HK1178512B

HK1178512B - Haloalkyl heteroaryl benzamide compounds

Info

Publication number: HK1178512B
Application number: HK13106211.5A
Authority: HK
Inventors: 珍-弗朗索瓦．罗西诺尔; J．爱德华．森普尔
Original assignee: 罗马克实验室有限公司
Priority date: 2009-05-12
Filing date: 2010-05-11
Publication date: 2017-07-28

Description

Haloalkyl heteroaryl benzamide compounds

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application No. 61/177,626 filed on 12.5.2009, the entire contents of which are incorporated herein by reference.

Statement regarding government funded research or development

The present invention is funded by the NIAID contract NO 1-AI-30046. The united states government has certain rights in this invention.

Technical Field

The present invention relates to novel heterocyclic compounds, pharmaceutically acceptable salts thereof, compositions containing the compounds and salts, and methods of treating viral diseases using those compounds, salts, and compositions. The invention also relates to methods of inhibiting the activity of viral pathogens in humans and animals. The present invention also relates to methods of treating Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), and related viral pathogen infections in humans and animals.

Background

The present invention generally relates to thiazolide (thiazolide) compounds. In particular, the invention relates to haloalkyl substituted thiazoles.

Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV), both of which cause more than about 5 billion chronic infections worldwide, are major public health problems. Both viruses cause significant progressive liver disease and are a major risk factor for primary hepatocellular carcinoma. Current standard of care for both viral infections, while effective in many cases, is still not optimal and in most cases does not result in a virological or clinical "cure". Development of drug resistance in HBV, including strains with resistance to a variety of currently used agents, is an emerging clinical problem, and drug resistance in HCV therapy is expected to be a significant clinical problem in the future.

Disclosure of Invention

The present invention provides novel compounds and pharmaceutical compositions for the treatment of viral pathogens as well as methods of synthesizing the compounds and methods of using the compounds for the treatment and inhibition of viral infections. The compounds of the present invention are haloalkyl heteroaryl benzamides.

In one embodiment, the present invention provides a compound of formula (I) and pharmaceutically acceptable salts or esters thereof:

wherein:

R₁to R₅And R₁₀Independently selected from the group consisting of: hydrogen, CN, NO₂Halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkynyl, alkenyloxyalkyl, alkenyloxyalkenyl, alkenyloxyalkynyl, alkynyloxyalkyl, alkoxyalkylamino, hydroxyalkyl, acyl, acyloxy, aroyloxy, arylalkyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, alkoxycarbonyloxy, carbamoyl, carbamoyloxy, alkylamino, dialkylamino, alkylaminoalkyl, amido, alkylamido, dialkylamido, perhaloalkoxy, alkylthio, perhaloalkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonylalkyl, alkynylsulfonylalkyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, heteroarylalkyloxycarbonyl, alkoxycarbonyloxy, alkoxycarbonyl, heteroarylalkyloxycarbonyl, alkoxycarbonyloxy, carbamoyloxy, alkylamino, dialkylamino, alkylaminoalkyl, acylamido, Cycloalkylalkylsulfonylalkyl, arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl, aryl, aryloxy, arylthio, arylalkylthio, alkylthio, perhaloalkylthio, arylamino, arylalkylamino, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy or heterocycloalkenyloxy, all of which are optionally substituted as described below;

wherein R is₆Selected from the group consisting of haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, S (O)_mC(R₇R₈)_nCF₃And C (R)₇R₈)_nCF₃；

Wherein W, X and Y are independently S, O, N, NR₉Or CR₁₀Wherein at least two of W, X and Y are S, O, N or NR₉；

Wherein R is₇、R₈And R₉Independently selectFrom: hydrogen, fluorine, chlorine, alkyl, perhaloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or R₇And R₈Taken together by the atoms to which they are attached to form a 3-to 8-membered cycloalkyl ring or a 4-to 8-membered heterocycloalkyl ring, either ring being optionally substituted as described below;

m is an integer of 0 to 2; and is

n is an integer of 0 to 5.

These compounds are useful in the treatment of disorders and conditions caused by viral pathogens.

In another embodiment, the invention provides or contemplates a composition comprising a compound of formula I and a carrier.

In another embodiment, the invention provides or contemplates a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides or contemplates a method of treating a viral infection, said method comprising administering to a human or animal suffering from a viral infection a therapeutically effective amount of a compound of formula I.

In a more specific embodiment, the present invention provides or contemplates a method of treating HCV infection, comprising administering to a human or animal suffering from a viral infection a therapeutically effective amount of a compound of formula I.

In a more specific embodiment, the present invention provides or contemplates a method of treating HBV infection, comprising administering a therapeutically effective amount of a compound of formula I to a human or animal suffering from a viral infection.

In other embodiments, the invention provides or designs methods of inhibiting or modulating a viral pathogen. In other embodiments, the present invention provides or contemplates a method of treating a viral-mediated disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of the present invention or a composition of compounds of the present invention. In other embodiments, the present invention provides or contemplates methods of treating HCV, HBV, and other viral infections, comprising administering a pharmaceutical composition of the present invention to a patient in need thereof. For example, the patient has chronic HCV infection. The invention also contemplates the use of a compound disclosed herein in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition or modulation of viral activity.

Detailed Description

The singular form ("a" or "an") means "one(s)" or "more(s)" unless otherwise specified.

In one embodiment, the present invention provides or designs compounds of formula I, wherein R₁To R₅Independently hydrogen, cyano, fluorine, chlorine, bromine, hydroxyl, alkyl, alkoxy, acyloxy, aroyloxy, heteroaroyloxy, heteroarylalkanoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkylthio, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, all of which are optionally substituted as described below.

R₆Selected from perhaloalkyl, S (O)_mC(R₇R₈)_nCF₃Or C (R)₇R₈)_nCF₃；

R₇、R₈And R₉Independently hydrogen, fluoro, chloro, alkyl or perhaloalkyl, any of these groups being optionally substituted;

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, alkyl amide,Dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy, or heterocycloalkenoxy; and is

m and n are independently integers equal to 0, 1 or 2.

In a more particular embodiment, the present invention provides or designs compounds of formula I wherein R₁、R₂Or R₃Independently a hydroxyl group, an acyloxy group, an aroyloxy group, an arylalkylacyloxy group, an arylalkenoyloxy group, a heteroarylacyloxy group, a heteroarylalkanoyloxy group, a heteroarylalkoyloxy group, an alkoxycarbonyloxy group or a carbamoyloxy group, any of which groups may be optionally substituted.

In another more particular embodiment, the present invention provides or designs compounds of formula I wherein R₁、R₂And R₃One of them is hydroxyl or acetoxy.

In another more particular embodiment, the present invention provides or designs compounds of formula I wherein R₃Or R₄Is halogen.

In yet a more particular embodiment, the present invention provides or designs compounds of formula I wherein R₁、R₂And R₃One of them is hydroxyl or acetoxy, and, wherein, R₄Is halogen.

In yet a more particular embodiment, the present invention provides or designs compounds of formula I wherein R₁Is hydroxy or acetoxy, and, wherein, R₂、R₃Or R₄Is halogen.

In another more particular embodiment, the present invention provides or designs compounds of formula I wherein R₃Or R₄Is methyl or methoxy.

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Selected from: perhaloalkyl or C (R)₇R₈)_nCF₃Wherein R is₇And R₈Is as defined above.

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Is perfluoroalkyl or perchloroalkyl.

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Is perfluoro or perchloro C₁-C₃An alkyl group.

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Is trifluoromethyl.

In another embodiment, the present invention provides or contemplates a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier (e.g., diluent or excipient). In other embodiments, the invention provides or contemplates methods of making and using the compounds and compositions. In a more specific embodiment, the present invention provides or contemplates pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention and methods of using these compositions in the treatment of HCV, HBV and other viral infections.

In a subgeneric embodiment, the invention provides or designs compounds of formula I, wherein W is O and X or Y isN or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W is O and X and Y are N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W is S and X or Y is N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W is S and X and Y are N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W is N and X or Y is O.

In another embodiment, the invention provides or designs compounds of formula I wherein W is N and X or Y is S.

In another embodiment, the invention provides or designs compounds of formula I wherein W is N and X or Y is N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein two of W, X and Y are N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W, X and Y are N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W is CR₁₀One of X or Y is O and the other is N or NR₉。

In a subgeneric embodiment, the invention provides or designs compounds of formula I, wherein W is O, and X or Y is N or NR₉。

In another embodiment, the invention provides or designs compounds of formula I wherein W is N or NR₉And X or Y is O.

In another embodiment, the invention provides or designs compounds of formula I wherein W is N or NR₉And X or Y is S.

In another embodiment, the invention provides or designs compounds of formula I wherein W is N, X or Y is N or NR₉And R is₆Is SO₂CF₃Or SO₂CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein W is N, X or Y is N or NR₉And R is₆Is CF₂CH₃、CF₂CF₃Or CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein two of W, X and Y are N or NR₉And R is₆Is CF₂CH₃、CF₂CF₃Or CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein two of W, X and Y are N or NR₉And R is₆Is SO₂CF₃Or SO₂CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein W, X and Y are N or NR₉And R is₆Is SO₂CF₃Or SO₂CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein W, X and Y are N or NR₉And R is₆Is CF₂CH₃、CF₂CF₃Or CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein one of X or Y is O and the other is N or NR₉And R is₆Is methyl, fluoromethyl or trifluoromethyl.

