3,4-Disubstituted coumarin and quinolone compounds

Abstract

The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative.

Description

FIELD OF THE INVENTION

The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative. The invention provides a synthetic process for the preparation of 3,4-disubstituted coumarin and quinolone derivatives using mild reaction conditions, which provides a high substituent tolerance and is appropriate for use in solid phase syntheses for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.

BACKGROUND OF THE INVENTION

Strategies in new drug discovery often look to natural products for leads in finding new chemical compounds with therapeutic properties. One of the recurring problems in drug discovery is the availability of organic compounds derived from natural sources. Techniques employing combinatorial chemistry attempt to overcome this problem by allowing the high throughput synthesis and testing of hundreds or thousands of related synthetic compounds, called a chemical library. In designing the synthesis of a prospective therapeutic compound or a chemical library, one often looks to natural chemical motifs which are known to have broad biological activity. Coumarin and Quinolone derivatives are of particular interest due to their frequent occurrence in nature and range of biological activities.

Coumarins are widely distributed in the plant kingdom. Approximately 50 naturally occurring coumarin derivatives have been identified. Derivatives of both coumarin and quinolone posses a range of biological activities. To avoid confusion, the coumarin and quinolone derivatives described herein are numbered according to the following convention:

Infection with the Hepatitis C virus (HCV) represents a serious world-wide health crisis. In more than 70% of infected individuals, the virus evades clearance by the immune system leading to a persistent HCV infection. The long term effects of persistent HCV infection range from an apparently healthy carrier state to chronic hepatitis, liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. HCV is a leading cause of chronic liver disease. The best therapy currently available for treatment of HCV infection uses a combination of pegylated α-interferon and ribavirin. However, many of the patients treated with this therapy fail to show a sufficient antiviral response. Additionally, interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Thus, it is vital that more effective treatments be identified.

SUMMARY OF THE INVENTION

The present invention provides 3,4-disubstituted coumarin and quinolone derivatives having the formula I wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
  • a is 0 to 6;
  • X is selected from O and N—R⁴;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • Y is selected from O and N—R⁵;
    • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
      • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
        • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
    • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

The invention also provides a synthetic process for the preparation of compounds of the formula I. The process uses mild reaction conditions, which provides a high substituent tolerance. Thus, the process is applicable to the preparation of a wide variety of 3,4-disubstituted coumarin and quinolone derivatives with diverse substitution patterns. Additionally, the process is appropriate for use with combinatorial synthesis techniques. Thus, the process provides a method for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.

The invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention in a therapeutically effective amount.

DETAILED DESCRIPTION OF THE INVENTION

The term “halo” or “halogen” as used herein includes fluorine, chlorine, bromine and iodine.

The term “alkyl” as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms. The term “lower alkyl” as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. The alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The term “alkenyl” as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals containing from two to 8 carbon atoms. The alkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The term “alkynyl” as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond. The term alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl, and the like. The alkynyl group may be optionally substituted with one or more substituents selected from halo, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The term “cycloalkyl” as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

The term “cycloalkenyl” as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like. The cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

The term “aralkyl” as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted. The aralkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The terms phosphate and phosphonate as used herein refer to the moieties having the following structures, respectively:

The term “heterocyclic group” or “heterocyclic ring” as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like. Aromatic heterocyclic groups, also termed “heteroaryl” groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. The term heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two atoms are common to two adjoining rings (the rings are “fused”) wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like. The heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The terms “aryl”, “aromatic group”, or “aromatic ring” as used herein contemplates substituted or unsubstituted single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (naphthyl, quinoline, etc.). The polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are “fused”) wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO₂, CO₂R, C(O)R, —O—R, —N(R′)(R″), —N(R)C(O)R, —N(R)SO₂R, —SR, —C(O)N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), SO₂, —SOR, —SO₃R, —SO₂N(R′)(R″), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

Each R is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl. Each R′ and R″ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R′ and R″ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom.

The term “heteroatom”, particularly as a ring heteroatom, refers to N, O, and S.

All value ranges, for example those given for n and m, are inclusive over the entire range. Thus, a range of 0 to 4 would include the values 0, 1, 2, 3 and 4.

The present invention provides compounds of the formula I: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹³)C(O)R , —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • X is selected from O and N—R⁴;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • bis 0 to 6;
  • Y is selected from O and N—R⁵;
    • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
      • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
        • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
    • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

The substances according to the invention may be present as salts. In the context of the invention, preference is given to pharmaceutically acceptable salts. Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. (see, Berge et al. J. Pharm. Sci. 1977, 66, 1-19.)

