WO2014075618A1

WO2014075618A1 - Heterocyclic ring-containing 5-hydroxy indole derivative and use thereof

Info

Publication number: WO2014075618A1
Application number: PCT/CN2013/087136
Authority: WO
Inventors: 宫平; 赵燕芳; 刘亚婧; 翟鑫; 唐启东
Original assignee: 沈阳药科大学
Priority date: 2012-11-15
Filing date: 2013-11-14
Publication date: 2014-05-22
Also published as: CN102924443B; TW201418250A; TWI609015B; CN102924443A

Abstract

The present invention relates to a heterocyclic ring-containing 5-hydroxy indole derivative as represented by formula I, comprising a racemate of the derivative, an optical isomer of same, and a pharmaceutically acceptable salt and/or hydrate thereof, where substituent R₁, R₂, X, Y, and Z have the meanings as provided in the description. The compound of formula I is applicable in preparing a medicament for treatment and/or prevention of viral infections, and particularly for preparing an anti-hepatitis B virus medicament and anti-influenza virus medicament.

Description

5-hydroxyindole derivative containing a heterocyclic ring and use thereof

The present invention relates to a series of 5-hydroxyindole derivatives containing a heterocyclic ring, and uses thereof, and pharmaceutical compositions containing the compound as an active ingredient, and in the preparation thereof for the treatment and/or prevention of viral infections, particularly Use in hepatitis B virus and influenza virus infection drugs. Background technique:

Viral infections can cause a variety of diseases that seriously endanger human health and life. To date, more than 3,000 viruses have been discovered worldwide, and new viruses are still being discovered. According to statistics, 60-65% of epidemic infectious diseases are caused by viral infection. Due to the complexity of the interaction between the virus and the host, most antiviral drugs have a lower toxicity or antiviral effect on the human body when they exert therapeutic effects. This is also the reason for the slow development of antiviral drugs. As far as the current structure of antiviral drugs is concerned, the drugs available for clinical use are still scarce and far from meeting the needs of preventing and treating toxic diseases. It is of great significance to study antiviral drugs with novel antiviral mechanisms, strong antiviral activity and low toxicity.

The 5-hydroxyindole-3-carboxylate derivative was originally studied as a novel anti-influenza virus drug. Grinev AH" et al. Khim-Farm Zh, 1987, 21(1), 52; Parisheva EK et al. Khim Farm Zh, 1988, 22(5). 565; Mezentseva MV et al. Khim Farm Zh, 1990, 24 (10), 52; Otova SA, et al. Khim Farm Zh, 1992, 26(1), 52; Zotova SA et al. Khim Farm Zh, 1995, 29(1), 51 and other literature reports

The synthesis and pharmacological activity of 5-hydroxyindole-3-carboxylate compounds have shown that some of the compounds have anti-influenza activity and have pharmacological effects of inducing interferon production and enhancing human immunity.

In 1993, a structural derivative of this type, 1-methyl-4-[(dimethylamino)methyl]-2-(phenylthiomethyl)-5-hydroxy-6-bromo, was developed by the former Soviet Union VNIKhFI. -1H-indole-3-carboxylic acid ethyl ester hydrochloride (Arbidol, PCT Int Appl. WO 9008135 (RUSS), 1990-6-26) is marketed in Russia for the treatment and prevention of influenza A and B and acute Viral respiratory infections. Our group, with Abidol as the lead compound, further modified and optimized its structure, and successively obtained a series of novel 5-hydroxyindole-3-carboxylate derivatives, and applied for it successively. Related patents.

In 2003, CN1482118 discloses a novel 5-hydroxy-3-carboxylate steroid derivative and a process for the preparation thereof, which describe a 5-hydroxy-3-carboxylate steroid or a pharmaceutically acceptable salt thereof. It has a significant inhibitory effect on influenza virus and respiratory virus, and provides a new and highly effective anti-influenza virus drug.

In 2004, CN1706827 discloses 5-hydroxyindole-3-carboxylate derivatives and uses thereof, and describes 5-hydroxyindole-3-carboxylate derivatives of another structure or a pharmaceutical thereof The accepted salt can be used for the preparation of a medicament for the treatment and/or prevention of viral infections, in particular for the preparation of anti-hepatitis B virus and anti-human immunodeficiency virus drugs.

Among the virological indicators of HBV, HBeAg is an important marker of HBV replication and infection. In the process of HBV infection, HBeAg can synergize with human leukocyte antigen to regulate the host's immune response, inhibit the cytotoxic activity of host T cells, form immune tolerance to HBV infection, and make HBV escape immune clearance, enabling asymptomatic carriers. Long-term storage in the group. The HBeAg seroconversion that occurs after antiviral therapy is more important than the reduction in HBV-DNA levels: patients receive a sustained response, improved prognosis, and improved immunity to HBV; indicating that HBV replication is continuously controlled.

On the basis of the previous period, further studies on 5-hydroxy steroids have been carried out, and it has been found that the introduction of sulfur-containing heterocycles such as thiadiazolyl, thiazolyl and thiazolidinone groups at the 2-position of the anthracene ring can greatly Increase the activity of the compound on hepatitis B virus HBeAg secretion. Summary of the invention:

The present invention relates to a 5-hydroxyindole derivative containing a heterocyclic ring of the formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

« is (dC ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl;

R ₂ is (CC alkyl group;

X is hydrogen, halogenated;

Y is - R ₃ R4 _;

R ₃ and the same or different, each independently selected from (C Cs)alkyl, (C ₃ -C ₆ )cycloalkyl, optionally substituted by 1 to 3 identical or different;

Or R ₃ and together with the nitrogen atom to which they are attached form a mercapto group, a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, in addition to the nitrogen attached to R ₃ and Outside the atom, optionally 1 to 4 hetero atoms selected from N, 0 and S, the heterocyclic group and the heteroaryl group optionally having 1 to 3 identical or different R ₈ substitutions;

Representative of (CC ₄ )alkyl, (dC ₄ )alkoxy, halo, hydroxy, cyano, carboxy, ester, nitro;

(0) _m

Z is a CH ₂ —(CH ₂ ) _n —Q ; m is 0, 1, 2;

n is an integer between 0 and 4;

Q is s,

R ₅ is hydrogen, (dC ₄ )alkyl, dC ₄ alkoxy, hydroxy, optionally hydroxy, amino or halogenated (dC ₄ )alkyl or (dc alkoxy, (dc alkylthio, free) , salt-forming, esterified and amidated carboxyl, halogenated,

(CrC ₄ )alkyl acyl, nitro, cyano, amino, (dC ₄ )alkylamido or substituted by mono or bis[(dC ₆ )alkyl)]

Or R ₅ is (C ₆ -C _1Q )aryl or 5-10 membered heteroaryl, which are optionally substituted by 1 to 3 identical or different R ₉ , wherein the heteroaryl and heterocyclic are Optionally containing from 1 to 3 heteroatoms selected from N, 0 or S;

