CA3071900C - Substituted penta- fused hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof - Google Patents

Abstract

A type of substituted penta- fused hexa-heterocyclic compounds having selective inhibition for PIKfyve kinase and the general formula (see above formula) wherein, X1, X2, X3, X4, X5, X6 may comprise a combination of: (see formula I) (see formula II) (see formula III) (see formula IV) (see formula V) (see formula VI) (see formula VII) (see formula VIII), a pharmaceutically acceptable salt and pharmaceutically acceptable solvate thereof, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PIKfyve in vivo, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.

Description

Specification SUBSTITUTED PENTA- FUSED HEXA-HETEROCYCLIC COMPOUNDS, PREPARATION METHOD THEREFOR, DRUG COMBINATION AND USE THEREOF Technical Field The invention relates to the field of medicinal chemistry, and in particular a type of compounds having selective inhibition for PlKfyve kinase, a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PlKfyve in vivo, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.

Background Art Tumor is a serious threat to human health and life. According to data released by the World Health Organization in 2003, there were 10 million malignant tumor patients worldwide in 2000, and 6.2 million deaths due to malignant tumors, accounting for 12% to 25% of the total death. It is expected that by 2020, there will be 15 million new cases worldwide each year. In recent years, targeted therapeutic drugs imatinib, crizotinib, osimertinib, etc. have been approved successively, benefiting a large number of patients. These drugs selectively inhibit key protein molecules in tumor cell growth and proliferation processes, such as BCR-ABL, ALK, EGFR, etc., and therefore have the advantages of high efficacy, small side effects, etc.

PlKfyve is a phospholipase that can further phosphorylate phosphatidylinositol-3-phosphate to form phosphatidylinositol-3,5-diphosphate. It can perform multiple regulatory functions in vivo, such as regulating release of exosomes, endocytic pathway, etc. When PlKfyve kinase activity is inhibited, cells exhibit significant vacuolation (EMBO Reports 2008, 9, 164-174). In recent years, more and more studies have shown that PlKfyve also plays an important role in promoting tumor growth and metastasis. For example, PlKfyve is involved in the invasion and migration of tumor cells (J Biol. Chern. 2011; 286, 32105-32114; Biochem. J. 2014 461, 383-390); in mouse embryonic fibroblasts overexpressing K-RasG , inhibition of PlKfyve can inhibit serum protein-dependent cell proliferation (Dev. Cell 2016, 38, 536-547); simultaneous inhibition of PlKfyve and cell surface nutrient transporters can kill LS180, SW480, MDA-MB-231 and other tumor cells (J. Clin. Invest. 2016, 126, 4088-4102); in non-Hodgkin's lymphoma cells, the action of small molecule inhibitors on PlKfyve can effectively kill a variety of such cells, and shows good therapeutic effects in animal models (Blood 2017, 129, 1768-1778); inhibition of PlKfyve can induce methuosis of tumor cells (ACS Omega 2018, 3, 6097-6103). It is expected to be applied to the treatment of refractory tumors that have no targeted drug yet (such as triple negative breast cancer) or are drug resistant. Therefore, PlKfyve has become a new target for tumor treatment, and the development of new PlKfyve inhibitors useful for the treatment of PlKfyve-mediated cancer or other related diseases, as well as 1 IEC170116PCT 85953755 refractory tumors, has good application value.

Summary of Invention After extensive and in-depth research, the inventors of the present invention have designed and synthesized a series of substituted penta- fused hexa-heterocyclic compounds having novel structures, high safety and high activity for PlKfyve kinase, and have studied antitumor activity of this novel type of derivatives.

The present invention provides a compound having the general formula: or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.

The definitions of substituents and symbols are described in detail below.

One object of the present invention is to provide a compound having PlKfyve inhibitory activity, and a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof. 2 85953755 Another object of the present invention is to provide a compound having the general formula: or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, Xi, X2, X3, X4, X5, Xe and their adjacent carbon atoms form a general formula selected from the group consisting of: R3 R3 R3 R3 || ’ III ’ IV wherein, in the formula I 1 R1 is selected from the group consisting of: 2) z< , wherein one of Z1, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; and 2a 85953755 wherein, L2 isNHCO or CONH; R5 is zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 isH orC1-C6 alkyl; R2 is selected from the group consisting of: 2) zi , wherein one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; and 2b 85953755 L2 is NHCO, CONH, NHCONH, NHCSNH or CO; R5 is: when L2 is NHCO, CONH, NHCONH or NHCSNH, R5 is , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, chloro, fluoro, methyl, trifluoromethyl, methoxy, —N trifluoromethoxy and x—/ ; or when L2 is NHCO, R5 is amino-substituted C1-C6 alkyl, wherein the C1-C6 alkyl is methyl, ethyl or propyl; or when L2 is CONH, R5 is substituted heteroaryl, wherein the substituted heteroaryl is pyrazolyl substituted by multiple C1-C6 alkyl groups; or when L2 is CO, R5 is°x-/J or optionally substituted by C1-C6 alkyl; R7 is selected from the group consisting of H, C1-C6 alkyl and halogen; R9 is H or C1-C6 alkoxy; wherein, when one of R7and R9 is a non-hydrogen group, the other is hydrogen; R3 is -H or C1-C6 alkyl; R3 L2 is NHCO or CONH; 2c 85953755 R5 is zi , wherein Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H and trifluoromethyl; or Z2 and Zsare independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and R7 isHorC1-C6 alkyl; R3 is -H or C1-C6 alkyl; R3 in the formula III m R1 is selected from the group consisting of: Br 2) zi , wherein one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; L1 is NHCONH or NHCSNH, R4 is zi , wherein one or two of Z1, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; and 2d 85953755 L2 isNHCO or CONH; R5 is zi , wherein one of Zi, Z2, Z3, Z*, Zs is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 isHorC1-C6 alkyl; R2 is selected from the group consisting of: 1) H , wherein, L2 is NHCO or CONH; R5 is zi , wherein, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, trifluoromethyl, trifluoromethoxy, methyl and methoxy; or Z2 and Z3 or Z2 and Zt, respectively, are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and —l/ N—r" R7 isH orC1-C6 alkyl; 2) amino substituted by pyridyl-methyl; and 3) s : R3 is -H or C1-C6 alkyl; R3 in the formula IV IV 2e 85953755 L2 isNHCO or CONH; R5 is zi , wherein Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, trifluoromethyl and trifluoromethoxy; orZ2 and Z3 are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and R7 isH orC1-C6 alkyl; R3 is -H orC1-C6 alkyl; in the formula V v R1 is selected from the group consisting of: 2) consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 z< , wherein one of Z1, Z2, Z3, Z4, Zs is selected from the group fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, HOOC- and C1-C6 alkoxyformyl; 2f 85953755 L1 is NHCO, CONH, NHCONH or NHCSNH; z« zA- Zs^kz^ R4 is zi , wherein one or two of Zi, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl and C1-C3 alkoxy; or Z2 R4is zi , wherein one of Z1, Z2, Z3, Z4 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino and hydroxy;/ T 1 /r5 4) H , wherein, L2 is NHCO, CONH, NHSO2, NHCONH or NHCSNH; R5 is zi , wherein one or two of Z1, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, trifluoromethyl, trifluoromethoxy, nitro, cyano, methoxy, acetamido (-NHAc), amino, methylsulfonylamino (-NHMs), R7 is H, methyl, fluoro, 5) amino substituted by unsubstituted phenyl or amino substituted by the following substituted phenyl: phenyl mono-substituted by methylsulfonylamino, or phenyl di-substituted by heterocyclyl; 6) pyridylamino; 7) C3-C6 cycloalkylamino; and 2g 85953755 R2 is selected from the group consisting of: 2) zi , wherein one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano and C1-C3 alkylsulfonyl; L2 is NHCO, CONH, NHSO2, NHCONH or NHCSNH; Z4 Z3^^K/Z5 R5 is zi , wherein one or two of Z1, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino, di-C1-C3 alkyl-substituted amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl, C1-C3 alkyl and C1-C3 alkoxy; R7 is H or C1-C6 alkyl; or ; and 2h 85953755 R3 is -H or C1-C6 alkyl; R3 in the formula VI VI L2 isNHCO or CONH; à R5 is zi , wherein one or two of Z1, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted and C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl; R7 isH orC1-C6 alkyl; R3 is -H, halogen, C1-C6 alkyl orC3-C7 cycloalkyl; L1 isNHCO or CONH; 2i 85953755 R4 is zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; or R4 is zi , wherein one of Z1, Z2, Z3, Z4 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino and hydroxy; R2 is selected from the group consisting of: I I 1 1 I 1) " or — ; and L2 isNHCO or CONH; R5 is zi , wherein one of Z1, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 is H or C1-C6 alkyl. 2j 85953755 Another object of the present invention is to provide a method for the preparation of the above compound.

Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.

Another object of the present invention is to provide use of the above compound and a pharmaceutical composition comprising the above compound in the manufacture of a medicament for preventing or treating PIKfyve-mediated cancer or other related diseases, as well as refractory tumors.

Another object of the present invention is to provide a method of treating cancer, comprising administering to a subject an effective amount of the compound or the composition of the present invention.

Description of the drawings Fig. 1 shows that the compound which inhibits PlKfyve causes vacuolation of cells. a. V-c-19 (1 pmol/L) induces vacuolation of MDA-MB-231 cells, with good time dependence. b. V-c-19 (1 pmol/L) induces vacuolation of MDA-MB-231 cells, with good concentration dependence.

Fig. 2 shows the determination of dissociation equilibrium constant Kd of compound and PlKfyve (replicate 1 and replicate 2 denote 2 replicates tested for each compound).

Fig. 3 shows that the representative compound V-c-17 which inhibits PlKfyve causes lysosomal dysfunction. Under the action of V-c-17 or the control compound apilimod, immature cathepsins A and D gradually increase, with good dose dependence.

Fig. 4 shows that the representative compound l-a-1 can effectively inhibit tumor growth in a xenograft model of triple negative breast cancer cells (MDA-MB-231). In the MDA-MB-231 xenograft mice model, the drug is administered via tail vein at doses 5 mg/kg, 20 mg/kg every day. a) The administration group can effectively inhibit the increase of tumor volume, with good dose dependence; b) the final tumor weight in the administration group is significantly smaller than that in the control group, with good dose dependence.

Fig. 5 shows that the representative compound V-c-17 can effectively inhibit tumor growth in a xenograft model of non-Hodgkin's lymphoma cells (Jeko-1). In the JeKo-1 xenograft mice model, the drug is administered via tail vein at doses 25 mg/kg once a day or twice a day. a) The administration group can effectively inhibit the increase of tumor volume, with good dose dependence; b) the final tumor weight in the administration group is significantly smaller than that in the control group, with good dose dependence.

Specific modes for carrying out the invention Various specific embodiments, modes and examples are described herein, including exemplary embodiments and definitions, to understand the claimed invention. While the following detailed description sets forth specific preferred embodiments, those stalled in the art will appreciate that these embodiments are illustrative only, and that the present invention can be practiced in other ways. For the purpose of determining infringement, the scope of the present invention will cover any one or more of the appended claims, including equivalents thereof, and elements or limitations equivalent to those recited. 3 IEC170116PCT The present invention is achieved by the following technical solutions.

In one aspect, the present invention provides a compound having the general formula: 1) substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being selected from: halogen atom, C6-C10 aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino or hydroxy, wherein the substituent is linked to the C6-C10 aryl or heteroaryl directly or optionally via NHCO, CONH, SO2NH, NHSO2, NHCONH, NHCSNH or CO; 2) substituted or unsubstituted C6-C10 arylamino, heteroarylamino, C1-C6 alkylamino, C3-C7 cycloalkylamino, C1-C6 oxygen-containing alkylamino or C3-C7 oxygen-containing cycloalkylamino, the substituent thereof being selected from: halogen atom, C6-C10 aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, Cl-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino or hydroxy, wherein the substituent is optionally linked to the C6-C10 arylamino, heteroarylamino, C1-C6 alkylamino, C3-C7 cycloalkylamino, C1-C6 oxygen-containing alkylamino, or C3-C7 oxygen-containing cycloalkylamino via NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, R1, R2 are selected from: 1) substituted or unsubstituted phenyl, pyridyl, furyl, thienyl, benzofuryl, benzothienyl, benzodioxolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrimidinyl, indolyi or quinolyl, the substituent thereof being selected from halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino or hydroxy; 4 IEC170116PCT R4 2) L‘ , wherein, L1 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH, R4 is selected from H, substituted or unsubstituted C6-C10 aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino or hydroxy C3-C7 cycloalkyl; A 31 H /RS l2 wherein, r is selectedfrom NHCO, CONH, SO2NH, NHSO2, NHCONH, NHCSNH or CO, Rs is selected from substituted or unsubstituted C6-C10 aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino or hydroxy C3-C7 cycloalkyl; y1 n 4) h , wherein, n = 0, 1 or 2‘ one of Y1, Y“ Y3 is selected from N; Rsis selected from H, halogen atom or C1-C6 alkyl; 5) methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, pyrrolidinyl, piperidyl, morpholinyl, 4-aminopiperidyl, 4-N,A/-dimethylaminopiperidyl, 3,5-dimethylmorpholinyl or /V-methylpiperazinyl; R3 is selected from H, halogen, substituted or unsubstituted alkyl or cycloalkyl, the substituent thereof being selected from halogen, amino, hydroxy or alkylsiloxy; preferably, the pharmaceutically acceptable salt is: an inorganic acid salt, selected from hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate; or an organic acid salt, selected from formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, a-ketoglutarate, a-glycerophosphate, alkyl sulfonate or aryl sulfonate; preferably, said alkyl sulfonate is methyl sulfonate or ethyl sulfonate; said aryl sulfonate is benzenesulfonate or p-toluenesulfonate and the like.

In the first aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: IEC170116PCT R3 / 1) optionally substituted heteroaryl, preferably selected from: ,s- pwherein, R1 is selected from: 3) H wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; most preferably, L2 is NHCO; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; Zs R5 is preferably zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: 6 preferably zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano; Z5 ' , •'or ' ; 2) optionally substituted C6-C10 aryl, in the case of being substituted, the substituent thereof being C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro or cyano; most preferably zi , wherein Z3, Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy, methyl; Ff more preferably z» , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy, C1-C3 alkyl; z. .R® L2 IEC170116PCT 1) optionally substituted heteroaryl, preferably selected from: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl; Z$ most preferably, R5 is being H; z< , wherein Z2 or Z4 is trifluoromethyl, the rest R7 is selected from H or C1-C6 alkyl; preferably, R7 is methyl; R2 is selected from: more preferably, R5 is z< , wherein Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy, trifluoromethyl; Z5 preferably z’ , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro or cyano; Zs fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano; Zs or 2) optionally substituted C6-C10 aryl, in the case of being substituted, the substituent thereof being C1-C6 alkyl, C1-C3 alkoxy, C1-C3 3) H L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH, NHCSNH or CO; preferably NHCO, CONH, NHCONH, NHCSNH or CO; R5 is selected from substituted or unsubstituted C6-C10 aryl, heteroaryl, more preferably z< , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy, C1-C3 alkyl, C1-C3 alkoxy; Zs Z; most preferably z< , wherein Z3, Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy, methyl, methoxy; R® _R5 1 2 7 IEC170116PCT optionally substituted heterocyclyl, C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino or hydroxy C3-C7 cycloalkyl; preferably, R5 is selected from: .z. when L2 is NHCO, CONH, NHCONH or NHCSNH, R5 is * , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano, C1-C6 alkyl substituted by optionally substituted heterocyclyl; preferably, wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, chloro, fluoro, methyl, — N-7''z ; trifluoromethyl, methoxy, trifluoromethoxy, most preferably: Z2 or Z4 is selected from the following groups, the rest being H: H, trifluoromethyl, methoxy, trifluoromethoxy, methyl, chloro, fluoro; or Z? and Z3 or Z2 and Z4, respectively, are independently selected from — trifluoromethyl, chloro or N-7''/ ; or when L2 is NHCO, R5 further is amino-substituted C1-C6 alkyl, wherein preferably the C1-C6 alkyl is methyl, ethyl or propyl, more preferably the C1-C6 alkyl is methyl; or when L2 is CONH, R5 further is substituted heteroaryl, wherein preferably the substituted heteroaryl is pyrazolyl substituted by multiple C1-C6 4-^5/ alkyl groups; most preferably the substituted heteroaryl is * ; or when L2 is CO, R5 further is optionally substituted heterocyclyl, preferably °"-' or HN'^ optionally substituted by C1-C6 alkyl, wherein preferably the heterocyclyl is R7 is selected from or , 1) H, halogen, optionally substituted heterocyclyl; 2) substituted or unsubstituted C1-C6 alkyl, the substituent thereof being optionally substituted heterocyclyl, di-C1-C3 alkyl-substituted amino; 3) di-substituted amino, the substituent thereof being selected from C1-C3 alkyl, di-C1-C3 alkylamino-substituted C1-C3 alkyl; 8 IEC170116PCT N N preferably, R7 is H, methyl, fluoro, .NN I N I , I , ^Nx-or I ; R9 is selected from H or C1-C6 alkoxy; preferably, R9 is H or methoxy; wherein, when R7and R9 both are non-hydrogen groups, they dont exist at the same time; 9 IEC170H6PCT R3 is selected from: -H or C1-C6 alkyl; preferably selected from: -H or -CH3.

In the second aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: R3 wherein, R1 is selected from: optionally substituted heteroaryl, preferably selected from: z Y 1 /rS R is selected from: H , wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; Zs R5 is preferably 2’ , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl, C1-C6 alkyl substituted by optionally substituted heterocyclyl; Zs most preferably, R5 is z’ , wherein Z2 or Z4 is selected from the10 IEC170116PCT following groups, the rest being H: H, trifluoromethyl; or Z2 and Z3 are independently selected from the following groups, the rest being H: —N N— trifluoromethyl, x—f ; R7 is selected from H or C1-C6 alkyl; preferably, R7 is methyl; h ,in its entirety, ismost preferably selected from: CF, 0 cf3 , or AA R3 is selected from: -H or C1-C6 alkyl; preferably selected from: -H or -CH3.

In the third aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: R3 in wherein, R1 is selected from: 1) optionally substituted heteroaryl, preferably selected from: * or 2) optionally substituted C6-C10 aryl, in the case of being substituted, the substituent thereof being C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro or cyano; preferably zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro or cyano; more preferably z’ , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy; 11 IEC170116PCT MM 3 OMe or most preferably, R4 is z’ , wherein Z2 or Z4 is trifluoromethyl, the rest being H; or Z2 and Z4are independently selected from the following groups, the rest being H: bromo, methoxy; R* , in its entirety, is most preferably selected from: Br more preferably, R4 is 2i , wherein Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy, trifluoromethyl; or Z2 and Z4 are independently selected from the following groups, the rest being H: bromo, methoxy, amino, hydroxy; A*A, H H ’ R4 is preferably , wherein one or two of Z^ Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl; Zs most preferably z’ , wherein Z3, Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy; ^R*L’ , wherein,L1 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or 3) NHCSNH; L1 preferably NHCONH or NHCSNH, R4 is selected from H or substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; & z3 % 4) H , wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; most preferably, L2 is CONH; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; 12 IEC170116PCT z« z^P* R5 is preferably zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl; more preferably, R is * , wherein Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy, trifluoromethyl; z« Za^^Ay25 zJyY most preferably, R5 is being H; z, , wherein Z2 or Z4 is trifluoromethyl, the rest R7 is selected from H or C1-C6 alkyl; preferably, R7 is methyl; R2 is selected from: R‘ more preferably, Rs is z’ , wherein, Z2 or Z4 is selected from the following groups, the rest being H: H, trifluoromethyl, trifluoromethoxy, methyl, methoxy; or Z2 and Z3 or Z2and Z4, respectively, are independently selected R is preferably 2i , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl, C1-C6 alkyl substituted by optionally substituted heterocyclyl; Zs .R® L2 1) H .wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; zs —N N— from the following groups, the rest z< being H: trifluoromethyl, '—f ; _ 2^0/. Za-^A/2® Z2 J z most preferably, R is * , wherein, Z2 or Z4 is trifluoromethyl, the rest being H; or Z2 and Z3 or Z2 and Z4, respectively, are independently selected from the following groups, the rest being H: trifluoromethyl, /—\ R7 is selected from H or C1-C6 alkyl; preferably, R7 is methyl; 13 IEC170116PCT 2) amino optionally substituted by heteroaryl-C1-C6 alkyl; preferably amino N=x HN~r /=\ substituted by pyridyl-methyl; most preferably or N J Ok J ; 3) optionally substituted heteroaryl, preferably selected from: ; ; 4 A—' R3 is selected from: -H or C1-C6 alkyl; preferably selected from: -H or -CH3.

In the fourth aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: R3 XI R2 IV wherein, R1 is selected from: optionally substituted heteroaryl, preferably selected from: z T 1 xrS R is selected from: H , wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; R5 is preferably z< , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, C1-C6 alkyl substituted by optionally substituted heterocyclyl; 14 IEC170116PCT most preferably, R5 is z< , wherein Z2 or Z4 is selected from the following groups, the rest being H: H, trifluoromethyl, trifluoromethoxy; or Z2 and Z3are independently selected from the following groups, the rest being H: trifluoromethyl, —f ; R7 is selected from H or C1-C6 alkyl; preferably, R7 is methyl; , in its entirety, is most preferably selected from: In the fifth aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: V wherein, R1 is selected from: 2) optionally substituted C6-C10 aryl, in the case of being substituted, the substituent thereof being C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano, HOOC- or C1-C6 alkoxyformyl; IEC170116PCT Zs more preferably , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, fluoro, chloro, amino, hydroxy, C1-C3 alkyl, HOOC-, ethoxyformyl (EtOOC-); Z3 preferably z* , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, HOOC-, C1-C6 alkoxyformyl; Zs most preferably, R4 is zi , wherein Z2 or Z4 or Z3 is selected from the following groups, the rest being H: H, chloro, amino, trifluoromethyl; or Zi and Z4 are independently selected from the following groups, the rest being H: bromo, methoxy; or R4 is preferably * , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl, C1-C3 alkoxy; z5 preferably, R4 is z' , wherein Z2 is selected from the following groups, the R4 is preferably zi , wherein one of Z1.Z2.Z3.Z4 is selected from the following groups, the rest being H: H, halogen, amino, hydroxy; more z, z2 most preferably zi , wherein Z3, Z2 or Z4 is selected from the following groups, the rest being H: H, chloro, amino, hydroxy, HOOC-, ethoxyformyl (EtOOC-); zr4*-1 , wherein, 3) L1 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L1 is NHCO, CONH, NHCONH or NHCSNH; R4 is selected from H, substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted pyridyl; z. Zs 16 IEC170116PCT rest being H: H, chloro, amino, hydroxy; most preferably, R4 is wherein Z2 is amino, the rest being H; Zl in its entirety, is most preferably selected from: 4) H , wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is selected from NHCO, CONH, NHSO2, NHCONH or NHCSNH, R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; XL R is preferably * , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl, C1-C3 alkoxy, C1-C6 amido, C1-C6 alkylsulfamido, C1-C3 fluorine-containing alkoxy, nitro, cyano, C1-C6 alkyl substituted by optionally substituted heterocyclyl, optionally substituted heteroaryl; XTR is more preferably z’ , wherein one or two of Z1, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, fluoro, chloro, trifluoromethyl, trifluoromethoxy, nitro, cyano, methoxy, acetamido 17 IEC170116PCT (-NHAc), amino, methylsulfonylamino (-NHMs), most preferably, R5 is wherein, Z2 or Z4 is H or -OCF3; or Z3 is H, -NO2, -CN or -OMe; or Z2 or one of Z4, Z3 is H, -CF3 or -NHAc; or one of Zi and Z5, or one of Z2 and Z4, or Z3 is H, -NH2 or -NHMs; or Z2 and Z4 are independently selected from -CF3 or N ; or Z2 and Z3 are — N ~~ '' independently selected from -CF3 or x ' ; or Z1 and Z4 are independently selected from -CF3, -OMe, -F or -Cl; the rest being H; R7 is selected from 1) H, optionally substituted heterocyclyl, C1-C6 alkoxy; 2) substituted or unsubstituted C1-C6 alkyl, the substituent thereof being optionally substituted heterocyclyl, di-C1-C3 alkyl-substituted amino; 3) di-substituted amino, the substituent thereof being selected from C1-C3 alkyl, di-C1-C3 alkylamino-substituted C1-C3 alkyl; preferably, R7 is H, methyl, methoxy, 18 IEC170116PCT ca 03071900 2020-02-03 19 IEC170H6PCT ca 03071900 2020-02-03 H N. most preferably selected from: NHM» or 5) amino substituted by optionally substituted phenyl, preferably amino substituted by unsubstituted phenyl or amino substituted by the following substituted phenyl: phenyl mono-substituted by methylsulfonylamino, phenyl di-substituted by heterocyclyl; IEC170116PCT 6) heteroaryl-substituted amino, preferably pyridylamino, most preferably: HN^ HN^/ * , HN 7) C3-C6 cycloalkylamino, preferably or 8) optionally substituted heterocyclyl, preferably R2 is selected from: 1) optionally substituted heteroaryl, 2) optionally substituted C6-C10 aryl, in the case of being substituted, the substituent thereof being C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano or C1-C6 alkylsulfonyl; preferably z’ , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano, C1-C3 alkylsulfonyl; more preferably zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy, C1-C3 alkoxy, C1-C3 alkylsulfonyl; most preferably z’ , wherein Z3is selected from the following groups, the rest being H: H, fluoro, chloro, methoxy, methylsulfonyl (-Ms); 21 IEC170116PCT z5 trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted N ; C1-C6 alkyl, C1-C3 alkyl or C1-C3 alkoxy substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl; Z„Zs Zj most preferably, R5 is z, , wherein, Z2 or Z4 is selected from the following groups, the rest being H: H, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, amino, dimethylamino, trifluoromethoxy, hydroxy; or Z2 and Z3 or Z2 and A. respectively, are independently selected from the following R5 is more preferably z' , wherein one or two of Zi, Z2, Z3, Z4, Zg are independently selected from the following groups, the rest being H: H, fluoro, chloro, bromo, amino, di-C1-C3 alkyl-substituted amino, hydroxy, —N N-^ 1 ' U Z' groups, the rest being H: trifluoromethyl, ; R7 R5 is preferably z’ , wherein one or two of Zi, Z2| Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, di-C1-C3 alkyl-substituted amino, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, optionally substituted heteroaryl, C1-C6 alkyl substituted by optionally substituted heterocyclyl; 3) H , wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH, NHCSNH; preferably, L2 is NHCO, CONH, NHSO2, NHCONH, NHCSNH; Rs is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; Zj _RS L2 R7 is selected from H or C1-C6 alkyl; preferably, R7 is H or methyl; H , in its entirety, is most preferably selected from: 22 IEC170116PCT 4) amino optionally substituted by C3-C7 cycloalkyl, amino substituted by optionally substituted heteroaryl, or amino substituted by C1-C6 alkyl optionally substituted by heteroaryl; preferably amino substituted by the following groups: C3-C6 cydoalkyl, heteroaryl optionally substituted by C1-C6 alkyl or C1-C6 alkyl optionally substituted by heteroaryl; most preferably selected from the following substituted amino: arNl Cl üXi -xy I I I I I «■**"«* I 'or ; 5) optionally substituted heterocyclyl, 23 IEC170116PCT preferably heterocyclyl substituted by di-(C1-C6 alkyl)amino or heterocyclyl substituted by C1-C6 alkyl-substituted heteroaryl, most preferably selected from: R3 is selected from: -H or C1-C6 alkyl; preferably selected from: -H or -CH3.

In the sixth aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: VI wherein, R1 is selected from: optionally substituted heteroaryl, preferably selected from: R2 is selected from: H , wherein, L2 is selected from NHCO, CONH, SO2NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; R5 is preferably zi , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, optionally substituted heteroaryl, C1-C6 alkyl substituted by optionally substituted heterocyclyl; 4. R5 is more preferably zi .wherein one or two of Z1.Z2.Z3, Z4, Z5 are independently selected from the following groups, the rest being H: H, fluoro, chloro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted t C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl; 24 IEC170116PCT Z4 5 Z^' most preferably, Rû is , wherein, Z2 or Z, is selected from the following groups, the rest being H: H, fluoro, trifluoromethyl, trifluoromethoxy; or Z2 and Z3 or Z2 and Z4, respectively, are independently selected from the 1 1 —n N following groups, the rest being H: trifluoromethyl, —/ R3 is selected from: -H, halogen, C1-C6 alkyl or C3-C7 cycloalkyl; preferably selected from: -H, fluoro, chloro, C1-C3 alkyl or C3-C7 cycloalkyl; most preferably selected from: -H, -Br, -CH3 or In the seventh aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: wherein, VII IEC170116PCT R1 is selected from: L1 f3c or R2 is selected from: its entirety, is most preferably selected from: h2n r4 , wherein, R4 is preferably , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 z.Zs Zs fluorine-containing alkyl; more preferably, R4 is z> , wherein Z2 or Z4 is preferably, R4 is zi , wherein Z2 is selected from the following groups, the z, z Z* selected from the following groups, the rest being H: H, chloro, amino, hydroxy, & Zj zs L1 is selected from NHCO or CONH; L1 preferably NHCO; R4 is selected from H, substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted pyridyl; Zs rest being H: H, chloro, amino, hydroxy; most preferably, R4 is wherein Z2 is amino, the rest being H; z* trifluoromethyl; most preferably, R. is * zi , wherein Z2 or Z4 is trifluoromethyl, the rest being H; or Zj R4 is preferably z, , wherein one of Zi,Z2, Z3, Z4 is selected from the following groups, the rest being H: H, halogen, amino, hydroxy; more Za z2 Z, 1) amino optionally substituted by C3-C7 cycloalkyl or amino substituted by optionally substituted heteroaryl; preferably selected from amino substituted by cyclopropyl or amino substituted by heteroaryl that is optionally substituted by C1-C6 alkyl; HN^ most preferably selected from the following substituted amino: 26 IEC170116PCT 2) optionally substituted heterocyclyl, preferably selected from heterocyclyl substituted by di-(C1-C6 alkyl)amino or heterocyclyl substituted by C1-C6 alkyl, In the eighth aspect, according to a specific embodiment of the present invention, the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof has the following structure: VIII R® H L2 , in its entirety, is most preferably selected from:27 wherein, R1 is selected from: optionally substituted heteroaryl, preferably selected from: yy fSlft L2 is selected from NHCO, CONH, SO^NH, NHSO2, NHCONH or NHCSNH; preferably, L2 is NHCO or CONH; R5 is selected from substituted or unsubstituted C6-C10 aryl, preferably substituted or unsubstituted phenyl; z.

Zj Z5 R5 is preferably z« , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl; z/yA most preferably, R5 is zi , wherein Z2 or Z< is selected from the following groups, the rest being H: H, trifluoromethyl; R7 is selected from H or C1-C6 alkyl; preferably, R7 is H or methyl; R7 .R5 IEC170116PCT Unless otherwise indicated, the above groups and substituents have the ordinary meanings in the field of medicinal chemistry.

It should be noted that C1-C6 oxygen-containing alkyl refers to a group in which C1-C6 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxymethyl and the like. Similarly, C1-C3 oxygen-containing alkyl refers to a group in which C1-C3 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups.

The term “aryl” or “C6-C10 aryl” refers to a C6-10 mono-, di-or poly-carbocyclic hydrocarbon having from 1 to 2 ring systems which are optionally further fused or attached to each other by a single bond, wherein at least one of the carbon rings is “aromatic", and the term “aromatic” refers to a fully conjugated re-electron bond system. The aryl ring may be optionally further fused or attached to aromatic or non-aromatic carbocyclic rings or heterocyclic rings. Non-limiting examples of the aryl group are phenyl, a- or p-naphthyl.

The term “heteroaryl” refers to an aromatic heterocyclic ring, which is usually a 5- to 8-membered heterocyclic ring having from 1 to 3 heteroatoms selected from N, O or S; a heteroaryl ring may be optionally further fused or attached to aromatic or non-aromatic carbocyclic rings or heterocyclic rings. Non-limiting examples of the heteroaryl group are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuryl, benzothienyl, benzo 1,3-dioxolane (benzodioxolane), isoindolinyl, benzoimidazolyl, indazolyl, quinolyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-indolinyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.

The term “C6-C10 arylamino” refers to a group formed by attaching a -NHor nitrogen-containing group to the “aryl” or “C6-C10 aryl” defined above, the attaching position of the group to the rest of the compound being on the -NHor nitrogen-containing group.

Similarly, the term “heteroarylamino” refers to a group formed by attaching a -NH- or nitrogen-containing group to the “heteroaryl" defined above, the attaching position of the group to the rest of the compound being on the -NHor nitrogen-containing group.

The term “heterocyclyl” (also referred to as “heterocycloalkyl”) refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of the heterocyclic group are, for example, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, 28 IEC170116PCT thiazolidinyl, dihydrofuryl, tetrahydrofuryl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl and the like.

The term “optionally substituted heterocyclyl” refers to the group formed in the situation the above-mentioned "heterocyclyl” is substituted by one or more “C1-C6 alkyl”, “C1-C3 alkyl”, “C3-C6 cycloalkyl”.

The term “C1-C6 alkyl" refers to any straight-chain or branched-chain group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and the like.

The term “C1-C3 alkyl” refers to any straight-chain or branched-chain group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

Unless otherwise indicated, the term “C3-C7 cycloalkyI” refers to a hydrocarbon of a 3-7 membered monocyclic system having a saturated ring, and the C3-C7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Similarly, the term “C3-C6 cycloalkyl” refers to a hydrocarbon of a 3-6 membered monocyclic system having a saturated ring, and the C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term “C1-C6 fluorine-containing alkyl” refers to a group in which C1-C6 alkyl skeleton is substituted by one or more fluoro groups, for example, tetrafluoromethane, monofluoromethyl, difluoroethyl, trifluoromethyl, and the like.

Similarly, the term “C1-C3 fluorine-containing alkyl” refers to a group in which C1-C3 alkyl skeleton is substituted by one or more fluoro groups, for example, tetrafluoromethane, monofluoromethyl, difluoroethyl, trifluoromethyi, and the like.

The term “C1-C6 acyl” refers to -C(=O)-H or -C(=O)-C1-C5 alkyl, for example, formyl, acetyl, propionyl, butyryl, and the like.

The term “C1-C6 amido” refers to H-C (=O)-NH- or -NH-C (=O)-C1-C5 alkyl, for example, formamido, acetamido, propionamido, butyramido and the like.

The term “C1-C6 alkylsulfonylamino” refers to -NH-S (=O)a-C1-C6 alkyl, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino and the like.

The terms "alkoxy”, “cycloalkoxy” and derivatives thereof refer to any of the above-mentioned alkyl (for example, Ci-Cg alkyl, C1-C3 alkyl and the like), cycloalkyl (for example, C3-C6 cycloalkyl), which is attached to the remainder of molecules through oxygen atom (-O-).

From all of the above description, it will be apparent to those skilled in the art that any group whose name is a compounded name, for example, “fluorine-containing oxygen-containing alkyl" shall mean to conventionally construct from the moiety that is derived, such as the oxygen-containing alkyl substituted by the fluoro, wherein the alkyl is as defined above. Similarly, “fluorine-containing alkoxy” is another example. For still another example, “arylamino” shall mean to conventionally construct from the moiety that is derived, such as the amino substituted by the aryl, wherein the aryl is as defined above. Similarly, the meaning of “heteroarylamino" can be understood.

Similarly, any term such as alkylamino, dialkylamino, alkoxycarbonyl, 29 IEC170116PCT alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclyl carbonylamino, cycloalkyloxycarbonyl, alkoxyformyl and the like includes groups, wherein alkyl, alkoxy, aryl, C3-C7 cycloalkyl and heterocyclyl moieties are as defined above.

According to the present invention and unless otherwise provided, any of the above groups may optionally be substituted at any of its free positions by one or more groups, for example by 1 to 6 groups, the groups being independently selected from: halogen atom, nitro, oxo (=O), cyano, C1-C6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxy alkyl, hydroxyalkylamino, hydroxyheterocyclyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, heterocyclyl-aIkyI, C3-C7 cycloalkyl, cycloalkyl-alkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-heterocyclyl, alkyl-cydoalkyl, alkyl-aryl-alkyl, alkyl-heteroaryl-alkyl, alkyl-heterocyclyl-alkyl, alkyl-cycloalkyl-alkyl, alkyl-heterocyclyl-heterocyclyl, heterocyclyl-heterocyclyl, heterocyclyl-alkyl-heterocyclyl, heterocyclyl-alkylamino, alkyl-heterocyclyl-alkyl-amino, hydroxy, alkoxy, aryloxy, heterocydyloxy, alkyl-heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino, ureido, alkylamino, amino-alkylamino, dialkylamino, dialkylamino-heterocyclyl, dialkylamino-alkylamino, arylamino, aryl alkylamino, diarylamino, heterocyclylamino, alkyl-heterocyclylamino, alkyl-heterocyclylcarbonyl, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkyl-heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, alkoxycarbonylamino-alkylamino, alkoxycarbonylheterocyclyl-alkylamino, alkoxy-aryl-alkyl, hydroxyamino-carbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate.

Further, if appropriate, each of the above substituents may be further substituted by one or more of the above-exemplified groups.

In this respect, the term “halogen atom” refers to a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

The term “cyano” refers to -CN residue. The term “nitro” refers to -NO2 group.

As used herein, unless otherwise indicated, the term "prodrug” refers to a derivative that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs can become active compounds only by carrying out the reaction under biological conditions, or they are inactive in their non-reacted form. Prodrugs can be generally prepared using known methods, for example, those methods described in 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed. 5th edition).

IEC170116PCT Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.

The term “treatment” as used herein generally refers to obtaining the desired pharmacological and/or physiological effect. The effect can be preventive according to complete or partial prevention of disease or its symptoms; and/or can be therapeutic according to partial or complete stabilization or cure of disease and/or side effects due to the disease. The term “treatment" as used herein encompasses any treatment on a patient's disease, including: (a) preventing the disease or symptom that occurs in a patient who is susceptible to the disease or symptom but not yet diagnosed to suffer from the disease; (b) suppressing symptoms of the disease, i.e., stopping its development; or (c) relieving symptoms of the disease, i.e., causing degeneration of the disease or symptom.

According to a specific embodiment of the present invention relating to the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, the compound is one of the compounds described in the examples below.

In another aspect, the present invention provides a pharmaceutical composition comprising the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate thereof according to any one of the above embodiments, and a pharmaceutically acceptable carrier, diluent or excipient.

Methods for preparing a pharmaceutical composition comprising a certain amount of an active ingredient, are known or are obvious for a person skilled in the art according to the contents as disclosed in the invention. For example, as described in REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), methods for preparing a pharmaceutical composition comprise incorporating a suitable pharmaceutically acceptable excipient, carrier, diluent, etc.

The known methods for preparing a pharmaceutical preparation according to the invention include the conventional mixing, dissolving or freeze-drying methods. The compound according to the invention can be used to prepare into a pharmaceutical composition, which is administered to a patient by various routes suitable for the selected administration mode, for example, oral, or parenteral route (intravenous, intramuscular, topical, or subcutaneous route).

Therefore, the compound of the invention in combination with a pharmaceutically acceptable carrier (such as an inert diluent or an assimilable edible carrier) can be administered systemically, e.g., orally. They can be encapsulated into a hard or soft shell gelatin capsule, or pressed into a tablet. For the treatment by oral administration, an active compound can be combined with one or more excipients, and be used in a form of a deglutible tablet, a buccal tablet, a troche, a capsule, an elixir, a suspension, a syrup, a wafer, etc. The composition and preparation shall comprise at least 0.1% of an active compound. The ratio of the composition to the preparation can be varied certainly, and the composition can account for about 1 wt% to about 99 wt% of 31 IEC170116PCT a given unit dosage form. In such a therapeutically active composition, the active compound is in an amount sufficient to obtain an effective dosage level.

A tablet, a troche, a pill, a capsule, and the like may include: a binder, such as tragacanth gum, arabic gum, maize starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrant, such as maize starch, potato starch, and alginic acid etc; a lubricant, such as magnesium stearate; and a sweeting agent, such as sucrose, fructose, lactose or aspartame; or a flavoring agent, such as peppermint, wintergreen oil or cherry flavor. When the unit dosage form is a capsule, in addition to the above types of materials, it may comprise a liquid carrier, such as vegetable oil or polyethylene glycol. Various other materials may be present as a coating or change the physical form of a solid unit dosage form in other manners. For example, a tablet, a pill or a capsule may be coated with gelatin, wax, shellac or sugar etc. A syrup or elixir can comprise an active compound, sucrose or fructose as a sweeting agent, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate as preservative, a dye and a flavoring agent (such as a cherry flavor or an orange flavor). Certainly, any material for preparing any unit dosage form should be pharmaceutically acceptable and be substantively not toxic in its applied amount. In addition, an active compound can be incorporated into a sustained release preparation and a sustained release device.

