TRIAZOLE ANTIMICROBIAL DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE THEREOF

Abstract

The present disclosure provides a triazole antibacterial derivative and a pharmaceutical composition thereof and a use thereof and in particular relates to a compound represented by the following formula (I), and a racemate, a stereoisomer, a tautomer, an oxynitride or a pharmaceutically acceptable salt thereof:

##STR00001##

The compound of the present disclosure has a desirable water solubility and can be formulated into an injection for use without adding a cosolvent having a potential safety risk (such as hydroxypropyl--cyclodextrin, sulfobutylether--cyclodextrin, and the like), facilitating drug administration for patients, and greatly improving clinical safety. The drug can be used even by patients with moderate or severe renal impairment, thereby expanding the application scope of the drug.

Claims

1. A compound represented by the formula (I), a racemate, a stereoisomer, a tautomer, an oxynitride or a pharmaceutically acceptable salt thereof: ##STR00044## wherein, R.sub.1 is selected from the group consisting of ##STR00045## X.sub.1 is selected from a pharmaceutically acceptable anion; X.sub.2, X.sub.3, X.sub.4 are independently selected from the group consisting of F, Cl, Br, I; R.sub.2, R.sub.4 may be the same or different, independently selected from H, or C.sub.1-40 alkyl which is unsubstituted or optionally substituted by one or more R.sub.a; R.sub.3 is selected from C.sub.1-40 alkyl which is unsubstituted or optionally substituted by one or more R.sub.b; R.sub.5, R.sub.6 may be the same or different, independently selected from H, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.m: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, C(O)R.sub.f; Ar is selected from the following groups which are unsubstituted or optionally substituted by one or more R.sub.c: C.sub.6-20 aryl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl comprises 1-5 heteroatoms independently selected from N, O and S; R.sub.7 is selected from the following groups which are unsubstituted or optionally substituted by one or more R.sub.c: C.sub.1-40 alkyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, Y.sub.2P(O)(OM.sub.1)(OM.sub.2), C(O)R.sub.f or (CH.sub.2CH.sub.2O).sub.zR.sub.b; R.sub.8 is selected from H, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.b: C.sub.1-40 alkyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, NR.sub.dR.sub.e, CONR.sub.dR.sub.e, C(O)Y.sub.2R.sub.f, Y.sub.2C(O)R.sub.f, Y.sub.2P(O)(OM.sub.1)(OM.sub.2), Y.sub.2S(O).sub.2OM.sub.3; Y.sub.1, Y.sub.2 may be the same or different, independently selected from the group consisting of a chemical bond, O, S, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.a: NH, C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, (CH.sub.2CH.sub.2O).sub.j; each R.sub.a may be the same or different, independently selected from H, C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, F, Cl, Br, I, OH, SH, CN, O, NR.sub.dR.sub.e, C(O)Y.sub.2R.sub.f, Y.sub.2C(O)R.sub.f, CONR.sub.dR.sub.e, Y.sub.2P(O)(OM.sub.1)(OM.sub.2) or Y.sub.2S(O).sub.2OM.sub.3; each R.sub.b may be the same or different, independently selected from H, F, Cl, Br, I, OH, SH, CN, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.a: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, C.sub.3-20 cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, [(CH.sub.2).sub.nO].sub.m, NR.sub.dR.sub.e, CONR.sub.dR.sub.e, C(O)Y.sub.2R.sub.f, Y.sub.2C(O)R.sub.f, Y.sub.2P(O)(OM.sub.1)(OM.sub.2), Y.sub.2S(O).sub.2OM.sub.3; each R.sub.c may be the same or different, independently selected from F, Cl, Br, I, OH, SH, CN, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.a: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, C.sub.3-20 cycloalkyloxy, 3-20 membered heterocyclyloxy, C.sub.6-20 aryloxy, 5-20 membered heteroaryloxy, NR.sub.dR.sub.e, CONR.sub.dR.sub.e, C(O)Y.sub.2R.sub.f, Y.sub.2C(O)R.sub.f, Y.sub.2P(O)(OM.sub.1)(OM.sub.2), Y.sub.2S(O).sub.2OM.sub.3; each R.sub.d, R.sub.e may be the same or different, independently selected from H, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.m: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, CONR.sub.fR.sub.g, C(O)Y.sub.2R.sub.f, Y.sub.2C(O)R.sub.f, Y.sub.2P(O)(OM.sub.1)(OM.sub.2), Y.sub.2S(O).sub.2OM.sub.3; each R.sub.f, R.sub.g may be the same or different, independently selected from H, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.m: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, COOH, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl; Each R.sub.m may be the same or different, independently selected from H, F, Cl, Br, I, OH, SH, CN, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.a: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, NR.sub.dR.sub.e, CONR.sub.dR.sub.e, C(O)Y.sub.2R.sub.f, Y.sub.2C(O)R.sub.f, Y.sub.2P(O)(OM.sub.1)(OM.sub.2), Y.sub.2S(O).sub.2OM.sub.3; M.sub.1, M.sub.2, M.sub.3 may be the same or different, independently selected from H, or C.sub.1-40 alkyl which is unsubstituted or optionally substituted by one or more R.sub.b; n, m, j, z may be the same or different, independently selected from an integer of 1 or more, for example, an integer of 1 to 20, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

2. The compound, racemate, stereoisomer, tautomer, oxynitride or pharmaceutically acceptable salt thereof according to claim 1, wherein: X.sub.1 may represent an anion formed by ionization of an inorganic acid or an organic acid; for example, X.sub.1 may represent a monovalent anion formed by ionization of inorganic or organic acids; alternatively, when a plurality of cations are present in the structure of the compound of formula (I), X.sub.1 may represent a plurality of monovalent anions formed by ionization of inorganic or organic acids, preferably 2 or 3 monovalent anions formed by ionization of inorganic or organic acids; alternatively, when a plurality of cations in the structure of the compound of the formula (I) share a polyvalent anion, X.sub.1 may also represent a part of the polyvalent anion, for example, 1/2, 1/3, 2/3 of the polyvalent anion; alternatively, X.sub.1 may also represent a mixture of the above monovalent anions, or a mixture of polyvalent anions, or a mixture of monovalent anions and polyvalent anions; the inorganic acid is, for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; the organic acid is, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, lauryl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, algae acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerol phosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid; for example, X.sub.1 may represent one or more selected from the group consisting of Cl.sup., Br.sup., I.sup., HSO.sub.4.sup., NO.sub.3.sup., 1/2SO.sub.4.sup.2, SO.sub.4.sup.2, 3/2SO.sub.4.sup.2, H.sub.2PO.sub.4.sup., HPO.sub.4.sup.2, 1/2HPO.sub.4.sup.2, 3/2HPO.sub.4.sup.2, 1/3PO.sub.4.sup.3, 2/3PO.sub.4.sup.3, PO.sub.4.sup.3; R.sub.2 may be selected from H, or C.sub.1-40 alkyl, such as methyl, which is unsubstituted or optionally substituted by one or more R.sub.a; R.sub.3 may be selected from C.sub.1-40 alkyl unsubstituted or optionally substituted by one or more R.sub.b; for example, R.sub.3 may be C.sub.1-40 alkyl substituted by 1, 2 or 3 groups which are independently selected from C.sub.1-6 alkyl, NH.sub.2, COOH, OH, CONH.sub.2, N(CH.sub.3).sub.2, NH(CH.sub.3), NHCONH.sub.2, NH(CH.sub.2).sub.kCH.sub.3 or hydroxyphenyl (such as o-hydroxyphenyl, m-hydroxyphenyl or p-hydroxyphenyl); for example, R.sub.3 may be selected from (CH.sub.2).sub.kNH.sub.2, CH(NH.sub.2)(CH.sub.2).sub.kNH.sub.2, CH(NH.sub.2)(CH.sub.2).sub.kCOOH, (CH.sub.2).sub.kCH(NH.sub.2)COOH, (CH.sub.2).sub.kCOOH, CH(NH.sub.2)(CH.sub.2).sub.kNHCONH.sub.2, CH(NH.sub.2)(CH.sub.2).sub.kCONH.sub.2, CH(NH.sub.2)(CH.sub.2).sub.kOH, CH(NH.sub.2)(CH.sub.2).sub.kCH(OH)CH.sub.3, CH(NH.sub.2)(CH.sub.2).sub.k(C.sub.6H.sub.4)OH, CH(NH.sub.2)(CH.sub.2).sub.kNH(CH.sub.2).sub.pCH.sub.3, (CH.sub.2).sub.kNH(CH.sub.2).sub.pCH.sub.3, (CH.sub.2).sub.kN(CH.sub.3).sub.2; Ar may be selected from the following group optionally substituted by one or more R.sub.c: C.sub.6-10 aryl, 5-10 membered heteroaryl; for example, Ar may be selected from pyridyl, phenyl, and specifically may be ##STR00046## wherein the 2-position C atom of the pyridyl is bonded to the N atom, and the 3-position C atom of the pyridyl is bonded to the methylene group; R.sub.7 may be selected from the following group optionally substituted by one or more R.sub.c: C.sub.1-40 alkyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, OP(O)(OM.sub.1)(OM.sub.2), SP(O)(OM.sub.1)(OM.sub.2), P(O)(OM.sub.1)(OM.sub.2), C(O)R.sub.f or (CH.sub.2CH.sub.2O).sub.zR.sub.b; for example, R.sub.7 may be selected from the following groups: C.sub.1-40 alkyl, 3-20 membered heterocyclyl, C.sub.3-20 cycloalkyl, (CH.sub.2CH.sub.2O).sub.zR.sub.b, wherein the groups are optionally substituted by 1, 2 or 3 groups independently selected from OP(O)(OH).sub.2, COOH, NH.sub.2, SH, OH, NHCH.sub.3, OC(O)CH.sub.2NHCH.sub.3, CH.sub.2OH; for example, R.sub.7 may be (CH.sub.2).sub.kOP(O)(OH).sub.2, (CH.sub.2).sub.kCOOH, (CH.sub.2).sub.kCH(NH.sub.2)COOH, [(CH.sub.2).sub.zO]k-OP(O)(OH).sub.2, (CH.sub.2).sub.kSH, (CH.sub.2).sub.kCH[NH(CH.sub.3)]COOH, (CH.sub.2).sub.kOH, (CH.sub.2).sub.kNH.sub.2 or ##STR00047## R.sub.8 may be selected from H or the following groups optionally substituted by one or more R.sub.b: C.sub.1-40 alkyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, 5-20 membered heteroaryl, NR.sub.dR.sub.e, CONR.sub.dR.sub.e, C(O)OR.sub.f, OC(O)R.sub.f, C(O)R.sub.f, OP(O)(OM.sub.1)(OM.sub.2), SP(O)(OM.sub.1)(OM.sub.2), P(O)(OM.sub.1)(OM.sub.2), OS(O).sub.2OM.sub.3; for example, R.sub.8 may be selected from the following groups: C.sub.1-40 alkyl, 3-20 membered heterocyclyl or C.sub.3-20 cycloalkyl, wherein the groups are optionally substituted by 1, 2 or 3 groups independently selected from OP(O)(OH).sub.2, COOH, NH.sub.2, SH, OH, NHCH.sub.3, OC(O)CH.sub.2NHCH.sub.3, CH.sub.2OH; for example, R.sub.8 may be (CH.sub.2).sub.kOP(O)(OH)(OH) or (CH.sub.2).sub.kCOOH; Y.sub.1, Y.sub.2 may be the same or different, independently selected from the group consisting of a chemical bond, O, S, or the following groups which are unsubstituted or optionally substituted by one or more R.sub.a: CH.sub.2, NH; k, p may be the same or different, independently selected from an integer of 0 to 16, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sub.a, R.sub.b, R.sub.c, R.sub.d and z independently have the definitions described above.