When one or more chiral centers are present in the compounds of the present invention, the individual isomers and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. In certain embodiments, compounds of the invention may exist in several tautomeric forms. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. Compounds of the invention may exist in various hydrated forms.

It is understood that when n is a value greater than 1, each R¹ group may be selected independently. Thus, when more than one R¹ group is present, the R¹ groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values.

In preferred embodiments of the invention, R² is selected from aryl and aralkyl.

In one embodiment of the invention, Y is selected to be a O to give a compound of the formula II: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • a is 0 to 6;
  • X is selected from O and N—R⁴;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
    • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment of the invention, X of a compound according to formula II is selected to be a O to give a compound of the formula III: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and
    • a is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R² and R³ of a compound according to formula III are selected to be a —CH₂—R⁶ and —CH₂—R⁷, respectively, to give a compound of the formula IV: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁶ is selected from the group consisting of aryl and heteroaryl;
  • R⁷ is selected from the group consisting of aryl, heteroaryl, —C(O)R³¹, —C(O)N(R³²)(R³³), —C(O)OR³¹, —C(O)N(R³²)(R³³), and —N(R³²)(R³³),
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached
      • form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a preferred embodiment for compounds of the formula IV, R⁷ is selected to be an aryl or heteroaryl groups.

In another embodiment of the invention, R² of a compound according to formula III is selected to be a benzyl group to give a compound of the formula V: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two RI substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸¹, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R⁸¹, —N(R⁸¹)SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • m is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R⁶ and R⁷ of a compound according to formula IV are selected to be phenyl groups, to give a compound of the formula VI: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸¹, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R , —N(R⁸¹)SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • m is 0 to 5;
  • each R⁹ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁹¹, C(O)R⁹¹, —O—R⁹¹, —N(R⁹²)(R⁹³), —N(R⁹¹)C(O)R⁹¹, —N(R⁹¹)SO₂R⁹¹, —SR⁹¹, —C(O)N(R⁹²)(R⁹³), —OC(O)R⁹¹, —OC(O)N(R⁹²)(R⁹³), SO₂, —SOR⁹¹, —SO₃R⁹¹, —SO₂N(R⁹²)(R⁹³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁹¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁹² and R⁹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁹² and R⁹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • p is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

Exemplary compounds of the formula VI include the following structures:

In a another embodiment of the invention, X of a compound according to formula II is selected to be a N—R⁴ to give a compound of the formula VII: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
    • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a preferred embodiment for compounds of the formula VII, R3 is selected to be —CH═N—R³⁴, to give a compound of the formula VIl_a wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6; and
  • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a preferred embodiment for compounds of the formula VII and VII_a, R² is selected to be an aryl or heteroaryl groups. I further preferred embodiments, R⁴ is H.

Exemplary compounds of the formula VII_a include the following structures:

In further preferred embodiment of the invention, R² and R³ of a compound according to formula VII are selected to be a —CH₂—R⁶ and —CH₂—R⁷, respectively, to give a compound of the formula VIII: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • R⁶ is selected from the group consisting of aryl and heteroaryl;
  • R⁷ is selected from the group consisting of aryl, heteroaryl, —C(O)R³¹, —C(O)N(R³²)(R³³), —C(O)OR³¹, —C(O)N(R³²)(R³³), and —N(R³²)(R³³),
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a preferred embodiment for compounds of the formula VIII, R⁷ is selected to be an aryl or heteroaryl groups.

In another embodiment of the invention, R² of a compound according to formula VII is selected to be a benzyl group to give a compound of the formula IX: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R⁸¹, —N(R⁸¹)SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R , —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • m is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R⁶ and R⁷ of a compound according to formula VIII are selected to be phenyl groups, to give a compound of the formula X: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸¹, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R⁸¹, —N(R⁸¹)SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • m is 0 to 5;
  • each R⁹ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁹¹, C(O)R⁹¹, —O—R⁹¹, —N(R⁹²)(R⁹³), —N(R⁹¹)C(O)R⁹¹, —N(R⁹¹)SO₂R⁹¹, —SR⁹¹, —C(O)N(R⁹²)(R⁹³), —OC(O)R⁹¹, —OC(O)N(R⁹²)(R⁹³), SO₂, —SOR⁹¹, —SO₃R⁹¹, —SO₂N(R⁹²)(R⁹³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁹¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁹² and R⁹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁹² and R⁹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • p is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment of the invention, Y is selected to be a N—R⁵ to give a compound of the formula XI: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹¹), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • X is selected from O and N—R⁴;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
    • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment of the invention, X of a compound according to formula XI is selected to be a O to give a compound of the formula XII: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
    • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R² and R³ of a compound according to formula XII are selected to be a —CH₂—R⁶ and —CH₂—R⁷, respectively, to give a compound of the formula XIII: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹,
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • b is 0 to 6;
  • R⁶ is selected from the group consisting of aryl and heteroaryl;
  • R⁷ is selected from the group consisting of aryl, heteroaryl, —C(O)R³¹, —C(O)N(R³²)(R³³), —C(O)OR³¹, —C(O)N(R³²)(R³³), and —N(R³²)(R³³),
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; or a pharmaceutically acceptable salt or hydrate thereof.