In another embodiment, the invention provides or designs compounds of formula I wherein one of X or Y is O and the other is N or NR₉And, wherein R is₆Is SO₂CF₃Or SO₂CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein one of X or Y is O and the other is N or NR₉And, wherein R is₆Is methyl, fluoromethyl or trifluoromethyl.

In another embodiment, the invention provides or providesCompounds of formula I are contemplated wherein one of X or Y is O and the other is N or NR₉And, wherein R is₆Is SO₂CF₃Or SO₂CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Is methyl, fluoromethyl or trifluoromethyl.

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Is SO₂CF₃Or SO₂CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein R₆Is CF₂CH₃、CF₂CF₃Or CH₂CF₃。

In another embodiment, the invention provides or designs compounds of formula I wherein R₁To R₅Three of which are H.

In another embodiment, the invention provides or designs compounds of formula I wherein R₂To R₅Two of which are H.

In another embodiment, the invention provides or designs compounds of formula I wherein R₂To R₅Three of which are H.

In another embodiment, the invention provides or designs compounds of formula I wherein R₂To R₅Is H.

In another embodiment, the invention provides or designs compounds of formula I wherein R₁To R₅One of them is O-R₁₂Wherein R is₁₂Is H or C₁-C₆Alkanoyl, the latter optionally substituted with 1 to 3 halogens.

In another embodiment, the invention provides or designs compounds of formula I,wherein R is₆Is C optionally substituted by 1 to 3 halogen₁-C₃An alkyl group.

In another embodiment, the invention provides or designs compounds of formula I wherein R₁Is hydroxyl or alkanoyloxy.

In another embodiment, the invention provides or designs compounds of formula I wherein R₁Is hydroxy or C₁-C₃An alkanoyloxy group.

In another embodiment, the present invention provides or designs a compound of formula II:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkylOxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which is optionally substituted; and

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkyloxy, or a pharmaceutically acceptable salt thereof, Heterocyclic alkoxy or heterocyclic alkenyloxy.

In an additional embodiment, the present invention provides or designs a compound of formula II, wherein: r₁₀Selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In yet a more particular embodiment, the present invention provides or designs compounds of formula II, wherein

R₁Selected from the following groups: hydroxy, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy or carbamoyloxy groups, to processes for their preparation and to their use as medicamentsAny of the radicals may be optionally substituted, and

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or heterocycloalkoxy, any of which may be optionally substituted.

In a more particular embodiment, the present invention provides or designs compounds of formula II, wherein R is₁Is hydroxy or C₁-C₃An alkanoyloxy group.

In yet a more particular embodiment, the present invention provides or designs compounds of formula II wherein R₁Is hydroxy or acetoxy; and is

R₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

In yet a more particular embodiment, the present invention provides or designs a compound of formula I: 2- (5- (trifluoromethyl) thiazol-2-ylcarbamoyl) phenylacetate and 2-hydroxy-N- (5- (trifluoromethyl) thiazol-2-yl) benzamide.

In another subgeneric embodiment, the invention provides or designs compounds of formula III below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkylCycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which being optionally substituted; and

In a more specific embodiment, the present invention provides or designs compounds of formula III, wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In yet a more particular embodiment, the present invention provides or designs compounds of formula III, wherein:

R₁selected from the following groups: a hydroxyl group, an acyloxy group, an aroyloxy group, an arylalkanoyloxy group, an arylalkenoyloxy group, a heteroarylacyloxy group, a heteroarylalkanoyloxy group, a heteroarylenoyloxy group, an alkoxycarbonyloxy group or a carbamoyloxy group, any of which may be optionally substituted, and

In another more particular embodiment, the present invention provides or designs compounds of formula III, wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, substituted aryl,Heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl or heterocycloalkoxy, any of which may be optionally substituted.

In a more particular embodiment, the present invention provides or designs compounds of formula III, wherein R₁Is hydroxy or C₁-C₃An alkanoyloxy group.

In another embodiment, the present invention provides or designs a compound of formula III, wherein: r₁Selected from hydroxyl or acetoxy; and R is₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

In another subgeneric embodiment, the invention provides or designs compounds of formula IV below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, any of which may be optionally substituted; and

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxy-alkoxycarbonylAlkylcarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy or heterocycloalkenoxy.

In a more particular embodiment, the present invention provides or designs a compound of formula IV wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, alkyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl;

with the proviso that when R₄When is Br, R₁₀And not unsubstituted phenyl.

In a more specific subgeneric embodiment, the invention provides or designs compounds of formula IV wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthioA group, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or heterocycloalkoxy, any of which may be optionally substituted.

In yet a more particular embodiment, the present invention provides or designs compounds of formula IV wherein R₁Is hydroxy or acetoxy, and, R₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

Examples of this more specific embodiment include the compounds 2- (4- (trifluoromethyl) thiazol-2-ylcarbamoyl) phenylacetate and 2-hydroxy-N- (4- (trifluoromethyl) thiazol-2-yl) benzamide.

In another embodiment, the present invention provides or designs a compound of formula V below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, any of which is optionally substituted; and

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkaneA group, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonylamino, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy or heterocycloalkenyloxy.

In a more particular embodiment, the present invention provides or designs compounds of formula V, wherein:

In additional embodiments, the present invention provides or designs compounds of formula V, wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxyAlkylcarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl or heterocycloalkoxy, any of which may be optionally substituted.

R₁is hydroxy or acetoxy; and is

R₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

In another embodiment, the present invention provides or designs a compound of formula VI:

wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,Alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonylamino, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylalkylthio, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy, or heterocycloalkenoxy.

In a more specific embodiment, the present invention provides or designs compounds of formula VI, wherein:

In yet a more particular embodiment, the present invention provides or designs compounds of formula VI wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxyAlkylcarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl or heterocycloalkoxy, any of which may be optionally substituted.

In a more particular embodiment, the present invention provides or designs compounds of formula VI, wherein R₁Is hydroxy or acetoxy; and, R₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

R₁is hydroxy or acetoxy, and

R₂to R₅And R₁₀Is hydrogen.

In additional embodiments, the present invention provides or designs compounds of formula VII below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, as defined aboveAny of all groups is optionally substituted; and

In a more specific subgeneric embodiment, the invention provides or contemplates a compound of formula VII, wherein:

R₁₀selected from: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In a more particular embodiment, the present invention provides or designs a compound of formula VII, wherein:

In a more particular embodiment, the present invention provides or designs compounds of formula VII, wherein R₁Is hydroxy or acetoxy; and, R₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

In yet a more particular embodiment, the present invention provides or designs compounds of formula VII, wherein:

R₁is hydroxy or acetoxy, and

R₂to R₅And R₁₀Is hydrogen.

In another embodiment, the present invention provides or designs a compound of formula VIII below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxyAlkenylacyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which being optionally substituted; and

In some embodiments, the compounds of the present invention have the structure of formula VIII, wherein:

In other embodiments, the compounds of the present invention have the structure of formula VIII, wherein:

R₁selected from the following groups: hydroxy, acyloxy, aroyloxyAn arylalkyloxy group, an arylalkenoyloxy group, a heteroarylacyloxy group, a heteroarylalkanoyloxy group, a heteroarylalkoyloxy group, an alkoxycarbonyloxy group or a carbamoyloxy group, any of which may be optionally substituted, and

In a more particular embodiment, the present invention provides or designs compounds of formula VIII, wherein R₁Is hydroxy or acetoxy; and, R₃、R₄Or R₂To R₅And R₁₀All are hydrogen.

In yet a more particular embodiment, the present invention provides or designs a compound of formula VIII wherein: r₁Is hydroxy or acetoxy, and, R₂To R₅And R₁₀Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula IX below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroylOxy, arylalkyloxy, arylalkenoyloxy, heteroaryloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted; and

In some embodiments, the compounds of the present invention have the structure of formula IX, wherein:

In other embodiments, the compounds of the invention have the structure of formula IX, wherein:

R₁selected from: a hydroxyl group or an acetoxy group, and,

R₂to R₅And R₁₀Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula X:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, substituted aryl, substituted,Heteroaryl alkenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted;

R₉selected from the following groups: hydrogen, fluorine, chlorine, alkyl or perhaloalkyl, any of which may be optionally substituted, and

In some embodiments, the compounds of the present invention have the structure of formula X, wherein:

In other embodiments, the compounds of the present invention have the structure of formula X, wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or heterocycloalkoxy, any of which may be optionally substituted, and

R₉selected from the following groups: hydrogen, alkyl or perhaloalkyl, any of which may be optionally substituted.

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen; and is

R₉Is an alkyl group which may be optionally substituted.

