ECHINOCANDIN ANALOGUES AND PREPARATION METHOD THEREFOR

Abstract

The present invention relates to an echinocandin analogue and a preparation method therefor. The compound can be used for preventing or treating fungal infection, or for preventing, stabilizing or inhibiting fungal growth or killing fungi. An exemplary compound is represented by formula I, wherein the definitions of R.sub.1, R.sub.2, R.sub.3 and G groups are as described in the description.

##STR00001##

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or isomer thereof, ##STR00088## wherein R.sub.1 is selected from the group consisting of hydroxy, 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.b CH.sub.2CH.sub.2X.sub.1, NH(CH.sub.2CH.sub.2O).sub.b CH.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 and (OCH.sub.2CH.sub.2).sub.b(NHCH.sub.2CH.sub.2).sub.eX.sub.2; R.sub.2 is selected from the group consisting of hydrogen, R.sub.B1R.sub.B2N—, CH.sub.2CH.sub.2NR.sub.B1R.sub.B2, CH.sub.2C(O)NR.sub.B1R.sub.B2, C.sub.1-10 lower alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, cyclohydrocarbyl, heterocyclyl and PEG; R.sub.3 is selected from the group consisting of H, OSO.sub.3H and CH.sub.2NR.sub.B1R.sub.B2; G is a C.sub.10-42 fatty unit; R.sub.A1, R.sub.A2, R.sub.A3 and R.sub.A4 are independently selected from the group consisting of hydrogen, deuterium, halogen, lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene ##STR00089## R.sub.B1 and R.sub.B2 are independently selected from the group consisting of H, —C(O)R.sub.J and lower alkyl; X.sub.1 is independently N(R.sub.C1R.sub.C2R.sub.C3) or the structure ##STR00090## wherein ring A is an optionally substituted, saturated or unsaturated, monocyclic or fused ring containing one or more N atoms; R.sub.C1, R.sub.C2 and R.sub.C3 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 lower haloalkyl and deuterated C.sub.1-6 lower alkyl, and at least one of R.sub.C1, R.sub.C2 and R.sub.C3 is not hydrogen; each R.sub.F is independently selected from the group consisting of H, deuterium, hydroxy, hydroxyalkyl, 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 a substituent substituted with one or more substituents selected from the group consisting of deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile groups, hydroxy, halogen, SR′, NR′(R″), COOR′ and CONR′(R″); X.sub.2 is N(R.sub.D1R.sub.D2R.sub.D3) or X.sub.1 structure; R.sub.D1, R.sub.D2 and R.sub.D3 are independently selected from the group consisting of H, C.sub.1-6 lower alkyl, C.sub.1-6 lower haloalkyl and deuterated C.sub.1-6 lower alkyl; R′ and R″ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkenyl and —C(O)R.sub.J; R.sub.J is selected from the group consisting of hydrogen, deuterium, C.sub.1-10 lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene; a is an integer from 0 to 5; b is an integer from 1 to 5; c is an integer from 1 to 2; d is an integer from 0 to 3; e is an integer from 1 to 5; k is an integer from 0 to 20; j is an integer from 0 to 5; and n is an integer from 1 to 7.

2. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of 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 and (OCH.sub.2CH.sub.2).sub.b(NHCH.sub.2CH.sub.2).sub.eX.sub.2; R.sub.2 is selected from the group consisting of hydrogen, R.sub.B1R.sub.B2N—, CH.sub.2CH.sub.2NR.sub.B1R.sub.B2, CH.sub.2C(O)NR.sub.B1R.sub.B2, C.sub.1-10 lower alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, cyclohydrocarbyl, heterocyclyl and PEG; R.sub.3 is selected from the group consisting of H, OSO.sub.3H and CH.sub.2NR.sub.B1R.sub.B2; G is a C.sub.10-36 lipophilic unit; R.sub.A1, R.sub.A2, R.sub.A3 and R.sub.A4 are independently selected from the group consisting of hydrogen, deuterium, halogen, lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene ##STR00091## R.sub.B1 and R.sub.B2 are independently selected from the group consisting of H, —C(O)R.sub.J and lower alkyl; X.sub.1 is independently N(R.sub.C1R.sub.C2R.sub.C3) or the structure ##STR00092## wherein ring A is an optionally substituted, saturated or unsaturated, monocyclic or fused ring containing one or more N atoms; R.sub.C1, R.sub.C2 and R.sub.C3 are independently selected from the group consisting of H, C.sub.1-6 lower haloalkyl and deuterated C.sub.1-6 lower alkyl, and at least one of R.sub.C1, R.sub.C2 and R.sub.C3 is not hydrogen; each R.sub.F is independently selected from the group consisting of H, deuterium, hydroxy, hydroxyalkyl, 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 the group consisting of deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl and alkynyl; X.sub.2 is N(R.sub.D1R.sub.D2R.sub.D3) or X.sub.1 structure; R.sub.D1, R.sub.D2 and R.sub.D3 are independently selected from the group consisting of H, C.sub.1-6 lower alkyl, C.sub.1-6 lower haloalkyl and deuterated C.sub.1-6 lower alkyl; R′ and R″ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkenyl and —C(O)R.sub.J; R.sub.J is selected from the group consisting of hydrogen, C.sub.1-10 lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene; a is an integer from 0 to 5; b is an integer from 1 to 5; c is an integer from 1 to 2; d is an integer from 0 to 3; e is an integer from 1 to 5; k is an integer from 0 to 20; j is an integer from 0 to 5; and n is an integer from 1 to 7.

3. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein X.sub.1 is selected from the group consisting of the following structures: ##STR00093## wherein each R.sub.F is independently selected from the group consisting of H, deuterium, hydroxy, hydroxyalkyl, 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 the group consisting of deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl and alkynyl; R.sub.q1 and R.sub.q2 are independently H or C.sub.1-6 lower alkyl optionally substituted with one or more substituents selected from the group consisting of deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile groups, hydroxy, halogen, SR′, NR′(R″), COOR′ and CONR′(R″); R′ and R″ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkenyl and —C(O)R.sub.J; R.sub.J is selected from the group consisting of hydrogen, deuterium, C.sub.1-10 lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene; f is an integer from 0 to 16; g is an integer from 0 to 16; h is an integer from 0 to 9; i is an integer from 0 to 4; n is an integer from 1 to 7; and p is an integer from 1 to 3;

4. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein G is selected from the group consisting of ##STR00094## wherein X is independently selected from the group consisting of O, C(R.sub.B1)(R.sub.B2), NR.sub.p4— and S; R.sub.T is C.sub.1-5 linear or branched alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, alkyl, cyclohydrocarbyl and cyclohydrocarbylene ##STR00095## R.sub.p1, R.sub.p2 and R.sub.p3 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-10 lower alkyl, C.sub.1-10 lower haloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, cyclohydrocarbyl, heterocyclyl and PEG; m is an integer from 0 to 4; n is an integer from 1 to 7; R.sub.p4 is hydrogen or C.sub.1-6 lower alkyl; R.sub.B1 and R.sub.B2 are each independently selected from the group consisting of H, —C(O)R.sub.J and C.sub.1-10 lower alkyl, wherein R.sub.J is selected from the group consisting of hydrogen, deuterium, C.sub.1-10 lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene.

5. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein G is selected from the group consisting of ##STR00096## ##STR00097## ##STR00098##

6. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein G is selected from the group consisting of: ##STR00099##

7. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein G is selected from the group consisting of: ##STR00100##

8. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein G is selected from the group consisting of: ##STR00101##

9. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of ##STR00102## ##STR00103##

10. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of: ##STR00104##

11. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of: ##STR00105##

12. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of: ##STR00106##

13. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of: ##STR00107##

14. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of: ##STR00108##

15. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein the compound of formula I is: ##STR00109## wherein G.sub.1 is selected from the group consisting of ##STR00110## wherein R.sub.p1, R.sub.p2 and R.sub.p3 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-6 lower alkyl, C.sub.1-6 lower haloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, cyclohydrocarbyl, heterocyclyl and PEG; X is independently selected from the group consisting of O, C(R.sub.B1)(R.sub.B2), NR.sub.p4— and S; R.sub.p4 is hydrogen or C.sub.1-3 lower alkyl; R.sub.T is C.sub.1-5 linear or branched alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, amino, alkoxy, amino, NR′(R″), halogen, cyclohydrocarbyl and cyclohydrocarbylene ##STR00111## and when R.sub.p1, R.sub.p2 and R.sub.p3 are all H and X is O, R.sub.T is not —C.sub.5H.sub.11; when X is O and R.sub.T is —C.sub.5H.sub.11, at least one of R.sub.p1, R.sub.p2 and R.sub.p3 is not H; when R.sub.T is —C.sub.5H.sub.11 and R.sub.p1, R.sub.p2 and R.sub.p3 are all H, X is not O; R.sub.B1 and R.sub.B2 are each independently selected from the group consisting of H, —C(O)R.sub.J and C.sub.1-10 lower alkyl; R.sub.J is selected from the group consisting of hydrogen, C.sub.1-10 lower alkyl, cyclohydrocarbyl and cyclohydrocarbylene; m is independently an integer from 0 to 4; and n is an integer from 1 to 7.

16. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein the compound of formula I is: ##STR00112## wherein R.sub.G1, R.sub.G2, R.sub.G3 and R.sub.G4 are independently selected from the group consisting of hydrogen, deuterium, halogen and lower alkyl, and at least one of R.sub.G1, R.sub.G2, R.sub.G3 and R.sub.G4 is not hydrogen.

17. The compound of formula I or the pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein the compound of formula I is: ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137##

18. The compound according to claim 1, wherein the pharmaceutically acceptable salt thereof is selected from the group consisting of an acetate salt, a trifluoroacetate salt and a formate salt.

19. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or isomer thereof according to claim 1, and a pharmaceutically acceptable excipient.

20. A method of treating and/or preventing a fungal infection in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt or isomer thereof according to claim 1.

21. A method of preventing, stabilizing or inhibiting the growth of fungi or killing fungi in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt or isomer thereof according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG. 1 shows changes in histamine concentration after intravenous administration of compounds.

[0105] FIG. 2 shows a comparison of the histamine concentrations at 30 min after intravenous administration of compounds.

DETAILED DESCRIPTION

[0106] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0107] Experimental procedures without specific conditions indicated in the following examples, are generally conducted according to conventional conditions, or according to conditions recommended by the manufacturers of the starting materials or commercial products. Reagents without specific origins indicated are commercially available conventional reagents.

[0108] Anidulafungin and caspofungin were both purchased from Taizhou KEDE Chemical. Rezafungin was synthesized according to CN103889221A.

HPLC Purity Analysis Method:

[0109]

TABLE-US-00001 Instrument HPLC (Agilent 1260) Chromatography Welch Xtimate C18 (3 μm, 4.6 mm × 150 mm) column Oven 30° C. temperature Mobile phase Time (min) A: 0.05% TFA in water B: 0.05% TFA in ACN Gradient: 0.0 95 5 program 15.00 50 50 21.00 47 53 30.00 5 95 30.10 95 5 35.00 95 5 Flowrate 1.0 mL/min Detector UV 214 nm Eluent ACN Calculation Area % method

LC-MS Analysis Method:

[0110]

TABLE-US-00002 Instrument LCMS (Agilent 6120) Chromatography Welch Boltimate C18 (4.6 × 50 mm × 2.7 μm) column Mobile phase Time (min) A: 0.05% FA in water B: 0.05% FA in can Gradient 0.01 90 10 program 5.5 5 95 7.0 5 95 7.1 90 10 9.0 90 10 Flowrate 0.8 mL/min Oven 40° C. temperature Detector UV 214 nm Ion source ESI Mass range of 100~2000 scanning Mode Positive polarity

Example 1

Step 1

[0111] ##STR00044##

[0112] Compound SM1 (510 mg, 5.04 mmol) was dissolved in acetone (5.1 mL), and methyl p-toluenesulfonate (938 mg, 5.04 mmol) was added dropwise. The reaction mixture was heated at reflux for 4 h, and a white solid precipitated. The reaction mixture was filtered, and the filter cake was dried in vacuo to give compound SM2 (385 mg, 98% purity, 26.7% yield). MS: 116.1[M.sup.+].

Step 2

[0113] ##STR00045##

[0114] Anidulafungin (114 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and phenylboronic acid (24 mg, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 10 mL of acetonitrile was added, followed by addition of compound SM2 (170 mg, 0.6 mmol) and p-toluenesulfonic acid (86 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (79 mg, 97.6% purity, 60.8% yield). HRMS: 1237.6021[M.sup.+].

[0115] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.98-8.01 (m, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.71-7.78 (m, 4H), 7.63 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 5.40-5.42 (m, 1H), 5.00-5.05 (m, 1H), 4.58-4.80 (m, 7H), 4.41 (d, J=4.4 Hz, 1H), 4.34-4.36 (m, 2H), 4.25-4.32 (m, 2H), 3.97-4.24 (m, 8H), 3.89-3.96 (m, 1H), 3.82-3.87 (m, 1H), 3.48-3.53 (m, 1H), 3.12-3.17 (m, 6H), 2.45-2.57 (m, 4H), 2.27-2.35 (m, 1H), 2.05-2.15 (m, 2H), 1.79-1.87 (m, 5H), 1.40-1.53 (m, 4H), 1.26-1.32 (m, 6H), 1.10 (d, J=6.8 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H).

Example 2

Step 1

[0116] ##STR00046##

[0117] Compound SM3 (1.29 g, 10 mmol) was dissolved in acetone (13 mL), and iodomethane (1.42 g, 10 mmol) was added dropwise. The reaction mixture was heated at reflux for 4 h, and a white solid precipitated. The reaction mixture was filtered, and the filter cake was dried in vacuo to give compound SM4 (2.54 g, 98% purity, 89.2% yield). MS: 144.1 [M.sup.+].

##STR00047##

[0118] Anidulafungin (114 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and phenylboronic acid (24 mg, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 10 mL of acetonitrile was added, followed by addition of compound SM4 (171 mg, 0.6 mmol) and D-(+)-camphorsulfonic acid (120 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (61 mg, 97.0% purity, 46.2% yield). HRMS: 1265.6327[M.sup.+].

[0119] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.01 (d, J=8.3 Hz, 2H), 7.83 (dd, J=0.49, 8.3 Hz, 2H), 7.71-7.79 (m, 4H), 7.63 (d, J=8.80 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.80 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 5.34-5.41 (m, 1H), 5.00-5.05 (m, 1H), 4.58-4.80 (m, 7H), 4.40 (d, J=4.4 Hz, 1H), 4.32-4.38 (m, 2H), 4.25-4.32 (m, 2H), 4.18-4.22 (m, 1H), 4.15-4.24 (m, 1H), 3.81-4.15 (m, 8H), 3.43-3.52 (m, 2H), 3.21 (d, J=6.6 Hz, 3H), 3.04 (d, J=6.6 Hz, 3H), 2.42-2.59 (m, 2H), 2.24-2.36 (m, 1H), 2.05-2.12 (m, 2H), 1.80-1.88 (m, 9H), 1.42-1.53 (m, 5H), 1.28 (d, J=6.4 Hz, 6H), 1.10 (d, J=6.9 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H).

Example 3

[0120] ##STR00048##

[0121] Anidulafungin (114 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and phenylboronic acid (24 mg, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 10 mL of dioxane was added, followed by addition of compound SM5 (73 mg, 0.6 mmol) and p-toluenesulfonic acid (86 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (68 mg, 97.8% purity, 52.3% yield). HRMS: 1243.5924[M.sup.+].

[0122] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.97 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.69-7.75 (m, 4H), 7.61 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 5.45 (d, J=17.6 Hz, 2H), 5.36 (s, 1H), 5.05 (s, 1H), 4.73-4.77 (m, 1H), 4.58-4.61 (m, 3H), 4.16-4.40 (m, 6H), 3.81-4.10 (m, 8H), 3.63-3.73 (m, 2H), 3.46-3.50 (m, 1H), 3.20 (s, 6H), 2.42-2.53 (m, 2H), 2.26-2.29 (m, 1H), 2.05-2.11 (m, 2H), 1.78-1.84 (m, 2H), 1.40-1.52 (m, 4H), 1.25-1.30 (m, 7H), 1.07 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 4

[0123] ##STR00049##

[0124] Echinocandin B (50 mg, 0.06 mmol) and mono-tert-butyl octadecanedioate (24.43 mg, 1.1 eq.) were dissolved in DMF (2 mL), and the resulting solution was stirred in an ice-water bath. TBTU (28.9 mg, 1.5 eq.) and DIPEA (15.5 mg, 2 eq.) were added. The reaction mixture was stirred in the ice-water bath for another 1.5 h, quenched with water (5.0 mL), and extracted with ethyl acetate (5 mL×5). The organic phases were combined, washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give a product (55.2 mg, 97.1% purity, 80% yield). HRMS: 1150.6482[M+1].