R ₉ is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC ₄ ) alkenyl, (CrC ₄ ) alkynyl, (CrC ₄ )alkylthio, hydroxy(CrC ₄ )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C ₄ )alkylamido, (CrC ₄ )alkylsulfinyl, (CrC ₄ )alkylsulfonyl, (CrC ₄ ) alkane Oxymethyl group, (dC ₄ ) Alkyl acyl, carbamoyl, N dc alkylcarbamoyl, N, N-di(dc alkylcarbamoyl, aminosulfonyl, A dC alkylaminosulfonyl, N, N-di (dC alkyl) Aminosulfonyl and (d-Cg)alkylene

The invention preferably also relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

« is (dC ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl;

R ₂ is (CC alkyl group;

X is hydrogen, halogenated;

Y is - R ₃ R4 _;

(0) _m

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4;

Q is s,

R ₅ is hydrogen, (dC ₄ )alkyl, (dC ₄ )alkoxy, hydroxy, (dC ₄ )alkyl or (CrC ₄ )alkoxy optionally substituted by (hydroxy, amino or _3⁄4 ), (CrC ₄ )alkylthio, (free, salt-forming, esterified or amidated) carboxyl, halogenated, (CrC ₄ )alkyl acyl, nitro, cyano, amino, (CrC ₄ ) alkane An amide group or an amino group substituted with a mono or di(CrC ₆ )alkyl group; Or R ₅ is phenyl or 5-6 membered heteroaryl, wherein said heteroaryl optionally contains 1-3 heteroatoms selected from N, 0 or S, and R _{5 is} optionally 1-3 The same or different R ₉ substitutions;

R ₉ is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (dC ₄ )alkenyl, (dC ₄ ) alkynyl, (dC ₄ )alkylthio, hydroxy(dC ₄ )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C ₄ )alkylamido, (CrC ₄ )alkylsulfinyl, (CrC ₄ )alkylsulfonyl, (CrC ₄ ) alkane Oxymethyl, (dC ₄ ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkylcarbamoyl, aminosulfonyl, A dC alkylaminosulfonyl, N, N-di(dC alkylaminosulfonyl and (d-Cg)alkylenedioxy.

The invention further relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

among them,

« is (dC ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl;

R ₂ is (C )alkyl;

X is hydrogen, halogenated;

Y is - R ₃ R4 _;

(0) _m

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4; O

0 is ^R 5 ;

R ₅ is phenyl or a 5-6 membered heteroaryl group, wherein the heteroaryl group optionally contains 1-3 heteroatoms selected from N, 0 or S, and R _{5 is} optionally 1-3 identical Or a different R ₉ substitution;

R ₉ is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC ₄ ) alkenyl, (CrC ₄ ) alkynyl, (CrC ₄ )alkylthio, hydroxy(CrC ₄ )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C ₄ )alkylamido, (CrC ₄ )alkylsulfinyl, (CrC ₄ )alkylsulfonyl, (CrC ₄ ) alkane Oxymethyl, (dC ₄ ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkylcarbamoyl, aminosulfonyl, A dC alkylaminosulfonyl, N, N-di(dC alkylaminosulfonyl and (d-Cg)alkylenedioxy.

1^ is methyl, ethyl, propyl, isopropyl, cyclopropyl;

R ₂ is (C )alkyl;

X is hydrogen, bromine or fluorine;

Y is - R ₃ R4 _;

R ₃ and the same or different, respectively selected from (CC ₄ ) alkyl, cyclopropyl;

Or R ₃ and together with the nitrogen atom to which they are attached form a mercapto group, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1H-1, 2,4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1H-tetrazol-1-yl;

(0) _m

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2; n is an integer between 0 and 4;

Q is "^, ^s R _{5 ;}

R ₅ is hydrogen, (dC ₄ )alkyl, (dC ₄ )alkoxy, hydroxy, (dC ₄ )alkyl or (CrC ₄ )alkoxy optionally substituted by (hydroxy, amino or _3⁄4 ), (CrC ₄ )alkylthio, (free, salt-forming, esterified and amidated) carboxyl, halogenated, (CrC ₄ )alkyl acyl, nitro, cyano, amino, (CrC ₄ ) alkane An amide group or an amino group substituted with a mono or di(CrC ₆ )alkyl group;

Or R ₅ is phenyl or 5-6 membered heteroaryl, wherein said heteroaryl optionally contains 1-3 heteroatoms selected from N, 0 or S, and R _{5 is} optionally 1-3 The same or different R ₉ substitutions;

The invention particularly preferably relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof, as defined below,

1^ is methyl, ethyl, propyl, isopropyl, cyclopropyl;

R ₂ is (C )alkyl;

X is hydrogen, bromine or fluorine;

Y is - R ₃ R4 _;

Or R ₃ and together with the nitrogen atom to which they are attached form a mercapto group, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1H-1, 2,4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1H-tetrazo Zin-1-yl;

(0) _m

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4;

N^ ^R 5 , - N

Q is s

R ₅ is hydrogen, (dC ₄ )alkyl, phenyl optionally substituted by 1 to 3 identical or different R ₉ ;

R ₉ is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC ₄ ) alkenyl, (CrC ₄ ) alkynyl, (CrC ₄ )alkylthio, hydroxy(CrC ₄ )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C ₄ )alkylamido, (CrC ₄ )alkylsulfinyl, (CrC ₄ )alkylsulfonyl, (CrC ₄ ) alkane Oxymethyl, (dC ₄ ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkylcarbamoyl, aminosulfonyl, A dC alkylaminosulfonyl, N, N-di(dC alkylaminosulfonyl and (d-Cg)alkylene

among them,

1^ is methyl, ethyl, propyl, isopropyl, cyclopropyl;

R ₂ is (C )alkyl; X is hydrogen, bromine;

Y is - R ₃ R4 _;

Or R ₃ and together with the nitrogen atom to which they are attached form a mercapto group, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1H-1, 2,4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1H-tetrazol-1-yl; Representative (CC ₄ )alkyl, (dC ₄ )alkoxy, halo, hydroxy, cyano, carboxy, ester, nitro; (0) _m

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4;

0

0 is ^R 5 ;

R ₉ is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC ₄ ) alkenyl, (CrC ₄ ) alkynyl, (CrC ₄ )alkylthio, hydroxy(CrC ₄ )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C ₄ )alkylamido, (CrC ₄ )alkylsulfinyl, (CrC ₄ )alkylsulfonyl, (CrC ₄ ) alkane Oxymethyl, (dC ₄ ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N, N-di (dC alkylcarbamoyl, aminosulfonyl, A dC alkylaminosulfonyl, N, N-di(dC alkylaminosulfonyl and (d-Cg)alkylenedioxy.

