ECHINOCANDIN-BASED DRUG, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention discloses a new compound, such as a compound of formula I, or a pharmaceutically acceptable salt thereof or an isomer thereof. The compound has a good fungal inhibitory effect, can be used for effectively preventing or treating fungal infections, and is a new generation of echinocandin-based drugs with higher efficiency.

Claims

1. A compound as shown in formula I, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: X, Y and Z are each independently selected from C or N; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 are each independently selected from hydrogen, deuterium, halogen, cyano, thiocyano, isothiocyano or C.sub.1-10 lower alkyl; R.sub.7 is selected from C.sub.1-10 lower alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, cyclic hydrocarbonyl or heterocyclyl; R.sub.1 is selected from hydroxyl, hydrogen, deuterium, halogen, cyano, thiocyano, isothiocyano, O[C(R.sub.A1)(R.sub.A2)].sub.a[C(R.sub.A3)(R.sub.A4)].sub.jX.sub.1, NH[C(R.sub.A1)(R.sub.A2)].sub.a[C(R.sub.A3)(R.sub.A4)].sub.jX.sub.1, O(CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, O(CH.sub.2CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, O(CH.sub.2CH.sub.2NH).sub.bCH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2NH).sub.bCH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, NH[(CH.sub.2(CH.sub.2).sub.cO)].sub.bCH{CH.sub.2[OCH.sub.2(CH.sub.2).sub.c].sub.dX.sub.1}.sub.2, O[(CH.sub.2(CH.sub.2).sub.cO)].sub.bCH{CH.sub.2[OCH.sub.2(CH.sub.2).sub.c].sub.dX.sub.1}.sub.2 or (OCH.sub.2CH.sub.2).sub.b(NHCH.sub.2CH.sub.2).sub.eX.sub.2, R.sub.A1, R.sub.A2, R.sub.A3 and R.sub.A4 are independently selected from hydrogen, deuterium, halogen, C.sub.1-10 lower alkyl, cyclic hydrocarbonyl or cyclic hydrocarbylene , X.sub.1 is independently N(R.sub.C1R.sub.C2R.sub.C3) or the following structure ; ring A is an optionally substituted, saturated or unsaturated, monocyclic ring or fused ring containing one or more N atoms; R.sub.C1, R.sub.C2 and R.sub.C3 are independently selected from H, C.sub.1-6 alkyl, halogenated C.sub.1-6 lower alkyl and deuterated C.sub.1-6 lower alkyl, and at least one of R.sub.C1, R.sub.C2 or R.sub.C3 is not hydrogen, each R.sub.F is independently selected from H, deuterium, hydroxyl, hydroxylalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR, SOR, SO.sub.2R, NR(R), COOR and CONR(R), wherein the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxylalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, a nitrile group, hydroxyl, halogen, SR, NR(R), COOR or CONR(R); X.sub.2 is N(R.sub.D1R.sub.D2R.sub.D3) or the structure of X.sub.1; R.sub.D1, R.sub.D2 and R.sub.D3 are independently selected from H, C.sub.1-6 lower alkyl, halogenated C.sub.1-6 lower alkyl or deuterated C.sub.1-6 lower alkyl; R and R are independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkenyl or C(O)R.sub.J; R.sub.J is selected from hydrogen, deuterium, C.sub.1-10 lower alkyl, cyclic hydrocarbonyl or cyclic hydrocarbylene; and a is an integer of 0-5, b is an integer of 1-5, c is an integer of 1-2, d is an integer of 0-3, e is an integer of 1-5, k is an integer of 0-20, j is an integer of 0-5, and n is an integer of 1-7.

2. The compound, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 1, wherein R.sub.1 is selected from O(C(R.sub.A1)(R.sub.A2)).sub.a(C(R.sub.A3)(R.sub.A4)).sub.jX.sub.1, NH(C(R.sub.A1)(R.sub.A2)).sub.a(C(R.sub.A3)(R.sub.A4)).sub.jX.sub.1, O(CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, O(CH.sub.2CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, O(CH.sub.2CH.sub.2NH).sub.bCH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2NH).sub.bCH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2CH.sub.2O).sub.bCH.sub.2CH.sub.2X.sub.1, NH[(CH.sub.2(CH.sub.2).sub.cO)].sub.bCH{CH.sub.2[OCH.sub.2(CH.sub.2).sub.c].sub.dX.sub.1}.sub.2, O[(CH.sub.2(CH.sub.2).sub.cO)].sub.bCH{CH.sub.2[OCH.sub.2(CH.sub.2)].sub.dX.sub.1}.sub.2 or (OCH.sub.2CH.sub.2).sub.b(NHCH.sub.2CH.sub.2).sub.eX.sub.2, R.sub.A1, R.sub.A2, R.sub.A3 and R.sub.A4 are independently selected from hydrogen, deuterium, halogen, C.sub.1-10 lower alkyl, cyclic hydrocarbonyl or cyclic hydrocarbylene, X.sub.1 is independently N(R.sub.C1R.sub.C2R.sub.C3) or the following structure : Ring A is an optionally substituted, saturated or unsaturated, monocyclic ring or fused ring containing one or more N atoms; R.sub.C1, R.sub.C2 and R.sub.C3 are independently selected from H, halogenated C.sub.1-6 lower alkyl and deuterated C.sub.1-6 lower alkyl, and at least one of R.sub.C1, R.sub.C2 or R.sub.C3 is not hydrogen; each R.sub.F is independently selected from H, deuterium, hydroxyl, hydroxylalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR, SOR, SO.sub.2R, NR(R), COOR or CONR(R), wherein the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxylalkyl, alkenyl or alkynyl; X.sub.2 is N(R.sub.D1R.sub.D2R.sub.D3) or the structure of X.sub.1; R.sub.D1, R.sub.D2 and R.sub.D3 are independently selected from H, C.sub.1-6 lower alkyl, halogenated C.sub.1-6 lower alkyl or deuterated C.sub.1-6 lower alkyl; R and R are independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkenyl or C(O)R.sub.J; R.sub.J is selected from hydrogen, C.sub.1-10 lower alkyl, cyclic hydrocarbonyl or cyclic hydrocarbylene; and a is an integer of 0-5, b is an integer of 1-5, c is an integer of 1-2, d is an integer of 0-3, e is an integer of 1-5, k is an integer of 0-20, j is an integer of 0-5, and n is an integer of 1-7.

3. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 1, wherein X.sub.1 is selected from the following structures: wherein each R.sub.F is independently selected from H, deuterium, hydroxyl, hydroxylalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR, SOR, SO2R, NR(R), COOR and CONR(R), wherein the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxylalkyl, alkenyl or alkynyl; R.sub.q1 and R.sub.q2 are independently H or C.sub.1-6 lower alkyl, the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxylalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, a nitrile group, hydroxyl, halogen, SR, NR(R), COOR or CONR(R); R and R are independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkenyl or C(O)R.sub.J; R.sub.J is selected from hydrogen, deuterium, C.sub.1-10 lower alkyl, cyclic hydrocarbonyl or cyclic hydrocarbylene; and f is an integer of 0-16, g is an integer of 0-16, h is an integer of 0-9, i is an integer of 0-4, n is an integer of 1-7, and p is an integer of 1-3.

4. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 1, wherein R.sub.1 is selected from hydroxyl, hydrogen, deuterium or one of the following structures: .

5. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 4, wherein R.sub.1 is selected from hydroxyl, hydrogen or one of the following structures: , , , , , , , .

6. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 4, wherein R.sub.1 is selected from hydroxyl or one of the following structures: , , , .

7. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 1, wherein R.sub.7 is selected from C.sub.3-6 lower alkyl.

8. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 1, wherein R.sub.7 is selected from n-butyl or n-pentyl.

9. The compound as shown in formula I, or the pharmaceutically acceptable salt thereof or the isomer thereof according to claim 1, wherein the structural formula of the compound is one of the structures as follows: .

10. Use of the compound, or the pharmaceutically acceptable salt thereof or the isomer thereof according to any one of claims 1 to 9 in the preparation of a drug for inhibiting the growth of fungi or killing fungi.

11. Use of the compound, or the pharmaceutically acceptable salt thereof or the isomer thereof according to any one of claims 1 to 9 in the preparation of a drug for treating or preventing a fungal infection or a disease caused by a fungal infection.

12. The use according to claim 11, wherein the fungus is selected from one or more of the following genera: Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. lusitaniae, C. tropicalis, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus or A. ochraceus.

13. The use according to claim 11, wherein the disease caused by a fungal infection is selected from tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, chromophytosis, thrush, vaginal candidiasis, respiratory candidiasis, biliary tract candidiasis, esophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North America blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal rhino-sinusitis or chronic paranasal inflammation.

14. The use according to claim 11, wherein the disease caused by a fungal infection is selected from candidal bacteremia or invasive candidiasis.

15. An antifungal pharmaceutical composition, wherein the antifungal pharmaceutical composition comprises the compound, or the pharmaceutically acceptable salt thereof or the isomer thereof according to any one of claims 1 to 9.

16. Intermediate II of the compound of formula I: II wherein the definitions of X, Y, Z, and R.sub.2 to R.sub.12 correspond to those in the compound of formula I; and C(O)R.sub.13 constitutes carboxyl, acyl halide, an ester group and an anhydride group.

17. The intermediate II according to claim 16, wherein R.sub.13 is selected from OH, Cl, OC(O)CH.sub.3, and R.sub.g1; and R.sub.g1 is selected from or .

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0094] FIG. 1. Blood drug concentration-time curves after intravenous injection of rezafungin and example 16 in rats

[0095] FIG. 2. Blood drug concentration-time curves after intravenous injection of example 16 and example 19 in rats

DETAILED DESCRIPTION OF EMBODIMENTS

[0096] The technical solutions of the present invention will be described clearly and completely below. Obviously, the described embodiments are merely some of, rather than all of, the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without involving any inventive effort fall within the scope of protection of the present invention.

[0097] For the experimental methods in which no specific conditions are specified in the embodiments of the present invention, conventional conditions or conditions suggested by the raw materials or commodity manufacturers are generally used. The reagents for which the specific source is not specified, are conventional commercially available reagents.

[0098] Caspofungin was purchased from Taizhou Kede Chemical Co., Ltd.. Rezafungin was synthesized according to CN 103889221 A.

HPLC Purity Analysis Method:

TABLE-US-00001 Instrument HPLC (SHIMADZU LC-20AT) Chromatographic Xtimate Phenyl-Hexyl column (4.6 mm 150 mm, 3 m) Furnace 35 C. temperature Mobile phase A: 50 mM ammonium gradient Time formate + 0.1% B: C: procedure (min) trifluoroacetic acid ACN MeOH 0 65 20 15 20 25 50 25 30 5 70 25 35 5 70 25 35.1 65 20 15 45 65 20 15 Flow rate 1.0 mL/min Detector UV 254 nm Eluent ACN Calculation method Area %

LC-MS Analysis Method:

TABLE-US-00002 Instrument UPLC-MS (Waters ACQ-ZQ) Chroma- ZORBAX SB-Aq tographic (2.1 mm 30 mm, 3.5 m) column Mobile phase A: Aqueous gradient Time solution B: procedure (min) of 0.1% FA Analytical ACN 0 65 35 0.5 55 45 1.5 25 75 2 10 90 2.5 2 95 2.51 65 35 3 65 35 Flow rate 0.5 mL/min Furnace 40 C. detector Detector UV 200 nm Ion source ESI Mass 90-100 scan range Mode Positive polarity

Example 1

##STR00028##

Methyl 6-bromo-2-naphthoate (704 mg, 2.60 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (186.4 mg, 0.26 mmol, 0.1 eq.), and CuI (50.5 mg, 0.26 mmol, 0.1 eq.) were added to a thick-walled pressure-resistant reactor tube. Vacuumizing and replacement with nitrogen were performed, and repeated three times. 1-Eth-1-ynyl-4-(pentyloxy)benzene (500 mg, 2.00 mmol, 1 eq.), DIPEA (0.92 mL, 5.30 mmol, 2 eq.) and 1,4-dioxane (9 mL) were then added to the system under nitrogen atmosphere. After feeding was completed, the tube was sealed and heated to 80 C., and the mixture was stirred overnight. After the reaction was completed, the solvent was removed by using a rotary evaporator to obtain an oily substance. The oily substance was dissolved with DCM. The organic phase was washed with water and brine in sequence, and dried with anhydrous sodium sulfate. The crude product obtained after concentration was separated and purified by column chromatography (PE:EA=100:1) to obtain 403.4 mg of compound SM1 as a yellow solid, with a yield of 40%. MS[M+H].sup.+: 373.