[0125] .sup.1H NMR (400 MHz, DMSOd.sub.6): δ 9.31 (s, 1H), 8.06-7.94 (m, 3H), 7.40 (s, br, 1H), 7.29 (d, 1H, J=9.2 Hz), 7.02 (d, 2H, J=8.4 Hz), 6.68 (d, 2H, J=8.0 Hz), 5.45 (d, 1H, J=6.4 Hz), 5.19 (d, 1H, J=3.2 Hz), 5.14 (d, 1H, J=4.4 Hz), 5.10 (d, 1H, J=5.2 Hz), 5.04-4.91 (m, 3H), 4.75-4.64 (m, 4H), 4.42 (s, 1H), 4.36-4.28 (m, 2H), 4.21-4.16 (m, 3H), 4.04-4.01 (m, 1H), 4.00-3.93 (m, 3H), 3.88-3.84 (m, 1H), 3.79-3.77 (m, 1H), 3.71-3.68 (m, 1H), 3.19 (t, 1H, J=8.0 Hz), 2.35-2.34 (m, 1H), 2.24-2.15 (m, 3H), 2.08-2.08 (m, 2H), 1.90-1.82 (m, 2H), 1.69-1.59 (m, 1H), 1.47-1.43 (m, 5H), 1.39 (s, 9H), 1.24 (s, 24H), 1.08-1.06 (m, 6H), 0.96 (d, 3H, J=6.8 Hz).

Example 5

Step 1

[0126] ##STR00050##

[0127] N-(2-hydroxyethyl)-pyrrolidine (2.30 g, 20 mmol) was dissolved in 40 mL of acetone, and iodomethane (2.84 g, 1.0 eq.) was slowly added. The reaction mixture was heated at reflux with stirring for 4 h and concentrated until half of the solvent remained, and a solid precipitated. The solid was collected by filtration and dried to give compound SM6 as a white solid (4.88 g, 95% yield). MS: 130.0[M.sup.+].

[0128] .sup.1H NMR (400 MHz, D.sub.2O): δ 4.09 (d, 2H, J=2.0 Hz), 3.63-3.56 (m, 6H), 3.15 (s, 3H), 2.26 (s, 4H).

Step 2

[0129] ##STR00051##

[0130] Anidulafungin (300 mg, 0.26 mmol) and phenylboronic acid (64.2 mg, 2 eq.) were dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness. Anhydrous acetonitrile (10 mL) was added, followed by addition of compound SM6 (422.7 mg, 6 eq.) and p-toluenesulfonic acid (340 mg, 7.5 eq.). The reaction mixture was stirred at room temperature under nitrogen for 5 h, quenched with aqueous sodium acetate solution, and concentrated to give a crude product, which was then purified by preparative HPLC to give an acetate salt (259 mg, 96.5% purity, 76% yield). HRMS: 1251.6174[M.sup.+].

[0131] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.00 (d, 2H, J=8.4 Hz), 7.83 (d, 2H, J=8.0 Hz), 7.77 (m, 4H), 7.63 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.03 (d, 2H, J=8.8 Hz), 6.78 (d, 2H, J=8.8 Hz), 5.45 (d, 1H, J=2.0 Hz), 5.06 (d, 1H, J=3.2 Hz), 4.81-4.76 (m, 1H), 4.62-4.60 (m, 3H), 4.41 (d, 1H, J=4.4 Hz), 4.36-4.33 (m, 2H), 4.28-4.25 (m, 2H), 4.22-4.18 (m, 1H), 4.11-3.83 (m, 8H), 3.68-3.42 (m, 8H), 3.09 (s, 3H), 2.55-2.44 (m, 2H), 2.33-2.27 (m, 1H), 2.23-2.03 (m, 6H), 1.92 (s, 3H), 1.87-1.80 (m, 2H), 1.55-1.40 (m, 4H), 1.28 (d, 6H, J=5.6 Hz), 1.09 (d, 3H, J=7.2 Hz), 0.92 (t, 3H, J=6.4 Hz).

Example 6

[0132] ##STR00052##

[0133] Echinocandin B (100 mg, 0.12 mmol) and semaglutide side chain (100.9 mg, 1.0 eq.) were dissolved in DMF (4 mL), and the resulting solution was stirred in an ice-water bath. TBTU (58 mg, 1.5 eq.) and DIPEA (31 mg, 2 eq.) were added. The reaction mixture was stirred in the ice-water bath for another 1.5 h and added dropwise to 100 mL of ice water, and a solid precipitated. The solid was collected by filtration, dried, and slurried with acetonitrile to give a product (120 mg, 95.8% purity, 61.5% yield). HRMS: 1625.8989[M+1].

[0134] .sup.1H NMR (400 MHz, DMSO.sub.d6): δ 9.31 (s, 1H), 8.05 (d, 2H, J=7.6 Hz), 7.95 (d, 1H, J=8.4 Hz), 7.90-7.88 (m, 1H), 7.73-7.69 (m, 2H), 7.43-7.31 (m, 2H), 7.02 (d, 2H, J=8.4 Hz), 6.69 (d, 2H, J=8.0 Hz), 5.52 (d, 1H, J=5.6 Hz), 5.20 (d, 1H, J=2.8 Hz), 5.15 (d, 1H, J=3.6 Hz), 5.10 (d, 1H, J=5.6 Hz), 5.01-4.91 (m, 3H), 4.80-4.60 (m, 4H), 4.42 (s, 1H), 4.37-4.33 (m, 3H), 4.22-4.17 (m, 2H), 4.05-3.57 (m, 11H), 3.57 (s, br, 9H), 3.48-3.45 (m, 2H), 3.43-3.40 (m, 2H), 3.30-3.28 (m, 2H), 3.21-3.18 (m, 3H), 2.36-2.33 (m, 1H), 2.24-2.05 (m, 7H), 1.94-1.84 (m, 3H), 1.76-1.62 (m, 2H), 1.47 (s, br, 5H), 1.39 (s, 18H), 1.24 (s, 24H), 1.08-1.06 (m, 6H), 0.96 (d, 3H, J=6.8 Hz).

Example 7

[0135] ##STR00053##

[0136] The compound of Example 6 (100 mg, 0.0615 mmol) and phenylboronic acid (15 mg, 2 eq.) were dissolved in THF (4 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness. Compound SM7 (101.6 mg, 6 eq.) and p-toluenesulfonic acid (53 mg, 5 eq.) were added. The reaction mixture was stirred at room temperature under nitrogen for another 5 h, quenched with aqueous sodium acetate solution, and concentrated to give a crude product, which was then purified by preparative HPLC to give a trifluoroacetate salt (44.9 mg, 96.5% purity, 40% yield). HRMS: 1710.9867[M.sup.+].

[0137] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.48 (d, 1H, J=8.4 Hz), 8.41 (d, 1H, J=8.8 Hz), 8.23 (d, 1H, J=7.6 Hz), 8.04-7.99 (m, 2H), 7.60-7.54 (m, 2H), 7.15 (d, 2H, J=8.0 Hz), 6.77 (d, 2H, J=8.4 Hz), 5.51 (d, 1H, J=9.6 Hz), 5.05-4.89 (m, 1H), 4.60-4.45 (m, 4H), 4.37-4.32 (m, 3H), 4.28-4.25 (m, 3H), 4.13-3.82 (m, 10H), 3.76-3.63 (m, 10H), 3.59-3.56 (m, 3H), 3.54-3.56 (m, 3H), 3.53-3.46 (m, 3H), 3.41-3.38 (m, 3H), 3.21 (m, 9H), 2.55-2.44 (m, 2H), 2.36-2.21 (m, 6H), 2.17-2.06 (m, 2H), 1.92-1.83 (m, 2H), 1.64-1.56 (m, 4H), 1.49 (s, 9H), 1.46 (s, 9H), 1.31 (s, 24H), 1.22 (d, 6H, J=6.4 Hz), 1.08 (d, 3H, J=6.4 Hz).