An active compound can also be administered intravenously or intraperitoneally by infusion or injection. An aqueous solution of an active compound or a salt thereof can be prepared, optionally, by mixing it with a non-toxic surfactant. A dispersible formulation in glycerol, liquid polyethylene glycol, glycerin triacetate and a mixture thereof and in oil can also be prepared. Under the common conditions of storage and use, the preparations comprise a preservative in order to suppress the growth of microbes.

A pharmaceutical dosage form suitable for injection or infusion can include a sterile aqueous solution or a dispersible formulation or a sterile powder comprising an active ingredient (optionally encapsulated into a liposome) of an immediate preparation such as a solution or a dispersible formulation suitable for sterile injection or infusion. Under all the conditions, the final dosage form shall be sterile, liquid and stable under the production and storage conditions. A liquid carrier can be a solution or a liquid disperse medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid macrogol, etc), vegetable oil, a non-toxic glyceride and a suitable mixture thereof. A suitable fluidity can be retained, for example, by the formation of liposome, by retaining the desired particle size in the presence of a dispersing agent, or by using a surfactant. The effect of suppressing microbes can be obtained by various antibacterial agents and antifungal agents (such as paraben, chlorbutol, phenol, sorbic acid, and thiomersal, etc). In many conditions, an isotonizing agent, such as sugar, buffer agent or NaCI, is preferably comprised. By the use of a composition of delayed absorbents (e.g., aluminium monostearate and gelatin), an extended absorption of an injectable composition can be obtained. 32 IEC170H6PCT A sterile injectable solution can be prepared by mixing a desired amount of an active compound in a suitable solvent with the desired various other ingredients as listed above, and then performing filtration and sterilization. In the case of a sterile powder for the preparation of a sterile injectable solution, the preferred preparation method is vacuum drying and freeze drying techniques, which will result in the production of the powder of the active ingredient and any other desired ingredient present in the previous sterile filtration solution.

A useful solid carrier includes crushed solid (such as talc, clay, microcrystalline cellulose, silicon dioxide, and aluminum oxide etc). A useful liquid carrier includes water, ethanol or ethylene glycol or water-ethanol/ ethylene glycol mixture, in which the compound of the invention can be dissolved or dispersed in an effective amount, optionally, with the aid of a non-toxic surfactant. An adjuvant (such as a flavor) and an additional antimicrobial agent can be added to optimize the property for a given use.

A thickener (such as synthetic polymer, fatty acid, fatty acid salt and ester, fatty alcohol, modified cellulose or modified inorganic material) can also be used with a liquid carrier to form a coatable paste, gel, ointment, soap and the like, and be directly applied to the skin of a user.

As used herein, the term “subject” refers to a patient or other animal that receives a compound or pharmaceutical composition of the present invention to treat, prevent, ameliorate and/or alleviate the disease or condition mentioned in the present invention, particularly a mammal, for example, a human, a dog, a monkey, a cow, a horse and the like.

As used herein, the term “effective amount” or “required amount" refers to a dose that can achieve in a subject the treatment, prevention, amelioration and/or alleviation of the disease or condition mentioned in the present invention.

A therapeutically effective amount of a compound or an active salt or derivative thereof not only depends on the specific salt selected, but also depends on the administration mode, the nature of the disease to be treated and the age and state of a patient, and finally depends on the decision made by an attending physician or a clinical physician.

Above preparation can be present in a unit dosage form, which is a physical dispersion unit comprising a unit dose, suitable for administration to a human body and other mammalian body. A unit dosage form can be capsule(s) or tablet(s). Depending on the particular treatment involved, the amount of an active ingredient in a unit dose can be varied or adjusted between about 0.1 and about 1000 mg or more.

In addition, the present invention further includes use of various new drug dosage forms such as milk liposomes, microspheres and nanospheres, for example, medicaments prepared with the use of a particulate dispersion system including polymeric micelles, nanoemulsions, submicroemulsions, microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles) and the like.

In another aspect, the present invention further provides a preparation method of the compound according to any of the above embodiments, comprising the following steps: 33 IEC170116PCT reaction conditions: (a) coupling reaction of carbon-carbon bond formation of heteroaryl chloride and boronic acid or boronic acid ester catalyzed by metal palladium, or coupling reaction of carbon-nitrogen bond formation of heteroaryl chloride and amine compound catalyzed by metal palladium, or nucleophilic substitution reaction of heteroaryl chloride with amine compound under alkaline condition, or nucleophilic substitution reaction of heteroaryl chloride with amine compound under acidic condition; (b) coupling reaction of carbon-carbon bond formation of heteroaryl chloride and boronic acid or boronic acid ester catalyzed by metal palladium, or coupling reaction of carbon-nitrogen bond formation of heteroaryl chloride and amine compound catalyzed by metal palladium, or nucleophilic substitution reaction of heteroaryl chloride with amine compound under acidic condition. wherein, the heteroaryl chloride includes the following types: the boronic acid or boronic acid ester is selected from substituted or unsubstituted C6-C10 aryl or heteroaryl boronic acid or boronic acid ester; the amine compound is selected from substituted or unsubstituted C6-C10 arylamine, heteroarylamine, C1-C6 alkylamine, C3-C7 cycloalkylamine, C1-C6 34 IEC170116PCT 85953755 oxygen-containing alkylamine or C3-C7 oxygen-containing cycloalkylamine. See above for details.

The metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or tris(dibenzylideneacetone) dipalladium; the alkaline condition refers to a condition in which any of the following substances exists: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; the acidic condition refers to a condition in which any of the following substances exists: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluene sulfonic acid, camphorsulfonic acid.

In another aspect, the present invention further provides use of the compound according to any one of the above embodiments, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a pharmaceutical composition comprising the compound in the manufacture of a medicament for preventing or treating PlKfyve-mediated cancers and other diseases.

Experimental Section Regarding the examples described below, the compounds of the present invention are synthesized using the methods described herein or other methods well known in the art.

General methods of purification and analysis Thin layer chromatography was carried out on a silica gel GF254 precoated plate (Qingdao Marine Chemical Plant). Column chromatography was carried out by silica gel (300-400 mesh, Yantai Zhifu Huangwu Silica Gel Development Test Factory) under medium pressure or by a pre-packed silica gel cartridge (ISCO or Welch) with the use of an ISCO Combiflash Rf200 rapid purification system. The ingredient was visualized by UV light (X: 254 nm) or iodine vapor. When necessary, the compound was prepared by preparative HPLC and purified by a Waters® Symmetry C18 (19 x 50 mm, 5 p.m) column or a Waters® X Terra RP 18 (30 x 150 mm, 5 pm) column, wherein a Waters® preparative HPLC 600 equipped with a 996 Waters® PDA detector and Micromass mod. ZMD single quadrupole mass spectrometry (electrospray ionization, cationic mode) were used. Methodi: Phase A: 0.1% TFA/MeOH 95/5; Phase B: MeOH/H2O 95/5. Gradient: proceeding at 10 to 90% B for 8 min, keeping at 90% B for 2 min; flow rate 20 mL/min. Method 2: Phase A: 0.05% NH4OH/MeOH 95/5; Phase B: MeOH/H2O 95/5. Gradient: proceeding at 10 to 100% B for 8 min, keeping at 100% B for 2 min. Flow rate 20 mL/min. 1H-NMR spectra were recorded via a Broker Avance 600 spectrometer (for 1H) operated at 600 MHz. Chemical shift (6) was reported in parts per million (ppm) and coupling constant (J) in Hz. The tetramethylsilane signal was used as a reference (0= 0 ppm). The following abbreviations were used for peak splitting: s = singlet; br. s. = broad signal; d = doublet; t = triplet; m = multiplet; dd = doublet of doublets. 85953755 Electrospray (ESI) mass spectra were obtained via Finnigan LCQ ion trap.

Unless otherwise indicated, all final compounds were homogeneous (with purity not less than 95%), as determined by high performance liquid chromatography (HPLC). HPLC-UV-MS analysis for evaluation of compound purity was performed by combining an ion trap MS device and an HPLC system SSP4000 (Thermo Separation Products) equipped with an autosampler LC Pal (CTC Analytics) and a UV6000LP diode array detector (UV detection 215-400 nm). Device control, data acquisition and processing were performed with Xcalibur 1.2 software (Finnigan). HPLC chromatography was carried out at room temperature and a flow rate of 1 mL/min using a Waters® X Terra RP 18 column (4.6 x 50 mm; 3.5 pm). Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 90:10, mobile phase B was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; proceeding at a gradient of 0 to 100% B for 7 min and then keeping at 100% B for 2 min before rebalancing.

Reagent purification was carried out in accordance with the book Purification of Laboratory Chemicals (Perrin, D. D., Armarego, W. L. F. and Perrins Eds, D. R.; Pergamon Press: Oxford, 1980). Petroleum ether was 60-90°C fraction, ethyl acetate, methanol and dichloromethane were all analytically pure.

Mode of carrying out the invention Some of the raw materials and intermediates involved in the synthesis process are described below: 1. ci CAS: 5912-18-5, Efe, Shanghai; 2. ci obtained from the reaction of 1 and methyl iodide (CAS:74-88-4, Xiya Reagent, Shandong); SEM Cl M - 3. ci obtained from the reaction of 1 and 2-(trimethylsilyl) ethoxymethyl chloride (CAS:76513-69-4, Efe, Shanghai); 4. ci CAS: 90213-66-4 Shuya, Shanghai; 36 obtained from the reaction of 4 and methyl iodide (CAS:74-88-4, Xiya Reagent, Shandong); 6. 7. 8.

CIX.NX.NH2 XI ycHo ci CAS: 50270-27-4, Bide, Shanghai; ci CAS: 5451-40-1, Bide, Shanghai; ci obtained from the reaction of 7 and methyl iodide (CAS:74-88-4, Xiya Reagent, Shandong); CAS: 63200-54-4, PharmaBlock, Nanjing, Jiangsu; obtained from the reaction of 9 and methyl iodide (CAS:74-88-4, Xiya Reagent, Shandong); Cl 11. obtained from the reaction of 9 and 2-(trimethylsilyl) ethoxymethyl chloride (CAS:76513-69-4, Efe, Shanghai); CAS: 63744-22-9, Shuya, Shanghai; CAS: 16234-14-3, PharmaBlock, Nanjing, Jiangsu; CAS: 18740-39-1, Chemlin, Jiangsu;. 37 IEC170116PCT obtained by the steps of reacting 4-methyl-3-nitroaniline (CAS: 99-55-8, Energy, Shanghai) and m-trifluoromethylbenzoyl chloride (CAS: 2251-65-2, Energy, Shanghai) to , and then reducing nitro; The following intermediates are obtained in a similar manner: The involved raw materials are: p-trifluoromethylbenzoyl chloride (CAS: 329-15-7, Energy, Shanghai), 3-methyl-4-nitroaniline (CAS: 611-05-2, Energy, Shanghai), m-nitroaniline (CAS: 99-09-2, Energy, Shanghai), p-acetylaminobenzoyl chloride (CAS: 16331-48-9, Energy, Shanghai), p-cyanobenzoyl chloride (CAS: 6068-72-0, Energy, Shanghai), p-nitrobenzoyl chloride (CAS: 122-04-3, Energy, Shanghai), m-trifluoromethylphenylsulfonyl chloride (CAS: 777-44-6, Energy, Shanghai). obtained by the steps of reacting 3-nitro-4-methylbenzoic acid (CAS: 96-98-0, Energy, Shanghai) and m-trifluoromethylaniline (CAS: 98-16-8, Energy, Shanghai) to obtain Ci ? , and then reducing nitro, The following intermediates are obtained in a similar manner: 38 IEC170116PCT CP3 The involved raw materials are: m-nitrobenzoic acid (CAS: 121-92-6, Energy, Shanghai), m-bis(trifluoromethyl)aniline (CAS: 328-74-5, Energy, Shanghai), m-methoxyaniline (CAS: 536-90-3, Energy, Shanghai), m-trifluoromethoxyaniline (CAS: 1535-73-5, Energy, Shanghai), m-toluidine (CAS: 108-44-1, Energy, Shanghai), 3-methylsulfonylaminoaniline (CAS: 37045-73-1, Accela ChemBio, Shanghai), m-chloroaniline (CAS: 108-42-9, Energy, Shanghai), 3-amino-4-chlorotrifluorotoluene (CAS: 121-50-6, Energy, Shanghai), 2-fluoro-5-trifluoromethylaniline (CAS: 535-52-4, Energy, Shanghai), 2-methoxy-5-trifluoromethylaniline (CAS: 349-65-5, Energy, Shanghai), m-fluoroaniline (CAS: 372-19-0, Energy, Shanghai), 4-methoxy-3-nitrobenzoic acid (CAS: 89-41-8, Bidepharm, Shanghai), 2-methoxy-5-nitrobenzoic acid (CAS: 40751-89-1, Shuya, Shanghai), 4-fluoro-3-nitrobenzoic acid (CAS: 453-71-4, Shuya, Shanghai), 5-amino-1,3-dimethylpyrazole (CAS: 3524-32-1, J&K, Beijing), morpholine (CAS: 110-91-8, Aladdin, Shanghai), Af-methylpiperazine (CAS: 109-01-3, Energy, Shanghai), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (CAS: 641571-11-1, Bidepharm, Shanghai), 853296-94-3, Pharmlanch, Shanghai), (CAS: (CAS: 39 IEC170116PCT obtained by the steps of reacting (CAS: 859213-39-1, J&K, Beijing) and 2-amino-4-nitrotoluene (CAS: 99-55-8, Energy, Shanghai) to obtain Br , then reacting the above obtained product with M-methylpiperazine (CAS: 109-01-3, Energy, Shanghai) to obtain , and finally reducing nitro; 18. obtained by the steps of reacting m-trifluoromethylaniline (CAS: 98-16-8, Energy, Shanghai) and bis(trichloromethyl)carbonate (CAS: 32315-10-9, Energy, Shanghai) to obtain m-trifluoromethylphenyl thioisocyanate, then reacting the above obtained product with 4-methyl-3-nitroaniline (CAS: 99-55-8, Energy, Shanghai) to L Ji u JlJl O2N N N ^^ CF3 obtain h h , and finally reducing nitro; The following intermediates are obtained in a similar manner: The involved raw materials are: 2-chloro-5-aminotrifluorotoluene (CAS: 320-51-4, Efe, Shanghai), 5-bromo-2-methoxyaniline (CAS: 6358-77-6, Bidepharm, Shanghai), thiophosgen (CAS: 463-71-8, Energy, Shanghai); 19. pyridine-3-boronic acid (CAS: 1692-25-7, Energy, Shanghai); 20. pyridine-4-boronic acid (CAS: 1692-15-5, Energy, Shanghai); IEC170116PCT 21. phenylboronic acid (CAS: 98-80-6, Adamas, Switzerland); 22. p-methylphenylboronic acid (CAS: 5720-05-8, Energy, Shanghai); 23. p-hydroxyphenylboronic acid (CAS: 71597-85-8, Bide, Shanghai); 24. m-hydroxyphenylboronic acid (CAS: 87199-18-6, Energy, Shanghai); 25. p-chlorophenylboronic acid (CAS: 1679-18-1, Energy, Shanghai); 26. m-chlorophenylboronic acid (CAS: 63503-60-6, Energy, Shanghai); 27. 3-furanboronic acid (CAS: 55552-70-0, Energy, Shanghai); 28. 3-thiopheneboronic acid (CAS: 6165-69-1, Energy, Shanghai); 29. 4-aminophenylboronic add, Hydrochloride (CAS: 80460-73-7, Energy, Shanghai); 30. 3-aminophenylboronic acid, Hydrochloride (CAS: 80460-73-7, J&K, Beijing); 31. 4-methoxyphenylboronic acid (CAS: 5720-07-0, Energy, Shanghai); 32. 2-furanboronic acid (CAS: 13331-23-2, Energy, Shanghai); 33. 2-thiopheneboronic acid (CAS: 6165-68-0, Energy, Shanghai); 34. benzofuran-2-boronic acid (CAS: 13331-23-2, Energy, Shanghai); 35. benzothiophene-2-boronic acid (CAS: 6165-68-0, Energy, Shanghai); 36. 4-aminomethylpyridine (CAS: 3731-53-1, Energy, Shanghai); 37. 3-aminomethylpyridine (CAS: 3731-52-0, Energy, Shanghai); 38. 4-ethoxycarbonylphenylboronic acid (CAS: 4334-88-7, Energy, Shanghai); 39. 4-dimethylaminopiperidine (CAS: 50533-97-6, Accela ChemBio, Shanghai); 40.2,6-dimethylmorpholine (CAS: 141-91-3, Energy, Shanghai); 41. cyclopropylamine (CAS: 765-30-0, Energy, Shanghai); 42. 4-aminopyridine (CAS: 504-24-5, Xiya, Shanghai); 43. 3-aminopyridine (CAS: 462-08-8, Energy, Shanghai); 44. 2-amino-5-methylpyridine (CAS: 1603-41-4, Shuya, Shanghai); 44. 2-amino-4-methylpyridine (CAS: 695-34-1, Accela ChemBio, Shanghai); 45. 3,4-(methylenedioxy)phenylboronic add (CAS: 94839-07-3, Energy, Shanghai); 46. p-fluorophenylboronic acid (CAS: 1765-93-1, Adamas, Switzerland); 47. p-methylsulfonylphenylboronic acid (CAS: 149104-88-1, Energy, Shanghai).

The embodiments of the present invention are described in detail below by way of specific examples, but in any case they cannot be construed as limiting the present invention.

Synthetic route of compounds l-a-1, l-b-1, l-c-1: 41 IEC170116PCT SEMClwCHjI method A 2». R1- SEM 2b,R’ Me methodB or C 4a, R’-SBM 4b, R**M« Synthesis of compound 2a: Method A: compound 1 (6 g, 32 mmol) was dissolved in 30 mL of dried /V,A/-dimethylformamide, and stirred in an ice-water bath for 10 min, to which was added sodium hydride (1.9 g, 48 mmol) in portions, followed by stirring for 15 min, then to the reaction system was added dropwise 2-(trimethylsilyl) ethoxymethyl chloride (6.8 mL, 38.4 mmol), followed by stirring at room temperature until complete reaction (monitored by LC-MS). After the reaction was stopped, 300 mL of water and 250 mL of ethyl acetate were added slowly to the reaction soltuion under low temperature conditions, the solution was separated, the organic phase was washsed with water twice, dried with anhydrous sodium sulfate, filtered, concentrated and separated by silica gel column chromatography (petroleum ether), to obtain compound 2 (colorless liquid, 8.79 g, 87% yield).

MS (ESI) m/z: 318 [M+H]+.

Synthesis of compound 2b: From compound 1 (187 mg, 1.0 mmol) and methyl iodide (124 pL, 2.0 mmol), through Method A, 2 (200 mg, 100% yield) was obtained.

MS (ESI) m/z: 202 [M+H]+.

Synthesis of compounds 4a, 4c: Method B: compound 2a (500 mg, 1.58 mmol), arylamine compound 3 (465 mg, 1.58 mmol), tri(dibenzylideneacetone) dipalladium (72 mg, 0.08 mmol), 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (57 mg, 0.12 mmol) and potassium carbonate (654 mg, 4.74 mmol) were dispersed in t-butanol, air was replaced with nitrogen, followed by heating in an oil bath preheated to 100°C with stirring until complete reaction (monitored by TLC). After the reaction stopped, the system was cooled and filtered to remove solids, the filter cake was rinsed with MeOH, and the filtrate was collected, concentrated, and separated by silica gel column chromatography, to obtain compounds 4a (540 mg, 60% yield) and 4c (77 mg, 8.5% yield).

MS (ESI) m/z: 575 [M+Hf. 42 IEC170116PCT Synthesis of compound 4b: Method C: compounds 2b (201 mg, 1 mmol) and 3 (294 mg, 1 mmol) were heated at 85°C in t-butanol (5 mL) under the action of trifluoroacetic add (89 pL, 1.2 mmol) until complete reaction (monitored by LC-MS). After cooling, ethyl acetate (50 mL) was added, the system was washed with saturated sodium bicarbonate twice, dried with anhydrous sodium sulfate, filtered, concentrated and separated by silica gel column chromatography (petroleum ether/ ethyl acetate) to obtain compound 4b (280 mg, 61% yield).

MS (ESI) m/z: 459 [M+H]*. Synthesis of compound 5a: Method D: compound 4a (288 mg, 0.5 mmol), 3-pyridineboronic add (73 mg, 0.6 mmol), PdCI2 (dppf)-CH2CI2 (41 mg, 0.05 mmol) and Na2CO3 (265mg, 2.5 mmol) were dispersed in 1,4-dioxane/H2O (4/1 mL) in a reaction bottle, air was replaced with nitrogen, followed by heating at 100°C until complete reaction (monitored by LC-MS). The reaction solution was filtered to remove insolubles, and the filtrate was concentrated, and purified by silica gel column chromatography to obtain the target product 5a (500 mg, 81% yield).

MS (ESI) m/z: 618 [M+HJ*.

Synthesis of compound l-a-1: Method E: compound 5a (200 mg, 0.32 mmol) was stirred in TFA (2mL) at room temperature until complete reaction (monitored by LC-MS), concentrated, to which was added MeOH/THF/LiOH (1 M aq.) (2/2/2 mL), followed by stirring at room temperature until complete reaction (monitored by LC-MS). The precipitated solid was filtered, washed with water, and dried to obtain thetarget product 142 mg, in 91% yield.

Compound l-b-1 was synthesized from 4b through Method D; compound l-c-1 was synthesized from 4c through Method D, Method E. Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure nH NMR and/or MS data l-a-1 7.8 Hz, 1H), 7.88 (d, J= 2.0 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.57 (dd, J = 8.3, 2.1 Hz, 1H), M !L M » ’H NMR (600 MHz, DMSO-d6): 6 11.49 (s, 1H), 10.47 (s, 1H), 9.09 (d, J = 1.8 Hz, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.26- 8.21 (m, 2H), 7.95 (d, J = 7.43 (dd, J = 7.9, 4.7 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 3.3, 2.5 Hz, 1H), 6.78 (s, 1H), 6.54 (dd, J = 3.4, 2.0 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z: 488 [M+H]+. l-a-2 iXX 1H NMR (600 MHz, DMSO-d6) 5 11.39 (s, 1H), 10.45 (s, 1H), 8.27 (s, 2H), 8.25 (d, J = 7.9 Hz, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.91 (d, J= 1.3 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.58 (dd, J = 8.2, 2.1 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.32 (dd, J = 15.2, 7.9 Hz, 2H), 7.19 (dd, J = 3.3, 2.5 Hz, 1H), 6.73 (s, 1H), 6.50 (dd, J = 3.4, 43 IEC170116PCT 2.0 Hz, 1H), 2.24 (s, 3H). MS (ESI) m/z. 487 [M+H]*. l-a-3 ’H NMR (600 MHz, DMSO-d6) 5 12.14 (s, 1H), 10.62 (s, 1H), 10.10 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H). 8.27 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.69- 7.65 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 7.42- 7.31 (m, 3H), 6.55 (s, 1H), 2.38 (s, 3H), 2.24 (s, 3H). MS (ESI) m/z: 501 [M+Hf. l-a-4 ’H NMR (600 MHz, DMSO-de) 6 11.44 (s, 1H), 10.47 (s, 1H), 8.30 (d, J = 6.5 Hz, 2H), 8.27 (d, J =7.9 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 6.83 (s, 1H), 6.54 (s, 1H), 2.25 (s, 3H). MS (ESI) /n/z: 521 [M+H]+ l-a-5 L H M H ’H NMR (600 MHz, DMSO-de) B 11.43 (s, 1H), 10.47 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.26 (d, J= 7.9 Hz, 1H), 7.96- 7.91 (m, 3H), 7.87 (d, J = 2.0 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.59 (dd, J = 8.3, 2.1 Hz, 1H), 7.47 - 7.43 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.23- 7.19 (m, 1H), 6.75 (s, 1H), 6.53 (dd, J= 3.4, 2.0 Hz, 1H), 2.24 (s, 3H). MS (ESI) m/z 521 (M+H]+. l-a-6 jQl n a ^H NMR (600 MHz, DMSO-cfe) 5 11.35 (s, 1H), 10.45 (s, 1H), 9.36 (s, 1H), 8.27 (s, 2H), 8.24 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.82 (d, J= 2.1 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.61 (dd, J = 8.3, 2.1 Hz, 1H), 7.33 (dd, J = 6.0, 3.9 Hz, 2H), 7.30- 7.27 (m, 1H), 7.19- 7.16 (m, 2H), 6.70 (ddd, J = 8.0, 2.5, 0.9 Hz, 1H), 6.63 (s, 1H), 6.49 (dd, J = 3.4, 2.1 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z 503 IM+H]+. l-a-7 TFA sait H NMR (600 MHz, DMSO-d6) 5 12.18 (s, 1H), 10.64 (s, 1H), 10.38 -10.17 (m, 1H), 10.05 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 (dd, J = 8.3, 2.2 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.45 (d, J= 8.3 Hz, 1H), 7.33 (s, 1H), 6.98-6.92 (m, 2H), 6.77 ~6.60 (m, 1H), 6.48 (s, 1H), 2.24 (s, 3H). MS (ESI) m/z: 503 [M+H]*. 44 IEC170116PCT l-a-8 JÛL n a 3 s XX nH NMR (600 MHz, DMSO-d6) 6 11.30 (s, 1H), 10.44 (s, 1H), 8.27 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.60 (dd, J - 8.3, 2.1 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.15 (t, J = 2.9 Hz, 2H), 7.02 (dd, J = 12.2, 4.8 Hz, 2H), 6.62 (s, 1H), 6.51 (dt, J = 7.1, 2.1 Hz, 1H), 6.48 (dd, J = 3.4, 2.1 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z: 502 [M+Hf. l-a-9 Tl N .B ’H NMR (600 MHz, DMSO-d6) 6 11.21 (s, 1H), 10.45 (s, 1H), 8.28 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.95 (dd, J = 7.8, 0.7 Hz, 1H), 7.82 (d, J= 2.1 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.62- 7.59 (m, 2H), 7.58 (dd, J = 8.3, 2.1 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.09 (dd, J - 3.4, 2.5 Hz, 1H), 6.60 (s, 1H), 6.59- 6.55 (m, 2H), 6.44 (dd, J = 3.4, 2.0 Hz, 1H), 5.19 (s, 2H), 2.23 (s, 3H). MS (ESI) m/z: 502 [M+H]+. l-a-10 J 1H NMR (600 MHz, DMSO-d6) 5 11.54 (s, 1H), 10.47 (s, 1H), 8.59 (d, J = 6.0 Hz, 2H), 8.40 (s, 1H), 8.28 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.89- 7.84 (m, 3H), 7.78 (t, J- 7.8 Hz, 1H), 7.59 (d, J- 6.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 2.9 Hz, 1H), 6.87 (d, J= 5.6 Hz, 1H), 6.55 (s, 1H), 2.24 (s, 3H). MS (ESI) m/z: 488 [M+Hf. l-a-11 1H NMR (600 MHz, DMSO-d6) ô 11.35 (s, 1H), 10.46 (s, 1H), 8.28 (s, 1H), 8.25 (d, J - 7.9 Hz, 1H), 8.21 (s, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.84- 7.82 (m, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.58- 7.55 (m, 2H), 7.54 (dd, J = 5.0, 3.0 Hz, 1H), 7.32 (d, J= 8.5 Hz, 1H), 7.15 (dd, J = 3.3, 2.5 Hz, 1H), 6.71 (s, 1H), 6.49 (dd, J = 3.2, 2.1 Hz, 1H), 2.24 (s, 3H). MS (ESI) m/z: 493 [M+HJ*. l-a-12 J 1H NMR (600 MHz, DMSO-d6) 6 11.33 (s, 1H), 10.46 (s, 1H), 8.29 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 6.64-6.59 (m, 1H), 6.49 (s, 1H), 2.24 (s, 3H). MS (ESI) m/z: 477 [M+Hf. l-a-13 J NMR (600 MHz, DMSO-d6) 5 11.43 (s, 1H), 10.48 (s, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.86- 7.82 (m, 3H), 7.57 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.43 (d, 1H), IEC170116PCT 7.40 (dd, J = 10.8, 4.5 Hz, 2H), 7.33- 7.29 (m, 1H), 7.20 (dd, J = 3.4, 2.5 Hz, 1H), 6.65 (s, 1H), 6.40 (dd, J = 3.4, 2.0 Hz, 1H), 2.34 (s, 3H). MS (ESI) m/z 487 [M+H]+. l-a-14 f,cX1bAq^ 'H NMR (600 MHz, DMSO-d6) 5 11.48 (s, 1H), 10.48 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.95 (t, J= 1.9 Hz, 1H), 7.84 (dd, J= 7.9, 1.9 Hz, 1H), 7.77- 7.72 (m, 1H), 7.57 (t, J= 8.0 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.45- 7.41 (m, 2H), 7.38 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.23 (dt, J = 5.4, 2.7 Hz, 1H), 6.68 (s, 1H), 6.39 (dd, J = 3.4, 2.1 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z. 521 [M+H]*. l-a-15 TFAsalt ‘'H NMR (600 MHz, DMSO-d6) 6 12.28 (s, 1H), 10.56 (s, 1H), 10.05 (s, 1H), 8.22 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (dd, J = 11.0, 3.1 Hz, 2H), 7.78 (d, J= 8.6 Hz, 2H), 7.62 (d, J = 8.5 Hz, 3H), 7.59 (t, J= 8.1 Hz, 1H), 7.44 (d, J =7.7 Hz, 1H), 7.37 (s, 1H), 6.61 (s, 1H), 6.52 (s, 1H), 2.33 (s, 3H). MS (ESI) m/z. 521 [M+H]*. l-a-16 ’H NMR (600 MHz, DMSO-d6) 6 11.40 (s, 1H), 10.48 (s, 1H), 9.38 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.95 (d, J= 1.3 Hz, 1H), 7.84 (dd, J= 7.9, 1.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.20- 7.15 (m, 2H), 6.71 (dd, J = 7.9, 1.8 Hz, 1H), 6.57 (s, 1H), 6.40 (dd, J = 3.2, 2.0 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z: 503 [M+H]*. l-a-17 Wyl! 1H NMR (600 MHz, DMSO-^) 6 11.33 (s, 1H), 10.48 (S, 1H), 9.51 (s, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.83 (dd, J= 7.9, 1.8 Hz, 1H), 7.69- (m, 2H), 7.58 (t, J = 10.0, 6.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 7.7, 0.8 Hz, 1H), 7.14 (dd, J = 3.4, 2.5 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.37 (dd, J = 3.4, 2.0 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z: 503 [M+H]*. l-a-18 N ” PjCXXnA^^NH TH NMR (600 MHz, DMSO-d6) 5 11.34 (s, 1H), 10.47 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.04 (d, J= 8.3 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.83 (dd, J= 7.9, 1.7 Hz, 1H), 7.57 (t, J= 8.0 Hz, 1H), 7.52 (d, J= 8.1 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 7.17 (dd, J = 3.3, 2.6 Hz, 1H), 7.12 (t, J= 1.8 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 46 IEC170116PCT 6.51 (dd, J = 7.8, 1.3 Hz, 1H), 6.37 (dd, J = 3.4, 2.0 Hz, 1H), 5.07 (s, 2H), 2.32 (s, 3H).

MS (ESI) m/z: 502 [M+H]+. l-a-19 VyH « TFAsalt nH NMR (600 MHz, DMSO-d6) 5 11.25 (s, 1H), 10.48 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 7.9, 1.7 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.57- 7.53 (m, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.43 (dd, J= 7.7, 0.8 Hz, 1H), 7.10 (dd, J= 3.4, 2.5 Hz, 1H), 6.59- 6.54 (m, 2H), 6.52 (s, 1H), 6.33 (s, 1H), 5.22 (s, 2H), 2.33 (s, 3H). MS (ESI) m/z: 502 [M+Hf. l-a-20 o 3 " XX NMR (600 MHz, DMSO-de): 5 11.52 (s, 1H), 10.48 (s, 1H), 9.04 (d, J = 2.1 Hz, 1H), 8.52 (t, J = 3.0 Hz, 2H), 8.22 (s, 1H), 8.17 (tt, J= 8.0, 1.9 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.85 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 7.6, 5.0 Hz, 2H), 7.26- 7.18 (m, 1H), 6.68 (s, 1H), 6.41 (dd, J - 3.3, 2.1 Hz, 1H), 2.34 (s, 3H). MS (ESI) m/z: 488 [M+HJ*. l-a-21 NX^| F3^A0C ’H NMR (600 MHz, DMSO-d6) 6 11.58 (s, 1H), 10.49 (s, 1H), 8.59 (d, J = 4.6 Hz, 2H), 8.56 (s, 1H), 8.22 (S, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 7.9, 1.7 Hz, 1H), 7.81 (d, J= 5.4 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.29- 7.26 (m, 1H), 6.76 (s, 1H), 6.43 (dd, J = 3.4, 2.0 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z: 488 [M+Hf. l-a-22 S~~. o 1H NMR (600 MHz, DMSO-d6) 5 11.39 (s, 1H), 10.47 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 8.05 (d, J - 8.3 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.83 (dd, J= 7.9, 1.8 Hz, 1H), 7.77 (dd, J = 2.5, 1.7 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.53 (t, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.43 (d, J= 7.7 Hz, 1H), 7.16 (dd, J= 3.4, 2.5 Hz, 1H), 6.61 (s, 1H), 6.37 (dd, J = 3.4, 2.0 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z: 493 [M+Hf. l-a-23 xx xXh p3C $ iCX ‘‘H NMR (600 MHz, DMSO-d6) 5 11.36 (s, 1H), 10.47 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.05 (d, J- 8.2 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J= 1.6 Hz, 1H), 7.82 (dd, J=7.9, 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.16- 7.12 (m, 1H), 6.81 (d, J = 1.0 Hz, 1H), 6.47 (s, 1H), 6.34 (dd, J = 3.3, 2.0 Hz, 1H), 2.32 (s, 3H). MS (ESI) m/z: 477 [M+Hf. 47 IEC170116PCT l-a-24 y 0l.n b TFAsalt nH NMR (600 MHz, DMSO-d6) 5 12.27 (s, 1H), 10.56 (s, 1H), 9.81 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.79 (dd, J = 5.1, 1.4 Hz, 1H), 8.41 (d, J= 8.1 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.10 (dd, J= 8.5, 2.2 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.0, 1.8 Hz, 1H), 7.75 (dd, J= 8.1, 5.1 Hz, 1H), 7.71 (d, J= 8.5 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 2.9 Hz, 1H), 6.66 (s, 1H), 6.60-6.46 (m, 1H), 3.73 (s, 2H), 3.46- 3.37 (m, 2H), 3.15- 3.01 (m, 2H), 3.01 - 2.87 (m, 2H), 2.82 (s, 3H), 2.53- 2.42 (m, 2H), 2.35 (s, 3H). MS (ESI) m/z: 600 [M+H]*. l-a-25 TFAsalt nH NMR (600 MHz, DMSO-d6) 5 11.93 (s, 1H), 10.52 (s, 1H), 9.03 (s, 1H), 8.85 (d, J = 6.5 Hz, 2H), 8.32 (d, J =6.5 Hz, 2H), 8.21 (d, J = 2.1 Hz, 1H), 8.09 (dd, J= 8.5, 1.8 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.45- 7.39 (m, 1H), 6.91 (s, 1H), 6.51 (s, 1H), 3.70 (s, 2H), 3.40 (s, 2H), 3.05 (s, 2H), 2.93 (s, 2H), 2.80 (s, 3H), 2.44 (s, 2H), 2.33 (s, 3H). MS (ESI) m/z: 600 [M+H]*. l-a-26 1H NMR (600 MHz, Acetone) 5 7.71 (s, 1H), 7.31 (s, 1H), 7.00 (d, J- 8.0 Hz, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 8.6 Hz, 2H), 6.27 (dd, J= 14.7, 6.9 Hz, 3H), 6.14 (s, 2H), 6.00 (d, J = 3.5 Hz, 1H), 5.84 (s, 1H), 5.39 (d, J = 3.3 Hz, 1H), 2.39 (s, 2H), 2.09 (br. s, 8H), 1.59 (s, 3H). MS (ESI) m/z: 586 [M+H]*. l-a-27 'CuS.^^ ’H NMR (600 MHz, DMSO-d6) ’H NMR (600 MHz, DMSO-cfe) 5 11.68 (s, 1H), 10.60 (s, 1H), 9.07 (s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.94 (d, J = 5.2 Hz, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.37 (d, J = 5.1 Hz, 2H), 6.68 - 6.65 (m, 1H), 3.58 (s, 2H), 3.55-3.52 (m, 4H), 2.57 (br. s, 2H), 2.48- 2.42 (m, 2H), 2.34 (s, 3H). MS (ESI) m/z: 586 [M+H]*. l-a-28 'oAX h lJU TFAsalt M NMR (600 MHz, DMSO-cfe) 5 12.19 (s, 1H), 10.59 (s, 1H), 9.66 (s, 1H), 9.07 (s, 1H), 8.75 (s, 1H), 8.37 (d, 7.4 Hz, 1H), 8.13 (d, J = 6.2 Hz, 2H), 8.03 (d, J ~ 1.5 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.72 (d, J- 7.1 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.46 (S, 1H), 7.39- 7.35 (m, 1H), 6.67 (s, 1H), 6.48 (d, 3.6 Hz, 1H), 4.33 (s, 2H), 3.82 (s, 2H),3.50 (s, 2H), 3.15 (s, 2H), 2.80 (s, 3H), 2.35 (s, 3H), 2.34 (s, 2H). 48 IEC170H6PCT MS (ESI) m/z: 479 [M+HJ*. l-a-29 ’H NMR (600 MHz, DMSO-d6) 5 11.58 (s, 1H), 10.54 (d, J = 28.0 Hz, 1H), 8.71 - 8.50 (m, 3H), 8.16 (s, 1H), 8.03 - 7.96 (m, 2H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.84- 7.81 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.27 (dd, J = 8.6, 5.7 Hz, 1H), 6.85- 6.68 (m, 1H), 6.47- 6.44 (m, 1H), 3.54 (s, 2H), 3.49- 3.40 (m, 8H) 2.34 (s, 3H), 2.30 (s, 3H). MS (ESI) m/z: 600 [M+H]+. l-a-30 ’H NMR (600 MHz, DMSO-d6) ô 10.58 (s, 1H), 9.16 (s, 1H), 8.62 (s, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.25 (s, 1H), 8.06 (d, J- 8.7 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.66- 7.63 (m, 1H), 7.62- 7.57 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.35-7.33 (m, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 7.01 (s, 1H), 6.67 (s, 1H). MS (ESI) m/z: 474 [M+H]+. l-a-31 CF3 ^H NMR (600 MHz, DMSO-d6) 6 11.55 (s, 1H), 10.76 (s, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.50 -8.52 (m, 3H), 8.21- 8.16 (m, 1H), 8.01 (s, 1H), 7.87 (dd, J = 7.9, 1.8 Hz, 1H), 7.77 (s, 1H), 7.55 (d, J= 8.1 Hz, 1H), 7.42 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.24 (dd, J = 3.3, 2.6 Hz, 1H), 6.70 (s, 1H), 6.42 (dd, J = 3.2, 2.1 Hz, 1H), 2.36 (s, 3H). (ESI) m/z: 556 [M+H]+. l-a-32 TFA salt 1H NMR (600 MHz, DMSO-d6) 5 11.51 (s, 1H), 10.15 (s, 1H), 9.04 (d, J = 1.8 Hz, 1H), 8.51 (dd, J = 5.6, 2.4 Hz, 2H), 8.20- 8.14 (m, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.81 (dd, J - 7.9, 1.8 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.37- 7.34 (m, 1H), 7.23 (dt, J = 11.3, 4.9 Hz, 2H), 6.70 - 6.64 (m, 2H), 6.41 (dd, J = 3.4, 2.0 Hz, 1H), 3.73 (s, 3H), 2.33 (s, 3H). MS (ESI) m/z: 450 [M+HJ*. l-a-33 N^ÇÔ TFA sait 1H NMR (600 MHz, DMSO-d6) 5 12.06 (s, 1H), 10.47 (s, 1H), 9.65 (s, 1H), 9.05 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.38 (d, J = 7.0 Hz, 1H), 7.99 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.76 (d, J = 9.5 Hz, 1H), 7.73 (dd, J = 7.9, 5.1 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.3 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.63 (s, 1H), 6.52 (s, 1H), 2.34 (s, 3H). MS (ESI) m/z: 504 [M+H]+. l-a-34 Cuu IX? f^j] Q H nH NMR (600 MHz, DMSO-d6) 5 11.52 (s, 1H), 10.11 (s, 1H), 9.05 (d, J = 1.8 Hz, 1H), 8.54- 8.48 (m, 2H), 8.20- 8.15 (m, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.82 (dd, J = 7.9, 1.8 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 49 IEC170116PCT 7.50 (d, J - 8.1 Hz, 1H), 7.43 (ddd, J = 8.0, 4.7, 0.7 Hz, 1H), 7.25- 7.18 (m, 2H), 6.91- 6.87 (m, 1H), 6.68 (s, 1H), 6.43 (dd, J = 3.4, 2.0 Hz, 1H), 2.33 (s, 3H), 2.28 (s, 3H). MS (ESI) m/z: 434 [M+Hf. l-a-35 H NMR (600 MHz, DMSO-d6) 8 11.52 (s, 1H), 10.33 (s, 1H), 9.04 (d, J = 1.8 Hz, 1H), 8.52 (dd, J = 4.8, 1.6 Hz, 2H), 8.18- 8.15 (m, 1H), 7.95 (dd, J= 5.5, 2.0 Hz, 2H), 7.82 (dd, J = 7.9, 1.8 Hz, 1H), 7.71- 7.68 (m, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 4.7 Hz, 1H), 7.36 (t, J= 8.1 Hz, 1H), 7.23 (dd, J= 3.4, 2.5 Hz, 1H), 7.14 (ddd, J - 8.0, 2.1, 0.9 Hz, 1H), 6.67 (s, 1H), 6.41 (dd, J = 3.4, 2.0 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z: 455 [M+Hf. l-a-36 nH NMR (600 MHz, DMSO-d0) 5 11.54 (s, 1H), 10.36 (s, 1H), 9.04 (d, J = 1.9 Hz, 1H), 8.57 (s, 1H), 8.53 (d, J= 3.6 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.73 (d, J= 11.9 Hz, 1H), 7.54 (dd, J = 13.2, 8.6 Hz, 2H), 7.45 (dd, J = 8.0, 4.7 Hz, 1H), 7.36 (dd, J « 15.2, 8.1 Hz, 1H), 7.25- 7.22 (m, 1H), 6.93 - 6.89 (m, 1H), 6.67 (s, 1H), 6.41 (s, 1H), 2.33 (s, 3H). MS (ESI) m/z: 438 [M+Hf. l-a-37 3H NMR (600 MHz, DMSO-d6) 5 11.54 (d, J = 2.6 Hz, 1H), 10.52 (s, 1H), 9.10 (d, J= 2.2 Hz, 1H), 8.78 (s, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.25 (dt, J- 8.0, 2.0 Hz, 2H), 7.96 (d, 7.9 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.61- 7.56 (m, 2H), 7.49- 7.44 (m, 2H), 7.29-7.24 (m, 2H), 7.11 (s, 1H), 6.62 (dd, J = 3.5, 2.0 Hz, 1H), 3.94 (s, 3H). MS (ESI) m/z: 504 [M+H]+. !-a-38 FSC'C^N'^0-’*’ ’H NMR (600 MHz, MeOD-d») 5 9.05 (s, 1H), 8.51 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.15- 8.07 (m, 2H), 7.91 (d, J= 7.6 Hz, 1H), 7.84 (s, 1H), 7.53 (dd, J = 16.0, 7.9 Hz, 2H), 7.41 (dd, J = 13.8, 8.6 Hz, 2H), 7.26 (d, J= 3.6 Hz, 1H), 6.96 (s, 1H), 6.53 (d, J = 3.4 Hz, 1H). MS (ESI) m/r. 492 [M+Hf. l-a-39 CUyH NMR (600 MHz, DMSO-d6) ô 11.47 (s, 1H), 9.12- 9.08 (m, 2H), 8.89 (s, 1H), 8.51 (dd, J = 4.7, 1.5 Hz, 1H), 8.28 (s, 1H), 8.25- 8.21 (m, 1H), 7.99 (s, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.56 (d, J - 8.6 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.41 (dd, J - 7.9, 4.7 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.23- 7.21 (m, 1H), 7.18 (dd, J = 8.2, 2.2 Hz, 1H), 6.78 (s, 1H), 6.54 (dd. J = 3.4, 2.0 Hz, 50 IEC170116PCT 1H), 2.20 (s, 3H). MS (ESI) m/z: 503 [M+HJ*. l-a-40 "vY'a" 1H NMR (600 MHz, DMSO-d6) 5 11.48 (s, 1H), 10.05 (d, J= 14.1 Hz, 2H), 9.09 (s, 1H), 8.50 (d, J = 3.7 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.53 (dd, J = 16.8, 8.8 Hz, 2H), 7.43 (d, J = 7.7 Hz, 1H), 7.37 (dd, J = 7.5, 4.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.23- 7.18 (m, 2H), 6.84 (s, 1H), 6.61 (s, 1H), 2.25 (s, 3H). MS (ESI) m/z: 519 [M+H]\ l-a-41 ’H NMR (600 MHz, DMSO-d6) 5 11.87 (s, 1H), 10.31 (d, J = 6.3 Hz, 2H), 9.05 (s, 2H), 8.64 (d, J = 4.3 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.7, 2.4 Hz, 1H), 7.63 (d, J= 9.1 Hz, 2H), 7.54 (dd, J = 7.9, 4.9 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.33- 7.30 (m, 1H), 7.25- 7.22 (m, 1H), 6.82 (s, 1H), 6.70 (s, 1H), 2.26 (s, 3H). MS (ESI) m/z: 554 [M+Hf. l-a-42 H NMR (600 MHz, DMSO-d6) 5 11.61 (s, 1H), 9.06 (dd, J = 2.3, 0.8 Hz, 1H), 8.62 (s, 1H), 8.58 (dd, J = 4.8, 1.6 Hz, 1H), 8.24 (dt, J = 8.0, 1.9 Hz, 1H), 7.50 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 3.5, 2.5 Hz, 1H), 7.22 (dd, J = 7.7, 1.7 Hz, 1H), 6.73 (s, 1H), 6.46 (s, 1H), 3.67- 3.25 (m, 8H), 2.31 (s, 3H). MS (ESI) m/z: 414 [M+H]+. l-a-43 znJ LA nH NMR (600 MHz, DMSO-d6) 5 11.52 (s, 1H), 9.04 (d, J = 1.8 Hz, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 8.37 (s, 1H), 8.20-8.15 (m, 1H), 7.44- 7.39 (m, 2H), 7.23 (dd, J = 6.6, 3.4 Hz, 2H), 7.16-7.12 (m, 1H), 6.73 (s, 1H), 6.45 (dd, J = 3.3, 2.0 Hz, 1H), 2.30 (s, 3H), 2.18 (br. s, 4H), 2.11 (s, 3H), 1.77 (br. s, 4H).

