (dd, J = 7.7, 1.0 Hz, 1H), 4.84 (t, J = 5.7 Hz, 2H), 3.58 (dd, J = 10.7, 5.6 Hz, 2H), 3.50 (dd, J = 10.7, 5.8 Hz, 2H), 2.63 (s, 3H), 1.25 (s, 3H).

[0627] Example 100: Synthesis of compound S123

[0628] Compound S123 was synthesized according to the synthetic method of S1-S5, using the corresponding starting materials.

[0629] ESI-MS: 403.2 [M+H]+

[0630] 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (dd, J = 8.5, 1.7 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.66 (t, J = 8.1 Hz, 2H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.9, 2.5 Hz, 1H), 6.91 - 6.85 (m, 1H), 5.02 (s, 2H), 4.57 (t, J = 8.5 Hz, 1H), 4.08 (dd, J = 10.7, 8.2 Hz, 1H), 2.66 (s, 4H).

[0631] Example 101 : Synthesis of compound S124

[0632] Compound S124 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0633] ESI-MS: 451.2 [M+H]+

[0634] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.61 (dt, J = 8.4, 1.3 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.70 - 7.57 (m, 3H), 7.40 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.8, 2.6 Hz, 1H), 6.92 (dd, J = 7.7, 1.0 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 3.29 - 3.23 (m, 2H), 3.12 - 3.01 (m, 2H), 2.62 (s, 3H), 2.08 (d, J = 13.0 Hz, 4H).

[0635] Example 102: Synthesis of compound S125

[0636] Compound S125 was synthesized according to the synthetic method of S1 to S5 using corresponding starting materials.

[0637] ESI-MS: 404.2 [M+H]+

[0638] 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (dd, J = 8.6, 1.8 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.5, 7.2 Hz, 2H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.8, 2.6 Hz, 1H), 6.92 - 6.85 (m, 1H), 5.02 (d, J = 9.9 Hz, 1H), 4.57 (t, J = 8.5 Hz, 1H), 4.08 (dd, J = 10.7, 8.2 Hz, 1H), 2.66 (s, 3H).

[0639] Example 103: Synthesis of compound S126

[0640] Compound S126 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0641] ESI-MS: 421.2 [M+H]+

[0642] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.62 (dd, J = 8.7, 1.8 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 6.94 - 6.86 (m, 1H), 5.06 (t, J = 5.9 Hz, 1H), 4.56 (dt, J = 7.8, 5.0 Hz, 1H), 3.77 (q, J = 3.8, 2.3 Hz, 2H), 3.62 (s, 3H), 2.66 (s, 3H).

[0643] Example 104: Synthesis of compound S127

[0644] Compound S127 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0645] ESI-MS: 421.2 [M+H]+

[0646] 1H NMR (400 MHz, DMSO-d6) δ 11.64 (d, J = 5.7 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.51 (dt, J = 8.1, 3.7 Hz, 2H), 7.47 - 7.42 (m, 1H), 7.35 - 7.21 (m, 2H), 7.13 (s, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 5.86 (d, J = 7.4 Hz, 1H), 4.98 (t, J = 5.7 Hz, 1H), 4.47 - 4.35 (m, 1H), 3.69 (t, J = 5.5 Hz, 2H), 2.66 (s, 3H).

[0647] Example 105: Synthesis of compound S128

[0648] Compound S128 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0649] ESI-MS: 488.2 [M+H]+

[0650] 1H NMR (400 MHz, DMSO-d6) δ 9.15 (dd, J = 4.2, 1.7 Hz, 1H), 8.83 - 8.74 (m, 1H), 8.12 (s, 1H), 7.80 (dd, J = 8.5, 4.2 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.24 (dd, J = 8.9, 2.5 Hz, 1H), 7.12 (s, 1H), 6.93 (d, J = 1.6 Hz, 1H), 4.97 (d, J = 5.7 Hz, 1H), 4.33 (dd, J = 8.8, 3.6 Hz, 1H), 4.14 - 4.02 (m, 1H), 2.71 (s, 3H), 1.07 (d, J = 6.3 Hz, 3H).

[0651] Example 106: Synthesis of compound S129

[0652] Compound S129 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0653] ESI-MS: 474.2 [M+H]+

[0654] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 4.2, 1.8 Hz, 1H), 8.85 (dd, J = 8.5, 1.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.5, 4.2 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.25 (dd, J = 8.9, 2.5 Hz, 1H), 7.14 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.49 - 4.40 (m, 1H), 3.70 (t, J = 5.4 Hz, 2H), 2.70 (s, 3H).