among them,

1^ is methyl, ethyl, propyl, isopropyl, cyclopropyl;

R ₂ is (C )alkyl; X is hydrogen, bromine;

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4;

0

0 is ^R 5 ;

R ₅ is phenyl, furyl, pyrrolyl, thienyl, pyridyl, and R ₅ is optionally substituted by 1 to 3 identical or different R ₉ ;

among them,

1^ is methyl, ethyl, propyl, isopropyl, cyclopropyl;

R ₂ is (C )alkyl; X is hydrogen, bromine;

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4;

0

0 is ^R 5 ;

R ₅ is furan-2-yl, pyridin-2-yl, thiophen-2-yl;

Very particularly preferred derivatives of the general formula I, including racemates or optical isomers thereof, and pharmaceutically acceptable salts and/or hydrates thereof, are:

环Cyclopropyl-4-[(dimethylamino)methyl]-2-[(4-phenylthiazol-2-yl)thiomethyl]-5-hydroxy-6-bromo-1H-indole-3 - ethyl carboxylate;

1-cyclopropyl-4-[(morpholin-4-yl)methyl]-2-[(4-phenylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo- 1H-indole-3-carboxylic acid ethyl ester;

环Cyclopropyl- 4-[(dimethylamino)methyl]-2-[(4-phenylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H-indole- 3-carboxylic acid ethyl ester;

环Cyclopropyl- 4-[(dimethylamino)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfinylmethyl]-5-hydroxyl Ethyl 6-bromo-1H-indole-3-carboxylate;

环Cyclopropyl-4-([tetrahydropyrrol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfonylmethyl] - 5-hydroxy-6- Ethyl bromide-^-indole-3-carboxylate;

1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-phenylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1H - anthracene-3-carboxylic acid ethyl ester;

1-Cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-phenylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H- Ethyl-3-carboxylate;

1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(thiazol-2-yl)thiomethyl]-5-hydroxy-6-bromo-1H-indole-3- Ethyl carboxylate;

1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(thiazol-2-yl)thiomethyl]-5-hydroxy-6-bromo-1H-indole哚-3-carboxylic acid ethyl ester;

1-Methyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1H- Ethyl-3-carboxylate;

1-methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo -1H- oxime-3-carboxylic acid ethyl ester;

1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(thiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H-indole-3 - ethyl carboxylate;

1-Cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(thiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H- Ethyl-3-carboxylate;

I-methyl-4-[(dimethylamino)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1H-indole Ethyl-3-carboxylate;

1-Methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[thiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1H-indole Ethyl-3-carboxylate;

1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6 - ethyl bromide-1H-indole-3-carboxylate;

1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfinylmethyl]-5-hydroxy-6-bromo-1H - anthracene-3-carboxylic acid ethyl ester;

1-Cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H-吲哚 Ethyl-3-carboxylate;

1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfinylmethyl] - Ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylate;

1-methyl-4-[(2-methylimidazolyl-1-yl)methyl]-2-[(5-methyl- 1 ,3,4-thiadiazol-2-yl)sulfinyl Ethyl] 5-hydroxy- 6-bromo-^-indole-3-carboxylate.

i-Methyl 4-[(tetrahydropyrrol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl -5-Hydroxy-6-bromo-^"anthracene-3-carboxylate;

1-Methyl-4-[(morpholin-4-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl] -5-hydroxy-6-bromo-^-indole-3-carboxylate;

i-Methyl-4-[(dimethylamino)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl] -5- Ethyl hydroxy-6-bromo-^-indole-3-carboxylate;

1-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio Methyl]-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester;

1-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-2-[[2-[2-(3-trifluoromethylphenyl)-4-oxothiazoline Ethyl 3-methyl]ethylthio]methyl]-5-hydroxy-6-bromo-1H-indole-3-carboxylate;

1-Methyl-4-[(diethylamino)methyl]-2-[[2-[2-(4-methoxyphenyl)-4-oxothiazolin-3-yl]ethylthio Methyl]-5-hydroxy-6-bromo-indole-3-carboxylate;

I-methyl-4-[(dimethylamino)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylsulfinyl]methyl] - Ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylate;

1-cyclopropyl-4-[(morpholin-4-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylsulfinyl] Methyl]-5-hydroxy-6-bromo-indole-3-carboxylate;

1-cyclopropyl-4-[(dimethylamino)methyl]-2-[[2-[2-(pyridin-4-yl)-4-oxothiazolin-3-yl]ethylthio] Methyl]-5-hydroxy-6-bromo-indole-3-carboxylate;

1-Methyl-4-[(imidazolyl-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio]methyl] - Ethyl 5-hydroxy-6-bromo-^-indole-3-carboxylate;

1-Methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio] Methyl] -5- Ethyl hydroxy-6-bromo-1H-indole-3-carboxylate;

1-Methyl-4-[(imidazol-1-yl)methyl]-2-[[2-[2-(3-trifluoromethylphenyl)-4-oxothiazolin-3-yl] Ethylthio]methyl]-5-hydroxy-6-bromo-indole-3-carboxylate;

1-cyclopropyl-4-[(2-methylimidazol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethyl Sulfonyl: ethyl]ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylate.

Moreover, the heterocyclic 5-hydroxyindole derivative of the formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid according to some usual methods in the art to which the present invention pertains. The acid may include an inorganic or organic acid, and a salt formed with the following acids is particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid, and the like.

The compounds of the invention may exist in stereoisomeric forms which may be enantiomers or diastereomers. The invention relates both to enantiomers or diastereomers, as well as to their respective mixtures, which, like diastereomers, can be separated into stereoisomeric single components in a manner known per se.

Furthermore, the invention also includes prodrugs of the compounds of the invention. According to the invention, prodrugs are derivatives of the compounds of formula I which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) It is converted to the corresponding biologically active form.

The term "halo" as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo; "alkyl" means a straight or branched alkyl; "cycloalkyl" means a substituted Or an unsubstituted cycloalkyl group; "alkenyl" means a straight or branched alkenyl group; "alkynyl" means a straight or branched alkynyl group; "aryl" means a hydrogen removed from an aromatic hydrocarbon. An organic group derived from an atom, such as a phenyl group or a naphthyl group; a 5-10 membered heteroaryl group includes a hetero atom containing one or more selected from N, 0 and S, wherein a cyclic system of each heteroaryl group may be used. Is monocyclic or polycyclic, the cyclic system is aromatic, containing a total of 5-10 atoms, such as imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1, 2, 3)- and (1, 2, 4)-triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, a benzofuranyl group, a benzimidazolyl group, a benzothiazolyl group, a fluorenyl group, a quinolyl group or the like; a 5-10 membered heterocyclic group includes one or more hetero atoms selected from N, 0 and S, each of which Miscellaneous The cyclic system of the radical may be monocyclic or polycyclic, but non-aromatic, the cyclic system containing a total of 5-10 atoms, optionally including 1 or 2 Examples of the carbon-carbon double bond or the carbon-carbon oxime bond include a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, a thiazolinyl group and the like. Particular compounds of the invention may have asymmetric centers and therefore exist in different enantiomers and diastereomers. The present invention relates to all optical isomers, racemates and mixtures thereof of the compounds of the invention. "Blancher" means a mixture containing equal amounts of a pair of enantiomers.