##STR00029##

[0099] SM1 (403.4 mg, 1.08 mmol, 1 eq.) was dissolved in THF (10 mL). NaOH (86.7 mg, 2.10 mmol, 2 eq.) was dissolved in H.sub.2O (10 mL). The aqueous solution of NaOH was added to a reaction system, and the reaction was placed in a 60 C. oil bath pan, and heated and stirred. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH until an acidic state was reached. Suction filtration was performed. The filter cake was washed with water to obtain 369.7 mg of compound SM2 as a yellow solid, with a yield of 95%. MS[MH].sup.: 357.

##STR00030##

[0100] Echinocandin B hydrochloride (200 mg, 0.23 mmol, 1 eq.), SM2 (85.8 mg, 0.23 mmol, 1 eq.) and CDMT (50.3 mg, 0.28 mmol, 1.2 eq.) were dissolved in DMF (2.4 mL), and then NMM (0.078 mL, 0.71 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to preparative HPLC (prep-HPLC) purification and separation to obtain 135 mg of a compound as a white solid, with a purity of 97% and a yield of 49%. HRMS[MH].sup.: 1136.5260.

[0101] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.41 (s, 1H), 8.05 (s, 1H), 7.93 (dd, J=15.7, 5.4 Hz, 3H), 7.61 (dd, J=8.5, 1.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.36 (d, J=3.1 Hz, 1H), 5.02 (d, J=3.2 Hz, 1H), 4.70 (dd, J=11.8, 5.2 Hz, 1H), 4.57 (s, 4H), 4.35 (dd, J=19.1, 5.4 Hz, 3H), 4.26 (s, 3H), 4.08 (s, 1H), 4.02 (t, J=6.5 Hz, 3H), 3.86 (d, J=19.3 Hz, 2H), 3.41 (t, J=9.2 Hz, 1H), 2.57-2.40 (m, 2H), 2.25 (s, 1H), 2.18-2.03 (m, 2H), 1.85-1.76 (m, 2H), 1.51-1.39 (m, 4H), 1.28 (dd, J=12.5, 6.3 Hz, 6H), 1.07 (d, J=6.9 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H).

Example 2

##STR00031##

[0102] Example 1 (170 mg, 0.14 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (35 mg, 0.19 mmol, 1.3 eq.) were dissolved in dry THF (1.4 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (400 mg, 1.40 mmol, 10 eq.) was added, then a mixed solution of TFA (0.425 mL) and acetonitrile (1.5 mL) was added to dissolve the reactants, and stirring was performed for 6 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 105 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 95% and a yield of 57%. HRMS[M].sup.+:1223.6167.

[0103] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.44 (s, 1H), 8.08 (s, 1H), 8.01-7.95 (m, 3H), 7.64 (dd, J=8.5, 1.4 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.43 (s, 1H), 5.05 (d, J=3.2 Hz, 1H), 4.77 (d, J=5.1 Hz, 1H), 4.59 (dd, J=10.7, 7.1 Hz, 3H), 4.39 (d, J=4.2 Hz, 1H), 4.33 (d, J=8.6 Hz, 2H), 4.24 (dd, J=7.9, 1.6 Hz, 2H), 4.21-4.16 (m, 1H), 4.11 (s, 1H), 4.01 (dd, J=13.0, 6.6 Hz, 4H), 3.91 (dd, J=9.7, 7.0 Hz, 2H), 3.83 (d, J=10.8 Hz, 1H), 3.66-3.45 (m, 4H), 3.13 (s, 9H), 2.55-2.43 (m, 2H), 2.31 (dd, J=16.1, 7.2 Hz, 1H), 2.08 (dd, J=15.4, 9.5 Hz, 2H), 1.84-1.77 (m, 2H), 1.46 (ddd, J=20.2, 11.3, 6.5 Hz, 4H), 1.27 (d, J=6.3 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 3

##STR00032##

[0104] Methyl 6-bromoquinoline-2-carboxylate (500 mg, 1.80 mmol, 1 eq.), 1-eth-1-ynyl-4-(pentyloxy)benzene (0.36 mL, 1.80 mmol, 1 eq.) and CuI (35.7 mg, 0.18 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (18 mL), and then triethylamine (0.78 mL, 5.60 mmol, 3 eq.) was added. Vacuumizing and replacement with nitrogen were performed and repeated three times. Pd(PPh.sub.3).sub.2Cl.sub.2 (131 mg, 0.18 mmol, 0.1 eq.) was added to the reaction system under nitrogen atmosphere. Refluxing was performed overnight at 80 C. After the reaction was completed, the solvent was removed, and the crude product was purified by column chromatography to obtain 200 mg of compound SM3 as a white solid, with a yield of 28%. MS[M+H].sup.+: 374.2.

##STR00033##

[0105] SM3 (200 mg, 0.53 mmol, 1 eq.) was dissolved in THF (5 mL), and heated and stirred at 65 C., and an aqueous solution (0.5 mL) of NaOH (43 mg, 1.08 mmol, 4 eq.) was added to the reaction system. After 1 h, the reaction solution changed from clear to turbid. TLC showed that the reaction was finished. 2M HCl (aq.) was added to adjust pH value until an acidic state is reached. Suction filtration was performed to obtain 160 mg of compound SM4 as a green solid, with a yield of 83%. MS[M+H].sup.+: 360.

##STR00034##

[0106] Echinocandin B hydrochloride (371 mg, 0.44 mmol, 1 eq.), SM4 (160 mg, 0.44 mmol, 1 eq.) and CDMT (93.6 mg, 0.53 mmol, 1.2 eq.) were dissolved in DMF (4 mL), and then NMM (0.14 mL, 1.30 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 268 mg of a compound as a white solid, with a purity of 97% and a yield of 52%.

[0107] HRMS[MH].sup.:1137.6155.

[0108] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.44 (d, J=8.6 Hz, 1H), 8.21-8.11 (m, 3H), 7.88 (dd, J=8.8, 1.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.46 (d, J=2.7 Hz, 1H), 5.04 (d, J=2.8 Hz, 1H), 4.76 (dd, J=11.9, 4.8 Hz, 1H), 4.64-4.54 (m, 4H), 4.37 (d, J=2.7 Hz, 1H), 4.32 (d, J=7.6 Hz, 2H), 4.26-4.17 (m, 3H), 4.05-3.96 (m, 4H), 3.92-3.80 (m, 2H), 3.41 (t, J=9.1 Hz, 1H), 2.59-2.40 (m, 2H), 2.34 (d, J=13.6 Hz, 1H), 2.18-2.04 (m, 2H), 1.80 (dd, J=13.8, 7.2 Hz, 2H), 1.53-1.38 (m, 4H), 1.29-1.23 (m, 6H), 1.07 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H).

Example 4

##STR00035##

[0109] Example 3 (268 mg, 0.23 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (55.7 mg, 0.30 mmol, 1.3 eq.) were dissolved in dry THF (2.3 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (1.94 g, 7.00 mmol, 30 eq.) was added, then a mixed solution of TFA (0.5 mL) and acetonitrile (2.0 mL) was added to dissolve the reactants, and stirring was performed for 6 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 151 mg of a compound (acetate) as a white solid was obtained through prep-HPLC purification, with a purity of 91% and a yield of 52%. HRMS[M].sup.+:1224.5755.

[0110] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.48 (d, J=8.6 Hz, 1H), 8.19 (dd, J=18.6, 8.8 Hz, 3H), 7.91 (d, J=10.4 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.64 (s, 1H), 5.08 (s, 1H), 4.84-4.75 (m, 2H), 4.60 (dd, J=13.7, 4.1 Hz, 3H), 4.40 (d, J=4.1 Hz, 1H), 4.33 (t, J=8.6 Hz, 2H), 4.29-4.21 (m, 2H), 4.20-4.12 (m, 1H), 4.10-3.97 (m, 6H), 3.93-3.82 (m, 2H), 3.67-3.55 (m, 2H), 3.50-3.46 (m, 1H), 3.16 (s, 9H), 2.49 (ddd, J=22.3, 9.7, 4.8 Hz, 2H), 2.42-2.31 (m, 1H), 2.11-1.99 (m, 2H), 1.90 (s, 3H), 1.86-1.77 (m, 2H), 1.50-1.39 (m, 4H), 1.24 (dd, J=8.8, 6.4 Hz, 6H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 5

##STR00036##

[0111] Methyl 6-bromo-2-naphthoate (4 g, 15.08 mmol, 1 eq.) was dissolved in dioxane (15 mL), and replacement with nitrogen was performed. Under the protection of nitrogen, trimethylsilylacetylene (2.08 mL, 15.08 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (1.05 g, 1.51 mmol, 0.1 eq.) and CuI (288 mg, 1.50 mmol, 0.1 eq.) were sequentially added, and triethylamine (6.29 mL, 45.26 mmol, 3 eq.) was finally added. The mixture was stirred for 2.5 h at room temperature, and extracted with water and EA. The EA phase was subjected to rotary evaporation, and separated and purified by column chromatography to obtain 4.14 g of compound SM5 as a yellow solid, with a yield of 97%. MS[M+H].sup.+: 283.0.

##STR00037##

[0112] SM2 (1 g, 3.54 mmol, 1 eq.) was dissolved in dioxane (6 mL) and MeOH (6 mL). Potassium carbonate (735 mg, 5.31 mmol, 1.5 eq.) was added. The mixture was stirred for 2 h at room temperature. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation to obtain 413 mg of compound SM6 as a yellow solid, with a yield of 55%.

##STR00038##

[0113] 2-Bromo-5-hydroxypyridine (1 g, 5.70 mmol, 1 eq.), bromopentane (0.9 ml, 6.80 mmol, 1.2 eq.) and potassium carbonate (2.4 g, 17.00 mmol, 3 eq.) were dissolved in acetonitrile (50 mL), and the mixture was heated, refluxed, and stirred at 90 C. After 2 h, TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed, ethyl acetate and water were added for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 1.3 g of compound SM7 as a green oil, with a yield of 92%.

##STR00039##

[0114] SM6 (156.4 mg, 0.74 mmol, 1 eq.), SM7 (200 mg, 0.81 mmol, 1.1 eq.) and CuI (14 mg, 0.074 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (7 mL), and then triethylamine (0.3 mL, 2.20 mmol, 3 eq.) was added. Vacuumizing and replacement with nitrogen were performed and repeated three times. Pd(PPh.sub.3).sub.2Cl.sub.2 (52 mg, 0.07 mmol, 0.1 eq.) was added to the reaction system under nitrogen atmosphere. The resulting mixture was heated and stirred overnight at 80 C. After the reaction was completed, the solvent was removed. DCM was added for dissolving, and column chromatography purification was performed to obtain 167 mg of compound SM8 as a yellow solid, with a yield of 60%.

##STR00040##

[0115] SM8 (167 mg, 0.44 mmol, 1 eq.) was dissolved in THF (4 mL), and heated and stirred at 60 C., and an aqueous solution (1 mL) of NaOH (35.8 mg, 0.89 mmol, 2 eq.) was added to the reaction system. The reaction system was heated at 70 C. and refluxed overnight. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH until an acidic state is reached, and then a solid was precipitated. Suction filtration was performed to obtain 100 mg of compound SM9 as a yellow solid, with a yield of 62%. MS[MH].sup.: 358.

##STR00041##

[0116] Echinocandin B hydrochloride (93 mg, 0.11 mmol, 1 eq.), SM9 (40 mg, 0.23 mmol, 1 eq.) and CDMT (23 mg, 0.13 mmol, 1.2 eq.) were dissolved in DMF (1.1 mL), and then NMM (0.036 mL, 0.33 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 67 mg of a compound as a white solid, with a purity of 96% and a yield of 52%. HRMS[MH].sup.: 1137.4491.