Example 8

[0138] ##STR00054##

[0139] The trifluoroacetate salt of the compound of Example 7 (24 mg, 0.014 mmol) was dissolved in TFA (1 mL), and the resulting solution was stirred in an ice-water bath for 5 h and concentrated to dryness. The residue was purified by preparative HPLC to give a trifluoroacetate salt (7.2 mg, 97.8% purity, 30% yield). HRMS: 1598.8629[M.sup.+].

Example 9

Step 1

[0140] ##STR00055##

[0141] Echinocandin B (200 mg, 0.2397 mmol) and SM8 (89 mg, 1.0 eq.) were dissolved in DMF (5 mL), and the resulting solution was stirred in an ice-water bath. TBTU (115 mg, 1.5 eq.) and DIPEA (62 mg, 2 eq.) were added. The reaction mixture was stirred in the ice-water bath for another 1.5 h and purified by reversed-phase column chromatography to give a product (234 mg, 85% yield). MS: 1152.5[M+1].

[0142] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.96 (d, 2H, J=6.0 Hz), 7.77-7.69 (m, 6H), 7.62 (d, 2H, J=8.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.02 (d, 2H, J=8.8 Hz), 6.78 (d, 2H, J=8.4 Hz), 5.37 (d, 1H, J=2.8 Hz), 5.05-5.02 (m, 1H), 4.89-4.88 (m, 1H), 4.70-4.58 (m, 5H), 4.39-4.33 (m, 3H), 4.28-4.22 (m, 3H), 4.10-4.07 (m, 2H), 4.03-4.00 (m, 1H), 3.93-3.83 (m, 2H), 3.45-3.40 (m, 1H), 2.55-2.44 (m, 2H), 2.25-2.06 (m, 3H), 1.98-1.91 (m, 2H), 1.46-1.37 (m, 2H), 1.31-1.27 (m, 6H), 1.08 (d, 3H, J=6.8 Hz), 0.77-0.74 (m, 1H), 0.50-0.46 (m, 2H), 0.10-0.06 (m, 2H).

Step 2

[0143] ##STR00056##

[0144] SM9 (140 mg, 0.1214 mmol) and phenylboronic acid (0.728 mg, 2 eq.) were dissolved in THF (5 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness. Compound SM7 (200 mg, 6 eq.), p-toluenesulfonic acid (105 mg, 5 eq.) and anhydrous acetonitrile (5 mL) were added. The reaction mixture was stirred at room temperature under nitrogen for 5 h, quenched with aqueous sodium acetate solution, and concentrated to give a crude product, which was then purified by preparative HPLC to give an acetate salt (102 mg, 95.8% purity, 65% yield). HRMS: 1237.6022[M.sup.+].

[0145] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.99 (d, 2H, J=8.4 Hz), 7.82 (d, 2H, J=8.0 Hz), 7.78-7.71 (m, 4H), 7.62 (d, 2H, J=8.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.03 (d, 2H, J=8.4 Hz), 6.78 (d, 2H, J=8.4 Hz), 5.46 (d, 1H, J=8.4 Hz), 5.08-5.05 (m, 1H), 4.90-4.77 (m, 2H), 4.63-4.59 (m, 3H), 4.41-4.33 (m, 3H), 4.29-4.26 (m, 2H), 4.21-4.18 (m, 1H), 4.11-3.90 (m, 7H), 3.84 (d, 1H, J=11.2 Hz), 3.64-3.62 (m, 1H), 3.67-3.48 (m, 2H), 3.17 (s, 9H),), 2.55-2.44 (m, 2H), 2.34-2.27 (m, 1H), 2.13-2.02 (m, 2H), 1.97-1.90 (m, 2H), 1.46-1.41 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 1.10 (d, 3H, J=6.8 Hz) 0.80-0.74 (m, 1H), 0.50-0.46 (m, 2H), 0.10-0.06 (m, 2H).

Example 10

Step 1

[0146] ##STR00057##

[0147] N-(2-hydroxyethyl)-pyrrolidine (6.5 g, 50 mmol) was dissolved in 25 mL of acetonitrile, and iodomethane (7.09 g, 1.0 eq.) was slowly added. The reaction mixture was heated at reflux with stirring for 4 h and concentrated until half of the solvent remained, and a solid precipitated. The solid was collected by filtration and dried to give compound SM10 as a white solid (12.1 g, 90% yield). MS: 144.0[M.sup.+].

Step 2

[0148] ##STR00058##

[0149] Anidulafungin (100 mg, 0.0877 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and phenylboronic acid (21.4 mg, 0.1754 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 10 mL of dioxane was added, followed by addition of compound SM10 (162.6 mg, 0.6 mmol) and p-toluenesulfonic acid (75.5 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (47.6 mg, 97.1% purity, 41% yield). HRMS: 1265.6324[M.sup.+].

[0150] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.98 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.70-7.76 (m, 4H), 7.61 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (d, J=1.6 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.74-4.78 (m, 1H), 4.58-4.61 (m, 3H), 4.16-4.40 (m, 6H), 3.81-4.10 (m, 8H), 3.38-3.65 (m, 7H), 3.09 (s, 3H), 2.42-2.53 (m, 2H), 2.26-2.28 (m, 1H), 2.03-2.12 (m, 2H), 1.90 (s, 3H), 1.78-1.83 (m, 6H), 1.38-1.63 (m, 6H), 1.26-1.30 (m, 7H), 1.08 (d, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 11

Step 1

[0151] ##STR00059##

[0152] Echinocandin B (300 mg, 0.36 mmol) and SM11 (147 mg, 1.1 eq.) were dissolved in DMF (15 mL), and the resulting solution was stirred in an ice-water bath. TBTU (174 mg, 1.5 eq.) and DIPEA (141 mg, 3 eq.) were added. The reaction mixture was stirred in the ice-water bath for another hour and purified by reversed-phase column chromatography (MECN/H.sub.2O) to give compound SM12 (392 mg, 96% purity, 70.6% yield). MS: 1158.5[M+1].

##STR00060##

[0153] SM12 (100 mg, 0.086 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and phenylboronic acid (21.3 mg, 0.173 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 10 mL of dioxane was added, followed by addition of compound SM7 (108 mg, 0.777 mmol) and camphorsulfonic acid (100 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give a formate salt (39.5 mg, 97.0% purity, 35.5% yield). HRMS: 1243.5936[M.sup.+].

[0154] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.54 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.70-7.76 (m, 4H), 7.61 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (s, 1H), 5.04 (s, 1H), 4.71-4.78 (m, 1H), 4.48-4.58 (m, 4H), 4.16-4.42 (m, 7H), 4.05 (t, J=6.4 Hz, 3H), 3.81-4.01 (m, 3H), 3.47-3.65 (m, 4H), 3.22 (s, 9H), 2.42-2.53 (m, 2H), 2.25-2.32 (m, 1H), 2.00-2.11 (m, 2H), 1.73-1.88 (m, 4H), 1.59-1.66 (m, 2H), 1.26-1.37 (m, 8H), 1.08 (d, J=6.8 Hz, 3H).

Example 12

[0155] ##STR00061##

[0156] Anidulafungin (200 mg, 0.175 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen, and phenylboronic acid (42.8 mg, 0.351 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 20 mL of dioxane was added, followed by addition of compound SM13 (235 mg, 1.58 mmol) and p-toluenesulfonic acid (151 mg, 0.877 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (2 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (48.3 mg, 97.7% purity, 21.3% yield). HRMS: 1234.6581[M.sup.+].

Example 13

Step 1

[0157] ##STR00062##

[0158] N-methyl-D-prolinol (1.15 g, 10 mmol) was dissolved in 20 mL of acetone, and iodomethane (1.56 g, 1.1 eq.) was slowly added. The reaction mixture was heated at reflux with stirring for 4 h and concentrated until half of the solvent remained, and a solid precipitated. The solid was collected by filtration and dried to give compound SM14 as a white solid (2.44 g, 95% yield). MS: 130.0[M.sup.+].