MS (ESI) m/z: 427 [M+HJ*. l-a-44 CkxN^N v> s C nH NMR (600 MHz, DMSO-de) 5 11.53 (s, 1H), 10.46 (s, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.54 (dd, J = 4.7, 1.5 Hz, 1H), 8.40 (s, 1H), 8.23- 8.20 (m, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.46 (dd, J = 7.9, 4.8 Hz, 1H), 7.35 (dd, J = 8.3, 2.1 Hz, 1H), 7.31 (d, J= 8.4 Hz, 1H), 7.23 (dd, J = 3.3, 2.1 Hz, 1H), 6.75 (s, 1H), 6.48 (d, J = 2.1 Hz, 1H), 3.78- 3.75 (m, 2H), 2.22 (s, 3H). MS (ESI) m/z: 373 [M+H]+. l-a-45 N^yO*1 0 V* r j h NMR (600 MHz, DMSO-d6) 5 11.52 (s, 1H), 10.19 (s, 1H), 9.04 (dd, J = 2.3, 0.7 Hz, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.49 (s, 1H), 8.17 (ddd, J= 8.0, 2.2, 1.7 Hz, 1H), 7.94 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 51 IEC17011âPCT 7.51 (d, J = 8.1 Hz, 1H), 7.43 (ddd, J - 8.0, 4.8, 0.8 Hz, 1H), 7.23 (dd, J = 3.4, 2.5 Hz, 1H), 6.69 (s, 1H), 6.42 (dd, J = 3.4, 2.0 Hz, 1H), 5.98 (s, 1H), 3.56 (s, 3H), 2.33 (s, 3H), 2.10 (s, 3H). MS (ESI) m/z: 438 [M+Hf. l-a-46 ^H NMR (600 MHz, MeOD) 6 9.17 (s, 1H), 8.80- 8.76 (m, 1H), 8.57 (dt, J = 8.1, 1.9 Hz, 1H), 8.30- 8.28 (m, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.17 (d, J= 2.5 Hz, 1H), 7.91 (d, J =7.3 Hz, 1H), 7.79 (dd, J = 8.0, 5.0 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.57 (dd, J = 8.7, 2.5 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 6.80 (d, J= 3.6 Hz, 1H), 3.60- 3.51 (m, 2H), 3.45- 3.38 (m, 2H), 3.22 - 3.08 (m, 4H), 2.92 (s, 3H). MS (ESI) m/z: 572[M+Hf. l-a-47 nH NMR (600 MHz, DMSO-d6) 5 12.00 (s, 1H), 10.66- 10.59 (m, 1H), 9.81 (br. s,1H), 9.25 (s, 1H), 9.19 (br. s, 1H), 8.79 (s, 1H), 8.53- 8.47 (m, 2H), 8.25- 8.21 (m, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.90- 7.86 (m, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.67- 7.63 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.50- 7.45 (m, 1H), 6.48 (dt, J = 2.7, 1.3 Hz, 1H), 4.53 (s, 2H), 2.79 (s, 6H). MS (ESI) m/z: 531 [M+H]+. l-a-48 nH NMR (600 MHz, MeOD) 5 9.08 (s, 1H), 8.79- 8.75 (m, 1H), 8.46 (dt, J = 8.1, 1.8 Hz, 1H), 8.17-8.15 (m, 1H), 8.08 (d, J= 2.2 Hz, 1H), 8.03 (dd, J = 8.6, 2.2 Hz, 1H), 7.92 (dd, J = 7.8, 1.9 Hz, 1H), 7.78 (dd, J = 8.1, 5.1 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.46- 7.43 (m, 2H), 7.37 (d, J = 3.5 Hz, 1H), 6.97 (s, 1H), 6.58 (s, 1H), 3.57- 3.52 (m, 2H), 2.94- 2.90 (m, 5H), 2.81 (s, 6H). MS (ESI) m/z: 574 IM+H]+. l-a-49 O4 MS (ESI) m/z: 572 [M+HJ*. l-a-50 ^yO 'cèo1^ MS (ESI) m/z: 586 [M+Hf.

IEC170116PCT l-b-1 * 1H NMR (600 MHz, DMSO-d6): 5 10.47 (d, J = 6.3 Hz, 1H), 9.16 (s, 1H), 8.54 (d, J = 4.1 Hz, 1H), 8.43 (d, J = 5.0 Hz, 1H), 8.31 (dd, J = 5.1, 2.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.89-7.85 (m, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.45 (dd, J= 7.8, 4.7 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 6.80 (d, J= 6.7 Hz, 1H), 6.52 (dd, J = 5.6, 3.4 Hz, 1H), 3.83 (s, 3H), 2.24 (s, 3H). MS (ESI) m/r 502 [M+Hf. l-b-2 ft 'H NMR (600 MHz, DMSO-d6) 5 10.47 (s, 1H), 8.63-8.59 (m, 2H), 8.45 (s, 1H), 8.28 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.95- 7.92 (m, 2H), 7.85 (d, J= 2.1 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.59 (dd, J= 8.3, 2.1 Hz, 1H), 7.35 (d, J= 8.5 Hz, 1H), 7.31 (d, J = 3.5 Hz, 1H), 6.88 (s, 1H), 6.52 (d, J = 3.5 Hz, 1H), 3.83 (s, 3H), 2.23 (s, 3H). MS (ESI) m/r. 502 [M+Hf. l-b-3 B XX H NMR (600 MHz, Acetone-d6): 5 9.84 (s, 1H), 9.20 (s, 1H), 8.51 (d, J= 3.5 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.84 (s, 1H), 7.55 (t, J= 8.0 Hz, 1H), 7.51 (d, J= 7.9 Hz, 1H), 7.42 (d, J= 7.8 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.22 (d, J = 3.4 Hz, 1H), 6.88 (d, J = 4.2 Hz, 1H), 6.47-6.39 (m, 1H), 3.90 (s, 3H), 2.39 (s, 3H). MS (ESI) m/r 502 [M+Hf. l-b-4 TFA sait 1H NMR (600 MHz, MeOD-d4) 5 8.65- 8.59 (m, 2H), 8.25- 8.19 (m, 2H), 8.16 (d, J= 2.0 Hz, 1H), 7.97 (d, J= 1.9 Hz, 1H), 7.92 (dd, J= 8.3, 2.1 Hz, 1H), 7.84 (dd, J = 7.9, 2.0 Hz, 1H), 7.56- 7.50 (m, 2H), 7.42 (d, J- 7.8 Hz, 1H), 7.25 (d, J= 3.5 Hz, 1H), 6.91 (s, 1H), 6.43 (d, J= 3.5 Hz, 1H), 3.89 (s, 3H), 2.36 (s, 3H). MS (ESI) m/r 502 [M+Hf. l-b-5 ’H NMR (600 MHz, CDCI3) 6 9.12 (d, J= 2.2 Hz, 1H), 8.52 (dd, J= 4.8, 1.5 Hz, 1H), 8.41 (s, 1H), 8.27 (dt, J = 8.0, 2.0 Hz, 1H), 7.86 (dd, J = 8.7, 2.2 Hz, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 7.9, 1.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 7.06 (d, J= 3.5 Hz, 1H), 6.77 (s, 1H), 6.30 (s, 1H), 6.22 (d, J= 3.4 Hz, 1H), 3.89 (s, 3H), 3.59 (s, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 2.04 (br. s, 4H), 1.26 (br. s, 4H). MS (ESI) m/r 614 [M+Hf. 53 IEC170116PCT l-b-6 QA Anyn) 'AflYC ’H NMR (600 MHz, CDCI3) 6 8.86 (s, 1H), 8.53- 8.46 (m, 2H), 7.88- 7.82 (m, 3H), 7.81 - 7.77 (m, 2H), 7.73-7.65 (m, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 3.5 Hz, 1H), 6.77 (s, 1H), 6.42 (s, 1H), 6.22 (d, J = 3.5 Hz, 1H), 3.91 (s, 3H), 3.59 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 1.27 (s, 4H), 1.21 (d, J= 6.1 Hz, 4H). MS (ESI) m/z: 614 [M+H]+. l-b-7 1H NMR (600 MHz, DMSO-d6) 5 10.51 (s, 1H), 9.15 (s, 1H), 8.80 (s, 1H), 8.55 (d, J= 3.4 Hz, 1H), 8.33 - 8.30 (m, 1H), 8.25 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 7.59- 7.56 (m, 2H), 7.46 (dd, J = 10.4, 6.8 Hz, 2H), 7.31 (d, J= 3.5 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H), 6.60 (d, J= 3.5 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H). MS (ESI) m/z: 518 [M+Hf. l-b-8 Cux o nH NMR (600 MHz, DMSO-d6) 5 10.52 (s, 1H), 8.84 (s, 1H), 8.62 (d, J = 5.7 Hz, 2H), 8.25 (s, 1H), 7.94 -7.97 (m, 3H), 7.62- 7.58 (m, 2H), 7.55 (dd, J = 8.8, 2.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 3.4 Hz, 1H), 7.27 (d, J= 8.9 Hz, 1H), 7.21 (s, 1H), 6.61 (d, J = 3.4 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H). MS (ESI) m/z: 518 [M+Hf. l-c-1 H NMR (600 MHz, DMSO-d6) 5 11.25 (s, 1H), 10.36 (d, J = 7.4 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 8.02 (s, 1H), 7.96 (d, J= 7.9 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.75 (d, J= 1.5 Hz, 1H), 7.74 (d, J= 1.3 Hz, 1H), 7.55 (t, J= 7.7 Hz, 2H), 7.48- 7.44 (m, 1H), 7.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.19 (d, J= 8.3 Hz, 1H), 7.12 (dd, J = 3.4, 2.4 Hz, 1H), 6.79 (s, 1H), 6.41 (dd, J = 3.5, 2.0 Hz, 1H), 2.26 (s, 2H). MS (ESI) m/z: 487 [M+Hf. l-c-2 s XX XX? H NMR (600 MHz, DMSO-d6) 5 11.28 (s, 1H), 10.38 (d, J= 4.4 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.96 (d, J= 7.5 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.64 (s, 1H), 7.43 (dd, J = 8.2, 2.0 Hz, 1H), 7.36 (s, 1H), 7.35 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.13 (q, J= 4.3, 3.6 Hz, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.43 (t, J= 2.6 Hz, 1H), 2.39 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z: 501 [M+Hf. 54 IEC170116PCT l-c-3 1H NMR (600 MHz, DMSO-de) 5 11.29 (s, 1H), 10.40 (s, 1H), 8.30 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.05 (d, J= 2.2 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.78 (t, J* 7.8 Hz, 1H), 7.72 (s, 1H), 7.71 (s, 1H), 7.45 (dd, J= 8.2, 2.2 Hz, 1H), 7.23 (d, J~ 8.3 Hz, 1H), 7.14 (dd, J= 3.4, 2.4 Hz, 1H), 7.12 (s, 1H), 7.11 (s, 1H), 6.76 (s, 1H), 6.46 (dd, J = 3.5, 1.9 Hz, 1H), 3.84 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z: 517 [M+H]+ l-c-4 ’H NMR (600 MHz, CDCI3) 5 10.53 (s, 1H), 8.56 (s, 1H), 8.38-8.34 (m, 1H), 8.27 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.72- 7.68 (m, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.58 (dt, J = 6.5, 1.9 Hz, 1H), 7.45-7.37 (m, 2H), 7.21- 7.16 (m, 2H), 6.71- 6.67 (m, 1H), 6.63 (s, 1H), 6.42 (dd, J = 3.6, 1.9 Hz, 1H), 6.37-6.31 (m, 1H), 2.34 (s, 3H). MS (ESI) m/z: 522 [M+Hf. l-c-5 Cl *H NMR (600 MHz, DMSO-d6) 5 11.23 (t, J = 2.3 Hz, 1H), 10.36 (s, 1H), 9.60 (s, 1H), 8.30 (s, 1H), 8.26 (d, J- 7.9 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.96 (d, J= 7.7 Hz, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.42 (dd, J = 8.2, 2.2 Hz, 1H), 7.33 (t, J- 8.1 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.15 (dd, 6.7, 1.5 Hz, 2H), 7.13- 7.10 (m, 1H), 6.87- 6.84 (m, 1H),6.75 (s, 1H), 6.40 (dd, J= 3.5, 1.9 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z: 503 [M+Hf. l-c-6 ’H NMR (600 MHz, DMSO-d6) 5 11.17 (t, J= 2.2 Hz, 1H), 10.35 (d, J = 5.9 Hz, 1H), 8.29 (t, J= 1.7 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.98 (s, 1H), 7.97-7.94 (m, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.41 (dd, J= 8.2, 2.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.09 (dd, J = 3.5, 2.4 Hz, 1H), 6.97 (t, J = 2.0 Hz, 1H), 6.86 (dt, J = 7.7, 1.2 Hz, 1H), 6.72 (s, 1H), 6.64 (ddd, J- 7.9, 2.3, 1.0 Hz, 1H), 6.41 (dd, J= 3.5, 2.0 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z: 502 [M+HJ*. l-c-7 ^H NMR (600 MHz, DMSO-d6) 5 11.30 (s, 1H), 10.38 (s, 1H), 8.29 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.99 (d, J= 2.1 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 1H), 7.22 (d,J=3.3Hz,1H), 7.21 (s,1H), 7.16 (t, J = 2.9 Hz, 1H), 7.01 (s, 1H), 6.72 (dt, J= 5.1, 2.5 Hz, 2H), 2.24 (s, 3H). MS (ESI) m/z: 477 [M+H]+. 55 IECJ70116PCT Synthetic route of compounds ll-a-1, ll-b-1: l-c-8 1H NMR (600 MHz, DMSO-cfe) 5 11.29 (s, 1H), 10.36 (s, 1H), 8.29 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.70 (d, J= 3.9 Hz, 1H), 7.42 (dd, J = 8.2, 2.2 Hz, 1H), 7.25 (dd, J= 5.0, 3.6 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 7.17 - 7.13 (m, 1H), 6.94 (s, 1H), 6.64 (dd, J = 3.6, 2.0 Hz, 1H), 2.25 (s, 3H).

MS (ESI) m/z: 493 [M+H]+. l-c-9 ’ s XXXX? NMR (600 MHz, DMSO-d6) ô 11.39 (d, J = 2.3 Hz, 1H), 10.39 (s, 1H), 8.30 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.80- 7.75 (m, 2H), 7.72- 7.69 (m, 2H), 7.47 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (t, J =7.6 Hz, 1H), 7.33 (t, J =7.5 Hz, 1H), 7.27 (s, 1H), 7.25-7.21 (m, 2H), 6.86 (dd, J= 3.4, 1.9 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 527 [M+H]+. l-c-10 1H NMR (600 MHz, DMSO-cfe) 5 11.39 (t, J = 2.3 Hz, 1H), 10.38 (s, 1H), 8.30 (s, 1H), 8.27 (d, J= 8.0 Hz, 1H), 8.09 (s, 1H), 8.05 (dd, J = 6.8, 1.9 Hz, 2H), 7.98 (dd, J = 6.9, 1.9 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.48- 7.39 (m, 3H), 7.25- 7.20 (m, 2H), 7.02 (s, 1H), 6.79 (dd, J = 3.6, 1.9 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 543 [M+H]+. l-c-11 1H NMR (600 MHz, DMSO-cfe) 5 11.34 (s, 1H), 10.35 (s, 1H), 8.74 (s, 1H), 8.73 (s, 1H), 8.30 (s, 1H), 8.26 (d, J= 7.8 Hz, 1H), 8.11 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.79 (dd, J = 7.8,7.8 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.73 (s, 1H), 7.41 (dd, J = 8.3, 2.1 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.18 (t, J = 3.0 Hz, 1H), 6.88 (s, 1H), 6.47 (dd, J = 3.5, 1.9 Hz, 1H), 2.26 (s, 3H). MS (ESI) m/z: 488 [M+HJ*. l-c-12 1H NMR (600 MHz, DMSO-cfe) 5 11.34 (s, 1H), 10.37 (s, 1H), 8.94 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.15 (d, J= 8.1 Hz, 1H), 8.07-8.14 (m, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.58 (dd, J = 7.7, 4.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 2.26 (s, 3H). MS (ESI) m/z: 488 [M+Hf. 56 IEC170116PCT Cl NaSMo (aq) MeOH method F 6a R3«H 6b R3- Me pyridln-3-ylboronic acid method O SMe 8a R3 = H 8b R3 — Me mCPBA DCM, -30 °C method G SOMe method C 9aR3-H 9b Rj= Me ll-a-1 R3 = H ll-b-1 R3 = Me Compound 6b was synthesized from 6a through Method A. MS (ESI) m/z: 202 [M+H]*.

Synthesis of compound 7: Method F: compound 6 (2 mmol) was dissolved in MeOH, and stirred at OX? , to which was added NaSMe (20% aq, 1.8 eq.), followed by naturally warming to room temperature, and reacting overnight, monitored by TCL until complete conversion, to which was added DCM. The system was washed with water, and the organic phase was concentrated to obtain a while solid, which was directly used for the next step reaction. 7a: MS (ESI) mfr. 200 [M+H]*; 7b: MS (ESI) mfr 214 [M+H]*. compound 8 was synthesized from compound 7 and 3-pyridineboronic acid through Method D. 8a: MS (ESI) mfr 243 [M+H]*; 8b: MS (ESI) mfr. 257 [M+H]*. Synthesis of compound 9: Method G: compound 8 (1 mmol) was dissolved in DCM (5 mL), to which was slowly added dropwise a solution of mCPBA (1.5 eq.) in DCM (5 mL) at -30‘C, followed by keeping at this temperature for 2-4 h, monitored by TLC until complete conversion, to which was added DCM for dilution. The system was washed with saturated NaHCOaaqueous solution, and the organic phase was concentrated, and purified by silica gel column chromatography, to obtain a yellowish solid. 9a: MS (ESI) mfr 259 [M+H]*; 9b: MS (ESI) m/z: 273 [M+H]*.

Compounds ll-a-1, ll-b-1 were respectively synthesized from 9a, 9b and 3 through Method C.

Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure ’H NMR and/or MS datanH NMR (600 MHz, DMSO-de) 5 11.83 (s, 1H), 10.49 (s, 1H), 9.39 (d, J = 2.0 Hz, 1H), 9.16 (s, 1H), 8.56 (dd, J = 4.7, 1.6 ll-a-1 Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J ~ 7.9 Hz, 1H), 8.06 57 IEC170116PCT ca 03071900 2020-02-03 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.79 (t, J- 7.9 Hz, 1H), 7.62 (dd, J = 8.3, 2.1 Hz, 1H), 7.43 (dd, J = 8.1,4.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.24- 7.22 (m, 1H), 6.45 (s, 1H), 2.25 (s, 3H). MS (ESI) m/z: 489 [M+H]+. ll-a-2 H NMR (600 MHz, DMSO-d6) Ô 11.89 (s, 1H), 10.52 (s, 1H), 9.36 (d, J = 1.6 Hz, 1H), 9.28 (s, 1H), 8.55 (dd, J = 4.7, 1.7 Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.27 (d, J= 1.6 Hz, 1H), 8.24 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.87 (dd, J = 7.9, 1.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.2, 4.5 Hz, 1H), 7.27 (dd, J = 3.2, 2.6 Hz, 1H), 6.55 (s, 1H), 2.38 (s, 3H). MS (ESI) m/z: 489 (M+H]+. ll-a-3 1H NMR (600 MHz, DMSO-d6) 5 11.89 (s, 1H), 10.48 (s, 1H), 9.35 (d, J = 1.8 Hz, 1H), 9.27 (s, 1H), 8.55 (dd, J = 4.7, 1.7 Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.08 (d, J= 8.4 Hz, 1H), 7.87 (dd, J = 7.9, 1.8 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.53 (d, J= 8.1 Hz, 1H), 7.41 (dd, J = 8.0, 5.3 Hz, 1H), 7.28- 7.26 (m, 1H), 6.55 (s, 1H), 3.59 (s, 2H), 2.50- 2.42 (m, 4H), 2.37 (s, 3H), 2.36 - 2.30 (m, 4H). MS (ESI) m/z: 601 [M+H]+. ll-a-4 H NMR (600 MHz, DMSO-d6) 6 11.97 (s, 1H), 10.53 (s, 1H), 9.31 (s, 1H), 8.59 (d, J = 5.7 Hz, 2H), 8.30 (d, J = 1.7 Hz, 1H), 8.25 (s, 1H), 8.12-8.10 (m, 2H), 8.08 (s, 1H), 7.87 (dd, J- 8.0, 1.8 Hz, 1H), 7.61 (t, J= 8.1 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.34- 7.31 (m, 1H), 6.58-6.54 (m, 1H), 2.37 (s, 3H). MS (ESI) m/z\ 489 [M+Hf. ll-a-5 H NMR (600 MHz, DMSO-d6) 6 11.98 (s, 1H), 10.52 (s, 1H), 9.30 (s, 1H), 8.59 (d, J = 5.6 Hz, 2H), 8.32 (s, 1H), 8.22 (s, 1H), 8.13 - 8.10 (m, 3H), 7.86 (d, J = 9.3 Hz, 1H), 7.71 (d, J= 8.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.33 (s, 1H), 6.58 (s, 1H), 3.67 (s, 2H), 3.08- 3.00 (m, 2H), 2.95 - 2.88 (m, 2H), 2.80 (s, 3H), 2.56- 2.54 (m, 4H), 2.38 (s, 3H). MS (ESI) m/z: 601 [M+Hf. 58 IEC170116PCT ll-b-1 1H NMR (600 MHz, DMSO-d6) 6 10.49 (s, 1H), 9.44 (s, 1H), 9.21 (s, 1H), 8.60 (dt, J = 7.9, 1.9 Hz, 1H), 8.58 (d, J = 4.6 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.63 (dd, J= 8.2, 2.1 Hz, 1H), 7.45 (dd, J = 7.8, 4.8 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 6.43 (s, 1H), 3.83 (s, 3H), 2.24 (s, 3H). MS (ESI) m/z: 503 [M+Hf. ll-b-2 °î>- 1H NMR (600 MHz, DMSO-d6) 5 10.53 (s, 1H), 9.41 (d, J= 1.8 Hz, 1H), 9.33 (s, 1H), 8.58- 8.55 (m, 2H), 8.27- 8.23 (m, 2H), 8.09 (d, J = 9.1 Hz, 1H), 7.88 (dd, J- 7.9, 1.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.44- 7.41 (m, 1H), 7.32 (d, J = 3.4 Hz, 1H), 6.53 (s, 1H), 3.85 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 503 [M+Hf. ll-b-3 1H NMR (600 MHz, DMSO-d6) 5 10.49 (s, 1H), 9.40 (s, 1H), 9.33 (s, 1H), 8.59-8.55 (m, 2H), 8.25 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.42 (dd, J = 7.4, 5.2 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 6.53 (s, 1H), 3.85 (s, 3H), 3.58 (s, 2H), 2.56- 2.54 (m, 4H), 2.48- 2.39 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H). MS (ESI) m/z: 615 [M+Hf. ll-b-4 ^H NMR (600 MHz, DMSO-d6) 6 10.54 (s, 1H), 9.38 (s, 1H), 8.62 (d, J = 5.8 Hz, 2H), 8.28 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 5.9 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 3.3 Hz, 1H), 6.56 (s, 1H), 3.86 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z: 503 [M+H]+. ll-b-5 1H NMR (600 MHz, DMSO-d6) 5 10.53 (s, 1H), 9.51 (s, 1H), 8.79 (d, J = 5.5 Hz, 2H), 8.44 (d, J = 5.5 Hz, 2H), 8.26 (s, 1H), 8.23 (d, J ~ 2.1 Hz, 1H), 8.13- 8.10 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.45 (d, J= 3.4 Hz, 1H), 6.60 (s, 1H), 3.88 (s, 3H), 3.68 (s, 2H), 3.44- 3.37 (m, 2H), 3.08- 3.01 (m, 2H), 2.95- 2.90 (m, 2H), 2.81 (s, 3H), 2.42- 2.38 (m, 2H), 2.36 (s, 3H). MS (ESI) m/z: 615 [M+H]+. 59 IEC170116PCT Synthetic route of compounds lll-a-1, lll-b-1: 11aR3-H 11b R1» Me R3 13aRa-H 13bR’=Me pyridln-3-ytt»ronlc acid method D lll-a-1 RJ=H lll-b-1 R3=Me Synthesis of compound 11a: Method H: compound 10 (211 mg, 1.0 mmol) was dissolved in ethanol (5 mL) and stirred at -78°C, to which was slowly added hydrazine hydrate (53 pL, 1.1 mmol), monitored by TLC until complete reaction, to which was added ethyl acetate (50 mL). The system washed with water once, and the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated and separated by silica gel column chromatography to obtain compound 11a (127 mg, 67% yield).

MS (ESI) m/z: 190 [M+Hf. compound 11b was synthesized from 10 and methylhydrazine through Method H.

MS (ESI) m/z: 204 [M+Hf. Synthesis of compound 13: Compound 11 (0.5 mmol) and 12 (0.5 mmol) were reacted in t-butanol (2 mL) in a microwave reactor at 150°C for 4 h, concentrated and separated by silica gel column chromatography to obtain the compound. 13a: MS (ESI) m/z: 490 [M+Hf; 13b: MS (ESI) m/z: 504 [M+Hf.

Compounds lll-a-1, lll-a-2 were respectively synthesized from 13a, 13b and 3-pyridineboronic acid through Method D.

Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure qH NMR and/or MS dataqH NMR (600 MHz, DMSO-d6) 6 10.53 (s, 1H), 10.09 (s, 1H), 9.38 (s, 1H), 8.66 (d, J = 27.9 Hz, 2H), 8.34 (s, 1H), 8.23 (s, 2H), 8.07 lll-a-1 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.6 Hz, 3H), 7.45 (d, J = 7.8 Hz, 1H), 2.36 (s, 3H). MS (ESI) m/z: 490 [M+H]+. 60 IEC170116PCT lll-b-1 jÿ' P nH NMR (600 MHz, CDCI3) 5 9.58 (s, 1H), 9.51 (s, 1H), 8.61 (dd, J = 7.9, 1.9 Hz, 1H), 8.49 (d, J= 4.8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.87 (dd, J = 21.7, 8.1 Hz, 2H), 7.44 - 7.32 (m, 3H), 7.28 (dt, J = 9.5, 3.0 Hz, 1H), 6.73 (s, 1H), 3.94 (d, J= 1.8 Hz, 3H), 2.24 (s, 3H). MS (ESI) m/z: 504 [M+H]+. lll-b-2 qH NMR (600 MHz, DMSO-d6) 5 10.53 (s, 1H), 9.96 (s, 1H), 8.34 (d, J = 7.3 Hz, 2H), 8.23 (d, J= 2.0 Hz, 1H), 8.14-8.01 (m, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.59 (q, J = 7.9 Hz, 2H), 7.50- 7.37 (m, 4H), 4.01 (s, 3H), 2.35 (s, 3H). MS (ESI) m/z: 503 [M+Hf. lll-b-3 ’H NMR (600 MHz, DMSO-d6) 6 10.53 (s, 1H), 10.03 (s, 1H), 8.32 (s, 1H), 8.28 (s, 3H), 8.25 (t, J= 1.9 Hz, 1H), 8.08- 8.03 (m, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.58 (dd, J = 8.1,4.5 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.49-7.42 (m, 2H), 4.02 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z: 537 [M+Hf. lll-b-4 '“H NMR (600 MHz, DMSO-d6) ô 10.51 (s, 1H), 9.94 (s, 1H), 9.47 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.16 (s, 1H), 8.06 (d, J= 8.4 Hz, 1H), 7.97-7.90 (m, 1H), 7.76 (d, J= 9.3 Hz, 2H), 7.64 - 7.53 (m, 2H), 7.50 - 7.42 (m, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.83 (dd, J = 7.8, 2.3 Hz, 1H), 3.99 (s, 3H), 2.34 (s, 3H).

MS (ESI) m/z: 519 [M+H]+. lll-b-5 "xà^ 1H NMR (600 MHz, DMSO-d6) 10.54 (s, 1H), 9.84 (s, 1H), 8.27 (s, 1H), 8.24 (d, J= 1.9 Hz, 1H), 8.09-8.05 (m, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.48- 7.45 (m, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.66 (ddd, J = 7.9, 2.5, 1.0 Hz, 1H), 5.11 (s, 2H), 4.00 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z: 518 [M+H]+. lll-b-6 ’H NMR (600 MHz, DMSO-d6) 5 10.52 (s, 1H), 10.00 (s, 1H), 8.34 (d, J = 8.1 Hz, 2H), 8.23 (s, 2H), 8.09- 8.04 (m, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.60- 7.55 (m, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.45 (d, J = 7.7 Hz, 1H), 4.00 (s, 3H), 2.34 (s, 3H). MS (ESI) m/z. 537 [M+HJ*. lll-b-7 1H NMR (600 MHz, DMSO-d6) 5 10.52 (s, 1H), 9.82 (s, 1H), 9.81 (s, 1H), 8.23 (d, J = 7.1 Hz, 2H), 8.18 (d, J= 8.3 Hz, 2H), 8.07 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (d, J= 7.7 Hz, 1H), 6.77 (d, J= 8.4 Hz, 2H), 3.97 (s, 3H), 2.34 (s, 3H). MS (ESI) 61 IEC170116PCT ca 03071900 2020-02-03 m/z: 519 [M+H]+. lll-b-8 1H NMR (600 MHz, DMSO-d6) 5 10.52 (s, 1H), 8.23 (d, J = 10.7 Hz, 2H), 8.07 (dd, J = 18.3, 8.3 Hz, 3H), 7.90 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.55 (d, J » 8.0 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.71- 6.66 (m, 1H), 6.54 (d, J = 8.4 Hz, 2H), 5.53 (s, 2H), 3.95 (s, 3H), 2.34 (s, 3H). MS (ESI) m/z: 518 [M+HJ*. lll-b-9 - teA8, ^H NMR (600 MHz, DMSO-d6) 6 10.51 (s, 1H), 9.74 (s, 1H), 8.26 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.09- 8.04 (m, 1H), 8.03-7.95 (m, 1H), 7.90 (dd, J- 7.9, 1.9 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 - 7.42 (m, 1H), 3.93 (s, 3H), 2.35 (s, 3H). MS (ESI) m/z: 493 [M+H]+. lll-b-10 ’H NMR (600 MHz, DMSO-d6) 5 10.53 (s, 1H), 9.99 (s, 1H), 9.46 (s, 1H), 8.72 - 8.53 (m, 2H), 8.29 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 4.5 Hz, 1H), 7.96 (d, J= 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.68 (d, J= 8.3 Hz, 1H), 7.49 (dd, J = 7.9, 4.8 Hz, 1H), 7.40 (d, J= 8.3 Hz, 1H), 4.00 (s, 3H), 2.23 (s, 3H). MS (ESI) m/z: 504 [M+Hf. lll-b-11 nH NMR (600 MHz, DMSO-d6) 5 10.48 (s, 1H), 10.09 (s, 1H), 9.42 (s, 1H), 8.63 (dd, J = 4.8, 1.7 Hz, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 8.6, 2.2 Hz, 1H), 7.94 (d, J= 8.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.57 (d, J= 8.1 Hz, 1H), 7.46 (dd, J = 8.1,4.8 Hz, 1H), 4.02 (s, 3H), 3.55 (s, 2H), 2.45 - 2.31 (m, 8H), 2.35 (s, 3H), 2.16 (s, 3H). MS (ESI) m/r. 616 [M+H]*. lll-b-12 HN.

Ô H NMR (600 MHz, Methanol-d4) 6 8.66 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 4.8 Hz, 1H), 7.99 (s, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.38 (dd, J= 7.9, 4.9 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.84 (dd, J = 7.9, 2.3 Hz, 1H), 4.90 (s, 2H), 3.99 (s, 3H). MS (ESI) m/z: 332 [M+H]+. lll-b-13 hL cN 1H NMR (600 MHz, Methanol-d4) 6 8.46 (d, J = 5.3 Hz, 2H), 8.04 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 5.2 Hz, 2H), 7.15 (t, J= 7.8 Hz, 1H), 6.82 (dd, J = 7.9, 2.3 Hz, 1H), 4.95 (s, 2H), 4.02 (s, 3H). MS (ESI) m/z: 332 [M+Hf. 62 IEC170116PCT lll-b-14 à qH NMR (600 MHz, Methanol-d4) 6 8.71 (d, J = 2.0 Hz, 1H), 8.54 (t, J = 1.9 Hz, 1H), 8.41 (dd, J = 4.9, 1.7 Hz, 1H), 8.13 (dt, J = 7.8, 1.3 Hz, 1H), 8.01 (d, J= 9.8 Hz, 2H), 7.93 (s, 1H), 7.63 (dd, J = 8.3, 2.1 Hz, 1H), 7.60 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.42- 7.37 (m, 2H), 7.30- 7.27 (m, 1H), 4.95 (s, 2H), 4.03 (s, 3H). MS (ESI) m/z: 519 [M+H]* lll-b-15 "à 1H NMR (600 MHz, DMSO-d6) 5 10.18 (s, 1H), 10.09 (s, 1H), 8.86 (t, J = 5.9 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.46 (dd, J= 4.8, 1.5 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.79- 7.77 (m, 1H), 7.64-7.60 (m, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.46 (q, J = 8.0 Hz, 2H), 7.34 (dd, J = 7.9, 4.7 Hz, 1H), 4.87 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H). MS (ESI) m/z: 535 [M+H]*. lll-b-16 1H NMR (600 MHz, Methanol-d4) 6 8.50 (s, 1H), 8.45- 8.41 (m, 2H), 8.21 (d, J = 7.7 Hz, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.70 (dd, J = 8.3, 1.9 Hz, 1H), 7.52- 7.46 (m, 4H), 7.44- 7.40 (m, 2H), 4.91 (s, 2H), 4.01 (s, 3H). MS (ESI) m/z: 535 [M+H]*. lll-b-17 HN. ô TFA sait H NMR (600 MHz, DMSO-d6) 5 10.27 (s, 1H), 9.30 (s, 1H), 8.87 (t, J = 5.7 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 7.9, 4.8 Hz, 1H), 7.30 (dd, J = 8.8, 2.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.90 (d, J = 5.6 Hz, 2H), 3.97 (s, 3H), 3.83 (s, 3H). MS (ESI) m/z: 576 [M+H]*. lll-b-18 HN. ô TFA sait 1H NMR (600 MHz, DMSO-d6) 5 9.55 (s, 1H), 8.87 (d, J = 6.2 Hz, 1H), 8.72 (s, 1H), 8.47 (dt, J= 5.8, 1.7 Hz, 2H), 8.41 (d, J= 2.7 Hz, 2H), 8.12 (s, 1H), 8.08 (dd, J = 7.8, 1.4 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.72- 7.69 (m, 1H), 7.42 - 7.36 (m, 2H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.91 (d, J= 5.9 Hz, 2H), 3.98 (s, 3H), 3.90 (s, 3H). MS (ESI) m/z: 560 [M+H]*. lll-c-1 nH NMR (600 MHz, DMSO-d6) 6 10.49 (s, 1H), 9.37 (s, 1H), 9.35 (s, 1H), 8.78 (d, J = 4.7 Hz, 1H), 8.58 (d, J= 8.0 Hz, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.09 (d, J= 8.3 Hz, 1H), 7.77 (d, J= 8.0 Hz, 63 IEC170116PCT 1H), 7.60 (t, J = 8.3 Hz, 2H), 7.45 (dd, J = 7.9, 3.3 Hz, 2H), 3.91 - 3.85 (m, 3H), 2.39 (s, 3H). MS (ESI) m/z: 504 [M+Hf.