[0655] Example 107: Synthesis of compound S130

[0656] Compound S130 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0657] ESI-MS: 488.2 [M+H]+

[0658] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 4.2, 1.8 Hz, 1H), 8.85 (dd, J = 8.5, 1.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.5, 4.2 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.25 (dd, J = 8.9, 2.5 Hz, 1H), 7.14 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.49 - 4.40 (m, 1H), 3.70 (t, J = 5.4 Hz, 2H), 2.70 (s, 3H).

[0659] Example 108: Synthesis of compound S131

[0660] Compound S131 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0661] ESI-MS: 446.2 [M+H]+

[0662] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.59 (dd, J = 8.5, 1.7 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.59 (dd, J = 8.5, 4.2 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 8.8, 2.6 Hz, 1H), 6.99 (d, J = 7.7 Hz, 2H), 6.90 (s, 1H), 3.64 (dt, J = 11.7, 3.8 Hz, 2H), 3.42 (ddd, J = 13.1, 10.9, 3.0 Hz, 2H), 2.67 (s, 3H), 1.97 (q, J = 4.5, 3.8 Hz, 4H).

[0663] Example 109: Synthesis of compound S132

[0664] Compound S132 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0665] ESI-MS: 514.2 [M+H]+

[0666] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 4.2, 1.8 Hz, 1H), 8.83 (dd, J = 8.5, 1.8 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.81 - 7.69 (m, 2H), 7.55 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.8, 2.5 Hz, 1H), 7.04 (s, 1H), 6.96 - 6.84 (m, 2H), 3.67 (dt, J = 11.6, 3.9 Hz, 2H), 3.57 - 3.45 (m, 2H), 2.69 (s, 3H), 1.99 (dt, J = 9.8, 3.8 Hz, 4H).

[0667] Example 110: Synthesis of compound S133

[0668] Compound S133 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0669] ESI-MS: 440.2 [M+H]+

[0670] 1H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.76 (m, 1H), 8.70 (d, J = 5.3 Hz, 1H), 7.91 (dd, J = 8.5, 1.1 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.43 (s, 1H), 7.14 - 7.08 (m, 2H), 6.61 (d, J = 5.3 Hz, 1H), 4.94 (t, J = 5.7 Hz, 1H), 4.41 (dt, J = 7.9, 5.1 Hz, 1H), 3.68 (t, J = 5.5 Hz, 2H), 2.67 (s, 3H).

[0671] Example 111: Synthesis of compound S134

[0672] Compound S134 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0673] ESI-MS: 417.2 [M+H]+

[0674] 1H NMR (400 MHz, DMSO-d6) δ 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.77 (s, 1H), 8.69 (d, J = 8.0 Hz, 1H), 8.59 - 8.53 (m, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.62 - 7.50 (m, 3H), 7.39 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H), 4.87 (t, J = 5.5 Hz, 1H), 4.46 (dd, J = 7.5, 5.7 Hz, 1H), 3.65 - 3.51 (m, 2H), 2.42 (s, 3H).

[0675] Example 112: Synthesis of compound S135

[0676] Compound S135 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0677] ESI-MS: 423.2 [M+H]+

[0678] 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 0.9 Hz, 1H), 7.66 (dd, J = 18.2, 8.4 Hz, 2H), 7.55 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4, 7.5 Hz, 1H), 7.17 - 7.07 (m, 2H), 6.42 (d, J = 7.5 Hz, 1H), 4.97 (t, J = 5.7 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.70 (t, J = 5.5 Hz, 2H), 2.68 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).

[0679] Example 113: Synthesis of compound S136

[0680] Compound S136 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0681] ESI-MS: 437.2 [M+H]+

[0682] 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.45 - 7.35 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 7.14 - 7.09 (m, 2H), 6.44 (d, J = 7.5 Hz, 1H), 5.00 (d, J = 5.7 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 4.32 (dd, J = 8.7, 3.5 Hz, 1H), 4.08 (q, J = 5.9 Hz, 1H), 2.70 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H).

[0683] Example 114: Synthesis of compound S137

[0684] Compound S137 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0685] ESI-MS: 427.2 [M+H]+

[0686] 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 17.3, 8.4 Hz, 2H), 7.51 (d, J = 2.5 Hz, 1H), 7.44 (s, 1H), 7.10 (ddd, J = 19.5, 8.6, 3.3 Hz, 3H), 6.39 (dd, J = 8.3, 2.8 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 8.0 Hz, 1H), 4.18 (d, J = 1.1 Hz, 3H), 3.70 (t, J = 5.4 Hz, 2H), 2.68 (s, 3H).

[0687] Example 115: Synthesis of compound S138

[0688] Compound S138 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0689] ESI-MS: 422.2 [M+H]+

[0690] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 0.9 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.58 - 7.50 (m, 3H), 7.43 (s, 2H), 7.37 - 7.27 (m, 2H), 7.12 (dd, J = 8.8, 2.5 Hz, 1H), 6.45 (dd, J = 7.3, 0.9 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 2.71 (s, 3H).