Step 2

[0159] ##STR00063##

[0160] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in THF (5 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness. Compound SM14 (135.2 mg, 6 eq.), p-toluenesulfonic acid (75.6 mg, 5 eq.) and anhydrous dioxane (5 mL) were added. The reaction mixture was stirred at room temperature under nitrogen for 5 h, quenched with aqueous sodium acetate solution, and concentrated to give a crude product, which was then purified by preparative HPLC to give an acetate salt (57.5 mg, 95.8% purity, 50% yield). HRMS: 1251.6173[M.sup.+].

[0161] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.98 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.69-7.76 (m, 4H), 7.61 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 5.03 (d, J=3.2 Hz, 1H), 4.92-4.93 (m, 1H), 4.74-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.38 (d, J=4.0 Hz, 1H), 4.32-4.34 (m, 2H), 4.24-4.28 (m, 2H), 4.16-4.20 (m, 1H), 4.06-4.10 (m, 1H), 3.97-4.04 (m, 4H), 3.81-3.92 (m, 4H), 3.46-3.63 (m, 3H), 3.21 (s, 3H), 3.00 (s, 3H), 2.42-2.52 (m, 2H), 2.26-2.31 (m, 2H), 1.92-2.15 (m, 5H), 1.90 (s, 3H), 1.78-1.85 (m, 2H), 1.40-1.52 (m, 4H), 1.25-1.28 (m, 6H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (t, J=6.8 Hz, 3H).

Example 14

Step 1

[0162] ##STR00064##

[0163] Compound SM15 (1.02 g, 10.08 mmol) was dissolved in acetonitrile (10 mL), and methyl p-toluenesulfonate (1.88 g, 10.08 mmol) was added dropwise. The reaction mixture was heated at reflux for 4 h. The solvent was removed by rotary evaporation to give crude compound SM16, which was directly used in the next step. MS: 116.1[M.sup.+].

Step 2

[0164] ##STR00065##

[0165] Anidulafungin (1.14 g, 1 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen, and phenylboronic acid (244 mg, 2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 50 mL of dioxane was added, followed by addition of compound SM16 (2.86 g, 10 mmol) and camphorsulfonic acid (1.16 g, 5 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (10 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (563 mg, 95.4% purity, 43.4% yield). HRMS: 1237.6023[M.sup.+].

[0166] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.97 (d, J=8.3 Hz, 2H), 7.80-7.82 (m, 2H), 7.69-7.76 (m, 4H), 7.61 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.35-5.36 (m, 1H), 5.02-5.03 (m, 1H), 4.86 (d, J=5.1 Hz, 1H), 4.74 (dd, J=5.3, 12.1 Hz, 1H), 4.44-4.65 (m, 5H), 4.39 (d, J=4.4 Hz, 1H), 4.31-4.33 (m, 2H), 4.22-4.26 (m, 2H), 4.06-4.20 (m, 4H), 4.02 (t, J=6.5 Hz, 3H), 3.81-3.98 (m, 4H), 3.51-3.69 (m, 2H), 3.43-3.50 (m, 1H), 3.19 (s, 3H), 2.60-2.72 (m, 1H), 2.34-2.56 (m, 3H), 2.21-2.33 (m, 1H), 1.97-2.14 (m, 2H), 1.75-1.87 (m, 5H), 1.39-1.52 (m, 4H), 1.24-1.28 (m, 6H), 1.07 (d, J=6.8 Hz, 3H), 0.92-1.01 (m, 3H).

Example 15

Step 1

[0167] ##STR00066##

[0168] Echinocandin B (250 mg, 0.3 mmol) and SM17 (114 mg, 1.0 eq.) were dissolved in DMF (2.5 mL), and the resulting solution was stirred in an ice-water bath. TBTU (145 mg, 1.5 eq.) and DIPEA (78 mg, 2.0 eq.) were added. The reaction mixture was stirred in the ice-water bath for another hour and purified by reversed-phase column chromatography (MECN/H.sub.2O) to give compound SM18 (298 mg, 97% purity, 72.6% yield). MS: 1158.5[M+1].

Step 2

[0169] ##STR00067##

[0170] SM18 (150 mg, 0.13 mmol) was dissolved in tetrahydrofuran (7.5 mL) under nitrogen, and phenylboronic acid (31.6 mg, 0.259 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 7.5 mL of dioxane was added, followed by addition of compound SM7 (108 mg, 0.777 mmol) and camphorsulfonic acid (150 mg, 0.65 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give a formate salt (57 mg, 97.8% purity, 34.1% yield). HRMS: 1243.5928[M.sup.+].

[0171] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.55 (s, 1H), 7.61-7.81 (m, 9H), 7.15 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.37 (d, J=2.4 Hz, 1H), 5.03 (d, J=3.2 Hz, 1H), 4.71-4.76 (m, 1H), 4.58-4.61 (m, 4H), 4.14-4.40 (m, 6H), 3.81-4.08 (m, 8H), 3.46-3.65 (m, 3H), 3.16 (s, 9H), 2.42-2.54 (m, 2H), 2.25-2.31 (m, 1H), 2.01-2.12 (m, 2H), 1.78-1.85 (m, 2H), 1.38-1.53 (m, 4H), 1.25-127 (m, 6H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 16

Step 1

[0172] ##STR00068##

[0173] Echinocandin B (400 mg, 1.12 mmol) and SM19 (930 mg, 1.0 eq.) were dissolved in DMF (8 mL), and the resulting solution was stirred in an ice-water bath. TBTU (359 mg, 1.0 eq.) and DIPEA (288 mg, 2.0 eq.) were added. The reaction mixture was stirred in the ice-water bath for another hour and purified by reversed-phase column chromatography (MECN/H.sub.2O) to give compound SM20 (890 mg, 89.6% purity, 70.1% yield). MS: 1138.5[M+1].

Step 2

[0174] ##STR00069##

[0175] SM20 (200 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen, and phenylboronic acid (42.8 mg, 0.351 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 8 mL of dioxane was added, followed by addition of compound SM7 (146 mg, 1.05 mmol) and camphorsulfonic acid (204 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (123 mg, 97.6% purity, 54.6% yield). HRMS: 1223.6224[M.sup.+].

[0176] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.98 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.72-7.78 (m, 4H), 7.59 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 5.42 (d, J=2.0 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.87 (s, 1H), 4.74-4.78 (m, 1H), 4.56-4.61 (m, 3H), 4.16-4.40 (m, 6H), 3.81-4.11 (m, 6H), 3.46-3.62 (m, 3H), 3.14 (s, 9H), 2.64-2.68 (m, 2H), 2.42-2.53 (m, 2H), 2.26-2.29 (m, 1H), 2.04-2.12 (m, 2H), 1.91 (s, 3H), 1.62-1.68 (m, 2H), 1.35-1.40 (m, 6H), 1.26-1.27 (m, 6H), 1.07 (d, J=7.2 Hz, 3H), 0.91 (t, J=6.8 Hz, 3H).

Example 17

Step 1

[0177] ##STR00070##

[0178] Echinocandin B (162 mg, 0.195 mmol) and SM21 (70 mg, 1.0 eq.) were dissolved in DMF (1.4 mL), and the resulting solution was stirred in an ice-water bath. TBTU (84.6 mg, 1.5 eq.) and DIPEA (50 mg, 2.0 eq.) were added. The reaction mixture was stirred in the ice-water bath for another hour and purified by reversed-phase column chromatography (MECN/H.sub.2O) to give compound SM22 (94 mg, 73% purity, 32.9% yield). MS: 1139.5[M+1].

Step 2

[0179] ##STR00071##

[0180] SM22 (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL) under nitrogen, and phenylboronic acid (21.4 mg, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM7 (73.5 mg, 6.0 eq) and camphorsulfonic acid (102 mg, 5.0 eq). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (31 mg, 96.1% purity, 27.5% yield). HRMS: 1224.6163[M.sup.+].

[0181] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.96 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.65-7.72 (m, 4H), 7.48 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.71-6.78 (m, 4H), 5.43 (d, J=2.0 Hz, 1H), 5.04 (d, J=3.6 Hz, 1H), 4.91-4.93 (m, 1H), 4.73-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.16-4.40 (m, 6H), 3.81-4.10 (m, 6H), 3.46-3.62 (m, 3H), 3.11-3.14 (m, 11H), 2.42-2.53 (m, 2H), 2.26-2.31 (m, 1H), 2.02-2.12 (m, 2H), 1.91 (s, 3H), 1.62-1.67 (m, 2H), 1.38-1.44 (m, 4H), 1.26 (d, J=6.0 Hz, 6H), 1.08 (d, J=6.8 Hz, 3H), 0.96 (t, J=6.8 Hz, 3H).