3. The compound, racemate, stereoisomer, tautomer, oxynitride or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt comprises but not limited to: an alkali metal salt, alkaline earth metal salt, ammonium salt of the compound of formula (I), or a salt formed by the compound of formula (I) with an organic base which provides a physiologically acceptable cation, for example, a salt formed by the compound of formula (I) with sodium ion, potassium ion, calcium ion, magnesium Ionic, N-methylglucamine, dimethyl glucosamine, ethyl glucosamine, lysine, dicyclohexylamine, 1,6-hexamethylenediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol; as an example, the pharmaceutically acceptable salt comprises a salt formed by COOH group with sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethyl glucosamine, ethyl glucosamine, lysine, dicyclohexylamine, 1,6-hexamethylenediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol; when 1, 2 or 3 of M.sub.1, M.sub.2 and M.sub.3 are H, the pharmaceutically acceptable salts comprises, for example, salts formed by OP(O)(OM.sub.1)(OM.sub.2), P(O)(OM.sub.1)(OM.sub.2), OS(O).sub.2OM.sub.3 or S(O).sub.2OM.sub.3 with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methyl glucosamine, dimethyl glucosamine, ethyl glucosamine, lysine, dicyclohexylamine, 1,6-hexamethylenediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol or 1-amino-2,3,4-butanetriol; alternatively, the compound of formula (I) is formed to an acid addition salt with an acid selected from: inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, lauryl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid; for example, the pharmaceutically acid addition salt of the compound of formula (I) has the structure as shown by the following formula (IA): ##STR00048## wherein A represents an acid which forms an acid addition salt with the compound of formula (I); a represents the number of molecules of A; for example, a may be selected from an integer of 1 or more, such as 1, 2, 3, 4 or 5; c represents the number of molecules of the compound in the square bracket, that is, the compound of formula (I); for example, c may be selected from an integer of 1 or more, such as 1, 2, 3, 4 or 5; provided that the product of the number of basic sites (such as N atoms) capable of being protonated in the compound of formula (I) and c=the product of the number of protons that A can ionize and a; preferably, wherein X.sub.1 may be the same as or different from the anion formed by ionization of A; A is selected from the group consisting of hydrochloric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, phosphoric acid, fumaric acid, citric acid, tartaric acid or lactic acid; a is preferably 1, 2 or 3; c is preferably 1, 2 or 3.

4. The compound, racemate, stereoisomer, tautomer, oxynitride or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) may has a structure represented by the following formula (I): ##STR00049## wherein each group has the definition described above.

5. The compound, racemate, stereoisomer, tautomer thereof, oxynitride or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is selected from the following compounds: ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##

6. A preparation method of the compound according to claim 1, comprising preparing the compound of formula (I) by using a compound represented by the following formula (II) as a starting material: ##STR00064## wherein, X.sub.2, X.sub.3 and X.sub.4 have the definitions described above; for example, the compound represented by the following formula (II) can be used as a starting material to prepare the compound represented by the formula (I): ##STR00065## wherein, X.sub.2, X.sub.3 and X.sub.4 have the definitions described above; preferably, the preparation method may comprise, for example, reacting the compound of formula (II) with a compound of R.sub.z-L, wherein R.sub.z is selected from R.sub.1 or R.sub.1 which may be derivatized to R.sub.1 having the definition described above, and L is a leaving group such as the group X.sub.1 which can be converted to X.sub.1 in formula (I); for example, X.sub.1 may be selected from the group consisting of Cl, Br or I; for example, X.sub.1 may be converted from L in R.sub.z-L, or may be converted from an anion of another compound used in the reaction, such as an anion of a catalyst, or may be obtained by an optional salt-transforming step; the preparation process can be carried out in the presence of a catalyst; the preparation method can be carried out in the absence of a solvent or in the presence of a solvent; if necessary, one or more of the functional groups of the compound of formula (II) and/or compound of Rz-L may be protected with a protecting group (PG) and then the reaction is carried out; if necessary, after completion of the reaction, the protecting group can be removed for subsequent reaction or to obtain the target compound; when R.sub.z is selected from R.sub.1, R.sub.1 may represent a group which can be further reacted to obtain R.sub.1; preferably, the compound represented by the formula (II) or (II) as the substrate in the reaction does not undergo a configuration conversion.

7. The preparation method according to claim 6, comprising but not limited to, one or more of the following methods: 1) a hydroxymethyl-substituted arylamine or heteroarylamine is reacted with a desired acylating reagent under basic conditions to form the corresponding amide A-1, which is reacted with a carboxylic acid optionally containing a protecting group in the presence of a condensing agent to give compound A-2, and then the compound A-2 and the compound of formula (II) are reacted to obtain compound A-3, which is optionally deprotected to give compound A-4, and the compound A-4 may optionally be further subjected to a salt-forming and/or salt-transforming step: ##STR00066## wherein, L.sub.1 is a leaving group, such as a halogen, and may be selected from the group consisting of F, Cl, Br, and I; X.sub.1 is independently selected from a pharmaceutically acceptable anion; for example, X.sub.1 may be converted from L of the compound A-2 or an anion of the catalyst, or may be obtained by an optional salt-transforming step; R.sub.3p represents R.sub.3 or R.sub.3PG; each of the other groups independently has the definition described above; represents a step optionally to be or not to be carried out; 2) a substituted alcohol, substituted amine or substituted thiol optionally containing a protecting group is reacted with an acylating reagent under basic conditions to form compound B-1, which is reacted with the compound of formula (II) to obtain compound B-2, and then the compound B-2 is optionally deprotected to give compound B-3, which may optionally be further subjected to a salt-forming and/or salt-transforming step: ##STR00067## wherein R.sub.7p represents R.sub.7 or R.sub.7PG; X.sub.1 is independently selected from a pharmaceutically acceptable anion; for example, X.sub.1 may be converted from L of the compound B-1 or an anion of the catalyst, or may be obtained by an optional salt-transforming step; each of the other groups independently has the definition described above; represents a step optionally to be or not to be carried out; 3) a diol as a starting material is reacted with phosphorus oxychloride di-tert-butyl ester under basic conditions to form compound C-1, which is then acylated to obtain compound C-2, and the compound C-2 is reacted with the compound of formula (II) to give compound C-3; and the compound C-3 is deprotected to give compound C-4, which may optionally be further subjected to a salt-forming and/or salt-transforming step: ##STR00068## wherein R.sub.9 is (CH.sub.2).sub.h, and h is an integer of 1 to 12, for example, 1, 2, 3, 4, 5 or 6; or R.sub.9 is [(CH.sub.2).sub.2O].sub.x(CH.sub.2).sub.y, and x, y are independently selected from an integer of 1 to 12, for example, x, y are independently selected from 1, 2 or 3; X.sub.1 is independently selected from a pharmaceutically acceptable anion; for example, X.sub.1 may be converted from L of the compound C-2 or an anion of the catalyst, or may be obtained by an optional salt-transforming step; each of the other groups independently has the definition described above; represents a step optionally to be or not to be carried out; 4) the starting material D-1 is reacted with an iodoalkane to form compound D-2, and the compound D-2 is reacted with the compound represented by formula (II) to obtain compound D-3, which is deprotected under acidic conditions to give compound D-4, and the compound D-4 may optionally be further subjected to a salt-forming and/or salt-transforming step: ##STR00069## wherein X.sub.1 is independently selected from a pharmaceutically acceptable anion; for example, X.sub.1 may be converted from L of the compound D-2 or an anion of the catalyst, or may be obtained by an optional salt-transforming step; each of the other groups independently has the definition described above; represents a step optionally to be or not to be carried out; 5) the compound represented by the formula (II) is reacted with a chloroacetic acid ester reagent to obtain compound E-1, which is further subjected to a hydrolysis reaction to obtain compound E-2, and the compound E-2 may optionally be further subjected to a salt-forming and/or salt-transforming step: ##STR00070## wherein, each of the other groups independently has the definition described above; R.sub.10 is preferably methyl, ethyl, isopropyl or t-butyl; represents a step optionally to be or not to be carried out.

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), the racemate, stereoisomer, tautomer, oxynitride or pharmaceutically acceptable salt thereof according to claim 1.

9. The pharmaceutical composition according to claim 8, wherein it may also optionally comprise a pharmaceutically acceptable auxiliary material, such as a carrier, excipient; the auxiliary material may be one or more selected from the group consisting of a disintegrant, a glidant, a lubricant, a diluent or a filler, a binder and a colorant.

10. A method of preventing or treating diseases, such as diseases caused by fungi (including, but not limited to, Candida albicans, Aspergillus fumigatus), comprising the step of administering the compound of formula (I), the racemate, stereoisomer, tautomer, oxynitride and pharmaceutically acceptable salt thereof according to claim 1 to a subject.

Description

DETAILED DESCRIPTION

[0140] The compounds of the general formula of the present disclosure, as well as the preparation methods and applications thereof, will be further described in detail below in conjunction with specific examples. The following examples are merely illustrative of the present disclosure and are not to be construed as limiting the scope of the present disclosure. The technology that is implemented based on the above-described contents of the present disclosure is encompassed within the scope of the present disclosure.

[0141] The starting materials and reagents used in the following examples are commercially available or can be prepared by known methods unless otherwise stated.

Example 1 Preparation of Compound (QR16001) and its Sulfate

[0142] 1.1 Preparation of Compound (QR16001-001)

[0143] Under a nitrogen atmosphere, 80 mL dichloromethane, 2-methylamino-3-pyridinemethanol (2.0 g, 0.014 mol) and 1.87 g N,N-diisopropylethylamine were added, and the reaction system was cooled to 15 to 20 C. followed by addition of a solution of 2.0 g (0.014 mol) 1-chloroethyl chloroformate in dichloromethane (20 mL) drop by drop. The reaction mixture was kept at the temperature of 15 to 20 C. for 16 hours.

[0144] To the above reaction mixture, Boc-glycine (2.8 g, 0.016 mol, CAS No.: 4530-20-5) and 0.24 g 4-dimethylaminopyridine (DMAP) were added, at a temperature of 15 to 20 OC, dissolved, and added with 2.48 g 1-ethyl-3-(3-dimethylaminopropyl) carbonyldiimide hydrochloride (CAS No.: 25952-53-8), and after the completion of addition, kept at the temperature of 15 to 20 OC for 8 h. The end of the reaction was judged by TLC. The reaction mixture was washed with 0.1 M hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography to give 2.8 g colorless oil of Compound (QR16001-001). 1.2 Preparation of Compound (QR16001-002) 70 mL acetonitrile and 2.7 g (QR16001-001) were added, stirred to dissolve, and then added with 1.75 g voriconazole, sodium iodide (0.10 g, 0.13 eq.). The reaction system was heated to 50-60 C. for 5 h, and the end of the reaction was judged by TLC. The reaction mixture was concentrated to give a crude oily material, which was purified by silica gel column chromatography to give 2.0 g Compound (QR16001-002).