Synthetic route of compounds IV-a-1, IV-b-1: 14a R* «H 14b R3* Me 15a R3 H15bR’=M« IV-a-1R’-H IV-b-1R’-Ma Compounds IV-a-1, IV-b-1 were respectively synthesized from 14a, 14b through Method C, Method D in sequence.

Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure 1H NMR and/or MS data1H NMR (600 MHz, DMSO-cfe) 5 10.49 (s, IV-a-1 X-N R U qA « 1H), 9.53 - 9.29 (m, 2H), 8.61 - 8.52 (m, 2H), 8.33- 8.25 (m, 3H), 8.17 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 490 [M+H]+.

IV-a-2 k'vSt'n fl H H *H NMR (600 MHz, MeOD) 5 8.91 (s, 1H), 8.54 (dd, J = 4.6, 1.6 Hz, 2H), 8.38 (dd, J = 4.6, 1.6 Hz, 2H), 8.30 (s, 1H), 8.20 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 7.9, 1.7 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 2.52 (s, 3H). MS (ESI) m/z: 490 [M+H]+.

IV-a-3 1H NMR (600 MHz, DMSO-cfe) 5 10.59 (s, 1H), 9.63 (s, 1H), 9.34 (d, J = 1.7 Hz, 1H), 8.55 (dd, J = 4.7, 1.7 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.09 (d, J= 8.2 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z: 490 [M+Hf.

IV-a-4 o N " 0 MS (ESI) m/z: 602 [M+Hf. 64 IEC170116PCT IV-a-5 TFAsalt MS (ESI) m/z: 602 [M+H]+.

IV-a-6 1H NMR (600 MHz, DMSO-d6) 6 10.48 (s, 1H), 9.56 (s, 1H), 9.34 (s, 1H), 8.58 (d, J = 4.2 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 6.0 Hz, 1H), 7.94 (s, 1H), 7.86- 7.72 (m, 2H), 7.57 - 7.46 (m, 2H), 7.45 - 7.35 (m, 1H), 7.09 (d, J = 7.3 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 506 [M+H]+.

IV-a-7 'H NMR (600 MHz, DMSO-de) 6 10.51 (s, 1H), 9.58 (s, 1H), 8.66- 8.54 (m, 2H), 8.42 - 8.33 (m, 2H), 8.11 (s, 2H), 7.97 (s, 1H), 7.89 - 7.75 (m, 2H), 7.59 - 7.41 (m, 2H), 7.09 (d, J - 7.8 Hz, 1H), 2.39 (s, 3H). MS (ESI) m/z: 506 [M+Hf.

IV-b-1 *H NMR (600 MHz, DMSO-cfe) 5 10.47 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.34- 8.23 (m, 3H)), 8.20 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.79 (t, J = 7.4 Hz, 1H), 7.69 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 6.92 (s, 1H), 2.28 (s, 3H). MS (ESI) m/z: 479 [M+H]+.

IV-b-2 ’H NMR (600 MHz, DMSO-d6) 5 10.53 (s, 1H), 9.63 (s, 1H), 9.38 (d, J= 1.3 Hz, 1H), 8.59 (dd, J = 4.7, 1.5 Hz, 1H), 8.56- 8.52 (m, 1H), 8.31 (d, J = 3.2 Hz, 2H), 8.25 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.47 - 7.39 (m, 2H), 3.88 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 504 [M+H]+.

IV-b-3 nH NMR (600 MHz, DMSO-d6) 3 10.54 (s, 1H), 9.65 (s, 1H), 8.62 (s, 2H), 8.35 (d, J = 3.4 Hz, 2H), 8.26 (s, 1H), 8.19 - 8.05 (m, 3H), 7.87 (s, 1H), 7.68- 7.38 (m, 3H), 3.88 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 504 [M+Hf.

IV-b-4 ’H NMR (600 MHz, DMSO-cfe) 3 10.53 (s, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.18 (d, J- 0.9 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.80 (dd, J= 7.9,1.7 Hz, 1H), 7.70 (t, J= 1.6 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.46 (dd, J- 11.7, 8.0 Hz, 2H), 6.92 (d, J = 1.6 Hz, 1H), 3.83 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 493 [M+H]\ 65 IEC170116PCT IV-b-5 ’H NMR (600 MHz, DMSO-d6) 5 10.54 (s, 1H), 9.37 (s, 1H), 8.44 (d, J= 1.9 Hz, 1H), 8.28 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.11 (dd, J= 3.1, 1.1 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.82 (dd, J= 7.9, 1.9 Hz, 1H), 7.70 (dd, J= 5.0, 1.2 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.52 (dd, J = 5.0, 3.0 Hz, 1H), 7.49 (d, J' 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 3.84 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 509 [M+Hf IV-b-6 ’H NMR (600 MHz, DMSO-d6) 5 10.47 (s, 1H), 9.04 (s, 1H), 8.35- 8.24 (m, 4H), 8.20 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 3.80 (s, 3H), 2.27 (s, 3H). MS (ESI) m/z: 493 [M+H]+.

IV-b-7 1H NMR (600 MHz, DMSO-d6) 5 10.49 (s, 1H), 9.45 (s, 1H), 9.40 (d, J= 1.9 Hz, 1H), 8.62 - 8.54 (m, 2H), 8.30 (s, 1H), 8.28 - 8.25 (m, 2H), 8.14 (d, J= 1.9 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.59 (dd, J= 8.2, 2.1 Hz, 1H), 7.43 (dd, J = 7.5, 5.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 2.25 (s, 3H). MS (ESI) m/z: 504 IM+HJ*.

IV-b-8 nA^N s-^ ’H NMR (600 MHz, DMSO-d6) 5 10.48 (s, 1H), 9.15 (s, 1H), 8.31 (s, 1H), 8.28 (d, J= 7.9 Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 8.19 (d, J = 2.9 Hz, 1H), 7.96 (d, J= 7.7 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.55- 7.50 (m, 2H), 7.28 (d, J = 8.2 Hz, 1H), 3.81 (d, J- 9.9 Hz, 3H), 2.26 (s, 3H). MS (ESI) m/z: 509 [M+H]+ IV-b-9 TFAsalt MS (ESI) m/z: 616 [M+H]* IV-b-10 Cr^ ° rt TFAsalt MS (ESI) m/z: 616 [M+Hf.

IV-b-11 *H NMR (600 MHz, DMSO-d6) Ô 10.49 (s, 1H), 9.62 (s, 1H), 9.38 (s, 1H), 8.56 (ddd, J = 11.7, 8.0, 3.2 Hz, 2H), 8.30 (s, 2H), 7.95 (s, 1H), 7.85 (dd, J = 7.9, 1.7 Hz, 1H), 7.81 (dd, J = 8.3, 1.1 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.43 (dd, J = 7.9, 4.8 Hz, 1H), 7.09 (d, J 66 IEC170116PCT = 8.2 Hz, 1H), 3.88 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 520 [M+H]+.

IV-b-12 ’H NMR (600 MHz, DMSO-cfe) 6 10.50 (s, 1H), 9.64 (s, 1H), 8.63 (s, 2H), 8.35 (d, J = 6.6 Hz, 2H), 8.15 (s, 2H), 7.96 (s, 1H), 7.87 - 7.74 (m, 2H), 7.50 (dd, J = 19.4, 8.2 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 520 [M+H]+.

IV-b-13 'n b X» o u w ^H NMR (600 MHz, DMSO-cfe) 5 10.48 (s, 1H), 9.26 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.85 - 7.77 (m, 2H), 7.70 (s, 1H), 7.57-7.40 (m, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 3.82 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 509 [M+Hf.

Compounds V-a-1, V-b-1 were respectively synthesized from 16a, 16b through Method C, Method D in sequence.

Synthetic route of compound V-c-1: Compound V-c-1 was synthesized from 16c through Method D, Method B, Method E in sequence.

Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural charactenzation data.

No. Structure 1H NMR and/or MS data1H NMR (600 MHz, DMSO-cfe) 5 11.27 (s, 1H), V-a-1 HN 10.68 (s, 1H), 9.68 (s, 1H), 9.60 (s, 1H), 8.75 (d, J = 7.7 Hz, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 8.23 (d, J= 7.9 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.67- 7.61 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 7.45- 7.40 (m, 1H), 6.63 (s, 1H). MS (ESI) 67 IEC170116PCT m/z: 475 [M+H]*.

V-a-2 1H NMR (600 MHz, DMS0-d6) 5 12.81 (s, ÏH), 11.37 (s, 1H), 10.52 (s, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.48 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.2, 2.0 Hz, 1H), 8.06 (s, 2H), 7.76 (dd, J = 7.9, 1.9 Hz, 1H), 7.66 (t, J = 2.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 - 7.45 (m, 2H), 6.48 (dd, J= 3.1, 1.7 Hz, 1H), 2.47 (s, 3H). MS (ESI) m/z: 478 [M+H]+.

V-a-3 ]H NMR (600 MHz, DMSO-cfe) 5 11.37 (s, 1H), 10.51 (s, 1H), 9.44 (d, J= 1.5 Hz, 1H), 8.72 (s, 1H), 8.62 (dt, J = 8.0, 1.9 Hz, 1H), 8.54 (dd, J = 4.7, 1.7 Hz, 1H), 8.43 (d, J= 2.0 Hz, 1H), 8.31 (s, 1H), 8.28 (d, J= 7.9 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.73 (t, J = 2.9 Hz, 1H), 7.55 (dd, J = 8.2, 2.1 Hz, 1H), 7.39 (dd, J = 7.9, 4.7 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.60 (dd, J= 2.9, 1.9 Hz, 1H), 2.34 (s, 3H). MS (ESI) m/z: 489 [M+H]+.

V-a-4 nH NMR (600 MHz, DMSO-cfe) 5 11.48 (s, 1H), 10.52 (s, 1H), 8.78 (s, 1H), 8.58 (d, J= 6.1 Hz, 2H), 8.43 (dd, J- 3.9, 2.2 Hz, 1H), 8.30 (s, 1H), 8.28 (d, J= 7.9 Hz, 1H), 8.24 (dd, J ~ 4.6, 1.5 Hz, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.75 (t, J = 2.9 Hz, 1H), 7.52 (ddd, J = 8.1, 3.9, 2.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 2.9, 2.0 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z: 489 [M+H]+.

V-a-5 hn-z^anA^ H NMR (600 MHz, DMSO-d6) 5 11.47 (s, 1H), 10.53 (s, 1H), 9.41 (d, J = 1.6 Hz, 1H), 8.82 (s, 1H), 8.66 (d, J = 1.7 Hz, 1H), 8.59 (dt, J = 8.0, 1.9 Hz, 1H), 8.53 (dd, J= 4.7, 1.7 Hz, 1H), 8.24 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 7.9, 1.7 Hz, 1H), 7.75 (t, J = 2.5 Hz, 1H), 7.60 (t, J- 8.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 7.9, 4.7 Hz, 1H), 6.62 (s, 1H), 2.45 (s, 3H). MS (ESI) m/z: 489 [M+Hf.

V-a-6 ’H NMR (600 MHz, DMSO-cfe) 5 11.54 (s, 1H), 10.56 (s, 1H), 8.82 (s, 1H), 8.75 (d, J= 1.6 Hz, 1H), 8.54 (dd, J= 4.5, 1.5 Hz, 2H), 8.26 (s, 1H), 8.20 (dd, J = 4.5, 1.5 Hz, 2H), 8.09 (d, J = 8.6 Hz, 1H), 7.81 (dd, J- 7.9, 1.8 Hz, 1H), 7.79 (t, J = 2.8 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 6.65 (dd, J = 2.8, 1.8 Hz, 1H), 2.46 (s, 3H). MS (ESI) m/z: 489 [M+Hf.

V-a-7 "1^ 10.67 'H (s, 1H), NMR (s, 8.60 (600 1H), (d, MHz, 9.42 J = 6.4 DMSO-cfe) (s,Hz, 1H), 1H), 8.80 58.54 11.46 (s,-1H), 8.50 (s, 8.71 1H), (m, 68 IEC170116PCT 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.83 (d, J= 7.7 Hz, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.39 - 7.34 (m, 1H), 6.62 (s, 1H), 2.47 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z: 569 [M+Hf.

V-a-8 ’H NMR (600 MHz, DMSO-d6) 5 11.54 (s, 1H), 10.68 (s, 1H), 8.83 (s, 1H), 8.76 (d, J= 1.8 Hz, 1H), 8.55 (d, J= 6.0 Hz, 2H), 8.31 (s, 1H), 8.21 (s, 1H), 8.20 (dd, J = 4.5, 1.6 Hz, 2H), 8.18 (s, 1H), 7.83 (dd, J = 7.9, 1.8 Hz, 1H), 7.80 (t, J = 2.9 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 6.65 (dd, J= 3.0, 2.0 Hz, 1H), 2.47 (s, 3H), 2.19 (d, J = 0.8 Hz, 3H). MS (ESI) m/z: 569 [M+Hf.

V-a-9 nH NMR (600 MHz, DMSO-d6) 5 12.29 (s, 1H), 10.56 (s, 1H), 9.95 (s, 1H), 9.32 (s, 1H), 8.74 (s, 1H), 8.70 (d, J = 6.4 Hz, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.71 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 3.69 (s, 2H), 3.48 - 3.37 (m, 2H), 3.10 - 3.00 (m, 2H), 2.98- 2.88 (m, 2H), 2.81 (s, 3H), 2.44 (s, 3H), 2.42 - 2.35 (m, 2H). MS (ESI) m/z: 601 [M+Hf.

V-a-10 ’H NMR (600 MHz, DMSO-d6) 6 11.59 (s, 1H), 10.50 (s, 1H), 8.85 (s, 1H), 8.74 (d, J= 1.5 Hz, 1H), 8.54 (dd, J= 4.6, 1.5 Hz, 2H), 8.22 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 4.6, 1.5 Hz, 2H), 8.07 (dd, J = 8.5, 1.7 Hz, 1H), 7.80 (dd, J = 7.9, 1.6 Hz, 1H), 7.78 (t, J = 2.5 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 3.57 (s, 2H), 2.46 (s, 3H), 2.44 - 2.27 (m, 8H), 2.18 (s, 3H). MS (ESI) m/z: 601 [M+Hf.

V-a-11 ’H NMR (600 MHz, DMSO-d6) 5 11.76 (s, 1H), 10.54 (s, 1H), 9.07 (s, 1H), 8.70 (d, J= 2.1 Hz, 1H), 8.30 (t, J=1.6 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.08 (dt, J= 8.3, 1.3 Hz, 1H), 7.79 (dd, J = 7.9, 1.9 Hz, 1H), 7.73 (t, J = 2.9 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.47- 7.42 (m, 1H), 7.35- 7.28 (m, 3H), 6.57 (dd, J = 3.0, 1.9 Hz, 1H), 2.46 (s, 3H). MS (ESI) m/z: 488 [M+Hf.

V-a-12 N iT à ° 1H NMR (600 MHz, DMSO-d6) 5 12.54 (s, 1H), 10.59 (s, 1H), 10.51 (s, 1H), 8.39 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.09- 8.04 (m, 1H), 7.97 (t, J = 2.9 Hz, 1H), 7.94 (dd, J = 8.0, 1.8 Hz, 1H), 7.60 (t, J= 8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.46 (d, J = 7.3 Hz, 2H), 7.36 (s, 1H), 7.21 (t, J - 7.9 Hz, 1H), 6.93- 6.83 (m, 1H), 6.67 (t, J = 69 IEC170116PCT 2.3 Hz, 1H), 2.43 (s, 3H). MS (ESI) m/z: 503 [M+Hf.

V-a-13 1H NMR (600 MHz, DMSO-d6) 5 11.44 (s, 1H), 10.54 (s, 1H), 8.74 (d, J= 1.9 Hz, 1H), 8.72 (s, 1H), 8.34- 8.29 (m, 2H), 8.24 (d, J - 2.0 Hz, 1H), 8.10-8.04 (m, 1H), 7.77 (dd, J= 7.9, 1.9 Hz, 1H), 7.73 (t, J = 2.9 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.36- 7.30 (m, 2H), 6.57 (dd, J = 3.0, 2.0 Hz, 1H), 2.44 (s, 3H). MS (ESI) m/z. 504 [M+Hf.

V-a-14 7H NMR (600 MHz, DMSO-d6) 5 12.32 (s, 1H), 10.56 (s, 1H), 10.09 (s, 1H), 8.53 (d, J= 1.9 Hz, 1H), 8.28 (d, J= 2.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.05 (dd, J = 8.3, 1.9 Hz, 1H), 7.94 (t, J= 3.0 Hz, 1H), 7.91 (dd, J = 7.9, 1.8 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.7, 3.8 Hz, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.44 (d,J- 7.7 Hz, 1H), 6.68 (t, J= 2.4 Hz, 1H), 2.44 (s, 3H). MS (ESI) m/z: 522 [M+Hf.

V-a-15 H NMR (600 MHz, DMSO-d6) 5 11.41 (s, 1H), 10.48 (s, 1H), 8.89 (q, J= 3.2, 2.5 Hz, 1H), 8.78 (s, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.57 (dt, J = 7.7, 1.5 Hz, 1H), 8.20 (t, J' 2.0 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.90 (dt, J = 7.6, 1.5 Hz, 1H), 7.81 (dd, J= 8.0, 1.9 Hz, 1H), 7.74 (t, J= 2.9 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.51 (d, J= 8.2 Hz, 1H), 7.49- 7.41 (m, 2H), 6.61 (dd, J = 3.0, 1.9 Hz, 1H), 2.45 (s, 3H). MS (ESI) m/z: 532 [M+Hf.

V-a-16 1H NMR (600 MHz, DMSO-d6) 6 12.34 (s, 1H), 10.52 (s, 1H), 10.21 (s, 1H), 8.75 (d, J- 1.8 Hz, 1H), 8.45 (s, 1H), 8.44 (dt, J= 7.8, 1.4 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.09 - 8.03 (m, 2H), 7.97 - 7.92 (m, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.58 (t, J= 8.1 Hz, 2H), 7.43 (d, J=7.8Hz, 1H), 6.70 (dd, J = 3.0, 1.9 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.25 (t, J= 7.1 Hz, 3H). MS (ESI) m/z: 560 [M+H]+.

V-a-17 1H NMR (600 MHz, DMSO-de) 5 11.31 (s, 1H), 10.51 (s, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.3, 1.9 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.76 (dd, J = 7.9, 1.8 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.53- 6.42 (m, 3H), 5.32 (s, 2H), 2.43 (s, 3H). MS (ESI) m/z: 503 [M+Hf 70 IEC170116PCT V-a-18 1H NMR (600 MHz, DMSO-cfe) 5 12.44 (s, 1H), 10.57- 10.35 (m, 2H), 9.85 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.62- 7.57 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 2.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.67 (q, J= 1.8 Hz, 1H), 2.41 (s, 3H). MS (ESI) 504 [M+H]*.

V-a-19 H NMR (600 MHz, DMSO-cfe) 5 11 06 (s, 1H), 10.58 (s, 1H), 8.43 (s, 1H), 8.27 (d, J = 8.2 Hz, 2H), 8.24 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 8.06 - 7.98 (m, 3H), 7.93 (dd, J = 7.9, 1.8 Hz, 1H), 7.60 (t, J= 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (d, J =7.7 Hz, 1H), 6.72 (t, J = 2.4 Hz, 1H), 1.21 (s, 3H). MS (ESI) m/z: 532 [M+H]*.

V-a-20 EtOjC'^’^ ^H NMR (600 MHz, DMSO-cfe) 6 12.27 (s, 1H), 10.57 (s, 1H), 10.01 (s, 1H), 8.58 (s, 1H), 8.32 (d, J = 8.2 Hz, 2H), 8.26 (d, J = 1.9 Hz, 1H), 8.07 (dd, J = 8.2, 2.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.95 (t, J = 3.0 Hz, 1H), 7.90 (dd, J = 7.9, 1.8 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 2.4 Hz, 1H), 4.31 (q, J= 7.1 Hz, 2H), 2.44 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI) m/z: 560 [M+H]*.

V-a-21 0i H ï L /> MS (ESI) m/z: 296 [M+H]*.

V-a-22 TFAsalt ‘‘H NMR (600 MHz, DMSO-cfe) 5 12.55 (s, 1H), 10.56 (s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.30 (dd, J = 9.2, 2.2 Hz, 1H), 7.98 (t, J = 8.5 Hz, 2H), 7.89 (t, J = 2.9 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 4.13-4.11 (m, 4H), 3.86-3.84 (m, 4H). MS (ESI) m/z: 416 [M+H]*.

V-a-23 ]H NMR (600 MHz, DMSO-cfe) 5 11.54 (s, 1H), 10.62 (s, 1H), 8.73 (t, J = 2.0 Hz, 1H), 8.37 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.21 - 8.14 (m, 1H), 8.01- 7.93 (m, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.61 (d, J= 3.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 3.88 - 3.80 (m, 8H). MS (ESI) m/z: 416 [M+H]*.

V-a-24 0 8.82 <H NMR (s, 1H), (6008.50 MHz, (d, DMSO-cfe) J = 7.8 Hz, 5 10.80 1H), 8.28 (s, 1H), (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.86 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 71 IEC170116PCT 7.63 (t, J = 8.0 Hz, 1H), 7.49 (d, J= 7.8 Hz, 1H), 6.67 (s, 1H), 4.09 (s, 4H), 3.86- 3.84 (m, 4H).

MS (ESI) m/z:468 [M+Hf.

V-a-25 TFA sait 1H NMR (600 MHz, DMSO-d6) 6 12.69 (s, 1H), 10.83 (s, 1H), 10.20 (s, 1H), 8.75 (t, J= 1.9 Hz, 1H), 8.34- 8.30 (m, 2H), 8.02- 8.00 (m, 2H), 7.92 (t, J = 3.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 6.69 (dd, J = 2.9, 1.4 Hz, 1H), 5.00 (s, 2H), 3.65 (s, 1H), 3.42 (s, 2H), 2.79 (d, J = 1.8 Hz, 6H), 2.23 (d, J = 11.7 Hz, 2H), 1.83 (qd, J = 12.3, 4.1 Hz, 2H). MS (ESI) m/z: 509 [M+Hf.

V-a-26 5 }H NMR (600 MHz, DMSO-d6) 5 11.47 (s, 1H), 10.73 (s, 1H), 8.95 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 6.1 Hz, 2H), 7.57 (s, 1H), 7.47 (s, 1H), 6.56 (s, 1H), 4.63 (d, J = 13.0 Hz, 2H), 3.82- 3.71 (m, 1H), 3.14 (s, 2H), 2.24 (s, 6H), 1.94 (d, J= 11.7 Hz, 2H), 1.53 (q, J= 10.7 Hz, 2H). MS (ESI) m/z: 509 [M+Hf.

V-a-27 TFA sait qH NMR (600 MHz, DMSO-d6) 5 12.64 (s, 1H), 10.54 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.29 (dd, J = 9.2, 2.0 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 7.62 (td, J= 8.0, 3.3 Hz, 1H), 6.95 (d, J = 9.1 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 4.73 (s, 2H), 3.79 (ddd, J = 10.4, 6.2, 2.5 Hz, 2H), 3.06 (s, 2H), 1.27 (d, J = 6.2 Hz, 6H). MS (ESI) m/z: 444 [M+Hf.

V-a-28 nH NMR (600 MHz, DMSO-d6) 5 11 65 (s, 1H), 10.62 (s, 1H), 8.76 (t, J = 1.9 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J= 7.9 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.95- 7.93 (m, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.48 (t, J = 7.8 Hz, 1H), 6.56 (s, 1H), 4.51 (s, 2H), 3.81- 3.73 (m, 2H), 2.83 (t, J = 11.4 Hz, 2H), 1.25 - 1.23 (m, 6H). MS (ESI) m/z 496 (M+Hf.

V-a-29 9- TFA sait ’H NMR (600 MHz, DMSO-d6) 5 12.56 (s, 1H), 10.55 (s, 1H), 8.67 (d, J= 1.6 Hz, 1H), 8.63 (t, J = 1.7 Hz, 1H), 8.28 (dd, J = 9.2, 2.2 Hz, 1H), 7.98 (dd, J = 8.1, 1.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 2.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 4.13 -4.09 (m, 4H), 1.79 - 1.75 (m, 6H).MS (ESI) m/z: 414 [M+Hf.

V-a-30 9. 10.79 ]H NMR (s,(600 1H), MHz, 8.69 (t, DMSO-d6) J = 1.8 Hz, 5 12.44 1H), 8.33 (s, 1H), (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.04 - 7.96 (m, 3H), 7.82 (dd, J - 9.7, 5.4 Hz, 2H), 7.64 (t, J = 72 IEC170116PCT TFA sait 7.9 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 4.12 - 4.09 (m, 4H), 1.78 - 1.73 (m, 6H). MS (ESI) m/z: 466 [M+Hf.

V-a-31 Q ’H NMR (600 MHz, DMSO-cfe) 5 11.43 (s, 1H), 10.73 (s, 1H), 8.95 (t, J = 1.7 Hz, 1H), 8.62 - 8.57 (m, 1H), 8.30 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.00- 7.95 (m, 1H), 7.62 (td, J = 7.9, 4.1 Hz, 2H), 7.55 (t, J= 2.9 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 6.55 (dd, J = 2.9, 1.2 Hz, 1H), 3.88- 3.85 (m, 4H), 1.73 - 1.67 (m, 6H). MS (ESI) m/z: 466 [M+HJ*.

V-a-32 9. ’H NMR (600 MHz, DMSO-cfe) 5 11.27 (s, 1H), 10.02 (s, 1H), 8.68 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.99 (dd, J= 8.7, 2.5 Hz, 1H), 7.88 (dd, J= 8.0, 1.1 Hz, 1H), 7.49 (s, 1H), 7.40- 7.35 (m, 1H), 6.60 (s, 2H), 6.50 (d, J = 8.7 Hz, 1H), 6.47 (d, J = 2.7 Hz, 1H), 3.88 (t, J = 6.5 Hz, 4H), 2.02 (t, J « 6.5 Hz, 4H).

MS (ESI) m/z: 400 [M+H]+.

V-a-33 qh TFA sait ’H NMR (600 MHz, DMSO-cfe) 5 12.41 (s, 1H), 10.82 (s, 1H), 8.71 (t, J - 1.7 Hz, 1H), 8.34- 8.29 (m, 2H), 8.02 (dd, J = 8.1, 1.3 Hz, 1H), 7.99- 7.94 (m, 2H), 7.82- 7.76 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 6.59 (dd, J = 2.8, 1.7 Hz, 1H), 3.98- 3.95 (m, 4H), 2.03- 2.01 (m, 4H).

MS (ESI) m/z: 452 [M+Hf.

V-a-34 1H NMR (600 MHz, DMSO-cfe) 6 12.32 (s, 1H), 10.60 (s, 1H), 9.34 (s, 1H), 8.74 (s, 1H), 8.68 (d, J = 1.8 Hz, 1H), 8.34 (dd, J - 9.2, 2.0 Hz, 1H), 7.98 (S, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 6.59 (s, 1H), 3.34 (s, 1H), 1.00 (d, J= 5.9 Hz, 2H), 0.78- 0.76 (m, 2H). MS (ESI) m/z: 386 [M+Hf.

V-a-35 HN^ A NMR (600 MHz, DMSO-cfe) 5 12.09 (s, 1H), 10.79 (s, 1H), 9.16 (s, 1H), 8.78 (s, 1H), 8.34 (s, 1H), 8.31 (d, J= 7.9 Hz, 1H), 8.03-7.97 (m, 3H), 7.82 (t, J = 7.7 Hz, 2H), 7.65 (t, J- 8.0 Hz, 1H), 6.61- 6.58 (m, 1H), 3.32 (d, J = 3.7 Hz, 1H), 1.00 (q, J = 6.7 Hz, 2H), 0.78 - 0.74 (m, 2H).MS (ESI) m/z: 438 [M+Hf.

V-a-36 Q VU 0 H T U [ I nH NMR (600 MHz, MeOD) 5 8.19 (d, J - 1.9 Hz, 1H), 8.15 - 8.13 (m, 1H), 7.93 - 7.89 (m, 2H), 7.60 (d, J= 3.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.44 (d, J ~ 8.0 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.18 - 7.13 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.43 (d, J = 3.0 Hz, 1H), 2.43 (s, 3H). 73 IEC170116PCT V-a-37 ç JQt h CFa 1H NMR (600 MHz, DMSO-d6) 6 12.16 (brs, 1H), 10.60 (s, 1H), 9.68 (s, 1H), 9.30 (t, J = 2.0 Hz, 1H), 8.97 (dt, J= 5.7, 1.5 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.24- 8.22 (m, 1H), 8.09-8.05 (m, 1H), 7.95 (t, J = 3.0 Hz, 1H), 7.88 (dd, J = 7.9, 1.9 Hz, 1H), 7.80- 7.72 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 6.79 (brs, 1H), 6.72 (dd, J = 3.1, 1.9 Hz, 1H), 2.45 (s, 3H).

V-a-38 Q 1H NMR (600 MHz, DMSO-d6) 5 12.01- 11.93 (m, 1H), 10.54 (s, 1H), 9.53 (s, 1H), 9.14-9.09 (m, 2H), 8.67 - 8.64 (m, 1H), 8.50 (d, J = 1.9 Hz, 1H), 8.21 (d, J= 1.9 Hz, 1H), 8.13 (dd, J= 8.3, 2.0 Hz, 1H), 7.89- 7.85 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 6.92- 6.88 (m, 2H), 6.63 (dd, J = 3.0, 1.9 Hz, 1H), 2.44 (s, 3H).

V-a-39 9\X^N o 1H NMR (600 MHz, DMSO-d6) 6 12.47 (brs, 1H), 11.92 (brs, 1H), 10.51 (s, 1H), 10.01 (s, 1H), 8.32 (brs, 1H), 8.26- 8.22 (m, 1H), 8.09 (brs, 1H), 8.06 (dd, J = 8.9, 1.7 Hz, 1H), 7.86 (dd, J = 8.0, 1.9 Hz, 1H), 7.65 (t, J = 3.0 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.52 (d, J= 8.1 Hz, 1H), 7.48 - 7.44 (m, 1H), 6.32 (t, J = 2.5 Hz, 1H), 3.93 (h, J= 7.0 Hz, 1H), 2.40 (s, 3H), 1.87 -1.75 (m, 2H),1.60-1.48 (m, 2H), 1.47- 1.29 (m, 4H) V-a-40 9 r9 ~yN^NH s n ’H NMR (600 MHz, DMSO-d6) 6 12.47 (brs, 1H), 11.92 (brs, 1H), 10.51 (s, 1H), 10.01 (s, 1H), 8.32 (brs, 1H), 8.26 - 8.22 (m, 1H), 8.09 (brs, 1H), 8.06 (dd, J = 8.9, 1.7 Hz, 1H), 7.86 (dd, J = 8.0, 1.9 Hz, 1H), 7.65 (t, J = 3.0 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.52 (d, J= 8.1 Hz, 1H), 7.48 - 7.44 (m, 1H), 6.32 (t, J = 2.5 Hz, 1H), 3.93 (h, J = 7.0 Hz, 1H), 2.40 (s, 3H), 1.87 -1.75 (m, 2H),1.60-1.48 (m, 2H), 1.47-1.29 (m, 4H). MS (ESI) m/z: 495 [M+H]+.

V-a-41 Y *H NMR (600 MHz, DMSO-d6) 5 12.43 (brs, 1H), 12.15 (s, 1H), 10.53 (s, 1H), 10.22 (s, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.26 - 8.23 (m, 1H), 8.12 (brs, 1H), 8.09- 8.06 (m, 1H), 7.88 (dd, J = 7.9, 1.9 Hz, 1H), 7.66 (t, J= 3.0 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.47 - 7.44 (m, 1H), 6.40 (t, J = 2.5 Hz, 1H), 2.60- 2.54 (m, 1H), 2.36 (s, 3H), 0.84- 0.67 (m, 2H), 0.62- 0.51 (m, 2H). MS (ESI) m/z 467 [M+Hf.

V-a-42 VU „ ^H NMR (600 MHz, DMSO-d6) 5 12.40 (s, 1H), 12.17 (brs, 1H), 10.53 (s, 1H), 10.21 (s, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.24 - 8.22 (m, 1H), 8.10- 8.07 (m, 1H), 7.88 (dd, J= 7.9, 1.9 Hz, 74 IEC170116PCT 1H), 7.68 (t, J = 3.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.47 - 7.44 (m, 1H), 6.35 (dd, J = 2.9, 2.1 Hz, 1H), 3.62- 3.54 (m, 4H), 2.39 (s, 3H), 1.60-1.54 (m, 2H), 1.53 _ 1.44 (m, 4H). MS (ESI) m/z: 495 [M+H]+.

V-a-43 o ’H NMR (600 MHz, DMSO-d6) 5 12.61 (brs, 1H), 12.22 (brs, 1H), 10.55 (s, 1H), 10.28 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.25- 8.23 (m, 1H), 8.09-8.05 (m, 1H), 7.90 (dd, J= 7.9, 1.9 Hz, 1H), 7.71 (t, J= 3.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.48 - 7.44 (m, 1H), 6.38 (dd, J = 2.9, 2.0 Hz, 1H), 3.67- 3.62 (m, 4H), 3.62- 3.57 (m, 4H), 2.39 (s, 3H). MS (ESI) m/z: 497 [M+H]+.

V-a-44 ç^C” n 7H NMR (600 MHz, DMSO-cfe) 6 10.98- 10.94 (m, 1H), 10.48 (s, 1H), 8.69 (d, J= 1.9 Hz, 1H), 8.33 (s, 1H), 8.24 - 8.21 (m, 1H), 8.09- 8.05 (m, 1H), 7.66 (dd, J = 7.8, 1.9 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 2.9 Hz, 1H), 7.46- 7.44 (m, 1H), 7.42 (dd, J = 7.8, 0.8 Hz, 1H), 6.17 (dd, J = 2.9, 2.0 Hz, 1H), 3.61- 3.51 (m, 4H), 2.42 (s, 3H), 2.23- 2.16 (m, 4H), 2.04 (s, 3H). MS (ESI) m/z 510 [M+H]+.

V-a-45 1H NMR (600 MHz, DMSO-d6) 5 12.08 (brs, 1H), 10.56 (s, 1H), 8.44 (s, 1H), 8.25-8.21 (m, 1H), 8.11- 8.06 (m, 1H), 7.97 (s, 1H), 7.90- 7.85 (m, 2H), 7.61 (t, J= 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48- 7.45 (m, 1H), 7.16-7.12 (m, 1H), 6.68 (s, 1H), 6.61 (t, J = 2.4 Hz, 1H), 2.42 (s, 3H). MS (ESI) m/z: 478 [M+HJ*.

V-a-46 ? n 1H NMR (600 MHz, DMSO-cfe) 5 11.59- 11.54 (m, 1H), 10.58 (s, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.74 (s, 1H), 8.35 - 8.33 (m, 1H), 8.10- 8.06 (m, 1H), 7.80 (dd, J= 7.9, 1.9 Hz, 1H), 7.77 (t, J = 2.9 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.53- 7.49 (m, 2H), 7.48- 7.45 (m, 2H), 7.31 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.22 (td, J = 7.5, 1.0 Hz, 1H), 6.62 (dd, J = 3.0, 2.0 Hz, 1H), 2.48 (s, 3H). MS (ESI) m/z: 528 [M+H]+.

V-a-47 M XX^”^^CF3 ’H NMR (600 MHz, DMSO-cfe) 5 11.36- 11.29 (m, 1H), 11.26-11.21 (m, 1H), 10.55 (s, 1H), 8.68 (d, J= 1.8 Hz, 1H), 8.59 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.24- 8.22 (m, 1H), 8.09-8.05 (m, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.83 (dd, J = 7.9, 1.9 Hz, 1H), 7.66 (t, J = 2.9 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.45 (ddt, J = 7.8, 1.7, 0.8 Hz, 1H), 7.34 (dt, J= 8.1, 1.0 Hz, 1H), 7.01 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 6.91 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.50 75 IEC170116PCT (dd, J= 3.0, 1.8 Hz, 1H), 2.47 (s, 3H). MS (ESI) m/z: 527 [M+H]+.

V-a-48 ^1% q 1H NMR (600 MHz, DMSO-d6) 5 12.08 (s, 1H), 10.57 (s, 1H), 9.71 (brs, 1H), 9.31 (d, J = 2.2 Hz, 1H), 8.82 (dd, J = 5.0, 1.5 Hz, 1H), 8.70 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 8.03 (s, 1H), 7.97 (d, J= 7.9 Hz, 1H), 7.91 (t, J= 3.0 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.56 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.3, 2.3 Hz, 1H), 6.69 (dd, J= 3.0, 2.0 Hz, 1H), 2.22 (s, 3H). MS (ESI) m/z: 525 [M+Hf.

V-a-49 nH NMR (600 MHz, DMSO-d6) 6 12.12 (brs, 1H), 9.87 (brs, 1H), 9.60 (s, 1H), 9.41 (s, 1H), 8.88- 8.76 (m, 2H), 8.12 (d, J = 2.1 Hz, 1H), 8.09 - 8.07 (m, 1H), 7.93 (t, J = 3.0 Hz, 1H), 7.75 (s, 1H), 7.60- 7.55 (m, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.30- 7.27 (m, 2H), 7.24 (dd, J = 8.3, 2.2 Hz, 1H), 6.70 (dd, J = 3.0, 2.0 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z: 504 [M+Hf.

V-a-50 n H H HN^^^N^N^z^CFa ’H NMR (600 MHz, DMSO-d6) 6 11.93 (brs, 1H), 10.20 (s, 1H), 10.17 (s, 1H), 9.88 (brs, 1H), 9.33 (d, J= 2.1 Hz, 1H), 8.80 (dd, J = 5.1, 1.5 Hz, 1H), 8.72 (d, J = 7.9 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.94- 7.89 (m, 2H), 7.75 (dd, J = 8.0, 1.9 Hz, 1H), 7.72 (dd, J= 8.1, 5.2 Hz, 1H), 7.55 (t, J= 8.0 Hz, 1H), 7.46 (d, J= 7.8 Hz, 1H), 7.37 (d, J= 8.3 Hz, 1H), 7.31 (dd, J = 8.2, 2.2 Hz, 1H), 6.71- 6.67 (m, 1H), 2.31 (s, 3H). MS (ESI) m/z: 520 [M+Hf.

V-a-51 ’H NMR (600 MHz, DMSO-d6) ô 12.25 (brs, 1H), 10.27 (s, 1H), 10.03 (brs, 1H), 9.33 (brs, 1H), 8.85- 8.78 (m, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.44 (s, 1H), 7.98-7.94 (m, 1H), 7.90 (dd, J = 8.0, 1.8 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.76 (t, J= 6.7 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.11 (t, J =7 A Hz, 1H), 6.74-6.68 (m, 1H), 2.43 (s, 3H). MS (ESI) m/z: 421 [M+Hf.

V-a-52 1H NMR (600 MHz, DMSO-d6) 5 12.04 (s, 1H), 10.42 (s, 1H), 9.83 (s, 1H), 9.32 (d, J= 2.1 Hz, 1H), 8.79 (dd, J= 5.1, 1.6 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.49- 8.44 (m, 1H), 7.98 (t, J = 2.1 Hz, 1H), 7.94 (t, J = 3.0 Hz, 1H), 7.88 (dd, J = 7.9, 1.9 Hz, 1H), 7.76- 7.72 (m, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.17 (ddd, J= 8.0, 2.1,0.9 Hz, 1H), 6.71 (dd, J= 3.0, 1.9 Hz, 1H), 2.43 (s, 3H). MS (ESI) m/z: 455 [M+Hf. 76 IEC170116PCT V-a-53 M A XI i*YY'n-^Ach! 1H NMR (600 MHz, DMS0-d6) 5 12.13 (s, 1H), 10.20 (s, 1H), 10.11 (s, 1H), 9.26 (s, 1H), 8.79 (d, J = 5.1 Hz, 1H), 8.72 (d, J = 8.1 Hz, 1H), 8.37 (s, 1H), 7.93 (d, J= 3.0 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.77 (dd, J = 8.1, 5.2 Hz, 1H), 7.57- 7.51 (m, 3H), 7.22 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.72 (t, J= 2.3 Hz, 1H), 2.40 (s, 3H), 2.28 (s, 3H). MS (ESI) m/z: 435 [M+H]+.

V-a-54 ri IN H ’H NMR (600 MHz, DMSO-d6) 6 12.08 (brs, 1H), 10.45 (s, 1H), 9.85 (brs, 1H), 9.33 (s, 1H), 8.79 (d, J = 5.0 Hz, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.49 - 8.45 (m, 1H), 7.94 (t, J = 3.0 Hz, 1H), 7.88 (dd, J = 8.0, 1.9 Hz, 1H), 7.78 (dt, J= 11.8, 2.3 Hz, 1H), 7.74 (dd, J = 8.1, 5.1 Hz, 1H), 7.61- 7.54 (m, 2H), 7.44 - 7.36 (m, 1H), 6.98- 6.91 (m, 1H), 6.71 (dd, J = 3.0, 2.0 Hz, 1H), 2.44 (s, 3H). MS (ESI) m/z: 439 [M+HJ*.