Example 18

[0182] ##STR00072##

[0183] Anidulafungin (100 mg, 0.088 mmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen, and phenylboronic acid (21.4 mg, 0.175 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM23 (75.6 mg, 0.526 mmol) and p-toluenesulfonic acid (75.5 mg, 0.438 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (2 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (35 mg, 97.3% purity, 30.9% yield). HRMS: 1229.6268[M.sup.+].

[0184] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.97 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.69-7.76 (m, 4H), 7.61 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 5.04 (d, J=2.8 Hz, 1H), 4.88 (s, 1H), 4.74-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.15-4.40 (m, 6H), 3.81-4.11 (m, 6H), 3.46-3.50 (m, 1H), 3.14 (s, 9H), 2.42-2.54 (m, 2H), 2.25-2.32 (m, 1H), 2.01-2.11 (m, 2H), 1.91 (s, 3H), 1.77-1.84 (m, 2H), 1.38-1.53 (m, 4H), 1.27 (d, J=5.6 Hz, 6H), 1.07 (d, J=7.6 Hz, 3H), 0.97 (t, J=6.8 Hz, 3H).

Example 19

Step 1

[0185] ##STR00073##

[0186] Echinocandin B (161 mg, 0.193 mmol) and SM24 (80 mg, 1.0 eq.) were dissolved in DMF (3.2 mL), and the resulting solution was stirred in an ice-water bath. TBTU (93 mg, 1.5 eq.) and DIPEA (50 mg, 2.0 eq.) were added. The reaction mixture was stirred in the ice-water bath for another hour and purified by reversed-phase column chromatography (MECN/H.sub.2O) to give compound SM25 (165 mg, 95.9% purity, 71.6% yield). MS: 1194.5[M+1].

##STR00074##

[0187] SM25 (100 mg, 0.084 mmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen, and phenylboronic acid (20.4 mg, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM7 (70 mg, 6.0 eq) and camphorsulfonic acid (97.6 mg, 5.0 eq). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (33 mg, 97.2% purity, 29.4% yield). HRMS: 1279.5720[M.sup.+].

[0188] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.97 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.69-7.76 (m, 4H), 7.62 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.42 (d, J=2.0 Hz, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.88 (s, 1H), 4.73-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.16-4.40 (m, 6H), 3.81-4.11 (m, 8H), 3.46-3.62 (m, 3H), 3.15 (s, 9H), 2.42-2.53 (m, 2H), 2.23-2.32 (m, 3H), 2.04-2.11 (m, 2H), 1.93 (s, 3H), 1.87-1.90 (m, 2H), 1.76-1.82 (m, 2H), 1.26 (d, J=6.4 Hz, 6H), 1.08 (d, J=6.8 Hz, 3H).

Example 20

Step 1

[0189] ##STR00075##

[0190] SM-26 (590 mg, 1 eq.) was dissolved in 10 mL of acetonitrile, and methyl p-toluenesulfonate (1.2 g, 1.1 eq.) was added. The reaction mixture was heated at reflux with stirring for 4 h and concentrated, and the residue was slurried with acetone petroleum ether to give compound SM-27 as a white solid (1.6 g, 95% yield). MS: 117.1[M.sup.+].

Step 2

[0191] ##STR00076##

[0192] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in THF (5 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness. Compound SM-27 (151 mg, 6 eq.), p-toluenesulfonic acid (75.4 mg, 5 eq.) and anhydrous dioxane (5 mL) were added. The reaction mixture was stirred at room temperature under nitrogen for 5 h, quenched with aqueous sodium acetate solution, and concentrated to give a crude product, which was then purified by preparative HPLC to give a formate salt (60 mg, 97.8% purity, 55.6% yield). HRMS: 1237.6024[M.sup.+].

[0193] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.56 (s, 1H), 8.02 (d, 2H, J=10.8 Hz), 7.82 (d, 2H, J=8.4 Hz), 7.77 (m, 4H), 7.63 (d, 2H, J=8.4 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz), 6.78 (d, 2H, J=8.8 Hz), 5.42 (d, 1H, J=2.4 Hz), 5.06 (d, 1H, J=2.8 Hz), 4.92-4.88 (m, 2H), 4.81-4.72 (m, 2H), 4.63-4.58 (m, 3H), 4.42 (d, 1H, J=4.0 Hz), 4.29-3.81 (m, 14H), 3.52-3.38 (m, 1H), 3.19 (s, 6H), 2.57-2.43 (m, 4H), 2.34-2.27 (m, 1H), 2.13-2.04 (m, 2H), 1.87-1.80 (m, 2H), 1.55-1.40 (m, 4H), 1.29 (d, 6H, J=6.0 Hz), 1.08 (d, 3H, J=6.8 Hz), 0.99 (t, 3H, J=6.8 Hz).

Example 21

[0194] ##STR00077##

[0195] The trifluoroacetate salt of the compound of Example 6 (24 mg, 0.014 mmol) was dissolved in TFA (1 mL), and the resulting solution was stirred in an ice-water bath for 5 h and concentrated to dryness. The residue was purified by preparative HPLC to give a trifluoroacetate salt (7.2 mg, 97.8% purity, 30% yield). HRMS: 1513.7743[M+1].

Example 22

Step 1

[0196] ##STR00078##

[0197] Compound SM-29 (5.4 g, 52.3 mmol) was dissolved in acetone (54 mL), and methyl p-toluenesulfonate (10.23 g, 54 mmol) was added dropwise. The reaction mixture was heated at reflux for 2 h, and a white solid precipitated. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried in vacuo to give compound SM-30 (6.5 g, 98% purity, 42.9% yield). MS: 118.12[M.sup.+].

Step 2

[0198] ##STR00079##

[0199] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) under nitrogen, and the resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM-30 (152.3 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (53 mg, 96.1% purity, 46.5% yield). HRMS: 1239.6225[M.sup.+].

[0200] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.98 (d, J=8.4 Hz, 2H), 7.81 (d, J=7.2 Hz, 2H), 7.69-7.76 (m, 4H), 7.61 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.44 (s, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.85 (m, 1H), 4.74-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.39 (d, J=4.0 Hz, 1H), 4.32-4.34 (m, 2H), 4.24-4.27 (m, 2H), 4.16-4.20 (m, 1H), 3.81-4.07 (m, 8H), 3.74 (m, 1H), 3.46-3.50 (m, 1H), 3.11 (s, 9H), 2.42-2.53 (m, 2H), 2.28-2.36 (m, 1H), 2.02-2.11 (m, 2H), 1.90 (s, 3H), 1.78-1.85 (m, 2H), 1.43-1.52 (m, 7H), 1.25-1.27 (m, 6H), 1.08 (d, J=6.4 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 23

Step 1

[0201] ##STR00080##

[0202] Compound SM-31 (2.15 g, 20.84 mmol) was dissolved in acetone (21.5 mL), and methyl p-toluenesulfonate (4.08 g, 22 mmol) was added dropwise. The reaction mixture was heated at reflux for 2 h, and a white solid precipitated. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried in vacuo to give compound SM-32 (3.2 g, 98% purity, 53% yield). MS: 118.12[M.sup.+].

Step 2

[0203] ##STR00081##

[0204] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) under nitrogen, and the resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM-32 (152.3 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (39 mg, 99.6% purity, 34.2% yield). HRMS: 1239.6226[M.sup.+].