In a preferred embodiment for compounds of the formula XIII, R⁶ is selected to be an aryl or heteroaryl groups.

In another embodiment of the invention, R² of a compound according to formula XII is selected to be a benzyl group to give a compound of the formula XIV: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • R⁵is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • b is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸¹, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R^{81, —N(R81})SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • m is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R⁶ and R⁷ of a compound according to formula XIII are selected to be phenyl groups, to give a compound of the formula XV: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • b is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R⁸¹, —N(R⁸¹)SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • m is 0 to 5;
  • each R⁹ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁹¹, C(O)R⁹, —O—R⁹¹, —N(R⁹²)(R⁹³), —N(R⁹¹)C(O)R⁹¹, —N(R⁹¹)SO₂R⁹¹, —SR⁹¹, —C(O)N(R⁹²)(R⁹³), —OC(O)R⁹¹, —OC(O)N(R⁹²)(R⁹³), SO₂, —SOR⁹¹, —SO₃R⁹¹, —SO₂N(R⁹²)(R⁹³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁹¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁹² and R⁹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁹² and R⁹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • p is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

Exemplary compounds of the formula XV include the following structures:

In a another embodiment of the invention, X of a compound according to formula XI is selected to be a N—R⁴ to give a compound of the formula XVI: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
    • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
    • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R² is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • b is 0 to 6;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R² and R³ of a compound according to formula XVI are selected to be a —CH₂—R⁶ and —CH₂—R⁷, respectively, to give a compound of the formula XVII: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • b is 0 to 6;
  • R⁶ is selected from the group consisting of aryl and heteroaryl;
  • R⁷ is selected from the group consisting of aryl, heteroaryl, —C(O)R³¹, —C(O)N(R³²)(R³³), —C(O)OR³¹, —C(O)N(R³²)(R³³), and —N(R³²)(R³³),
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached
      • form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In a preferred embodiment for compounds of the formula XVII, R⁶ is selected to be an aryl or heteroaryl groups.

In another embodiment of the invention, R² of a compound according to formula XVI is selected to be a benzyl group to give a compound of the formula XVIII: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, S₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R³ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_aC(O)R³¹, —(CH₂)_aC(O)N(R³²)(R³³), (CH₂)_aC(O)OR³¹, —(CH₂)_aC(O)N(R³²)(R³³), —(CH₂)_aN(R³²)(R³³), —CH═N—R³⁴,
    • R³¹ selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R³² and R³³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R³² and R³³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • R³⁴ is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
    • a is 0 to 6;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • b is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸¹, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R⁸¹, —N(R⁸¹)SO₂R⁸¹, —SR⁸¹, —C(O)N(R⁸²)(R⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR₈₁, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • m is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

In further preferred embodiment of the invention, R⁶ and R⁷ of a compound according to formula XVII are selected to be phenyl groups, to give a compound of the formula XIX: wherein:

• • each R¹ is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R¹¹, —N(R¹²)(R¹³), —N(R¹¹)C(O)R¹¹, —N(R¹¹)SO₂R¹¹, —SR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹²)(R¹³), —OC(O)R¹¹, —OC(O)N(R¹²)(R¹³), CN, CF₃, NO₂, SO₂, —SOR¹¹, —SO₃R¹¹, —SO₂N(R¹²)(R¹³), -alkyl-O—R¹¹, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
    • additionally or alternatively two R¹ substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R¹;
      • each R¹¹ is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
      • each R¹² and R¹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R¹² and R¹³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
  • n is 0 to 4;
  • R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁴¹, —(CH₂)_bC(O)N(R⁴²)(R⁴³), —(CH₂)_bC(O)OR⁴¹, and —(CH₂)_bC(O)N(R⁴²)(R⁴³),
    • each R⁴¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁴² and R⁴³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁴² and R⁴³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
    • b is 0 to 6;
  • R⁵ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —(CH₂)_bC(O)R⁵¹, —(CH₂)_bC(O)N(R⁵²)(R⁵³), and —(CH₂)_bC(O)OR⁵¹;
    • each R⁵¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • R⁵² and R⁵³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
      • or R⁵² and R⁵³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • b is 0 to 6;
  • each R⁸ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁸¹, C(O)R⁸¹, —O—R⁸¹, —N(R⁸²)(R⁸³), —N(R⁸¹)C(O)R⁸¹, —N(R⁸¹)SO₂R⁸¹, —SR^{, —C(O)N(R82})(⁸³), —OC(O)R⁸¹, —OC(O)N(R⁸²′)(R⁸³), SO₂, —SOR⁸¹, —SO₃R⁸¹, —SO₂N(R⁸²)(R⁸³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁸¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁸² and R⁸³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁸² and R⁸³ may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
  • m is 0 to 5;
  • each R⁹ is independently selected from the group consisting of halo, alkyl, CN, NO₂, CO₂R⁹¹, C(O)R⁹¹, —O—R⁹¹, —N(R⁹²)(R⁹³), —N(R⁹¹)C(O)R⁹¹, —N(R⁹¹)SO₂R⁹¹, —SR⁹¹, —C(O)N(R⁹²)(R⁹³), —OC(O)R⁹¹, —OC(O)N(R⁹²)(R⁹³), SO₂, —SOR⁹¹, —SO₃R⁹¹, —SO₂N(R⁹²)(R⁹³), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
    • each R⁹¹ is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
    • each R⁹² and R⁹³ are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R⁹² and R⁹³ may be taken together with the nitrogen to which they are attached, form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
  • p is 0 to 5;
  • or a pharmaceutically acceptable salt or hydrate thereof.

The substances according to the invention may also be present as salts. In the context of the invention, preference is given to pharmaceutically acceptable salts. Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. (see, Berge et al. J. Pharm. Sci. 1977, 66, 1-19.)

When one or more chiral centers are present in the compounds of the present invention, the individual isomers and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. In certain embodiments, compounds of the invention may exist in several tautomeric forms. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. Compounds of the invention may exist in various hydrated forms.

It is understood that when n is a value greater than 1, each R¹ group may be selected independently. Thus, when more than one R¹ group is present, the R¹ groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values.

In another aspect of the invention, a synthetic process for the preparation of compounds of the invention is provided. The inventive process uses mild reaction conditions, which provides a high substituent tolerance. The product is obtained in high yield and high purity. A process of the present invention is illustrated by Scheme I:

A₁ and A₂ may be treated with an alcohol (HO—R²) or amine (H₂N—R²) in the presence of an appropriate base. LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner. The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.

In other embodiments, compounds of the invention may be prepared according the reactions provided in Scheme 2:

A₃ and A₄ may be treated with an activated benzyl group in the presence of an appropriate base. LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner. The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.

In other embodiments, compounds of the invention may be prepared in the manner described in Scheme 3:

A₄ may be treated with an activated benzyl group in the presence of an appropriate base. LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner. The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.

It may be advantageous to employ a temporary protecting group in achieving the final product. The phrase “protecting group” as used herein means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2^nd ed.; Wiley: New York, 1991).

The compounds and processes disclosed herein are useful in the production of a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening. Derivatives of coumarin and quinolone posses a range of biological activities. Coumarin-based and quinolone-based compounds have shown efficacy, for example, as antivirals. Particularly, the compounds of the present invention may be used to prevent or treat infection with HCV.

The identification of inhibitors of HCV replication and/or proliferation has been facilitated by the development of a cell based system to study HCV replication and assay for HCV inhibitors. Inhibition of HCV replication may be performed using the HCV Replicon Assay developed in the laboratories of Bartenschlager (Lohman et al, Science 285, 110-113, 1999) and Rice (Blight et al, Science 290, 1972-1974, 2000). The assay is performed using the Huh-Luc-Neo cell line (Lohman et al, Science 285, 110-113, 1999). Huh-Luc-Neo cells are a human hepatoma cell line (Huh-7) stably expressing a bi-cistronic subgenomic replicon containing the HCV IRES in which the structural proteins of HCV had been deleted and replaced by a construct containing sequences coding for the firefly luciferase reporter gene, the neomycin selectable marker and the EMCV IRES to direct expression of a truncated HCV genome expressing the structural proteins NS3, NS4A, NS4B, NS5A, and NS5B. HCV targets through which inhibitors could act to inhibit replication include the NS3 protease, the helicase/ATPase, NS5A, the NS5B- RNA dependent RNA polymerase, and the HCV IRES.