[0117] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.46 (s, 2H), 8.26 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.98 (t, J=6.4 Hz, 3H), 7.91 (dd, J=8.9, 2.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.36 (d, J=3.0 Hz, 1H), 5.02 (d, J=3.2 Hz, 2H), 4.71 (dd, J=12.9, 6.3 Hz, 1H), 4.65-4.53 (m, 3H), 4.39 (dd, J=15.0, 3.0 Hz, 1H), 4.32 (d, J=8.0 Hz, 2H), 4.28-4.19 (m, 5H), 4.14-4.06 (m, 1H), 3.99 (d, J=7.8 Hz, 1H), 3.93-3.86 (m, 1H), 3.82 (d, J=10.8 Hz, 1H), 3.44-3.38 (m, 1H), 2.59-2.41 (m, 2H), 2.31-2.21 (m, 1H), 2.10 (d, J=12.7 Hz, 2H), 1.93-1.84 (m, 2H), 1.56-1.39 (m, 4H), 1.28 (dd, J=12.4, 6.3 Hz, 6H), 1.07 (dd, J=6.8, 4.1 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 6

##STR00042##

[0118] 2-Bromo-5-pyrimidinol (1 g, 5.71 mmol, 1 eq.) was dissolved in acetonitrile (30 mL), bromopentane (2.1 mL, 17.14 mmol, 3 eq.) was added, and potassium carbonate (2.370 g, 17.14 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 1.24 g of compound SM10 as a brown oil, with a yield of 89%.

##STR00043##

[0119] SM6 (500 mg, 2.04 mmol, 1 eq.) was dissolved in dioxane (8 mL), and replacement with nitrogen was performed. Under the protection of nitrogen, SM10 (428 mg, 2.04 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (143 mg, 0.20 mmol, 0.1 eq.), CuI (155 mg, 0.81 mmol, 0.4 eq.) and triethylamine (0.85 mL, 6.12 mmol, 3 eq.) were sequentially added. The mixture was stirred at 80 C. for 6 h. The solvent was removed. Extraction was performed with water and EA. The EA phase was subjected to rotary evaporation, and separated and purified by column chromatography to obtain 287 mg of compound SM11 as a yellow solid, with a yield of 38%. MS[M+H].sup.+: 375.0.

##STR00044##

[0120] SM11 (287 mg, 0.76 mmol, 1 eq.) was dissolved in THF (7 mL). Sodium hydroxide (186 mg, 4.60 mmol, 6 eq.) was dissolved in water (1 mL) and added to the system. The system was stirred at 60 C. for 5 h, and the solvent was removed. The system was extracted with water and DCM for the first time. Dilute hydrochloric acid was added to the aqueous phase to adjust the pH until an acidic state is reached. The aqueous phase was extracted with DCM, and the solvent was removed to obtain 270 mg of crude product SM12 as a yellow-brown liquid, with a yield of 97%. MS[M+H].sup.+: 361.0.

##STR00045##

[0121] Echinocandin B hydrochloride (313 mg, 0.37 mmol, 1 eq.) was dissolved in DMF (4 mL), and SM12 (135 mg, 0.37 mmol, 1 eq.), NMM (0.12 mL, 1.12 mmol, 3 eq.) and CDMT (79 mg, 0.45 mmol, 1.2 eq.) were sequentially added. The reaction was performed for 6 h at room temperature, and 23.5 mg of a product was obtained through prep-HPLC purification, with a purity of 95% and a yield of 5%. HRMS[MH].sup.: 1138.3973.

[0122] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.47-8.39 (m, 2H), 8.24 (s, 1H), 8.06-7.95 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.37 (d, J=8.8 Hz, 1H), 5.02 (d, J=5.4 Hz, 2H), 4.73-4.66 (m, 1H), 4.64-4.54 (m, 3H), 4.39-4.30 (m, 3H), 4.26-4.16 (m, 5H), 4.08 (s, 1H), 3.99 (d, J=8.2 Hz, 1H), 3.85 (dd, J=22.6, 9.0 Hz, 2H), 3.45-3.38 (m, 2H), 2.50 (ddd, J=36.4, 17.3, 6.5 Hz, 2H), 2.25 (dd, J=18.5, 4.2 Hz, 1H), 2.18-2.03 (m, 2H), 1.90-1.82 (m, 2H), 1.55-1.39 (m, 4H), 1.27 (dd, J=10.4, 6.4 Hz, 6H), 1.07 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 7

##STR00046##

[0123] 4-Bromo-2,3-difluorophenol (0.35 mL, 4.70 mmol, 1 eq.), bromopentane (0.7 ml, 5.70 mmol, 1.2 eq.) and potassium carbonate (2 g, 14.00 mmol, 3 eq.) were dissolved in acetonitrile (47 mL), and the mixture was heated, refluxed, and stirred at 90 C. After 1.5 h, TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed, ethyl acetate and water were added for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 1.2 g of compound SM13 as a black oil, with a yield of 92%.

##STR00047##

[0124] SM6 (378 mg, 1.80 mmol, 1 eq.), SM13 (553 mg, 2.00 mmol, 1.1 eq.) and CuI (14 mg, 0.18 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (7 mL), and then triethylamine (0.3 mL, 5.50 mmol, 3 eq.) was added. Vacuumizing and replacement with nitrogen were performed and repeated three times. Pd(PPh.sub.3).sub.2Cl.sub.2 (126 mg, 0.18 mmol, 0.1 eq.) was added under nitrogen atmosphere. The resulting mixture was heated and stirred overnight at 80 C. TLC showed a clear new spot. The solvent was removed. DCM was added for dissolving, and column chromatography purification was performed to obtain 101 mg of compound SM14 as a white solid, with a yield of 11%.

##STR00048##

[0125] SM14 (101 mg, 0.24 mmol, 1 eq.) was dissolved in THF (2 mL), and heated and stirred at 60 C., and an aqueous solution (0.5 mL) of NaOH (50 mg, 1.23 mmol, 5 eq.) was added to the reaction system. The reaction system was heated at 75 C. and refluxed overnight. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH until an acidic state is reached, and then a solid was precipitated. Suction filtration was performed to obtain 75 mg of compound SM15 as a white solid, with a yield of 76%. MS[MH].sup.: 393.

##STR00049##

[0126] Echinocandin B hydrochloride (159 mg, 0.19 mmol, 1 eq.), SM15 (75 mg, 0.19 mmol, 1 eq.) and CDMT (40 mg, 0.22 mmol, 1.2 eq.) were dissolved in DMF (2 mL), and then NMM (0.06 mL, 0.57 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 128 mg of a compound as a white solid, with a purity of 96% and a yield of 57%. HRMS[MH].sup.: 1172.4577.

[0127] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.41 (s, 1H), 8.09 (s, 1H), 8.00-7.90 (m, 3H), 7.62 (dd, J=8.5, 1.4 Hz, 1H), 7.35-7.28 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.95 (t, J=7.5 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.37 (d, J=2.9 Hz, 1H), 5.03 (d, J=3.3 Hz, 1H), 4.92 (s, 1H), 4.70 (dd, J=11.9, 5.2 Hz, 1H), 4.59 (dd, J=14.6, 7.2 Hz, 3H), 4.34 (dd, J=18.0, 5.3 Hz, 3H), 4.28-4.19 (m, 3H), 4.12 (t, J=6.4 Hz, 3H), 3.99 (d, J=8.1 Hz, 1H), 3.92-3.80 (m, 2H), 3.44-3.37 (m, 1H), 2.58-2.41 (m, 2H), 2.25 (t, J=8.5 Hz, 1H), 2.18-2.03 (m, 2H), 1.88-1.80 (m, 2H), 1.46 (ddd, J=22.2, 12.3, 6.9 Hz, 4H), 1.28 (dd, J=13.3, 6.3 Hz, 6H), 1.06 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 8

##STR00050##

[0128] Example 7 (347 mg, 0.29 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (70 mg, 0.38 mmol, 1.3 eq.) were dissolved in dry THF (6 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (2.4 g, 8.80 mmol, 30 eq.) was added, then a mixed solution of TFA (0.85 mL) and acetonitrile (4.5 mL) was added to dissolve the reactants, and stirring was performed for 6 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 74 mg of a compound (acetate) as a white solid was obtained through prep-HPLC purification, with a purity of 95% and a yield of 19%. HRMS[M].sup.+: 1259.5431.

[0129] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.46 (s, 1H), 8.14 (s, 1H), 8.00 (dd, J=15.9, 5.8 Hz, 3H), 7.66 (dd, J=8.5, 1.5 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.96 (dd, J=12.0, 4.5 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.42 (d, J=2.5 Hz, 1H), 5.04 (d, J=3.3 Hz, 1H), 4.79 (dd, J=12.0, 5.0 Hz, 2H), 4.58 (t, J=5.1 Hz, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.35-4.31 (m, 2H), 4.25 (td, J=7.1, 3.1 Hz, 2H), 4.20-4.16 (m, 1H), 4.12 (dd, J=12.6, 6.1 Hz, 3H), 4.00 (d, J=11.3 Hz, 2H), 3.91 (dd, J=9.8, 7.0 Hz, 2H), 3.83 (d, J=10.9 Hz, 1H), 3.60 (d, J=4.8 Hz, 1H), 3.47 (d, J=7.0 Hz, 1H), 3.13 (s, 9H), 2.53-2.44 (m, 2H), 2.29 (d, J=8.9 Hz, 1H), 2.10-2.04 (m, 2H), 1.87-1.83 (m, 2H), 1.50-1.41 (m, 4H), 1.27 (d, J=6.3 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.97 (s, 3H).

Example 9

##STR00051##

[0130] 2-Fluoro-4-iodophenol (1 g, 4.20 mmol, 1 eq.) was dissolved in acetonitrile (20 mL), bromopentane (1.56 mL, 12.60 mmol, 3 eq.) was added, and potassium carbonate (1.743 g, 12.60 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 1.237 g of compound SM16 as a yellow liquid, with a yield of 95%.

##STR00052##

[0131] SM16 (293 mg, 0.95 mmol, 1 eq.) was dissolved in dioxane (10 mL), and replacement with nitrogen was performed. Under the protection of nitrogen, SM6 (200 mg, 0.95 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (67 mg, 0.09 mmol, 0.1 eq.), CuI (73 mg, 0.38 mmol, 0.4 eq.) and triethylamine (0.4 mL, 2.85 mmol, 3 eq.) were sequentially added. The mixture was stirred overnight at room temperature. TLC showed that the reaction was finished. The solvent was removed. Extraction was performed with water and DCM. The solvent was removed to obtain a crude product, and the crude product was separated and purified by column chromatography to obtain 282 mg of compound SM17 as a white solid, with a yield of 76%.

##STR00053##

[0132] SM17 (282 mg, 0.72 mmol, 1 eq.) was dissolved in THF (7 mL). Sodium hydroxide (123 mg, 2.89 mmol, 6 eq.) was dissolved in water (1 mL) and added to the system. The system was stirred at 60 C. for 5 h. TLC showed that the reaction was finished. The solvent was removed. Extraction was performed with water and DCM for the first time. Dilute hydrochloric acid was added to the aqueous phase to adjust the pH until an acidic state is reached. The aqueous phase was extracted with DCM, and the solvent was removed to obtain 255 mg of crude product SM18 as a white solid, with a yield of 94%.

##STR00054##

[0133] Echinocandin B hydrochloride (366 mg, 0.43 mmol, 1.2 eq.) was dissolved in DMF (5 mL), and SM18 (138 mg, 0.36 mmol, 1 eq.), NMM (0.13 mL, 1.09 mmol, 3 eq.) and CDMT (77 mg, 0.43 mmol, 1.2 eq.) were sequentially added. The reaction was performed for 6 h at room temperature, and 180 mg of a product was obtained through prep-HPLC purification, with a purity of 95% and a yield of 35%. HRMS[M+Na].sup.+: 1178.4604.

[0134] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.41 (d, J=10.8 Hz, 1H), 8.06 (s, 1H), 7.92 (dd, J=14.1, 8.5 Hz, 3H), 7.69 (d, J=9.5 Hz, 1H), 7.58 (d, J=6.8 Hz, 2H), 7.31 (dd, J=14.6, 4.8 Hz, 2H), 7.15 (t, J=7.1 Hz, 3H), 6.76 (d, J=8.5 Hz, 2H), 5.37 (d, J=2.8 Hz, 1H), 5.04 (d, J=5.2 Hz, 2H), 4.70 (dd, J=11.9, 5.1 Hz, 1H), 4.59 (dd, J=14.7, 7.5 Hz, 3H), 4.34 (dd, J=18.2, 5.3 Hz, 3H), 4.27-4.18 (m, 3H), 4.09 (t, J=6.4 Hz, 3H), 3.99 (d, J=8.3 Hz, 1H), 3.92-3.79 (m, 2H), 3.41 (t, J=9.0 Hz, 1H), 2.57-

[0135] 2.41 (m, 2H), 2.25 (s, 1H), 2.11 (dd, J=16.3, 10.0 Hz, 2H), 1.87-1.78 (m, 2H), 1.51-1.40 (m, 4H), 1.28 (dd, J=13.4, 6.3 Hz, 6H), 1.06 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 10

##STR00055##

[0136] Example 9 (100 mg, 0.08 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (20 mg, 0.11 mmol, 1.3 eq.) were dissolved in dry THF (1.5 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (238 g, 0.86 mmol, 10 eq.) was added, then a mixed solution of TFA (0.25 mL) and acetonitrile (1 mL) was added to dissolve the reactants, and stirring was performed for 6 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 27.6 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 25%. HRMS[M].sup.+: 1241.5522.