In some embodiments, the compounds of the present invention have the structure of formula XI:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, any of which may be optionally substituted;

R₉selected from the following groups: hydrogen, fluoro, chloro, alkyl or perhaloalkyl, any of which groups may be optionally substituted; and

In some embodiments, the compounds of the present invention have the structure of formula XI, wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cyclicAlkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In a further embodiment, the compounds of the invention have the structure of formula XI, wherein:

R₁selected from the following groups: a hydroxyl group, an acyloxy group, an aroyloxy group, an arylalkanoyloxy group, an arylalkenoyloxy group, a heteroarylacyloxy group, a heteroarylalkanoyloxy group, a heteroarylenoyloxy group, an alkoxycarbonyloxy group or a carbamoyloxy group, any of which may be optionally substituted;

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or heterocycloalkoxy, any of which may be optionally substituted; and

In some embodiments, the compounds of the invention have the structure of formula XI, wherein R is₁Selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen; and is

R₉Is an alkyl group which may be optionally substituted.

In some embodiments, the compounds of the present invention have the structure of formula XII below:

wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkyloxy, or a pharmaceutically acceptable salt thereof, Heterocyclic ringsAlkoxy or heterocycloalkenyloxy.

In some embodiments, the compounds of the present invention have the structure of formula XII, wherein:

In other embodiments, the compounds of the present invention have the structure of formula XII, wherein:

R₉selected from: hydrogen, alkyl or perhaloalkyl, any of which may be optionally substituted.

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen; and is

R₉Is an alkyl group which may be optionally substituted.

In some embodiments, the compounds of the invention have the structure of formula XIII:

wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonylalkylSulfonyl, alkylsulfonylamino, alkylsulfonyl, arylsulfonyl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy or heterocycloalkenoxy.

In some embodiments, the compounds of the invention have the structure of formula XIII, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen; and is

R₉Is an alkyl group which may be optionally substituted.

In some embodiments, the compounds of the present invention have the structure of formula XIV:

wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, N-substituted heteroaryloxy-carbonyl,Carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonylamino, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy or heterocycloalkenyloxy.

In some embodiments, the compounds of the present invention have the structure of formula XIV, wherein:

R₁and R₂Independently is hydroxy, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, or carbamoyloxy, any of which may be optionally substituted;

R₃selected from the following groups: acyloxy, aroyloxy, arylalkyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, or carbamoyloxy, any of which may be optionally substituted; and

In other embodiments, the compounds of the invention have the structure of formula XIV, wherein:

R₁selected from the following groups: hydroxy, acyloxyA group, an arylacyloxy group, an arylalkylacyloxy group, an arylalkenoyloxy group, a heteroarylacyloxy group, a heteroarylalkanoyloxy group, a heteroarylenoyloxy group, an alkoxycarbonyloxy group or a carbamoyloxy group, any of which may be optionally substituted;

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XV:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, peralkyl, cycloalkylalkoxy, hydroxyalkyl, alkoxycarbonyloxy, substituted alkoxyHaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted; and

In some embodiments, the compounds of the present invention have the structure of formula XV, wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkaneA group, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In other embodiments, the compounds of the present invention have the structure of formula XV, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XVI:

wherein:

In some embodiments, the compounds of the present invention have the structure of formula XVI, wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amidoDialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In other embodiments, the compounds of the present invention have the structure of formula XVI, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XVII:

wherein:

In some embodiments, the compounds of the present invention have the structure of formula XVII, wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, arylsulfonylA group, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkenyl.

In other embodiments, the compounds of the present invention have the structure of formula XVII, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XVIII:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl,Alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which being optionally substituted;

In some embodiments, the compounds of the present invention have the structure of formula XVIII, wherein:

R₁₀selected from the following groups: hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloAlkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkenyl.

In other embodiments, the compounds of the present invention have the structure of formula XVIII, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen; and

R₉is methyl.

In some embodiments, the compounds of the present invention have the structure of formula XIX:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, any of which is optionally substituted;

In some embodiments, the compounds of the present invention have the structure of formula XIX, wherein:

In other embodiments, the compounds of the invention have the structure of formula XIX, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅And R₁₀Is hydrogen; and

R₉is methyl.

In some embodiments, the compounds of the present invention have the structure of formula XX:

wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or heterocycloalkoxy, any of which may be optionally substituted;

R₆selected from the following groups: perhaloalkyl, S (O)_mC(R₇R₈)_nCF₃Or C (R)₇R₈)_nCF₃；

R₇And R₈Independently selected from the group consisting of: hydrogen, fluoro, chloro, alkyl or perhaloalkyl, any of which groups may be optionally substituted;

m is an integer of 0 to 2;

n is an integer of 0 to 2; and

when R is₆When the compound is trifluoromethyl, the following conditions are provided:

when R is₁When selected from hydroxy or acetoxy, R₂To R₅Not being hydrogen;

when R is₁When it is hydroxy, R₄Can not be selected from Cl and Br; and is

When R is₃When it is acetoxy, R₁、R₂、R₄And R₅May not be hydrogen.

R₁selected from hydroxyl or acetoxy;

R₂to R₅Is hydrogen, and

R₆is perfluoroethyl, CF₃CH₂-and CH₃CF₂-。

In some embodiments, the compounds of the present invention have the structure of formula XXI below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkylalkoxy, alkoxy, alkoxyalkoxy, cycloalkoxy, aralkyloxy, alkoxycarbonyloxy, carbamoyloxySulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted.

In other embodiments, the compounds of the invention have the structure of formula XXI, wherein:

In some embodiments, the compounds of the present invention have the structure of formula XXI, wherein:

R₁selected from hydroxyl or acetoxy; and

R₂to R₅Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XXII below:

wherein:

R₁to R₅Independently hydrogen, CN, F, ClBr, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted.

In other embodiments, the compounds of the invention have the structure of formula XXII, wherein:

In some embodiments, the compounds of the present invention have the structure of formula XXII, wherein:

R₁selected from hydroxyl or acetoxy; and

R₂to R₅Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XXIII below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkylacyloxy, arylalkenyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted.

In other embodiments, the compounds of the invention have the structure of formula XXIII, wherein:

In some embodiments, the compounds of the present invention have the structure of formula XXIII, wherein:

R₁selected from hydroxyl or acetoxy; and

R₂to R₅Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XXIV below:

wherein:

In other embodiments, the compounds of the invention have the structure of formula XXIV, wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, arylOxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl or heterocycloalkoxy, any of which may be optionally substituted.

In some embodiments, the compounds of the present invention have the structure of formula XXIV, wherein:

R₁selected from hydroxyl or acetoxy; and

R₂to R₅Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XXV below:

wherein:

In other embodiments, the invention provides or designs compounds of formula XXV, wherein:

R₁selected from the following groups: hydroxy, acyloxy, arylAcyloxy, arylalkyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, or carbamoyloxy, any of which may be optionally substituted;

In some embodiments, the compounds of the present invention have the structure of formula XXV, wherein:

R₁selected from hydroxyl or acetoxy; and

R₂to R₅Is hydrogen.

In some embodiments, the compounds of the present invention have the structure of formula XXVI below:

wherein:

R₁to R₅Independently hydrogen, CN, F, Cl, Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroarylalkanoyloxy, heteroarylalkoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxyHaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, any of which may be optionally substituted; and

In some embodiments, the compounds of the present invention have the structure of formula XXVI, wherein:

R₁selected from hydroxyl or acetoxy;

R₂to R₅Is hydrogen; and

R₉is methyl.

In some embodiments, the compounds of the present invention have the structure of formula XXVII below:

wherein:

In some embodiments, the compounds of the present invention have the structure of formula XXVII, wherein:

R₂to R₅Independently hydrogen, CN, NO₂F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl or heterocycloalkaneOxy, any of the above groups may be optionally substituted.

R₁selected from hydroxyl or acetoxy;

R₂to R₅Is hydrogen; and

R₉is methyl.

In some embodiments, the compounds of the present invention have the structure of formula XXVIII below:

wherein:

In some embodiments, the compounds of the present invention have the structure of formula XXVIII, wherein:

R₁selected from the following groups: hydroxy, acyloxy, arylacyloxy, arylalkylacyloxy, arylalkenoyloxy, heteroarylacyloxy, heteroAn arylalkylacyloxy group, a heteroarylalkenoyloxy group, an alkoxycarbonyloxy group or a carbamoyloxy group, any of which may be optionally substituted;

R₁selected from hydroxyl or acetoxy;

R₂to R₅Is hydrogen; and

R₉is methyl.

The disclosed compounds include compounds of formula (I), salts and solvates thereof. For example, in some embodiments, the compounds of the present invention may be salts or solvates.

Many of the compounds of the present invention can exist in the form of more than one stereoisomer. All descriptions relating to compounds of the present invention are intended to include all diastereoisomeric and enantiomeric forms of those compounds.

Because the compounds of the present invention are useful in the diagnosis and treatment of disease, isotopically labeled forms of these compounds are encompassed by the present disclosure and claims. All references to elements in the compounds of the present invention are intended to include all isotopes of those elements, including labile isotopes. For example, "hydrogen" or H as referred to in formulas or claims is intended to include deuterium (D) and tritium (T).