[0691] Example 116: Synthesis of compound S139

[0692] Compound S139 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0693] ESI-MS: 441.2 [M+H]+

[0694] 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 10.8 Hz, 2H), 7.16 - 7.06 (m, 3H), 6.42 (dd, J = 8.3, 2.8 Hz, 1H), 4.99 (d, J = 5.7 Hz, 1H), 4.31 (dd, J = 8.7, 3.5 Hz, 1H), 4.18 (d, J = 1.1 Hz, 3H), 4.08 (ddd, J = 8.3, 6.0, 2.9 Hz, 1H), 2.69 (s, 3H), 1.07 (d, J = 6.3 Hz, 3H).

[0695] Example 117: Synthesis of compound S140

[0696] Compound S140 was synthesized according to the synthetic method of S10 using the corresponding starting materials.

[0697] ESI-MS: 480.2 [M+H]+

[0698] 1H NMR (400 MHz, DMSO-d6) δ 9.53 (m, 2H), 8.48 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.41 (dd, J = 8.3, 2.8 Hz, 1H), 5.04 (d, J = 10.1 Hz, 1H), 3.79 - 3.70 (m, 4H), 2.66 (s, 3H).

[0699] Example 118: Synthesis of compound S141

[0700] Compound S141 was synthesized according to the synthetic methods of S1 to S5 using the corresponding starting materials.

[0701] ESI-MS: 474.2 [M+H]+

[0702] 1H NMR (400 MHz, DMSO-d6) δ 9.15 (dd, J = 4.2, 1.7 Hz, 1H), 8.84 - 8.76 (m, 1H), 8.11 (dd, J = 1.9, 1.0 Hz, 1H), 7.80 (dd, J = 8.5, 4.2 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.45 (s, 1H), 7.23 (dd, J = 8.8, 2.5 Hz, 1H), 7.13 (s, 1H), 6.90 (d, J = 1.7 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.49 - 4.39 (m, 1H), 3.70 (t, J = 5.3 Hz, 2H), 2.70 (s, 3H).

[0703] Example 119: Synthesis of compound S142

[0704] Compound S142 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0705] ESI-MS: 408.2 [M+H]+

[0706] 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.5 Hz, 2H), 7.27 - 7.20 (m, 2H), 7.14 - 7.05 (m, 2H), 6.96 (dd, J = 8.8, 2.5 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.24 (dd, J = 3.1, 0.9 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.42 (dt, J = 8.0, 5.1 Hz, 1H), 3.80 (s, 3H), 3.70 (t, J = 5.5 Hz, 2H), 2.67 (s, 3H).

[0707] Example 120: Synthesis of compound S143

[0708] Compound S143 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0709] ESI-MS: 422.3 [M+H]+

[0710] 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.9 Hz, 1H), 7.45 - 7.35 (m, 3H), 7.28 - 7.21 (m, 2H), 7.13 - 7.07 (m, 2H), 6.97 (dd, J = 8.9, 2.5 Hz, 1H), 6.56 - 6.52 (m, 1H), 6.23 (dd, J = 3.1, 0.9 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 4.31 (dd, J = 8.7, 3.5 Hz, 1H), 4.12 - 4.04 (m, 1H), 3.80 (s, 3H), 2.68 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0711] Example 121: Synthesis of compound S144

[0712] Compound S144 was synthesized according to the synthetic method of S1-S5 using corresponding starting materials.

[0713] ESI-MS: 405.2 [M+H]+

[0714] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 4.5 Hz, 1H), 8.89 (d, J = 8.6 Hz, 1H), 8.59 (s, 1H), 7.76 - 7.48 (m, 6H), 7.44 (s, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 7.13 (s, 1H), 5.12 - 4.83 (m, 1H), 4.45 (dt, J = 7.7, 5.1 Hz, 1H), 3.71 (d, J = 5.2 Hz, 2H), 2.67 (s, 3H).

[0715] Example 122: Synthesis of compound S145

[0716] Compound S145 was synthesized according to the synthetic method of S10 using corresponding starting materials.

[0717] ESI-MS: 423.2 [M+H]+

[0718] 1H NMR (400 MHz, DMSO-d6) δ 9.90 - 9.76 (m, 2H), 9.04 (s, 2H), 8.76 (s, 2H), 8.50 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 12.9 Hz, 2H), 7.59 - 7.53 (m, 3H), 7.33 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 8.7, 2.2 Hz, 1H), 5.08 (d, J = 9.7 Hz, 1H), 3.77 (m, 4H), 2.64 (s, 3H).

[0719] Example 123: Synthesis of compound S146

[0720] Compound S146 was synthesized according to the synthetic procedure of S10 using corresponding starting materials.