[0205] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.97 (d, J=8.4 Hz, 2H), 7.69-7.81 (m, 6H), 7.61 (d, J=8.4 Hz, 2H), 7.15 (d, J=Hz8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.34 (d, J=2.8 Hz, 1H), 5.02 (d, J=2.4 Hz, 1H), 4.85 (m, 1H), 4.73-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.39 (d, J=4.4 Hz, 1H), 4.32-4.34 (m, 2H), 4.24-4.28 (m, 2H), 4.17-4.21 (m, 1H), 3.79-4.10 (m, 8H), 3.66 (m, 1H), 3.46-3.50 (m, 1H), 3.12 (s, 9H), 2.42-2.53 (m, 2H), 2.25-2.31 (m, 1H), 2.03-2.11 (m, 2H), 1.89 (s, 3H), 1.78-1.84 (m, 2H), 1.37-1.53 (m, 7H), 1.25-1.28 (m, 6H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 24

Step 1

[0206] ##STR00082##

[0207] Compound SM-33 (2.2 g, 21.3 mmol) was dissolved in acetone (22 mL), and methyl p-toluenesulfonate (4.17 g, 22.4 mmol) was added dropwise. The reaction mixture was heated at reflux for 2 h, and a white solid precipitated. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried in vacuo to give compound SM-34 (2.05 g, 98% purity, 33% yield). MS: 118.12[M.sup.+].

Step 2

[0208] ##STR00083##

[0209] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) under nitrogen, and the resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM-34 (152.3 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative chromatography to give an acetate salt (29 mg, 97.5% purity, 25.4% yield). HRMS: 1239.6223[M.sup.+].

[0210] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.96 (d, J=7.2 Hz, 2H), 7.69-7.80 (m, 6H), 7.61 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.01 (d, J=7.6 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.50 (s, 1H), 5.04 (d, J=3.2 Hz, 1H), 4.85 (m, 1H), 4.78-4.79 (m, 1H), 4.55-4.60 (m, 3H), 4.30-4.36 (m, 4H), 4.22-4.27 (m, 2H), 4.16-4.20 (m, 1H), 3.80-4.10 (m, 6H), 3.52-3.55 (m, 1H), 3.34-3.43 (m, 2H), 3.18 (s, 9H), 2.42-2.51 (m, 2H), 2.24-2.30 (m, 1H), 2.05-2.13 (m, 2H), 1.90 (s, 3H), 1.78-1.84 (m, 2H), 1.40-1.51 (m, 4H), 1.27 (t, J=7.2 Hz, 6H), 1.20 (d, J=5.2 Hz, 3H), 1.07 (d, J=7.2 Hz, 3H), 0.97 (t, J=6.8 Hz, 3H).

Example 25

Step 1

[0211] ##STR00084##

[0212] SM-35 (505 mg, 1 eq.) was dissolved in 5 mL of acetone, and methyl p-toluenesulfonate (1.02 g, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 2 h and filtered, and the filter cake was rinsed with acetone to give compound SM-36 as a white solid (1.22 g, 85% yield). MS: 116.2[M.sup.+].

Step 2

[0213] ##STR00085##

[0214] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) under nitrogen, and the resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM-36 (151.2 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated to give a crude product, which was then purified by preparative HPLC to give an acetate salt (50 mg, 96.2% purity, 44% yield). HRMS: 1238.4225 [M.sup.+].

[0215] .sup.1H NMR (400 MHz, METHANOL-d.sub.4): δ 8.02 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.0 Hz), 7.78-7.71 (m, 4H), 7.63 (d, 2H, J=6.8 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz), 6.81 (d, 2H, J=7.2 Hz), 5.52 (d, 1H, J=1.6 Hz), 5.08 (d, 1H, J=3.2 Hz), 4.84-4.76 (m, 1H), 4.63-4.60 (m, 6H), 4.42 (d, 1H, J=4.4 Hz), 4.36-4.33 (m, 2H), 4.27-4.23 (m, 2H), 4.18-4.15 (m, 1H), 4.06-4.00 (m, 4H), 3.96-3.90 (m, 2H), 3.86-3.83 (m, 1H), 3.74-3.46 (m, 4H), 3.18 (s, 3H), 3.11 (s, 3H), 2.60-2.30 (m, 4H), 2.10-2.04 (m, 2H), 1.91 (s, 3H), 1.85-1.80 (m, 2H), 1.53-1.40 (m, 4H), 1.29-1.26 (m, 6H), 1.10 (d, 3H, J=7.2 Hz), 0.99 (t, 3H, J=7.2 Hz).

Example 26

Step 1

[0216] ##STR00086##

[0217] SM-37 (505 mg, 1 eq.) was dissolved in 5 mL of acetone, and methyl p-toluenesulfonate (1.02 g, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 2 h and filtered, and the filter cake was rinsed with acetone to give compound SM-38 as a white solid (1.29 g, 90% yield). MS: 116.2[M.sup.+].

Step 2

[0218] ##STR00087##

[0219] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) under nitrogen, and the resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to dryness to remove the solvent. 4 mL of dioxane was added, followed by addition of compound SM-38 (151.2 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N aqueous sodium acetate solution (1 mL), and concentrated to give a crude product, which was then purified by preparative HPLC to give an acetate salt (40 mg, 96.2% purity, 34% yield). HRMS: 1238.4225[M.sup.+].

[0220] .sup.1H NMR (400 MHz, METHANOL-d.sub.4): δ 8.00 (d, 2H, J=8.4 Hz), 7.82 (d, 2H, J=8.4 Hz), 7.78-7.71 (m, 4H), 7.63 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz), 6.78 (d, 2H, J=8.4 Hz), 5.44 (d, 1H, J=2.4 Hz), 5.06 (d, 1H, J=2.8 Hz), 4.83-4.77 (m, 1H), 4.63-4.60 (m, 6H), 4.42 (d, 1H, J=4.0 Hz), 4.36-4.33 (m, 2H), 4.27-4.25 (m, 2H), 4.20-4.18 (m, 1H), 4.06-4.00 (m, 4H), 3.94-3.90 (m, 2H), 3.86-3.78 (m, 1H), 3.71-3.46 (m, 4H), 3.25 (s, 3H), 3.19 (s, 3H), 2.58-2.41 (m, 4H), 2.32-2.28 (m, 2H), 1.92 (s, 3H), 1.86-1.80 (m, 2H), 1.53-1.40 (m, 4H), 1.32-1.27 (m, 6H), 1.10 (d, 3H, J=7.2 Hz), 0.99 (t, 3H, J=7.2 Hz).

[0221] High Resolution Mass Spectrometry Method:

TABLE-US-00003 Instrument Thermo-UItiMate 3000 Q Exactive Chromatography Waters BEH C18 1.7 U 2.1 × 50 mm column Mobile phase A: 0.1% FA in water B: 0.1% FA in acetonitrile Gradient Time (min) B(%) 0 10 1 10 5 90 7 90 9 10 Column 40° C. temperature Flowrate 0.3 mL/min Conditions for Polarity: Positive polarity mass Scanning range: 100-1500 m/z spectrometry 133-2000 m/z

Test Example 1: Test Method for Antifungal Activity

[0222] After a test compound was serially diluted, an MIC (minimum inhibitory concentration) assay was performed on the standard Candida strain and an MEC (minimum effective concentration) assay on the standard Aspergillus strain. The MIC assay was performed according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI M27-A3) and the MEC assay according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI M38-A2).

[0223] Preparation of Fungal Inoculation Liquid

[0224] Candida:

[0225] The frozen strain was passaged at least twice, and a single colony was picked and resuspended in normal saline or sterile water in a tube. The suspension was vortexed and adjusted to 0.5 McF (1×10.sup.6 to 5×10.sup.6 CFU/mL) using a spectrophotometer at wavelength 530 nm. The suspension was 50-fold diluted with normal saline and then 20-fold diluted with 1×RPMI 1640 broth (1×10.sup.3 to 5×10.sup.3 CFU/mL). 10 μL of the suspension was applied to an SDA plate for colony counting, with a range from about 10 to 50 single colonies.

[0226] After complete dissolution was achieved at room temperature in the prepared susceptibility testing plate, the bacterial suspension was added to a 96-well plate at 100 μL per well using a multi-channel pipette. At this time, the bacterium concentration in each well should be 0.5×10.sup.3 to 2.5×10.sup.3 CFU/mL.