Since the 5-hydroxyindole compound of the above formula I according to the present invention has an antiviral action, particularly anti-HBV and anti-influenza activity, it can be used as a medicament for the preparation of a therapeutic and/or prophylactic viral infection. In particular, infections caused by viruses such as HBV, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus, and adenovirus.

The compound according to the present invention can be used as an active ingredient for the preparation of a therapeutic and/or prophylactic agent for hepatitis B, influenza, acute viral respiratory infection and influenza, and the present invention also provides a method for treating or preventing the above-mentioned diseases, including giving or suffering from A patient having this condition has a therapeutically effective amount of a compound according to the invention.

The present invention includes a pharmaceutical composition comprising a 5-hydroxyindole compound of the formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The compounds of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.

The pharmaceutical compositions of the present invention may be formulated in a number of dosage forms containing some of the excipients commonly used in the pharmaceutical arts; for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations (e.g. Injectable solutions or suspensions, or injectable dry powders, ready to use by adding water for injection before injection; topical preparations (eg ointments or solutions).

The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, and includes: a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, a stabilizer, a suspending agent, and a non-pigment. , flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.

Moreover, the clinical dose of the 5-hydroxy steroid of the formula I for use in a patient can be based on: the active ingredient is in the body The therapeutic efficacy and bioavailability, their metabolic and excretion rates, and the age, sex, and disease period of the patient are appropriately adjusted, but the daily dose for adults should generally be 10-500 mg, preferably 50-300 mg. Accordingly, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, in view of the above effective dose, each unit preparation should contain 10-500 mg of the 5-hydroxyindole compound of the above formula I, preferably 50-300 mg. These preparations may be administered several times at intervals (preferably one to six times; as directed by a physician or pharmacist).

The following Scheme A-C describes the preparation of the compounds of formula I of the present invention, all of which are prepared by the methods described in these schematic schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schematics or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All of the variable factors applied in these schematics are as defined below or as defined in the claims.

According to the formula I or a compound of the formula of the present invention, in the route A, Y is -NR ₃ R4, wherein R ₃ , the same or different, are respectively selected from hydrogen, amino, d-doalkyl, C ₃ -C ₇ a cycloalkyl group, a C ₂ -C _1Q alkenyl group and a C ₂ -C _1Q alkynyl group, which may be optionally substituted by 1 to 3; or R ₃ , together with the nitrogen atom to which they are attached, form a 5-10 membered hetero a cyclo group, which may contain, in addition to R ₃ and a bonded nitrogen atom, from 1 to 4 heteroatoms selected from N, 0 and S, except for R ₃ and the attached nitrogen atom, The ring group optionally includes 1 or 2 carbon-carbon double bonds or hydrazine

a bond, the heterocyclic group may be optionally substituted by 1 to 3; Q is

The substituents Ri, R ₂ and R _{5 are} as defined in the Summary of the Invention.

Route A

According to the compound of the formula I according to the invention, in Scheme B, the substituents X, R _{2 are} as defined in the claims; Q, R ₃ and R4 are as defined for the substituents of the compounds in Scheme A.

Route B

Compound B1 can be prepared according to the synthesis method provided in Scheme A. Compound B-1 is reacted with sodium perborate (NaB0 ₃ ) as an oxidant in glacial acetic acid at 40 ° C to 60 ° C by changing the ratio and reaction of the oxidizing agent. At time, monooxide B-2 and double oxide B-3 are obtained, and then the Mannich reaction is carried out to obtain compounds B-4 and B-5 of formula I or formula II.

According to the formula I or the formula of the formula of the present invention, in the route C, Y is -NR ₃ R4, -S(CH ₂ ) _r R ₈ , r is an integer between 1-4, and Ri, R ₂ and Z are as A compound of formula II as defined in the claims, R ₃ , and together with the nitrogen atom to which they are attached form a fluorenyl group or a 5-10 membered heteroaryl group, which may be in addition to the nitrogen atom attached to R ₃ and Containing from 1 to 4 heteroatoms selected from N, 0 and S, the heteroaryl group may be optionally substituted by from 1 to 3 identical or different R ₈ ; other substituents are as defined in the formula Π compound.

C-1 C-2

Route C

Compound C-1 can be obtained by the synthesis method provided in Schemes A and B, and compound C-1 is reacted with compound HNR ₃ R4 or HS(CH ₂ )mR ₈ , and the organic solvent used for the reaction is ethanol-water (1 _: 1) Solvent, reaction temperature is 60-80 °C, reaction time is 4-12 h, reaction is completed, concentrated reaction solution, dichloromethane extraction, combined, dried, evaporated to dryness, recrystallized from ethanol or methanol or column Analysis gave Compound C-2 of Formula I or Formula II. Detailed ways:

The examples are intended to illustrate and not to limit the scope of the invention. The nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-300, and the mass spectrum was determined by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.

Preparation of mercaptans or thiophenol intermediates

Partial mercaptans or thiophenols are commercially available; other thiols or thiophenols are prepared as follows: Method 1 : Preparation of s"

100 mL of carbon disulfide (1.6 mole) was added to a three-necked flask, and the temperature was lowered to -5 ° C. A 15% ammonia-ethanol solution (300 mL) was added dropwise, and the mixture was further stirred at -5 ° C for 4 h. The mixture was filtered under suction, washed with diethyl ether and dried to give 152 g of yel.

Add 100 mL (0.85 mol) of acetophenone to 150 mL of ethanol, and add phenyl trimethylammonium tribromide (PTT) 320 g (0.85 mol) in batches at a temperature not higher than -5 °C. After completion, the mixture was stirred for 30 min, suction filtered, and the filtrate was concentrated under reduced pressure to give 164 g of colorless liquid α-bromoacetophenone, content 95%, yield 92%.

Add 40% chloroacetaldehyde 100 mL (0.61 mol) to 100 mL water, control the temperature below 5 °C, add 67 g (0.61 mol) of ammonium dithiocarbamate in batches, add to the temperature, continue to stir at room temperature 2 h, a white solid was precipitated, suction filtered, and the filter cake was washed with a small amount of ethanol and water, respectively, and dried to give a white solid thiazole-2-thiol 66.2 g, yield 93%.

According to the preparation method of thiazole-2-thiol, a white solid 4-methylthiazole-2-thiol was obtained by using chloroacetone and ammonium dithiocarbamate as a raw material and ethanol as a solvent, and the yield was 87%.