In another embodiment, the present invention provides or contemplates a kit comprising in a cell at least one pharmaceutical composition comprising an effective amount of at least one compound of the present invention in a pharmaceutically acceptable carrier. In some embodiments, the kit further comprises written instructions for administration of the pharmaceutical composition. In some embodiments, the written instructions for administration relate to the indications mentioned elsewhere in the disclosure of the invention. In some embodiments, the written instructions for administration relate to the dosage regimen mentioned elsewhere in the present disclosure.

The following terms used in the description of the present invention have the meanings as indicated below:

the term "salt" is used in its broadest sense. For example, the term salt includes acid and base salts having an ion of the compound of the present invention. In some embodiments, the term salt may be a subclass of salts referred to as pharmaceutically acceptable salts, which are salts of the compounds of the present invention that are pharmacologically active and which are neither biologically nor otherwise undesirable. In all embodiments, the salts may be formed with acids such as, but not limited to: hydrogen, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, and undecanoate. In all embodiments, the salt may be formed with a base, such as, but not limited to: hydroxides, ammonium salts, alkali metal salts (e.g., lithium, sodium and potassium salts), alkaline earth metal salts (e.g., calcium, magnesium, aluminum salts), salts with organic bases (e.g., ammonia, methylamine, diethylamine, ethanolamine, dicyclohexylamine, N-methylmorpholine, N-methyl-D-glucamine), and salts with amino acids (e.g., arginine and lysine). Basic nitrogen-containing groups may be quaternized with agents including lower alkyl halides such as methyl chloride, methyl bromide and methyl iodide, ethyl chloride, ethyl bromide and ethyl iodide, propyl chloride, propyl bromide and propyl iodide and butyl chloride, butyl bromide and butyl iodide; the dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; the long-chain halides such as decyl chloride, decyl bromide and decyl iodide, lauryl chloride, lauryl bromide and lauryl iodide, myristyl chloride, myristyl bromide and myristyl iodide, and stearyl chloride, stearyl bromide and stearyl iodide; the aralkyl halides, such as benzyl bromide and phenethyl bromide.

The terms "therapeutically acceptable salt" and "pharmaceutically acceptable salt" as used herein represent salts or zwitterionic forms of the compounds of the present invention, which are water or oil soluble or dispersible; the salt or zwitterionic form is suitable for treating disease without excessive toxicity, irritation and allergic response; the salt or zwitterionic form is commensurate with a reasonable benefit/risk ratio; and the salt or zwitterionic form is effective for their intended use. The salts may be prepared during the final isolation and purification of the compound or separately by reacting the appropriate compound in free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, trimethylbenzenesulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, Propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-toluenesulfonate) and undecanoate. Also, the basic groups in the compounds of the invention may be quaternized with: methyl chloride, methyl bromide and methyl iodide, ethyl chloride, ethyl bromide and ethyl iodide, propyl chloride, propyl bromide and propyl iodide, and butyl chloride, butyl bromide and butyl iodide; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decyl chloride, decyl bromide and decyl iodide, lauryl chloride, lauryl bromide and lauryl iodide, myristyl chloride, myristyl bromide and myristyl iodide, and sterol chloride, sterol bromide and sterol iodide; and benzyl bromide and phenethyl bromide. Examples of acids that may be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts may also be formed by coordination of the compound with an alkali or alkaline earth metal ion. Thus, the present invention contemplates the use of the sodium, potassium, magnesium and calcium salts of the compounds of the present invention, and the like.

Base addition salts can be prepared during the final isolation and purification of the compounds by reaction of the carboxyl, phenol or similar group with a suitable base such as a hydroxide of a metal cation, a carbonate of a metal cation or a bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N-benzhydrylbenzylamine, 1-diphenylhydroxymethylamine, and N, N' -diphenylmethylvinyldiamine. Other representative organic amines useful for forming base addition salts include ethylene diamine, ethanolamine, diethanolamine, piperidine, and piperazine.

The term "solvate" is used in its broadest sense. For example, the term solvate includes hydrates formed when a compound of the invention contains one or more bound water molecules.

The term "acyl" as used herein, alone or in combination, refers to a carbonyl group attached to an alkyl, alkenyl, aryl, heteroaryl, heterocycle, or any other group, wherein the atom attached to the carbonyl group is carbon. The "acetyl" group means-C (O) CH₃A group. Examples of acyl groups include alkanoyl groups such as formyl, acetyl, propionyl, and mixed alkyl-aryl groups such as benzoyl.

The term "acylamino" includes an amino group substituted with an acyl group. An example of an "acylamino" group is acetylamino (CH)₃C (O) NH-. The term "alkenyl" as used herein, alone or in combination, refers to a straight, branched, or cyclic unsaturated hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms (or 3 to 20 ring members in the case of a cyclic group), or a group containing any combination of straight or branched and cyclic groups having one or more double bonds and containing 2 to 20 carbon atoms (or 3 to 20 ring members in the case of a cyclic group). In many embodiments, the alkenyl group contains 2 to 6 carbon atoms. The term "alkenyl group" is used in its broadest sense. Alkenylene refers to a carbon-carbon double bond system linked at two or more positions, such as ethenylene [ (-CH ═ CH-), (-C:: C-)]. For example, the term "(C)₂-C₈) Alkenyl groups "comprise straight, branched and cyclic hydrocarbon groups having at least one double bond containing from 2 to 8 carbon atoms. Examples of suitable alkenyl groups include ethenyl (also known as vinyl), propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, tert-butenyl, 1, 3-butadienyl, n-pentenyl, n-hexenyl, cycloalkenyl groups (e.g., cyclohexenyl and 1, 3-cyclopentadienyl), cycloalkenylalkyl groups (e.g., cyclohexenylmethyl), alkenylcycloalkyl groups (e.g., methylenecyclohexyl), and the like. The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as defined herein. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopentyloxy, and the like.

The term "alkoxyalkoxy" as used herein, alone or in combination, refers to one or more alkoxy groups attached to the parent molecular moiety through another alkoxy group. Examples include ethoxyethoxy, methoxypropoxyethoxy, ethoxypentoxyethoxyethoxy, and the like.

The term "alkoxyalkyl", as used herein, alone or in combination, refers to an alkoxy group attached to the parent molecular moiety through an alkyl group. The term "alkoxyalkyl" also includes alkoxyalkyl groups having one or more alkoxy groups attached to an alkyl group, i.e., forming monoalkoxyalkyl and dialkoxyalkyl groups.

The term "alkoxycarbonyl," as used herein, alone or in combination, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. Examples of such "alkoxycarbonyl" groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and hexyloxycarbonyl.

The term "alkoxycarbonylalkyl" includes groups having a substituted alkyl group such as the "alkoxycarbonyl" groups described above. More preferred alkoxycarbonylalkyl groups are "lower alkoxycarbonylalkyl" having a lower alkoxycarbonyl group attached to 1 to 6 carbon atoms as described above. Examples of these lower alkoxycarbonylalkyl groups include methoxycarbonylmethyl.

The term "alkyl" as used herein, alone or in combination, refers to a straight, branched, or cyclic alkyl group or a group consisting of any combination of straight, branched, and/or cyclic groups, which groups are saturated aliphatic hydrocarbon groups containing 1 to 20 carbon atoms. In many embodiments, the alkyl group contains 1 to 10 carbon atoms. In many other embodiments, the alkyl group contains 1 to 6 carbon atoms. The term "alkyl group" is used in its broadest sense. As described herein, an alkyl group may be optionally substituted. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, neopentyl, isopentyl, hexyl, cyclohexyl, trans 1, 2-diethylcyclohexyl, octyl, nonyl, and the like. For example, the abbreviation "(C)₁-C₆) The alkyl radical "comprises (C)₃-C₆) Cycloalkyl radicals and also straight-chain and branched alkyl radicals, and "O (C)₁-C₈) Alkyl groups "include straight-chain O (C)₁-C₈) Alkyl radical, branched O (C)₁-C₆") -alkyl group and cyclic O (C)₁-C₆) -an alkyl group. The term "alkenyl", as used herein, alone or in combination, refers to a saturated aliphatic radical derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, e.g., methylene (-CH)₂-), ethylene and 1, 3-cyclobutene.

The term "alkylamino" as used herein, alone or in combination, refers to an amino group attached to the parent molecular moiety through an alkyl group.

The term "alkylaminocarbonyl," as used herein, alone or in combination, refers to an alkylamino group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include N-methylaminocarbonyl and N, N-dimethylcarbonyl.

The terms "alkylcarbonyl" and "alkanoyl" as used herein, alone or in combination, refer to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl (also known as acetyl), ethylcarbonyl (also known as propionyl), and 2-methyl-cyclopentylcarbonyl, and the like.

The term "alkylene" as used herein, alone or in combination, refers to an alkenyl group in which one of the carbon atoms in a carbon-carbon double bond belongs to the moiety attached to the alkenyl group.

The term "alkylsulfinyl," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through a sulfinyl group. Examples of alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

The term "alkylsulfonyl" as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, t-butylsulfonyl, and the like.