V-a-55 zx OPX /=2 O=/ o 1H NMR (600 MHz, DMSO-d6) 5 12.30 (brs, 1H), 10.14 (s, 1H), 10.10 (brs, 1H), 9.31 (d, J = 2.3 Hz, 1H), 8.80 (dd, J= 5.1, 1.5 Hz, 1H), 8.73 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.96 (t, J = 3.0 Hz, 1H), 7.88 (dd, J = 7.9, 1.9 Hz, 1H), 7.75 (dd, J = 8.1, 5.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.37 (t, J = 2.2 Hz, 1H), 7.18 (ddd, J = 8.1, 2.0, 1.1 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 3.0, 1.9 Hz, 1H), 6.51 (ddd, J= 8.0, 2.4, 1.0 Hz, 1H), 2.42 (s, 3H). MS (ESI) m/z: 437 [M+H]+.

V-a-56 K ’H NMR (600 MHz, DMSO-d6) 5 12.46 (brs, 1H), 10.51 (s, 1H), 10.21 (brs, 1H), 9.30 (d, J = 2.3 Hz, 1H), 8.79 (dd, J = 5.1, 1.6 Hz, 1H), 8.71 (dt, J = 8.2, 2.0 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 7.99- 7.96 (m, 2H), 7.92 (dd, J = 8.0, 1.9 Hz, 1H), 7.74 (dd, J = 8.1, 5.1 Hz, 1H), 7.64 (ddd, J = 8.4, 2.0, 1.0 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.03 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 6.72 (dd, J- 3.0, 1.8 Hz, 1H), 2.43 (s, 3H). MS (ESI) m/z: 436 [M+H]+.

V-a-57 €V H T o11 1 1 MS (ESI) m/z: 499 [M+H]+.

V-a-58 > » MS (ESI) m/z: 451 [M+H]+. 77 IEC170116PCT V-a-59 o HI H I 11 aX " 1H NMR (600 MHz, DMSO-cfe) 5 12.13 (s, 1H), 10.51 (s, 1H), 9.88 (s, 1H), 9.32 (s, 1H), 8.77 (d, J = 5.0 Hz, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H), 7.95 - 7.92 (m, 2H), 7.90 (dd, J = 8.0, 1.9 Hz, 1H), 7.82- 7.79 (m, 1H), 7.70 (dd, J= 8.1, 5.0 Hz, 1H), 7.56 (d, J= 8.1 Hz, 1H), 7.49 (t, J= 8.2 Hz, 1H), 7.09 (ddt, J = 8.2, 2.2, 1.0 Hz, 1H), 6.70 (dd, J = 3.0, 1.9 Hz, 1H), 2.44 (s, 3H). MS (ESI) m/z: 505 [M+H]+.

V-a-60 Av 'H NMR (600 MHz, DMSO-d6) 5 12.17 (s, 1H), 10.12 (s, 1H), 9.98 (s, 1H), 9.31 (d, J= 2.2 Hz, 1H), 8.79 (dd, J= 5.1, 1.6 Hz, 1H), 8.73 (d, J= 8.1 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 7.95 (t, J = 3.0 Hz, 1H), 7.89 (dd, J= 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 8.1, 5.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.29- 7.25 (m, 1H), 7.20 (t, J = 8.1 Hz, 1H), 6.71 (dd, J = 3.0, 1.9 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 2.93 (s, 6H), 2.43 (s, 3H). MS (ESI) m/z: 464 [M+H]+ V-b-1 ^H NMR (600 MHz, DMSO-d6) 5 10.50 (s, 1H), 9.28 (s, 1H), 8.53 (d, J = 3.7 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 2.9 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 7.6, 4.8 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 4.20 (s, 3H), 2.25 (s, 3H). MS (ESI) m/z: 503 [M+H]+.

V-b-2 nH NMR (600 MHz, DMSO-d6) 5 10.50 (s, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 2H), 8.40 (s, 1H), 8.31 (s, 1H), 8.28 (d, J=7.9 Hz, 1H), 8.22 (d, J= 2.1 Hz, W), 8.08 (dd, J = 4.5, 1.6 Hz, 2H), 7.98 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 3.1 Hz, 1H), 7.54 (dd, J = 8.2, 2.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 3.1 Hz, 1H), 4.21 (s, 3H), 2.25 (s, 3H). MS (ESI) m/z: 503 [M+H]+.

V-b-3 OyN CFj 0 A 1H NMR (600 MHz, DMSO-d6) 5 10.57 (s, 1H), 9.24 (dd, J = 2.2, 0.8 Hz, 1H), 8.54 - 8.51 (m, 2H), 8.47- 8.44 (m, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J= 8.3 Hz, 1H), 7.86 (dd, J = 7.9, 1.9 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.61 (t, J= 8.1 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.36 (ddd, J = 8.0, 4.7, 0.8 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 4.23 (s, 3H), 2.35 (s, 3H). MS (ESI) m/z: 503 [M+H]+. 78 IEC170116PCT V-b-4 1H NMR (600 MHz, DMSO-d6) 5 10.59 (s, 1H), 8.55 (d, J = 5.9 Hz, 2H), 8.53 (s, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 5.9 Hz, 2H), 7.86 (dd, J= 7.9, 1.5 Hz, 1H), 7.66 (d, J- 3.0 Hz, 1H), 7.61 (t, J- 8.0 Hz, 1H), 7.54 (d, 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 3.0 Hz, 1H), 4.25 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z: 503 [M+H]+.

V-b-5 " Ay- ’H NMR (600 MHz, DMSO-d6) 5 10.71 (s, 1H), 9.26 (s, 1H), 8.54- 8.50 (m, 2H), 8.46 (d, J - 7.9 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.73 (s, 1H), 7.64 (d, J = 2.9 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.37 (dd, J = 7.8, 4.7 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 4.24 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z: 583 [M+H]+.

V-b-6 y. TFA salt H NMR (600 MHz, DMSO-cfe) 6 10.59 (s, 1H), 9.19 (s, 1H), 9.07 (s, 1H), 8.72 (s, 1H), 8.60 (d, J= 6.8 Hz, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.57 (d, J = 8.3 Hz, 1H), 6.64- 6.61 (m, 1H), 4.28 (s, 3H), 3.70 (s, 2H), 3.45- 3.37 (m, 2H), 3.08- 3.00 (m, 2H), 2.97- 2.90 (m, 2H), 2.80 (s, 3H), 2.46- 2.39 (m, 2H), 2.36 (s, 3H). MS (ESI) m/z: 615 [M+Hf.

V-b-7 ^H NMR (600 MHz, DMSO-cfe) 5 10.57 (s, 1H), 8.54 (d, J = 6.0 Hz, 2H), 8.51 (s, 1H), 8.44 (d, J = 1.3 Hz, 1H), 8.24 (d, J= 1.9 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.05 (dd, J = 4.6, 1.4 Hz, 2H), 7.85 (dd, J » 7.9, 1.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H), 4.25 (s, 3H), 3.66 (s, 2H), 3.18 - 2.93 (m, 4H), 2.74- 2.66 (m, 4H), 2.55 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z: 615 [M+H]+.

V-b-8 Ck , TFA salt *H NMR (600 MHz, DMSO-cfe) 5 9.40 (s, 2H), 9.28 (s, 1H), 9.05 (s, 1H), 8.59- 8.53 (m, 2H), 8.44 (s, 1H), 8.13 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.42 (d, J= 7.7 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 4.23 (s, 3H). MS (ESI) m/z: 504 [M+H]+.

V-b-9 o. 1H NMR (600 MHz, DMSO-cfe) 5 10.25 (s, 1H), 10.19 (s, 1H), 9.46 (s, 1H), 9.08 (s, 1H), 8.49 (t, J = 6.5 Hz, 2H), 8.39 (s, 1H), 7.99 (d, J = 9.9 Hz, 2H), 7.81 (d, J = 3.0 Hz, 1H), 7.77 (t, J - 7.6 Hz, 2H), 7.58 (t, J = 8.1 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 6.62 (d, J = 3.0 Hz, 1H), 4.23 (s, 3H). 79 IEC170116PCT MS (ESI) m/z: 520 [M+Hf.

V-b-10 x^x/^ 1H NMR (600 MHz, DMSO-cfe) 5 9.51 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 4.2, 2.4 Hz, 2H), 8.48 (d, J = 2.5 Hz, 1H), 8.41- 8.37 (m, 2H), 8.32 - 8.28 (m, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.63 (d, J= 3.0 Hz, 1H), 7.50 (dd, J = 8.3, 4.7 Hz, 1H), 7.39- 7.32 (m, 2H), 7.12 (dd, J ~ 8.6, 2.5 Hz, 1H), 7.00 (d, J - 8.7 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 4.20 (s, 3H), 3.90 (s, 3H). MS (ESI) m/z: 545 [M+Hf.

V-b-11 û„, 1H NMR (600 MHz, DMSO-cfe) 5 10.32 (s, 1H), 9.55 (s, 1H), 9.38 (s, 1H), 9.10 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 8.3 Hz, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.46 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.83 - 7.79 (m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.33 (dd, J = 8.7, 2.4 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.63 (d, J = 3.0 Hz. 1H), 4.23 (s, 3H), 3.83 (s, 3H). MS (ESI) m/z: 561 [M+Hf.

V-b-12 TFA sait ’H NMR (600 MHz, DMSO-cfe) 5 10.66 (s, 1H), 9.22 (s, 1H), 9.16 (s, 1H), 8.62 (s, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.41 (t, J* 7.9 Hz, 1H), 7.33 (d, J =7.8 Hz, 1H), 6.73 (d, J= 3.1 Hz, 1H), 4.12 (s, 3H). MS (ESI) m/z: 504 [M+Hf.

V-b-13 H NMR (600 MHz, DMSO-cfe) 5 10.72 (s, 1H), 10.30 (s, 1H), 10.24 (s, 1H), 8.56 (d, J = 7.2 Hz, 2H), 8.53 (s, 1H), 8.14 (d, J= 7.9 Hz, 1H), 7.98 -7.93 (m, 3H),7.88 (d,J= 3.1 Hz, 1H),7.80 (d, J = 8.4 Hz, 1H), 7.63-7.55 (m, 2H), 7.47 (t, J= 7.8 Hz, 2H), 6.71 (d, J = 3.1 Hz, 1H), 4.12 (s, 3H).MS (ESI) m/z: 520 [M+H]+.

V-b-14 ^^'NH 0,X^^"XX^'1^'"^ 1H NMR (600 MHz, DMSO-cfe) 6 10.56 (s, 1H), 10.18 (s, 1H), 8.68 (s, 1H), 8.63 (d, J= 7.1 Hz, 2H), 8.46 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 6.9 Hz, 2H), 7.96 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 3.1 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 8.6, 2.5 Hz, 1H), 6.97 (d, 8.7 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 4.23 (s, 3H), 3.86 (s, 3H). MS (ESI) m/z: 545 [M+Hf.

V-b-15 *X^Vx^^ ’H NMR (600 MHz, DMSO-cfe) 5 10.73 (s, 1H), 10.32 (s, 1H), 9.34 (s, 1H), 8.59 (s, 1H), 8.56 (d, J = 7.2 Hz, 2H), 8.26 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 6.9 Hz, 2H), 7.88 (d, J = 3.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.32 (dd, J= 8.7, 2.5 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.71 80 IEC170116PCT (d, J - 3.1 Hz, 1H), 4.12 (s, 3H), 3.84 (s, 3H).

MS (ESI) m/z: 561 [M+H]+.

V-b-16 1H NMR (600 MHz, DMSO-cfe) 5 10.02 (s, 1H), 8.72 (s, 1H), 8.65 (dd, J = 2.5, 0.5 Hz, 1H), 8.55 (s, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.83 (d, J * 7.8 Hz, 1H), 7.77 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.60 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 6.64 (s, 2H), 6.51 (dd, J = 8.7, 0.5 Hz, 2H), 6.23 (s, 1H), 4.15 (s, 3H), 3.65 (s, 3H), 2.20 (s, 3H).MS (ESI) m/z: 454 [M+H]+.

V-b-17 ’H NMR (600 MHz, DMSO-cfe) 5 10.64 (s, 1H), 8.77 (s, 1H), 8.39 (s, 1H), 8.32 (t, J = 9.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.85 (dd, J= 8.0, 1.2 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 4.18 (s, 3H), 3.67 (s, 3H), 2.22 (s, 3H). MS (ESI) m/z: 506 (M+Hf.

V-b-18 ’H NMR (600 MHz, DMSO-cfe) 5 10.09 (s, 1H), 8.82 (t, J = 1.8 Hz, 1H), 8.68 - 8.66 (m, 1H), 8.16 (s, 1H), 8.04 (dd, J = 8.7, 2.5 Hz, 2H), 7.83 (ddd, J= 8.1, 2.1,0.9 Hz, 1H), 7.71 (dd, J=8.5, 1.9 Hz, 1H), 7.63 (d, J= 2.9 Hz, 1H), 7.42 (t, J= 7.9 Hz, 1H), 6.73 (s, 2H), 6.56- 6.52 (m, 2H), 4.14 (s, 3H), 2.29 (s, 3H). MS (ESI) m/z: 451 FM+H]+.

V-b-19 X1- ’H NMR (600 MHz, DMSO-cfe) 5 10.64 (s, 1H), 8.99 (s, 1H), 8.86 (t, 1.9 Hz, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.37- 8.33 (m, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.91 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.72 (dd, J = 8.6, 2.4 Hz, 1H), 7.65 (d, J= 3.0 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 6.55 (d, J ~ 3.0 Hz, 1H), 4.16 (s, 3H), 2.29 (s, 3H). MS (ESI) m/z: 503 [M+Hf.

V-b-20 TFA sait' 3H NMR (600 MHz, DMSO-cfe) 6 10.47 (s, 1H), 8.79 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 5.8 Hz, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.81 (d, J= 9.4 Hz, 1H), 7.75 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 7.07 (d, J - 5.9 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.56 (s, 1H), 4.19 (s, 3H), 2.46 (s, 3H). MS (ESI) m/z: 451[M+Hf.

V-b-21 *H NMR (600 MHz, DMSO-cfe) 5 10.63 (s, 1H), 9.00 (s, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.17- 8.13 (m, 2H), 8.09 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (t, J* 7.7 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.49 (t, J= 7.9 Hz, 1H), 6.89 (d, J= 4.8 Hz, 1H), 6.55 (d, J = 2.9 Hz, 1H), 4.13 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 503 [M+H]*. 81 IEC170116PCT V-b-22 'H NMR (600 MHz, DMSO-d6) 6 10.75 (s, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.60 (dt, J = 7.8, 1.4 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 5.0 Hz, 1H), 8.14- 8.09 (m, 2H), 8.03 (dt, J = 7.7, 1.5 Hz, 1H), 7.69- 7.65 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.48 (d, J ~ 7.7 Hz, 1H), 6.89 (dd, J = 5.2, 1.5 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H), 4.15 (s, 3H), 2.35 (s, 3H). MS (ESI) m/z: 503 [M+HJ*.

V-b-23 TFA sait nH NMR (600 MHz, DMSO-d6) 6 9.87 (s, 1H), 9.74 (s, 1H), 8.97 (s, 1H), 8.75 (d, J = 5.5 Hz, 2H), 8.40 (s, 1H), 8.08 (s, 1H), 8.05 (d, J = 5.8 Hz, 2H), 7.84 (d, J = 3.0 Hz, 1H), 7.67- 7.62 (m, 3H), 7.55 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H), 5.14 (d, J = 5.7 Hz, 2H), 4.24 (s, 3H). MS (ESI) m/z: 518 [M+H]+.

V-b-24 1H NMR (600 MHz, DMSO-d6) 5 10.11 (s, 1H), 10.05 (s, 1H), 8.51- 8.44 (m, 2H), 8.33 (t, J = 1.9 Hz, 1H), 8.03- 7.98 (m, 2H), 7.80 (dd, J = 8.1, 2.0 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.51 - 7.44 (m, 5H), 7.36 (t, J= 7.9 Hz, 1H), 6.41 (d, J = 3.0 Hz, 1H), 4.83 (d, J = 5.7 Hz, 2H), 4.14 (s, 3H). MS (ESI) m/z 534 [M+H]+.

V-b-25 9^ TFA sait 5.7 Hz, 2H), 4.23 (s, 3H), 3.89 (s, 3H). MS (ESI)m/z: 559 [M+Hf. ’H NMR (600 MHz, DMSO-d6) 6 9.70 (s, 1H), 8.88 (s, 1H), 8.71 (d, J = 5.0 Hz, 2H), 8.50 (s, 1H), 8.44 (s, 1H), 8.40 (d, J= 2.4 Hz, 1H), 7.94 (d, J = 4.9 Hz, 2H), 7.81 (d, J = 2.9 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.14 (dd, J - 8.7, 2.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.57 (d, J = 3.0 Hz, 1H), 5.11 (d, J = V-b-26 9... qH NMR (600 MHz, DMSO-cfe) 5 10.20 (s, 1H), 9.24 (s, 1H), 8.47 (dd, J = 4.5, 1.5 Hz, 2H), 8.37 (t, J= 1.8 Hz, 1H), 8.34 (d, J= 2.5 Hz, 1H), 8.01 - 7.98 (m, 1H), 7.55 (dd, J = 7.9, 1.1 Hz, 1H), 7.51 (t, J= 5.8 Hz, 1H), 7.48 (d, J = 6.0 Hz, 2H), 7.45 (d, J= 3.0 Hz, 1H), 7.34 (t, J=7.9Hz, 1H), 7.30 (dd, J = 8.8, 2.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 4.83 (d, J = 5.7 Hz, 2H), 4.13 (s, 3H), 3.82 (s, 3H).MS (ESI) m/z: 575 [M+HJ*.

V-b-27 % nH NMR (600 MHz, DMSO-cfe) 5 9.69 (s, 1H), 9.60 (s, 1H), 8.91 (s, 1H), 8.88 (s, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.50 (t, J= 1.9 Hz, 1H), 8.29 (d, J - 7.9 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 13.1,4.9 Hz, 2H), 7.60 (dd, J= 7.9, 5.1Hz, 1H), 7.52 (dt, J = 11.5, 7.9 Hz, 2H), 7.32 (d, J = 7.6 82 IEC170116PCT Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 5.05 (d, J = 5.8 Hz, 2H), 4.20 (s, 3H). MS (ESI) m/z: 518 [M+Hr. . _ V-b-28 ^H NMR (600 MHz, DMSO-cfe) 5 10.46- 10.42 (m, 2H), 8.87 (d, J = 13.6 Hz, 2H), 8.61 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 12.3, 5.5 Hz, 2H), 7.68- 7.62 (m, 2H), 7.57 (t, J = 7.9 Hz, 2H), 7.48 (d, J= 7.6 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 5.05 (d, J = 5.8 Hz, 2H), 4.19 (s, 3H). MS (ESI) m/z: 534 [M+Hf.

V-b-29 ’H NMR (600 MHz, DMSO-cfe) 5 9.75 (s, 1H), 8.97- 8.94 (m, 2H), 8.65 (s, 1H), 8.51 (d, J = 2.5 Hz, 2H), 8.39 (d, J= 2.4 Hz, 2H), 7.81 (d, J = 3.0 Hz, 1H), 7.77- 7.68 (m, 2H), 7.51 (d, J = 5.1 Hz, 2H), 7.13 (dd, J= 8.7, 2.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.56 (d, J = 3.0 Hz, 1H), 5.08 (d, J = 5.7 Hz, 2H), 4.21 (s, 3H), 3.89 (s, 3H).MS (ESI) m/z. 559 [M+Hf.

V-b-30 1H NMR (600 MHz, DMSO-cf6) 5 10.43 (s, 1H), 9.54 (s, 1H), 8.90 (d, J * 10.6 Hz, 2H), 8.63 (d, J« 4.9 Hz, 1H), 8.52 (t, J =1.9 Hz, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.94- 7.91 (m, 1H), 7.81 (d, J- 3.0 Hz, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.57 (t, J = 7.9 Hz, 1H), 7.33 (dd, J = 8.8, 2.5 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.56 (d, J = 3.0 Hz, 1H), 5.08 (d, J = 5.8 Hz, 2H), 4.20 (s, 3H), 3.83 (s, 3H). MS (ESI) m/z: 575 [M+H]+.

V-b-31 FsCJC^'^^ TFA sait nH NMR (600 MHz, DMSO-cfe) 6 10.77 (s, 1H), 8.86 (t, J = 1.8 Hz, 1H), 8.33 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.7 Hz, 2H), 7.95 (d, J= 8.0 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 2.7 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 4.10 (s, 3H), 3.20 - 3.17 (m, 1H), 1.01 - 0.97 (m, 2H), 0.84 - 0.80 (m, 2H). MS (ESI) m/z: 452 [M+H]+.

V-b-32 TFAsalt^" ’H NMR (600 MHz, DMSO-cfe) 5 10.57 (s, 1H), 8.82 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 9.2, 2.0 Hz, 1H), 8.21 (d, J = 12.7 Hz, 1H), 8.01 (t, J = 9.3 Hz, 1H), 7.90 (dt, J = 8.0, 3.9 Hz, 1H), 7.74 (d, J- 2.9 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 6.98 (d, J- 9.2 Hz, 1H), 6.53 (t, J = 4.7 Hz, 1H), 4.11 (s, 3H), 3.22- 3.19 (m, 1H), 1.02 - 0.98 (m, 2H), 0.86- 0.83 (m, 2H). MS (ESI) m/z: 400 [M+HfV-b-33 9, ’H NMR (600 MHz, DMSO-cfe) 5 10.10 (s, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.03- 7.98 (m, 2H), 7.90 (dd, J= 8.1, 1.1 83 IEC170116PCT Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.45 (t, J= 7.9 Hz, 1H), 6.69 (s, 2H), 6.52 (t, J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.84 (t, J= 6.5 Hz, 4H), 1.95 (t, J = 6.6 Hz, 4H). MS (ESI) m/z: 414 [M+H]+.

V-b-34 1H NMR (600 MHz, DMS0-d6) 5 10.59 (s, 1H), 8.72 (t, J- 1.8 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.17 - 8.15 (m, 1H), 7.97 (d, J= 7.8 Hz, 1H), 7.94 (dd, J = 8.0, 1.1 Hz, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.55 (d,J- 3.1 Hz, 1H), 7.44 (t, J= 7.9 Hz, 1H), 6.49 (d, J= 3.1 Hz, 1H), 3.98 (s, 3H), 3.78 (t, J= 6.6 Hz, 4H), 1.94- 1.91 (m, 4H). MS (ESI) m/z: 466 [M+H]+.

V-b-35 ’H NMR (600 MHz, DMS0-d6) 5 10.08 (s, 1H), 8.69 (t, J = 1.9 Hz, 1H), 8.64 (dd, J = 2.4, 0.5 Hz, 1H), 8.11- 8.09 (m, 1H), 8.02 (dd, J= 8.8, 2.5 Hz, 1H), 7.88 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.64 (d, J= 3.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.74 (s, 2H), 6.56 (d, J = 3.1 Hz, 1H), 6.54 (dd, J = 8.8, 0.5 Hz, 1H), 3.97 (s, 3H), 3.45- 3.40 (m, 4H), 1.79- 1.72 (m, 4H), 1.68- 1.61 (m, 2H). MS (ESI) m/z: 428 [M+HJ*.

V-b-36 TFA sait ’H NMR (600 MHz, DMSO-d6) 5 10.61 (s, 1H), 8.74 (t, J = 1.7 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.96- 7.93 (m, 1H), 7.81 (d, J » 7.8 Hz, 1H), 7.65 (d, J = 3.1 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.57 (d, J= 3.1 Hz, 1H), 3.97 (s, 3H), 3.43 -3.38 (m, 4H),1.78-1.73(m, 4H),1.66(d, J= 4.8 Hz, 2H). MS (ESI) m/z: 496 [M+H]+.

V-b-37 1H NMR (600 MHz, DMSO-d6) 5 10.05 (s, 1H), 8.72 (s, 1H), 8.66 (d, J= 2.5 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 8.00 (dd, J = 8.7, 2.4 Hz, 1H), 7.90- 7.87 (m, 1H), 7.62 (d, J = 3.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.61 (s, 2H), 6.56 (dd, J - 3.1, 0.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H), 3.85 (d, J= 12.6 Hz, 2H), 2.98 (t, J = 12.0 Hz, 2H), 2.50 - 2.43 (m, 1H), 2.30 (s, 6H), 1.96 (d, J - 11.2 Hz, 2H), 1.67 (qd, J = 12.2, 3.2 Hz, 2H). MS (ESI) m/z: 471 [M+H]+.

V-b-38 TFA sait 1H NMR (600 MHz, DMSO-d6) 5 10.76 (s, 1H), 8.82 (t, J= 1.8 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H), 7.98 (t, J = 7.5 Hz, 1H), 7.96 (dd, J = 8.1, 1.2 Hz, 1H), 7.84 (d, J=3.1 Hz, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.57 (t, J= 7.9 Hz, 1H), 6.66 (d, J= 3.1 Hz, 1H), 4.28 (d, J = 12.8 Hz, 2H), 4.01 (s, 3H), 3.54 (dd, J = 11.8, 8.6 Hz, 1H), 3.26 (t, J= 12.4 Hz, 2H), 2.81 (d, J = 4.3 Hz, 6H), 2.18 (d, J = 10.8 Hz, 2H), 1.90 (qd, J = 12.2, 3.7 Hz, 2H). MS (ESI) m/z: 523 [M+H]+. 84 IEC170116PCT V-b-39 nH NMR (600 MHz, DMSO-cfe) 5 9.05 (s, 1H), 8.96 (s, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.63 (d, J = 3.1 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.52 (t, J= 7.9 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.58 (d, J- 3.1 Hz, 1H), 3.96 (s, 3H), 3.85 (d, J = 12.8 Hz, 2H), 2.99 (t, J = 11.8 Hz, 2H), 2.36 (t, J = 11.1 Hz, 1H), 2.24 (s, 6H), 1.93 (d, J = 11.1 Hz, 2H), 1.65 (qd, J - 12.3, 3.5 Hz, 2H). MS (ESI) m/z: 538 [M+H]+.

V-b-40 1H NMR (600 MHz, DMSO-cfe) ô 10.51 (s, 1H), 8.72- 8.66 (m, 2H), 8.36 (dd, J = 9.3, 2.1 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.94- 7.91 (m, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.52 (t, J =7.9 Hz, 1H), 7.03 (d, J = 9.3 Hz, 1H), 6.62 (d, J = 3.1 Hz, 1H), 3.98 (s, 3H), 3.85- 3.81 (m, 4H), 3.64 -3.61 (m, 4H).MS (ESI) m/z: 430 [M+H]+.

V-b-41 TFA sait 1H NMR (600 MHz, DMSO-cfe) 5 10.67 (s, 1H), 8.75 (s, 1H), 8.35 (s, 1H), 8.32 (d, J - 7.9 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.98 (dd, J = 16.1,4.5 Hz, 2H), 7.81 (t, J = 7.8 Hz, 1H), 7.78 (d, J= 3.0 Hz, 1H), 7.53 (t, J= 8.0 Hz, 1H), 6.63 (d, J- 3.1 Hz, 1H), 3.99 (s, 3H), 3.85- 3.83 (m, 4H), 3.62- 3.58 (m, 4H). MS (ESI) m/z: 482 [M+H]+.

V-b-42 TFA sait ’H NMR (600 MHz, DMSO-cfe) 5 10.55 (s, 1H), 8.78 (s, 1H), 8.68 (d, J= 1.9 Hz, 1H), 8.36 (dd, J = 9.3, 2.2 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.87 (dd, J= 8.1, 1.2 Hz, 1H), 7.84 (d, J = 3.0 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.05 (d, J= 9.3 Hz, 1H), 6.64 (d, J = 3.1 Hz, 1H), 4.10 (d, J - 12.5 Hz, 2H), 3.98 (s, 3H), 3.83- 3.79 (m, 2H), 3.02- 2.97 (m, 2H), 1.20 (d, J = 6.2 Hz, 6H).

MS (ESI) m/z: 458 [M+H]+.

V-b-43 TFA sait 1H NMR (600 MHz, DMSO-cfe) S 10.71 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.95 - 7.92 (m, 1H), 7.81 (t, J = 7.6 Hz, 2H), 7.56 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 3.0 Hz, 1H), 4.03 (d, J - 12.5 Hz, 2H), 3.98 (s, 3H), 3.83 (dd, J = 8.5, 6.3 Hz, 2H), 2.95 (t, J= 11.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H). MS (ESI) m/z: 510 [M+H]*.

V-b-44 1H NMR (600 MHz, DMSO-cfe) 5 10.60 (s, 1H), 8.86 (s, 1H), 8.03 (d, J= 8.2 Hz, 2H), 7.99 (d, J = 7.5 Hz, 1H), 7.91 (dd, J = 14.8, 6.0 Hz, 2H), 7.63 (d, J- 8.2 Hz, 2H), 7.59 (t, J = 7.8Hz, 1H), 6.66 (s, 1H), 4.21 (d, J= 12.6 Hz, 2H), 3.98 (s, 3H), 3.79 (s, 2H), 3.07 (t, J = 11.6 Hz, 2H), 1.20 (d, J = 5.9 Hz, 6H). MS (ESI) m/z: 488 [M+Hf. 85 IEC170116PCT ca 03071900 2020-02-03 V-b-45 TFAralt 1H NMR (600 MHz, DMSO-cfe) 3 9.49 (s, 1H), 9.40 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.57- 7.50 (m, 4H), 7.31 (d, J = 7.6 Hz,1H), 6.64 (d, J = 3.1 Hz, 1H), 4.07 (s, 2H), 3.98 (s, 3H), 3.82 (s, 2H), 2.99 (t, J = 11.3 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H). MS (ESI) m/z: 525 [M+Hf.

V-c-1 o/p H 0 “ 1H NMR (600 MHz, DMSO-cfe) 3 11.93- 11.74 (m, 1H), 9.69 (s, 1H), 9.41 (s, 1H), 9.29 (d, J = 2.3 Hz, 1H), 8.79 (dd, J = 4.8, 1.6 Hz, 1H), 8.51 (dt, J= 7.9, 2.0Hz, 1H), 7.92 (t, J= 2.1 Hz, 1H), 7.82 (t, J = 3.0 Hz, 1H), 7.68 (dd, J = 7.9, 4.8 Hz, 1H), 7.54 (dd, J = 8.0, 2.0 Hz, 1H), 7.21 (t, J = 8.1 Hz, 1H), 6.76 -6.71 (m, 1H), 6.47 (dd, J- 3.0, 1.7 Hz, 1H), 3.03 (s, 3H). MS (ESI) m/z: 381 [M+Hf.

V-c-2 sV V 0 0 qH NMR (600 MHz, DMSO-d6) 3 11.82- 11.65 (m, 1H), 9.29 (dd, J = 2.4, 0.8 Hz, 1H), 8.97 (s, 1H), 8.78 (dd, J= 4.8, 1.6 Hz, 1H), 8.47 (dt, J = 7.9, 2.0 Hz, 1H), 7.79 (t, J= 3.0 Hz, 1H), 7.65 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.17 (d, J = 2.1 Hz, 2H), 6.45 (dd, J= 3.0, 1.7 Hz, 1H), 6.10 (t, J = 2.1 Hz, 1H), 3.79- 3.71 (m, 8H), 3.14-3.05 (m, 8H). MS (ESI) m/z: 458 [M+Hf.

V-c-3 o NHz *H NMR (600 MHz, DMSO-cfe) 5 11.85 (t, J = 2.4 Hz, 1H), 10.22 (s, 1H), 9.54 (s, 1H), 9.30 (d, J = 2.3 Hz, 1H), 8.77 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (dt, J = 7.9, 1.9 Hz, 1H), 8.47 (q, J = 1.4 Hz, 1H), 8.08 (dt, J = 6.5, 2.4 Hz, 1H), 7.82 (t, J - 3.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.63 (dd, J= 8.3, 5.2 Hz, 1H), 7.45- 7.39 (m, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.50 (dd, J = 3.0, 1.6 Hz, 1H).

MS (ESI) m/z: 422 [M+H]+.

V-c-4 ÇÇ\ °à„. 1H NMR (600 MHz, DMSO-cfe) 5 11.83- 11.76 (m, 1H), 10.56 (s, 1H), 9.53 (s, 1H), 9.30 (d, J= 2.4 Hz, 1H), 8.76 (dd, J= 4.8, 1.6 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1H), 8.50 (dt, J = 8.0, 2.0 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.81 (t, J = 3.0 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.50- 7.43 (m, 3H), 6.50 (dd, J= 3.1, 1.7 Hz, 1H). MS (ESI) m/z: 475 [M+Hf.

V-c-5 ^H NMR (600 MHz, DMSO-cfe) 6 11.65 (s, 1H), 10.59 (s, 1H), 9.48 (s, 1H), 8.61 (t, J = 2.0 Hz, 1H), 8.31 (s, 1H), 8.16 (dd,J- 6.6, 2.9 Hz, 2H), 8.12 - 8.06 (m, 2H), 7.76 (t, J = 2.6 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.60 - 7.52 (m, 5H), 7.50- 7.41 (m, 1H), 6.48 (d, J = 2.9 Hz, 1H).

MS (ESI) m/z: 474 [M+Hf. 86 1BC170H6PCT V-c-6 1H NMR (600 MHz, DMSO-d6) 6 11.74 (s, 1H), 10.25 (s, 1H), 9.79 (s, 1H), 9.25 (dd, J = 2.4, 0.8 Hz, 1H), 8.74 (dd, J = 4.8, 1.6 Hz, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8.46 (dt, J = 7.9, 1.9 Hz, 1H), 8.40 (s, 1H), 7.79-7.76 (m, 2H), 7.60 (dd, J = 7.9, 1.9 Hz, 1H), 7.58 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.53 (ddd, J= 8.2, 2.1, 0.9 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 7.29 (t, J= 8.1Hz, 1H), 6.94 (ddd, J= 8.1, 2.3, 0.9 Hz, 1H), 6.41 (dd, J = 3.1, 1.7 Hz, 1H), 3.02 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 514 [M+Hf.

V-c-7 æM ô 3H NMR (600 MHz, DMSO-d6) 6 11.74 (s, 1H), 10.48 (s, 1H), 9.26 (dd, J = 2.3, 0.9 Hz, 1H), 8.74 (dd, J = 4.8, 1.6 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.46 (ddd, J = 7.9, 2.3, 1.7 Hz, 1H), 8.42 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.10 - 8.06 (m, 1H), 7.78 (t, J = 3.0 Hz, 1H), 7.63 (dd, J = 7.9, 1.9 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.57 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.47- 7.43 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 6.42 (dd, J = 3.0, 1.6 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 489 [M+H]+.

V-c-8 (P^ O^NH i^X 1H NMR (600 MHz, DMSO-d6) 5 11.72 (s, 1H), 10.42 (s, 1H), 9.25 (dd, J = 2.3, 0.9 Hz, 1H), 8.73 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (d, J = 1.9 Hz, 1H), 8.46 (dt, J = 8.0, 1.9 Hz, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.80 (ddd, J = 8.2, 2.0, 0.9 Hz, 1H), 7.77 (t, J = 3.0 Hz, 1H), 7.61 (dd, J = 7.8, 1.9 Hz, 1H), 7.56 (ddd, J= 7.9, 4.8, 0.9 Hz, 1H), 7.48 (t, J = 8.2 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.10-7.06 (m, 1H), 6.41 (dd, J= 3.0, 1.6 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 505 [M+H]+.

V-c-9 Cr^NH xl FaC^^-CFa ’H NMR (600 MHz, DMSO-d6) 5 11.74 (d, J = 2.6 Hz, 1H), 10.76 (s, 1H), 9.26 (dd, J= 2.3, 0.9 Hz, 1H), 8.73 (dd, J = 4.8, 1.6 Hz, 1H), 8.58 (d, J= 1.8 Hz, 1H), 8.56-8.54 (m, 2H), 8.46 (dt, J = 8.0, 1.9 Hz, 1H), 8.42 (s, 1H), 7.81 (s, 1H), 7.78 (t, J = 3.0 Hz, 1H), 7.65 (dd, J = 7.8, 1.9 Hz, 1H), 7.57 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 6.42 (dd, J = 3.1, 1.6 Hz, 1H), 2.39 (s, 3H). MS (ESI) m/z: 557 [M+H]+.

V-c-10 *A>- H NMR (600 MHz, DMSO-d6) 5 11.76- 11.71 (m, 1H), 10.61 (s, 1H), 9.27 (dd, J= 2.3, 0.8 Hz, 1H), 8.72 (dd, J= 4.8, 1.7 Hz, 1H), 8.59 (d, J= 1.9 Hz, 1H), 8.46 (dt, J = 7.9, 1.9 Hz, 1H), 8.42 - 8.39 (m, 1H), 8.32 (t, J = 2.0 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 8.20- 8.16 (m, 1H), 7.77 (t, J = 3.0 Hz, 1H), 7.72 (s, 1H), 7.65 (dd, J= 7.8, 2.0 87 IEC170116PCT Hz, 1H), 7.57 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 7.51- 7.48 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.42 (dd, J = 3.1, 1.6 Hz, 1H), 2.39 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z: 569 [M+H]+.

V-c-11 A cAnh A H NMR (600 MHz, DMSO-d6) 5 11.73 (s, 1H), 10.42 (s, 1H), 9.26 (d, J = 2.2 Hz, 1H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.46 (dt, J- 7.9, 1.9 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.6, 2.2 Hz, 1H), 7.77 (d, J = 3.1 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 7.9, 1.9 Hz, 1H), 7.56 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.41 (d, J = 3.0 Hz, 1H), 3.57 (s, 2H), 2.45- 2.30 (m, 8H), 2.37 (s, 3H), 2.16 (s, 3H). MS (ESI) m/z: 601 [M+H]+.

V-c-12 o/ô "A A MeCL-k Y 1 1H NMR (600 MHz, DMSO-de) 5 11.89- 11.62 (m, 1H), 9.44 (s, 1H), 9.27 (d, J = 2.2 Hz, 1H), 8.74 (dd, J = 4.8, 1.6 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J= 2.2 Hz, 1H), 7.78 (t, J= 3.1 Hz, 1H), 7.61- 7.56 (m, 2H), 7.54 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 6.43 (dd, J = 3.1, 1.6 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 519 [M+H]+.

V-c-13 |P*| O^NH FAXCF *H NMR (600 MHz, DMSO-d6) 5 11.74 (t, J = 2.4 Hz, 1H), 10.26 (s, 1H), 9.27 (d, J = 2.2 Hz, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.46 (dt, J= 8.0, 2.0 Hz, 1H), 8.41 (s, 1H), 8.11 (dd, J = 6.9, 2.4 Hz, 1H), 7.78 (t, J = 3.0 Hz, 1H), 7.68- 7.62 (m, 2H), 7.60- 7.54 (m, 2H), 7.38 (d, J = 7.9 Hz, 1H), 6.42 (dd, J = 3.1, 1.6 Hz, 1H), 2.39 (s, 3H); MS (ESI) m/z: 507 [M+Hf.

V-c-14 <xju H I I IjAh cAnh XjL 1H NMR (600 MHz, DMSO-d6) 5 12.06 (s, 1H), 10.13 (s, 1H), 9.26 (d, J - 2.3 Hz, 1H), 8.99- 8.84 (m, 1H), 8.79 (dd, J = 4.9, 1.7 Hz, 1H), 8.53- 8.44 (m, 2H), 8.07 (d, J = 2.2 Hz, 1H), 7.88 (t, J= 3.0 Hz, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.44 (d, J = 7.9 Hz, 1H), 6.46 (dd, J = 3.0, 1.6 Hz, 1H), 2.39 (s, 3H). MS (ESI) m/z: 523 [M+H]+.

V-c-15 o 1H NMR (600 MHz, DMSO-d6) 5 11.69 (t, J = 2.3 Hz, 1H), 9.26 (d, J = 2.2 Hz, 1H), 8.97 (s, 1H), 8.73 (dd, J= 4.8, 1.6 Hz, 1H), 8.67 (s, 1H), 8.50 (dt, J= 7.9, 2.0 Hz, 1H), 8.09 (s, 1H), 8.06 - 8.02 (m, 2H), 7.75 (t, J = 3.1 Hz, 1H), 7.59 (dd, J = 7.9, 4.8 Hz, 1H), 7.57- 7.54 (m, 1H), 7.51 (t, J= 7.9 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.15- 7.06 (m, 2H), 6.40 (dd, J = 3.1, 1.7 Hz, 88 IEC170116PCT ca 03071900 2020-02-03 1H), 2.23 (s, 3H). MS (ESI) m/z: 504 [M+H]+.

V-c-16 nH NMR (600 MHz, DMSO-d6) 5 11.70 (s, 1H), 10.01 (s, 1H), 9.87 (s, 1H), 9.27-9.22 (m, 1H), 8.75 (dt, J = 4.9, 1.4 Hz, 1H), 8.47 - 8.42 (m, 1H), 8.16 (s, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.76-7.71 (m, 1H), 7.63- 7.58 (m, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.33- 6.29 (m, 1H), 2.29 (s, 3H). MS (ESI) m/z: 520 [M+H]+.