[0721] ESI-MS: 492.2 [M+H]+

[0722] 1H NMR (400 MHz, DMSO-d6) δ 9.80 (d, J = 87.8 Hz, 2H), 9.16 (dd, J = 4.2, 1.7 Hz, 1H), 8.78 (dd, J = 8.8, 1.7 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H), 7.81 (dd, J = 8.5, 4.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 1.7 Hz, 1H), 5.05 (q, J = 9.6 Hz, 1H), 3.78 (q, J = 12.1, 8.6 Hz, 4H), 2.68 (s, 3H).

[0723] Example 124: Synthesis of compound S147

[0724] Compound S147 was synthesized according to the synthetic procedure of S10 using corresponding starting materials.

[0725] ESI-MS: 492.2 [M+H]+

[0726] 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 2H), 9.14 (dd, J = 4.2, 1.8 Hz, 1H), 8.83 (dd, J = 8.6, 1.8 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 8.9, 2.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.03 (d, J = 10.3 Hz, 1H), 3.77 (dq, J = 21.9, 12.6 Hz, 4H), 2.69 (s, 3H).

[0727] Example 125: Detection of TRPM3 antagonistic activity of compounds

[0728] 1. Cell culture and transfection

[0729] Human embryonic kidney 293T (HEK 293T) cells for transient transfection were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and 1% double antibiotics. The pcDNA3.4 vector containing human TRPM3 was transiently transfected into HEK 293T cells, and the transfection efficiency was observed 24 h after transfection and the cells were plated for seeding. The functional studies were performed 72 h after transfection.

[0730] 2. Intracellular Ca2+ measurement 2+ Measurement

[0731] The fluorescence assay was performed in 96-well plates. The fluorescence indicator Fluo-4 / AM and different concentrations of TRPM3 inhibitors were added to the TRPM3-expressing HEK 293T cells and incubated at 37 °C for 1 h. Then the 96-well plates were placed in a multifunctional enzyme label instrument Flex Station 3, and the fluorescence intensity before and after the addition of the TRPM3 agonist PregS was detected using 494 nm and 516 nm as the excitation and emission wavelengths, respectively. To ensure the accuracy of the test results, the background fluorescence signal was subtracted to calculate the fluorescence change rate (AF / F0) of each well, so as to more accurately evaluate the effect of different concentrations of TRPM3 inhibitors on intracellular Ca2+ flux and TRPM3 channel activity. 2+ Measurement

[0732] The results are shown in the table, and the compounds have TRPM3 antagonistic activity. The TRPM3 IC50 value ranges represented by activity ranges A, B and C are as follows: “A” indicates IC50 < 1 mM; “B” indicates 1 mM < IC50 < 20 mM; and “C” indicates IC50 > 20 mM.

[0733] It will be apparent to those skilled in the art that the application is not limited to the details of the above-exemplified embodiments and that the present application can be implemented in other particular forms without departing from the spirit or essential characteristics of the present application. The presently disclosed embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the application being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. No feature of the application is to be construed as a limitation, and no disavowal of any claim element is intended.