[0227] Aspergillus (Operation in Class II Biosafety Cabinet):

[0228] Aspergillus was passaged onto an SDA plate and cultured at 35° C. for 48 h to 7 d to induce sporulation. Colonies on the plate were covered with about 1 mL of 0.85% normal saline or sterile water (polysorbate 20 was added at a final concentration of 0.1%-0.01%). The medium was gently wiped on its surface with a tip or a sterile cotton swab (be careful not to break the medium), and the spore hyphae suspension was transferred to a sterile tube and let stand for 3-5 min so that the heavy particles settled. The homogeneous upper layer of the suspension was transferred to a new sterile tube, which was then sealed and vortexed for 15 s (be careful as the suspension may produce an aerosol when the cover is removed). The concentration of the suspension was adjusted until an OD value of 0.09-0.13 was achieved using a spectrophotometer at 530 nm. The suspension was 50-fold diluted with 1×RPMI 1640. 100 μL of sample was added to each well of the 96-well plate within 2 h after dilution (the final spore concentration in the susceptibility testing plate was at 0.4×10.sup.4 to 5×10.sup.4 CFU/mL). Colony counting: The suspension diluted with RPMI 1640 was further diluted 10-fold, and 10 μL of the dilution was applied to an SDA plate, cultured at 28° C., and observed every day; colonies were immediately counted upon being visible to the naked eye.

[0229] Culture

[0230] The assay plate for yeast-type fungi was incubated in an incubator at 35° C. with 85% humidity for 24 h, and then the MIC value was read. For echinocandin drugs, Aspergillus was incubated at 28° C. for 21-26 h, and then the MEC results were read.

[0231] MIC or MEC Interpretation

[0232] Yeast-type fungi: A disposable sealing film was applied to the 96-well plate, and the mixture was well mixed by shaking. Observation was performed through a plate reader with the naked eye. Comparisons were made to the growth control, and the minimum compound concentration corresponding to >50% growth inhibition was defined as MIC. Pictures were taken and saved using an automatic plate reader.

[0233] Aspergillus: For echinocandin drugs, comparisons were made to the growth control under a plate reader, and the minimum drug concentration that could cause the hyphae to form small, round, compact hyphal particles was defined as MEC. For accurate determination of MEC values, the plate must not be vortexed before reading.

TABLE-US-00004 TABLE 1 Bacteriostatic activity assay results for compounds (first batch) Candida Candida Candida Candida Meyerozyma Candida Aspergillus Initial assay albicans glabrata parapsilosis krusei guilliermondii tropicalis flavus concentration ATCC ATCC ATCC ATCC ATCC ATCC ATCC Compound (μg/mL) 90029 15126 22019 6258 6260 750 28539 Anidulafungin 16 0.016 0.125 0.5 0.063 1 0.016 0.031 Caspofungin 16 0.063 0.25 1 1 1 0.016 0.031 acetate Rezafungin 16 0.125 0.125 2 0.25 2 0.016 0.031 acetate Final product 16 0.125 0.125 2 0.125 4 0.016 0.031 of Example 5 Final product 16 0.25 0.5 2 0.5 4 0.031 0.031 of Example 10 Final product 16 0.031 0.031 1 0.031 2 0.016 0.031 of Example 1 Final product 16 0.125 0.125 1 0.125 2 0.016 0.031 of Example 2 Final product 16 0.031 0.25 2 0.25 2 0.016 0.031 of Example 3 Final product 16 2 4 4 4 2 4 16 of Example 7 Final product 16 0.125 0.5 4 0.5 2 0.031 0.031 of Example 11 Final product 16 0.031 / 1 0.047 1 0.016 0.031 of Example 13 Note: 1. Candida parapsilosis ATCC 22019 and Candida krusei ATCC6258 were quality control strains. According to CLSI-M60, the 24 h MIC of ANI for ATCC 22019 is (0.25-2) μg/mL, and that of CAS is (0.25-1) μg/mL; the 24 h MIC of ANI for ATCC6258 is (0.03-0.12) μg/mL, and that of CAS is (0.12-1) μg/mL.

TABLE-US-00005 TABLE 2 Bacteriostatic activity assay results for compounds (second batch) Candida Candida albicans + Candida Candida tropicalis 50% albicans albicans (amphotericin- Candida human Candida Candida (azole drug- (azole drug- resistant Initial assay albicans serum albicans glabrata resistant resistant strain) concentration ATCC ATCC ATCC ATCC strain) strain) ATCC Compound (μg/mL) 90028 90028 44858 36583 R357 R358 200956 Rezafungin 16 0.25 0.25 0.25 0.25 0.25 0.25 0.25 acetate Final 16 0.25 0.25 0.25 0.5 0.5 0.25 0.25 product of Example 13 Final 16 0.25 0.5 0.25 0.25 0.25 0.25 0.25 product of Example 16 Final 16 0.25 0.25 0.25 0.5 0.5 0.25 0.25 product of Example 17 Final 16 0.25 0.25 0.25 0.5 0.5 0.25 0.25 product of Example 22 Final 16 0.25 0.25 0.25 0.25 0.25 0.125 0.25 product of Example 23 Final 16 0.25 0.25 0.125 0.25 0.5 0.0625 0.125 product of Example 24 Final 16 0.25 0.125 0.125 0.25 0.25 0.25 0.25 product of Example 25 Final 16 0.25 0.25 0.25 0.25 0.5 0.25 0.25 product of Example 26

[0234] The assay data show that a significant number of the example compounds of the present disclosure have excellent antifungal activity, and some of the compounds have more excellent antifungal activity compared to the positive drugs.

Test Example 2: Plasma Histamine Concentrations of Compounds and Pharmacokinetic Study

[0235] Test Method:

[0236] 12 SD rats were divided into 2 groups of 6 (half are male and half female). The rats were observed at least once a day. The body weights were measured once before administration. Administration was performed by single intravenous injection for 20 min per animal. PK measurement was performed once before administration and 5 min, 30 min, 1 h, 4 h, 8 h, 24 h, 48 h, 72 h and 96 h after administration. A histamine assay was performed once before administration and 30 min, 4 h, 8 h and 24 h after administration.

[0237] The dose design is shown in the table below:

TABLE-US-00006 Dose for Concentration for Volume for Number of Route of administration administration administration animals Group administration (mg/kg) (mg/mL) (mL/kg) Male Female 1 (Example 13 Intravenous 10 2 5 3 3 final product injection group) 2 (Rezafungin Intravenous 10 2 5 3 3 acetate group) injection

[0238] The results are mainly as follows:

[0239] General State Observation

[0240] A transient slight decrease in activity occurred in 2 females in group 2 (⅔ of the rats) on the day of administration.

[0241] Apart from that, the SD rats in each group were in good general conditions, showed normal spontaneous locomotor activity, had clean skin and hair, and showed normal defecation and urination, and no other abnormality was observed.

[0242] Histamine Assay

[0243] A transient increase in the histamine level was caused in both group 1 and group 2 by intravenous administration. The plasma histamine concentration peaked at 30 min, showed a tendency to recover at 4 h, and substantially returned to the normal level at 8-24 h, as shown in FIG. 1. 30 min after administration, the mean histamine concentration in the plasma of the rats in group 2 was 1333.0 ng/mL, which is 4.5 times significantly (p=0.046) higher than that in group 1 (296.6 ng/mL), as shown in FIG. 2. The ability of the group 1 compound to induce increases in the histamine level in rats is significantly lower than that of the group 2 compound when they are administered at the same dose.

[0244] Pharmacokinetics

[0245] The pharmacokinetic parameters in animals after administration to group 1 or group 2 are shown in the table below:

TABLE-US-00007 T.sub.1/2 C.sub.max AUC.sub.0-96 AUC.sub.0-inf CL MRT.sub.IV Vd.sub.SS Group Sex h μg/mL hr*μg/mL hr*μg/mL mL/min/kg hr L/kg 1 Male 27.7 8.0 173.9 191.2 0.9 37.1 1.9 Female 25.5 9.3 179.6 195.0 0.9 34.6 1.8 2 Male 28.0 7.8 190.5 212.1 0.8 38.4 1.8 Female 27.9 8.6 205.8 227.2 0.8 39.1 1.8

[0246] The assay data show that after administration at the same dose by single intravenous injection, group 1 and group 2 are close to each other in the plasma drug exposure levels (C.sub.max and AUC) and shows no significant sex-related difference, and the other pharmacokinetic parameters each have substantially equivalent values for both groups. In conclusion, after administration at the same dose (10 mg/kg) by single intravenous injection, the plasma drug exposure levels of the final product of Example 13 and rezafungin acetate are close, while the ability of the final product of Example 13 to induce increases in the histamine level in rats is significantly lower than that of rezafungin acetate, suggesting that the final product of Example 13, when applied clinically, will not easily cause allergies compared to rezafungin.