According to the preparation method of 4-methylthiazole-2-thiol, α-bromoacetophenone and ammonium dithiocarbamate are used as raw materials to prepare 4-phenylthiazole-2-thiol as a white solid. 91%.

Preparation of General Method 1 (Route Α):

Step Α: Preparation of 3-hydrocarbylamino-2-butenoate (A-1)

Install the gas generating device, add 300 mL of 50% sodium hydroxide solution to the three-necked flask, and add methylamine solution or ethylamine aqueous solution (1.4 mol) dropwise to the slightest heat to introduce the methylamine or ethylamine gas. In acetoacetate (1.3 mol), the reaction is exothermic, stirred, and the reaction solution is cooled in a water bath. The reaction temperature is maintained at 35-40 ° C. After the aeration is completed, the room temperature is maintained. Stir for 17 h. To the reaction liquid, 300 mL of diethyl ether was added, and the organic layer was separated. The organic layer was washed with water to pH 8, dried over anhydrous sodium sulfate and evaporated to dryness to give 3-methylamino (ethylamino)-2-butenoic acid. The ester, the yield is 70-90%, and the obtained concentrate is directly used in the next step.

For a hydrocarbon group having a C ₃ -C ₆ alkyl group, a C ₃ -C ₇ cycloalkyl group and a substituted alkyl group or a cycloalkyl group, the 3-hydrocarbylamino-2-butenoic acid ester can be directly used without a gas generating device. The hydrocarbyl-substituted amine was dropped into acetoacetate and prepared according to the above method.

Step B: Preparation of 1-hydrocarbyl-2-methyl-5-hydroxyindole-3-carboxylate (A-2)

Phenylhydrazine (0.096 mol) was dissolved in 100 mL of 1,2-dichloroethane, heated to 60 ° C, stirred until dissolved completely, and the compound Al was added dropwise, and the reaction was refluxed for 8 h. After cooling to room temperature, it was allowed to stand overnight, and the solid was precipitated, suction filtered, washed with cold acetone, dried, and then recrystallized from acetone to give compound A-2, yield: 40 60 %.

Step C: 1-Hydroxy-2-methyl-5-acetoxy-1H-indole-3-carboxylate (A-3)

Add compound A-2 (0.05 mol) to acetone 80 mL, add pyridine 10 mL (0.1 mol), stir until completely dissolved, add 5.5 mL (0.075 mol) of acetyl chloride, and control the reaction temperature below 30 °C. After completion of the dropwise addition, the reaction was stirred at room temperature for 4 h, and the reaction mixture was poured into ice water with stirring, and the mixture was allowed to stand overnight to precipitate a solid, which was filtered, washed with water and dried to give compound A-3, yield 75-90%.

Step D: Preparation of 1-hydrocarbyl-2-bromomethyl-5-acetoxy-6-bromo-1H-indole-3-carboxylate (A-4) Compound A-3 (0.04 mol) was added In 50 mL of carbon tetrachloride, it was heated to reflux until the solid was completely dissolved. Add a catalytic amount of benzoyl peroxide, add 5.1 mL (0.1 mol) of dry bromine to the reaction droplets under reflux with heating, drop, reflux for 5 h, complete reaction, allow to stand, cool, suction filtration, water wash, methanol wash The compound V was obtained in a yield of 65%-85%.

Step E: Preparation of 1-hydrocarbyl-2-(substituted thiomethyl)-5-hydroxy-6-bromo-1H-indole-3-carboxylate (A-5) In 40 mL of methanol, hydrogen peroxide was added. Potassium 5 g (0.09 mol) and substituted thiophenol or thiol (0.03 mol), stirred at room temperature for 2 h, then add compound A-4 (0.03 mol) in portions, stir at room temperature for 6-8 h, neutralize with dilute hydrochloric acid Liquid to neutral, a large amount of solid precipitated, suction filtration, washing with water, washing with methanol, washing with ethyl acetate, recrystallization from ethanol to give a white solid, which was dried to give compound A-5, yield: 60%-90%.

Step H: 1-Hydroxy-4-[(fatty amino)methyl]-2-(substituted thiomethyl)-5-hydroxy-6-bromo-1H-indole-3-carboxylate (A- 6) Preparation

Fatty amine (0.032 mol), 37% formaldehyde solution 1.1 mL (0.014 mol) and compound A-5 (0.013 mol) Add 50 mL of glacial acetic acid in turn, react at 50-55 ° C for 6-8 h, distill off acetic acid under reduced pressure, pour the concentrate into 20 mL of water, add 20% sodium hydroxide solution to adjust the pH to 10, dichloro The aqueous layer was extracted with methylene chloride.

The obtained oil is dissolved in acetone 30 mL, and an appropriate amount of diethyl ether is added dropwise thereto, and the mixture is allowed to stand for crystallizing, filtered, washed with a small amount of acetone and washed with diethyl ether to obtain A-6 in a yield of 40 to 70%;

Or the oil is dissolved in acetone 30 mL, and the hydrochloric acid ethanol solution is added dropwise to pH 1-2, a small amount of diethyl ether is added dropwise to the turbidity, and left to stand overnight, and the crystallized to obtain A-6 hydrochloride, the yield is 40-70. %

The compounds of Examples 1-27 were prepared according to Preparation 1, respectively (see Table 1).

Example iH - drawing R (300 Hz) chemical name structure

No. δ (ppm) or MS m/z

1-cyclopropyl-4-[(morpholin-4-yl;) A.

-2-[[2-[2-(thiophen-2-yl)-4-

19 oxothiazole-3-yl]ethylthio]methyl 679.1, 680.7[M+H]yl]-5-hydroxy-6-bromo-1H-indole

Ethyl-3-carboxylate

1-cyclopropyl-4-[(dimethylamino) A

N J .

Benzyl]-2-[[2-[2-(pyridin-4-yl)-4-

20 oxothiazoline-3-yl]ethylthio] 632.1, 633.6[M+H]methyl]-5-hydroxy-6-bromo-1H-indole

哚-3-carboxylic acid ethyl ester

1-cyclopropyl-4-[(tetrahydropyrrole-1-yl)methyl]-2-[[2-[2-(furan-2-

21 yl)-4-oxothiazol-3-yl]ethylsulfide 647.1, 648.6[M+H]yl]methyl]-5-hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester

1-cyclopropyl-4-[(morpholin-4-yl;)-

N J .

Benzyl]-2-[[2-[2-(furan-2-yl)-4-

22 oxothiazole-3-yl]ethylthio]methyl 663.1, 664.6[M+H] group]-5-hydroxy-6-bromo-1H-indole

Ethyl-3-carboxylate

1

1-cyclopropyl-4-[[(dimethylamino))

Methyl]-2-[[2-[2-(furan-2-)

23 base) -4-oxothiazol-3-yl]ethylsulfide 621.1, 622.6[M+H]yl]methyl]-5-hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester

1

1-cyclopropyl-4-[[(dimethylamino) ^N \ .