The term "alkylthio", as used herein, alone or in combination, refers to an alkyl thioether (R-S-) group, wherein the term alkyl is as defined above. Examples of suitable alkylsulfanyl groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, ethoxyethylthio, methoxypropoxyethylthio, ethoxypentyloxyethylthio, and the like.

The term "alkylthioalkyl" includes alkylthio groups attached to an alkyl group. Alkylthioalkyl groups include alkyl groups having from 1 to 6 carbon atoms and "lower alkylthioalkyl" groups of the alkylthioalkyl groups described above. Examples of such groups include methylthiomethyl.

The term "alkynyl" as used herein, alone or in combination, in its broadest sense, refers to a straight, branched, or cyclic unsaturated hydrocarbon group having one or more carbon-carbon triple bonds and containing 2 to 20 carbon atoms and groups containing any combination of straight, branched, and/or cyclic groups having one or more carbon-carbon triple bonds and containing 2 to 20 carbon atoms. In many embodiments, alkynyl groups contain 2 to 6 carbon atoms. In many other embodiments, alkynyl groups contain 2 to 4 carbon atoms. "Alkynylene" refers to a carbon-carbon triple bond attached at two positions, for example, ethynylene (-C:: C-, -C ≡ C-). For example, (C)₂-C₈) Alkynyl groups include straight, branched and cyclic hydrocarbon chains having at least one triple bond containing from 2 to 8 carbon atoms, and unless otherwise specified, this term includes, but is not limited to: substituents such as ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyyn-2-yl, 3-methylbutyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3-dimethylbutyn-1-yl, and the like.

The term "amido", employed herein, alone or in combination, refers to an amino group, as described below, attached to the parent molecular moiety through a carbonyl or sulfonyl group. The term "C-amido", as used herein, alone or in combination, refers to-C (═ O) -NR with R as defined herein₂A group. The term "N-amido", as used herein, alone or in combination, refers to an RC (═ O) NH-group having R as defined herein.

The term "amino", as used herein, alone or in combination, refers to-NRR ', wherein R and R' are independently selected from the group consisting of: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclyl, heterocycloalkenyl or heterocycloalkyi, wherein the aryl, the aryl part of the arylalkenyl, the arylalkyl, the heteroaryl part of the heteroarylalkenyl and the heteroarylalkyl, the heterocycle, the heterocycloalkenyl and the heterocycle part of the heterocycloalkyi may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halogen, haloalkoxy, haloalkyl, hydroxy-alkyl, nitro or oxygen.

The term "aminoalkyl", as used herein, alone or in combination, refers to an amino group attached to the parent molecular moiety through an alkyl group. Examples include aminomethyl, aminoethyl, and aminobutyl. The term "alkylamino" refers to an amino group that has been substituted with one or two alkyl groups. Suitable "alkylamino" groups can be monoalkylated or dialkylated groups such as N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The terms "aminocarbonyl" and "carbamoyl" as used herein, alone or in combination, refer to an amino-substituted carbonyl group, wherein the amino group can be a primary amino group or a secondary amino group containing a substituent selected from the group consisting of: alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl groups, and the like.

The term "aminocarbonylalkyl" as used herein, alone or in combination, refers to an aminocarbonyl group attached to an alkyl group as described above. Examples of such groups are aminocarbonylmethyl. The term "amidino" refers to-C (NH) NH₂A group. The term "cyanoamidino" refers to-C (N-CN) NH₂A group.

The terms "arylalkenyl" or "arylalkenyl", employed herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

The terms "aralkoxy" or "arylalkoxy," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkoxy group.

The terms "aralkyl" or "arylalkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

The terms "aralkylamino" or "arylalkylamino," as used herein, alone or in combination, refer to an arylalkyl group attached to the parent molecular moiety through a nitrogen atom, wherein the nitrogen atom is substituted with hydrogen.

The terms "arylalkylene" or "arylalkylene", as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkylene group.

The terms "arylalkylthio" or "arylalkylthio", as used herein, alone or in combination, refers to an arylalkyl group attached to the parent molecular moiety through a sulfur atom.

The term "arylalkynyl" or "arylalkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

The term "aralkoxycarbonyl" as used herein, alone or in combination, refers to a group of the formula aralkyl-O-C (O) -wherein the term "aralkyl" has the meaning described above. Examples of aralkoxycarbonyl groups are benzyloxycarbonyl ("Z" or "Cbz") and 4-methoxyphenylmethoxycarbonyl ("MOS").

The term "aralkoyl", as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkane carboxylic acid (alkanocarboxylic acid), e.g., benzoyl, phenylacetyl, 3-phenylpropionyl (phenylpropanoyl), 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorophenylpropionyl, 4-aminophenylpropionyl, 4-methoxyphenylacryloyl, and the like. The term "aroyl" refers to an acyl group derived from an aryl carboxylic acid, the "aryl" having the meaning given below. Examples of such aroyl groups include substituted and unsubstituted benzoyl or naphthoyl groups, such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6- (benzyloxycarbonyl) -2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxycarboxamido) -2-naphthoyl, and the like.

The term "aryl" as used herein, alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings, wherein the rings may be linked together in a pendant manner or may be fused. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthryl, phenanthryl and biphenyl. The aryl groups of the present invention may be optionally substituted with one, two, three, four or five substituents independently selected from the groups defined herein.

The term "arylamino," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an amino group, e.g., N-phenylamino, and the like.

The terms "arylcarbonyl" and "aroyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through a carbonyl group.

The term "aryloxy", as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

The term "arylsulfonyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.

The term "arylthio," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through a sulfur atom.

The term "carboxy (or carboxyl)" whether used alone or in combination with other terms (e.g., carboxyalkyl), refers to-CO₂H。

The terms "benzo" and "benzene (benz)" as used herein, alone or in combination, mean derived from benzeneA divalent group C of₆H₄Is as follows. Examples include benzothiophenes and benzimidazoles.

The term "carbamoyloxy," as used herein, alone or in combination, refers to an amino-substituted carbonyl group (e.g., RR' NC (═ O) O-) attached to the parent molecular moiety through an oxygen atom, wherein the amino group can be a primary amino group or a secondary amino group containing substituents selected from the group consisting of: alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, and the like.

The term "O-carbamoyl" as used herein, alone or in combination, refers to an-oc (O) NR group having R as defined herein.

The term "C-linked" as used herein, alone or in combination, refers to any substituent group attached to the parent molecular moiety through a carbon-carbon bond.

The term "N-carbamoyl" as used herein, alone or in combination, refers to a roc (o) NH-group having R as defined herein.

The term "carbonate" as used herein, alone OR in combination, refers to an-O-C (═ O) OR group having R as defined herein.

The term "carbonyl", as used herein, includes formyl [ -C (O) H ], when used alone, and-C (O) -groups when used in combination.

The term "carboxy" as used herein refers to-C (O) OH or a corresponding "carboxylate ester", such as a carboxylate derivative or a carboxylate ester derivative. An "O-carboxy" group refers to an RC (O) O-group, wherein R is defined herein. A "C-carboxy" group refers to a-C (O) OR group, wherein R is as defined herein.

The term "cyano," as used herein, alone or in combination, refers to-CN.

The term "cycloalkyl" as used herein, alone or in combination, refers to a saturated or partially saturated monocycloalkyl group, bicycloalkyl group or tricycloalkyl group wherein each ring portion contains 3 to 12 carbon atom ring members, preferably 3 to 7 carbon atom ring members and each ring portion may optionally be a benzo fused ring system, optionally substituted as described herein. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2, 3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include fused ring systems (e.g., decahydronaphthalene, octahydronaphthalene) and polycyclic (multicenter) saturated or partially unsaturated types. The latter isomer types are generally illustrated by bicyclo [2, 2, 2] octane, bicyclo [1, 1, 1] pentane, camphor and bicyclo [3, 2, 1] octane.

The term "cycloalkenyl" as used herein, alone or in combination, refers to a partially unsaturated monocyclic, bicyclic, or tricyclic group wherein each cyclic portion contains 3 to 12, preferably 5 to 8, carbon atom ring members and each cyclic portion may optionally be a benzo fused ring system, optionally substituted as described herein. Examples of such cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctadienyl, -1H-indenyl, and the like.

The term "cycloalkylalkyl" as used herein, alone or in combination, refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. Examples of such cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl, and the like.

The term "cycloalkenylalkyl" as used herein, alone or in combination, refers to an alkyl group as defined above substituted with a cycloalkenyl group as defined above. Examples of such cycloalkenylalkyl groups include 1-methylcyclohex-1-enyl-, 4-ethylcyclohex-1-enyl-, 1-butylcyclopent-1-enyl-, 3-methylcyclopent-1-enyl-, and the like.

The term "ester" as used herein, alone or in combination, refers to a carbonyloxy- (C ═ O) O-group bridging two groups at a carbon atom. Examples include ethyl benzoate, n-butyl cinnamate, phenyl acetate, and the like.

The term "ether" as used herein, alone or in combination, refers to an oxy group that bridges two groups at a carbon atom.