[0137] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.11 (s, 1H), 8.02-7.96 (m, 3H), 7.67-7.63 (m, 1H), 7.34-7.29 (m, 2H), 7.14 (t, J=8.8 Hz, 3H), 6.76 (d, J=8.5 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.79 (dd, J=12.1, 5.1 Hz, 1H), 4.59 (dd, J=10.6, 7.4 Hz, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.33 (d, J=8.3 Hz, 2H), 4.25 (dd, J=8.3, 6.4 Hz, 2H), 4.20-4.15 (m, 1H), 4.10 (t, J=6.5 Hz, 3H), 4.00 (d, J=11.4 Hz, 2H), 3.94-3.87 (m, 2H), 3.83 (d, J=10.7 Hz, 1H), 3.65-3.52 (m, 2H), 3.51-3.46 (m, 1H), 3.13 (s, 9H), 2.55-2.42 (m, 2H), 2.34-2.27 (m, 1H), 2.08 (dd, J=24.0, 4.3 Hz, 2H), 1.86-1.80 (m, 2H), 1.51-1.41 (m, 4H), 1.27 (d, J=6.3 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 11

##STR00056##

[0138] 4-Iodo-2-chlorophenol (1 g, 3.90 mmol, 1 eq.), bromopentane (0.6 ml, 4.70 mmol, 1.2 eq.) and potassium carbonate (1.6 g, 11.00 mmol, 3 eq.) were dissolved in acetonitrile (40 mL), and the mixture was heated, refluxed, and stirred at 90 C. After 1.5 h, TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed, ethyl acetate and water were added for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 1.0 g of compound SM19 as a yellow oil, with a yield of 78%.

##STR00057##

[0139] SM6 (432 mg, 2.00 mmol, 1 eq.), SM19 (800 mg, 2.40 mmol, 1.0 eq.) and CuI (39 mg, 0.20 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (24 mL), and then triethylamine (0.8 mL, 6.10 mmol, 3 eq.) was added. Vacuumizing and replacement with nitrogen were performed and repeated three times. Pd(PPh.sub.3).sub.2Cl.sub.2 (144 mg, 0.20 mmol, 0.1 eq.) was added under nitrogen atmosphere. The resulting mixture was heated and stirred overnight at 80 C. TLC showed a clear new spot and the weak signals of raw materials SM3 and SM25. The solvent was removed. DCM was added for dissolving, and column chromatography purification was performed to obtain 261 mg of compound SM20 as a white solid, with a yield of 25%.

##STR00058##

[0140] SM20 (261 mg, 0.64 mmol, 1 eq.) was dissolved in THF (7 mL), and heated and stirred at 70 C., and then an aqueous solution (1.5 mL) of NaOH (129 mg, 3.20 mmol, 5 eq.) was added to the reaction system. The reaction system was heated at 70 C. and refluxed overnight. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH value until an acidic state is reached, and then a solid was precipitated. Suction filtration was performed to obtain 233 mg of compound SM21 as a white solid, with a yield of 92%.

##STR00059##

[0141] Echinocandin B hydrochloride (150 mg, 0.17 mmol, 1 eq.), SM21 (75 mg, 0.17 mmol, 1 eq.) and CDMT (38 mg, 0.22 mmol, 1.2 eq.) were dissolved in DMF (1.8 mL), and then NMM (0.06 mL, 0.53 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 138 mg of a compound as a white solid, with a purity of 96% and a yield of 65%. HRMS[MH].sup.: 1170.4768.

[0142] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.40 (s, 1H), 8.07 (s, 1H), 7.92 (dt, J=13.2, 8.7 Hz, 3H), 7.61-7.56 (m, 2H), 7.47 (dd, J=8.6, 2.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.7 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.37 (d, J=2.9 Hz, 1H), 5.03 (d, J=3.2 Hz, 1H), 4.74-4.66 (m, 2H), 4.64-4.55 (m, 3H), 4.34 (dd, J=18.7, 5.3 Hz, 3H), 4.27-4.19 (m, 3H), 4.10 (t, J=6.3 Hz, 3H), 3.99 (d, J=8.1 Hz, 1H), 3.85 (dd, J=21.2, 9.1 Hz, 2H), 3.41 (t, J=9.1 Hz, 1H), 2.57-2.41 (m, 2H), 2.29-2.21 (m, 1H), 2.16-2.04 (m, 2H), 1.84 (dd, J=14.5, 6.5 Hz, 2H), 1.49 (ddd, J=24.5, 11.7, 5.2 Hz, 4H), 1.28 (dd, J=12.5, 6.3 Hz, 6H), 1.06 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 12

##STR00060##

[0143] Example 11 (100 mg, 0.08 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (20 mg, 0.11 mmol, 1.3 eq.) were dissolved in dry THF (1.5 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (235 mg, 0.85 mmol, 10 eq.) was added, then a mixed solution of TFA (0.25 mL) and acetonitrile (1.5 mL) was added to dissolve the reactants, and stirring was performed for 6 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 28 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 26%. HRMS[M].sup.+: 1257.5352.

[0144] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.11 (s, 1H), 8.05-7.96 (m, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.48 (dd, J=8.5, 2.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.90 (s, 1H), 4.81-4.75 (m, 1H), 4.58 (d, J=6.5 Hz, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.33 (d, J=7.9 Hz, 2H), 4.29-4.23 (m, 2H), 4.21-4.15 (m, 1H), 4.11 (t, J=6.3 Hz, 3H), 4.00 (d, J=11.3 Hz, 1H), 3.93-3.88 (m, 1H), 3.83 (d, J=10.8 Hz, 1H), 3.68-3.44 (m, 4H), 3.13 (s, 9H), 2.56-2.41 (m, 2H), 2.35-2.25 (m, 1H), 2.08 (dd, J=15.3, 9.7 Hz, 2H), 1.88-1.81 (m, 2H), 1.49 (ddd, J=24.5, 11.6, 5.1 Hz, 4H), 1.27 (d, J=6.2 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 13

##STR00061##

[0145] 4-Bromo-2,6-difluorophenol (1 g, 4.78 mmol, 1 eq.) was dissolved in acetonitrile (20 mL), bromopentane (1.8 mL, 14.35 mmol, 3 eq.) was added, and potassium carbonate (1.984 g, 14.35 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 1.317 g of compound SM22 as a yellow liquid, with a yield of 99%.

##STR00062##

[0146] SM22 (1 g, 3.58 mmol, 1 eq.) was dissolved in triethylamine (17 mL), and trimethylsilylacetylene (0.51 mL, 3.58 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (252 mg, 0.35 mmol, 0.1 eq.) and CuI (68 mg, 0.35 mmol, 0.1 eq.) were added. Replacement with nitrogen was performed. The resulting mixture was stirred at 90 C. for 2 h in a microwave reactor. TLC showed the completion of the reaction and the formation of a new spot. Column chromatography separation and purification was performed to obtain 922 mg of compound SM23 as a yellow liquid, with a yield of 87%.

##STR00063##

[0147] SM23 (922 mg, 3.11 mmol, 1 eq.) was dissolved in MeOH (10 mL) and THF (10 mL). Potassium carbonate (654 mg, 4.66 mmol, 1.5 eq.) was added. The mixture was stirred for 3 h at room temperature. TLC showed the completion of the reaction, the formation of a new spot, and the disappearance of the raw materials. The resulting mixture was extracted with water and DCM, and the solvent was removed to obtain 600 mg of crude product SM24 as a yellow oil, with a yield of 86%.

##STR00064##

[0148] Methyl 6-bromo-2-naphthoate (639 mg, 2.41 mmol, 1 eq.) was dissolved in triethylamine (12 mL), and SM24 (540 mg, 2.41 mmol, 1 eq.), (PPh.sub.3).sub.2PdCl.sub.2 (169 mg, 0.24 mmol, 0.1 eq.) and CuI (46 mg, 0.24 mmol, 0.1 eq.) were added. Replacement with nitrogen was performed. The resulting mixture was reacted at 90 C. under microwave condition, and stirred for 2 h. TLC showed the formation of a new spot and the disappearance of the raw materials. Column chromatography separation and purification was performed to obtain 662 mg of compound SM25 as a yellow solid, with a yield of 67%.

##STR00065##

[0149] SM25 (662 mg, 1.62 mmol, 1 eq.) was dissolved in THF (9 mL). NaOH (259 mg, 6.48 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The reaction system was stirred overnight at 60 C. TLC showed a spot of product. After THF was subjected to rotary evaporation, extraction was performed with water and EA for the first time. The aqueous phase was remained for acidifying, and a solid was precipitated. Suction filtration and drying were performed to obtain 621 mg of compound SM26 as a yellow solid, with a yield of 97%.

##STR00066##

[0150] SM26 (236 mg, 0.59 mmol, 1 eq.) was dissolved in DMF (6 mL), echinocandin B hydrochloride (500 mg, 0.59 mmol, 1 eq.) and CDMT (126 mg, 0.71 mmol, 1.2 eq.) were sequentially added, and NMM (0.20 mL, 1.79 mmol, 3 eq.) was finally added. The mixture was stirred for 4 h at room temperature. 211 mg of a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 30%. HRMS[M+Na].sup.+: 1196.4405.

[0151] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.41 (s, 1H), 8.10 (s, 1H), 7.94 (dd, J=16.1, 7.7 Hz, 3H), 7.65-7.61 (m, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.36 (s, 1H), 5.03 (s, 2H), 4.70 (dd, J 11.8, 5.1 Hz, 1H), 4.64-4.53 (m, 3H), 4.39-4.30 (m, 3H), 4.27-4.15 (m, 5H), 4.09 (s, 1H), 3.99 (d, J=8.4 Hz, 1H), 3.93-3.80 (m, 2H), 3.41 (t, J=9.1 Hz, 1H), 2.58-2.40 (m, 2H), 2.25 (s, 1H), 2.18-2.04 (m, 2H), 1.81-1.72 (m, 2H), 1.54-1.39 (m, 4H), 1.28 (dd, J=13.2, 6.2 Hz, 6H), 1.06 (d, J=6.9 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

Example 14

##STR00067##

[0152] Example 13 (150 mg, 0.12 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (30 mg, 0.16 mmol, 1.3 eq.) was added. After the resulting mixture was stirred for 1 h at room temperature, the solvent was removed, and then dry THF (3 mL) was added for rotary evaporation. Choline tosylate (352 mg, 1.27 mmol, 10 eq.) was added, and TFA (0.38 mL) mixed with acetonitrile (3 mL) was added to the system. The system was stirred for 3 h at room temperature. LCMS showed the formation of a product. 57 mg of a white solid (acetate) was obtained through prep-HPLC purification, with a purity of 98% and a yield of 28%. HRMS[M].sup.+: 1259.5494.

[0153] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.14 (s, 1H), 8.02-7.97 (m, 3H), 7.66 (d, J=8.5 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (s, 1H), 5.05 (d, J=3.0 Hz, 1H), 4.81-4.77 (m, 1H), 4.60 (d, J=11.6 Hz, 4H), 4.39 (d, J=4.3 Hz, 1H), 4.34 (s, 2H), 4.25 (dd, J=10.0, 5.7 Hz, 3H), 4.19 (t, J=6.4 Hz, 3H), 4.11 (s, 1H), 4.00 (d, J=10.9 Hz, 2H), 3.94-3.88 (m, 2H), 3.83 (d, J=10.6 Hz, 1H), 3.50 (d, J=6.9 Hz, 1H), 3.13 (s, 9H), 2.54-2.43 (m, 2H), 2.30 (s, 1H), 2.07 (d, J=12.8 Hz, 2H), 1.90 (s, 3H), 1.79-1.74 (m, 2H), 1.48-1.39 (m, 4H), 1.27 (d, J=6.2 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

Example 15

##STR00068##

[0154] 4-Bromo-2,5-difluorophenol (1 g, 4.78 mmol, 1 eq.) was dissolved in acetonitrile (25 mL), bromopentane (1.8 mL, 14.35 mmol, 3 eq.) was added, and potassium carbonate (1.984 g, 14.35 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 1.280 g of crude compound SM27 as a yellow liquid, with a yield of 96%.