Expression of HCV IRES driven luciferase reporter activity and HCV RNA is measured to obtain indirect and direct measures of replication of HCV RNA respectively. Inhibitors of HCV replication and/or proliferation are determined by initially identifying molecules that inhibit expression of the HCV IRES driven luciferase reporter in this HCV Replicon Luciferase Assay. Cell viability assays and control cell based luciferase assays are then run on hits identified in the HCV Replicon Luciferase Assay to eliminate cytoxic compounds and non-specific compounds which act by inhibiting the luciferase enzyme. Validated inhibitors of HCV replication and/or proliferation are identified by evaluating HCV Replicon Luciferase hits that are specific and non-cytoxic and demonstrating that these compounds inhibit expression of HCV RNA using a quantitative PCR based approach (Taqman) using primers and probes specific for HCV RNA (HCV Replicon RNA Assay).

The HCV Replicon Assay may be used to predict compound efficacy in treatment and/or prevention of HCV infection as well as inhibition of HCV replication and/or proliferation. The HCV Replicon encompasses a multiplicity of viral and host targets through which an inhibitor could work to inhibit HCV Replication. Viral targets expressed in the HCV Replicon include the HCV IRES (for translation), NS3 Protease, the HCV Helicase/ATPase, NS5A phosphorylation, and the NS5B polymerase. Without being limited to theory, it is believed that the compounds of the present invention inhibit HCV replication. The compounds of the invention may inhibit replication as by acting on the IRES, NS3 protease, NS5B polymerase, Helicase/ATPase, or NS5A phosphorylation.

Thus, in another embodiment, the present invention provides pharmaceutical compositions comprising an anti-HCV effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier or auxiliary agent. As used herein, the terms “pharmaceutically acceptable salts” and “hydrates” refer to those salts and hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.

The invention also provides a method of treating HCV infection in a mammal, preferable a human, by administering to the mammal an effective amount of a compound of the present invention, a pharmaceutically acceptable salt or hydrate thereof, or a composition as described above. The compounds of the invention may be administered alone or may be administered in combination with other approved therapeutics, such as: an interferon (pegylated or not), preferably a-interferon, ribavirin, or interferon and ribavirin, or one or more other anti-HCV agent, such as an HCV protease inhibitor, HCV polymerase inhibitor, HCV IRES inhibitor, HCV Helicase and/or ATPase inhibitor, NS5A phosphorylation inhibitor, HCV NS2 inhibitor, or other HCV life cycle inhibitor. Combination therapies with may include a compound of the invention with multiple different inhibitors of HCV life cycle (immunomodulatory agents, Toll Like Receptor modulators, antisense therapeutics etc.). The agents that comprise a combination therapy may be administered together or separately, e.g., prior to, concurrently with or following the administration of the compound of the invention or pharmaceutically acceptable salt thereof. These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be employed in solid or liquid form including, for example, amorphous powder or crystalline form, in solution or in suspension. They may be administered in numerous different ways, such as orally, parenterally, topically, transdermally or by inhalation. Oral administration or administration by injection is preferred. The choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and well established pharmaceutical practice. The pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, and intralesional injection or infusion techniques.

Examples of liquid carriers include syrups, peanut oil, olive oil, water, saline and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, may be used. Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents.

The pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. Compounds of the invention may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Carriers for oral use (solid or liquid) may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. To prepare a capsule, it may be advantageous to use lactose and a liquid carrier, such as high molecular weight polyethylene glycols.

Compositions and dosage forms prepared in accordance with the present invention optionally may contain lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, capsules and the like. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, and capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and mixtures thereof also may be used. In addition, the active compound may be incorporated into sustained-release preparations and formulations. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Other suitable vehicles or carriers for the above noted formulations and compositions can be found in standard pharmaceutical texts, e.g. in “Remington's Pharmaceutical Sciences”, The Science and Practice of Pharmacy, 19.sup.th Ed. Mack Publishing Company, Easton, Pa., (1995).

When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition may be administered in vivo to mammals, such as man, to treat or prevent HCV virus infection. Such treatment may also be achieved using a compound of this invention in combination with other anti-viral agents which include, but are not limited to a-interferon and ribavirin. The additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.

EXAMPLES

General Methods

Reaction solvents were commercially purchased from Acros and Aldrich without further purification and reagents were used as received. Reactions for the synthesis of the starting material were monitored by thin-layer chromatography (TLC) on 0.25 mm precoated Merck Silica Gel 60 F₂₅₄, visualizing with ultraviolet light or phosphomolybdic acid stain. Flash column chromatography was performed on Merck Silica Gel 60 (230-400 mesh) using reagent grade hexanes, dichloromethane, methanol and ethyl acetate.

Reaction reagents were commercially purchased from Alrich and used as received. ¹H and ¹³C NMR spectra were recorded on a Varian 500 MHz spectrometer and are referenced to residual solvent peaks or to an internal reference of tetramethylsilane in CDCl₃. LC-MS were obtained on a Micromass ZQ mass spectrameter in ES+ mode with a Water 2790 HPLC system. HPLC condition: C18 column (3.5 μm, 2.1×50 mm, W93491F 26) using a flow rate of 0.4 mL/min in a gradient of 15˜100% CH₃CN in H2O in 9 min with 1 min wash.