The term "halo" or "halogen" as used herein, alone or in combination, refers to fluoro, chloro, bromo, or iodo.

The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

The term "haloalkyl" as used herein, alone or in combination, refers to an alkyl group having the above-mentioned meaning wherein one or more hydrogen atoms are replaced by halogen. Specifically included are monohaloalkyl, bishaloalkyl and polyhaloalkyl groups. For example, a monohaloalkyl group can have an iodine, bromine, chlorine, or fluorine atom within the group. The di-and polyhaloalkyl groups may have two or more of the same halogen atoms or a combination of different halogen groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "haloalkenyl" refers to a halohydrocarbyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF)₂-), chloromethylene (-CHCl-), and the like. Examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1, 1, 1-trifluoroethyl, perfluorodecyl, and the like.

The term "heteroalkyl", as used herein, alone or in combination, means a stable straight or branched chain or ring completely saturated or containing from 1 to 3 unsaturations, consisting of the stated number of carbon atoms and from 1 to 3 heteroatoms selected from O, N and S(iii) hydrocarbon-like groups wherein the nitrogen atom and the sulfur atom can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized, and combinations thereof. The heteroatoms O, N and S can be placed at any internal position of the heteroalkyl group. Up to two heteroatoms may be consecutive, e.g., -CH₂-NH-OCH₃。

The term "heteroaryl" as used herein, alone or in combination, refers to an aromatic five or six membered ring wherein at least one atom is selected from N, O and S, and the remaining ring atoms are carbon. The five-membered ring has two double bonds, and the six-membered ring has three double bonds. The heteroaryl group is attached to the parent molecular moiety through a substitutable carbon or nitrogen atom in the ring. The term "heteroaryl" also includes systems in which a heteroaryl ring is fused to an aryl group as defined herein, a heterocyclic group as defined herein, or other heteroaryl group. Examples of heteroaryl groups are benzothienyl, benzoxazolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, cinnolinyl, furanyl, imidazolyl, triazolyl [ e.g., 4H-1, 2, 4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc. ], tetrazolyl [ e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc. ], indazolyl, indolyl, isoxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxadiazolyl [ e.g., 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc. ], oxazolyl, isoxazolyl, purinyl, thiazolyl, isothiazolyl, thienopyridyl, thienyl, etc. ], oxazolyl, isoxazolyl, purinyl, thiazolyl, isothiazolyl, thiazoyl, thiadiazolyl, cinnolinyl, oxazolyl, triazolyl, etc, Thiadiazolyl [ e.g., 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc. ], pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrido [2, 3-d ] pyrimidinyl, pyrrolo [2, 3-b ] pyridyl, quinazolinyl, quinolinyl, thieno [2, 3-c ] pyridyl, tetrazolyl, triazinyl, and the like. The heteroaryl groups of the present invention may be optionally substituted with one, two, three, four or five substituents independently selected from the groups defined herein.

Examples of preferred heteroaryl groups include, but are not limited to, the following: thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, quinoxaline, tetrazolyl, oxazolyl, thiazolyl, triazolyl and isoxazolyl.

The terms "heteroarylalkyl" or "heteroarylalkyl", as used herein, alone or in combination, refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.

The terms "heteroarylalkenyl" or "heteroarylalkenyl", as used herein, alone or in combination, refers to a heteroaryl group attached to the parent molecular moiety through an alkenyl group.

The terms "heteroarylalkoxy" or "heteroarylalkoxy", as used herein, alone or in combination, refers to a heteroaryl group attached to the parent molecular moiety through an alkoxy group.

The terms "heteroarylalkylene" or "heteroarylalkylene," as used herein, alone or in combination, refers to a heteroaryl group attached to the parent molecular moiety through an alkylene group.

The term "heteroaryloxy," as used herein, alone or in combination, refers to a heteroaryl group attached to the parent molecular moiety through an oxygen atom.

The term "heteroarylsulfonyl," as used herein, alone or in combination, refers to a heteroaryl group attached to the parent molecular moiety through a sulfonyl group.

The terms "heterocycloalkyl" and interchangeable "heterocycle" as used herein, alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing one or more heteroatoms as ring members, wherein each of said heteroatoms may be independently selected from nitrogen, oxygen, and sulfur, and wherein, typically, there are from 3 to 8 ring members in each ring, respectively. The most common heterocycles contain 5 to 6 ring members. In some embodiments of the invention, the heterocycle contains 1 to 4 heteroatoms; in other embodiments, the heterocycle contains 1 to 2 heteroatoms. "heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and fused carbocyclic and benzo fused ring systems; furthermore, both terms also include systems in which a heterocyclic ring is fused to an aryl group as defined herein, or systems in which a heterocyclic ring is fused to other heterocyclic groups. Heterocyclic groups of the present invention include, for example, aziridinyl, azetidinyl, 1, 3-benzodioxyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxol, dihydro [1, 3] oxazolo [4, 5-b ] pyridyl, benzothiazolyl, indolinyl, dihydropyridinyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocyclic group may be optionally substituted unless specifically prohibited.

The term "heterocycloalkenyl" as used herein, alone or in combination, refers to a heterocyclic group attached to the parent molecular moiety through an alkenyl group.

The term "heterocycloalkoxy," as used herein, alone or in combination, refers to a heterocyclic group attached to the parent molecular group through an oxygen atom.

The term "heterocycloalkylalkyl" as used herein, alone or in combination, refers to an alkyl group as defined above wherein at least one hydrogen atom is replaced with a heterocycloalkyl group as defined above, e.g., pyrrolidinylmethyl, tetrahydrothienylmethyl, pyridylmethyl, and the like.

The term "heterocycloalkylene" as used herein, alone or in combination, refers to a heterocyclic group attached to the parent molecular moiety through an alkylene group.

The term "hydrazinyl", as used herein, alone or in combination, refers to two amino groups connected by a single bond, i.e., -N-.

The term "hydroxy" as used herein, alone or in combination, refers to-OH.

The term "hydroxyalkyl" as used herein, alone or in combination, refers to a straight or branched alkyl group having from 1 to about 10 carbon atoms, any of which from 1 to about 10 carbon atoms may be substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term "hydroxyalkyl", as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

The term "imino", as used herein, alone or in combination, means ═ N-.

The term "iminohydroxy", used herein, alone or in combination, refers to ═ N (oh) and ═ N-O-.

The phrase "in the backbone" refers to the longest continuous chain of carbon atoms or adjacent chains of carbon atoms starting from the point of attachment of the group to the compounds of the present invention.

The term "isocyanato" refers to the group-NCO.

The term "isothiocyanato" refers to the group-NCS.

The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

The term "lower" (e.g. in the term "lower alkyl"), as used herein, alone or in combination, refers to a compound containing from 1 to 6 (including 6) carbon atoms.

The term "mercaptoalkyl" as used herein, alone or in combination, refers to an R 'SR-group, wherein R and R' are as defined herein.

The term "mercaptoalkylthioalkyl" as used herein, alone or in combination, refers to the RSR' S-group, wherein R is as defined herein.

The term "alkylthio" as used herein, alone or in combination, refers to an RS-group, wherein R is as defined herein.

The term "null" refers to a lone pair of electrons.

The term "nitro" as used herein, alone or in combination, refers to-NO₂。

The term "optionally substituted" means that the preceding group may be substituted or unsubstituted. When substituted, the hydrogen atom attached to a carbon, nitrogen, sulfur or oxygen atom is substituted with a "substituent" which may include carbonyl (oxygen), carboxyl, lower alkylcarboxylate, lower alkylcarbonate, lower alkylcarbamate, halogen, hydroxyl, amino, amide, cyano, hydrazino, hydrazinocarbonyl, alkylhydrazino, dialkylhydrazino, arylhydrazino, heteroarylhydrazino, nitro, thio, sulfonic acid, trisubstituted silyl, urea, acyl, acyloxy, acylamino, acylthio, lower alkyl, lower alkylamino, lower dialkylamino, lower alkoxy, lower alkoxyalkyl, lower alkylthio, lower alkylsulfonyl, lower alkenyl, lower alkenylamino, lower amino, lower alkenyloxy, lower alkenylthio, lower alkenylsulfonyl, lower alkynyl, lower alkynylamino, lower dialkynylamino, lower alkoxy, lower alkoxylalkyl, lower alkylthio, lower alkylsulfonyl, lower alkenyl, lower alkenylamino, lower alkenyloxy, lower alkenylthio, lower alkenylsulfonyl, lower alkynyl, lower alkynylamino, lower dialkynylamino, lower, Lower alkynyloxy, lower alkynylthio, lower alkynylsulfonyl, lower cycloalkyl, lower cycloalkoxy, lower cycloalkylamino, lower cycloalkylthio, lower cycloalkylsulfonyl, lower cycloalkylalkyl, lower cycloalkylalkoxy, lower cycloalkylalkylamino, lower cycloalkylalkylthio, lower cycloalkylalkylsulfonyl, aryl, aryloxy, arylamino, arylthio, arylsulfonyl, arylalkyl, arylalkoxy, arylalkylamino, arylalkylthio, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylthio, heteroarylsulfonyl, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylamino, heteroarylalkylthio, heteroarylalkylsulfonyl, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylamino, heterocycloalkylsulfonyl, lower haloalkylsulfonyl, lower haloalkenyl, lower haloalkynyl, lowerLower perhaloalkyl, lower perhaloalkoxy, lower haloalkoxy and lower acyloxy. Two substituents may be linked together to form a fused four-, five-, six-or seven-membered carbocyclic ring or a heterocyclic ring consisting of zero to three heteroatoms, for example, to form methylenedioxy or ethylenedioxy. Optionally substituted groups may be unsubstituted (e.g., -CH)₂CH₃) Fully substituted (e.g., -CF)₂CF₃) Monosubstituted (e.g., -CH)₂CH₂F) Or any level of substitution between fully and mono-substituted (e.g., -CH)₂CF₃). When substituents are recited without limitation, both substituted and unsubstituted forms are contemplated. Where a substituent is limited to "substituted," the form of substitution is specifically intended. All pendant aryl, heteroaryl, and heterocyclic moieties may be further optionally substituted with one, two, three, four, or five substituents independently selected from the groups listed above.