[0145] 1.3 Preparation of Compound (QR16001)

[0146] 0.78 g Compound (QR16001-002) was dissolved in 10 mL dioxane at room temperature, cooled to 0 C., added with 10 mL 4 M HCl/dioxane solution dropwise. After the completion of addition, the reaction mixture was stirred at room temperature and the end of the reaction was judged by TLC. The reaction mixture was filtered to give 0.52 g onium hydrochloride salt of Compound (QR16001); ESI-MS: 615.2.

[0147] 1.4 Preparation of Compound (16001)

[0148] At room temperature, 0.5 g onium hydrochloride salt of Compound (QR16001) was dissolved in 30 mL purified water, added with 2.2 eq. NaOH, stirred for 1 h and extracted with dichloromethane, and the organic phase was dried and concentrated to give the corresponding free base of Compound (16001); ESI-MS: 615.2.

[0149] 1.5 Preparation of sulfate of Compound (SF16001)

[0150] 0.5 g Compound (QR16001) was dissolved in 30 mL purified water at room temperature, added with 30 g ion exchange resin (sulfate type), stirred at 0 C. for 3 to 5 h, filtered, and the filtrate was lyophilized to obtain 0.2 g amorphous sulfate of Compound (SF16001), which was identified by mass spectrometry and ion chromatography as the target product; ESI-MS: 615.2.

[0151] Referring to the preparation method of Compound (16001), the obtained product was reacted with an appropriate amount of base to obtain the corresponding free compound.

##STR00028##

[0152] The compound of the present disclosure can be obtained not only in the form of onium hydrochloride salt, but also onium hydrogeniodide salt or onium hydrobromide salt where the catalyst is NaBr or NaI or the catalyst exceeds a catalytic amount; onium sulfate, onium phosphate and onium nitrate salts can be prepared by using ion exchange resins, and each salt is freed with a suitable amount of base to obtain the corresponding anion product of the compound.

Example 2 Preparation of Compound (QR16002) and its Sulfate, Nitrate and Phosphate

[0153] 2.1 Preparation of Compound (QR16002-001) Referring to the preparation method of Compound (QR16001-001), Compound (QR16002-001) was obtained by using (S)-2,5-bis(di-tert-butoxycarbonylamino)pentanoic acid (CAS No. 57133-29-6) instead of Boc-glycine as a starting material.

[0154] 2.2 Preparation of Compound (QR16002-002)

[0155] Compound (QR16002-002) was prepared by taking the preparation method of Compound (QR16001-002) as a reference.

[0156] 2.3 Preparation of Compound (QR16002)

[0157] 0.80 g Compound (QR16002-002) was dissolved in 10 mL dioxane at room temperature, and the system was cooled to 0 C. after stirring, and added dropwise slowly with 10 mL 4 M HCl/dioxane solution at 0 C. After the completion of the addition, the reaction mixture was stirred at room temperature for 1 hour, and the end of the reaction was judged by TLC. The reaction mixture was filtered rapidly under nitrogen atmosphere, and the solid was washed successively with ethyl acetate and acetone, to obtain 0.54 g onium hydrochloride salt of Compound (QR16002); ESI-MS: 672.3.

[0158] 2.4 Preparation of Compound (16002)

[0159] Compound (16002), the corresponding free base of Compound (QR16002), was prepared by taking the preparation method of Compound (16001) as a reference; ESI-MS: 672.3.

[0160] 2.5 Preparation of Compound (SF16002)

[0161] Referring to the preparation method of Compound (SF160011), by using Compound (QR16002) as a raw material, the sulfate (SF16002) of Compound (QR16002) was obtained by ion exchange, and the target product was detected by ion chromatography; ESI-MS: 672.3.

[0162] Similarly, referring to the preparation method of Compound (16001), the obtained product was reacted with an appropriate amount of base to obtain the corresponding free compound 16010; ESI-MS: 672.3.

[0163] 2.6 Preparation of Nitrate and Phosphate of the Compound

[0164] As described above, referring to the preparation method of Compound (SF16002), by using ion exchange resins of phosphate type and nitrate type, the corresponding onium phosphate salt (QR16011; ESI-MS: 672.3) and onium nitrate salt (QR16012; ESI-MS: 672.3) were respectively obtained, which were identified by ion chromatography as the target products.

[0165] Referring to the preparation method of Compound (16001), the above onium salts were reacted with an appropriate amount of base, and the corresponding free base (16011; ESI-MS: 672.3) and (16012; ESI-MS: 672.3) were obtained.

##STR00029##

Example 3 Preparation of the Compound (QR16006) and (QR16008)

[0166] 3.1 Preparation of Compound (QR16006)

[0167] Referring to the preparation method of Compound (QR16002) in the above example, onium iodide hydrochloride salt (QR16006) was obtained by using 1.4 eq. sodium iodide; ESI-MS: 672.3.

[0168] Referring to the preparation method of Compound (16001), the obtained product was reacted with an appropriate amount of base to obtain the corresponding free compound (16006); ESI-MS: 672.3.

[0169] 3.2 Preparation of Compound (QR16008)

[0170] Referring to the preparation method of Compound (QR16002) in the previous example, onium bromide hydrochloride salt (QR16008) was obtained by using sodium bromide as a catalyst, the amount of which was 1.4eq.; ESI-MS: 672.3.

[0171] Referring to the preparation method of Compound (16001), the obtained product was reacted with an appropriate amount of base to obtain the corresponding free compound (16008); ESI-MS: 672.3.

Example 4 Preparation of Compound (QR16003)

[0172] Referring to the preparation method of Compound (QR16001), Compound (QR16003) was obtained by replacing Boc-glycine with tert-butoxycarbonyl-L-aspartic acid tert-butyl ester (CAS No.: 34582-32-6), which was detected by mass spectrometry and ion chromatography as the target product; ESI-MS: 673.2.

[0173] Referring to the preparation method of Compound (16001), the free base compound (16003) of Compound (QR16003) was obtained; ESI-MS: 672.3. Furthermore, the other onium salts were also obtained.

Example 5 Preparation of Compound (QR16004)

[0174] 5.1 Preparation of Compound (QR16004-001)

[0175] Referring to the preparation method of Compound (QR16001-001), Compound (QR16004-001) was obtained by using mono-tert-butyl succinate instead of Boc-glycine as a raw material.

[0176] 5.2 Preparation of Compound (QR16004-002)

[0177] Referring to the preparation method of Compound (QR16001-002), Compound (QR16004-002) was obtained by using Compound (QR16004-001) as a raw material.

[0178] 5.3 Preparation of Compound (16004)

[0179] Referring to the preparation method of Compound QR16001, the hydrochloride salt of Compound (16004) was obtained by using Compound (QR16004-002) as a raw material, and the formate of Compound (16004) was obtained by preparative HPLC, and the target products were identified as the target product by ion chromatography.

[0180] Referring to the preparation method of Compound (16001), the hydrochloride or formate of Compound (16004) was reacted with an appropriate amount of NaOH to give the corresponding free base (16004); ESI-MS: 658.2.

[0181] 5.4 Preparation of Compound (QR16004)

[0182] To 0.15 g Compound (16004) hydrochloride, 5 mL methanol was added, and 2.5 equivalent NaOH methanol solution was added dropwise at 0 C. The reaction mixture was stirred for 30 min, and added with 60 mL methyl tert-butyl ether, further stirred for 15 min, filtered to obtain the sodium salt of Compound (QR16004), which was identified as the target product by mass spectrometry and ion chromatography; ESI-MS: 658.2.

##STR00030##

Example 6 Preparation of Compound (QR16005)

[0183] Referring to the preparation method of Compound (QR16001), Compound (QR16005) was obtained by replacing Boc-glycine with QR16005-SM (the preparation method thereof referring to the Journal of Inorganic Biochemistry 98 (2004) 1933-1946), ESI-MS: 658.3.

##STR00031##

[0184] Referring to the preparation method of (16001) in the previous example, the free base (16005) of Compound (QR16005) was obtained; ESI-MS: 658.3.

Example 7 Preparation of Compound (QR16007)

[0185] Referring to the preparation method of Compound (QR16001), Compound (QR16007) was obtained by replacing Boc-glycine with (2S)-2,5-bis(tert-butoxycarbonylamino)pentanoic acid (CAS No. 57133-29-6) and replacing 2-methylamino-3-pyridinemethanol with 2-methylaminobenzyl alcohol; ESI-MS: 671.3.

[0186] Referring to the preparation method of (16001) in the previous examples, the corresponding free base (16007; ESI-MS: 671.3) of Compound (QR16007) was obtained, and other onium salts and corresponding free bases thereof were also obtained.

Example 8 Preparation of Compound (QR16009)

[0187] Referring to the preparation method of Compound (QR16001), Compound (QR16009) was obtained by replacing Boc-glycine with N-tert-butoxycarbonyl-L-citrulline (CAS No. 45234-13-7), ESI-MS: 715.3.

[0188] Referring to the preparation method of Compound (16001) in the previous example, the corresponding free base (16009) of the Compound (QR16009) was obtained by reacting it with a suitable amount of base; ESI-MS: 715.3.

Example 10 Preparation of Compound (QR16013), (SF16013) and (16013)

[0189] Referring to the preparation method of Compound (QR16001), Compound (QR16013) was obtained by replacing Boc-glycine with N-Boc-L-glutamine (CAS No. 13726-85-7), ESI-MS: 686.3.

[0190] By using Compound (QR16013) as a raw material, the sulfate (SF16013) of Compound (QR16013) was obtained referring to the preparation method of Compound (SF16001), and the target product was identified by mass spectrometry and ion chromatography; ESI-MS: 686.3.

[0191] Compound (QR16013) was used as a raw material, reacting with a suitable amount of base to obtain the corresponding free Compound (16013), referring to the preparation method of Compound (16001); ESI-MS: 686.3.

[0192] In the same manner, other onium salts and corresponding free bases were also be prepared.

Example 11 Preparation of Compound (QR16014), (SF16014) and (16014)

[0193] Referring to the preparation method of Compound (QR16001), Compound (QR16014) was obtained by replacing Boc-glycine with N-Boc-L-asparagine (CAS No. 7536-55-2), ESI-MS: 672.3. Compound (QR16014) was used as a starting material to give Compound (SF16014), referring to the preparation method of Compound (SF16001), and the target product was identified by mass spectrometry and ion chromatography; ESI-MS: 672.3.

[0194] Compound (QR16014) was used as a starting material to obtain the corresponding free Compound (16014), referring to the preparation method of Compound (16001); ESI-MS: 672.3.

Example 12 Preparation of Compound (QR16015), (SF16015) and (16015)

[0195] Referring to the preparation method of Compound (QR16001), Compound (QR16015) was obtained by replacing Boc-glycine with N-Boc-O-tert-butyldimethylsilyl-L-serine (CAS No. 90181-25-2, the preparation method thereof referring to Example 3 of the patent document CN103626825A); ESI-MS: 645.2.

[0196] Compound (QR16015) was used as a starting material to obtain Compound (SF16015), referring to the preparation method of Compound (SF16001), and the target product was identified by mass spectrometry and ion chromatography; ESI-MS: 645.2.

[0197] Compound (QR16015) was used as a starting material to obtain the corresponding free base (16015), referring to the preparation method of Compound (16001); ESI-MS: 645.2.