V-c-17 H ?Me X cX. ’H NMR (600 MHz, DMSO-d6) 5 11.87 (s, 1H), 10.48 (s, 1H), 9.33 (d, J = 2.2 Hz, 1H), 9.30 (d, J = 2.2 Hz, 1H), 8.76 (dd, J= 4.8, 1.6 Hz, 1H), 8.55 (dt, J= 7.9, 2.0 Hz, 1H), 8.31 (s, 1H), 8.12 (dd, J= 8.1, 2.0 Hz, 1H), 7.88 (s, 1H), 7.84 (t, J = 3.0 Hz, 1H), 7.65 (dd, J = 8.4, 2.2 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.56 (dd, J = 7.9, 4.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 3.0, 1.6 Hz, 1H), 4.01 (s, 3H). MS (ESI) m/z: 505 [M+Hf.

V-c-18 *H NMR (600 MHz, DMSO-d6) 5 11.79- 11.73 (m, 1H), 10.46 (s, 1H), 9.35 (s, 1H), 9.31 (d, J = 2.2 Hz, 1H), 8.77 (dd, J = 4.8, 1.7 Hz, 1H), 8.53 (dt, J = 7.9, 2.0 Hz, 1H), 8.39 - 8.36 (m, 1H), 8.34 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.82- 7.78 (m, 2H), 7.68- 7.65 (m, 1H), 7.63 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.31- 7.24 (m, 2H), 6.49 (dd, J = 3.1, 1.6 Hz, 1H). MS (ESI) m/z: 475 [M+H]+.

V-c-19 ’H NMR (600 MHz, DMSO-d6) 5 11.68 (s, 1H), 10.41 (s, 1H), 9.30- 9.25 (m, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.48 (dt, J = 8.0, 2.0 Hz, 1H), 8.31 (s, 1H), 8.30- 8.27 (m, 2H), 8.21 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.75 (t, J = 3.0 Hz, 1H), 7.60 (ddd, J = 7.9, 4.9, 1.0 Hz, 1H), 7.41 (dd, J= 8.2, 2.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 6.40 (dd, J = 3.0, 1.7 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 489 [M+Hf.

V-c-20 1H NMR (600 MHz, DMSO-d6) 5 11.75- 11.70 (m, 1H), 10.32 (s, 1H), 9.26 (dd, J = 2.3, 0.9 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.44 (dt, J = 7.9, 2.0 Hz, 1H), 8.11- 8.08 (m, 2H), 8.07 (s, 1H), 7.99- 7.95 (m, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.62 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.05-7.01 (m, 1H), 6.67 (dd, J = 8.2, 2.3 Hz, 1H), 6.39 (dd, J= 3.1, 1.7 Hz, 1H), 2.19 (s, 3H). MS (ESI) m/z: 525 [M+H]*. 89 IEC170116PCT V-c-21 A - o 1H NMR (600 MHz, DMSO-d6) 5 11.69 (s, 1H), 10.60 (s, 1H), 9.27 (dd, J = 2.3, 0.9 Hz, 1H), 8.74 (dd, J = 4.8, 1.6 Hz, 1H), 8.65 - 8.62 (m, 2H), 8.48 (ddd, J = 7.9, 2.4, 1.7 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.22-8.20 (m, 1H), 7.75 (t, J = 3.0 Hz, 1H), 7.60 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.41 (dd, J= 8.1, 2.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.40 (dd, J = 3.1, 1.7 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/k: 557 [M+H]* V-c-22 "6 T O 'H NMR (600 MHz, DMSO-d6) 6 10.39 (s, 1H), 9.28 (dt, J= 2.2, 1.1 Hz, 1H), 8.73 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (dt, J= 7.9, 2.0 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.24 (dd, J = 8.1, 1.9 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 3.1 Hz, 1H), 7.59 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.40 (dd, J= 8.1, 2.2 Hz, 1H), 7.21- 7.15 (m, 1H), 6.39 (d, J = 3.0 Hz, 1H), 3.67 (s, 2H), 2.48- 2.30 (m, 8H), 2.27 (s, 3H), 2.16 (s, 3H). MS (ESI) m/z: 601 [M+H]+.

V-c-23 Ç0 ô cf3 1H NMR (600 MHz, DMSO-d6) 5 11.68 (d, J = 2.6 Hz, 1H), 10.40 (s, 1H), 9.26 (dd, J = 2.3, 0.9 Hz, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.48 (dt, J = 7.9, 1.9 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.75 (t, J = 3.0 Hz, 1H), 7.60 (ddd, J= 7.9, 4.8, 0.9 Hz, 1H), 7.40 (dd, J= 8.1, 2.2 Hz, 1H), 7.21- 7.17 (m, 1H), 6.39 (dd, J= 3.1, 1.7 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 489 [M+H]*.

V-c-24 o>"ù N'*Yn W-nh à y 1H NMR (600 MHz, DMSO-cfe) 5 11.69- 11.63 (m, 1H), 10.37 (s, 1H), 9.24 (dd, J= 2.3, 0.9 Hz, 1H), 8.75 (dd, J= 4.8, 1.7 Hz, 1H), 8.42 (dt, J = 7.9, 1.9 Hz, 1H), 8.33 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H), 7.99-7.95 (m, 1H), 7.81 - 7.77 (m, 2H), 7.74 (t, J = 3.0 Hz, 1H), 7.64- 7.61 (m, 2H), 7.60 (dd, J = 8.6, 2.5 Hz, 1H), 6.39 (dd, J= 3.0, 1.7 Hz, 1H), 2.31 (s, 3H). MS (ESI) m/z: 489 (M+H]*.

V-c-25 Xn <Ah TFA sait 1H NMR (600 MHz, DMSO-cfe) 5 12.62 (s, 1H), 10.10 (s, 1H), 9.82 (s, 1H), 9.23 (d, J = 2.2 Hz, 1H), 8.87 (dd, J = 4.8, 1.6 Hz, 1H), 8.47 (dt, J = 8.0, 2.0 Hz, 1H), 7.99 (t, J = 3.0 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.0, 4.9 Hz, 1H), 7.69- 7.65 (m, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.25 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 6.81 (dd, J = 8.4, 1.2 Hz, 1H), 6.68- 6.64 (m, 1H), 6.50 (dd, J = 2.9, 1.6 Hz, 1H), 2.29 (s, 3H).MS (ESI) m/z: 436 [M+H]*. 90 IEC170116PCT V-c-26 H I ^NH A oAp] TFA sait 1H NMR (600 MHz, DMSO-d6) ô 12.68 (s, 1H), 10.57 (s, 1H), 10.30 (s, 1H), 9.93 (s, 1H), 9.26 - 9.21 (m, 1H), 8.88 (dd, J = 5.0, 1.7 Hz, 1H), 8.48 (dt, J = 8.0, 1.9 Hz, 1H), 8.02 (t, J = 3.0 Hz, 1H), 7.92 (dd, J = 7.8, 1.5 Hz, 1H), 7.78- 7.74 (m, 2H), 7.67 (dd, J = 8.6, 2.5 Hz, 1H), 7.63- 7.57 (m, 3H), 7.32 (ddd, J = 8.3, 6.9, 1.7 Hz, 1H), 6.52 (dd, J= 2.9, 1.5 Hz, 1H), 3.16 (s, 3H), 2.31 (s, 3H). MS (ESI) m/z: 514 [M+H]*.

V-c-27 'î 1H NMR (600 MHz, DMSO-d6) 6 12.22 (s, 1H), 10.12 (s, 1H), 9.26-9.19 (m, 1H), 9.14 (s, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.47 - 8.39 (m, 1H), 7.88 (t, J = 3.0 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.69 (ddd, J = 7.9, 4.9, 0.8 Hz, 1H), 7.64 (dd, J = 8.5, 2.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.26- 7.20 (m, 3H), 6.87 (dt, J = 7.4, 2.1 Hz, 1H), 6.44 (dd, J= 3.1, 1.4 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z: 437 [M+H]*.

V-c-28 N H 1 hj-A^N NHMs TFA sait 1H NMR (600 MHz, DMSO-d6) 5 12.62 (s, 1H), 10.36 (s, 1H), 10.00 (s, 1H), 9.83 (s, 1H), 9.25 - 9.22 (m, 1H), 8.87 (dd, J = 4.9, 1.6 Hz, 1H), 8.47 (dt, J = 8.1, 1.9 Hz, 1H), 8.00 (t, J = 3.0 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.76- 7.70 (m, 3H), 7.55 (d, J= 8.6 Hz, 1H), 7.52 (t, J= 7.8 Hz, 1H), 7.44 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.51 (dd, J = 3.0, 1.6 Hz, 1H), 3.07 (s, 3H), 2.30 (s, 3H). MS (ESI) m/z: 514 [M+H]*.

V-c-29 TFA sait ’H NMR (600 MHz, DMSO-d6) 5 12.65 (s, 1H), 10.33 (s, 1H), 10.19 (s, 1H), 9.89 (s, 1H), 9.24 (d, J = 2.2 Hz, 1H), 8.87 (dd, J = 4.9, 1.6 Hz, 1H), 8.47 (dt, J = 8.0, 1.9 Hz, 1H), 8.15 (t, J = 2.0 Hz, 1H), 8.00 (t, J = 3.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.76- 7.71 (m, 2H), 7.65 (dt, J = 7.8, 1.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.47 (t, J= 7.9 Hz, 1H), 6.51 (dd, J= 2.9, 1.5 Hz, 1H), 2.30 (s, 3H), 2.09 (s, 3H).

MS (ESI) m/z: 478 [M+H]*.

V-c-30 çÿù. 1H NMR (600 MHz, DMSO-d6) 5 11.67 (s, 1H), 10.47 (s, 1H), 9.23 (d, J= 2.2 Hz, 1H), 8.76 (dd, J= 4.8, 1.6 Hz, 1H), 8.43-8.36 (m, 3H), 8.25- 8.18 (m, 3H), 7.77 (d, J= 8.6 Hz, 1H), 7.74 (t, J = 3.0 Hz, 1H), 7.65- 7.62 (m, 2H), 7.58 (d, J = 8.6 Hz, 1H), 6.39 (t, J = 2.3 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z: 466 [M+H]*.

V-c-31 1H NMR (600 MHz, DMSO-d6) 5 11.67 (s, 1H), 9.67 (s, 1H), 9.24- 9.21 (m, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 8.41 (dt, J = 7.9, 2.0 Hz, 1H), 8.19 (s, 1H), 7.76- 7.72 (m, 3H), 7.65- 7.60 (m, 3H), 7.54 (dd, J = 8.7, 2.5 Hz, 1H), 6.64- 6.60 (m, 2H), 6.38 (dd, J = 3.1, 1.6 Hz, 1H), 91 IEC170116PCT 5.76 (br. s, 2H), 2.27 (s, 3H). MS (ESI) m/z: 436 [M+Hf.

V-c-32 TFA sait NMR (600 MHz, DMSO-d6) 5 12.53 (s, 1H), 10.22 (s, 1H), 10.21 (s, 1H), 9.70 (s, 1H), 9.23 (d, J - 2.5 Hz, 1H), 8.86 (dd, J = 4.8, 1.6 Hz, 1H), 8.45 (dt, J = 8.0, 1.9 Hz, 1H), 8.01- 7.95 (m, 3H), 7.78 (d, J = 2.4 Hz, 1H), 7.75- 7.69 (m, 2H), 7.54 (d, J = 8.6 Hz, 1H), 7.36- 7.31 (m, 2H), 6.49 (dd, J = 2.9, 1.6 Hz, 1H), 3.11 (s, 3H), 2.29 (s, 3H). MS (ESI) m/z: 514 [M+H]+.

V-c-33 çÿA- ô TFA sait 1H NMR (600 MHz, DMSO-d6) 6 12.51 (s, 1H), 10.25 (s, 1H), 10.17 (s, 1H), 9.66 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.86 (dd, J = 5.0, 1.6 Hz, 1H), 8.45 (dt, J = 7.9, 2.0 Hz, 1H), 7.98- 7.94 (m, 3H), 7.78 (d, J = 2.4 Hz, 1H), 7.75- 7.69 (m, 4H), 7.53 (d, J = 8.5 Hz, 1H), 6.49 (dd, J = 3.0, 1.7 Hz, 1H), 2.29 (s, 3H), 2.10 (s, 3H). MS (ESI) m/z: 478 [M+Hf. MS (ESI) m/z: 478 [M+Hf.

V-c-34 H T J” 'H NMR (600 MHz, DMSO-d6) 5 11.66 (t, J = 2.3 Hz, 1H), 10.38 (s, 1H), 9.24- 9.21 (m, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 8.41 (dt, J = 7.9, 2.0 Hz, 1H), 8.19 (s, 1H), 8.15 - 8.11 (m, 2H), 8.06- 8.01 (m, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.74 (t, J = 3.0 Hz, 1H), 7.65 - 7.62 (m, 2H), 7.57 (dd, J= 8.6, 2.5 Hz, 1H), 6.39 (dd, J= 3.1, 1.7 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z: 446 [M+Hf.

V-c-35 H'Ç o2i^ TFAsalt ’H NMR (600 MHz, DMSO-d6) 5 12.49 (s, 1H), 10.36 (s, 1H), 9.48 (s, 1H), 9.18 (d, J = 2.2 Hz, 1H), 8.88- 8.81 (m, 1H), 8.41 (dt, J = 8.1, 2.0 Hz, 1H), 7.96 (t, J = 3.1 Hz, 1H), 7.86- 7.80 (m, 2H), 7.72 (dd, J = 8.0, 5.0 Hz, 1H), 7.66- 7.61 (m, 1H), 7.61- 7.57 (m, 2H), 7.45 (d, J = 8.5 Hz, 1H), 7.05 (d, J= 2.4 Hz, 1H), 7.01 (dd, J = 8.6, 2.5 Hz, 1H), 6.46 (dd, J = 2.9, 1.6 Hz, 1H), 2.17 (s, 3H). MS (ESI) m/z: 457 [M+Hf.

V-c-36 TV 1H NMR (600 MHz, DMSO-d6) 5 12.56 (s, 1H), 10.35 (s, 1H), 10.24 (s, 1H), 9.59 (s, 1H), 9.19 (dd, J= 2.3, 0.8 Hz, 1H), 8.85 (dd, J = 4.9, 1.6 Hz, 1H), 8.42 (dt, J = 8.0, 1.9 Hz, 1H), 7.97 (t, J = 3.0 Hz, 1H), 7.77- 7.70 (m, 5H), 7.45 (d, J = 8.5 Hz, 1H), 7.05 (d, J= 2.5 Hz, 1H), 7.01 (dd, J = 8.5, 2.6 Hz, 1H), 6.48 (dd, J = 2.9, 1.5 Hz, 1H), 2.18 (s, 3H), 2.07 (s, 3H). MS (ESI) m/z: 514 [M+Hf.

V-c-37 ’H NMR (600 MHz, DMSO-d6) 5 12.65 (s, 1H), 10.33 (s, 1H), 10.19 (s, 1H), 9.89 (s, 1H), 9.24 (d, J = 2.2 Hz, 1H), 8.87 (dd, J = 4.9, 1.6 Hz, 1H), 8.47 (dt, J = 8.0, 1.9 Hz, 1H), 8.15 (t, J = 92 IEC170116PCT 2.0 Hz, 1H), 8.00 (t, J= 3.0 Hz, 1H), 7.83- 7.81 (m, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.76- 7.71 (m, 2H), 7.65 (dt, J = 7.8, 1.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.51 (dd, J = 2.9, 1.5 Hz, 1H), 2.30 (s, 3H), 2.09 (s, 3H).

MS (ESI) m/z: 487 [M+H]+.

V-c-38 0 A ^^-CFa ’H NMR (600 MHz, DMSO-d6) 5 11.73 (s, 1H), 10.50 (s, 1H), 8.78- 8.73 (m, 2H), 8.57 (d, J = 1.9 Hz, 1H), 8.46 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.11- 8.07 (m, 1H), 8.07- 8.04 (m, 2H), 7.82 (t, J = 3.0 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.49- 7.44 (m, 1H), 7.39 (d, J = 7.9 Hz, 1H), 6.44 (dd, J = 3.0, 1.7 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 489 [M+H]+. MS (ESI) m/z. 489 [M+HJ*.

V-c-39 ’H NMR (600 MHz, DMSO-d6) 6 11.72- 11.69 (m, 1H), 10.44 (s, 1H), 8.82 - 8.75 (m, 2H), 8.36- 8.24 (m, 4H), 8.10- 8.05 (m, 2H), 7.97 (d, J = 7.4 Hz, 1H), 7.84- 7.75 (m, 2H), 7.41 (dd, J = 8.1, 2.2 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.42 (dd, J= 3.1, 1.7 Hz, 1H), 2.27 (s, 3H).

MS (ESI) m/z: 489 [M+H]+.

V-c-40 ' A "Y “J A nH NMR (600 MHz, DMSO-d6) 6 10.39 (s, 1H), 8.89 (dd, J = 2.3, 0.9 Hz, 1H), 8.73 (dd, J= 4.8, 1.6 Hz, 1H), 8.32- 8.26 (m, 3H), 8.19 (d, J = 2.2 Hz, 1H), 8.14 (dt, J = 7.8, 1.9 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 3.1 Hz, 1H), 7.56 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 7.40 (dd, J= 8.1, 2.2 Hz, 1H), 7.18 (d, J= 8.3 Hz, 1H), 6.35 (d, J = 3.1 Hz, 1H), 3.42 (s, 3H), 2.24 (s, 3H). MS (ESI) m/z: 503 [M+H]+.

V-c-41 A.

NMR (600 MHz, DMSO-d6) 5 11.52 (s, 1H), 10.42 (s, 1H), 8.34- 8.31 (m, 2H), 8.29 (d, J = 7.9 Hz, 1H), 8.14- 8.08 (m, 3H), 7.96 (dt, J = 7.8, 1.2 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 3.1 Hz, 1H), 7.59 - 7.53 (m, 3H), 7.40 (dd, J = 8.2, 2.1 Hz, 1H), 7.21- 7.17 (m, 1H), 6.38 (d, J = 3.0 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z: 488 [M+Hf.

V-c-42 nH NMR (600 MHz, DMSO-d6) 5 11.45 (s, 1H), 10.43 (s, 1H), 8.34- 8.30 (m, 2H), 8.28 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.78 (t, J =7.8 Hz, 1H), 7.69 (d, J = 3.0 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.40 (dd, J= 8.2, 2.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.78 (dd, J = 3.5, 1.8 Hz, 1H), 6.33 (d, J = 3.0 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 478 [M+H]+. 93 IEC170116PCT V-c-43 ex 1H NMR (600 MHz, DMSO-d6) 5 12.23 (s, 1H), 10.52 (s, 1H), 9.32 (s, 1H), 8.30 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.15-8.11 (m, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.90 (t, J= 3.1 Hz, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 7.54 (dd, J = 8.3, 2.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.47 (t, J = 2.2 Hz, 1H), 2.26 (s, 3H). MS (ESI) m/z: 494 [M+H]+.

V-c-44 w lsw<CF3 ’H NMR (600 MHz, DMSO-d6) 6 11.66 (s, 1H), 10.45 (s, 1H), 8.43 (d, J= 2.1 Hz, 1H), 8.35 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 4.6 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 7.83 (d, J = 3.0 Hz, 1H), 7.82 - 7.75 (m, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z: 528 [M+H]*.

V-c-45 1H NMR (600 MHz, DMSO-d6) 5 11.74 (s, 1H), 10.44 (s, 1H), 8.55 (s, 1H), 8.31 (d, J= 1.9 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.22 (s, 1H), 8.18 (d, J= 2.2 Hz, 1H), 7.99- 7.93 (m, 2H), 7.92- 7.88 (m, 1H), 7.82 (d, J= 3.1 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.48- 7.40 (m, 3H), 7.22 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z: 544 [M+H]+.

V-c-46'ft 1H NMR (600 MHz, DMSO-d6) 5 11.51 (s, 1H), 10.42 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.70- 7.67 (m, 2H), 7.38 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 3.0 Hz, 1H), 6.12 (s, 2H), 2.28 (s, 3H). MS (ESI) m/z: 532 [M+H]+.

V-c-47 çcm a TFA sait ’H NMR (600 MHz, DMSO-d6) 5 12.23 (s, 1H), 10.52 (s, 1H), 9.32 (s, 1H), 8.30 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.90 (t, J= 3.1 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.3, 2.2 Hz, 1H), 7.30 (d, J= 8.2 Hz, 1H), 6.47 (t, J = 2.2 Hz, 1H), 2.26 (s, 3H). MS (ESI) m/z: 522 [M+Hf.

V-c-48 F ’H NMR (600 MHz, DMSO-d6) 5 11.58 (s, 1H), 10.43 (s, 1H), 8.33- 8.30 (m, 2H), 8.28 (d, J = 7.9 Hz, 1H), 8.22- 8.17 (m, 2H), 8.11 (s, 1H), 7.96 (dt, J = 7.9, 1.2 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 3.1 Hz, 1H), 7.43- 7.35 (m, 3H), 7.19 (d, J = 8.3 Hz, 1H), 6.38 (d, J = I 3.1 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z: 506 94 IEC170116PCT 95 [M+H]*.

V-c-49 H NMR (600 MHz, DMSO-cfe) 5 10.43 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.30-8.28 (m, 1H), 8.15-8.11 (m, 2H), 8.02 (s, 1H), 7.96 (ddd, J = 8.6, 1.8, 0.9 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.39 (dd, J = 8.1, 2.2 Hz, 1H), 7.18 (dd, J= 8.1, 0.8 Hz, 1H), 7.12-7.08 (m, 2H), 6.36 (d, J * 3.1 Hz, 1H), 3.84 (s, 3H), 2.28 (s, 3H). MS (ESI) m/z: 518 [M+H]*.

V-c-50 H NMR (600 MHz, DMSO-cfe) 5 11.64 (br. s, 1H), 10.42 (s, 1H), 8.38- 8.33 (m, 2H), 8.31 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.29- 8.27 (m, 1H), 8.22 (s, 1H), 8.13- 8.09 (m, 2H), 7.96 (dt, J = 7.8, 1.2 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 8.1, 2.3 Hz, 1H), 7.20 (d, 8.3 Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 3.30 (s, 3H), 2.27 (s, 3H).

MS (ESI) m/z: 566 [M+H]*.

V-c-51 1H NMR (600 MHz, DMSO-cfe) 6 11.60 (s, 1H), 9.43 (s, 1H), 8.63 (d, J= 1.8 Hz, 1H), 8.33 (d, J - 2.3 Hz, 1H), 8.27 (s, 1H), 8.14- 8.09 (m, 2H), 7.73 (d, J » 3.0 Hz, 1H), 7.60 - 7.51 (m, 5H), 7.36 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 6.41 (d, J= 3.1 Hz, 1H), 3.88 (s, 3H), 2.39 (s, 3H). MS (ESI) m/z: 518 [M+H]*.

V-c-52 H NMR (600 MHz, DMSO-cfe) 5 11.53 (t, J = 2.4 Hz, 1H), 9.42 (s, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 8.00 (d, J= 1.7 Hz, 1H), 7.73 (t, J- 3.0 Hz, 1H), 7.58 (dd, J = 7.8, 1.9 Hz, 1H), 7.52 (dd, J= 8.7, 2.3 Hz, 1H), 7.43- 7.42 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 3.5, 1.7 Hz, 1H), 6.37 (dd, J= 3.1, 1.7 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 508 [M+H]*.

V-c-53 ccrà J X XX ’H NMR (600 MHz, DMSO-d6) 6 11.63 (s, 1H), 9.39 (s, 1H), 8.49 (d, J= 1.8 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 3.8 Hz, 1H), 7.77 (d, J = 3.1 Hz, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.59 (dd, J = 7.9, 1.9 Hz, 1H), 7.52 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.31 (dd, J- 5.0, 3.7 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.39 (d, J = 3.0 Hz, 1H), 3.84 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 524 [M+H]*.

V-c-54 O^NH ’H NMR (600 MHz, DMSO-d6) 5 11.71 (s, 1H), 9.42 (s, 1H), 8.71 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.35 (s, 1H), 7.86 (d, J= 3.1 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 7.9, 1.8 Hz, 1H), 7.53 IEC170116PCT (dd, J = 8.7, 2.2 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.40- 7.34 (m, 2H), 7.26 (d, J = 8.6 Hz, 1H), 6.43 (d, J = 3.0 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z: 558 [M+H]*.

V-c-55 ou. ]H NMR (600 MHz, DMSO-d6) 5 11.83 (s, 1H), 9.39 (s, 1H), 8.61- 8.58 (m, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.34 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.86 (t, J- 3.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.60 (dd, J= 7.8, 1.7 Hz, 1H), 7.51 (dd, J= 8.7, 2.2 Hz, 1H), 7.47 - 7.43 (m,1H), 7.43-7.37 (m, 2H), 7.22 (d, J= 8.6 Hz, 1H), 6.45 (dd, J= 3.1, 1.5 Hz, 1H), 3.77 (s, 3H), 2.40 (s, 3H). MS (ESI) m/z: 574 [M+Hf.

V-c-56 *H NMR (600 MHz, DMSO-d6) 5 11.62 (s, 1H), 9.42 (s, 1H), 8.64 (d, J= 1.8 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 7.72- 7.68 (m, 2H), 7.66 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 7.8, 1.8 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 2.9 Hz, 1H), 6.10 (s, 2H), 3.88 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 562 [M+H]*.

V-c-57 O^NH ’H NMR (600 MHz, DMSO-d6) 5 11.68 (s, 1H), 9.44 (s, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.16 - 8.12 (m, 2H), 7.76 (t, J = 3.1 Hz, 1H), 7.62 - 7.57 (m, 3H), 7.54 (dd, J = 8.7, 2.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.28 (d, J= 8.6 Hz, 1H), 6.41 (dd, J = 3.1, 1.6 Hz, 1H), 3.88 (s, 3H), 2.38 (s, 3H).

MS (ESI) m/z: 552 [M+H]*.

V-c-58 "AuX nH NMR (600 MHz, DMSO-cfe) 5 11.76 (s, 1H), 9.45 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.21- 8.17 (m, 2H), 7.75 (t, J = 3.1 Hz, 1H), 7.58 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 (dd, J = 8.6, 2.3 Hz, 1H), 7.39 - 7.34 (m, 3H), 7.28 (d, J = 8.7 Hz, 1H), 6.41 (dd, J= 3.1, 1.6 Hz, 1H), 3.88 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 536 [M+H]*.

V-c-59 ' Me°x!xCF 1H NMR (600 MHz, DMSO-cfe) 5 11.54 (s, 1H), 9.42 (s, 1H), 8.67 (d, J= 1.8 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.21 (s, 1H), 8.14-8.10 (m, 2H), 7.71 (d, J = 3.1 Hz, 1H), 7.56 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 (dd, J = 8.8, 2.3 Hz, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.28 (d, J= 8.6 Hz, 1H),7.10- 7.05 (m, 2H), 6.39 (d, J = 3.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.39 (s, 3H). MS (ESI) m/z: 548 [M+H]*. 96 IEC170116PCT V-c-60 [jAs] CT^NH Ms Md°S^X.CF 1H NMR (600 MHz, DMSO-d6) 5 11.91 (br.. s, 1H), 9.47 (s, 1H), 8.56 (s, 1H), 8.42- 8.35 (m, 3H), 8.29 (s, 1H), 8.11- 8.05 (m, 2H), 7.79 (d, J = 3.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 6.42 (d, J = 3.1 Hz, 1H), 3.88 (s, 3H), 3.29 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z: 596 [M+Hf.

V-c-61 $x. ’H NMR (600 MHz, DMSO-d6) 6 11.64 (s, 1H), 10.50 (s, 1H), 8.63 (d, J- 1.8 Hz, 1H), 8.29 (s, 1H), 8.15-8.11 (m, 2H), 7.99 (s, 1H), 7.83 (dd, J = 8.2, 1.9 Hz, 1H), 7.72 (t, J = 3.0 Hz, 1H), 7.62 (dd, J = 7.8, 1.8 Hz, 1H), 7.54- 7.50 (m, 3H), 7.48 (t, J = 8.2 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.12- 7.05 (m, 1H), 6.39 (dd, J = 3.1, 1.6 Hz, 1H), 2.39 (s, 3H). MS (ESI) m/z: 504 [M+Hf.

V-c-62 H. ’H NMR (600 MHz, DMSO-d6) 5 11.64 (s, 1H), 10.48 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.50- 8.43 (m, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.84 - 7.80 (m, 1H), 7.76 (t, J = 3.0 Hz, 1H), 7.64 (dd, J= 7.8, 1.9 Hz, 1H), 7.48 (t, J = 8.2 Hz, 1H), 7.46 (d, J- 3.4 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.08 (ddt, J = 8.2, 2.3, 1.0 Hz, 1H), 6.80 (dd, J = 3.5, 1.8 Hz, 1H), 6.38 (dd, J = 3.0, 1.8 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 494 [M+Hf.

V-c-63 Cr'NH 7H NMR (600 MHz, DMSO-d6) 5 12.01 (s, 1H), 10.54 (s, 1H), 8.55- 8.45 (m, 2H), 8.37 (d, J = 3.7 Hz, 1H), 7.98 (s, 1H), 7.82 (dd, J = 8.3, 1.9 Hz, 1H), 7.78 (t, J = 3.0 Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.68 (dd, J = 7.8, 1.9 Hz, 1H), 7.47 (t, J = 8.2 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.30 (dd, J = 5.0, 3.8 Hz, 1H), 7.11- 7.02 (m, 1H), 6.40 (dd, J = 3.0, 1.5 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 510 [M+Hf.

V-c-64 <A0 o^nh o ’H NMR (600 MHz, DMSO-cfe) 5 11.75 (t, J = 2.4 Hz, 1H), 10.51 (s, 1H), 8.70 (d, J= 1.8 Hz, 1H), 8.39 (s, 1H), 8.02 (q, 1.4 Hz, 1H), 7.86 (t, J= 3.0 Hz, 1H), 7.84 (d, 0.9 Hz, 1H), 7.82 (dd, J = 8.0, 1.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.72 (dt, J = 7.8, 0.9 Hz, 1H), 7.64 (dd, J = 7.8, 1.9 Hz, 1H), 7.51- 7.45 (m, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.37- 7.33 (m, 1H), 7.11- 7.07 (m, 1H), 6.42 (dd, J= 3.1, 1.8 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z: 544 [M+Hf. 97 IEC170116PCT V-c-65 HX X 1H NMR (600 MHz, DMSO-d6) 5 12.37 (s, 1H), 10.59 (s, 1H), 8.90- 8.74 (m, 2H), 8.59 (d, J = 1.8 Hz, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.91 (t, J= 3.0 Hz, 1H), 7.82 (dd, J = 8.0, 1.9 Hz, 1H), 7.72- 7.66 (m, 2H), 7.50- 7.37 (m, 4H), 7.10-7.06 (m, 1H), 6.48 (dd, J= 3.1, 1.5 Hz, 1H), 2.41 (s, 3H). MS (ESI) m/z: 560 [M+Hf.

V-c-66 ]H NMR (600 MHz, DMSO-d6) 5 11.54 (t, J = 2.3 Hz, 1H), 10.43 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 7.99 - 7.96 (m, 1H), 7.79 (ddd, J = 8.3, 2.0, 0.9 Hz, 1H), 7.71- 7.67 (m, 2H), 7.65 (d, J= 1.7 Hz, 1H), 7.59 (dd, J= 7.8, 1.9 Hz, 1H), 7.48 (t, J = 8.2 Hz, 1H), 7.38-7.34 (m, 1H), 7.08 (ddt, J = 8.2, 2.3, 1.0 Hz, 1H), 7.05 (d, J= 8.1 Hz, 1H), 6.37 (dd, J = 3.0, 1.7 Hz, 1H), 6.11 (s, 2H), 2.38 (s, 3H). MS (ESI) m/z: 548 (M+H]*.

V-c-67 ecM 1H NMR (600 MHz, DMSO-d6) 5 11.86 (s, 1H), 10.55 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.42 (s, 1H), 8.22- 8.15 (m, 2H), 8.01 (d, J = 2.8 Hz, 1H), 7.87- 7.81 (m, 1H), 7.77 (t, J = 3.1 Hz, 1H), 7.66 (dd, J= 7.8, 1.9 Hz, 1H), 7.59-7.55 (m, 2H), 7.48 (t, J= 8.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.08 (ddd, J = 8.3, 2.3, 1.2 Hz, 1H), 6.41 (dd, J= 3.1, 1.6 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 538 [M+HJ*.

V-c-68 T (L. ’H NMR (600 MHz, DMSO-d6) 6 11.74 (d, J = 6.0 Hz, 1H), 10.56 - 10.50 (m, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 8.24- 8.15 (m, 2H), 7.99 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 (t, J = 3.1 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.48 (t, J = 8.2 Hz, 1H), 7.39- 7.29 (m, 3H), 7.08 (dd, J = 8.2, 2.3 Hz, 1H), 6.39 (dd, J = 3.0, 1.6 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 522 [M+H]+.

V-c-69 Q 3H NMR (600 MHz, DMSO-d6) G 11.78 (s, 1H), 10.56 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.18 - 8.13 (m, 2H), 8.01 (s, 1H), 7.83 (dd, J = 8.2, 1.9 Hz, 1H), 7.73 (t, J = 3.0 Hz, 1H), 7.64 (dd, J= 7.9, 1.9 Hz, 1H), 7.48 (t, J= 8.2 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06-7.04 (m, 2H), 6.39 (dd, J = 3.0, 1.6 Hz, 1H), 3.82 (s, 3H), 2.39 (s, 3H).

MS (ESI) m/z: 534 [M+H]+.

V-c-70 <IY^ ip», O^NH Ms O^OCFs 1H NMR (600 MHz, DMSO-d6) 5 11.78 (s, 1H), 10.48 (s, 1H), 8.55 (d, J= 1.9 Hz, 1H), 8.42 (s, 1H), 8.38- 8.33 (m, 2H), 8.10 - 8.06 (m, 2H), 7.99 (dq, J = 2.3, 1.2 Hz, 1H), 7.82 (ddd, J = 8.4, 2.0, 0.9 Hz, 1H), 7.80 (t, J = 2.9 Hz, 1H), 7.64 (dd, J - 7.8, 2.0 Hz, 1H), 7.48 (t, J = 8.2 98 IEC170116PCT Hz, 1H), 7.39- 7.35 (m, 1H), 7.08 (ddt, J= 8.3, 2.2, 1.0 Hz, 1H), 6.43 (dd, J=3.1, 1.2 Hz, 1H), 3.30 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z 582 (M+Hf.

V-c-71 H OYiO rr t A. HNy° u A. 5H NMR (600 MHz, DMSO-d6) 5 11.92 (s, 1H), 10.56 (d, J = 2.3 Hz, 1H), 9.40 (s, 1H), 8.84- 8.78 (m, 2H), 8.41 (d, J = 1.8 Hz, 1H), 8.38 - 8.32 (m, 2H), 8.18- 8.12 (m, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.63 (dt, J = 7.7, 1.8 Hz, 1H), 7.32- 7.23 (m, 2H), 6.49 (dd, J= 3.1, 1.6 Hz, 1H). MS (ESI) m/z: 475 [M+H]+.

V-c-72 H A HÇ° à,. MS (ESI) m/z: 474 [M+H]+.

V-c-73 <i/q "6 V Cl ^^CFa MS (ESI) m/z: 464 [M+H]+.

V-c-74 aÿü H6 HNz° Cl Œ3 1H NMR (600 MHz, DMSO-d6) 5 12.00 (s, 1H), 10.51 (s, 1H), 9.69 (s, 1H), 8.34-8.27 (m, 3H), 8.11 (t, J = 2.1 Hz, 1H), 7.98 (d, J= 7.8 Hz, 1H), 7.95 (d, J= 5.0 Hz, 1H), 7.89 (t, J= 3.0 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.70 (dt, J = 8.0, 1.5 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H), 6.50 (dd, J = 3.0, 1.7 Hz, 1H). MS (ESI) m/z: 480 [M+H]*.

V-c-75 ’H NMR (600 MHz, DMSO-d6) 5 11.84 (s, 1H), 10.54 (s, 1H), 9.49 (s, 1H), 8.59 (t, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.37 (d, J= 7.9 Hz, 1H), 8.12 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.90 (t, J = 3.0 Hz, 1H), 7.86- 7.78 (m, 3H), 7.58 (dt, J = 7.9, 1.8 Hz, 1H), 7.50 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.48 (dd, J = 3.0, 1.8 Hz, 1H). MS (ESI) m/z: 514 [M+H]+.

V-c-76 H AyA 1H NMR (600 MHz, DMSO-d6) 5 11.85 (s, 1H), 10.48 (s, 1H), 9.30 (s, 1H), 8.61 (s, 1H), 8.36- 8.30 (m, 2H), 8.21 (t, J = 1.9 Hz, 1H), 8.01 - 7.95 (m, 3H), 7.87 (t, J = 3.0 Hz, 1H), 7.84- 7.77 (m, 2H), 7.49 - 7.45 (m, 2H), 7.33- 7.28 (m, 2H), 6.49 (dd, J = 3.1, 1.6 Hz, 1H). MS (ESI) m/z: 530 [M+H]+. 99 IEC170116PCT * •' ta 03071900 2020-02-03 V-c-77 eu H P hn^o Cl X TFA sait 1H NMR (600 MHz, DMSO-cfe) 5 11.60 (d, J = 3.0 Hz, 1H), 10.49 (s, 1H), 9.23 (s, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.76 - 7.70 (m, 3H), 7.62 - 7.58 (m, 1H), 7.28- 7.22 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.42 (dd, J= 3.1, 1.7 Hz, 1H), 6.14 (s, 2H).

MS (ESI) m/z: 518 [M+H]+.

V-c-78 Çp“p X hC° ° Ox 1H NMR (600 MHz, DMSO-cfe) 5 12.07 (s, 1H), 10.52 (s, 1H), 9.83 (s, 1H), 8.33 (t, J- 2.0 Hz, 2H), 8.31 (d, J = 7.9 Hz, 1H), 8.22 - 8.17 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 3.0 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.55 (d, J = 7.9 Hz, 1H), 7.40- 7.30 (m, 2H), 6.52 (dd, J = 2.9, 1.6 Hz, 1H). MS (ESI) m/z: 508 [M+H]+. MS (ESI) m/z: 508 [M+H]+.

V-c-79 ççrp Y SCFj H NMR (600 MHz, DMSO-cfe) 5 11.73 (s, 1H), 10.52 (s, 1H), 9.28 (s, 1H), 8.40- 8.31 (m, 3H), 8.25 (dd, J = 8.4, 5.5 Hz, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.46- 7.38 (m, 2H), 7.32 - 7.22 (m, 2H), 6.45 (d, J = 3.0 Hz, 1H). MS (ESI) m/z: 492 [M+Hf.

V-c-80 çpap X HN^O OMe 1H NMR (600 MHz, DMSO-cfe) 5 11.64 (s, 1H), 10.52 (s, 1H), 9.19 (s, 1H), 8.39- 8.32 (m, 3H), 8.22- 8.16 (m, 2H), 7.97 (d, J = 7.7 Hz, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.70 (t, J = 3.0 Hz, 1H), 7.65 (dt, J = 7.3, 1.9 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.15- 7.10 (m, 2H), 6.42 (dd, J= 3.0, 1.6 Hz, 1H), 3.86 (s, 3H). MS (ESI) m/z: 504 [M+H]+.

V-c-81 X HN^O Ms cf3 H NMR (600 MHz, DMSO-cfe) 5 11.80 (s, 1H), 10.49 (s, 1H), 9.37 (s, 1H), 8.44- 8.40 (m, 2H), 8.39 - 8.34 (m, 3H), 8.32 (d, J = 7.9 Hz, 1H), 8.19-8.12 (m, 2H), 7.98 (d, J = 7.8 Hz, 1H), 7.86- 7.76 (m, 2H), 7.66 (dt, J = 7.0, 2.1 Hz, 1H), 7.31- 7.23 (m, 2H), 6.49 (dd, J= 3.1, 1.6 Hz, 1H), 3.32 (s, 3H). MS (ESI) m/z 552 [M+H]+.

V-c-82 o «P ^^cf3 MS (ESI) m/z: 575 [M+H]+. 100 IEC170116PCT V-c-83 OU.n O /=/ \ / \ / X xz 4^ZX MS (ESI) m/z: 573 [M+H]+.

V-c-84 \ z-x O x p o xz z^q MS (ESI) m/z: 587 [M+H]+.

V-c-85 ou? x f—o xz C<ZX MS (ESI) m/z: 573 [M+H]+.

V-c-86 O n / X y__/ MS (ESI) m/z: 532 [M+H]+.

V-c-87 1Ô H Y OifS O^NH ÔL ^/cf3 MS (ESI) m/z: 575 [M+H]+.

Synthetic route of compounds VI-a-1, VI-b-1: 101 IEC170116PCT ca 03071900 2020-02-03 method F pyridin-3-ylboronic acid method D 21a, R3 = H . 21b, R3 = Br J method G 22a R3«H 22b R3«Br Compound 21a was synthesized from 19 through Method F, Method D in sequence, MS (ESI) m/z 243 [M+H]+.