The terms "oxygen" or "oxa", as used herein, alone or in combination, refer to-O-.

The term "oxo" as used herein, alone or in combination, refers to double-bonded oxygen ═ O.

The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced with halogen atoms.

The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group wherein all of the hydrogen atoms are replaced with halogen atoms.

The term "phosphate ester" as used herein, alone or in combination, refers to the group-P (═ O) (OG1), wherein G and G1 are selected from the following groups: H. alkyl, alkenyl, alkynyl, aryl, heteroaryl, and the like.

The term "phosphite" as used herein, alone or in combination, refers to the group-P (═ O) (G) (OG1), wherein G and G1 are selected from the following groups: H. alkyl, alkenyl, alkynyl, aryl, heteroaryl, and the like.

The terms "sulfonate," "sulfonic acid," and "sulfonic acid group" as used herein, alone or in combination, refer to-SO₃H group and during the formation of the salt, -SO₃The anion of the H group is used as sulfonic acid.

The term "sulfanyl" as used herein, alone or in combination, refers to-S and-S-.

The term "sulfinyl", as used herein, alone or in combination, refers to-S (O) -.

The term "sulfonyl", as used herein, alone or in combination, refers to-SO₂-。

The term "N-sulfonamido" refers to RS (═ O) with R as defined herein₂An NH-group.

The term "S-sulfonamido" refers to-S (═ O) having R as defined herein₂NR₂A group.

The terms "thia" and "thio", as used herein, alone or in combination, refer to an-S-group or an ether in which the oxygen is replaced by sulfur. Oxidized derivatives of thio groups (i.e., sulfinyl and sulfonyl) are included in the definition of thia and thio.

The term "thioether", as used herein, alone or in combination, refers to a thio group that bridges two moieties at a carbon atom.

The term "thiol" as used herein, alone or in combination, refers to an-SH group.

The term "thiocarbonyl" as used herein, includes thioaldehyde groups-C (S) H when used alone, and-C (S) -groups when used in combination.

The term "N-thiocarbamoyl" refers to a ROC (S) NH-group having R as defined herein.

The term "O-thiocarbamoyl" refers to the-OC (S) NR group having R as defined herein.

The term "thiocyanate" refers to a-CNS group.

The term "trihalomethanesulfonamido" refers to X₃CS(O)₂An NR-group, X is halogen and R is as defined herein.

The term "trihalomethylsulfonyl" refers to X₃CS(O)₂-a group wherein X is halogen.

The term "trihalomethoxy" means X₃A CO-group, wherein X is halogen.

The term "trisubstituted silyl" as used herein, alone or in combination, refers to a silicon group substituted with the groups listed herein at the three free valences of the trisubstituted silyl group according to the definition of substituted amino. Examples include trimethylsilyl, t-butyldimethylsilyl, triphenylsilyl, and the like.

The term "urea" as used herein, alone or in combination, refers to-n (R) C (═ O) n (R) having R as defined herein.

The term "carrier" is used in its broadest sense. For example, the term carrier refers to any carrier, diluent, excipient, wetting agent, buffer, suspending agent, lubricant, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, flavoring agent, and sweetener. In some embodiments, the carrier may be a pharmaceutically acceptable carrier, which term is narrower in scope than the carrier, as the term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be suitable for use in a pharmaceutical composition.

The invention also relates to pharmaceutical compositions comprising an effective amount of at least one compound of the invention in a pharmaceutically acceptable carrier.

The term effective amount is used in its broadest sense. For example, the term refers to the amount required to produce the desired effect.

In some embodiments, the compounds of the present invention are present in a pharmaceutical composition in an amount effective for treating HCV infection (e.g., chronic HCV infection). "treating HCV infection" can involve: (i) preventing HCV infection in an animal susceptible to HCV infection but not diagnosed with HCV; (ii) inhibiting or slowing HCV infection, e.g., arresting the development of HCV infection; (iii) relieving chronic infection, e.g., healing infection; (iv) ameliorating symptoms in a subject having a chronic infection; and/or (v) prolonging the survival time of a subject having a chronic infection.

In any embodiment of the compound of formula (I), R₁To R₅May be the same, may be different or R₁To R₅Some of the members may be the same while others are different. Any combination is possible.

Examples of the compounds of the present invention may include, but are not limited to, the compounds listed in table 1 below:

TABLE 1

Table 2 indicates the melting points of the various compounds.

TABLE 2

For compounds having a trifluoromethyl group (-CF)₃) In respect of the above compounds, the inventors of the present invention also envisage that, instead of the trifluoromethyl group, a group selected from: -CF₂H，-CH₂CF₃，-CF₂CH₃，-CF₂CF₃，-SCF₃，-SO₂CF₃，-OCF₃and-CH₂CH₂CF₃。

The compounds of formula (I) can be synthesized by reacting aroyl derivatives with heteroaromatic amines as shown below under suitable reaction conditions, in which formula (I) R₆Is haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, S (O)_mC(R₇R₈)nCF₃And C (R)₇R₈)_nCF₃Any of (1), in the aroyl derivative, G₁Is hydroxy, chloro, fluoro, bromo, alkoxy, etc., and in the heteroaromatic amine W, X and Y are as defined above. In some embodiments, the reaction may be generally represented as follows:

in the examples of the present invention, the compounds (1) and (2) can be synthesized by the methods described in the following reaction schemes. 2-amino-5-trifluoromethyl-thiazole was synthesized by a modified procedure published by Laduron et al in J.fluorinenechem, 1995, 73, 83-86. The coupling of o-acetylsalicyloyl chloride and 2-amino-5-trifluoromethylthiazole in the presence of a suitable base, including a tertiary amine such as triethylamine, in a suitable inert solvent, such as methylene chloride, at a temperature of about 0 deg.C to about room temperature yields compound (1). Hydrolyzing the acetyl group of compound (1) with dilute hydrochloric acid at about room temperature to about 50 ℃ to form compound (2).

In a further example of the present invention, compounds (3) and (4) can be synthesized by the synthetic routes listed in the schemes below, using commercially available 2-amino-4-trifluoromethylthiazole as starting material.

The composition of the present invention may be formulated into a solid dosage form or a liquid dosage form or a paste or ointment, and may optionally contain additional active ingredients.

The pharmaceutical composition of the present invention contains a pharmaceutically acceptable carrier, which is not particularly limited and includes various carriers known to those of ordinary skill in the art, and includes wetting or dispersing agents, starch derivatives, excipients, and the like. Tablet embodiments may optionally contain a coating material that constitutes an enteric coating, i.e., a coating that is substantially insoluble in gastric secretions but substantially soluble in intestinal fluids.

In some embodiments, pharmaceutical compositions containing a compound of the invention are formulated for oral administration in a dosage form, and optionally in the form of a liquid, e.g., an emulsion or solution or a suspension in water or oil (e.g., peanut oil), or other liquid. Dosage forms of the non-aqueous micellar solution can be prepared according to the method disclosed in U.S. patent No. 5,169,846. Alternatively, the tablet can be prepared by performing, for example, the following steps: wet granulation; drying; and compression. Film coatings are typically formed with organic solvents.

The present invention is a method of treating an HCV infection (e.g., a chronic HCV infection) comprising administering to a subject an effective amount of at least one compound of the present invention. In some embodiments, the methods of treating an HCV infection (e.g., a chronic HCV infection) comprise administering to a subject at least one pharmaceutical composition comprising an effective amount of at least one compound of the present invention.

In some embodiments, the subject is selected from an animal. In some embodiments, the subject is selected from a mammal. In some embodiments, the subject is selected from pets, e.g., mice, dogs, cats, and the like. In some embodiments, the subject is selected from a human.

In some embodiments, the present invention provides a method of treating a viral infection in a subject, comprising administering to the subject an effective amount of at least one dose of at least one compound of the present invention. In some embodiments, the present invention provides a method of treating a viral infection in a subject, comprising administering to the subject at least one dose of an effective amount of at least one pharmaceutical composition comprising at least one compound of the present invention in a pharmaceutically acceptable carrier.