Methyl]-2-[[2-[2-(thiophene-2-)

24 yl)-4-oxothiazol-3-yl]ethylsulfide 637.1, 638.7[M+H]yl]methyl]-5-hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester A ^ ^ ⁵ Example iH - drawing R (300 Hz) chemical name structure

No. δ (ppm) or MS m/z

1

1-cyclopropyl-4-[(dimethylamino)methyl "N\.

Base]-2-[[2-[2-(3-trifluoromethyl)

25 base) -4-oxothiazol-3-yl]ethylsulfide 699.1, 700.6 [M+H] yl]methyl]-5-hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester

CF ₃

1

1-cyclopropyl-4-[(dimethylamino) A

-2-[[2-[2-(4-trifluoromethoxy)

26-phenyl)-4-oxothiazole-3-yl] 715.1, 716.6[M+H]ethylthio]methyl]-5-hydroxy-6-bromo

-1H-indole-3-carboxylate

1

1-cyclopropyl-4-[(dimethylamino) A

Base] -2-[[2-[2-(benzo[d][l,3]

Dioxol-5-yl)-4-oxo

27 675.1, 676.6[M+H] thiazole-3-yl]ethylthio]A

-5-hydroxy-6-bromo-1H-indole

Ethyl-3-carboxylate o

Preparation method 2

Step A: Preparation of 1-hydrocarbyl-2-substituted thiomethyl-5-hydroxy-6-substituted (hydrogen)-IH-indole-3-carboxylic acid ethyl ester (Bl) Preparation of compound B-1 can be carried out according to The synthetic method for preparing the general methods 1 and 2 is prepared.

Step B : Preparation of 1-hydrocarbyl-2-substituted sulfinylmethyl-5-hydroxy-6-substituted (hydrogen)-1H-indole-3-carboxylate (B-2)

In 50 mL of glacial acetic acid, add compound B1 (0.01 mol) and sodium perborate tetrahydrate (NaBO ₃ .4H ₂ O) 1.85 g (0.012 mol), stir, and raise the temperature to 40-60 ° C. 1-2 h, TLC was used to monitor the reaction time. After completion of the reaction, evaporated to dryness, water (25 mL), NaOH (10%) solution was adjusted to pH 10, extracted with dichloromethane, and the extracts were combined, washed with water, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated and evaporated. The solid was recrystallized from diethyl ether/yield to afford compound B-2, yield 60-80%.

Step C: Preparation of 1-hydrocarbyl-2-substituted sulfonylmethyl-5-hydroxy-6-substituted (hydrogen)-1H-indole-3-carboxylic acid ethyl ester (B-3) In 50 mL of glacial acetic acid, add compound B-1 (0.01 mol) and sodium perborate tetrahydrate (NaB0 ₃ .43⁄40) 3.85 g (0.025 mol), stir, and raise the temperature to 40-60 °C. 24-36 h, TLC was used to monitor the reaction time. After completion of the reaction, the mixture was evaporated to dryness, and water (25 mL) was added, and the mixture was adjusted to pH 10 with NaOH (10%) solution and extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride, washed with water and dried over anhydrous sodium sulfate. Filtration, evaporation to dryness and recrystallization from methanol gave Compound B-3, yield 50-80%.

Step D: 1-hydrocarbyl-4-substituted aminemethyl-2-substituted sulfinylmethyl (substituted sulfonylmethyl)-5-hydroxy-6-substituted(hydro)-1H-indole-3 -Preparation of ethyl carboxylate (B4 or B-5)

The target product B-4 or B-5 is obtained by reacting Compound B-2 or B-3 with a suitable fatty amine, 37% formaldehyde solution according to the procedure of Preparation 1, Step 1.

According to Preparation Method 2, the compounds of Examples 29-34 were prepared separately (see Table 2).

EXAMPLES ^ - NMR data (300 Hz) δ (ppm) or chemical name Structure

Serial number MS m/z

1-cyclopropyl-4-[(morpholin-4-(CDC1 ₃ ): δ 1.47 (t, 3H), 2.67 (s, 4H), yl)methyl] -2-[(4-phenyl 3.66 (s, 3H), 3.78 (s, 4H), 4.32-4.43 (m,

28 thiazol-2-yl)sulfinylmethyl 4H), 4.83 (d, 1H), 5.12 (d, 1H), 7.40 (m, yl) -5-hydroxy-6-bromo-1H- 3H), 7.47 ( s, 1H), 7.73 (m, 2H), 7.80 (s, ethyl ketone-3-carboxylate

1H).

1-cyclopropyl-4-[(dimethylamine 1

Methyl]-2-[(4-phenyl,

29 thiazole-2-yl)sulfonyl group 617.0, 618.6 [M+H]

-5-hydroxy-6-bromo -1H-

A

Methyl -3-carboxylate

1-cyclopropyl-4-[(dimethylamine 1

Methyl]-2-[(5-methyl ^N \ O (DMSO): δ 1.03-1.33 (m, 7H), 2.26 (d, -1,3,4-thiadiazol-2-yl) 6H) , 2.82 (s, 3H), 3.42 (m, 1H), 4.01 (s,

30

Sulfinylmethyl] -5-hydroxy 2H), 4.10 (q, 2H), 5.04 (d, 1H), 5.24 (d, •6-bromoindole-3-carboxy A ^s i 1H), 7.63 (s , 1H).

Ethyl acetate

1-cyclopropyl-4-[(morpholin-4-yl)methyl]-2-[[2-(2-benzene)

-4- oxothazoline -3-

31 689.1, 690.7[M+H]

Ethylsulfinyl]A

-5-Hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester Example ^ - NMR data (300 Hz) δ (ppm) or chemical name structure

Serial number MS m/z

1-cyclopropyl-4-[(dimethylamine 1

Methyl]-2-[(5-methyl N\ O

-1,3,4-thiadiazole-2-yl)

32 556.0, 556.5[M+H]

Sulfonylmethyl]-5-hydroxy-6-bromoindole-3-carboxylic acid

Ethyl ester A. . ^T

1-cyclopropyl-4-[(tetrahydropyridyl)

咯-1-yl)methyl] -2-[(5- 0 o

Methyl-1,3,4-thiadiazole-2-

33 582.7, 584.6 [M+H]

Sulfonylmethyl]-5-hydroxyl

•6-bromoindole-3-carboxylate

Ethyl acetate A.

1-cyclopropyl-4-[(tetrahydropyridyl)

咯-1-yl)methyl] -2-[(5- 0 o

Methyl-1,3,4-thiadiazole-2-

34 566.5, 568.5 [M+H]

Sulfonylmethyl]-5-hydroxyl

Ethyl 6-bromoindole-3-carboxylic acid ethyl ester A ^s

Preparation General 3 :

Preparation of compound C-l:

Compound C-1 can be obtained according to the preparation of General Procedure 1 or 2.