##STR00069##

[0155] SM27 (500 g, 1.79 mmol, 1 eq.) was dissolved in triethylamine (15 mL), and the resulting solution was added into a sealed tube. Replacement with nitrogen was performed by bubbling. Trimethylsilylacetylene (0.38 mL, 2.68 mmol, 1.5 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (126 mg, 0.17 mmol, 0.1 eq.) and CuI (34 mg, 0.17 mmol, 0.1 eq.) were added. The resulting mixture was stirred overnight in an oil bath at 90 C. TLC showed the completion of the reaction and the formation of a new spot. The solvent was removed, and the resulting product was dissolved in DCM. The organic phase was washed sequentially with an ammonium chloride solution, dilute hydrochloric acid and saturated brine. The solvent was removed to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 537 mg of compound SM28 as a yellow oil, with a yield of 99%.

##STR00070##

[0156] SM28 (537 mg, 1.81 mmol, 1 eq.) was dissolved in MeOH (9 mL) and THF (9 mL). Potassium carbonate (376 mg, 2.71 mmol, 1.5 eq.) was added. The resulting mixture was stirred for 3 h at room temperature. TLC showed the completion of the reaction, the formation of a new spot, and the disappearance of the raw materials. The resulting mixture was extracted with water and DCM, and the solvent was removed to obtain 402.5 mg of crude product SM29 as a yellow oil, with a yield of 99%.

##STR00071##

[0157] Methyl 6-bromo-2-naphthoate (592 mg, 2.23 mmol, 1 eq.) was dissolved in triethylamine (10 mL), and SM29 (500 mg, 2.23 mmol, 1 eq.), (PPh.sub.3).sub.2PdCl.sub.2 (157 mg, 0.22 mmol, 0.1 eq.) and CuI (43 mg, 0.22 mmol, 0.1 eq.) were added. Replacement with nitrogen was performed. The resulting mixture was stirred overnight in an oil bath at 90 C. TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed. The resulting mixture was extracted with water and DCM. The solvent was removed to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 678 mg of compound SM30 as a yellow solid, with a yield of 74%.

##STR00072##

[0158] SM30 (678 mg, 1.66 mmol, 1 eq.) was dissolved in THF (16 mL). NaOH (266 mg, 6.64 mmol, 4 eq.) was dissolved in water (2 mL) and added to the reaction system. The reaction system was stirred overnight at 60 C. TLC showed a spot of product. After THF was subjected to rotary evaporation, extraction was performed with water and DCM for the first time. The aqueous phase was remained for acidifying, extraction was performed with DCM, and the solvent was removed to obtain 418.6 mg of crude product SM31 as a yellow solid, with a yield of 64%.

##STR00073##

[0159] SM31 (71 mg, 0.18 mmol, 1 eq.) was dissolved in DMF (2 mL), echinocandin B hydrochloride (150 mg, 0.18 mmol, 1 eq.) and CDMT (38 mg, 0.21 mmol, 1.2 eq.) were sequentially added, and NMM (0.06 mL, 0.54 mmol, 3 eq.) was finally added. The resulting mixture was stirred for 4 h at room temperature. 83 mg of a compound as a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 39%. HRMS[M+Na].sup.+: 1196.4617.

[0160] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.42 (s, 1H), 8.10 (s, 1H), 8.01-7.92 (m, 3H), 7.62 (dd, J=8.5, 1.2 Hz, 1H), 7.33 (dd, J=11.1, 6.7 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.02 (dd, J=10.7, 7.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.36 (s, 1H), 5.02 (s, 2H), 4.69 (d, J=6.2 Hz, 1H), 4.61 (dd, J=14.9, 10.6 Hz, 3H), 4.34 (dd, J=18.9, 5.7 Hz, 3H), 4.26-4.18 (m, 3H), 4.09 (t, J=6.4 Hz, 3H), 3.99 (d, J=10.9 Hz, 1H), 3.88 (dd, J=18.5, 10.7 Hz, 2H), 3.43-3.38 (m, 1H), 2.60-2.39 (m, 2H), 2.30-2.20 (m, 1H), 2.18-2.03 (m, 2H), 1.88-1.80 (m, 2H), 1.52-1.39 (m, 4H), 1.28 (dd, J=11.6, 6.3 Hz, 6H), 1.06 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 16

##STR00074##

[0161] Example 15 (250 mg, 0.21 mmol, 1 eq.) was dissolved in dry THF (5 mL), and 3,4-dimethoxyphenylboronic acid (50 mg, 0.27 mmol, 1.3 eq.) was added. After the resulting mixture was stirred for 1 h at room temperature, the solvent was removed, and then dry THF (5 mL) was added for rotary evaporation. Choline chloride (297 mg, 2.12 mmol, 10 eq.) was added, and TFA (0.63 mL) mixed with acetonitrile (5 mL) was added to the system. The system was stirred for 3 h at room temperature. LCMS showed the formation of a product. 57 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 97% and a yield of 21%. HRMS[M].sup.+: 1259.5494.

[0162] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.12 (s, 1H), 8.02-7.95 (m, 3H), 7.65 (dd, J=8.5, 1.1 Hz, 1H), 7.33 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.02 (dd, J=10.7, 7.2 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (s, 1H), 5.05 (s, 1H), 4.81-4.75 (m, 1H), 4.60 (d, J=11.3 Hz, 3H), 4.39 (d, J=4.1 Hz, 1H), 4.33 (d, J=8.1 Hz, 2H), 4.24 (d, J=8.0 Hz, 2H), 4.21-4.16 (m, 1H), 4.09 (t, J=6.4 Hz, 3H), 4.00 (d, J=8.6 Hz, 2H), 3.96-3.88 (m, 2H), 3.82 (d, J=10.9 Hz, 1H), 3.58 (d, J=26.0 Hz, 2H), 3.51-3.46 (m, 1H), 3.13 (s, 9H), 2.55-2.41 (m, 2H), 2.30 (s, 1H), 2.09 (t, J=13.4 Hz, 2H), 1.83 (dd, J=14.3, 6.7 Hz, 2H), 1.50-1.40 (m, 4H), 1.27 (d, J=6.2 Hz, 6H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).

Example 17

##STR00075##

[0163] 4-Bromo-2,6-difluorophenol (2 g, 9.56 mmol, 1 eq.) was dissolved in acetonitrile (45 mL), bromooctane (1.65 mL, 9.56 mmol, 1 eq.) was added, and potassium carbonate (3.969 g, 28.70 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 3.092 g of crude product SM32 as a transparent liquid, with a yield of 99%.

##STR00076##

[0164] SM6 (1 g, 4.76 mmol, 1 eq.) and SM32 (1.53 g, 4.76 mmol, 1 eq.) were dissolved in triethylamine (20 mL), and (PPh.sub.3).sub.2PdCl.sub.2 (330 mg, 0.47 mmol, 0.1 eq.) and CuI (90 mg, 0.47 mmol, 0.1 eq.) were added. Replacement with nitrogen was performed. The resulting mixture was reacted at 90 C. for 2.5 h under microwave condition. TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed. The resulting mixture was extracted with water and DCM. The solvent was removed to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 766 mg of compound SM33 as a yellow solid, with a yield of 32%.

##STR00077##

[0165] SM33 (766 mg, 1.70 mmol, 1 eq.) was dissolved in THF (9 mL). NaOH (272 mg, 6.80 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The reaction system was stirred at 60 C. for 5 h. TLC showed a spot of product. After THF was subjected to rotary evaporation, extraction was performed with water and EA for the first time. The aqueous phase was remained for acidifying, extraction was performed with DCM, and the solvent was removed to obtain 531 mg of crude product SM34 as a yellow solid, with a yield of 71%.

##STR00078##

[0166] SM34 (391 mg, 0.89 mmol, 1 eq.) was dissolved in DMF (6 mL), echinocandin B hydrochloride (500 mg, 0.89 mmol, 1 eq.) and CDMT (126 mg, 1.07 mmol, 1.2 eq.) were sequentially added, and NMM (0.2 mL, 2.69 mmol, 3 eq.) was finally added. The resulting mixture was stirred for 4 h at room temperature. 409 mg of compound SM35 as a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 53%. HRMS[M+Na].sup.+: 1238.4876.

##STR00079##

[0167] SM35 (150 mg, 0.12 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (29 mg, 0.16 mmol, 1.3 eq.) was added. The resulting mixture was stirred for 1 h at room temperature, the solvent was removed, and then dry THF (3 mL) was added for rotary evaporation. Choline chloride (344 mg, 1.23 mmol, 10 eq.) was added, and TFA (0.38 mL) mixed with acetonitrile (3 mL) was added to the system. The system was stirred for 3 h at room temperature. LCMS showed the formation of a product. 34 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 98% and a yield of 28%. HRMS[M+H].sup.+: 1301.5963.

[0168] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.14 (s, 1H), 8.02-7.96 (m, 3H), 7.67-7.64 (m, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.42 (d, J=2.2 Hz, 1H), 5.05 (d, J=3.1 Hz, 1H), 4.78 (d, J=5.0 Hz, 1H), 4.58 (d, J=5.3 Hz, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.33 (d, J=7.8 Hz, 2H), 4.25 (dd, J=9.9, 5.6 Hz, 2H), 4.19 (t, J=6.3 Hz, 3H), 4.11 (s, 1H), 4.00 (d, J=11.0 Hz, 2H), 3.94-3.88 (m, 2H), 3.82 (d, J=10.8 Hz, 1H), 3.60-3.47 (m, 3H), 3.13 (s, 9H), 2.53-2.42 (m, 2H), 2.33-2.26 (m, 1H), 2.08 (t, J=12.2 Hz, 2H), 1.79-1.73 (m, 2H), 1.50 (d, J=7.6 Hz, 2H), 1.37-1.31 (m, 8H), 1.27 (d, J=6.2 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.92 (t, J=6.7 Hz, 3H).

Example 18

##STR00080##

[0169] 4-Bromo-2,5-difluorophenol (2 g, 9.50 mmol, 1 eq.), bromopropane (1 ml, 11.00 mmol, 1.2 eq.) and potassium carbonate (3.9 g, 28.00 mmol, 3 eq.) were dissolved in acetonitrile (45 mL), and the mixture was heated, refluxed, and stirred at 90 C. After 1.5 h, TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed, ethyl acetate and water were added for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 2.2 g of compound SM36 as a yellow oil, with a yield of 95%.

##STR00081##

[0170] SM36 (1 g, 4.00 mmol, 1 eq.), trimethylsilylacetylene (393 mg, 4.00 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (280 mg, 0.40 mmol, 0.1 eq.) and CuI (70 mg, 0.40 mmol, 0.1 eq.) were weighed and placed in a microwave reaction bottle. Triethylamine (15 mL) was added. Nitrogen was blown into the bottle by using a bubbling method to vent the air. After 15 min, the bottle was quickly covered for sealing, and the mixture was reacted under microwave condition for 3 h at 90 C. After the reaction was completed, there was no raw material left in the TLC dot plate. The solvent was removed, DCM was added for dissolving, and 690 mg of compound SM37 as a yellow oil was obtained by column chromatography, with a yield of 64%.

##STR00082##

[0171] SM37 (690 mg, 2.50 mmol, 1 eq.) and potassium carbonate (535 mg, 3.80 mmol, 1.5 eq.) were dissolved in THF (5 mL) and CH.sub.3OH (5 mL). The resulting mixture was stirred overnight at room temperature. TLC showed that the reaction was finished. The solvent was removed. Water and EA were added for extraction. The organic phase was dried and concentrated to obtain 471 mg of SM38 as a yellow oil, with a yield of 93%.

##STR00083##

[0172] SM38 (471 mg, 2.40 mmol, 1.2 eq), methyl 6-bromo-2-naphthoate (533 mg, 2.00 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (141 mg, 0.20 mmol, 0.1 eq.) and CuI (38 mg, 0.20 mmol, 0.1 eq.) were weighed and placed in a microwave reaction bottle. Triethylamine (15 mL) was added. Nitrogen was blown into the bottle by using a bubbling method to vent the air. After about 15 min, the bottle was quickly covered for sealing, and the mixture was reacted under microwave condition for 3 h at 90 C. After the reaction was completed, there was no raw material left in the TLC dot plate. The solvent was removed, DCM was added for dissolving, and 555 mg of compound SM39 as a yellow solid was obtained by column chromatography, with a yield of 72%.