Example 1

To the mixture of 1 (60 mg, 0.37 mmol) and K₂CO₃ (100 mg, 0.73 mmol) in acetone (3 mL), 2 (103 mg, 0.56 mmol) was added slowly. Then the reaction was stirred at 65° C. overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC (eluent: EtOAc/Petroleum ether=1:3) to give 3 (13.9 mg, 10%) as solid.

LC-MS (6.77 min, ES⁺): calcd: 478.10; Found: 479.48. ¹H NMR (CDCl₃): 7.72˜7.63 (m, 2H), 7.62˜7.52 (m, 3H), 7.52˜7.43 (m, 2H), 7.43˜7.34 (m, 3H), 7.314 (t, J=7.5 Hz, 1H), 5.13 (s, 2H), 3.977 (s, 2H).

LC-MS (6.81 min, ES⁺): calcd: 478.10; Found: 479.41. ¹H NMR (CDCl₃): 7.656 (d, J=8 Hz, 1H), 7.627 (AABB, J=80.5, 8.5 Hz, 4H), 7.57 (t, J=7.5 Hz, 1H), 7.455 (AABB, J=52, 8 Hz, 4H), 7.403 (d, J=8 Hz, 1H), 7.309 (t, J=7.5 Hz, 1H), 5.138 (s, 2H), 3.978 (s, 2H).

LC-MS (6.65 min, ES⁺): calcd: 370.16; Found: 371.45. ¹H NMR (CDCl₃): 7.72 (d, J=8.5 Hz, 1H), 7.523 (t, J=8.5 Hz, 1H), 7.376 (d, J=8 Hz, 1H), 7.297 (t, J=8 Hz, 1H), 7.31 (AABB, J=45.5, 9.5 Hz, 4H), 7.175 (AABB, J=81.5, 8 Hz, 4H), 5.072 (s, 2H), 3.913 (s, 2H), 2.421 (s, 3H), 2.314 (s, 3H).

LC-MS (6.68 min, ES⁺): calcd: 400.17; Found: 401.47. ¹H NMR (CDCl₃): 7.589 (d, J=8.5 Hz, 1H), 7.325 (d, J=7.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.224 (s, 1H), 7.216 (d, J=8.0 Hz, 1H), 7.171˜7.115 (m, 3H), 6.999 (d, J=7.5 Hz, 1H), 6.857˜6.835 (m, 2H), 5.006 (s, 2H), 3.890 (s, 2H), 3.874 (s, 3H), 2.4 (s, 3H), 2.298 (s, 3H).

LC-MS (6.71 min, ES⁺): calcd: 440.06; Found: 441.38. ¹H NMR (CDCl₃): 7.542 (d, J=9.5 Hz, 1H), 7.412 (s, 1H), 7.371 (s, 1H), 7.4˜7.35 (m, 1H), 7.3˜7.24 (m, 2H), 7.2˜7.15 (m, 3H), 6.9˜6.85 (m, 2H), 5.002 (s, 2H), 3.879 (s, 3H), 3.861 (s, 2H).

LC-MS (6.64 min, ES⁺): calcd: 400.17; Found: 401.47. ¹H NMR (CDCl₃): 7.595 (d, J=9.0 Hz, 1H), 7.4˜7.25 (m, 3H), 7.25˜7.15 (m, 2H), 7.15˜7.05 (m, 3H), 6.95˜6.85 (m, 2H), 5.01 (s, 2H), 3.886 (s, 3H), 3.872 (s, 2H), 2.33 (s, 3H), 2.207 (s, 3H).

LC-MS (6.33 min, ES⁺): calcd: 444.10; Found: 445.46. ¹H NMR (CDCl₃): 7.576 (d, J=9 Hz, 1H), 7.428 (q, J=15.5, 8 Hz, 1H), 7.223 (q, J=15, 8 Hz, 1H), 6.937 (t, J=7.5 Hz, 1H), 6.9˜6.82 (m, 3H), 6.763 (tt, J=8.5, 2H), 5.078 (s, 2H), 3.825 (s, 5H).

LC-MS (6.51 min, ES⁺): calcd: 444.10; Found: 445.41. ¹H NMR (CDCl₃): 7.516 (d, J=9.5 Hz, 1H), 7.3˜7.16 (m, 2H), 7.15˜6.94 (m, 4H), 6.9˜6.83 (m, 2H), 5.009 (s, 2H), 3.884 (s, 3H), 3.808 (s, 2H).