Preparation of Compound C-2

Add the compound C-lC0.02 moi;> to ethanol: water (I: lOmL, add HNRsI; hydrazine, aromatic amine or nitrogen-containing aromatic heterocycle) or HSCCH ₂ R ₈ C0.05 mol), the reaction solution The temperature is raised to 80 ° C, the reaction is carried out for 6-8 h, concentrated under reduced pressure, extracted with dichloromethane, combined, dried, evaporated to dryness, recrystallized from the solvent, or purified by silica gel column chromatography to give compound C-2. : 50-80%

According to Preparation Method 3, the compounds of Examples 35 to 65 were prepared (see Table 3).

Example ^-NMR data (300 Hz)

Chemical name

No. δ (ppm) or MS m/z

1-cyclopropyl-4-[(imidazol-1-(DMSO): δ 1.09 (m, 2H), 1.16-1.28 (m, yl)methyl] -2-[(4-phenyl 5H), 3.23 (m, 1H), 4.20 (q, 2H), 5.10 (s,

35 thiazol-2-yl)thiomethyl 2H), 5.74 (s, 2H), 6.75-6.78 (d, 2H), yl] 5-hydroxy-6-bromo-1H- 7.35-7.46 (m, 4H), 7.86-7.90 (m, 3H), ethyl ketone-3-carboxylate A, 8.07 (s, 1H).

LZ

9Cl.80/CT0ZN3/X3d 8T9S.0/M0Z OAV

HZ

9Cl .80/CT0ZN3/X3d 8T9S.0/M0Z OAV

61

9Cl.80/CT0ZN3/X3d 8T9S.0/M0Z OAV Example ^-NMR data (300 Hz) Chemical name structure

No. δ (ppm) or MS m/z

1-methyl-4-[(2-methyl meth)

Oxazol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazole-2-

56 551.0,552.5 [M+H] group)sulfinylmethyl]-5-hydroxyl

Ethyl 6-bromoindole-3-carboxylate

1-methyl-4-[(imidazole-1-N.

Methyl]-2-[[2-(2-benzene)

Keto-4-oxothiazole-3-yl)

57 628.1,629.6 [M+H] Ethylthio]methyl]-5-hydroxyl

•6-bromoindole-3-carboxylate

Ethyl acetate a" ^s

1-methyl-4-[(2-methyl meth)

Azole-1-yl) A N.

Base] -2-[[2-(2-phenyl-4-

58 Oxothiazoline-3-yl)ethyl 642.1,643.6 [M+H] thio]methyl]-5-hydroxyl

•6-bromoindole-3-carboxylate

Ethyl acetate

1-methyl-4-[(imidazole

-1- base) A

Base]-2-[[2-[2-(4-methoxy)

59 phenyl)-4-oxothiazole 658.1,659.6 [M+H] phenyl-3-yl]ethylthio]A

-5-Hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester

1-methyl-4-[(imidazole

N.

-1- base) A

Base]-2-[[2-[2-(3-trifluoro)

60 methylphenyl)-4-oxothio 696.1,697.6 [M+H]oxazoline-3-yl]ethylthio]A

-5-Hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester CF ₃

1-Cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[[2-(2-benzene).

-4- oxothazoline -3-

61 670.1,671.6 [M+H] group)ethylsulfinyl]A

-5-Hydroxy-6-bromo-1H- oxime-3-carboxylic acid ethyl ester

Pharmacological study of the product of the invention

Next, the thiazole-5-hydroxyindole derivative of the above formula I or formula II according to the present invention is screened for anti-hepatitis B virus activity and anti-HIV-1 protease activity in vitro.

I. Screening of anti-hepatitis B virus activity in vitro

The ability of the sample to inhibit hepatitis B virus DNA replication and HBsAg, HBeAg was determined by using 2.2.15 cells as the hepatitis B virus vector.

Test materials and methods: 1. Cell line: 2.2.15 cells;

2. Sample processing: The sample was dissolved in DMSO to prepare an appropriate concentration, and each sample was diluted 3 times with the culture solution for a total of 8 dilutions.

3. Positive control drug: Lamivudine (3TC), produced by Glaxo Wellcome.

4. Main reagents: Hepatitis B virus e antigen and s antigen radioimmunoassay kit, provided by Beijing North Biotechnology Research Institute; a ³² PdCTP, provided by China Furui Bioengineering Co., Ltd.

5. Test method: 2.2.15 cell type 96-well culture plate, 36 hours later, add the sample and positive control drug according to the above dilution, and set the cell control well at the same time. After 96 hours, replace the sample culture solution with different dilution concentration. Cell supernatant and 2.2.15 cells were collected on the 8th day of the seed plate. The secretion of HBsAg and HBeAg in the supernatant was detected by RIA method. The degree of HBV DNA replication in the cells was detected by dot blot method, and IC _5Q and SI were calculated respectively.

The test results are shown in Table 4.

Table 4 Screening results of anti-hepatitis B virus activity of compounds in vitro

HBsAg HBeAg DNA replication

TC ₅₀

Compound ic ₅₀ ic ₅₀ ic ₅₀

(ug ml) SI SI SI

(ug ml) (ug ml) (ug ml)

Example 2 43.11 - - <0. 23 2.37 1 1 Example 4 32.07 9.74 3.29 1. 49 21.52 1 1 Example 7 12.84 - - - - 1 1 Example 8 32.08 - - 3. 83 8.37 1 1 Example 10 32.08 - - 11. 97 2.68 1 1 Example 14 32.08 - - - - 1 1 Example 21 18.52 5.06 3.66 <0. 23 1.54 1 1 Example 29 240.37 - - <0. 23 3.84 1 1 Example 30 43.11 - - <0. 23 2.73 1 1 Example 31 32.08 - - <0. 23 24.63 1 1 Example 32 6.17 - - - - 1 1 Example 33 32.07 - - <0. 69 6.98 1 1 Example 34 240.37 47.26 5.09 <0. 69 7.58 1 1 Example 36 32.08 - - <0. 69 24.29 1 1 Example 37 80.12 - - - - 1 1 Example 38 18.52 4.79 3.87 <0.23 4.76 1 1 Example 39 55.56 - - - - 1 1 Example 40 32.08 - - <0. 23 3.74 1 1 Example 41 96.23 18.47 5.21 <2. 06 1,36 1 1 Example 42 55.56 - - - - 1 1 Example 43 80.12 - - <0. 69 5.68 1 1 Example 44 43.11 3.88 11.11 <0. 23 2.53 1 1 Example 45 43.11 3.26 13.22 <0. 23 4.16 1 1 Example 48 166.67 33.41 4.99 <2. 06 3.52 1 1 Example 49 80.12 - - <0. 69 3.63 1 1 Example 50 43.11 - - <0. 23 2.15 1 1 Example 51 32.07 - - <0. 23 3.64 1 1 Example 53 26.71 4.74 5.64 <0.23 6.83 1 1 Example 54 32.07 - - <0. 69 2.56 1 1 Example 56 32.07 - - <0. 23 3.56 1 1 Example 58 32.08 - - 10.21 3.14 1.62 4,31 Example 59 38.52 15.10 2.55 - - 34.42 9.75 Example 61 96.23 - - 7.65 12.58 4.28 6.46 Example 62 10.69 - - 3.21 3.34 3.64 2.94

3TC 288.68 - - - 12.56 22.98 "/" means untested activity II, anti-influenza virus activity screening

MDCK (hamster kidney) cells were used as viral hosts to determine the extent to which MDCK cells were induced by inhibition of influenza A virus.