Claims

1. A class of compounds represented by Formula I or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, characterized in that, Formula I wherein each of W1, W2, and W3is independently selected from -C(R9)-, -N-, -N(R8)-, -O-, or -S-; W4is selected from -C(R9)-, -N-, or W4is a bond; L is selected from -C(R 10 R 11 )-, -N(R 12 )-, -S- or -O-; R1, R2, R3, R4, R5, R6, R7and R9are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-14 alkyl, C 3-14 cycloalkyl, C 1-14 alkoxy, C 3-14 cycloalkoxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl, wherein the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-14 alkyl, C 3-14 cycloalkyl, halogen-substituted C 1-14 alkyl, C 1-14 alkoxy, C 3-14 cycloalkoxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl; X is selected from -NR 13 R 14 ; R 10 and R 11 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-14 alkyl, C 3-14 cycloalkyl, C 1-14 alkyloxy, C 3-14 cycloalkyloxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl, or R 10 , R 11 and the carbon atom directly attached thereto form a carbonyl, C 3-14 cycloalkyl or 3- to 14-membered heterocyclyl, wherein the aforementioned groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-14 alkyl, C 3-14 cycloalkyl, halogen-substituted C 1-14 alkyl, C 1-14 alkyloxy, C 3-14 cycloalkyloxy, 3- to 14-membered heterocyclyl, C 5-14 aryl or 5- to 14-membered heteroaryl; R8 and R 12 Each is independently selected from hydrogen, deuterium, hydroxyl, amino, C 1-14 Alkyl, C 3-14 cycloalkyl, C 1-14 Alkyloxy, C 3-14 Cycloalkyloxy, 3 to 14-membered heterocyclic groups, C 5-14 aryl or 5 to 14-membered heteroaryl, wherein the above groups are optionally further surrounded by one or more radicals selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, C 1-14 Alkyl, C 3-14 Cycloalkyl, halogenated C 1-14 Alkyl, C 1-14 Alkyloxy, C 3-14 Cycloalkyloxy, 3 to 14-membered heterocyclic groups, C 5-14 Substituted by aryl or 5 to 14 heteroaryl groups; R 13 selected from hydroxyl or R Y1 ; R 14 Selected from R Y2 or -S(O)2R Y3 Or R 13 R 14 Together with the nitrogen atom directly bonded thereto, it forms a saturated or unsaturated 3- to 14-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, or S, wherein the 3- to 14-membered heterocycle is optionally further bounded by one or more atoms selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, C 1-14 Alkyl, C 3-14 Cycloalkyl, halogenated C 1-14 Alkyl, C 1-14 Alkyloxy, C 3-14 Cycloalkyloxy, 3 to 14-membered heterocyclic groups, C 5-14 Substituted by aryl or 5 to 14 heteroaryl groups; R Y1 , R Y2 , R Y3 are independently from each other in each case independently selected from the group consisting of: hydrogen; saturated or unsaturated, unsubstituted, mono- or polysubstituted C 1-6 alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted C 1-6 heteroalkyl; saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered cycloalkyl; wherein said 3- to 14-membered cycloalkyl is optionally attached by -C 1-6 alkylene- or -C 1-6 heteroalkylene- linkages, said alkylene or heteroalkylene in each occurrence is saturated or unsaturated, unsubstituted, mono- or poly-substituted; saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered heterocycloalkyl; wherein said 3- to 14-membered heterocycloalkyl is optionally attached by -C 1-6 alkylene- or -C 1-6 heteroalkylene- linkages, said alkylene or heteroalkylene in each occurrence is saturated or unsaturated, unsubstituted, mono- or poly-substituted; unsubstituted, mono- or polysubstituted 6- to 14-membered aryl; wherein the 6- to 14-membered aryl is optionally attached via -C 1-6 alkylene- or -C 1-6 heteroalkylene- linkages, which alkylene or heteroalkylene in each case is saturated or unsaturated, unsubstituted, mono- or polysubstituted; or unsubstituted, mono- or poly-substituted 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl is optionally attached via -C 1-6 alkylene- or -C 1-6 heteroalkylene- linkages, which alkylene or heteroalkylene is in each case saturated or unsaturated, unsubstituted, mono- or poly-substituted; and wherein "monosubstituted or polysubstituted" in each case independently denotes substitution by one or more substituents, which are independently of each other selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CI, -CFCI2, -C 1-6 alkylene-CF3, -C 1-6 alkylene-CF2H, -C 1-6 alkylene-CFH2, -C 1-6 alkylene-O-CF3, -C l-6 alkylene-O-CF2H, -C 