Example 13 Preparation of Compound (QR16016), (SF16016) and (16016)

[0198] Referring to the preparation method of Compound (QR16001), Compound (QR16016) was obtained by replacing Boc-glycine with N-Boc-O-tert-butyldimethylsilyl-L-threonine (CAS No. 90181-26-3, the preparation method thereof referring to the preparation of 614b on page 377 of the patent document WO2013130660A), ESI-MS: 659.3.

[0199] The compound (QR16016) was used as a raw material, to obtain the corresponding sulfate Compound (SF16016), referring to the preparation method of Compound (SF16001), and the target product was identified by mass spectrometry and ion chromatography; ESI-MS: 659.3.

[0200] Compound (QR16016) was used as a starting material, to obtain the corresponding free compound (16016), referring to the preparation method of Compound (16001), ESI-MS: 659.3.

Example 14 Preparation of Compound (QR16017)

[0201] Referring to the preparation method of Compound (QR16001), Compound (QR16017) was obtained by replacing boc-glycine with (S)-2,6-di-tert-butoxycarbonylaminocaproic acid (CAS No.: 2484-46-7), ESI-MS: 686.3.

[0202] Compound (QR16017) was used as a starting material, to obtain Compound (SF16017), referring to the preparation method of Compound (SF16001), and the target product was identified by mass spectrometry and ion chromatography; ESI-MS: 686.3.

[0203] Compound (QR16017) was used as a starting material, to obtain the corresponding free Compound (16017), referring to the preparation method of Compound (16001); ESI-MS: 686.3.

Example 15 Preparation of Compound (QR16018) and (16018)

[0204] Referring to the preparation method of Compound (QR16001), Compound (QR16018) was obtained by replacing Boc-glycine with N-Boc-O-tert-butyldimethylsilyl-L-tyrosine (CAS No. 94732-15-7, the preparation method thereof referring to the preparation of Compound 14 on page 21 of WO2008106860A1), ESI-MS: 721.3.

[0205] Compound (QR16018) was used as a starting material to obtain Compound (16018), referring to the preparation method of Compound (16001), ESI-MS: 721.3.

Example 16 Preparation of Compound (QR16019)

[0206] Referring to the preparation method of Compound (QR16001), Compound (QR16019) was obtained by replacing boc-glycine with (S)-2-tert-butoxycarbonylamino-5-tert-butoxycarbon-ylmethylaminovaleric acid (the preparation method thereof referring to Bioorg. Med. Chem. Lett. 15 (2005), 3934-3941), ESI-MS: 686.3.

[0207] Compound (QR16019) was used as a starting material to obtain Compound (16019), referring to the preparation of the Compound (16001); ESI-MS: 686.3.

Example 17 Preparation of Compound (QR16020), (16020) and (SF16020)

[0208] Referring to the preparation method of Compound (QR16001), Compound (QR16020) was obtained by replacing Boc-glycine with Boc-sarcosine as a starting material (CAS No.: 13734-36-6), ESI-MS: 629.3.

[0209] Compound (QR16020) was used as a starting material to obtain Compound (16020), referring to the preparation method of the Compound (16001); ESI-MS: 629.3.

[0210] Compound (QR16020) was used as a starting material to obtain compound (SF16020), referring to the preparation method of Compound (SF16001) and the target product was identified by mass spectrometry and ion chromatography; ESI-MS: 629.3. Compound (SF16020) was used as a starting material, and reacted with an appropriate amount of base to obtain a corresponding free base, referring to the preparation method of Compound (16001).

Example 18 Preparation of the Compound (QR16021)

[0211] Referring to the preparation method of Compound (QR16001), Compound (QR16021) was obtained by replacing Boc-glycine with (S)-2-tert-butoxycarbonylamino-4-tert-butoxy-carbonylmethylaminobutyric acid (the preparation method referring to Bioorg. Med. Chem. Lett. 15 (2005) 3934-3941), ESI-MS: 672.3.

[0212] Compound (QR16021) was used as a starting material to obtain the corresponding free base Compound (16021), referring to the preparation method of Compound (16001); ESI-MS: 672.3.

Example 19 Preparation of Compound (QR16022)

[0213] 19.1 Preparation of Compound (QR16022-SM-002)

[0214] 5 g (QR16022-SM-001) was dissolved in DMF (50 mL) under nitrogen protection, added with 2 eq. potassium carbonate, stirred at room temperature for 5-10 min, added successively with 0.1 molar eq. CuI, 1.2 eq. methylamine hydrochloride, and then heated to 100 C. for 20 h. The end of the reaction was confirmed by TLC. The reaction mixture was filtered, concentrated, and purified by column chromatography to give 1.71 g Compound (QR16022-SM-002).

[0215] 19.2 Preparation of Compound (QR16022-SM)

[0216] 0.5 g Compound (QR16022-SM-002) and 1.5 eq. Boc anhydride were dissolved in 8 mL ethanol, added with about 50 mg Raney Ni, and the reaction was carried out for 18 hours under a hydrogen atmosphere. The end of the reaction was confirmed by TLC, and the reaction mixture was filtered, concentrated and purified by column chromatography to give 308 mg Compound (QR16022-SM). 19.3 Preparation of Compound (QR16022-001)

[0217] Under nitrogen protection, 0.01 mol (QR16022-SM), 80 mL dichloromethane and 0.01 mol N,N-diisopropylethylamine were added into s a flask. The reaction mixture in the flask was stirred and cooled to 15 to 20 OC, and added dropwise with 0.01 mol 1-chloroethyl chloroformate in dichloromethane (20 mL). After completion of the addition, the reaction mixture was kept at the temperature of 15 to 20 C. to further react for 16 h, added with 100 mL water, stirred and separated to different liquid phases. The organic phase was washed with brine, dried, filtered and concentrated to give the crude product, which was then purified by silica gel column chromatography to give 2.70 g Compound (QR16022-001).

[0218] 19.4 Preparation of Compound (QR16022-002)

[0219] 0.005 mol above-prepared compound (QR16022-001), 70 mL of acetonitrile were added into a flask, stirred and dissolved, added with 0.005 mol voriconazole and 0.1 eq. sodium iodide, and then heated to 50-60 C. to react for 5 h. The end of the reaction was judged by TLC. The reaction mixture was concentrated to give a crude oil, which was then purified by silica gel column chromatography to give 2.56 g Compound (QR16022-002).

[0220] 19.5 Preparation of Compound (QR16022)

[0221] 0.001 mol Compound (QR16022-002) was dissolved in 20 mL ethyl acetate at room temperature. The reaction mixture was stirred and dissolved, added with a solution of hydrogen chloride in ethyl acetate (5 mL, 4 mol/L) dropwise at 0 C. After the addition was completed, the temperature was raised to room temperature while keeping stirring. The end of the reaction was judged by TLC. The reaction mixture was filtered to give 0.45 g Compound (QR 16022), ESI-MS: 557.2.

[0222] 19.6 Preparation of Compound (16022)

[0223] Compound (QR16022) was used as a starting material to obtain Compound (16022), referring to the preparation method of Compound (16001); ESI-MS: 557.2.

##STR00032##

Example 20 Preparation of Compound (QR16023)

[0224] 20.1 Preparation of Compound (QR16023-SM-002)

[0225] The preparation method was referring to literature Chem. Asian J, 2014, 9, 739-743.

[0226] 20.2 Preparation of Compound (QR16023-SM)

[0227] The preparation method was referring to the preparation of Compound 27 on page 73 of patent document WO 2015/112801.

[0228] 20.3 Preparation of Compound (QR16023)

[0229] The preparation method was referring to the preparation method of (QR16022) in the above examples, and the target compound was obtained by replacing Compound (QR16022-SM) with (QR16023-SM); ESI-MS: 571.2.

[0230] The preparation route of Compound (QR16023-SM) was as follows:

##STR00033##

[0231] Compound (QR16023) was used as a starting material to obtain the corresponding free base Compound (16023) referring to the preparation method of Compound (16001); ESI-MS: 571.2.

Example 21 Preparation of Compound (16046) and (QR16046)

[0232] 21.1 Preparation of Compound (16046-001)

[0233] Under nitrogen protection, 0.01 mol ethylene glycol was dissolved in dichloromethane (45 mL), stirred and cooled to 5 to 5 C., added with pyridine (0.012 mol), and added with 0.01 mol phosphorus oxychloride di-tert-butyl ester dropwise (CAS No.: 56119-60-9), and the reaction mixture was kept for 2 h under the same temperature after the completion of the dropwise addition. The reaction was judged by TLC. The reaction mixture was added with 0.1M hydrochloric acid (30 mL), stirred, separated to different liquid phases and the organic phase was washed successively by 1N diluted hydrochloric acid, brine, dried, filtered, concentrated, and purified by silica gel column chromatography to give 2.10 g Compound (16046-001).

[0234] 21.2 Preparation of Compound (16046-002)

[0235] Under nitrogen protection, 0.005 mol Compound (16046-001) was dissolved in acetonitrile (60 mL), added with pyridine (0.012 mol), and added dropwise with 1-chloroethyl chloroformate (0.006 mol). The reaction mixture was kept under the same temperature for 2 h after the completion of addition. The end of the reaction was judged by TLC. The reaction mixture was added with 0.1M hydrochloric acid (30 mL), stirred, separated to different liquid phases and the organic phase was washed successively with saturated sodium bicarbonate, brine, dried, filtered, concentrated, and purified by silica gel column chromatography to give 1.20 g Compound (16046-002).

[0236] 21.3 Preparation of Compound (16046-003)

[0237] Under nitrogen protection, 0.0025 mol Compound (16046-002) was dissolved in acetonitrile (60 mL) added with 0.0025 mol voriconazole and 0.1 eq. sodium iodide, stirred and heated to 65-70 C. for 16 h, and the reaction was judged by TLC. The reaction mixture was cooled to room temperature, added with silica gel to mix and purified by column chromatography to give 0.65 g Compound (16046-003).

[0238] 21.4 Preparation of Compound (16046)

[0239] 0.002 mol Compound (16046-003) was dissolved in 10 mL ethyl acetate at room temperature, added with HCl/dioxane (4 mol/L, 5 mL) dropwise at 0 C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred. The end of the reaction was judged by TLC. The reaction mixture was filtered to give 0.68 g Compound (16046), ESI-MS: 5621.

[0240] 21.5 Preparation of Compound (QR16046)

[0241] Under nitrogen protection, 0.001 mol (16046) was dissolved in 5 mL methanol stirred and cooled to 5 to 5 C., and added with 0.002 mol sodium hydroxide aqueous solution (1 mL) dropwise. After the completion of addition, the reaction mixture was kept for 10 to 20 min at the same temperature. The reaction mixture was concentrated at room temperature with a small amount of methanol remaining, then added with MTBE toprecipitate solid, which was filtered to give 0.46 g Compound (QR16046), ESI-MS: 562.1.

##STR00034##

Example 22 Preparation of Compounds (16024) and (QR16024)

[0242] Starting from butanediol, the preparation method was carried out with reference to the preparation of Compound (16046) to give Compound (16024), ESI-MS: 590.1.

[0243] Compound (QR16024) was obtained referring to the preparation method of Compound (QR16046). ESI-MS: 590.1.

Example 23 Preparation of Compounds (16025) and (QR16025)

[0244] Starting from pentanediol, the preparation method was carried out with reference to Compound (16046) and (QR16046) to give Compound (16025, ESI-MS: 604.2) and a salt thereof (QR16025, ESI-MS: 604.2).