##STR00084##

[0173] SM39 (555 mg, 1.40 mmol, 1 eq.) was dissolved in THF (5 mL), and heated and stirred at 70 C., and then an aqueous solution (1 mL) of NaOH (234 mg, 5.80 mmol, 4 eq.) was added to the reaction system. The reaction system was heated at 70 C. and refluxed overnight. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH value until an acidic state is reached, and then a solid was precipitated. Suction filtration was performed to obtain 457 mg of compound SM40 as a white solid, with a yield of 85%.

##STR00085##

[0174] Echinocandin B hydrochloride (300 mg, 0.35 mmol, 1 eq.), SM40 (131 mg, 0.35 mmol, 1 eq.) and CDMT (75 mg, 0.43 mmol, 1.2 eq.) were dissolved in DMF (3.5 mL), and then NMM (0.118 mL, 1.07 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 235 mg of compound SM41 as a white solid, with a purity of 86% and a yield of 57%. MS[M+H].sup.+: 1146.

##STR00086##

[0175] SM41 (235 mg, 0.20 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (49 mg, 0.26 mmol, 1.3 eq.) were dissolved in dry THF (3 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (1.7 g, 6.10 mmol, 30 eq.) was added, then a mixed solution of TFA (0.5 mL) and acetonitrile (3 mL) was added to dissolve the reactants, and stirring was performed for 5 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 160 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 63%. HRMS[M].sup.+: 1231.5424.

[0176] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.13 (s, 1H), 8.02-7.96 (m, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.33 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.03 (dd, J=10.7, 7.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.42 (s, 1H), 5.05 (d, J=2.9 Hz, 1H), 4.79 (dd, J=12.0, 5.0 Hz, 1H), 4.60 (d, J=11.5 Hz, 3H), 4.39 (d, J=4.2 Hz, 1H), 4.33 (d, J=8.1 Hz, 2H), 4.25 (t, J=7.5 Hz, 2H), 4.21-4.16 (m, 1H), 4.11 (s, 1H), 4.06 (t, J=6.4 Hz, 3H), 4.00 (d, J=11.0 Hz, 1H), 3.95-3.88 (m, 2H), 3.83 (d, J=11.0 Hz, 1H), 3.55-3.47 (m, 2H), 3.13 (s, 9H), 2.55-2.42 (m, 2H), 2.30 (dd, J=11.5, 6.1 Hz, 1H), 2.08 (dd, J=15.1, 10.5 Hz, 2H), 1.86 (dd, J=14.0, 6.7 Hz, 2H), 1.27 (d, J=6.2 Hz, 6H), 1.10-1.05 (m, 6H).

Example 19

##STR00087##

[0177] 4-Bromo-2,5-difluorophenol (2 g, 9.50 mmol, 1 eq.), bromobutane (1 ml, 11.00 mmol, 1.2 eq.) and potassium carbonate (3.9 g, 28.00 mmol, 3 eq.) were dissolved in acetonitrile (45 mL), and the mixture was heated, refluxed, and stirred at 90 C. After 1.5 h, TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed, ethyl acetate and water were added for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 2.28 g of compound SM51 as a yellow oil, with a yield of 90%.

##STR00088##

[0178] SM42 (1 g, 3.70 mmol, 1 eq.), trimethylsilylacetylene (446 mg, 4.50 mmol, 1.2 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (265 mg, 0.37 mmol, 0.1 eq.) and CuI (72 mg, 0.37 mmol, 0.1 eq.) were weighed and placed in a microwave reaction bottle. Triethylamine (15 mL) was added. Nitrogen was blown into the bottle by using a bubbling method to vent the air. After 15 min, the bottle was quickly covered for sealing, and the mixture was reacted under microwave condition for 3 h at 90 C. After the reaction was completed, there was no raw material left in the TLC dot plate. The solvent was removed, DCM was added for dissolving, and 992 mg of compound SM43 as a yellow oil was obtained by column chromatography, with a yield of 93%.

##STR00089##

[0179] SM43 (992 mg, 3.50 mmol, 1 eq.) and potassium carbonate (731 mg, 5.20 mmol, 1.5 eq.) were dissolved in THF (5 mL) and CH.sub.3OH (5 mL). The resulting mixture was stirred overnight at room temperature. TLC showed that the reaction was finished. The solvent was removed. Water and EA were added for extraction. The organic phase was dried and concentrated to obtain 672 mg of SM44 as a yellow oil, with a yield of 91%.

##STR00090##

[0180] SM44 (672 mg, 3.20 mmol, 1.5 eq), methyl 6-bromo-2-naphthoate (568 mg, 2.10 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (150 mg, 0.20 mmol, 0.1 eq.) and CuI (40 mg, 0.20 mmol, 0.1 eq.) were weighed and placed in a microwave reaction bottle. Triethylamine (15 mL) was added. Nitrogen was blown into the bottle by using a bubbling method to vent the air. After 15 min, the bottle was quickly covered for sealing, and the mixture was reacted under microwave condition for 3 h at 90 C. After the reaction was completed, there was no raw material left in the TLC dot plate. The solvent was removed, DCM was added for dissolving, and 635 mg of compound SM45 as a yellow solid was obtained by column chromatography, with a yield of 75%.

##STR00091##

[0181] SM45 (635 mg, 1.60 mmol, 1 eq.) was dissolved in THF (7 mL), and heated and stirred at 70 C., and then an aqueous solution (1.5 mL) of NaOH (258 mg, 6.40 mmol, 4 eq.) was added to the reaction system. The reaction system was heated at 70 C. and refluxed overnight. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH value until an acidic state is reached, and then a solid was precipitated. Suction filtration was performed to obtain 586 mg of compound SM46 as a yellow solid, with a yield of 95%.

##STR00092##

[0182] Echinocandin B hydrochloride (300 mg, 0.35 mmol, 1 eq.), SM46 (136 mg, 0.35 mmol, 1 eq.) and CDMT (75 mg, 0.43 mmol, 1.2 eq.) were dissolved in DMF (3.5 mL), and then NMM (0.118 mL, 1.07 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 252 mg of compound SM47 as a white solid, with a purity of 99% and a yield of 60%. MS[M+H].sup.+: 1161.

##STR00093##

[0183] SM47 (252 mg, 0.20 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (51 mg, 0.28 mmol, 1.3 eq.) were dissolved in dry THF (3 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (1.79 g, 6.50 mmol, 30 eq.) was added, then a mixed solution of TFA (0.5 mL) and acetonitrile (3 mL) was added to dissolve the reactants, and stirring was performed for 5 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 93 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 96% and a yield of 34%. HRMS [M].sup.+: 1245.5582.

[0184] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.13 (s, 1H), 8.03-7.97 (m, 3H), 7.65 (dd, J=8.5, 1.4 Hz, 1H), 7.33 (dd, J=11.1, 6.7 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.03 (dd, J=10.7, 7.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.42 (d, J=2.5 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.79 (dd, J=12.0, 5.1 Hz, 1H), 4.59 (dd, J=10.7, 7.2 Hz, 4H), 4.39 (d, J=4.3 Hz, 1H), 4.33 (d, J=8.3 Hz, 2H), 4.25 (dd, J=8.2, 6.4 Hz, 2H), 4.20-4.16 (m, 1H), 4.10 (t, J=6.4 Hz, 3H), 4.00 (d, J=11.2 Hz, 1H), 3.95-3.88 (m, 2H), 3.83 (d, J=10.5 Hz, 1H), 3.60 (s, 1H), 3.49 (d, J=9.6 Hz, 2H), 3.13 (s, 9H), 2.53-2.42 (m, 2H), 2.30 (s, 1H), 2.10 (d, J=12.1 Hz, 2H), 1.85-1.79 (m, 2H), 1.54 (dd, J=15.1, 7.5 Hz, 2H), 1.27 (d, J=6.3 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (t, J=7.4 Hz, 3H).

Example 20

##STR00094##

[0185] 4-Bromo-2,5-difluorophenol (2 g, 9.56 mmol, 1 eq.) was dissolved in acetonitrile (45 mL), bromohexane (2.01 mL, 14.35 mmol, 1.5 eq.) was added, and potassium carbonate (3.969 g, 28.70 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 2.551 g of crude product SM48 as a transparent liquid, with a yield of 91%.

##STR00095##

[0186] SM48 (1 g, 3.41 mmol, 1 eq.) was dissolved in triethylamine (17 mL), and trimethylsilylacetylene (0.48 mL, 3.41 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (239 mg, 0.34 mmol, 0.1 eq.) and CuI (65 mg, 0.34 mmol, 0.1 eq.) were added. The resulting mixture was reacted at 90 C. for 3 h under microwave condition. TLC showed the completion of the reaction and the formation of a new spot. Column chromatography separation and purification was performed to obtain 851 mg of compound SM49 as a light yellow liquid, with a yield of 80%.

##STR00096##

[0187] SM49 (851 mg, 2.74 mmol, 1 eq.) was dissolved in MeOH (13 mL) and THF (13 mL). Potassium carbonate (569 mg, 4.11 mmol, 1.5 eq.) was added. The resulting mixture was stirred for 3 h at room temperature. TLC showed the completion of the reaction, the formation of a new spot, and the disappearance of the raw materials. The resulting mixture was extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 578 mg of SM50 as an oily liquid, with a yield of 88%.

##STR00097##

[0188] Methyl 6-bromo-2-naphthoate (644 mg, 2.42 mmol, 1 eq.) was dissolved in triethylamine (12 mL), and SM50 (578 mg, 2.42 mmol, 1 eq.), (PPh.sub.3).sub.2PdCl.sub.2 (170 mg, 0.24 mmol, 0.1 eq.) and CuI (46 mg, 0.24 mmol, 0.1 eq.) were added. Replacement with nitrogen was performed. The resulting mixture was stirred for 3 h at 90 C. under microwave condition. TLC showed the formation of a new spot and the disappearance of the raw materials. Column chromatography separation and purification was performed to obtain 854 mg of compound SM51 as a yellow solid, with a yield of 83%.

##STR00098##

[0189] SM51 (854 mg, 2.02 mmol, 1 eq.) was dissolved in THF (10 mL). NaOH (324 mg, 8.09 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The reaction system was stirred overnight at 60 C. TLC showed a spot of product. Acidifying was performed, and a solid was precipitated. Suction filtration and drying were performed to obtain 698 mg of compound SM52 as a yellow solid, with a yield of 84%.

##STR00099##

[0190] SM52 (300 mg, 0.73 mmol, 1 eq.) was dissolved in DMF (7 mL), echinocandin B hydrochloride (613 mg, 0.73 mmol, 1 eq.) and CDMT (155 mg, 0.88 mmol, 1.2 eq.) were sequentially added, and NMM (0.24 mL, 2.20 mmol, 3 eq.) was finally added. The resulting mixture was stirred for 4 h at room temperature. 435 mg of compound SM53 as a white solid was obtained through prep-HPLC purification, with a purity of 91% and a yield of 50%. HRMS [M+H].sup.+: 1210.4887.

##STR00100##

[0191] SM53 (335 mg, 0.28 mmol, 1 eq.) was dissolved in dry THF (7 mL), and 3,4-dimethoxyphenylboronic acid (67 mg, 0.36 mmol, 1.3 eq.) was added. The resulting mixture was stirred for 1 h at room temperature, the solvent was removed, and then dry THF (7 mL) was added for rotary evaporation. Choline chloride (394 mg, 2.82 mmol, 10 eq.) was added, and TFA (0.84 mL) mixed with acetonitrile (7 mL) was added to the system. The system was stirred for 3 h at room temperature. LCMS showed the formation of a product. 9 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 99% and a yield of 2%. HRMS[M].sup.+: 1273.5882.

[0192] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.12 (s, 1H), 8.01-7.96 (m, 3H), 7.70 (d, J=8.2 Hz, 1H), 7.33 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.02 (dd, J=10.8, 7.2 Hz, 1H), 6.76 (d, J=8.6 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 5.05 (d, J=3.2 Hz, 1H), 4.79 (dd, J=12.1, 5.1 Hz, 1H), 4.58 (d, J=6.4 Hz, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.33 (d, J=8.0 Hz, 2H), 4.27-4.22 (m, 2H), 4.20-4.16 (m, 1H), 4.09 (t, J=6.4 Hz, 3H), 4.00 (d, J=11.2 Hz, 1H), 3.94-3.87 (m, 2H), 3.82 (d, J=10.9 Hz, 1H), 3.64-3.46 (m, 4H), 3.13 (s, 9H), 2.53-2.42 (m, 2H), 2.34-2.27 (m, 1H), 2.08 (t, J=13.4 Hz, 2H), 1.84 (dd, J=14.3, 7.3 Hz, 2H), 1.54-1.48 (m, 2H), 1.38 (dd, J=7.2, 3.5 Hz, 4H), 1.27 (d, J=6.3 Hz, 6H), 1.07 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.0 Hz, 3H).