1-6 alkylene-O-CFH2, -C 1-6 alkylene-NH-C l-6 alkylene-CF3, -C 1-6 alkylene-N(C 1-6 alkyl)-C 1-6 alkylene-CF3, -C(=O)-C 1-6 alkyl, -C 1-6 alkylene-C(=O)-C 1-6 alkyl, -C(=O)OH, -C l-6 alkylene-C(=O)-OH, -C(=O)-OC 1-6 alkyl, -C l-6 alkylene-C(=O)-OC 1-6 alkyl, -C(=O)O-C 1-6 alkylene-CF3, -C(=O)-NH2, -C 1-6 alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 alkyl), -C l-6 alkylene-C(=O)-NH(C 1-6 alkyl), -C(=O)-N(C 1-6 alkyl)2, -C l-6 alkylene-C(=O)-N(C 1-6 alkyl)2, -C(=O)-NH(OH), -C l-6 alkylene-C(=O)-NH(OH), -OH, -C l-6 alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2CI, -OCFCI2, -O-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -O-C 1-6 alkylene-O-C 1-6 alkyl, -O-C 1-6 alkylene-NH2, -O-C 1-6 alkylene-NH-C l-6 alkyl, -O-C 1-6 alkylene-N(C l-6 alkyl)2, -O-C(=O)-C 1-6 alkyl, -C l-6 alkylene-O-C(=O)-C 1-6 alkyl, -O-C(=O)-O-C 1-6 alkyl, -C l-6 alkylene-O-C(=O)-O-C 1-6 alkyl, -O-C(=O)-NH(C 1-6 alkyl), -C l-6 alkylene-O-C(=O)-NH(C 1-6 alkyl), -O-C(=O)-N(C 1-6 alkyl)2, -C l-6 alkylene-O-C(=O)-N(C 1-6 alkyl)2, -O-S(=O)2-NH2, -C 1-6 alkylene-O-S(=O)2-NH(C 1-6 alkyl), -C l-6 alkylene-O-S(=O)2-NH(C 1-6 alkyl), -O-S(=O)2-N(C l-6 alkyl)2, -C l-6 alkylene-O-S(=O)2-N(C l-6 alkyl)2, -NH2, -NO, -NO2, -C l-6 alkylene-NH2, -NH(C l-6 alkyl), -N(3- to 14-membered cycloalkyl)(C l-6 alkyl), -N(C l-6 alkyl)-C l-6 alkylene-OH, -N(H)-C 1-6 alkylene-OH, -C l-6 alkylene-NH(C l-6 alkyl), -N(C l-6 alkyl)2, -C l-6 alkylene-N(C l-6 alkyl)2, -NH-C(=O)-C 1-6 alkyl, -C l-6 alkylene-NH-C(=O)-C 1-6 alkyl, -NH-C(=O)-O-C 1-6 alkyl, -C l-6 alkylene-NH-C(=O)-O-C 1-6 alkyl, -NHC(=O)-NH2, -C l-6 alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 alkyl), -C l-6 alkylene-NH-C(=O)-NH(C l-6 alkyl), -NH-C(=O)-N(C 1-6 alkyl)2, -C l-6 alkylene-NH-C(=O)-N(C 1-6 alkyl)2, -N(C l-6 alkyl)-C(=O)-C l-6 alkyl, -C l-6 alkylene-N(C l-6 alkyl)-C(=O)-C 1-6 alkyl, -N(C l-6 alkyl)-C(=O)-O-C 1-6 alkyl, -C l-6 alkylene-N(C l-6 alkyl)-C(=O)-O-C 1-6 alkyl, -N(C l-6 alkyl)-C(=O)-NH2, -C 1-6 alkylene-N(C 1-6 alkyl)-C(=O)-NH2, -N(C 1-6 alkyl)-C(=O)-NH(C 1-6 alkyl), -C 1-6 alkylene-N(C 1-6 alkyl)-C(=O)-NH(C 1-6 alkyl), -N(C 1-6 alkyl)-C(=O)-N(C 1-6 alkyl)2, -C 1-6 alkylene-N(C 1-6 alkyl)-C(=O)-N(C 1-6 alkyl)2, -NH-S(=O)2OH, -C 1-6 alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 alkyl, -C 1-6 alkylene-NH-S(=O)2-C 1-6 alkyl, -NH-S(=O)2-O-C 1-6 alkyl, -C 1-6 alkylene-NH-S(=O)-O-C 1-6 alkyl, -NH-S(=O)2-NH2, -C 1-6 alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 alkyl), -C 1-6 alkylene-NH-S(=0)2-N(C 1-6 alkyl), -NH-S(=0)2N(C 1-6 alkyl)2, -C 1-6 alkylene-NH-S(=0)2N(C 1-6 alkyl)2, -N(C 1-6 alkyl)-S(=0)2-OH, -C 1-6 alkylene-N(C 1-6 alkyl)-S(=0)2-OH, -N(C 1-6 alkyl)-S(=0)2-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)-S(=0)2-C 1-6 alkyl, -N(C 1-6 alkyl)-S(=0)2-O-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)-S(=0)2-O-C 1-6 alkyl, -N(C 1-6 alkyl)-S(=0)2-NH2, -C 1-6 alkylene-N(C 1-6 alkyl)-S(=0)2-NH2, -N(C 1-6 alkyl)-S(=0)2-NH(C 1-6 alkyl), -C 1-6 alkylene-N(C 1-6 alkyl)-S(=0)2-NH(C 1-6 alkyl), -N(C 1-6 alkyl)-S(=0)2-N(C 1-6 alkyl)2, -C 1-6 alkylene-N(C 1-6 alkyl)-S(=0)2-N(C 1-6 alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -S-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -S(=0)-C 1-6 alkyl, -C 1-6 alkylene-S(=0)-C 1-6 alkyl, -S(=0)2-C 1-6 alkyl, -C 1-6 alkylene-S(=0)2-C 1-6 alkyl, -S(=0)2-OH, -C 1-6 alkylene-S(=0)2-OH, -S(=0)2-O-C 1-6 alkyl, -C 1-6 alkylene-S(=0)2-O-C 1-6 alkyl, -S(=0)2-NH2, -C 1-6 alkylene-S(=0)2-NH2, -S(=0)2-NH(C 1-6 alkyl, -C 1-6 alkylene-S(=0)2-NH(C 1-6 alkyl), -S(=0)2-N(C 1-6 alkyl)2, -C 1-6 alkylene-S(=0)2-N(C 1-6 alkyl)2, 3- to 14-membered cycloalkyl, -C 1-6 alkylene-(3- to 14-membered cycloalkyl), 3- to 14-membered heterocycloalkyl, -C 1-6 alkylene-(3- to 14-membered heterocycloalkyl), -phenyl, -C 1-6 alkylene-phenyl, 5- to 14-membered heteroaryl, -C 1-6 alkylene-(5- to 14-membered heteroaryl), -0-(3- to 14-membered cycloalkyl), -0-(3- to 14-membered heterocycloalkyl), -0-phenyl, -0-(5- to 14-membered heteroaryl), -C(=0)-(3- to 14-membered cycloalkyl), -C(=0)-(3- to 14-membered heterocycloalkyl), -C(=0)-phenyl, -C(=0)-(5- to 14-membered heteroaryl), -S(=0)2-(3- to 14-membered cycloalkyl), -S(=0)2-(3- to 14-membered heterocycloalkyl), -S(=0)2-phenyl, or -S(=0)2-(5- to 14-membered heteroaryl). 