Example 24 Preparation of Compounds (16026) and (QR16026)

[0245] 24.1 Preparation of Compound (16026-001)

[0246] Under nitrogen protection, 0.01 mol (16026-SM) (CAS No.: 50595-15-8), 80 mL dichloromethane, 0.01 mol N,N-diisopropylethylamine were added into a reaction flask. The reaction mixture was stirred, cooled to 15 to 20 OC, and added with a solution of 0.01 mol 1-chloroethyl chloroformate in dichloromethane (20 mL) dropwise. The reaction mixture was kept at a temperature of 15 to 20 OC for 16 h, added with water, stirred, and separated to different liquid phases. The organic phase was washed with brine, dried, filtered, concentrated to give a crude product and purified by column chromatography to give Compound (16026-001).

[0247] 24.2 Preparation of Compound (16026-002)

[0248] 0.005 mol above-prepared compound (16026-001) and 70 mL acetonitrile were added into a reaction flask, stirred and dissolved, added with 0.005 mol voriconazole and 0.1 g sodium iodide, heated to 50-60 C. for 5 h. The end of the reaction was judged by TLC. The reaction mixture was concentrated to give a crude oily product, which was purified by column chromatography to give Compound (16026-002).

[0249] 24.3. Preparation of Compound (16026)

[0250] 0.001 mol Compound (16026-002) was dissolved in 20 mL ethyl acetate at room temperature, stirred and dissolved, and added with a solution of hydrogen chloride in ethyl acetate (5 mL, 4 mol/L) dropwise at 0 C. After the addition was completed, the temperature was raised to room temperature while stirring was continued for 1 h. The end of the reaction was judged by TLC. The reaction mixture was filtered to give Compound (16026), ESI-MS: 496.1.

[0251] 24.4 Preparation of Compound (QR16026)

[0252] Compound (QR16026) was obtained referring to the preparation method of Compound (QR16046); ESI-MS: 496.1.

##STR00035##

Example 25 Preparation of Compound (QR16027)

[0253] 25.1 Preparation of Compound (QR16027-SM)

[0254] 0.01 mol (QR16027-SM-001) was dissolved in tetrahydrofuran, added with 0.012 mol triethylamine, cooled to 5 to 5 C., added dropwise with 0.012 mol isopropyl chloroformate, reacted at room temperature for 3 hours, and filtered. The filtrate was added dropwise to an aqueous solution (5 mL) of 0.02 mol NaBH.sub.4 while the temperature of the reaction mixture was controlled within the range of 5 to 5 C. And then the reaction mixture reacted overnight at room temperature after the dropwise addition was completed. The reaction mixture was added successively 50 mL water and 50 mL ethyl acetate, stirred and separated to different liquid phases, and the organic phase was washed successively with diluted hydrochloric acid of pH=2, 1M sodium hydrogencarbonate and brine, dried, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to give 1.56 g Compound (QR16027-SM). The preparation route of the compound (QR16027-SM) was as follows:

##STR00036##

[0255] 25.2 Preparation of Compound (QR16027)

[0256] Referring to the preparation method of Compound (QR16026), Compound (QR16027) was obtained by replacing (16026-SM) with Compound (QR16027-SM); ESI-MS: 539.2.

[0257] 25.3 Preparation of Compound (16027)

[0258] Compound (16027) was obtained referring to the preparation method of Compound (16001); ESI-MS: 539.2.

Example 26 Preparation of Compound (16042)

[0259] 26.1 Preparation of Compound (16042-002)

[0260] 15 ml acetonitrile, 15 ml water and 3.96 g silver carbonate were added to a reaction flask, stirred for 5 minutes, added with 3 g di-tert-butyl phosphate, and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the di-tert-butyl phosphate silver salt (16042-001).

[0261] Toluene, 0.01 mol di-tert-butyl phosphate silver salt (16042-001), and 0.01 mol 1-chloro-1-iodomethane were added into a reaction flask, heated to 100 C. overnight, cooled to room temperature, filtered, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give 1.8 g Compound (16042-002).

[0262] 26.2 Preparation of Compound (16042-003)

[0263] Under nitrogen protection, 0.005 mol (16042-002) was dissolved in acetonitrile (100 mL), added with 0.01 mol voriconazole and 0.1 g sodium iodide, stirred and heated to 70 C. for 16 h. The end of the reaction was judged by TLC. The reaction mixture was cooled to room temperature, and purified by column chromatography to give 1.8 g compound (16042-003).

[0264] 26.3 Preparation of Compound (16042)

[0265] 0.5 g Compound (16042-003) was dissolved in 5 mL dichloromethane, stirred and dissolved, added dropwise with a solution of hydrogen chloride in dioxane, and then kept stirring at room temperature for reaction after the completion of dropwise addition. The end of the reaction was judged by TLC. The reaction mixture was kept standing still, and then the supernatant obtained was decanted and concentrated to give 0.260 g solid product (16042); ESI-MS: 460.1.

[0266] 26.4 Preparation of Compound (QR16042)

[0267] 3 mL methanol and 0.1 g compound (16042) were added into a reaction flask, stirred and dissolved, cooled to 0 C., added dropwise with a methanol solution of sodium hydroxide (13 mg NaOH dissolved in 4 mL methanol), stirred for 30 minutes, then added with 30 mL methyl tert-butyl ether, stirred for 15 mins, and filtered to give 52 mg Compound (QR16042), ESI-MS: 460.1.

##STR00037##

Example 27 Preparation of Compound (16028) and Compound (QR16028)

[0268] Starting from 1-chloro-1-iodoethane (CAS No. 594-00-3), the preparation was carried out with reference to Compound (16042) to give Compound (16028); ESI-MS: 474.1.

[0269] Compound (16028) was used as a starting material to obtain Compound (QR16028), referring to the preparation method of Compound (QR16042), ESI-MS: 474.1.

Example 28 Preparation of Compound (QR16029) and Compound (16029)

[0270] Starting from N-Boc-L-serine tert-butyl ester (CAS No. 7738-22-9), the preparation method was carried out with reference to Compound (QR16027) to give Compound (QR16029), ESI-MS: 474.1.

[0271] Referring to the preparation method Compound (16001), by reacting (QR16029) as a starting material with a suitable amount of a base, the free base Compound (16029) thereof was obtained; ESI-MS: 474.1.

Example 29 Preparation of Compound (16032) and Compound (QR16032)

[0272] Referring to the preparation method of Compound (16026), the target Compound (16032) was obtained by replacing the starting material 2-tert-butyl glycolate (CAS No. 50595-15-8) with bis-tert-butylphosphoric acid (CAS No. 33494-81-4); ESI-MS: 518.1.

[0273] Preparation of Compound (QR16032):

[0274] 5 mL methanol and 0.2 g Compound (16032) were added to a reaction flask, stirred and dissolved, cooled to 0 C., added with a methanol solution of sodium hydroxide (15 mg NaOH dissolved in 5 mL methanol) dropwise, stirred for 30 minutes, added with 30 mL methyl tert-butyl ether, stirred for 20 min, and filtered to give Compound (QR16032), ESI-MS: 518.1.

Example 30 Preparation of Compound (16030) and Compound (QR16030)

[0275] Starting from diethylene glycol, the preparation method was carried out with reference to (16046) and (QR16046) to give Compound (16030) and its salt (QR16030); ESI-MS: 606.1.

Example 31 Preparation of Compound of (16031)

[0276] 31.1 Preparation of Compound (16031-001)

[0277] 16031-SM (CAS 29167-28-0, preparation method referring to Burslem, G M, et al., Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups., Organic & Biomolecular Chemistry 14.15 (2016): 3782) was used as a starting material to obtain the product, referring to the preparation method of Compound (16026-001).

[0278] 31.2 Preparation of Compound (16031-002)

[0279] Using Compound (16031-001) as a reaction substrate, the target product was obtained referring to the preparation method of Compound (16026-002).

[0280] 31.3 Preparation of Compound (16031)

[0281] 15 mL dichloromethane and 0.001 mol Compound (16031-002) were added to a reaction flask, stirred and dissolved, added with trifluoroacetic acid dropwise, reacted at 0 C. overnight. The reaction mixture was concentrated under reduced pressure to give 0.35 g Compound (16031), ESI-MS: 498.1.

##STR00038##

Example 32 Preparation of Compound (16033) and Compound (QR16033)

[0282] Starting from triethylene glycol, the preparation method was carried out with reference to (16046) and (QR16046) to give Compound (16033, ESI-MS: 650.1) and its salt (QR16033, ESI-MS: 650.1).

Example 33 Preparation of Compound (QR16034) and Compound (16034)

[0283] 33.1 Preparation of Compound (QR16034-SM-002)

[0284] To a three-necked flask, L-cystine di-tert-butyl ester dihydrochloride (QR16034-SM-001) 7.68 g, DMF 180 mL, and triethylamine 3.84 g were added successively, stirred at room temperature for 5 min, added with 2 eq. Boc anhydride, and reacted at room temperature. The end of the reaction was judged by TLC. The reaction mixture was poured into water and extracted with MTBE. The obtained organic phase was washed by 1N HCl and saturated brine, dried, filtered, concentrated to give 8.10 g Compound (QR16034-SM-002).

[0285] 33.2 Preparation of Compound (QR16034-SM)

[0286] 1 g Compound (QR16034-SM-002) was added with 26 mL diethyl ether, under nitrogen protection, stirred to dissolve, cooled to 0 C., added with 1.4 mL acetic acid, and then added with 7.34 g activated zinc powder in batches, and kept reacting at the same temperature until the end of the reaction which was confirmed by TLC. The reaction mixture was filtered, and the filtrate was concentrated, added with 1N HCl, extracted with EtOAc. The organic phase was washed by saturated brine, dried and concentrated to 1.02 g Compound (QR16034-SM).

[0287] 33.3 Preparation of Compound (QR16034)

[0288] Referring to the preparation method of example (QR16026), Compound (QR16034) was obtained by replacing the starting material (16026-SM) with Compound (QR16034-SM). ESI-MS: 541.1.

[0289] 33.4 Preparation of Compound (16034)

[0290] Referring to the preparation method of Compound (16001), Compound (QR16034) was reacted with an appropriate amount of base to give Compound (16034); ESI-MS: 541.1.

[0291] The preparation route of Compound (QR16034-SM) was as follows:

##STR00039##

Example 34 Preparation of Compound (QR16035) and Compound (16035)

[0292] Referring to the preparation method of Compound (QR16034), Compound (QR16035) was obtained, ESI-MS: 555.2.

[0293] Referring to the preparation method of Compound (16001), Compound (QR16035) was reacted with an appropriate amount of base to give Compound (16035), ESI-MS: 555.2.

Example 35 Preparation of Compound (16036) and Compound (QR16036)

[0294] 35.1 Preparation of Compound (16036-001)

[0295] The preparation method was carried out with reference to the preparation of Compound (16026-001) in which benzyl thioglycolate (CAS No. 7383-63-3) was used instead of the starting material 2-tert-butyl glycolate (CAS No. 50595-15-8).

[0296] 35.2. Preparation of Compound (16036-002)

[0297] Compound (16036-001) was used as a starting material to obtain the title compound, referring to the preparation method of Compound (16026-002).

[0298] 35.3. Preparation of Compound (16036)

[0299] 15 mL methanol and 0.001 mol Compound (16036-002) were added into a reaction flask, stirred and dissolved, added with 0.1 g Pd/C catalyst, kept reacting under hydrogen at 25 C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to obtain Compound (16036). ESI-MS: 512.1.