Example 21

##STR00101##

[0193] 4-Bromo-2,5-difluorophenol (2 g, 9.56 mmol, 1 eq.) was dissolved in acetonitrile (45 mL), bromoheptane (2.25 mL, 14.35 mmol, 1.5 eq.) was added, and potassium carbonate (3.969 g, 28.70 mmol, 3 eq.) was finally added. The mixture was heated to 90 C., and refluxed and stirred for 4 h. TLC showed that the reaction was finished. After suction filtration, the filtrate was subjected to rotary evaporation, and extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 2.905 g of crude product SM54 as a transparent liquid, with a yield of 97%.

##STR00102##

[0194] SM54 (1 g, 3.25 mmol, 1 eq.) was dissolved in triethylamine (15 mL), and trimethylsilylacetylene (0.46 mL, 3.25 mmol, 1 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (229 mg, 0.32 mmol, 0.1 eq.) and CuI (62 mg, 0.32 mmol, 0.1 eq.) were added. The resulting mixture was reacted at 90 C. for 3 h under microwave condition. TLC showed the completion of the reaction and the formation of a new spot. Column chromatography separation and purification was performed to obtain 740 mg of compound SM55 as a light yellow liquid, with a yield of 70%.

##STR00103##

[0195] SM55 (740 mg, 2.28 mmol, 1 eq.) was dissolved in MeOH (11 mL) and THF (11 mL). Potassium carbonate (473 mg, 3.42 mmol, 1.5 eq.) was added. The resulting mixture was stirred for 3 h at room temperature. TLC showed the completion of the reaction. The resulting mixture was extracted with water and EA. The EA phase was subjected to rotary evaporation to obtain 495 mg of compound SM56 as a yellow oil, with a yield of 86%.

##STR00104##

[0196] Methyl 6-bromo-2-naphthoate (521 mg, 1.96 mmol, 1 eq.) was dissolved in triethylamine (15 mL), and SM56 (495 mg, 1.96 mmol, 1 eq.), (PPh.sub.3).sub.2PdCl.sub.2 (138 mg, 0.19 mmol, 0.1 eq.) and CuI (37 mg, 0.19 mmol, 0.1 eq.) were added. Replacement with nitrogen was performed. The resulting mixture was stirred for 3 h at 90 C. under microwave. TLC showed the formation of a new spot and the disappearance of the raw materials. Column chromatography separation and purification was performed to obtain 584 mg of compound SM57 as a yellow solid, with a yield of 68%.

##STR00105##

[0197] SM57 (584 mg, 2.02 mmol, 1 eq.) was dissolved in THF (5 mL). NaOH (214 mg, 8.09 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The reaction system was stirred for 3 h at 60 C. TLC showed the completion of the reaction. Acidifying was performed, and then suction filtration and drying were performed to obtain 683 mg of compound SM58 as a yellow solid, with a yield of 80%.

##STR00106##

[0198] SM58 (300 mg, 0.73 mmol, 1 eq.) was dissolved in DMF (7 mL), echinocandin B hydrochloride (593 mg, 0.73 mmol, 1 eq.) and CDMT (150 mg, 0.88 mmol, 1.2 eq.) were sequentially added, and NMM (0.23 mL, 2.20 mmol, 3 eq.) was finally added. The resulting mixture was stirred for 4 h at room temperature. 144 mg of compound SM59 as a white solid was obtained through prep-HPLC purification, with a purity of 91% and a yield of 16%. HRMS [M+Na].sup.+: 1224.4853.

[0199] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.41 (s, 1H), 8.09 (s, 1H), 7.94 (dd, J=17.0, 5.8 Hz, 3H), 7.62 (d, J=9.9 Hz, 1H), 7.33 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.02 (dd, J=10.7, 7.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.39-5.34 (m, 1H), 5.03 (d, J=5.6 Hz, 1H), 4.84 (s, 1H), 4.70 (dd, J=11.9, 5.2 Hz, 1H), 4.64-4.53 (m, 3H), 4.34 (dd, J=18.3, 5.2 Hz, 3H), 4.23 (dd, J=12.7, 7.0 Hz, 3H), 4.09 (t, J=6.4 Hz, 3H), 3.99 (d, J=8.1 Hz, 1H), 3.93-3.80 (m, 2H), 3.41 (t, J=9.2 Hz, 1H), 2.58-2.40 (m, 2H), 2.28-2.20 (m, 1H), 2.10 (ddd, J=25.0, 16.8, 8.2 Hz, 2H), 1.87-1.79 (m, 2H), 1.50 (dd, J=15.2, 7.4 Hz, 2H), 1.43-1.32 (m, 6H), 1.28 (dd, J=12.2, 6.2 Hz, 6H), 1.06 (d, J=6.9 Hz, 3H), 0.93 (t, J=6.8 Hz, 3H).

##STR00107##

[0200] SM59 (144 mg, 0.11 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (28 mg, 0.15 mmol, 1.3 eq.) was added. The resulting mixture was stirred for 1 h at room temperature, the solvent was removed, and then dry THF (7 mL) was added for rotary evaporation. Choline chloride (167 mg, 1.19 mmol, 10 eq.) was added, and TFA (0.36 mL) mixed with acetonitrile (3 mL) was added to the system. The system was stirred for 3 h at room temperature. LCMS showed the formation of a product. 21 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 97% and a yield of 13%. HRMS[M].sup.+: 1287.5902.

[0201] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.43 (s, 1H), 8.10 (s, 1H), 7.98-7.91 (m, 3H), 7.63 (dd, J=8.5, 1.3 Hz, 1H), 7.32 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.02 (dd, J=10.8, 7.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.44-5.37 (m, 1H), 5.06 (dd, J=8.3, 3.0 Hz, 1H), 4.79 (dd, J=12.1, 4.9 Hz, 1H), 4.59 (dd, J=11.5, 6.8 Hz, 3H), 4.39 (d, J=4.2 Hz, 1H), 4.37-4.31 (m, 2H), 4.25 (dd, J=11.6, 3.3 Hz, 2H), 4.22-4.17 (m, 1H), 4.12 (d, J=8.7 Hz, 1H), 4.08 (t, J=6.4 Hz, 2H), 3.99 (d, J=7.8 Hz, 2H), 3.95-3.88 (m, 2H), 3.82 (d, J=10.8 Hz, 1H), 3.61 (dd, J=11.9, 7.3 Hz, 1H), 3.55-3.45 (m, 2H), 3.12 (s, 9H), 2.54-2.41 (m, 2H), 2.29 (t, J=8.9 Hz, 1H), 2.08 (dd, J=12.0, 8.7 Hz, 2H), 1.82 (dd, J=14.6, 6.6 Hz, 2H), 1.51 (dd, J=14.8, 7.1 Hz, 2H), 1.42-1.32 (m, 6H), 1.27 (d, J=6.1 Hz, 6H), 1.07 (d, J=6.9 Hz, 3H), 0.92 (t, J=6.8 Hz, 3H).

Example 22

##STR00108##

[0202] 4-Bromo-2,3-difluorophenol (2 g, 9.50 mmol, 1 eq.), 1-bromooctane (1.98 ml, 11.00 mmol, 1.2 eq.) and potassium carbonate (4 g, 28.00 mmol, 3 eq.) were dissolved in acetonitrile (47 mL), and the mixture was heated, refluxed, and stirred at 90 C. After 1.5 h, TLC showed the formation of a new spot and the disappearance of the raw materials. The solvent was removed, ethyl acetate and water were added for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 3 g of compound SM60 as a black oil, with a yield of 97%.

##STR00109##

[0203] SM6 (2 g, 9.50 mmol, 1 eq.), SM60 (3 g, 9.50 mmol, 1 eq.) and CuI (550 mg, 0.47 mmol, 0.05 eq.) were dissolved in 1,4-dioxane (10 mL), and then DIPEA (3.3 mL, 19.00 mmol, 3 eq.) was added. Vacuumizing and replacement with nitrogen were performed and repeated three times. Pd(PPh.sub.3).sub.2Cl.sub.2 (550 mg, 0.47 mmol, 0.05 eq.) was added under nitrogen atmosphere. The resulting mixture was heated and stirred overnight at 80 C. TLC showed a clear new spot. The solvent was removed. DCM was added for dissolving, and column chromatography purification was performed to obtain 681 mg of compound SM61 as a white solid, with a yield of 16%.

##STR00110##

[0204] SM61 (681 mg, 1.50 mmol, 1 eq.) was dissolved in THF (6 mL), and heated and stirred at 60 C., and an aqueous solution (1 mL) of NaOH (242 mg, 6.00 mmol, 5 eq.) was added to the reaction system. The reaction system was heated at 75 C. and refluxed overnight. After the reaction was completed, 2M HCl (aq.) was added to adjust the pH value until an acidic state is reached, and then a solid was precipitated. Suction filtration was performed to obtain 595 mg of compound SM62 as a white solid, with a yield of 89%.

##STR00111##

[0205] Echinocandin B hydrochloride (600 mg, 0.71 mmol, 1 eq.), SM62 (315 mg, 0.71 mmol, 1 eq.) and CDMT (40 mg, 0.22 mmol, 1.2 eq.) were dissolved in DMF (2 mL), and then NMM (0.06 mL, 0.57 mmol, 3 eq.) was added. Stirring was performed for 1 h at room temperature. After the reaction was completed, the reaction solution was subjected to prep-HPLC purification and separation to obtain 579 mg of compound SM63 as a white solid, with a purity of 96% and a yield of 57%. MS[M+H].sup.+: 1216.

##STR00112##

[0206] SM63 (337 mg, 0.27 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (65 mg, 0.36 mmol, 1.3 eq.) were dissolved in dry THF (4 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. Choline tosylate (2.3 g, 8.30 mmol, 30 eq.) was added, then a mixed solution of TFA (0.85 mL) and acetonitrile (4 mL) was added to dissolve the reactants, and stirring was performed for 6 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 197 mg of a compound (acetate) as a white solid was obtained through prep-HPLC purification, with a purity of 95% and a yield of 54%. HRMS[M].sup.+: 1301.6172.

[0207] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.46 (s, 1H), 8.14 (s, 1H), 8.04-7.97 (m, 3H), 7.66 (dd, J=8.4, 1.4 Hz, 1H), 7.34-7.30 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.97 (d, J=7.5 Hz, 1H), 6.76 (d, J=8.6 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.79 (dd, J=12.0, 5.1 Hz, 2H), 4.61-4.56 (m, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.33 (d, J=8.2 Hz, 2H), 4.27-4.22 (m, 2H), 4.20-4.16 (m, 1H), 4.13 (t, J=6.4 Hz, 3H), 4.00 (d, J=11.4 Hz, 1H), 3.94-3.87 (m, 2H), 3.83 (d, J=11.4 Hz, 1H), 3.60 (d, J=4.9 Hz, 1H), 3.52-3.46 (m, 2H), 3.13 (s, 9H), 2.52-2.43 (m, 2H), 2.30 (t, J=9.0 Hz, 1H), 2.08 (dd, J=15.4, 9.4 Hz, 2H), 1.89 (s, 3H), 1.86-1.81 (m, 2H), 1.50 (d, J=8.0 Hz, 2H), 1.35 (d, J=16.1 Hz, 8H), 1.29-1.26 (m, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.91 (t, J=6.9 Hz, 3H).

Example 23

##STR00113##

[0208] N-methyl-D-prolinol (3 g, 26.04 mmol, 1 eq.) was dissolved in acetone (30 mL). Methyl p-toluenesulfonate (4.851 g, 26.04 mmol, 1 eq.) was slowly added. The resulting mixture was refluxed for 3 h at 60 C. LCMS showed that most of the substances were products. Solids were precipitated by adding petroleum ether, and suction filtration was performed. The filter cake was washed with petroleum ether and dried to obtain 6.69 g of product SM64, with a yield of 85%.

##STR00114##

[0209] Example 15 (300 mg, 0.25 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (60 mg, 0.33 mmol, 1.3 eq.) was added. After the resulting mixture was stirred for 1 h at room temperature, the solvent was subjected to rotary evaporation, and then dry THF (3 mL) was added for rotary evaporation. SM64 (2.308 g, 7.66 mmol, 30 eq.) was added, and TFA (0.75 mL) mixed with dry MeCN (3 mL) was added to the system. The system was stirred for 3 h at room temperature. LCMS showed the formation of a product. 40 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 88% and a yield of 12%. HRMS[M].sup.+: 1285.5715.