2.The compound of claim 1 or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, characterized in that, wherein each of W1, W2, W3and W4is independently selected from -C(R9)- or -N-, and 1 to 2 of W1, W2, W3and W4are -N-; L is selected from -C(R 10 R 11 )-, -N(R 12 )- or -O-; R1, R2, R3, R4, R5, R6, R7, and R9are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, amino, C 1-8 alkyl, C 3-8 alkyl, C 1-8 alkyl, C 3-8 alkyl, C 5-8 aryl, or 5- to 8-membered heteroaryl; wherein the above groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl; R 10 and R 11 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl, or R 10 , R 11 and the carbon atom directly attached thereto form a carbonyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, wherein the above groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl; R8and R 12 each independently is selected from hydrogen, deuterium, hydroxyl, amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl, wherein the above groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyloxy, C 3-8 cycloalkyloxy, 3- to 8-membered heterocyclyl, C 5-8 aryl or 5- to 8-membered heteroaryl; R 13 selected from hydroxyl or R Y1 ; R 14 selected from R Y2 or -S(O)2R Y3 ; Or R 13 R 14 Together with the nitrogen atom directly bonded thereto, it forms a saturated or unsaturated 3- to 8-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, or S, wherein the 3- to 8-membered heterocycle is optionally further bonded by one or more atoms selected from hydrogen, deuterium, halogen, cyano, nitro, azide, hydroxyl, amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-8 Alkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3- to 8-membered heterocyclic groups, C 5-8 Substituents of aryl or 5 to 8-membered heteroaryl groups. 3.The compound of claim 1 or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, characterized in that, L is selected from -C(R 10 R 11 )-, -N(R 12 )- or -O-; R1is selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, hydroxyl, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, azepanyl, morpholinyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino or aminomethyl; each of R2, R3, R4, R5, R6, R7and R9is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, hydroxyl, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, piperazinyl, morpholinyl, azepanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino or aminomethyl, each of R2, R3, R4, R5, R6, R7and R9is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, hydroxyl, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, piperazinyl, morpholinyl, azepanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino or aminomethyl, R 10 , R 11 each independently is selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, or R 10 , R 11 and the carbon atom directly attached thereto together form a carbonyl, cyclopropyl, cyclobutyl, cyclopentyl or oxetanyl; R8, R 12 each independently is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, trideuteromethoxy, methoxyethyl, ethoxyethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, or dideuteromethyl; R 13 selected from hydroxyl or R Y1 ; R 14 selected from R Y2 or -S(O)2R Y3 ; or R 13 , R 14 and the nitrogen atom to which they are directly attached together form a saturated or unsaturated 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S, wherein said 3- to 8-membered heterocyclic ring is optionally further substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, hydroxyl, amino, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azolidinyl, piperazinyl, morpholinyl, azocanyl, phenyl, diazole, triazole, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, dimethylamino, or aminomethyl. 4.The compound of claim 1 or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, characterized in that, R1is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethoxy, trifluoromethyl, trideuteromethyl, difluoromethyl, or dideuteromethyl; R2, R3, R4, R5, R6, R7, and R9are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azetidinyl, piperazinyl, morpholinyl, azocanyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, or dimethylamino; R 10 , R 11 each independently is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, trifluoromethoxy, trideuteromethoxy, trifluoromethyl, trideuteromethyl, or R 10 , R 11 and the carbon atom directly attached thereto form a carbonyl, cyclopropyl, cyclobutyl or oxetanyl; R8, R 12 each independently is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl, or trideuteromethyl.