LC-MS (6.78 min, ES⁺): calcd: 508.11; Found: 509.46. ¹H NMR (CDCl₃): 7.7˜7.63 (m, 2H), 7.6˜7.5 (m, 4H), 7.5˜7.42 (2H), 7.4˜7.33 (m, 1H), 6.85˜6.82 (m, 2H), 5.097 (s, 2H), 3.939 (s, 2H), 3.885 (s, 3H).

LC-MS (6.84 min, ES⁺): calcd: 508.11; Found: 509.45. ¹H NMR (CDCl₃): 7.614 (AABB, J=85.5, 8.5 Hz, 4H), 7.53 (d, J=8 Hz, 1H), 7.446 (AABB, J=55, 8 Hz, 4H), 6.875 (s, 1H), 6.866 (d, J=8 Hz, 1H), 5.106 (s, 2H), 3.94 (s, 2H), 3.884 (s, 3H).

LC-MS (6.68 min, ES⁺): calcd: 400.17; Found: 401.47. ¹H NMR (CDCl₃): 7.576 (d, J=8 Hz, 1H), 7.226 (AABB, J=8, 4 Hz, 4H), 7.19 (AABB, J=121, 8 Hz, 4H), 6.845 (s, 1H), 6.837 (d, J=8 Hz, 1H), 5.028 (s, 2H), 3.869 (s, 3H), 3.859 (s, 2H), 2.40 (s, 3H), 2.294 (s, 3H).

LC-MS (6.64 min, ES⁺): calcd: 442.12; Found: 443.40. ¹H NMR (CDCl₃): 7.438 (q, J=14.5, 8 Hz, 1H), 7.41 (s, 1H), 7.21 (q, J=15.5, 8.5 Hz, 1H), 7.16 (s, 1H), 6.942 (t, J=8 Hz, 1H), 6.881 (t, J=8 Hz, 1H), 6.81˜6.7 (m, 2H), 5.081 (s, 2H), 3.882 (s, 2H), 2.36 (s, 3H), 2.306 (s, 3H).

Example 2

POCl₃ was added slowly to the solution of 1 in DMF at −5˜−10° C. (ice bath). Then the mixture stirred for 1 hr at r.t. and for another 2 hrs at 60° C. After cooling down, the mixture was poured to the crushed ice in the flask and stored at 0° C. overnight. Then filtered, and washed down with 5% Na₂CO₃ solution and water followed by drying in vacuum to give 2.

4-Methyl aniline was dissolved in MeOH and added slowly to the mixture of 2 and Et₃N in MeOH and in a couple minutes the precipitation of 3 formed. After filtration, washing down with MeOH, and drying in vacuum amine was added to the solution 3 in THF and the mixture stirred overnight followed adding NaBH₄ to acquired 4. And VQ36344 is the result of the direct reduction of 3.

¹H NMR (CDCl₃): 7.581 (br, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.351 (d, J=7.5 Hz, 1), 7.301 (d, J=7.5 Hz, 1H), 7.023 (t, J=7.5 Hz, 1H), 7.017 (AABB, J=93, 7.5 Hz, 4H), 4.733 (s, 2H), 4.2 (br, 1H), 3.818 (s, 3H), 3.614 (d, J=7.5 Hz, 1H), 3.60 (d, J=6.5 Hz, 1H), 2.339 (s, 3H).

¹H NMR (CDCl₃): 8.471 (s, 1H), 8.394 (d, J=4.5 Hz, 1H), 7.579 (br, 1H), 7.437 (t, J=7.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.022 (t, J=7.0 Hz, 1), 7.014 (AABB, J=93.5, 8.0 Hz, 4H), 6.725 (t, J=6.0 Hz, 1H), 4.737 (s, 2H), 2.338 (s, 3).

¹H NMR (CDCl₃): 7.456 (t, J=8.0 Hz, 1H), 7.411 (d, J=8.0 Hz, 1H), 7.355 (d, J=8.0 Hz, 1H), 7.124 (t, J=8.0 Hz, 1H), 6.975 (AABB, J=132.5, 7.5 Hz, 4H), 6.064 (br, 1H), 2.333 (s, 3H), 2.031 (s, 3H).

Example 3

To the mixture of 1 (50 mg, 0.285 mmol) and K₂CO₃ (197 mg, 1.43 mmol) in acetone (3 mL), 2 (158 mg, 0.854 mmol) was added slowly. Then the reaction was stirred at 65° C. overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC (eluent: EtOAc/Petroleum ether=1:3) to give 3 (81.3 mg, 74.3%) and 4 (23.2 mg, 21.2%) as solids.