In some embodiments, the dosage of the compounds of the present invention for antiviral treatment or prevention may depend on the body weight of the subject and can be inferred by one of ordinary skill in the art without undue experimentation by reference to the following examples, which are for illustrative purposes and are not intended to limit the invention.

The compounds and compositions of the present invention may be administered locally or systemically by any method known to those of ordinary skill in the art. For example, the compounds and compositions of the present invention may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in a dosage form containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, or intraosseous injection and infusion techniques. The exact dosage regimen will vary depending upon a variety of factors including the age, weight, general health, sex, and diet of the patient; the determination of a particular administration procedure will be readily apparent to those skilled in the art.

Dosage levels of the active ingredient compound on the order of about 0.1mg/kg to about 100mg/kg are useful in treating the above-described conditions (e.g., 0.1 mg/kg-day). In some embodiments, the dose is from about 1mg/kg to about 10mg/kg, and in other embodiments, the dose is from about 2mg/kg to about 5 mg/kg. The specific dosage level for any particular patient will vary with a variety of factors including the activity and potential toxicity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, the time of administration, the rate of excretion, drug combination, the severity of the particular disease being treated, and the form of administration. Generally, the results of the in vitro dose-effect provide useful guidance for administering an appropriate dose to a patient. Studies in animal models are also useful. Factors to be considered in determining an appropriate dosage level are well known in the art.

Any dosing regimen for adjusting the timing and sequence of drug delivery can be used and repeated as needed to effect treatment. Such regimens may include repeated use or pre-administration and/or co-administration and/or post-administration via food, liquid or water.

As noted above, the present invention provides or contemplates kits comprising at least one compound of the present invention. The kit may take any form. For example, a kit includes one or more containers for holding a pharmaceutical composition. In some embodiments, the container includes written instructions for administering the pharmaceutical composition. In some embodiments, the container comprises a substrate for written instructions for administering the pharmaceutical composition. In some embodiments, the written instructions for administering the pharmaceutical composition are affixed to the container, for example, the written instructions are sometimes affixed to a surface when the container contains the prescription.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Examples

1. Feedstock and method

1.1 starting materials

All test compounds were provided by the Romark laboratory. Nitazoxanide (nitazoxanide) and tizoxanide (tizoxanide) were used as standards.

1.2HBV study

1.2.1 antiviral assays

HBV antiviral assays were performed as previously described [ Korba and Gerin, antiviral res.19: 55(1992)]. Confluent cultures of 2.2.15 cells were maintained on 96-well flat-bottom tissue culture plates (confluent cultures in this culture system were required for active, high levels of HBV replication equivalent to that observed in chronically infected individuals) [ Sells et al, J.Virol.62, 2863-2844 (1998); korba and Gerin (1992) ]. Cultures were treated with nine consecutive daily doses of test compound. The HBVDNA levels were assessed by quantitative blot hybridization 24 hours after the last treatment. Cytotoxicity was assessed 24 hours after the last treatment by uptake of neutral red dye.

1.2.3 production of HBV proteins

ETI-EBK for use other than HBeAg(Diasorin, Stillwater, MNUSA), cultures of 2.2.15 cells were treated according to standard methods and EIA-based semi-quantitative analysis of HBV proteins was performed as previously described [ Korba and Gerin, Antivir. Res.28, 225-242(1995)]. Samples were diluted (2 to 10 fold) to bring the levels to the dynamic response range of the EIA. The media samples were analyzed for HBsAg and HBeAg and the intracellular lysates for HBcAg. Intracellular HBVRNA was assessed by quantitative northern blot hybridization (Korba and Gerin, 1995).

1.3HCV study

Antiviral activity of test compounds was assessed in a 3 day assay using the cell line AVA5 (subgenomic CON1, genotype 1b) [ flight et al, Science290, 1972-. Antiviral activity was determined by blot hybridization analysis of intracellular hcv RNA (normalized to the level of cellular B-actin RNA in each culture sample), and cytotoxicity was assessed by uptake of neutral red dye 3 days after treatment. Additional studies were performed using Huh7 cells containing another HCV replicon (H/FL-Neo, full-length construct of genotype 1 a) [ Blight et al, J.Virol.77, 3181-3190(2003) ]. For studies involving human serum, standard media (containing 10% fetal bovine serum) and assay conditions were maintained.

1.4 description of the results

EC₅₀、EC₉₀And CC₅₀Values (± standard deviation s.d.]) Calculated by linear regression analysis using data combining all treated cultures (Korba and Gerin, 1992; okuse et al, 2005). EC (EC)₅₀And EC₉₀Is the drug concentration when a 2-fold or 10-fold decrease in intracellular hbv dna or hcv rna, respectively, is observed (relative to the average level in untreated cultures). CC (challenge collapsar)₅₀Is the drug concentration when a 2-fold decrease in neutral red dye uptake levels (relative to the average level in untreated cultures) is observed. Selectivity index (S.I.) for HBV analysis was calculated as CC₅₀/EC₉₀Selectivity index for HCV analysis (S.I.) was calculated as CC₅₀/EC₅₀。EC₉₀Values were used to calculate s.i. in HBV analysis as it is generally necessary to reduce HBVDNA levels by at least 3-fold to achieve statistical significance in this assay system (Korba and Gerin, 1992). For the combined treatment, the EC of the first compound listed is stated₅₀、EC₉₀、CC₅₀And s.i. The molar ratio of the compounds in each combination is also specified.

2. Results

TABLE 3 results of HBV extracellular virion analysis

Legend: a: 0.05-0.2; b: 0.2-0.8; c: 0.8-3.2; d: 3.2-4.0; e: greater than 4.0

Nitazoxanide (reference) tizoxanide (reference)

Table 4 shows data in the primary HCV replicon cell assay.

TABLE 4 Primary HCV replicon cell analysis

EC50& EC90 legend

A：0.005-0.05；B：0.05-0.5；C：0.5-1.0；D：1.0-5.0；E＞5.0

TABLE 5 antiviral Activity of thiazolides against paramyxoviruses, influenza A and coronaviruses in cellular assays

TABLE 6 antiviral Activity of thiazolides against rhinoviruses, respiratory syncytial viruses and herpes viruses in cellular assays

TABLE 7 antiviral Activity of thiazolides against Rotavirus (strain 2) and adenovirus in cellular assays

TABLE 8 antiviral Activity of Thiazolides against Corynoviruses in cellular assays

Claims

1. A compound of formula I:

wherein:

R₁is the following group: hydroxy or C₁-C₃Alkanoyloxy and R₂To R₅Is H;

wherein R is₆Is CF₃；

Wherein X is N, W is S, and Y is CR₁₀；

R₁₀Is H.

2. The compound of claim 1, wherein:

R₁is hydroxyl or acetoxy.

3. The compound of claim 1, wherein:

R₁is a hydroxyl group.

4. The compound of claims 1-3, wherein the compound is 2-hydroxy-N- (5- (trifluoromethyl) thiazol-2-yl) benzamide or a pharmaceutically acceptable salt thereof.

5. A compound according to claims 1-3, wherein the salt is selected from: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, toluenesulfonate, undecanoate, lithium, sodium, calcium, potassium, aluminum, ammonium, tetraethylammonium, methylammonium, dimethylammonium, N-methylmorpholine and ethylammonium.

6. The compound of any one of claims 1-3, wherein the compound is isotopically labeled.

7. A pharmaceutical composition comprising a compound of claims 1-5 and a pharmaceutically acceptable carrier.

8. Use of the pharmaceutical composition of claim 7 in the manufacture of a medicament for the treatment of a viral infection.

9. The use of claim 8, wherein the viral infection is hepatitis c virus.

10. The use of claim 8, wherein the viral infection is hepatitis b virus.

11. Use of a compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, in combination with another antiviral composition, for the manufacture of a medicament for the treatment of a viral infection.

12. The use of claim 11, wherein the other antiviral composition comprises a nucleoside analog.

13. The use of claim 11, wherein the additional antiviral composition comprises pegylated interferon.

14. Use of the pharmaceutical composition of claim 7 in the manufacture of a medicament for the treatment of a viral infection comprising administering the pharmaceutical composition of claim 7 to a patient in need thereof.

15. The use of claim 14, wherein the viral infection is selected from the group consisting of: respiratory viruses, herpes viruses and gastrointestinal viruses.

16. The use of claim 15, wherein the respiratory virus is selected from the group consisting of: parainfluenza virus, influenza a, influenza B, coronavirus, Rhinovirus (RHV) and Respiratory Syncytial Virus (RSV).

17. The use of claim 15, wherein the herpes virus is selected from the group consisting of: herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), Human Cytomegalovirus (HCMV), Varicella Zoster Virus (VZV) and Epstein-Barr virus (human herpes virus 4).

18. The use according to claim 15, wherein the gastrointestinal virus is selected from the group consisting of: rotaviruses and adenoviruses.

19. Use of a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the treatment of a rhabdovirus.