5. The compound of claim 1, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R 13 selected from R Y1 ; R 14 selected from R Y2 or -S(O)2R Y3 ; or R 13 , R 14 and the nitrogen atom to which they are directly attached form a saturated or unsaturated 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S, wherein the 3- to 6-membered heterocyclic ring is optionally further substituted by one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, amino, methyl, ethyl, isopropyl, cyclopropyl, azacyclohexyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxymethyl, trifluoromethyl, trideuteromethyl, dimethylamino, or aminomethyl.

6. The compound of claim 1, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein W4is a bond, W1, W2, W3together with the two carbon atoms to which they are attached form a thiazole ring.

7. The compound of claim 1, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein X is selected from the following structures:

8. The compound of claim 1, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein, The compound is selected from: Compound S1, as shown above; Compound S2, as shown above; Compound S3, as shown above; Compound S4, as shown above; Compound S5, as shown above; Compound S6, as shown above; Compound S7, as shown above; Compound S8, as shown above; Compound S9, as shown above; Compound S10, as shown above; Compound S11, as shown above; Compound S12, as shown above; Compound S13, as shown above; Compound S14, as shown above; Compound S15, as shown above; Compound S16, as shown above; Compound S17, as shown above; Compound S18, as shown above; Compound S19, as shown above; Compound S20, as shown above; Compound S21, as shown above; Compound S22, as shown above; Compound S23, as shown above; Compound S24, as shown above; Compound S25, as shown above; Compound S26, as shown above; Compound S27, as shown above; Compound S28, as shown above; Compound S29, as shown above; Compound S30, as shown above; Compound S31, as shown above; Compound S32, as shown above; Compound S33, as shown above; Compound S34, as shown above; Compound S35, as shown above; Compound S36, as shown above; Compound S37, as shown above; Compound S38, as shown above; Compound S39, as shown above; Compound S40, as shown above; Compound S41, as shown above; Compound S42, as shown above; Compound S43, as shown above; Compound S44, as shown above; Compound S45, as shown above; Compound S46, as shown above; Compound S47, as shown above; Compound S48, as shown above; Compound S49, as shown above; Compound S50, as shown above; Compound S51, as shown above; Compound S52, as shown above; Compound S53, as shown above; Compound S54, as shown above; Compound S55, as shown above; Compound S56, as shown above; Compound S57, as shown above; Compound S58, as shown above; Compound S59, as shown above; Compound S60, as shown above; Compound S61, as shown above; Compound S62, as shown above; Compound S63, as shown above; Compound S64, as shown above; Compound S65, as shown above; Compound S66, as shown above; Compound S67, as shown above; Compound S68, as shown above; Compound S69, as shown above; Compound S70, as shown above; Compound S71, as shown above; Compound S72, as shown above; Compound S73, as shown above; Compound S74, as shown above; Compound S75, as shown above; Compound S76, as shown above; Compound S77, as shown above; Compound S78, as shown above; Compound S79, as shown above; Compound S80, as shown above; Compound S81, as shown above; Compound S82, as shown above; Compound S83, as shown above; Compound S84, as shown above; Compound S85, as shown above; Compound S86, as shown above; Compound S87, as shown above; Compound S88, as shown above; Compound S89, as shown above; Compound S90, as shown above; Compound S91, as shown above; Compound S92, as shown above; Compound S93, as shown above; Compound S94, as shown above; Compound S95, as shown above; Compound S96, as shown above; Compound S97, as shown above; Compound S98, as shown above; Compound S99, as shown above; Compound S100, as shown above; Compound S101, as shown above; Compound S102, as shown above; Compound S103, as shown above; Compound S104, as shown above; Compound S105, as shown above; Compound S106, as shown above; Compound S107, as shown above; Compound S108, as shown above; Compound S109, as shown above; Compound S110, as shown above; Compound S111, as shown above; Compound S112, as shown above; Compound S113, as shown above; Compound S114, as shown above; Compound S115, as shown above; Compound S116, as shown above; Compound S117, as shown above; Compound S118, as shown above; Compound S119, as shown above; Compound S120, as shown above; Compound S121, as shown above; Compound S122, as shown above; Compound S123, as shown above; Compound S124, as shown above; Compound S125, as shown above; Compound S126, as shown above; Compound S127, as shown above; Compound S128, as shown above; Compound S129, as shown above; Compound S130, as shown above; Compound S131, as shown above; Compound S132, as shown above; Compound S133, as shown above; Compound S134, as shown above; Compound S135, as shown above; Compound S136, as shown above; Compound S137, as shown above; Compound S138, as shown above; Compound S139, as shown above; Compound S140, as shown above; Compound S141, as shown above; Compound S142, as shown above; Compound S143, as shown above; Compound S144, as shown above; Compound S145, as shown above; Compound S146, as shown above; Compound S147, as shown above.

9. Use of a compound of any one of claims 1-8, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, for the manufacture of a medicament for the treatment of pain.

10. Use of a compound of any one of claims 1-8, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, for the manufacture of a medicament for the treatment of neuropathic pain.

11. Use of a compound of any one of claims 1-8, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, for the manufacture of a medicament for the treatment of migraine.

12. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising a compound of any one of claims 1-8, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, tautomers thereof, and a pharmaceutically acceptable carrier.

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