Posaconazole derivative, pharmaceutical composition and use thereof

1. A compound represented by formula (I), a racemate, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

wherein, R is

 which are unsubstituted or substituted with one or more R a or R b ;

R t is

X 1 and X 2 are independently chosen from F, Cl, Br, or I;

X 3 is a pharmaceutically acceptable anion;

R 1 is R h ;

R h is

 O(O)C(NH 2 )CH 2 OH, or —OS(O) 2 OM 3 ;

R 2 and R 4 are independently H or C 1-40 alkyl that is unsubstituted or substituted with one or more R a ;

R 3 is a C 1-40 alkyl that is unsubstituted or substituted with one or more R b ;

R 5 and R 6 are independently H, or independent chosen from the following groups that are unsubstituted or optionally substituted with one or more R m : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, or —C(O)R f ;

Ar is chosen from the following groups that are unsubstituted or substituted with one or more R c : C 6-20 aryl, 5-20 membered heteroaryl, wherein the heteroaryl has 1-5 heteroatoms independently chosen from N, O, or S;

R 7 is chosen from the following groups that are unsubstituted or substituted with one or more R c : C 1-40 alkyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, —Y 2 P(O)(OM 1 )(OM 2 ), —C(O)R f , or —(CH 2 CH 2 O) z —R b , wherein z is an integer of 1 to 10;

R 8 is H, or chosen from the following groups that are unsubstituted or substituted with one or more R b : C 1-40 alkyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, NR d R e , —CONR d R e , —C(O)Y 2 R f , —Y 2 (O)CR f , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

R 9 is chosen from the following groups that are unsubstituted or substituted with one or more R b : R 10 —Y 3 —Y 4 —, R 11 —C(O)—Y 5 —Y 6 —, C 1-40 alkyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, —Y 2 —N(R 4 )—C(═NH)—NH 2 , —Y 3 —N(R 2 )—C(O)—Y 2 —N(R 4 )—C(═NH)—NH 2 , or —(CH 2 CH 2 O) z —H, wherein z is an integer of 1 to 10;

R 10 and R 11 are independently H, or are chosen from the following groups that are unsubstituted or substituted with one or more R b : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently chosen from a chemical bond, —O—, —S— or the following groups that are unsubstituted or substituted with one or more R a : —NH—, C 1-40 alkyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, or —(CH 2 CH 2 O) m , wherein m is an integer of 0 to 10;

provided that, when two or more of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are adjacent, the adjacent groups are not chemical bonds at the same time;

each R a is independently chosen from H, C 1-40 alkyl, C 1-40 alkoxy, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, F, Cl, Br, I, OH, SH, CN, ═O, NR d R e , —C(O)Y 2 R f , —Y 2 (O)CR f , —CONR d R e , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

each R b is independently chosen from H, F, Cl, Br, I, OH, SH, CN, or the following groups that are unsubstituted or substituted with one or more R a : C 1-40 alkyl, C 1-40 alkoxy, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C 6-20 aryl, C 6-20 aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, NR d R e , —CONR d R e , —C(O)Y 2 R f , —Y 2 (O)CR f , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

each R c is independently chosen from F, Cl, Br, I, OH, SH, CN, or the following groups that are unsubstituted or substituted with one or more R a : C 1-40 alkyl, C 1-40 alkoxy, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, NR d R e , —CONR d R e , —C(O)Y 2 R f , —Y 2 (O)CR f , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

each R d and R e are independently H, or chosen from the following groups that are unsubstituted or substituted with one or more R m : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, —CONR f R g , —C(O)Y 2 R f , —Y 2 (O)CR f , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

each R f and R g are independently H, or chosen from the following groups that are unsubstituted or substituted with one or more R m : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, COOH, 3-20 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl;

each R m is independently chosen from H, F, Cl, Br, I, OH, SH, CN, or the following groups that are unsubstituted or substituted with one or more R a : C 1-40 alkyl, C 1-40 alkoxy, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, NR d R e , —CONR d R e , —C(O)Y 2 R f , Y 2 (O)CR f , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ;

M 1 , M 2 , and M 3 are independently selected from H or C 1-40 alkyl that is unsubstituted or substituted with one or more R b ;

provided that when R is

 R 1 is not hydroxyl; and when R t is

 R 3 is not —CH 2 NHCH 3 ;

wherein the heterocyclyl and heteroaryl are independent from each other and each has 1-5 heteroatoms independently chosen from N, O or S.

2. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 , wherein:

X 1 and X 2 are independently chosen from F, C 1 or Br;

X 3 represents an acid ion generated by ionization of an inorganic acid or an organic acid;

R 2 is chosen from H, or C 1-40 alkyl that is unsubstituted or substituted with one or more R a ;

R 3 is selected from C 1-40 alkyl which is unsubstituted or optionally substituted with one or more R b ;

Ar is chosen from the following groups that are unsubstituted or substituted with one or more R c : C 6-10 aryl, 5-10 membered heteroaryl.

3. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 , wherein the pharmaceutically acceptable salt of the compounds of formula (I) is chosen from to:

alkali metal salts, alkaline earth metal salts, ammonium salts, salts of compounds of formula (I) with organic bases providing physiologically acceptable cations, or acid addition salts of compounds of formula (I) with an inorganic acid or an organic acid.

4. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of formula (I) is a compound of formula (I′):

5. A method for preparing the compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 , comprising reacting a compound of the formula (II)

with a compound of R z -L, wherein R z is R h or R t , wherein L is a leaving group representing a charged or uncharged atom or group that is detached during the reaction.

6. The method according to claim 5 , wherein the reacting step comprises one or more of the following reactions:

wherein, R′ represents

PG is a protecting group;

X 3 ′ is an organic substituent that is converted to X 3 in the reaction;

L 3 and L 4 are independently chosen from F, Cl, Br, or I.

7. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 .

8. A method of preventing or treating a disease caused by a fungus in a subject in need thereof, comprising administering to the subject an effective amount of the compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 .

9. The compound, racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein:

X 1 and X 2 are independently chosen from F, Cl or Br;

X 3 represents a monovalent acid ion generated by ionization of an inorganic or organic acid;

alternatively, when a plurality of cations are present in the structure of the compound of formula (I), X 3 represents a plurality of monovalent acid ions generated by ionization of an inorganic acid or an organic acid;

alternatively, when a plurality of cations in the structure of the compound of formula (I) share one polyvalent acid ion, X 3 represents a part of the polyvalent acid ion;

alternatively, X 3 represents a mixture of the monovalent acid ions as mentioned above, a mixture of the polyvalent acid ions as mentioned above, or a mixture of the monovalent acid ions and the polyvalent acid ions as mentioned above;

R 2 is H, or chosen from the following groups unsubstituted or substituted with one or more R a : methyl, ethyl, propyl, isopropyl, or tert-butyl;

R 3 is chosen from C 1-40 alkyl substituted with one, two, or three substituents independently chosen from C 1-6 alkyl, —NH 2 , —COOH, —OH, —CONH 2 , N(CH 3 ) 2 , NH(CH 3 ), NHCONH 2 , (C 6 H 4 )—OH, or NH(CH 2 ) k CH 3 ; and

Ar is chosen from pyridyl or phenyl.

10. The compound, racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 9 , wherein:

X 3 represents Cl − , Br − , I − , HSO 4 − , NO 3 − , ½SO 4 2− , SO 4 2− , 3/2SO 4 2− , H 2 PO 4 − , ½HPO 4 2− , 3/2HPO 4 2− , ⅓PO 4 3− , ⅔PO 4 3− , or PO 4 3− ;

R 3 is chosen from —(CH 2 ) k —NH 2 , —CH(NH 2 )—(CH 2 ) k —COOH,

 —(CH 2 ) k —COOH, —CH(NH 2 )—(CH 2 ) k —NH—CONH 2 , CH(NH 2 )—(CH 2 ) k —CONH 2 , —CH(NH 2 )—(CH 2 ) k —OH, —CH(NH 2 )—(CH 2 ) k —CH(OH)—CH 3 , —CH(NH 2 )—(CH 2 ) k —(C 6 H 4 )—OH, —CH(NH 2 )—(CH 2 ) k —NH—(CH 2 ) k —CH 3 , —(CH 2 ) k —NH—(CH 2 ) k —CH 3 , or —(CH 2 ) k —N(CH 3 ) 2 , wherein k is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

Ar is

 wherein the C atom at 2-position of the pyridyl is connected to N atom, and the C atom at 3-position is connected to methylene group.

11. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 10 , wherein:

R is

R 3a is a C 1-40 alkyl that is unsubstituted or substituted with one or more substituents chosen from OH or NR d R e ;

R h is chosen from

 —O(O)C(NH2)CH2OH, or , —OS(O) 2 OM 3 ,

R 9 is chosen from the following groups that are unsubstituted or substituted with one or more R b : R 10 —Y 4 —,R 11 —C(O)—Y 5 —Y 6 —, C 1-40 alkyl, C 1-40 alkoxy, —Y 2 —N(R 4 )—C(═NH)—NH 2 , —Y 3 —N(R 2 )—C(O)—Y 2 —N(R 4 )—C(═NH)—NH 2 , or —(CH 2 CH 2 O) z —H, wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R f is chosen from the following groups that are unsubstituted or substituted with one or more R m : C 1-40 alkyl, COOH, 3-20 membered heterocyclyl, C 6-20 aryl, and 5-20 membered heteroaryl;

each R m is independently chosen from H, F, Cl, Br, I, OH, SH, CN, or the following groups that are unsubstituted or substituted with one or more R a : C 1-40 alkyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, NR d R e , —CONR d R e , C(O)Y 2 R f , Y 2 (O)CR f , —Y 2 P(O)(OM 1 )(OM 2 ), or —Y 2 S(O) 2 OM 3 ; and

M 1 , M 2 , and M 3 are independently chosen from H, methyl, ethyl, or isopropyl.

12. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 11 , wherein:

R h is

R 1a is chosen from C 1-40 alkyl, C 6-20 aryl, C 6-20 arylalkyl, 5-20 membered heteroarylalkyl, 5-20 membered heteroaryl, which are unsubstituted or substituted with one or more C(O)OR f , —OP(O)(OM 1 )(OM 2 ), or —OS(O) 2 OM 3 ; and

R 1b is H or C 1-40 alkyl.

13. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 12 , wherein:

R is

R 1a is chosen from —(CH 2 ) k —C(O)OR f , —(CH 2 ) k —(C 6 H 4 )—C(O)OR f , —(CH 2 ) z —OP(O)(OM 1 )(OM 2 ), —(CH 2 ) k —(C 6 H 4 )—OP (O)(OM 1 )(OM 2 ), —(CH 2 ) k —(C 6 H 4 )—OS(O) 2 OM 3 , or —(CH 2 ) z —OS(O) 2 OM 3 , wherein k is an integer of 0 to10; and

R 1b is H, methyl, ethyl, or isopropyl.

14. The compound, racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 3 , wherein the pharmaceutically acceptable salt of the compounds of formula (I) is selected from the group consisting of:

salts of compounds of formula (I) formed with sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexamethylenediamine, ethanolamine, glycosamine, meglumine, sarcosine, serinol, trishydroxymethyl aminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol;

wherein the inorganic acid is selected from the group consisting of hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, and nitric acid, and

wherein the organic acid is selected from the group consisting of 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-hydroxyl) benzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, embonic acid, pectinic acid, persulfuric acid, 3-phenyl propionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl 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, gluconic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and thiocyanic acid.

15. The compound, racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 3 , wherein, when 1, 2 or 3 of M 1 , M 2 , and M 3 is/are H, the pharmaceutically acceptable salt of the compounds of formula (I) is selected a salt formed independently between —OP(O)(OM 1 )(OM 2 ), —P(O)(OM 1 )(OM 2 ), —OS(O) 2 OM 3 , or —S(O) 2 OM 3 with an ion that is sodium ion, potassium ion, or ammonium ion.

16. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of formula (I) is one of the following compounds and pharmaceutically acceptable salts thereof:

No.

Structure

0002

0003

0004

0005

0006

0007

0008

0010

0011

0012

0013

0014

0015

0016

0017

0018

0019

0020

0021

0022

0023

0024

0025

0026

0027

0028

0029

0030

0031

0032

0033

0034

0035

0036

0037

0038

0039

0040

0041

0042

0043

0044

0045

0046

0047

0047

0049

0051

0052

0053

0054

0055

0056

0057

0058

0062

0063

0064

0065

0066

0067

0068

0069

0070

0071

0072

0073

0074

0075

0076

0077

0078

0079

0080

0081

0082

0083

0084

0085

0086

0087

0088

0089

0090

0091

0092

0096

0097

0098

0099

0100

17. The compound, racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein the pharmaceutically acceptable salts of the compound of formula (I) is one of the following salts:

No.

Structure formula

ST0002

ST0003

ST0004

ST0005

ST0006

ST0007

ST0008

ST0010

ST0011

ST0012

ST0013

ST0014

ST0015

ST0016

ST0017

ST0018

ST0019

ST0020

ST0021

ST0022

ST0023

ST0024

ST0025

ST0026

ST0027

ST0028

ST0029

ST0030

ST0031

ST0032

ST0033

ST0034

ST0037

ST0038

ST0039

ST0040

ST0041

ST0042

ST0043

ST0044

ST0045

ST0046

ST0047

ST0048

ST0049

ST0052

ST0053

ST0054

ST0055

ST0056

ST0057

ST0058

ST0062

ST0063

ST0064

ST0065

ST0066

ST0067

ST0068

ST0069

ST0070

ST0071

ST0072

ST0073

ST0074

ST0075

ST0076

ST0077

ST0078

ST0079

ST0080

ST0081

ST0082

ST0083

ST0084

ST0085

ST0086

ST0087

ST0088

ST0089

ST0090

ST0091

ST0092

ST0100

ST0101

ST0102

ST0103

ST0104

ST0105

ST0106

18. The method according to claim 5 , wherein L is chosen from H, F, Br, Cl, I, mesylate ester group, or tosylate ester group, wherein

the compound of formula (II) is first reacted with R h -L 1 and the resulting compound is further reacted with R t -L 2 ; or, the compound of formula (II) is first reacted with R t -L 2 , and the resulting compound is further reacted with R h -L 1 , wherein L 1 and L 2 are leaving groups independently chosen from H, F, Br, Cl, I, mesylate ester group, or tosylate ester group.

19. The method according to claim 8 , wherein the fungus is Candida albicans or Aspergillus fumigatus .