[0210] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.12 (s, 1H), 8.03-7.95 (m, 3H), 7.65 (d, J=8.6 Hz, 1H), 7.33 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.02 (dd, J=10.7, 7.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 5.42 (d, J=6.8 Hz, 1H), 5.04 (d, J=5.3 Hz, 1H), 4.80 (s, 1H), 4.60 (d, J=12.0 Hz, 3H), 4.39 (d, J=4.2 Hz, 1H), 4.34 (d, J=8.0 Hz, 2H), 4.27 (dd, J=13.1, 6.3 Hz, 2H), 4.21-4.17 (m, 1H), 4.09 (t, J=6.4 Hz, 3H), 4.00 (d, J=8.8 Hz, 2H), 3.87 (dt, J=16.9, 9.4 Hz, 4H), 3.62-3.46 (m, 3H), 3.20 (s, 3H), 2.99 (s, 3H), 2.55-2.41 (m, 2H), 2.34-2.21 (m, 2H), 2.14-2.03 (m, 4H), 1.97-1.89 (m, 1H), 1.87-1.80 (m, 2H), 1.51-1.40 (m, 4H), 1.27 (dd, J=6.1, 3.3 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H). Example 24:

##STR00115##

[0211] SM47 (50 mg, 0.04 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (10 mg, 0.05 mmol, 1.3 eq.) were dissolved in dry THF (1 mL). The resulting solution was stirred for 1 h at room temperature, and concentrated to dryness. SM64 (389 mg, 1.2 mmol, 30 eq.) was added, then a mixed solution of TFA (0.1 mL) and CH.sub.3CN (2 mL) was added to dissolve the reactants, and stirring was performed for 5 h at room temperature under N.sub.2 atmosphere. After the reaction was completed, an aqueous solution of sodium acetate was added for quenching, and 25 mg of a compound (hydrochloride) as a white solid was obtained through prep-HPLC purification, with a purity of 90% and a yield of 45%. HRMS[M].sup.+: 1271.5322.

[0212] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.46 (s, 1H), 8.13 (s, 1H), 8.05-7.94 (m, 3H), 7.65 (dd, J=8.5, 1.5 Hz, 1H), 7.33 (dd, J=11.0, 6.7 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.03 (dd, J=10.8, 7.2 Hz, 1H), 6.76 (d, J=8.6 Hz, 2H), 5.41 (s, 1H), 5.07-5.01 (m, 1H), 4.79 (dd, J=11.8, 5.2 Hz, 2H), 4.59 (dd, J=10.8, 7.4 Hz, 3H), 4.39 (d, J=4.3 Hz, 1H), 4.36-4.30 (m, 2H), 4.30-4.22 (m, 2H), 4.21-4.15 (m, 1H), 4.10 (t, J=6.4 Hz, 3H), 4.00 (d, J=8.4 Hz, 2H), 3.93-3.79 (m, 4H), 3.67-3.41 (m, 4H), 3.20 (s, 3H), 2.99 (s, 3H), 2.54-2.41 (m, 2H), 2.34-2.20 (m, 2H), 2.09 (t, J=10.7 Hz, 3H), 1.97-1.88 (m, 1H), 1.82 (dt, J=12.4, 6.4 Hz, 2H), 1.54 (dq, J=14.8, 7.4 Hz, 2H), 1.27 (dd, J=6.2, 3.0 Hz, 6H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (t, J=7.4 Hz, 3H).

Experimental Example 1: Method for Testing Antifungal Activity

[0213] After gradient dilution of test compounds, an MIC assay was performed on a Candida standard strain, and an MEC assay was performed on an Aspergillus standard strain. The method for assaying minimum inhibitory concentration (MIC) was performed with reference to American Clinical and Laboratory Standards Institute (CLSI M27-A3) guidelines, and the method for assaying minimum effective concentration (MEC) was performed with reference to American Clinical and Laboratory Standards Institute (CLSI M38-A2) guidelines.

Preparation of Fungal Inoculation Solution

Candida:

[0214] A cryopreserved strain was passaged at least 2 times. A single colony was picked and resuspended in a physiological saline or sterile water tube, and the tube was subjected to vortex shaking. The Candida suspension was adjusted to 0.5 McF (110.sup.6-510.sup.6 CFU/mL) at a wavelength of 530 nm by using a spectrophotometer. After being diluted 50 times with physiological saline, the Candida suspension was diluted 20 times with 1RPMI 1640 broth (110.sup.3-510.sup.3 CFU/mL). 10 L of the diluted Candida suspension was coated on an SDA plate for colony counting, with a range of about 10-50 single colonies.

[0215] After a prepared drug sensitive plate was completely dissolved at room temperature, the Candida suspension was added to the 96-well plate by using a multi-channel pipettor at 100 L/well. At this time, the concentration of Candida in each well should be 0.510.sup.3-2.510.sup.3 CFU/mL.

Aspergillus (Operations were Performed in a Class II Biosafety Cabinet):

[0216] Aspergillus was passaged onto an SDA plate for cultivation for 48 h-7 d at 35 C. to induce sporulation. The colonies on the plate were covered with 0.85% physiological saline (1 mL) or sterile water (polysorbate 20 was added to a final concentration of 0.1%-0.01%). The surface of the culture medium was gently wiped with a sterile cotton swab (note: do not puncture the culture medium). The resuspension of spore hyphae was transferred to a sterile test tube, and left to stand for 3-5 min to precipitate heavier particles. The homogeneous suspension on the upper layer was transferred to a new sterile test tube, and the tube was capped closely, and subjected to vortex shaking for 15 s (note: the suspension can produce an aerosol when the cap is reopened). The concentration of the suspension was adjusted to an OD value of 0.09-0.13 at 530 nm by using a spectrophotometer. The suspension was diluted 50 times with 1RPMI 1640. Within 2 h after dilution, 100 L of the diluted suspension was added to each well in a 96-well plate (the concentration of spores in the final drug sensitive plate should be 0.410.sup.4-510.sup.4 CFU/mL).

[0217] Colony counting: The suspension after dilution with RPMI 1640 was further diluted 10 times, 10 L of the diluted suspension was coated on an SDA plate, cultivation was performed at 28 C., observation was performed every day, and counting was immediately performed after the colonies were visible to naked eyes.

Cultivation

[0218] A yeast-type fungus assay plate was placed in an incubator, and incubated for 24 h at 35 C. and 85% humidity, and then the MIC values were read. For echinocandin-based drugs, Aspergillus was incubated for 21-26 h at 28 C., and then the MEC results were read.

MIC or MEC Interpretation

[0219] Yeast-type fungi: A 96-well plate was attached with a disposable parafilm, shaken for uniformly mixing, and observed with naked eyes by using a plate reader microscope. Compared with a growth control, the minimum compound concentration corresponding to >50% growth inhibition was defined as MIC. Pictures were taken and saved by using an automated plate reader.

[0220] Aspergillus: For echinocandin-based drugs, compared to a growth control, the minimum drug concentration at which hyphae were able to form small, round and compact hyphal particles under a plate reader microscope was defined as MEC. In order to accurately determine MEC value, vortex oscillation should not be allowed before reading the plate.

TABLE-US-00003 TABLE 1 Test results of antifungal activity of compounds Candida Candida C. C. Candida Candida Starting assay albicans albicans parapsilosis krusei albicans albicans concentration ATCC ATCC ATCC ATCC ATCC ATCC Compound (g/mL) 90028 10231 22019 6258 MYA-574 64124 Caspofungin 16 0.12 0.12 0.5 0.25 0.015 0.12 Rezafungin 16 0.015 0.015 0.5 0.03 0.015 0.015 Example 8 16 0.015 0.03 0.5 0.12 0.015 0.015 Example 10 16 0.015 0.03 0.5 0.06 0.015 0.015 Example 14 16 0.015 0.03 0.25 0.06 0.015 0.015 Example 16 16 0.03 0.03 0.5 0.06 0.015 0.015 Example 18 16 0.06 0.06 2 0.5 0.015 0.06 Example 19 16 0.015 0.03 1 0.12 0.015 0.03 Notes: 1. C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 are quality-control strains. According to CLSI-M60, the 24 h MIC of caspofungin against ATCC 22019 is 0.25-1 g/mL, and the 24 h MIC of caspofungin against ATCC 6258 is 0.12-1 g/mL.

TABLE-US-00004 TABLE 2 Test results of antifungal activity of compounds Candida Candida Aspergillus Starting assay albicans albicans C. tropicalis C. glabrata fumigatus concentration ATCC ATCC ATCC ATCC ATCC Compound (g/mL) MYA-2876 MYA-427 750 15126 204305 Caspofungin 16 0.06 0.12 0.06 0.12 0.25 Rezafungin 16 0.015 0.015 0.015 0.06 0.015 Example 8 16 0.015 0.03 0.015 0.06 0.03 Example 10 16 0.015 0.03 0.015 0.06 0.015 Example 14 16 0.015 0.03 0.015 0.06 0.015 Example 16 16 0.015 0.03 0.015 0.06 0.015 Example 18 16 0.03 0.12 0.015 0.12 0.03 Example 19 16 0.015 0.03 0.015 0.12 0.03

TABLE-US-00005 Test results of antifungal activity of compounds Candida Candida Candida Candida Candida Starting assay albicans albicans albicans albicans albicans concentration ATCC ATCC ATCC ATCC ATCC Compound (g/mL) 76485 MYA-4788 MYA-1023 90029 18804 Caspofungin 16 0.06 0.06 0.06 0.06 0.06 Rezafungin 16 0.015 0.015 0.015 0.015 0.015 Example 8 16 0.015 0.015 0.015 0.015 0.015 Example 10 16 0.015 0.015 0.015 0.015 0.015 Example 14 16 0.015 0.015 0.015 0.015 0.015 Example 16 16 0.015 0.015 0.015 0.015 0.015 Example 18 16 0.06 0.06 0.03 0.03 0.03 Example 19 16 0.03 0.03 0.015 0.015 0.015

TABLE-US-00006 TABLE 4 Test results of antifungal activity of compounds Candida Candida Candida Pichia Cryptococcus Starting assay albicans albicans albicans guilliermondii neoformans concentration CMCC ATCC CICC ATCC ATCC Compound (g/mL) 98001 14053 1943 6260 208821 Caspofungin 16 0.06 0.03 0.06 0.12 16 Rezafungin 16 0.015 0.015 0.015 0.25 16 Example 8 16 0.015 0.015 0.03 0.25 8 Example 10 16 0.015 0.015 0.03 0.25 8 Example 14 16 0.015 0.015 0.03 0.25 8 Example 16 16 0.015 0.015 0.03 0.25 8 Example 18 16 0.03 0.03 0.06 0.5 >16 Example 19 16 0.015 0.015 0.03 0.5 16

Experimental Example 2: Study on Pharmacokinetic Properties in Rats

[0221] The pharmacokinetic properties of rezafungin, example 16 and example 19 in the blood plasma of SPF-grade SD rats (as test animals) after intravenous injection were studied.

TABLE-US-00007 TABLE 5 Experimental scheme of study on pharmacokinetic properties in rats Number Administration of Dosage Concentration volume Collection time Group animals Test sample (mg/kg) (mg/mL) (mL/kg) point A 4 Rezafungin 5 0.67 7.5 0.17 h, 6 h, 22 h, Example 16 5 0.67 7.5 30 h, 46 h, 54 h, 70 h post- administration B 3 Example 16 2.5 0.33 7.5 0.33 h, 4 h, 10 h, Example 19 2.5 0.33 7.5 24 h, 31 h, 48 h, 57.5 h, 72 h post- administration

[0222] The pharmacokinetic parameters are as shown in the table below

TABLE-US-00008 TABLE 6 Pharmacokinetic parameters in rats T.sub.1/2 C.sub.max AUC.sub.0-t AUC.sub.0-inf CL MRT.sub.0-t V.sub.z Group Test sample h mg/L mg/L h mg/L h L/h/kg h L/kg A Rezafungin 27.5 4.75 89 104 0.048 20.2 1.904 Example 16 34.8 11.95 326 424 0.012 24.2 0.591 B Example 16 37.3 6.08 206 275 0.009 26.1 0.49 Example 19 46.4 9.62 379 554 0.005 27.5 0.302

[0223] The experimental data showed that the drug exposure level (Cmax and AUC) and half-life (T.sub.1/2) of example 16 and example 19 in the blood plasma after single intravenous administration were significantly higher than those of rezafungin at the same dose, providing a new choice for clinical medication.