[0300] Referring to the preparation method of Compound (QR16046), the corresponding sodium salt (QR16036) was obtained; ESI-MS: 512.1.

##STR00040##

Example 36 Preparation of Compound (16037)

[0301] 36.1 Preparation of Compound (16037-001)

[0302] 16037-SM (CAS No. 127084-56-4, preparation method referring to Minch, Britt A., et al. Octakis(2-benzyloxyethylsulfanyl) Copper (II) Phthalocyanine: A New Liquid Crystalline Discotic Material with Benzyl-Terminated, Thioether-Linked Side Chains. Chemical of Materials 17.7 (2005).) was used as a starting material to obtain the title product, referring to the preparation method of Compound (16026-001).

[0303] 36.2 Preparation of Compound (16037-002)

[0304] Compound (16037-001) was used as a reaction substrate to obtain the title compound, referring to the preparation of Compound (16026-002).

[0305] 36.3 Preparation of Compound (16037)

[0306] 15 mL methanol and 0.001 mol Compound (16037-002) were added into a reaction flask, stirred to dissolve, added with 0.1 g Pd/C catalyst, kept reacting under hydrogen at 25 C. overnight. The reaction solution was filtered, and the filtrate was concentrated to give 0.48 g Compound (16037), ESI-MS: 498.14.

##STR00041##

Example 37 Preparation of Compound (16038) and Compound (QR16038)

[0307] Referring to the preparation method of Compound (16026), Compound (16038) was obtained by replacing the starting material 2-tert-butyl glycolate (CAS No. 50595-15-8) with t-butyl glycinate (CAS No. 6456-74-2); ESI-MS: 495.2.

[0308] Compound (QR16038) was obtained referring to the preparation method of Compound (QR16046), ESI-MS: 495.2.

Example 38 Preparation of Compound (QR16039) and Compound (16039)

[0309] Referring to the preparation method of Compound (16026), the starting material 2-tertiary-butyl glycolate (CAS No. 50595-15-8) was replaced with tert-butyl (S)-2-tert-butoxycarbonylamino-4-aminobutyrate (CAS No. 190447-69-9) to give Compound (QR16039), ESI-MS: 538.2.

[0310] Referring to the preparation method of Compound (16001), the free compound (16039) was also obtained; ESI-MS: 538.2.

Example 39 Preparation of Compound (QR16040) and Compound (16040)

[0311] 39.1 Preparation of Compound (QR16040-001)

[0312] 10 g D-xylose (QR16040-SM) was added to 20 mL anhydrous methanol added with 0.01 eq. ammonium chloride, stirred (suspension) and cooled to 0 C.; The reaction mixture gradually clarified after ammonia gas was fed for 30 minutes. After ammonia gas was continuously fed for another 1 h, the reaction solution was cooled and crystallized to obtain 3 g solid product (QR16040-001).

[0313] 39.2 Preparation of Compound (QR16040-002)

[0314] Under nitrogen protection, 15 g 2,2-dimethoxypropane, 40 mL anhydrous acetone were added, stirred, added with 1.6 eq. p-toluenesulfonic acid, stirred at room temperature for about 15 min, added with 3 g Compound (QR16040-001), stirred, precipitated a solid, and filtered to give 2.3 g Compound (QR 16040-002).

[0315] Preparation of 39.3 compound (QR16040-003)

[0316] 0.01 mol Compound (QR16040-002) was dissolve in 50 mL dichloromethane, stirred under nitrogen protection, cooled to 15 to 18 OC, added with 0.024 mol N,N-diisopropylethylamine, stirred and cooled to 15 to 20 OC, added dropwise with 0.011 mol 1-chloroethyl chloroformate in dichloromethane (20 mL), and after that the reaction mixture was kept at a temperature of 15 to 20 OC for 16 h. The reaction mixture was used in the next reaction without isolation.

[0317] 39.4 Preparation of Compound (QR16040-004)

[0318] While keeping the temperature of 15 to 20 OC, the above reaction mixture was added with 0.012 mol Boc-sarcosine, 0.003 mol DMAP, and 0.012 mol 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl), and then reacted for 2-3 h at the above temperature. The reaction mixture was then added with 50 mL 0.1N HCl, stirred, raised to room temperature, and separated to different liquid phases. The organic phase was washed with 0.1N HCl, saturated solution of sodium bicarbonate and brine, dried, filtered and concentrated to obtain 3.6 g crude product.

[0319] 39.5 Preparation of Compound (QR16040-005)

[0320] The title compound was obtained referring to the preparation method of Compound (QR16032-002).

[0321] 39.6 Preparation of Compound (QR16040)

[0322] The hydrochloride salt Compound (QR16040) was obtained referring to the preparation method of Compound (QR16032), ESI-MS: 640.2.

[0323] 39.7 Preparation of Compound (16040)

[0324] Compound (16040) was obtained referring to the preparation method of Compound (16001), ESI-MS: 640.2.

##STR00042##

Example 40 Preparation of Compound (QR16041) and Compound (16041)

[0325] Compound (QR 16041) was obtained referring to the preparation method of Compound (16026) in which the starting material 2-tert-butyl glycolate (CAS No. 50595-15-8) was replaced with tert-butyl N-(3-aminopropyl)carbamate (CAS No. 75178-96-0); ESI-MS: 494.2.

[0326] According to the above examples, Compound (QR16041) was reacted with an appropriate amount of base to give Compound (16041); ESI-MS: 494.2.

Example 41 Preparation of Compound (16043) and Compound (QR16043)

[0327] 41.1 Preparation of compound (16043-001)

[0328] Under nitrogen protection, 3.3 g voriconazole was dissolved in 100 mL acetonitrile, added with 0.1 eq. sodium bromide and 1.2 eq. t-butyl chloroacetate, heated to 65-70 C. for 16 h under stirring. The end of the reaction was judged by TLC. The reaction mixture was cooled to room temperature and purified by column chromatography to give 1.5 g Compound (16043-001).

[0329] 41.2 Preparation of Compound (16043)

[0330] 0.8 g Compound (16043-001) was dissolved in 20 mL ethyl acetate at room temperature, stirred and dissolved, and added with a solution of hydrogen chloride in ethyl acetate (10 mL, 4 mol/L) dropwise at 0 C. After the addition was completed, the temperature of the reaction mixture was raised to room temperature under continuous stirring. The end of the reaction was judged by TLC. The reaction mixture was filtered to give 0.48 g Compound (16043), ESI-MS: 408.1.

[0331] 41.3 Preparation of Compound (QR16043)

[0332] Compound (QR16043) was obtained referring to the preparation method of Compound (QR16042), ESI-MS: 408.1.

##STR00043##

Example 42 Preparation of Compound (16045) and Compound (QR16045)

[0333] Compound (16045) was obtained referring to the preparation of paragraphs 1.1 and 1.2 of Example 1, wherein Boc-glycine of Example 1 was replaced with dimethylglycine (CAS No. 1118-68-9) to give the compound (16045). ESI-MS: 643.3.

[0334] Compound (16045) was dissolved in 20 mL methanol, added with 3 eq. 4 N hydrochloric acid dropwise at room temperature, stirred and lyophilized to give the hydrochloride salt Compound (QR16045), which was determined by mass spectrometry and ion chromatography to as the target product; ESI-MS: 643.3.

[0335] Test of Biological Activity and Related Properties

Example I: Solubility Test of Compounds of the Present Disclosure

[0336] Experimental condition: 252 C.
Experimental instrument: Agilent 1260 HPLC
Dissolving medium: deionized water
Experimental method: 1 mg voriconazole and appropriate amount of each compound were weighed, placed in 1 ml deionized water separately, shaken vigorously for 30 s every 5 mins for 30 mins. The dissolution state of the mixture was observed, and the solubility of each compound was determined by HPLC using external calibration method. In the experiment, it was found that there was no significant difference in solubility between different onium salts of the same compound, such as QR16006, QR16008, SF16002, QR16011, QR16012 and QR16002, SF16001 and QR16001; SF16020 and QR16020. The solubility results of each compound were shown as follows:

TABLE-US-00001 TABLE 1 results of solubility test Compound No. Solubility (mg/mL) Voriconazole <1 QR16001 >50 QR16002 >50 QR16003 >50 QR16004 >50 QR16005 >50 QR16006 >50 QR16007 >50 QR16008 >50 QR16009 >50 SF16002 >50 QR16011 >50 QR16012 >50 QR16013 >50 QR16014 >50 QR16015 >50 QR16016 >50 QR16017 >50 QR16018 >50 QR16019 >50 QR16020 >50 QR16021 >50 QR16022 >50 QR16023 >50 QR16024 >50 QR16025 >50 QR16028 >50 QR16029 14.2 QR16030 >50 QR16032 >50 QR16033 >50 QR16034 12.5 QR16040 16.8 QR16042 >50 SF16001 >50 QR16045 >50 QR16046 >50

[0337] According to the above data, the example compounds of the present disclosure have effects superior to voriconazole, and their solubility in pure water is significantly higher than that of voriconazole. This advantage makes it possible to avoid the safety risk associated with the use of sulfobutyl ether -cyclodextrin as a solubilizer in the formulation.

Example II: Study of In Vitro Stability of the Compounds of the Present Disclosure

[0338] The metabolic stability of the compounds of the present disclosure in human (rat) plasma and intestinal S9 in vitro were detected in this example. 990 l of human (rat) plasma was taken from the human (rat) plasma reaction system, pre-incubated at 37 C. for 5 mins, and added with 10 l mother liquor of the compound to initiate the reaction. The human (rat) intestinal S9 stability test was carried out by adding the sample in the order according to the following table and incubating in a 37 C. water bath. The two reaction systems were set up three samples in parallel, while each sample was taken in an amount of 100 L at 1 min, 2 mins, 5 mins, 15 mins, and 30 mins after the reaction, added to the centrifuge tube containing 400 L of 0 C. pre-cooled internal standard working fluid and terminated the reaction. The sample was mixed by vortex for 1 min, centrifuged at 10,000g for 10 mins in a 4 C. pre-cooled high-speed centrifuge. The supernatant was taken for HPLC detection. The test results were calculated by a non-compartment model using WinNonlin (version 6.2 Pharsight, Mountain View, Calif.) to calculate the metabolic half-life.

[0339] Concentration of mother liquor of compounds: 1 mM

[0340] Reaction matrix: human (rat) plasma, intestinal S9 purchased from Shanghai Ruide Liver Disease Research Co., Ltd.

TABLE-US-00002 TABLE 2 Composition of the reaction system of each compound in human (rat) intestinal S9 Volume Initial Final composition (L) concentration concentration PBS buffer 740 0.1M 0.1M (pH 7.4) Intestinal S9 50 20 mg/mL 1 mg/mL 37 C. pre-incubation for 5 min Aqueous 10 1 mM 10 M solution of the compound NADPH regeneration system 1 mL Human MgCl.sub.2 100 mM 5 mM intestinal NADP 200 20 mM 1 mM incubation Glucose-6- 200 mM 10 mM system phosphate (rat) Glucose-6- 20 unit/mL 1 unit/mL S9 phosphate dehydrogenase

[0341] The metabolic half-lives of the compounds of the present disclosure in human (rat) plasma and intestinal S9 in vitro were detected in this example, wherein the half-lives of QR16003-QR16005, and QR16009 were similar, wherein QR16005 was shown as an example; the half-lives of QR16018, QR16019, QR16021-QR16023 were similar, wherein QR16022 was shown as an example; the half-lives of QR16024, QR16025, QR16032-QR16036, QR16038-QR16040 and QR16043 were similar, wherein QR16035 was shown as an example; the half-life of QR16026-QR16030, 16031 were similar, wherein QR16029 was shown as an example. In the experiment, it was also found that there was no significant difference in the experimental data of different onium salts of the same compound, such as QR16006, QR16008, SF16002, QR16011, QR16012 and QR16002; SF16001 and QR16001; SF16020 and QR16020. Therefore one experimental datum of such different onium salts of each compound was selected and listed in the following table.