Synthesis of compound 21b: Method J: compound 21a (484 mg, 2 mmol) and NBS (427 mg, 2.4 mmol) were stirred in ethanol (10 mL) at room temperature for 3 h, concentrated, and dissolved with ethyl acetate. The system was washed with water, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 591 mg, as a white solid, in 92% yield.

MS (ESI) m/z. 321 [M+H]*.

Compounds VI-a-1, VI-a-1 were respectively synthesized from 21a, 21b through Method G, Method C in sequence.

Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure ’H NMR and/or MS data VI-a-1 cf, XVyO 1H NMR (600 MHz, DMSO-d6) 5 10.51 (s, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.98 (s, 1H), 8.75 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.52 (dd, J= 4.7, 1.4 Hz, 1H), 8.39 (dt, J= 8.0, 1.8 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J= 7.9 Hz, 1H), 8.03 (d, J = 0.7 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.47 (dd, J = 8.2, 2.1 Hz, 1H), 7.41 (dd, J = 7.9, 4.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z 489 [M+H]+.

VI-a-2 ’H NMR (600 MHz, DMSO-d6) 5 10.55 (s, 1H), 9.18 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 8.28- 8.25 (m, 2H), 8.11 (d, J= 8.3 Hz, 1H), 8.05 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 102 IEC170116PCT 7.8, 4.9 Hz, 1H), 2.43 (s, 3H) MS (ESI) m/z: 489 [M+Hf.

VI-a-3 TFA sait NMR (600 MHz, DMSO-d6) 5 10.86 (s, 1H), 9.39 (s, 1H), 9.23 (s, 1H), 9.13 (s, 1H), 8.80 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.1,4.9 Hz, 1H), 2.44 (s, 3H), 2.34 (s, 3H). MS (ESI) m/z: 569 [M+H]+.

VI-a-4 TFA sait ’H NMR (600 MHz, DMSO-d6) 6 10.56 (s, 1H), 9.36 (s, 1H), 9.16 (s, 1H), 8.91 (s, 1H), 8.70 (d, J = 4.5 Hz, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.58 (s, 1H), 8.25 (d, J = 1.7 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.86- 7.82 (m, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.75- 7.70 (m, 2H), 7.51 (d, J = 8.1 Hz, 1H), 3.73 (s, 2H), 3.49- 3.38 (m, 2H), 3.12- 3.02 (m, 2H), 3.02 - 2.92 (m, 2H), 2.82 (s, 3H), 2.49 - 2.43 (m, 2H), 2.42 (s, 3H). MS (ESI) m/z: 601 [M+Hf.

VI-a-5 aÇr»Ta„. *H NMR (600 MHz, DMSO-d6) 5 10.52 (s, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 8.69 (d, J= 2.1 Hz, 1H), 8.58 (dd, J = 4.6, 1.5 Hz, 2H), 8.36 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 8.00 (dd, J = 4.5, 1.6 Hz, 2H), 7.99 (s, 1H), 7.83 (t, J= 7.8 Hz, 1H), 7.72 (d, J=1.1 Hz, 1H), 7.46 (dd, J= 8.2, 2.1 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 2.34 (s, 3H). MS (ESI) m/z: 489 [M+Hf.

VI-a-6 1H NMR (600 MHz, DMSO-d6) 5 10.59 (s, 1H), 9.16 (s, 1H), 8.91 (s, 1H), 8.76 (d, J= 1.8 Hz, 1H), 8.52 (dd, J = 4.6, 1.6 Hz, 2H), 8.28 (s, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 1.1 Hz, 1H), 7.89 (dd, J = 4.6, 1.6 Hz, 2H), 7.80 (dd, J= 7.8, 1.8 Hz, 1H), 7.74 (d, J=1.1 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.47 (d, J= 7.8 Hz, 1H), 2.43 (s, 3H). MS (ESI) m/z: 489 [M+Hf.

VI-a-7 ». 7H NMR (600 MHz, DMSO-d6) 5 10.72 (s, 1H), 9.21 (s, 1H), 8.92 (s, 1H), 8.76 (d, J= 1.8 Hz, 1H), 8.54 (dd, J = 4.5, 1.6 Hz, 2H), 8.35 (s, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J= 1.1 Hz, 1H), 7.89 (dd, J= 4.5, 1.6 Hz, 2H), 7.82 (dd, J = 7.9, 1.9 Hz, 1H), 7.75 (s, 1H), 7.74 (d, J= 1.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 2.44 (s, 3H), 2.19 (d, J = 0.7 Hz, 3H). MS (ESI) m/z: 569 [M+Hf. 103 IEC170116PCT VI-a-8 TFAs^^ NMR (600 MHz, DMSO-d6) 5 10.57 (s, 1H), 9.53 (s, 1H), 9.25 (s, 1H), 8.85 (d, J= 6.7 Hz, 2H), 8.51 (d, J= 1.6 Hz, 1H), 8.36 (d, J = 6.8 Hz, 2H), 8.25 (d, J = 2.1 Hz, 1H), 8.16- 8.13 (m, 2H), 7.87 (dd, J - 7.9, 1.8 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 3.73 (s, 3H), 3.48- 3.38 (m, 2H), 3.12- 3.02 (m, 2H), 3.00 - 2.91 (m, 2H), 2.82 (s, 3H), 2.48- 2.43 (m, 2H), 2.41 (s, 3H). MS (ESI) m/z: 601 [M+Hf.

VI-a-9 nH NMR (600 MHz, DMSO-d6) 5 10.49 (s, 1H), 9.16 (s, 1H), 9.11-9.07 (m, 1H), 8.76 (s, 1H), 8.66 (d, J= 1.7 Hz, 1H), 8.50 (dd, J= 4.7, 1.6 Hz, 1H), 8.26 (ddd, J= 8.0, 2.2, 1.7 Hz, 1H), 8.04 (d, J= 1.1 Hz, 1H), 7.95 (s, 1H), 7.81 (dd, J= 8.3, 1.1 Hz, 1H), 7.77 (dd, J= 7.9, 1.8 Hz, 1H), 7.70 (d, J= 1.1 Hz, 1H), 7.49 (dd, J= 11.6, 4.8 Hz, 2H), 7.35 (ddd, J = 8.0, 4.7, 0.8 Hz, 1H), 7.09 (dd, J = 8.9, 1.6 Hz, 1H), 2.42 (s, 3H). MS (ESI) m/z: 505 [M+H]+.

VI-a-10 ^i/XO TFA slat ° ‘'H NMR (600 MHz, DMSO-d6) 5 10.59 (s, 1H), 9.26 (s, 1H), 9.07 (s, 1H), 8.87 (s, 1H), 8.67- 8.65 (m, 3H), 8.39- 8.37 (m, 2H), 8.08 (s, 2H), 7.75 (s, 1H), 7.72-7.67 (m, 1H), 7.46 (dd, J = 8.2, 2.1 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.80 (br. s, 4H), 3.06 (br. s, 4H), 2.33 (s, 3H). MS (ESI) m/z: 588 [M+H]+.

VI-b-1 M ’H NMR (600 MHz, DMSO-d6) 5 10.51 (s, 1H), 9.21 (s, 2H), 8.54 (d, J= 3.6 Hz, 1H), 8.46 (t, J = 5.0 Hz, 2H), 8.38 (s, 1H), 8.33 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.51 (dd, J= 8.1, 2.0 Hz, 1H), 7.42 (dd, J= 7.9, 4.7 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z: 568 [M+Hf.

VI-b-2 Cw NMR (600 MHz, DMSO-cfe) 5 10.55 (s, 1H), 9.40 (s, 1H), 9.16 (d, J = 2.2 Hz, 1H), 8.55 (d, J= 1.7 Hz, 1H), 8.53 (dd, J= 4.7, 1.6 Hz, 1H), 8.40 (s, 1H), 8.38- 8.34 (m, 1H), 8.26 (s, 1H), 8.10 (d, J= 8.3 Hz, 1H), 7.87 (s, 1H), 7.83 (dd, J= 7.9, 1.8 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z: 568 [M+H]*.

VI-b-3 TFA sait ’H NMR (600 MHz, DMSO-cfe) 5 10.88 (s, 1H), 10.60 (s, 1H), 9.39 (s, 1H), 9.15 (d, J= 1.7 Hz, 1H), 8.57- 8.48 (m, 2H), 8.40 (s,1H), 8.38- 8.34 (m, 1H), 8.24 (d, J- 2.1 Hz, 1H), 8.16-8.12 (m, 1H), 7.88-7.84 (m, 2H), 7.71 (d, J- 8.1 Hz, 1H), 7.51 (d, J= 8.2 Hz, 1H), 104 IEC170116PCT 7.38 (dd, J = 7.9, 4.7 Hz, 1H), 3.67 (s, 2H), 3.07- 2.98 (m, 4H), 2.92- 2.84 (m, 4H), 2.73 (s, 3H), 2.40 (s, 3H). MS (ESI) m/z: 680 [M+Hf.

VI-b-4 ’H NMR (600 MHz, DMSO-d6) 5 10.50 (s, 1H), 9.39 (s, 1H), 9.16 (d, J = 1.6 Hz, 1H), 8.53 (d, J= 2.1 Hz, 2H), 8.40 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 15.9, 7.9 Hz, 2H), 7.37 (dd, J = 8.0, 4.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 2.41 (s, 3H). MS (ESI) m/z: 584 [M+Hf.

VI-b-5 A? ^H NMR (600 MHz, DMSO-d6) 5 10.43 (s, 1H), 9.39 (s, 1H), 9.17 (d, J = 1.6 Hz, 1H), 8.57- 8.49 (m, 2H), 8.41 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.79 (t, J= 11.9 Hz, 2H), 7.60 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.39 (d, J - 6.6 Hz, 2H), 6.94 (t, J = 8.5 Hz, 1H), 2.41 (s, 3H). MS (ESI) m/zt 518 [M+Hf.

VI-b-6 TFA sait ’H NMR (600 MHz, DMSO-d6) 5 10.56 (s, 1H), 9.31 (s, 1H), 9.28 (s, 1H), 8.72 (s, 1H), 8.65 (d, J= 4.1 Hz, 1H), 8.49 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 15.6 Hz, 2H), 8.05 (d, J= 8.1 Hz, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.52- 7.47 (m, 1H), 7.33 (d, J= 8.5 Hz, 1H), 3.88- 3.71 (m, 4H), 3.13- 2.83 (m, 4H), 2.31 (s, 3H). MS (ESI) m/z: 667 [M+H]+.

VI-b-7 TFA sait 1H), 8.16 (d, J= 1.2 Hz, 1H), 7.98 (d, J= 7.7 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.65 (dd, J =7.9, 5.1 Hz, 1H), 7.38 (dd, J = 8.2, 2.2 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 2.62 (s, 3H), 1H NMR (600 MHz, DMSO-d6) 5 10.44 (s, 1H), 8.94 (s, 1H), 8.83 (s, 1H), 8.66 (d, J= 4.9 Hz, 1H), 8.57 (d, J- 2.2 Hz, 1H), 8.35 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H), 8.29 (d, J = 7.7 Hz, 2.31 (s, 3H). MS (ESI) m/z: 503 [M+H]+.

VI-b-8 ca-Î ,A\ÿ ^H NMR (600 MHz, DMSO-d6) 6 10.56 (s, 1H), 9.21 (d, J = 2.2 Hz, 1H), 9.05 (s, 1H), 8.71 (d, J= 1.5 Hz, 1H), 8.64 (s, 1H), 8.51 (dd, J = 4.7, 1.5 Hz, 1H), 8.38 (dt, J = 8.0, 1.9 Hz, 1H), 8.26 (s, 1H), 8.11 (d, J= 8.5 Hz, 1H), 7.78 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.41 (s, 1H), 7.36 (dd, J= 8.0, 4.7 Hz, 1H), 2.42 (s, 3H), 2.24- 2.16 (m, 1H), 1.13- 1.06 (m, 2H), 0.84- 0.78 (m, 2H). MS (ESI) m/z: 529 [M+H]+. 105 IEC170116PCT VI-b-9 ’H NMR (600 MHz, DMSO-d6) 5 10.46 (s, 1H), 9.24 (dd, J = 2.3, 0.7 Hz, 1H), 8.87 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.49- 8.46 (m, 1H), 8.29 (s, 1H), 8.26 (d, J= 8.1 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 8.2, 2.2 Hz, 1H), 7.42- 7.40 (m, 1H), 7.39 (d, J = 0.8 Hz, 1H), 7.28 (d, J= 8.6 Hz, 1H), 3.71 (s, 2H), 2.46- 2.38 (m, 8H), 2.31 (s, 3H), 2.25- 2.17 (m, 1H), 1.13- 1.09 (m, 2H), 0.84- 0.79 (m, 2H). MS (ESI) m/z: 628 [M+Hf.

Synthetic route of compound Vll-a-1: Preparation of compound 25a: Method K: compound 23a (410 mg, 2 mmol), cyclopropylamine (166 pL, 2.4 mmol) and diisopropylethylamine (0.5 mL, 3 mmol) were reacted in 2-butanol at 75°C, monitored by TLC until complete reaction. The system was concentrated, and purified by column chromatography to obtain the target product 347 mg, in 77% yield. MS (ESI) m/z: 226 [M+H]+.

Compound VII-a-1 was prepared from 25a and 26 though above Method. Other such compounds could be synthesized by a similar method.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure 1H NMR and/or MS data1H NMR (600 MHz, DMSO-d6) 6 10.63 (s, 1H), VII-a-1 8.80 (s, 1H), 8.37 (s, 1H), 8.32 (d, J= 7.8 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.16 (d, J= 5.4 Hz, 1H), 8.05 (d, J= 3.4 Hz, 1H), 7.98 (t, J= 7.7 Hz, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.45 (d, J= 5.4 Hz, 1H), 1.23 (s, 1H), 0.91- 0.85 (m, 2H), 0.71 (m, 2H). MS (ESI) m/z: 455 [M+H]*.

VII-a-2 A HN Av/0 1H NMR (600 MHz, Chloroform-d) 5 8.63 (s, 1H), 8.43 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.00 (s, 2H), 7.87 (s, 1H), 7.80 (d, J= 5.5 Hz, 1H), 7.48 (d, J = 5.4 Hz, 2H), 6.55 (d, J = 8.6 Hz, 1H), 5.64 (s, 1H), 4.88 (s, 2H), 3.11 (s, 1H), 1.03 (m, J= 6.6 Hz, 2H), 0.83 (m, 2H). MS (ESI) m/z: 403 [M+H]+. 106 IEC170116PCT VII-a-3 ô 1H NMR (600 MHz, Methanol-d4) 5 8.72 (t, J = 1.9 Hz. 1H). 8.28 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.16 (dt, J = 7.8, 1.3 Hz, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.89 (ddd, J= 7.8, 1.9, 1.0 Hz, 1H), 7.85 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 7.72 (t, J= 7.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.43 (d, J= 5.6 Hz, 1H), 5.03 (dp, J= 14.2, 2.5 Hz, 2H), 3.22-3.14 (m,2H), 2.79 (tt, J= 11.5, 3.9 Hz, 1H), 2.42 (s, 6H), 2.14-2.07 (m, 2H), 1.59 (qd, J = 12.4, 4.0 Hz, 2H). MS (ESI) m/r. 526 [M+H]+.

VII-a-4 ’H NMR (600 MHz, Methanol-d4) 5 8.66-8.56 (m, 2H), 8.10 (dt, J= 7.8, 1.4 Hz, 1H), 8.00 (dd, J = 8.8, 2.5 Hz, 1H), 7.93 (d, J* 5.5 Hz, 1H), 7.83- 7.77 (m, 1H), 7.44- 7.37 (m, 2H), 6.60 (d, J= 8.8 Hz, 1H), 5.01- 4.93 (m, 2H), 3.11 (td, J = 13.2, 2.4 Hz, 2H), 2.63 (tt, J = 11.5, 3.9 Hz, 1H), 2.33 (s, 6H), 2.08- 2.00 (m, 2H), 1.53 (qd, J= 12.3, 3.8 Hz, 2H). MS (ESI) m/r. 474 (M+H]+.

VII-a-5 ’H NMR (600 MHz, Chloroform-c0 6 8.54 (t, J = 1.9 Hz, 1H), 8.32 (s, 1H), 8.23 (dt, J- 7.8, 1.3 Hz, 1H), 8.09 (d, J= 2.1 Hz, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.98 (d, J= 7.8 Hz, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.72 (d, J= 5.5 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.45 (d, J = 5.5 Hz, 1H), 4.74 (dq, J= 13.0, 1.4 Hz, 2H), 3.78 (dqd, J= 10.4, 6.2, 2.3 Hz, 2H), 2.92 (dd, J = 13.2, 10.5 Hz, 2H), 1.32 (d, J= 6.3 Hz, 6H). MS (ESI) m/r. 513 [M+H]+.

VII-a-6 1H NMR (600 MHz, Methanol-d4) 5 8.66 (t, J = 1.9 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.15 (dt, J = 7.8, 1.3 Hz, 1H), 8.07-8.03 (m, 2H), 7.82 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 7.50- 7.46 (m, 2H), 6.65 (d, J = 8.7 Hz, 1H), 4.84 (dd, J= 14.0, 1.7 Hz, 2H), 4.60 (s, 1H), 3.81 (dqd, J = 10.6, 6.2, 2.3 Hz, 2H), 2.96 (dd, J = 13.3, 10.5 Hz, 2H), 1.32 (d, J = 6.2 Hz, 6H). MS (ESI) mtr. 461 [M+Hf.

VII-a-7 ’H NMR (600 MHz, DMSO-d6) 5 10.64 (s, 1H), 8.76 (t, J = 1.9 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.28 (d, J= 5.5 Hz, 1H), 8.20 (dt, J = 7.8, 1.4 Hz, 1H), 8.02- 7.97 (m, 2H), 7.81 (t, J = 7.8 Hz,1H), 7.54 (d, J = 5.5 Hz, 1H),7.50 (t, J = 7.9 Hz, 1H), 4.07- 4.01 (m, 4H), 3.85- 3.80 (m, 4H). MS (ESI) m/r 485 [M+HJ*.

VII-a-8 0 2.2 ^H NMR Hz, 1H), (6008.42 MHz, (t,Chloroform-d) J= 1.9 Hz, 1H), 5 8.62 8.22(d, (dt, JJ= = 7.8,1.4 Hz, 1H), 8.06-7.92 (m, 3H), 7.75 (d, J = 5.5 Hz, 1H), 7.52- 7.45 (m, 2H), 6.54 (d, J 107 IEC170116PCT = 8.6 Hz, 1H), 4.92 (s, 2H), 4.11- 4.06 (m, 4H), 3.93- 3.87 (m, 4H). MS (ESI) m/z: 433 [M+Hf.

VII-a-9 ’H NMR (600 MHz, Chloroform-d) 5 8.50 (s, 1H), 8.35 (s, 1H), 8.26 (d, J= 7.8 Hz, 1H), 8.12 (d, J= 11.9 Hz, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.70 (d, J= 5.6 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 4.04 (t, J* 4.9 Hz, 4H), 1.83- 1.70 (m, 6H). MS (ESI) m/z: 483 [M+H]*.

VII-a-10 ’H NMR (600 MHz, DMSO-d6) 5 10.07 (s, 1H), 8.71 (t, J = 2.0 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H), 8.12 (dt, J= 7.7, 1.4 Hz, 1H), 7.98 (dd, J = 8.7, 2.5 Hz, 1H), 7.94 (ddd, J= 8.1, 2.2, 1.1 Hz, 1H), 7.50 (d, J= 5.5 Hz, 1H), 7.43 (t, J= 7.9 Hz, 1H), 6.61 (s, 2H), 6.49 (dd, J = 8.7, 0.8 Hz, 1H), 4.04 (t, J= 5.3 Hz, 4H), 1.77- 1.65 (m, 6H). MS (ESI) m/z: 431 [M+H]*.

VII-a-11 1H NMR (600 MHz, DMSO-cfe) ô 10.63 (s, 1H), 8.77 (t, J = 1.9 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.23- 8.19 (m, 2H), 7.98 (ddd, J = 7.9, 2.1, 1.0 Hz, 2H), 7.81 (t, J = 7.8 Hz, 1H), 7.50- 7.45 (m, 2H), 3.94 (s, 4H), 2.05 (s, 4H). MS (ESI) m/z: 469 [M+H]*.

VII-a-12 ’H NMR (600 MHz, Methanol-d4) 6 8.61- 8.57 (m, 2H), 8.12 (ddd, J= 7.8, 1.7, 1.1 Hz, 1H), 8.02 (dd, J = 8.8, 2.5 Hz, 1H), 7.96 (d, J= 5.5 Hz, 1H), 7.82 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 5.5 Hz, 1H), 6.63 (dd, J- 8.8, 0.8 Hz, 1H), 3.97 (s, 4H), 2.08 (s, 4H). MS (ESI) m/z: 417 [M+H]+.

VII-a-13 ’H NMR (600 MHz, Methanol-d4) ô 8.73 (t, J = 1.9 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.15-8.11 (m, 2H), 7.91 (d, J= 7.8 Hz, 1H), 7.81 (ddd, J= 8.0, 2.3, 1.1 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.67- 7.62 (m, 1H), 7.52-7.48 (m, 2H), 6.25 (s, 1H), 3.71 (s, 3H). 2.30 (s, 3H). MS (ESI) m/z: 506 [M+H]*.

VII-a-14 1H NMR (600 MHz, DMSO-cfe) 5 10.08 (s, 1H), 9.73 (s, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.23 (d, J= 5.4 Hz, 1H), 8.04- 7.95 (m, 2H), 7.86 (d,J- 8.0 Hz, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.43 (t, J- 7.9 Hz, 1H), 6.61 (s, 2H), 6.49 (d, J = 8.7 Hz, 1H), 6.19 (s, 1H), 3.61 (s, 3H), 2.21 (s, 3H). MS (ESI) m/z: 458 [M+H]*.

VII-a-15 ^H NMR (600 MHz, DMSO-cfe) 5 10.67 (s, 1H), 9.93 (s, 1H), 8.92 (s, 1H), 8.86 (t, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.34 (d, J= 8.0 Hz, 2H), 8.30 (d, J= 5.4 Hz, 1H), 8.13 (dt, J=7.7, 1.3 Hz, 108 IEC170116PCT Synthetic route of compound VIII-a-1: 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.98- 7.94 (m, 1H), 7.82 (t, J= 7.8 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.52 (t, J= 7.9 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 3.17 (s, 3H). MS (ESI) m/z: 507 [M+H]+.

VII-a-16 1H NMR (600 MHz, DMSO-cf6) 5 10.09 (s, 1H), 9.88 (s, 1H), 8.90 (d, J= 2.7 Hz, 1H), 8.82 (t, J = 1.9 Hz, 1H), 8.68- 8.64 (m, 1H), 8.32 (dd, J= 8.4, 2.7 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.06 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.88 (ddd, J= 8.1, 2.2, 1.1 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.62 (s, 2H), 6.50 (dd, J = 8.7, 0.7 Hz, 1H), 1.04 (d, J= 6.1 Hz, 3H). MS (ESI) m/z: 454 [M+Hf.

VII-a-17 hnaJ 'H NMR (600 MHz, DMSO-cfe) 5 10.40 (s, 1H), 10.10 (s, 1H), 8.90 (t, J= 2.0 Hz, 1H), 8.69- 8.64 (m, 1H), 8.30-8.22 (m, 3H), 8.12 (dt, J= 7.9, 1.4 Hz, 1H), 8.01 (dd, J= 8.7, 2.5 Hz, 1H), 7.87 (ddd, J= 8.1, 2.2, 1.1 Hz, 1H), 7.77 (dd, J = 8.6, 2.4 Hz, 1H), 7.53 (d, J = 5.4 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.63 (s, 2H), 6.51 (dd, J = 8.8, 0.8 Hz, 1H), 2.32 (d, J= 1.0 Hz, 3H). MS (ESI) m/z: 454 [M+H]+.

VII-a-18 JX qH NMR (600 MHz, DMSO-cfe) 5 10.68 (s, 1H), 10.42 (s, 1H), 8.89 (t, J= 1.9 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.34 (d, J= 7.8 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 5.1 Hz, 1H), 8.23 (dt, J = 7.8, 1.4 Hz, 1H), 8.17 (s, 1H), 8.01- 7.97 (m, 1H), 7.94 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.58-7.51 (m, 2H), 6.99 (dd, J= 5.1, 1.3 Hz, 1H), 2.41 (s, 3H). MS (ESI) m/z: 506 [M+H]+.

VII-a-19 .XX 1H NMR (600 MHz, DMSO-cfe) 5 10.40 (s, 1H), 10.10 (s, 1H), 8.86 (q, J =2.8, 1.8 Hz, 1H),8.66 (d, J = 2.5 Hz, 1H), 8.27 (dd, J = 18.4, 5.2 Hz, 2H), 8.22- 8.12 (m, 2H), 7.99 (dd, J = 8.7, 2.5 Hz, 1H), 7.89-7.81 (m, 1H), 7.54 (d, J= 5.4 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 5.0 Hz, 1H), 6.62 (s, 2H), 6.50 (d, J = 8.7 Hz, 1H), 2.41 (s, 3H). MS (ESI) m/z: 454 [M+H]+. 27a 28a VHM-1 Compound VIII-a-1 was prepared from 27a through Method C, Method D in sequence. 109 IEC170116PCT Other such compounds could be synthesized by similar methods.

In the following table it lists the specific compounds and their structural characterization data.

No. Structure 1H NMR and/or MS data1H NMR (600 MHz, DMSO-d6) 5 10.62 (s, 1H), VIII-a-1 1H), 7.85 (d, J = 6.0 Hz, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.67 (s, 1H), 7.52- TFA salt 9.38 (s, 2H), 8.87-8.76 (m, 2H), 8.35-8.27 (m, 2H), 8.10 (d, J= 2.1 Hz, 1H), 7.98 (d, J= 7.7 Hz, 7.42 (m, 2H), 7.19 (dt, J= 6.5, 2.3 Hz, 1H). MS (ESI) m/z: 491 [M+H]+.

VIII-a-2 *H NMR (600 MHz, DMSO-cfe) 5 10.60 (s, 1H), 9.23 (s, 1H), 8.68- 8.63 (m, 2H), 8.32 (s, 1H), 8.29 (d, J= 8.0 Hz, 1H), 8.08 (t, J= 2.1 Hz, 1H), 8.04- 8.01 (m, 2H), 7.99- 7.95 (m, 1H), 7.82 (d, J= 6.1 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J= 6.0 Hz, 1H), 7.67 (s, 1H), 7.50- 7.42 (m, 2H), 7.18 (dt, J = 7.7, 1.6 Hz, 1H). MS (ESI) m/z: 491 FM+Hf.

VIII-a-3 TX? TFAsalt 1H NMR (600 MHz, DMSO-cfe) 5 10.56 (s, 1H), 9.20 (s, 1H), 9.04 (s, 1H), 8.72 (d, J = 5.0 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 8.26 (d, J= 8.0 Hz, 1H), 7.96 (d, J= 7.8 Hz, 1H), 7.91 (d, J= 2.2 Hz, 1H), 7.81 (d, J= 6.1 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.73 (dd, J = 6.8, 3.4 Hz, 2H), 7.62 (dd, J= 8.3, 2.2 Hz, 1H), 7.40 (d, J- 8.4 Hz, 1H), 6.91 (s, 1H), 2.24 (s, 3H). MS (ESI) m/z: 505 [M+H]*.

VIII-a-4 tJQ FaC o XX ^H NMR (600 MHz, DMSO-cfe) 5 10.53 (s, 1H), 8.87 (s, 1H), 8.63- 8.61 (m, 2H), 8.30- 8.28 (m, 1H), 8.27-8.24 (m, 1H), 7.95 (ddd, J = 8.6, 1.9, 0.9 Hz, 1H), 7.89 (d, J= 2.2 Hz, 1H), 7.87-7.85 (m, 2H), 7.78 (d, J- 6.3 Hz, 2H), 7.71 (d, J = 6.1 Hz, 1H), 7.64 (dd, J = 8.3, 2.3 Hz, 1H), 7.40 (dd, J= 8.2, 0.8 Hz, 1H), 6.91 (s, 1H), 2.23 (s, 3H).

MS (ESI) mà: 505 [M+H]+.

VIII-a-5 N^L^N g NMR (600 MHz, DMSO-cfe) 6 10.59 (s, 1H), 9.31 (s, 1H), 9.14 (d, J- 2.3 Hz, 1H), 8.60 (dd, J = 4.7, 1.6 Hz, 1H), 8.33 (dt, J= 8.0, 1.9 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.08- 8.05 (m, 1H), 7.99 (t, J = 2.0 Hz, 1H), 7.78 (t, J= 5.7 Hz, 2H), 7.74 (d, J= 6.1 Hz, 1H), 7.72- 7.69 (m, 1H), 7.61 (q, J= 7.8 Hz, 2H), 7.50 (s, 1H), 7.50-7.48 (m, 1H), 7.47-7.45 (m, 1H). MS (ESI) m/z: 491 [M+Hf.

VIII-a-6 ’H NMR (600 MHz, DMSO-cfe) 5 10.60 (s, 1H), 9.35 (s, 1H), 8.76- 8.58 (m, 2H), 8.25 (d, J= 1.9 Hz, 1H), 8.07 (dd, J = 8.2, 1.9 Hz, 1H), 7.99 (t, J = 2.0 Hz, 1H), 7.97- 7.93 (m, 2H), 7.82- 7.76 no IEC170116PCT (m, 3H), 7.70 (dd, J = 7.8, 2.2 Hz, 1H), 7.62 (dt, J = 10.9, 7.9 Hz, 2H), 7.56 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H). MS (ESI) m/z: 491 [M+Hj*.

VIII-a-7 TEA salt nH NMR (600 MHz, DMSO-d6) 5 10.51 (s, 1H), 9.24 (s, 2H), 8.80 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 8.23 (s, 1H), 8.07-8.02 (m, 2H), 7.97 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 7.83- 7.77 (m, 2H), 7.64- 7.55 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 6.80 (s, 1H), 2.33 (s, 3H). MS (ESI) m/z: 505 [M+HJ*.

VIII-a-8 TEA salt ’H NMR (600 MHz, DMSO-d6) 6 10.52 (s, 1H), 9.05 (s, 1H), 8.63 (d, J= 5.2 Hz, 2H), 8.22 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.95 (dd, J = 7.9, 1.8 Hz, 1H), 7.86 (d, J= 5.3 Hz, 2H), 7.76 (s, 2H), 7.64- 7.55 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 6.76 (s, 1H), 2.32 (s, 3H). MS (ESI) m/z: 505 [M+H]+.

Biological activity assay.

I. Determination of vacuolation of MDA-MB-231 cells caused by inhibition of compounds on PlKfyve When the activity of pikfyve kinase is inhibited, vacuoles will be produced in cytoplasm. By observing the number of vacuoles under a microscope, the ability of compounds to inhibit the activity of pikfyve kinase can be known. Experimental method: 1. Cell plating: cells in logarithmic growth phase were made into a single cell suspension, counted with a cell counter and diluted to a cell concentration of about 2x105/mL. Then, the cells were inoculated into a 12-well plate, and cultured in a 37°C, 5% CO2 incubator. 2. Administrating agent to cell: after cell adherence, drug samples (each drug sample had two concentration gradients 1 pmol/L, 10 pmol/L) diluted with culture medium were added to cells, with DMSO as negative control. 3. Vacuolation test: after 24 and 48 hours of culture, photos were taken under an electron microscope to observe the degree of vacuolation.

In the following table it lists the vacuolation test results of some compounds. (In the table, “+” represents the degree of vacuolation; more indicates more obvious vacuolation; represents no vacuolation) No. 1 pM, 24 h 10 pM, h 24 1 pM, 48 h 10 pM, h 48 l-a-1 +++ +++ +++ +++ l-a-10 - ++ - ++ l-a-20 +++ ++++ +++ ++++ l-a-21 - - - l-a-24 « - - l-a-25 + -1- + + 111 IEC170116PCT l-a-26 - » w l-a-27 + + + • 4- - + - +4- - l-a-30 + + l-a-31 - - l-a-32 + •<-+ l-a-33 4 + + + ++ + + +++ ++ ++ +/2 + ++ ++ ++ ++ + + + ++ - + - ++ ++ l-a-34 4- ++ l-a-35 4- HH" l-a-38 + ++ l-a-40 + + l-a-45 - + l-b-1 ++ +++ l-b-2 - ++ l-b-3 + ++ l-b-4 - +/2 l-b-5 - + l-c-11 ++ ++ l-c-12 +++ '■HH' +++ ll-a-1 4-/2 4-/2 + 4- -F + + + - + ++ + ll-a-2 + + ll-a-4 4- ll-b-2 + + lll-b-1 + ++ Ill-b-2 - - - - lll-b-3 - +/2 +/2 lll-b-10 - - + 4- + + + +/2 + + - ++ ++ + - + - + lll-b-14 + + lll-b-15 « + IV-a-1 + ++ IV-a-2 + ++ IV-a-3 +/2 + IV-a-5 + IV-a-7 - ++ 112 IEC170116PCT IV-b-2 "1" + + 4- IV-b-7 + 4* +/2 +/2 +/2 + + + m> + - 4- IV-b-9 +/2 - IV-b-10 +/2 O» IV-b-11 4* 4- V-a-1 - 4- V-a-3 HH* 4- V-a-4 - - • - V-a-5 4-4- +++ 4-4- V-a-6 4-4- ++ 4*4- 4-4- V-a-7 • + - 4- V-a-8 4- ++ + 4-4- V-a-10 ++ - ++ - V-b-1 4-4- ++ +4- 4-4- V-b-2 - 4-4- - 4-4- V-b-3 + ++ 4- 4-4’ V-b-4 ++ ++ 4-4- 4-4- V-b-7 4- • 4 - V-b-29 + - - • V-b-30 • 4- - 4- V-c-1 — 4-b - 4-4- V-c-2 - - « V-c-3 4- ++ “Hh"!" 4-4*4' 4- 4‘4' 4-4- 4- 4*4’4* 4-4- 4*4*4* 4-4- V-c-4 4-4-4- V-c-6 4- +4-4- V-c-7 ++ 4- V-c-8 1 1 1 V-c-10 - ++ - 4-4- V-c-11 * • « - V-c-12 +++ 4-4*4" ++ ++ 4-4-4- • - ++ 4-4- 4-4-4- V-c-13 4-4- 4-4- V-c-14 Hh4“ 4-4- V-c-15 4-4- 4-4- 113 IEC170116PCT V-c-16 V-c-17 V-c-18 V-c-19 V-c-20 V-c-23 ++ ++ +++ +++ - ++ *1'"1"’ ++ +++ +++ - ++ ++ - 444 +++ ++ - +++++++++++- V-c-25 - - V-c-35 V-c-40 VI-a-2 VI-a-5VI-a-6VI-a-8 VI-b-4 VI-b-6 VI-b-7 VII-a-15 VII-a-16 - 4 4 - + + 4 - +++ 4 + +/2 - - - - + 4 +++++++/2-+-++4 - +/2 + - + + 4 +/2 - - - + 4 VII-a-17 VII-a-18 VII-a-19 VIII-a-1 VIII-a-2 VIII-a-3 VIII-a-4 VIII-a-5VIII-a-6 VIII-a-7 VIII-a-8 - 4- «++ ++ ++ + - + ++ am - + - +4 ++ ++ + + + +++ * - + im++ ++ ++ + + + 44 44 -+ ++++++++++++44 II. Determination of dissociation equilibrium constant (Kd value) of compound and PIKfyve protein The Kd value was determined by DiscoverX's KINOMEscan™ technology according to the following steps: 1. Preparation of magnetic beads: biotin-labeled small molecule ligand and avidin-coated magnetic beads were allowed to interact at room 114 IEC170116PCT 85953755 temperature for 30 minutes, and then added with excess biotin, followed by washing with a blocking solution (1% BSA, 0.05% Tween™20 , 1 mM DTT) to remove unbound ligand. 2. Binding reaction: in a 384 plate, 0.02 ml_ system, DNA-labeled protein, small molecule ligand-bound magnetic beads, and different concentrations of compound to be tested were mixed in a reaction solution (0.17 x PBS, 0.05% Tween™ 20, 6 mM DTT) at room temperature TM with shaking for 1 hr, to which was added an eluant (1 x PBS, 0.05% Tween 20) for elution. Magnetic beads were resuspended by an eluant (1 x PBS, 0.05% Tween™ 20, 0.5 pM non-biotin-labeled small molecule ligand), and shaken at room temperature for 30 min before separating out the eluant. 3. Determination of Kd value: the content of protein in the above eluate was determined by qPCR. Eleven 3-fold dilution concentrations were determined for the compound to be tested, with 3 DMSO controls for each concentration, and the Kd value was obtained by curve fitting. In the following table it lists the Kd values of some compounds.

No. V-c-1 V-c-2 V-c-10 V-c-11 V-c-12 V-c-13 V-c-14 V-c-15 V-c-16 Kd value (nM) 130 2000 3500 700 > 30000 16 20 140 110 No. V-c-19 V-c-20 V-c-21 V-c-22 V-c-23 V-c-24 V-c-38 V-c-39 V-c-4 Kd value (nM) 15 1000 910 21000 33 > 30000 > 30000 > 30000 33 No. V-c-43 V-c-51 V-c-52 V-c-53 V-c-6 V-c-61 V-c-62 V-c-63 V-c-8 Kd value (nM)> 30000> 30000> 30000> 3000016> 30000> 30000> 3000013 V-c-17 V-c-18 V-c-19 640 6.4 16 V-c-40 V-c-41 V-c-42 380 > 30000> 30000 V-c-9 29 III. Determination of IC50 value of compound for inhibiting tumor cell growth by MTS method Experimental method: 1. Cell plating: cells in logarithmic growth phase were counted and inoculated in a 96-well plate (20000 cells per well). 2. Administrating agent to cell: 10 mM compound mother solution in DMSO was subjected to 3 fold-gradient dilution, to set 8 concentrations, which were then added to various wells, with three replicates for each concentration, and three blank wells (only culture medium) and three negative controls (containing 0.1% DMSO) on each plate. 3. Determination of IC50 value: after 5 days of culture, 20 pL of MTS reaction solution was added, followed by uniform mixing, and incubation in a cell culture incubator (37°C; 5% CO2)for 1-4 hr. The OD value at 490 nm was measured with microplate reader OD490. The cell growth inhibition rate was calculated by the following formula: Cell growth inhibition rate%—1 - (ODexperimentalgroup-ODblankgroup)/(ODnegative group"ODbiank group) X 100% The semi-inhibitory concentration IC50 of the compound acting on cell 115 growth was calculated using GradPad Prism 5 software according to the measured cell growth inhibition rate.

In the following table it lists the IC50 value or the inhibition rates of some compounds at 10 pM against JeKo-1 cells 8 represents the cell growth inhibition rate of compounds at 10 pM.In the following table it lists the inhibition rates of compound l-a-1 at 3.3 No. IC50 value(pM) 2.04 No. IV-b-2 IV-b-7 V-a-5 V-a-6 V-b-1 V-b-4 V-c-12 V-c-13 V-c-14 V-c-15 V-c-16 V-c-17 V-c-18 V-c-19 V-c-20 V-c-22 V-c-23 V-c-4 V-c-6 V-c-7 V-c-8 VI-a-1 IC50 (yM) value 7.12 19.1%a 3.08 0.987 12.3%a 17.2%a 2.79 34.3% a 46.6% a 35.1% a 6.22 0.743 0.862 2.09 9.41 1.54 15.8%a 5.94 4.95 3.28 39.0% a7.49 No. VI-a-2 VI-a-6 VI-b-1 VI-b-2 VI-b-5 VI-b-7 VI-b-9 VIl-a-15 VII-a-16 VII-a-17 VII-a-18 VII-a-19 VIII-a-1 VIII-a-2 VIII-a-3 VIII-a-4 VIII-a-5 VIII-a-6 VIII-a-7 VIII-a-8 IC50 (PM) value38.6% 811.3%a17.5%®14.7%®16.9%®16.5%®37.0% a2.670.8241.152.561.522.713.262.0117.3%®5.146.323.172 l-a-1 l-a-20 l-a-25 l-b-1 l-b-2 l-b-3 l-b-4 l-c-11 l-c-12 Il-a-1 ll-a-2 ll-a-4 ll-b-2 lll-b-1 lll-b-10 lll-b-14 lll-b-15 lll-b-3 lll-c-1 IV-a-1 IV-a-2 IV-a-3 2.13 2.77 1.60 2.68 1.33 6.13 1.10 17.3%a 43.4%a 18.7% a 2.85 0.939 1.88 6.78 24.1%a 4.86 2.00 18.3% a 19.0% a 16.2% a pM against multiple tumor cells.

Cell Lines Inhibition rate% A375 SK-MEL-28 SK-MEL-30 A549 MDA-MB-231 MDA-MB-435S MCF-7 HCT116 93.9764.0361.8765.348.3956.2344.2355.83 BGC823 53.95 HepG2 64.85 116 IEC170116PCT IV. Determination of growth inhibition rates of compounds against PlKfyve-mediated tumor cells by Cell Titer Gio method Experimental method: 1. Cell plating: cells in logarithmic growth phase were counted and inoculated in 384-well plate. 2. Administrating agent to cell: compound (3.3 pM DMSO solution) or blank control (DMSO) was added to various wells, with two replicates for each well. 3. Determination of growth inhibition rate: after 5 days of culture (37°C; 5% CO2), CellTiter-Glo® was added, followed by shaking for 2 min, centrifugation (90xg) for 30 sec, and then standing at room temperature for 10 min. RLU was measured on PHERAstar Plus. The cell growth inhibition rate was calculated by the following formula: Cell growth inhibition rate%=1- RLUexpenmentaigraup/RLUDMsoXl00% In the following table it lists the inhibition rates of some compounds against Toledo and ST486 cells (3.3 10 pM).