Test materials and methods:

1. Virus strain: A type 3 virus 90-15 strains.

2. Sample processing: The sample is dissolved in DMSO to a suitable concentration before use, and the culture medium is diluted twice with a total of 8 dilutions.

3. Positive control drug: ribavirin (RBV;), produced by Hubei Keyi Pharmaceutical Factory.

4. Test Method: MDCK cells in 96-well culture plate, 24 hours after infection A / anti Ji / 90-15 strain 10_ ^3, 3 hours adsorption, the virus solution was discarded, according to the above dilution and positive control samples were added, at the same time provided Cell control wells and virus control wells were observed for 30 hours for cytopathic effect (CPE), and the half-inhibitory concentration (IC ₅ o) of the influenza virus A was determined by Reed-Muench method.

The measurement results are shown in Table 5. Table 5 Screening results of compounds against influenza virus activity in vitro

A / Ji defense / 90-15 strain

Compound TC ₅₀ ^g ml)

IC ₅₀ ^g ml) SI

Example 1 96.23 2.43 3.36 Example 9 32.08 10.23 2.5 Example 11 32.08 5.52 12.36 Example 13 80.12 4.28 5.85 Example 15 18.52 2.53 1.52 Example 18 32.08 11.02 5.83 Example 57 23.86 4.62 6.0 Example 60 10.69 8.46 5.27 Abby Dole 62.5 23.2 2.69 Ribavirin>1000 >33.81 >29.57

Claims

Rights request

A compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt thereof and/or hydrated

among them,

« is (dC ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl;

R ₂ is (C )alkyl; X is hydrogen, halogenated;

Y is - R ₃ R4 _;

Representative (CC ₄ )alkyl, (dC ₄ )alkoxy, halo, hydroxy, cyano, carboxy, ester, nitro; (0) _m

Z is a CH ₂ —(CH ₂ ) _n -Q ;

m is 0, 1, 2;

n is an integer between 0 and 4;

R ₅ is hydrogen, (dC alkyl, dC ₄ alkoxy, hydroxy, optionally hydroxy, amino or halo (dC焼) Or (dc alkoxy, (dc alkylthio, free, salt-forming, esterified or amidated carboxyl, halogenated,

(CrC ₄ )alkyl acyl, nitro, cyano, amino, (dC ₄ )alkylamido or substituted by mono or bis[(dC ₆ )alkyl)] or R ₅ is (C ₆ -C _1Q ) aryl Or a 5-10 membered heteroaryl group, which are optionally substituted by 1 to 3 identical or different R ₉ , wherein the heteroaryl and heterocyclic groups optionally contain 1-3 selected from N, 0 or a hetero atom of S;

2. A compound of formula I according to claim 1, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

Q is flying ^J , ^S 5

R ₅ is hydrogen, (dC ₄ )alkyl, (dC ₄ )alkoxy, hydroxy, (dC ₄ )alkyl or (CrC ₄ )alkoxy optionally substituted by (hydroxy, amino or _3⁄4 ), (CrC ₄ )alkylthio, (free, salt-forming, esterified or amidated) carboxyl, halogenated, (CrC ₄ )alkyl acyl, nitro, cyano, amino, (CrC ₄ ) alkane An amide group or an amino group substituted with a mono or di(CrC ₆ )alkyl group;

Or R ₅ is phenyl or 5-6 membered heteroaryl, wherein said heteroaryl optionally contains 1-3 heteroatoms selected from N, 0 or S, and R _{5 is} optionally 1-3 The same or different R ₉ substitutions.

3. A compound of formula I according to claim 2, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

among them, 1^ is methyl, ethyl, propyl, isopropyl, cyclopropyl;

X is hydrogen, bromine or fluorine;

Y is - R ₃ R4 _;

Q is "^, ^s R ₅ .

4. A compound of formula I according to claim 3, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

among them,

It is hydrogen, (dC ₄ )alkyl, phenyl optionally substituted by 1 to 3 identical or different R ₉ .

5. A compound of formula I according to claim 3, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

X is hydrogen and bromine;

0

0 is ^R 5 ;

R ₅ is phenyl or a 5-6 membered heteroaryl group, wherein the heteroaryl group optionally contains 1-3 heteroatoms selected from N, 0 or S, and R _{5 is} optionally 1-3 identical Or a different R ₉ substitution.

6. A compound of formula I according to claim 5, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

Wherein R ₅ is phenyl, furyl, pyrrolyl, thienyl, pyridyl, and R ₅ is optionally substituted by 1 to 3 identical or different R ₉ .

7. A compound of formula I according to claim 6, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof, Wherein R ₅ is furan-2-yl, pyridin-2-yl or thiophen-2-yl.

8. A derivative of the formula I below, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof:

环Cyclopropyl-4-([tetrahydropyrrol-1-yl)methyl]-2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfonylmethyl] - Ethyl 5-hydroxy-6-bromo-^-indole-3-carboxylate;

1-cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(thiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H-indole-3 -carboxylic acid Ethyl ester

1-Cyclopropyl-4-[(imidazol-1-yl)methyl]-2-[(4-methylthiazol-2-yl)sulfonylmethyl]-5-hydroxy-6-bromo-1H- Ethyl-3-carboxylate;

1-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-2-[[2-[2-(3-trifluoromethylphenyl)-4-oxothiazoline -3-base] B Ethyl thio]methyl]-5-hydroxy-6-bromo-1H-indole-3-carboxylate;

1-Methyl-4-[(2-methylimidazol-1-yl)methyl]-2-[[2-(2-phenyl-4-oxothiazolin-3-yl)ethylthio] Methyl]-5-hydroxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester;

A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof, as an active ingredient, and a pharmaceutically acceptable composition Acceptable excipients.

10. A compound according to any one of claims 1-8, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof, or a pharmaceutical composition according to claim 9 in the preparation of a therapeutic and / or the use of drugs to prevent viral infections.

11. The use of claim 10, wherein the virus is a hepatitis B virus or an influenza virus.