TABLE-US-00003 TABLE 3 Metabolic half-life of each compound in human (rat) plasma and intestinal S9 Human plasma Human intestinal S9 Rat plasma Rat intestinal S9 Compound T.sub.1/2 (min) T.sub.1/2 (min) T.sub.1/2 (min) T.sub.1/2 (min) QR16001 1.56 0.26 10.09 1.75 1.23 0.45 10.15 2.65 QR16002 0.76 0.20 14.75 2.16 0.89 0.33 14.85 4.25 QR16005 6.15 0.75 18.21 2.04 8.25 1.28 26.52 3.69 QR16008 9.49 1.31 30.25 4.90 10.58 2.95 32.52 7.82 QR16013 1.91 0.13 19.21 1.32 1.25 0.68 21.85 6.59 QR16014 0.83 0.19 17.15 2.25 0.87 0.56 18.55 5.69 QR16015 2.05 0.26 12.72 1.72 1.58 0.95 15.95 4.96 QR16016 2.12 1.07 15.72 0.98 1.95 0.87 19.62 3.69 QR16017 0.95 0.28 11.25 2.21 0.78 0.86 15.69 6.95 QR16020 1.44 0.62 16.94 1.62 1.25 0.39 20.95 6.66 QR16022 26.01 2.39 43.22 1.03 29.52 7.85 55.95 10.28 QR16029 27.56 2.43 40.56 2.34 22.85 8.88 53.52 8.55 QR16035 14.15 3.75 29.12 2.09 11.85 3.77 35.62 8.12 16037 7.75 0.56 10.75 1.97 7.65 0.78 15.96 6.88 QR16042 10.47 2.36 25.28 4.75 11.28 2.39 23.52 8.55 QR16045 8.95 0.12 32.97 8.45 8.88 0.55 27.85 6.58

[0342] It can be seen from the data in the table that the compounds of the present disclosure have similar half-lives in plasma of both human and rat and in two kinds of intestinal S9, and the results of pharmacological experiments in rats have reference significance for the study of the effects of drugs in human.

Example III: Test of Solid Stability of the Compound of the Present Disclosure

[0343] Experimental conditions: 25 C.2 C., relative humidity 60%2%
Experimental instrument: Agilent 1260 HPLC; chamber for stability test
Experimental method: each compound of the present disclosure was packaged (the inner packaging material was a penicillin bottle; the outer packaging material was a double-layer aluminum foil bag, and a desiccant was added inside and outside the package), placed in the chamber for stability test, at a temperature of 25 C.2 C. and a relative humidity of 60%2%. The degradation situation of the compounds for 30 days was examined. The contents of total impurities before and after 30 days of each compound were compared and the results were as follows:

TABLE-US-00004 TABLE 4 Results of solid stability test Content increase Content increase of total impurity of total impurity Compound (25 C., placed Compound (25 C., placed No. for 30 days) No. for 30 days) QR16001 0.53% SF16013 0.48% QR16002 1.02% SF16014 0.36% QR16003 1.37% SF16015 0.32% QR16006 1.14% QR16024 2.84% QR16007 0.73% QR16025 1.57% QR16008 1.05% QR 16028 1.52% QR16009 0.71% QR 16029 1.17% SF16002 0.67% QR 16030 0.94% QR16011 0.96% 16031 0.97% QR16012 0.92% QR16035 1.21% QR16013 0.42% QR16036 1.35% QR16014 0.53% 16037 2.15% QR16015 0.39% QR 16039 1.22% QR16016 0.62% QR 16040 2.84% QR16017 0.55% SF16001 0.37% QR16018 1.15% QR 16045 2.23% QR16019 0.88% QR 16046 0.79% QR16020 0.56% SF16020 0.62% QR16021 1.14% SF16016 0.49% QR16023 2.63% SF16017 0.46%

[0344] By analyzing the above data, it can be shown that the compounds of the present disclosure exhibited good stability when being placed at a temperature of 25 C.2 C. and a relative humidity of 60%2% for 30 days, wherein QR16001, QR16002, QR16013, QR16014, QR16015, QR16016, QR16017, QR16020 and the like, as well as their different salt types such as hydrochloride or sulfate, all exhibited better stability.

Example IV: Pharmacokinetics (PK) Study of Intravenous Administration of the Compounds of the Present Disclosure

[0345] Dosage for administration: 2.5 mg/kg (calculated as voriconazole)
Dosing volume for administration: 2.5 ml/kg
Drug concentration: 1 mg/mL (calculated as voriconazole)
Solvent medium for administration: physiological saline; since voriconazole was insoluble in the medium (physiological saline), commercially available voriconazole injection (Pfizer, product batch number Z467001) was used in the study as a control, that is, voriconazole (cyclodextrin) with sulfobutylether--cyclodextrin as a solubilizer was used.
Route of administration: tail vein injection
Experimental animals: SD rats, SPF grade, weighing 180-220 g, half male and half female; the SD rats were randomized into groups of 6 animals each, three males and three females in each group.
Experimental method: Blood samples were collected at different time points after tail vein administration, and the plasma concentrations of voriconazole were measured.

[0346] Among the PK parameters of voriconazole in plasma: the PK parameters of QR16003-QR16005 and QR16009 were similar, wherein QR16004 was shown as an example; the PK parameters of QR16018, QR16019, QR16021-QR16023 were similar, wherein QR16021 was shown as an example; the PK parameters of QR16024, QR16025, QR16032-QR16036, QR16038-QR16040 and QR16043 were similar, wherein QR16035 was shown as an example; the PK parameters of QR16026-QR16030 and 16031 compounds were similar, wherein QR16028 was shown as an example. In the experiment, it was found that there was no significant difference in experimental data of different onium salts of the same compound, such as QR16006, QR16008, SF16002, QR16011, QR16012 and QR16002, SF16001 and QR16001; SF16020 and QR16020. Therefore one experimental datum of such different onium salts of each compound was selected and listed in the following table.

TABLE-US-00005 TABLE 5 Main pharmacokinetic parameters of single intravenous administration of each compound in rats Compound T.sub.1/2 (h) AUC.sub.last (ng/mL*h) Voriconazole Voriconazole (cyclodextrin) 2.58 1.25 10856 2351 QR16001 2.14 0.98 10515 1985 QR16002 1.95 1.21 10152 3280 QR16004 2.92 1.62 9586 2352 QR16007 2.88 1.22 10278 3225 QR16013 2.25 0.85 10252 4526 QR16014 1.98 0.88 10156 3654 QR16015 2.85 1.78 10526 2695 QR16016 2.65 0.88 10477 1854 QR16017 2.78 0.75 10259 3285 QR16020 2.45 0.75 10122 3525 QR16021 2.97 1.12 7056 2532 QR16028 2.55 0.85 7256 3251 QR16035 2.74 0.81 8256 1256 16037 2.47 0.75 9120 3254 QR16042 2.88 0.21 7898 4251 QR16045 2.74 0.78 8586 1856 T.sub.1/2: half-life, AUC.sub.last: area under the time curve; : The parameter could not be calculated because voriconazole was not detected.

[0347] It can be seen from the data in the table that voriconazole is not detected in the control group of voriconazole dissolved in physiological saline. However, after intravenous administration to rats of the compound group of the present disclosure, the exposures of voriconazole were much higher than that of voriconazole dissolved in physiological saline, but similar with the positive drug voriconazole (cyclodextrin), indicating that most of the original drug has been converted to voriconazole after intravenous administration, which can avoid the safety risk caused by -cyclodextrin used as a solubilizer.

Example V: Pharmacokinetics (PK) Study of Gastrointestinal Administration of the Compounds of the Present Disclosure

[0348] Dosage for administration: 2.5 mg/kg (calculated as voriconazole)
Dosing volume for administration: 10 ml/kg
Drug concentration: 0.25 mg/mL
Solvent medium for administration: except for the positive voriconazole group using CMC-Na, the other groups using normal saline
Route of administration: gavage
Experimental animals: SD rats, SPF grade, weighing 180-220 g, half male and half female; the SD rats were randomized into groups of 6 animals each, three males and three females in each group.
Experimental method: After oral gavage, blood samples were collected at different time points to detect the plasma concentration of voriconazole, and the pharmacokinetic parameters of voriconazole were obtained: the PK parameters of QR16003-QR16005, QR16009 and QR16007 were similar, wherein QR16009 was shown as an example; the PK parameters of QR16018-QR16019, QR16021-QR16025 compounds were similar, wherein QR16023 was shown as an example; the PK parameters of QR16026-QR16030, 16031, QR16046 were similar, wherein QR16030 was shown as an example; the PK parameters of QR16032-QR16036, QR16038-QR16041, QR16043 were similar, wherein QR16036 was shown as an example. It was also found that there were no significant differences in PK parameters of different onium salts of the same compound, such as QR16006, QR16008, SF16002, QR16011, QR16012 and QR16002, SF16001 and QR16001; SF16020 and QR16020. Therefore one experimental datum of such different onium salts of each compound was selected and listed in the following table.

TABLE-US-00006 TABLE 6 Main pharmacokinetic parameters of single gastrointestinal administration of rats in each compound C.sub.max T.sub.1/2 AUC.sub.last Compound (ng/mL) (h) (ng/mL*h) Voriconazole (CMC-Na) 412 102 2.95 1.65 4252 1235 QR16001 789 362 3.21 1.28 8562 1125 QR16002 895 178 2.65 0.58 8654 1085 QR16008 825 256 2.65 0.58 8745 2365 QR16009 925 121 1.98 0.87 7225 1310 QR16013 895 178 1.95 0.77 8855 2152 QR16014 1022 365 2.88 0.85 8332 2996 QR16015 996 365 2.78 1.23 8144 1468 QR16016 885 344 2.24 1.25 8332 3254 QR16017 952 421 2.95 1.25 8695 2958 QR16020 815 365 2.45 0.68 8562 2586 QR16023 358 105 2.75 1.41 4553 1252 QR16030 362 152 2.54 1.05 4324 1362 QR16036 625 214 2.62 0.78 5954 1895 16037 859 358 2.78 0.74 8562 1895 QR16042 785 325 2.58 1.21 6656 1456 QR16045 562 158 2.59 0.88 7859 2256 C.sub.max: peak of drug blood concentration, T.sub.1/2: half-life, AUC.sub.last: area under the time curve

[0349] The above experimental results showed that the exposures of voriconazole after gastrointestinal administration of the compounds in rats were higher than or similar as that of the positive drug voriconazole (CMC-Na), indicating that most of the compound of the present disclosure are converted to voriconazole, and have high bioavailabilities.