No. Inhibition rate% (Toledo)99.52 43.06 < 10% 99.55 93.93 95.82 96.33 19.27 94.84 95.35 95.57 99.65 99.56 99.60 99.55 99.65 95.21 97.26 99.66 99.51 64.25 94.89 97.30 53.31 49.11 98.83 Inhibition rate%(ST486)98.4235.2018.0176.1769.8691.3450.9637.6792.9896.1572.3385.2552.2457.5460.3395.6795.9870.6333.2923.7757.1427.2355.7829.969.5757.10 l-a-1 V-c-1 V-c-2 V-c-4 V-c-6 V-c-7 V-c-8 V-c-9 V-c-10 V-c-11 V-c-12 V-c-13 V-c-14 V-c-15 V-c-16 V-c-17 V-c-18 V-c-19 V-c-20 V-c-21 V-c-22 V-c-23 V-c-24 V-c-38 v-c-39 V-c-40 V. Lysosomal dysfunction caused by inhibition of compound V-c-17 on PlKfyve (Fig. 3) 117 IEC170116PCT After treatment with V-c-17 for 24 hr, JeKo-1 cells were lysed and tested by Wstern Blot. It showed that immature cathepsin A and cathepsin D increased, and had good concentration dependence. This was similar to the treatment result with the known PlKfyve inhibitor apilimod.

VI. Compound l-a-1 effectively inhibited tumor growth in a xenograft model of triple negative breast cancer cells, with good dose dependence (Fig. 4). 1. 4-6 weeks old female nude mice were injected subcutaneously with about 5x106 MDA-MB-231 cells; 2. When tumor volume (length * width x height x 0.5) reached about 100 mm3, the mice were randomly divided into three groups: control group, group with a dose of 5 mg/kg once a day, and group with a dose of 20 mg/kg once a day, and the initial tumor volume was recorded. 3. The drug or the control solvent was administered intravenously on time every day, the tumor volume was measured every day, and the procedures were continued for 12 days; 4. In the last day, the mice were killed 6 hours after administration, the tumor grown under skin was completely peeled off, and the tumor weight was recorded.

VII. Compound V-c-17 effectively inhibited tumor growth in a xenograft model of non-Hodgkin's lymphoma cells (Jeko-1), with good dose dependence (Fig. 5). 1. 4-6 weeks old female nude mice were injected subcutaneously with about 1xio7 JeKo-1 cells; 2. When tumor volume (length x width x height x n/4) reached about 100 mm3, the mice were randomly divided into four groups: control group, V-c-17 group with a dose of 25 mg/kg once a day, V-c-17 group with a dose of 25 mg/kg twice a day, and apilimod group with a dose of 25 mg/kg once a day, and the initial tumor volume was recorded. 3. The drug or the control solvent was administered intravenously on time every day, the tumor volume was measured every day, and the procedures were continued for 7 days; 4. In the last day, the mice were killed 6 hours after administration, the tumor grown under skin was completely peeled off, and the tumor weight was recorded. 118 IEC170116PCT

Claims (11)

1. 85953755 CLAIMS: 1. A compound having the general formula: or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, Xi, X2, X3, X4, Xs, Xe and their adjacent carbon atoms form a general formula selected from the group consisting of: wherein, R3 in the formula I I R1 is selected from the group consisting of: 2) zi , wherein oneofZi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen- 119 85953755 containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; and 3) h ; wherein, L2 isNHCO or CONH; R5 is zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 isH orC1-C6 alkyl; R2 is selected from the group consisting of: 2) zi , wherein one ofZi,Z2,Z3,Z4,Z5 is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen¬ containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; and 120 85953755 L2 is NHCO, CONH, NHCONH, NHCSNH or CO; R5 is: Z4 Z3^X,Z5 when L2 is NHCO, CONH, NHCONH or NHCSNH, R5 is zi , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, chloro, fluoro, methyl, trifluoromethyl, methoxy, —N K N—7 '■ trifluoromethoxy and 7—7 ; or when L2 is NHCO, R5 is amino-substituted C1-C6 alkyl, wherein the C1-C6 alkyl is methyl, ethyl or propyl; or when L2 is CONH, R5 is substituted heteroaryl, wherein the substituted heteroaryl is pyrazolyl substituted by multiple C1-C6 alkyl groups; or when L2 is CO, R5is0''^ or optionally substituted by C1-C6 alkyl; R7 is selected from the group consisting of H, C1-C6 alkyl and halogen; R9 is H or C1-C6 alkoxy; wherein, when one of R7and R9 is a non-hydrogen group, the other is hydrogen; R3 is -H or C1-C6 alkyl; R3 R1 R“ L2 is NHCO or CONH; 121 85953755 R5 is zi , wherein Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H and trifluoromethyl; orZ2 and Zsare independently selected from the group consisting of the following groups, the rest being H: —N x ' ' trifluoromethyl and R7 isHorC1-C6 alkyl; R3 is -H orC1-C6 alkyl; r3 in the formula III m R1 is selected from the group consisting of: Br 2) , wherein one of Z1, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; JL ^r4 3) V , wherein, L1 is NHCONH or NHCSNH, Z4 R4 is zi , wherein one or two of Z1, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; and 122 85953755 4) h ( wherein, L2 isNHCO or CONH; R5 is zi , wherein one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 isHorC1-C6 alkyl; R2 is selected from the group consisting of: 1) h , wherein, L2 is NHCO or CONH; Z3^CZ= T* A1* R5 is a , wherein, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, trifluoromethyl, trifluoromethoxy, methyl and methoxy; or Z2 and Z3 or Z2 and Z4, respectively, are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and R7 isHorC1-C6 alkyl; 2) amino substituted by pyridyl-methyl; and 3) R3 is -H or C1-C6 alkyl; in the formula IV iv 123 85953755 L2 is NHCO or CONH; R5 is a , wherein Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, trifluoromethyl and trifluoromethoxy; orZ2 and Z3 are independently selected from the group consisting of the following groups, the rest —N N—/ being H: trifluoromethyl and x—/ R7 isH orC1-C6 alkyl; R3 is -H orC1-C6 alkyl; in the formula V v R1 is selected from the group consisting of: 2) zi , wherein one of Z1, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, HOOC- and C1-C6 alkoxyformyl; L1 is NHCO, CONH, NHCONH or NHCSNH; 124 85953755 R4 is zi , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl and C1-C3 alkoxy; or Z3 R4is zi , wherein one of Z1, Z2, Z3, Z4 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino and hydroxy; n7 R5 4) h , wherein, L2 is NHCO, CONH, NHSO2, NHCONH or NHCSNH; R5 is zi , wherein one or two of Z1, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, trifluoromethyl, trifluoromethoxy, nitro, cyano, methoxy, acetamido (-NHAc), amino, methylsulfonylamino (-NHMs), R7 is H, methyl, fluoro, 5) amino substituted by unsubstituted phenyl or amino substituted by the following substituted phenyl: phenyl mono-substituted by methylsulfonylamino, or phenyl di-substituted by heterocyclyl; 6) pyridylamino; 7) C3-C6 cycloalkylamino; and 8) or J- ; R2 is selected from the group consisting of: 125 85953755 2) zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano and C1-C3 alkylsulfonyl; L2 is NHCO, CONH, NHSO2, NHCONH or NHCSNH; Z4 R5is zi , wherein one ortwoofZi,Z2,Z3,Z4,Z5 are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino, di-C1-C3 alkyl-substituted amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted ; C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl, C1-C3 alkyl and C1-C3 alkoxy; R7 isH orC1-C6 alkyl; 126 85953755 R3 is -H orC1-C6 alkyl; R3 NyW R2 in the formula VI VI L2 isNHCO or CONH; R5 is a , wherein one or two of Zi, Z2, Z3, Z*, Zs are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted and C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl; R7 isHorC1-C6 alkyl; R3 is -H, halogen, C1-C6 alkyl orC3-C7 cycloalkyl; in the formula VII vn L1 isNHCO or CONH; R4 is zi , wherein one of Z1, Zz, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; or 127 85953755 ÇÇ R4 is * , wherein one of Zi, Z2, Z3, Z4 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino and hydroxy; R2 is selected from the group consisting of: L2 isNHCO or CONH; R5 is zi , wherein one of Z1, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 is H or C1-C6 alkyl.
2. 2. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: 128 85953755 wherein, R1 is selected from the group consisting of: 2) zi , wherein one ofZi,Z2,Z3,Z4,Z5 is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen¬ containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; and 3) h , wherein, L2 isNHCO or CONH; R5 is zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 isHorC1-C6 alkyl; R2 is selected from the group consisting of: 129 85953755 or 2) z< , wherein one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen¬ containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; and L2 is NHCO, CONH, NHCONH, NHCSNH or CO; R5 is: when L2 is NHCO, CONH, NHCONH or NHCSNH, R5 is wherein one or two of Zi, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: H, chloro, fluoro, methyl, trifluoromethyl, methoxy, —N N—7 trifluoromethoxy and 7—7 ; or when L2 is NHCO, R5 is amino-substituted C1-C6 alkyl, wherein the C1-C6 alkyl is methyl, ethyl or propyl; or when L2 is CONH, R5 is substituted heteroaryl, wherein the substituted heteroaryl is pyrazolyl substituted by multiple C1-C6 alkyl groups; or ^N'r ^n77 when L2 is CO, R5isOx^ or HN^ optionally substituted by C1-C6 alkyl, R7 is H, C1-C6 alkyl or halogen; R9 isHorC1-C6 alkoxy; 130 85953755 wherein, when one of R7 *and R9 is a non-hydrogen group, the other is hydrogen; R3 is -HorC1-C6 alkyl.
3. 3. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate z4 L I thereof, wherein, when R1 is zi , one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy and C1-C3 alkyl.
4. 4. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, F4 Z3^ÆzZs X X wherein, when R1 is zi , Z3, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy and methyl.
5. 5. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is h , L2 is NHCO.
6. 6. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, ' N wherein, when R1 is h R5 is Z2^T zi A , wherein Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy and trifluoromethyl.
7. 7. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, 131 85953755 Z4 wherein, when R1 is h z2 T'' , R5 is zi , wherein Z2 or Z4 is trifluoromethyl, the rest being H.
8. 8. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is h , R7 is methyl.
9. 9. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate Z4 thereof, wherein, when R2 is zi , one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy, C1-C3 alkyl and C1-C3 alkoxy.
10. 10. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is zi , Z3, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy, methyl and methoxy.
11. 11. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h z4 , L2 is NHCO, CONH, NHCONH or NHCSNH, and R5 is z< , wherein, Z2 or Z4 is selected from the group consisting of the following 132 85953755 groups, the rest being H: H, trifluoromethyl, methoxy, trifluoromethoxy, methyl, chloro and fluoro; or Z2 and Z3 or Z2 and Z4, respectively, are independently selected from the group consisting of trifluoromethyl, chloro and 12. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , L2 is NHCO, and R5 is amino-substituted C1- C6 alkyl, wherein the C1-C6 alkyl is methyl. 13. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h L2 is CONH, and R5 is substituted heteroaryl, wherein, the substituted heteroaryl is 14. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , and L2 is CO, wherein, R5 is or 15. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h R7 is H, methyl, or fluoro. 133 85953755 16. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h ; R9 js H or methoxy. 17. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , h , as a whole, is selected from the group consisting of: 134 85953755 18. The compound as defined in claim 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, R3 is -H or -CH3. 19. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: L2 isNHCO or CONH; R5 is zi , wherein Z2 or Z* is selected from the group consisting of the following groups, the rest being H: H and trifluoromethyl; orZ2 and Zsare independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and x—z ; R7 is H orC1-C6 alkyl; 135 85953755 R3 is -HorC1-C6 alkyl. 20. The compound as defined in claim 19 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is R7 is methyl. 21. The compound as defined in claim 19 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is from the group consisting of: h , as a whole, is selected 22. The compound as defined in claim 19 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, R3 is -H or -CH3. 23. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: wherein, R1 is selected from the group consisting of: 136 85953755 Z3xT^Zs TT 2) zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro and cyano; L1 is NHCONH or NHCSNH, .Zs z2^ R4 is zi , wherein one or two of Z1, Z2, Z3, Z4, Zs are independently selected from the group consisting of the following groups, the rest being H: halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; and 4) h ( wherein, L2 isNHCO or CONH; R5 is zi , wherein one of Z1, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; R7 isHorC1-C6 alkyl; R2 is selected from the group consisting of: 1) h , wherein, L2 isNHCO or CONH; R5 is zi , wherein, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, trifluoromethyl, trifluoromethoxy, methyl and methoxy; or Z2 and Z3 or Z2and Z4, respectively, are independently selected from the the 137 85953755 —N N group consisting of following groups, the rest being H: trifluoromethyl and R7isHorC1-C6 alkyl; 2) amino substituted by pyridyl-methyl; and R3is -HorC1-C6 alkyl. 24. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate Z4 23x^k/Z5 thereof, wherein, when R1 is zi , one of Zi, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino and hydroxy. 25. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is zi , Z3, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino and hydroxy. 26. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, .24 Z3^XxZ5 wherein, when R1 is , R4 is zi , Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy and trifluoromethyl; or Z2 and Z4are independently selected from the group consisting of the following groups, the rest being H: bromo, amino and hydroxy. 27. The compound as defined in claim 23 or a stereoisomer thereof, a 138 85953755 pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Z2 f, R4 is zi , Z2 or Z4 is trifluoromethyl, the rest wherein, when R1 is being H. 28. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is , as a whole, is 29. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is h , L2 is CONH. 30. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is h , R5 is zi , Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy and trifluoromethyl. 31. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, z4 Z3^k/Z5 wherein, when R1 is rest being H. h , R5 is zi , Z2 or Z4 is trifluoromethyl, the 139 85953755 32. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is h ; r7 js methyl. 33. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , r5 js Zi , Z2 or Z4 is trifluoromethyl, the rest being H; or Z2 and Z3 or Z2 and Z4, respectively, are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and 34. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is R7 is methyl. 140 85953755 35. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , h , as a whole, is selected from the group consisting of: 36. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the amino substituted by pyridyl-methyl is 37. The compound as defined in claim 23 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, R3 is -H or -CH3. 38. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: IV wherein, 141 85953755 R2 is h ( wherein, L2 isNHCO or CONH; R5 is zi , wherein Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, trifluoromethyl and trifluoromethoxy; orZ2 and Z3 are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl and x—7 ; R7 isHorC1-C6 alkyl; R3 is -HorC1-C6 alkyl. 39. The compound as defined in claim 38 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h ; r7 js methyl. 40. The compound as defined in claim 38 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, 142 85953755 41. The compound as defined in claim 38 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, R3 is -H or -CH3. 42. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: v wherein, R1 is selected from the group consisting of: 2) zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, HOOC- and C1-C6 alkoxyformyl; L1 is NHCO, CONH, NHCONH or NHCSNH; R4 is a , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy, C1-C3 fluorine-containing alkyl and C1-C3 alkoxy; or R4is zi , wherein one of Z1, Z2, Z3, Z4 is selected from the group consisting 143 85953755 of the following groups, the rest being H: H, halogen, amino and hydroxy; 4) h , wherein, L2 is NHCO, CONH, NHSO2, NHCONH or NHCSNH; R5is zi , wherein one or two of Zi,Z2,Z3,Z4,Z5 are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, trifluoromethyl, trifluoromethoxy, nitro, cyano, methoxy, acetamido (-NHAc), amino, by unsubstituted phenyl or amino substituted by the following substituted phenyl: phenyl mono-substituted by methylsulfonylamino, or phenyl di-substituted by heterocyclyl; 6) pyridylamino; 7)C3-C6 cycloalkylamino; and 8) —L~ , ~~L~ or -J-” ; R2 is selected from the group consisting of: 2) zi , wherein one of Z1, Z2, Z3, Z4, Zs is selected from the group consisting of the following groups, the rest being H: H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 144 methylsulfonylamino (-NHMs), R7 is H, methyl, fluoro, 5) amino substituted 85953755 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, halogen, amino, hydroxy, nitro, cyano and C1-C3 alkylsulfonyl; L2 is NHCO, CONH, NHSO2, NHCONH or NHCSNH; z4 Y T_ z2^V'a R5 is zi , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino, di-C1-C3 alkyl-substituted amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted ; C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1-C6 alkyl, C1-C3 alkyl and C1-C3 alkoxy; R7 isHorC1-C6 alkyl; R3 is -H or C1-C6 alkyl. 43. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is zi , one of Zi, Z2, Z3, Z4, Z5 is selected from the group 145 85953755 consisting of the following groups, the rest being H: H, fluoro, chloro, amino, hydroxy, C1-C3 alkyl, HOOC- and ethoxyformyl (EtOOC-). 44. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, z4 I L z2/y?A wherein, when R1 is zi , Z3, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy, HOOC- and ethoxyformyl (EtOOC-). 45. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Az wherein, when R1 is L , and R4 is z< , Z2 or Z4 or Z3 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino and trifluoromethyl; or Zi and Z4 are independently selected from the group consisting of the following groups, the rest being H: bromo and methoxy. 46. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Z3 JL JL /r4 ny^ wherein, when R1 is , and R4 is z< , Z2 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino and hydroxy. 47. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Z3 Z2y/yZ4 /r4 wherein, when R1 is Ll , and R4 is zi , Z2 is amino, the rest being H. 146 85953755 48. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, 49. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is H ,andR5is zi , ZaorZ* is H or-OCFs; orZs is H, -NO2, -CN or -OMe; or Z2 or one of Z4 and Z3 is H, -CF3 or -NHAc; or one of Z1 and Z5, or one of Z2 and Z4, or Z3 is H, -NH2 or -NHMs; or Z2 and Za are independently -CF3 >nA z- / —Nx / "r; or Z1 and Z* are or n ; or Z2 and Z3 are independently -CF3 or independently -CF3, -OMe, -F or -Cl; the rest being H. 50. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is h h , as a whole, is selected 147 85953755 from the group consisting of: 148 85953755 51. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the amino substituted by unsubstituted phenyl is , amino substituted by 149 85953755 HN phenyl mono-substituted by methylsulfonylamino is nhms, or amino substituted by phenyl di-substituted by heterocyclyl is 52. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Ç Ç HNV HN; wherein, the pyridylamino is ' or < . 53. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, 9 9 y HN^ HNy HNy wherein, the C3-C6 cycloalkylamino is ' , * or ' . 54. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate F4 z3yYy25 thereof, wherein, when R2 is zi , one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, amino, hydroxy, C1-C3 alkoxy and C1-C3 alkylsulfonyl. 150 z2^ y wherein, when R2 is z< , Z3 is selected from the group consisting of the following 55. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, ^x^Yx/25 85953755 groups, the rest being H: H, fluoro, chloro, methoxy and methylsulfonyl (-Ms). 56. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is , wherein, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, amino, dimethylamino, trifluoromethoxy and hydroxy; or Z2 and Z3 or Z2 and Z4, respectively, are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl, — N N 57. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , R7 is H or methyl. 58. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , h , as a whole, is selected from the group consisting of: 151 85953755 NH 59. The compound as defined in claim 42 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, R3 is -H or -CH3. 60. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: VI wherein, 152 85953755 R2 is h , wherein, L2 isNHCO or CONH; Z« R5 is zi , wherein one or two of Zi, Z2, Z3, Z4, Z5 are independently selected from the group consisting of the following groups, the rest being H: H, fluoro, chloro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl-substituted ~n and C1-C6 alkyl substituted by heterocyclyl that is optionally substituted by C1- C6 alkyl; R7 is H or C1-C6 alkyl; R3 is -H, halogen, C1-C6 alkyl or C3-C7 cycloalkyl. 61. The compound as defined in claim 60 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , and R5 is z< , Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, fluoro, trifluoromethyl and trifluoromethoxy; or Z2 and Z3 or Z2and Z4, respectively, are independently selected from the group consisting of the following groups, the rest being H: trifluoromethyl, 62. The compound as defined in claim 60 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, wherein, when R2 is R7 is methyl. 153 85953755 63. The compound as defined in claim 60 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , h , as a whole, is selected from the group consisting of: 64. The compound as defined in claim 60 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, R3 is -H, fluoro, chloro, C1-C3 alkyl or C3-C7 cycloalkyl. 65. The compound as defined in claim 60 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, vA wherein, R3 is -H, -Br, -CH3 or 66. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: VII wherein, 154 85953755 R1 is , wherein, L1 isNHCO or CONH; R4 R4 is zi , wherein one of Zi, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1-C3 fluorine-containing alkyl; or R4is z< , wherein one of Z1, Z2, Z3, Z4 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino and hydroxy; R2 is selected from the group consisting of: 67. The compound as defined in claim 66 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is , L1 is NHCO. 68. The compound as defined in claim 66 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is , and R4 is zi , wherein, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino, hydroxy and trifluoromethyl. 155 85953755 69. The compound as defined in claim 66 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is trifluoromethyl, the rest being H. , and R4 is zi , wherein, Z2 or Z4 is 70. The compound as defined in claim 66 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, wherein, when R1 is , and R4 is z< , wherein, Z2 is selected from the group consisting of the following groups, the rest being H: H, chloro, amino and hydroxy. 71. The compound as defined in claim 66 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is being H. , and R4 is zi , wherein, Z2 is amino, the rest 72. The compound as defined in claim 66 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R1 is as a whole, is 73. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound has the following structure: 156 85953755 R2 VIII wherein, , wherein, L2 isNHCO or CONH; Z4 R5 is z< , wherein one of Z1, Z2, Z3, Z4, Z5 is selected from the group consisting of the following groups, the rest being H: H, halogen, amino, hydroxy and C1- C3 fluorine-containing alkyl; R7 isHorC1-C6 alkyl. 74. The compound as defined in claim 73 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h ,andR5is zi , wherein, Z2 or Z4 is selected from the group consisting of the following groups, the rest being H: H and trifluoromethyl. 75. The compound as defined in claim 73 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, when R2 is h , R7 is H or methyl. 76. The compound as defined in claim 73 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, 157 85953755 wherein, when R2 is h , h , as a whole, is selected from the group consisting of: 77. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound is: 158 85953755 159 85953755 l-a-25 0X. n N h - \ /°zH.zxAbzZ”A A— CO ) co CXI -J- / l-a-27 A- 0A I\^nxJL„XnA/%xnh H V l-a-28 N. y J n h A T? AJUNM ~h H IL A l-a-29 CF3 '"N'A [bA 0 l-a-30 F3CX\Aq,nh l-a-31 ri m hcf3a y i#A ? L$ zx>r l-a-34 l-a-32 l-a-33nL II ?u AAf3co"^l-a-36 £Xv%-nM XX l-a-35 nOx/N NXX?nCAnAn XciAAnA^qahOyVNfxx-Vynh nîbH X JO-nA/^nhHl-a-37 <X> l-a-39nOy^A-n N l-a-38 C bX|N An" MeO^^ '■MYr f3C^TJHÏ HU„NH I l-a-40 l-a-41 nXXN -nIX? H H T H H I F3CXO ï>LccNH fÂ<A AAï-N.Q.NH l-a-42 nA>5 CI'A" O-XM/NH °-X X\ l-a-43 l-a-44 l-a-45 b« xCMzpIZ\=ZPa bbJ n^nAA0 - N N 160 85953755 161 85953755 l-c-8 AAA O l-c-9 8 l-c-10 F 3 °" il\#X T TAJXy F/>sA cXX#^# N H W 1-011 N R o XJ\ XXX/ O 'N'" l-c-12 ^XX'yV N H ° XJ\ XXX/ JJ ll-a-1 nXvn h XuAX X i h XXX ° ll-a-2 nXyn N N# 0 ll-a-3 "CW CF, hn-^X^Ay An-. JJ H ll-a-4 Il J H 3 ll-a-5 X/yN CF, "X ° X“Y ll-b-1 Ox# । h XX “yV-XA XXX ° ll-b-2 N.JJ HNYXy XJ H ll-b-3 8 fj O h»YYA'AX xnx ll-b-4 xx^x hX2Xh'^cfî ll-b-5 nHN^ A A° XX fX-y L *k YV n - II] H 162 lll-a-1 #nXO N-V ° #1 X3X^CFs lll-b-2 ? ifY lll-b-3 <v “ HNXJ xXï H lll-b-4 AnXX^oh HN N'^J^cFs ir h h 3 lll-b-5 85953755 xz zM oJ1 lll-b-6 LIJ H lll-b-7 NJCX n ? Ml nW^cF, r j h 3 lll-b-8 /MyNHz On^XX N hn-q£AMCFs t ? £1 lll-b-9 ^NH ? O HN LI] rYXN^':'5t^ H lll-b-11 Me o) 0 n"tn ° rX lll-b-12 OvXX», co HN à lll-b-13 <çr^ 2 HN Ô lll-b-14 x fXX ° [XX HN Ô lll-b-15 «J MnïtXXna । H HXXCF HN à lll-b-16 nyyCXKXXCFs CM H H HN lll-b-17 Br £r£CXnanX^ OMe HN o lll-b-18 Hr NaJ, VMjN H H I,,OMe HN NyXxXX'NX'ji Ô lll-c-1 XvMy 163 IV-a-1 hnXXnJO. cf3 1Y> hXj H T H IV-a-2 hnXX^yyCF3 nXn> 0 nJ IV-a-3 XlyM , CFi yy U { J H 85953755 O /— Z Z— HcrIZa ; ’X > O IV-a-5 ri h nAn o kA, « o IV-a-6 xôy u çr^ IV-a-7 Ær U IV-b-1 HNX^0y,cF3 nA-n kA rAi IV-b-2 hnA4"yy"S «Ay ° M N; IV-b-3 hn'0 ÀV U N.Y IV-b-4 IA h HN-VyWfa ° 0A IV-b-5 hnXCXX.- ff N-A=Ï [| CF?, ÀV U S" IV-b-6 T"! n i H L <fJ"N N\ IV-b-7 AY" N ^hT IV-b-8 Xt*') h yy s-4 IV-b-9 ïAia ° n y IV-b-10 hnX^y“aycf’ A", ° AA, a y IV-b-13 hn-^y ÏYnVn 0 M N\ 0"^ MM nIV-b-11 HN^y^yy0"3 IV-b-12 NN'^ nHn o W .a164 V-a-1 ,N_ _ । h n r f'S <: A7 a) KJ I \—' 2! !\J MHXZA vy0OIZh5 V-a-3 nYMn TAA ? 3 nMn T H H aH I J0 x ?~k -l^ zx o=\ vYs V-a-5 Ny^a hnAAnAJ jX JU H V-a-6 A =-. A ; A" A " 85953755 V-a-7 nr r 11 d " TAH 0» AO 1 JU H A V-a-8 CjU-^ TA y "Jh o A HNJULJA-y. AA H UN V-a-9 XyBn p nab HN^y-Y j fYYr u. V-a-10 ««AW Th Ï jVf Lt I Il J H V-a-11 VY h qY V-a-12 hnXX^AY"1 An J H oII A1 V-a-13 iVïWF! Yl H V-a-14 YX h hnYMyY Y" 1 H °n D ci Y A-y Xj N V-a-15 hnXXatCFs „A\ ° X HO.G,_ X JXJ Xj N V-a-16 Y1 h nM i H n LXX V-a-17 '^T^l h A^ Jk , ^CFi ...u- Uaô ° V-a-18 HN-X>\NYYGFi JX ° V-a-19 .. L JM ho,c^”AA V-a-20 hnVLn^ cf3 A«nj eio2c: AA V-a-22 "YX V-a-23 Ô V-a-24 X-,. N fj ? x5u H u V-a-25 '"n'" V-a-26 0„ JJ j xhu F,C nAQ|An V-a-27 Yr YuŸ V-a-28 Jr XY V-a-29 Y«YJ V-a-30 Cx uA/yY 165 85953755 V-a-31 o. ûwY V-a-32 A H2NKyryX V-a-33 F3cAX”j^X^^ V-a-34 A HN H2N^. V-a-35 V-a-36 HN 9 fl Y n-An ~ Hl HN. H [ H A. As. A V-a-37 V-a-38 V-a-39 9“ 0 9 0b X10=Szi hX s fi hnaAXXF3 A J ° H fl V-a-40 V-a-41 V-a-42 y ,N. _N. J yyvh nV h t h r n \ J J h^T 0 00 hNyAnMcf, Zjf Y nA" o H T I fl "yV-nAAf, HNi^ JI j n 3 XX * V-aA4 3 Il J H 3 V-a-43 V-a-45 ^nT „N Yk 1X1 J jj h 3 ? A XXM X-zx /\XAz zx-< ZIqb V-a-46 V-a-47 V-a-48 3 z^nACnh o £ h J 1 H /AN CLn YA O h T ? 1 1 nAN H T oH I 1 H HWNYVvf Y H [A HNJJ K"^CF3 XX °2 V-a-49 V-a-50 V-a-51 ~^NL As. Æ AÇA Hl H H ci>° H HN1 HN HN ,CF, onA A" s n Jz°=<0q 0 0 Xi H 166 85953755 V-a-52 V-a-53 V-a-54 uu UN Î fl JU H A>.^N AY Wn o h T ii I n A J H .yU W J f} HN^.,,AJV-C JU' M V-a-55 V-a-56 V-a-57 UU4X U" Whn.Yii Vj A? hNAs. nA.NH, <V HNrf .°Gn /V H JU H V-a-58 V-a-59 V-a-60 002 y^zx \ /~ X—A zz A ? n A z— \ V-b-1 N X;N , rF r TA T nUV A T Me H H Hwyyyu J'J 0 V-b-2 V-b-3 V-b-4 Ay X HNUUNyAG uu ° n^yVx JJ N AhnyAAA JU H NU Gnj0 p Nff A HhL A JJU V VA II 1 H V-b-5 V-b-6 A V-b"7 Gu GUV ~ r y \> ^3 "An7 T Me ou fiA1 » AAA JU H V, =—\ \ s x\ ez 4 ®y zz o/ yuo/ V-b-8 V-b-9 V-b-10 AU ex... feNH cX z J1o<>ZIO=<ZIGu B'YyYyyUA e xXH o H ex nX-N H F /> V-b-12 V-b-13 V-b-11 G Fl ^-^NH / h h NXrN u s u AX s XA 167 85953755 CDd O— ZI ZId. cpH V-b-14 ex bttVtYY H H Ï id My V-b-15 n ^-^NH z H « Y? bxxpcFn ? V-b-16 _Xn/ ^NH V-b-17 V-b-18 v\ V-b-19 QN NH h2ny% iMpXn YXnh z . ? ;• V-b-20 1 N V-b-21 xNH F,c.Oy.pr>; V-b-22 X n ° n^tn> fscXAnpyp V-b-23 9 NH l PYyY^ tip H o H lip I F /) V-b-24 9 NH l « H Np> F3CYVmnyYnX7 V-b-25 9 NH ! N'’’"'Mr-'N H H ii /> Br.IXN.xNu/\ A NY-<d V-b-26 A Ph H H A") Brp>NXN V-b-27 9 NH , J / H H I TN5 V-b-28 n \h NXyNs FsC^^N N V-b-29 NH tX H « X A o LA I V-b-30 9 NH 'tiTyX'17 ''Ap s '''"A 1 V-b-31 hnP V-b-32 A HNX IX aJIO Yr N ° Pm V-b-33 MMpô V-b-34 yJ V-b-35 V-b-36 V-b-37 168 85953755 k 9 YyY' XNX ; -> 7 V-b-38 , ô Yy-Y0' V-b-39 .0 4 J Ï H H V-b-40 ÛÏ / h^ny\ u(yXY V-b-41 Y ttAQ-SyCK,, V-b-42 XT N Yy° V-b-43 YcjY=-. V-b-44 V-b-45 XT y/.q'yyy H H V-c-1 ÇŸ Jy NHMs V-c-2 H CXI V "6 o V-c-3 H ;Y Y nh2 V-c-4 H O A ô.„ Gl"3 V-c-5 V-c-6 =1 XY O^'NH V-c-7 sv nJ Ô. ~'^N^ Ô °T^Af3 V-c-8 ,;X V-c-9 ="J h X f3X'~'Xf3 0AT V-c-10Y oYhZi Ô ° y^^OCFj 169 85953755 V-c-11 V-c-12 V-c-15 V-c-18 V-c-13 V-c-16 V-c-19 V-c-22 V-c-25 170 85953755 V-c-26 Çÿ" y I V-c-27 V-c-28 pzix O oAç NHMs /V Ô " JH nh2 V-c-29 V-c-30 zx0^o V-c-31 çÿ- oAQ iz’^Zx 1>Q <V Nf A Ha. I°Vi AAh, NHAc V-c-32 V-c-33 V-c-34 fT n-'j'vn TIY '6 0y2 6 »1I•^NHAc Y^ZZ 0TZ dz V-c-35 V-c-36 V-c-37 IZ y=y \=z AAh XA off.. Ô “t ^''NHAc ... „N N X, 0 yxMe V-c-38 11 V-c-39 V-c-40Yr Y. y gf3 7^ /N^N,A^ = ?Y O^NH àŒGF3 1Ç1 ô 7^0 "N \-ACF3 V-c-41 V-O42Z--. /LcuuY ""(Jk^0 Gr3 iV "Y z„. V-c-43 X A aH yj y-y CF3 V-c-44 V-c-45 V-c-46 F H I w Qu.M \ /z H I ^Nx ,N. A v Vs w C1^"cf3 H I „ ,N. A Py"f %o-vKrjY cf3 171 85953755 uLL \ / X xz F*- V-Z f— z 'J; X— %— Ô U W :> OQLL« O IZ \ /xyz^O X /X ? XH>‘ >x z=\ ° —0 \ z (0 zz y=/ ° V-c-50 = ; Ms "5 M-CF3 V-c-51 = Xx o^NH u V-c-52 Xo O^NH “XX, V-c-53 X'X " X oX„ MeO.! T 1 V-c-54 H | X" y O NH /=( MeO-^jk O XXGr3 v-c-55 H I ,hk A OH X H J X's O^NH X/ MeO^X 0xxCF3 V-c-56 «XO^NH TXXjl ^^cf3 V-c-57 XX X cXnh xX MeO^X XF3 V-c-58 pXX |X, cXh y V-c-59 Xi1 rjV cXhlH O MeOX. ome ULcF3 V-c-60 s V r'X O'"KNH “Xxuh3 V-c-61 = rX?cXnH . ô X. UC-l-3 V-c-62 = :-=i Çq cXnh ^^ocf3 V-c-63 >x Xs cXnh a OCF3 V-c-64 H I ^YN^NXx nV IJ H I 1 Xo cXnh w cjx ^^OCFg 172 85953755 V-c-65 H I CUp H T J. 8k'S O^NH 8^^ocf3 V-c-66 = y : 8? O'S cr8“ NH ocf3 “Op- § ZI 00 V-c-68 /U YF °8^^OCFa V-g-69 c. 8OMe °p V-c-70 8Ms °p oaCFs V-c-71 H cop UCF3 V-c-72 H ça ZN, ,N.q xL my° u CX. v-c-73 H cp p ur3 V-c-74 H '5 V-c-75 H cap "8 "V w aCFbr3 V-c-76 H €p"p \ s I k1 CxcF3 V-c-77 H cap gf3 V-c-78 H cap 8° "8 ^CF3 V-c-79 H cup A HN^.O . .. V-c-80 H cap QOMe ”8 8ArF G1-3 V-c-81 H cap XMS "8 CF3 V-c-82 1Ô H = ^“3 173 85953755 VI-a-1 o VI-a-2 nY^n o VI-a-3 Ol^ CFs NyA o HN AA H VI-a-6 A yvM^V VI-a-4 VI-a-5 V7 yx HN. A AxJ L N, YII yJ nH ~ t h r 1 HN^^,N^XArp if 1 n XkX 0 Y fi j HN^ /5. A AA JO* 3 VI-a-7 tl n^n o VI-a-8 Ü1 fF« VI-a-9 N (1 hnAAnXX0CF AsJ H VI-a-10 VI-b-1 VI-b-2 N'Y^ u pfA Y || J Cf3 YX ° (1 7Br ° OyY Yx ° Yn f3c^nAYH 174 85953755 VI-b-3 A T h h/VA T । 1 XT r ” ' VI-b-4 N Il 1 Br A 0 HN^yA nAOCF1 k. JJ M VI-b-5 CÇA NV^N o a VI-b-6 OyF-.NX vHN„ _N. „ nv JL.A L o yr 4i^cfs AA ° VI-b-7 AyU NvV 1 H H T yv ° V\ VI-b-8 A4 A J-^l/ L ll 0 T N /ksJk Jk /ts. .MHnX^v f3c 3 H H 1 VI-b-9 or .A "yA A-AA r-k^-O A il if CFs .-A4 o VII-a-1 A HN f3c'O^K^^X) VII-a-2 A HN VII-a-3 XNZ Ô o AA VII-a-4 ÔA''' HJA ,N. sY I H 7A />o kxj VII-a-7ÛNF3C-^kkL^N^^j^^ VII-a-5 Tr Ar A-o^ VII-a-6Xraa VII-a-8 0 nÀsv VII-a-90F3C-k^~y VII-a-10 VII-a-11 VII-a-12 V F3ckX^Ny^ANX? QAsA° VII-a-13 VnHN^' VII-a-14 HN^/ H,N^aa° ^N. A Ç VII-a-15 A"' FsC-k^yN A A"A° AA N^k^S 175 85953755 VII-a-16 HN n TH O Aa VII-a-17 ry HN^'^ VII-a-18 NX HN'XA F3czXN/yx^ 0 VII-a-19 N'A hnAA N nX-A o Aa VIII-a-1 Xi s n « VA F3C "f| VIII-a-2 VIII-a-3 Ax> F3CXX/yyh VIII-a-4 VIII-a-5 VIII-a-6 TX? ii । h * Oynys n î 1XYyA, n ? x" r3C f| || J ° FjC^5^'N H < J NH n NH 3 H < J VIII-a-7 VIII-a-8 S F3ckXN nX X|| u ."tAA H LA or 78. A pharmaceutical composition, comprising the compound as defined in any one of claims 1-77 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and optionally a pharmaceutically acceptable excipient. 79. A preparation method of the compound as defined in any one of claims 1-77, comprising the following steps: ci R2 176 85953755 step (a) coupling reaction of carbon-carbon bond formation of heteroaryl chloride and boronic add or boronic acid ester catalyzed by metal palladium, or coupling reaction of carbon-nitrogen bond formation of heteroaryl chloride and amine compound catalyzed by metal palladium, or nucleophilic substitution reaction of heteroaryl chloride with amine compound under alkaline condition, or nucleophilic substitution reaction of heteroaryl chloride with amine compound under acidic condition; and step (b) coupling reaction of carbon-carbon bond formation of heteroaryl chloride and boronic acid or boronic acid ester catalyzed by metal palladium, or coupling reaction of carbon-nitrogen bond formation of heteroaryl chloride and amine compound catalyzed by metal palladium, or nucleophilic substitution reaction of heteroaryl chloride with amine compound under acidic condition wherein, the heteroaryl chloride is: Cl Cl Vila > Villa IVb Vllb or villb the boronic acid or boronic acid ester is substituted or unsubstituted C6-C10 aryl or heteroaryl boronic acid or boronic acid ester; the amine compound is substituted or 177 85953755 unsubstituted C6-C10 arylamine, heteroarylamine, C1-C6 alkylamine, C3-C7 cycloalkylamine, C1-C6 oxygen-containing alkylamine or C3-C7 oxygen-containing cycloalkylamine; the metal palladium catalyst is palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or tris(dibenzylideneacetone) dipalladium; the alkaline condition is a condition in which any of the following substances exists: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride; the acidic condition is a condition in which any of the following substances exists: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluene sulfonic acid or camphorsulfonic acid. 80. Use of the compound as defined in any one of claims 1-77 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof or a pharmaceutical composition as defined in claim 78 for preventing or treating a PlKfyve-mediated disease in vivo. 81. Use of the compound as defined in any one of claims 1-77 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof or a pharmaceutical composition as defined in claim 78 for preventing or treating growth and metastasis of tumor with characteristics of K-RAS mutation or nutrient acquisition disorders or non-Hodgkin's lymphoma. 82. Use as defined in claim 80, wherein the PlKfyve-mediated disease is cancer. 83. Use as defined in claim 80, wherein the PlKfyve-mediated disease is breast cancer. 84. Use as defined in claim 80, wherein the PlKfyve-mediated disease is triple negative breast cancer. 178 85953755 85. Use of the compound as defined in any one of claims 1-77 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof or a pharmaceutical composition as defined in claim 78 for treating PlKfyve-mediated cancer. 86. Use as defined in claim 85, wherein the cancer is triple negative breast cancer or non-Hodgkin's lymphoma. 87. A compound or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound is V-c-17. 88. The compound as defined in claim 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein, the compound is l-a-1. 179