Example VI: Experimental Study on the Effect of Intravenous Administration of the Compound of the Present Disclosure Against Systemic Fungal Infection in Mice

[0350] 1. Experimental Material

[0351] 1.1 Experimental Instruments

[0352] Multiskan MK3 type enzyme labeling detector, water-blocking electrothermal constant temperature incubator, ZQ-F160 full temperature shaking incubator, MJX type intelligent mold incubator, SW-CT-IF type ultra-cleaning workbench, ultraviolet spectrophotometer.

[0353] 1.2 Experimental Reagents

[0354] Dimethyl sulfoxide, Sabouraud Dextrose Agar solid medium (SDA).

[0355] 1.3 Experimental Animals

[0356] ICR mice, weighing 18-22 g, male, provided by the Hubei Experimental Animal Center.

[0357] 1.4 Experimental Strain

[0358] The standard strain Candida albicans was purchased from the American Type Culture Collection, and the strain number was ATCC10231.

[0359] 2. Experimental Method

[0360] Before the experiment, a small amount of Candida albicans was picked from the SDA medium preserved at 4 C. by inoculation circle, and inoculated into 1 ml YPD (Yeast Extract Peptone Dextrose Medium, the same below) culture medium, under shake cultivation at 30 C., 200 rpm, activated for 16 hours to make the fungus in the late stage of the exponential growth phase. Blood cell counting plate was used to count. The concentration of the broth was adjusted to 1*10.sup.3-5*10.sup.3 CFU/ml with RPMI1640 (Roswell Park Memorial Institute 1640, the same below) culture medium. The Candida albicans monoclone on the SDA plate was picked and inoculated into 1 ml YPD medium, cultured at 35 C., 200 rpm for 16 hours to the late exponential growth phase, 1% of which was then inoculated in fresh medium for 6 hours, centrifuged at 1000g for 5 mins, washed three times with saline until the supernatant was colorless, while hemocytometer was used to count. The cell concentration was adjusted to 5*10.sup.6/ml. The tail vein injection of 0.1 ml/10 g was carried out to cause a systemic fungal infection in mice. The mice were randomized into groups of 10 each. Since voriconazole was insoluble in vehicle (physiological saline), the mice of the voriconazole group in the test were injected a commercially available voriconazole (Pfizer, product lot number Z467001), that is, sulfobutyl ether--cyclodextrin used as a solubilizer, while other groups used physiological saline as a solvent. After establishing a systemic fungal infection model in mice for 2 hours, each administration group was administered with 5 mg/kg (calculated as voriconazole) drug in the tail vein, with the volume for administration of 0.1 ml/10 g. The mice in the model group were administered 0.1 ml/10 g of 0.9% sodium chloride solution, once daily, for 5 consecutive days. The death situation of the mice was inspected and the survival time was recorded. After a total of 7 days of observation, all dead mice were treated with fire using ethanol.

[0361] 3. Experimental Results

[0362] The pharmacodynamic data of the intravenous administration of the compound of the present disclosure against systemic fungal infection in mice were shown in the following table. Wherein, the pharmacodynamic data of QR16003-QR16005, QR16009, QR16024-QR16030, QR16032-QR16033, QR16038-QR16043 and QR16046 were similar, wherein QR16004 was shown as an example; the pharmacodynamic data of QR16007, QR16018-QR16019, QR16021-QR16023, QR16040-QR16041 and QR16045 were similar, wherein QR16007 was shown as an example; the pharmacodynamic data of 16031, QR16034-QR16036, and 16037 were similar, wherein 16037 was shown as an example. It was found that in this experiment different onium salts of the same compound had similar pharmacodynamic data. For example the pharmacodynamic data of QR16006, QR16008, SF16002, QR16011 and QR16012 were similar to that of QR16002; the pharmacodynamic data of SF16001 was similar to that of QR16001; the pharmacodynamic data of SF16020 and QR16020 were similar. Therefore one experimental datum of such different onium salts of each compound was selected and listed in the following table.

TABLE-US-00007 TABLE 7 Systemic fungal infection (intravenous administration): survival rate of mice in each group after administration (%) Dose Time (day) Group (mg/kg) 1 2 3 4 5 6 7 Solvent group 90% 60% 30% 20% 20% 0% 0% voriconazole 5 100% 100% 100% 100% 100% 100% 90% (-cyclodextrin) QR16001 5 100% 100% 100% 100% 100% 100% 90% QR16002 5 100% 100% 100% 100% 100% 90% 90% QR16004 5 100% 100% 100% 90% 90% 80% 80% QR16007 5 100% 100% 100% 100% 100% 90% 90% QR16013 5 100% 100% 100% 100% 90% 90% 90% QR16014 5 100% 100% 100% 90% 90% 90% 90% QR16015 5 100% 100% 100% 100% 100% 90% 90% QR16016 5 100% 100% 100% 100% 100% 90% 90% QR16017 5 100% 100% 100% 100% 100% 100% 90% QR16020 5 100% 100% 100% 100% 90% 90% 90% 16037 5 100% 100% 90% 90% 90% 80% 80%

[0363] It can be seen from the data in the table that after 7 days of administration, the survival rates of the groups administrated with the compounds according to the present disclosure were significantly higher than that of the solvent group. Among the data, the survival rates of the mice on the 7th day in QR16001, QR16002, QR16007, QR16013, QR16014, QR16015, QR16016, QR16017 and QR16020 groups were similar with that of the mice in the positive drug voriconazole group, indicating that the efficacy of the compounds of the present disclosure is comparable to that of voriconazole, thereby having good efficiency. It is true that the survival rates of the mice on the 7th day of QR16004 and 16037 groups were slightly lower than that of the positive drug voriconazole group; however, in the voriconazole group of this experiment, voriconazole is in the form of commercially available voriconazole injection, which is solubilized with sulfobutylether--Cyclodextrin, whereas the compounds of the present disclosure were all dissolved in physiological saline, thereby avoiding the safety risk caused by -cyclodextrin used as a solubilizer.

Example VII: Experimental Study on the Effect of the Compound by Gastrointestinal Administration of the Present Disclosure on Systemic Fungal Infection in Mice

[0364] 1. Experimental Material

[0365] 1.1 Experimental Instruments

Multiskan MK3 type enzyme labeling detector, water-blocking electrothermal constant temperature incubator, ZQ-F160 full temperature shaking incubator, MJX type intelligent mold incubator, SW-CT-IF type ultra-cleaning workbench, ultraviolet spectrophotometer.

[0366] 1.2 Experimental Reagents

Dimethyl sulfoxide, Sabouraud dextrose agar solid medium.

[0367] 1.3 Experimental Animals

ICR mice, weighing 18-22 g, male, provided by the Hubei Experimental Animal Center.

[0368] 1.4 Experimental strain

[0369] The standard strain Candida albicans was purchased from the American Type Culture Collection, and the strain number was ATCC10231.

[0370] 2. Experimental Method

[0371] Before the experiment, a small amount of Candida albicans was picked from the SDA medium preserved at 4 C. by inoculation circle, inoculated into 1 ml of YPD culture medium, and cultured at 30 C. while being shaked at 200 rpm for 16 hours to make the fungus in the late stage of exponential growth. Blood cell counting plate was used to count, and the concentration of the broth was adjusted to 1*10.sup.35*10.sup.3 CFU/ml with RPMI1640 medium. The Candida albicans monoclone on the SDA plate was picked, inoculated into 1 ml YPD medium, cultured at 35 C., 200 rpm for 16 hours to the late exponential growth phase, 1% of which was then inoculated in fresh medium for 6 hours, centrifuged at 1000g for 5 mins, washed three times with saline until the supernatant was colorless, while hemocytometer was used to count. The cell concentration was adjusted to 5*10.sup.6/ml. The tail vein injection of 0.1 ml/10 g was carried out to cause a systemic fungal infection in mice. The mice were randomized into groups of 10 each. Voriconazole used was in the form of a suspension prepared with CMC-Na (Shanghai Panhong Chemical Technology Co., Ltd.), while other tested drugs were dissolved in saline and sonicated until clarified for administration. After establishing a systemic fungal infection model in mice for 2 hours, each group was administered by gavage with 5 mg/kg (calculated as voriconazole) drug, with the volume for administration of 0.1 ml/10 g. The mice in the model group were administered 0.1 ml/10 g of 0.9% sodium chloride solution, once daily, for 5 consecutive days. The death situation of the mice was inspected and the survival time was recorded. After a total of 7 days of observation, all dead mice were treated with fire using ethanol.

[0372] 3. Experimental Results

[0373] The pharmacodynamic data of the compound of the present disclosure administered by gavage against systemic fungal infection in mice were shown in the following table, wherein the pharmacodynamic data of QR16003-QR16005, QR16007, and QR16009 compounds were similar, wherein QR16009 was shown as an example; the pharmacodynamic data of QR16018-QR16019, QR16021-QR16025 were similar, wherein QR16023 was shown as an example; the pharmacodynamic data of QR16026-QR16030 and 16031 compound were similar, wherein QR16030 as an example; the pharmacodynamic data of QR16032-QR16036, QR16038-QR16041 and QR16043 were similar, wherein QR16036 was shown as an example; In the experiment, it was found that different onium salts of the same compound had comparable pharmacodynamic data. For example, the pharmacodynamic data of QR16006, QR16008, SF16002, QR16011 and QR16012 were similar with QR16002; the pharmacodynamic data of SF16001 was similar with QR16001; the pharmacodynamic data of SF16020 and QR16020 were similar. Therefore one experimental datum of such different onium salts of each compound was selected and listed in the following table.

TABLE-US-00008 TABLE 8 Systemic fungal infection (gavage): survival rate of mice in each group after administration (%) Dose Time (day) Group (mg/kg) 1 2 3 4 5 6 7 Solvent group 90% 80% 40% 20% 10% 0% 0% Voriconazole 5 100% 100% 90% 80% 60% 50% 50% (CMC-Na) QR16001 5 100% 100% 100% 100% 90% 80% 80% QR16002 5 100% 100% 100% 100% 90% 80% 80% QR16008 5 100% 100% 100% 100% 90% 80% 80% QR16009 5 100% 80% 80% 70% 70% 70% 70% QR16013 5 100% 100% 90% 90% 80% 80% 80% QR16014 5 100% 100% 100% 100% 90% 90% 80% QR16015 5 100% 100% 100% 100% 100% 80% 80% QR16016 5 100% 100% 90% 90% 90% 90% 80% QR16017 5 100% 100% 90% 90% 90% 90% 80% QR16020 5 100% 90% 90% 90% 90% 90% 80% QR16023 5 100% 90% 70% 70% 60% 60% 50% QR16030 5 100% 90% 80% 70% 60% 50% 50% QR16036 5 100% 90% 80% 80% 70% 60% 60% 16037 5 100% 100% 100% 100% 90% 80% 80% QR16042 5 100% 100% 90% 90% 80% 70% 70% QR16045 5 100% 100% 90% 90% 90% 90% 80%

[0374] It can be seen from the data in the above table that after 7 days administration, the amounts of corneal bacteria in the mice of the compound groups according to the present disclosure were greatly reduced as compared with that of the solvent group, indicating the therapeutic effect of the compounds of the present disclosure was very significant. The survival rates of mice on the 7th day of most of the compound groups were higher than that of the positive drug voriconazole group, indicating that the pharmaceutical effect of these compounds was superior to that of the voriconazole suspension prepared with CMC-Na, and the survival rates of mice on the 7th day of QR16023 and QR16030 groups were same with the positive drug voriconazole group, proving that their efficacy were equivalent to the voriconazole suspension prepared with CMC-Na.