LC-MS (6.42 min, ES⁺): calcd: 383.48; Found: 384.39. ¹H NMR (CDCl₃): 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.326 (dt, J=9.0, 2.0 Hz, 1H), 6.961 (t, J=7.5 Hz, 1H), 6.88 (AABB, J=46, 8.5 Hz, 8H), 6.66 (d, J=8.5 Hz, 1H), 3.42 (s, 2H), 3.188 (s, 2H), 2.146 (s, 6H).

Example 4

To the mixture of 1 (50 mg, 0.31 mmol) and K₂CO₃ (429 mg, 3.1 mmol) in acetone (3 mL), 2 (345 mg, 1.86 mmol) was added slowly. Then the reaction was stirred at 65° C. overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC (eluent: EtOAc/Petroleum ether=1:3) to give 3 (61.3 mg, 25.6%), 4 (43.9 mg, 38.3%) and 5 (12.6 mg, 8.6%) as solids.

LC-MS (6.90 min, ES⁺): calcd: 473.60; Found: 474.48. ¹H NMR (CDCl₃): 7.92 (d, J=8.5 Hz, 1H), 7.165 (t, J=8.5 Hz, 1H), 6.947 (AABB, J=33.5, 8.5 Hz, 4H), 6.931 (AABB, J=49, 8.5 Hz, 4H), 6.922 (t, J=8.5 Hz, 1H), 6.71 (AABB, J=189, 8.5 Hz, 4H), 6.52 (d, J=8.5 Hz, 1H), 5.0 (br, 2H), 3.583 (s, 1H), 3.557 (s, 1H), 3.452 (s, 1H), 3.427 (s, 1H), 2.273 (s, 3H), 2.21 (s, 6H).

Example 5

HCV Replicon Luciferase Assay

Day 0 Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free+PS+2 mM glutamine; 100 μl/well). The compounds to be tested are added to the experimental wells (10 μl/well at 10× assay concentration) and the cells are then incubated (5% CO₂, 37° C.) for 48 h.

Day 2 Reagent Preparation and Luciferase Assay: The Bright-Glo Luciferase Assay Buffer (Promega) is thawed and equilibrated to room temperature prior to use. The lyophilized Bright-Glo Luciferase Assay Substrate is equilibrated to room temperature prior to use. 10 ml of Bright-Glo Luciferase Assay Buffer is transferred to 1 vial of Bright-Glo Luciferase Assay Substrate bottle and mixed by gently with a Vortex. 100 ul of Bright-Glo Luciferase Assay reagent (Bright-Glo Luciferase Assay Buffer+Bright-Glo Luciferase Assay Substrate Mixture) is added to each well. The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer. The data is analyzed and IC50s are determined using GraphPad Prism 4 software. Hits validated in the Replicon Luciferase assay have IC50s<8.0 μM and show<30% inhibition of Cell Viability at a compound concentration of 100 μM (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon Luciferase Assay conditions).

Example 6

HCV Replicon RNA Assay

Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free+PS+2 mM glutamine; 100 μl/well). The compounds to be tested are added to the experimental wells (10 μl/well at 10× assay concentration) and the cells are then incubated (5% CO₂, 37° C.).

Day 1, Media Change and Compound Treatment: 24 hours after the initial compound treatment the cell culture media is aspirated from the wells and fresh Growth Medium is added (DMEM phenol red free+PS+2 mM glutamine; 100 μl/well). The compounds to be tested are then added to the appropriate experimental wells (10 μl/well at 10 × assay concentration) and the cells are then incubated (5% CO2, 37° C.) for an additional 24 hrs.

Day 2, RNA Isolation and cDNA Synthesis: The cells are washed with 1× Phosphate Buffered Saline (PBS) once. Cells are then lysed and RNA is isolated in 96 well format using a vacuum manifold and the RNAeasy 96 kit (Qiagen) according to the manufacturer's suggested protocol. cDNA is then synthesized from RNA isolated from each well using the Taqman Reverse Transcription Reagents kit (Applied Biosystems) according to manufacturer's suggested protocol.

Day 3, Quantitative PCR Based Measurement of HCV RNA (Taqman Assay): Quantitative PCR analysis to measure HCV RNA expression from cDNA synthesized on Day 2 is performed using the ABI 9700 HT Sequence Detection System (Applied Biosystems) as previously described (Lohman et al, Science 285, 110-113, 1999). The data is analyzed and IC50s are determined using GraphPad Prism 4 software. Hits validated in the Replicon RNA Assay have IC50s<8.0 μM and show <30% inhibition of Cell Viability at a compound concentration of 50 μM (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon RNA Assay conditions).

Example 7

CellTiter-Glo Cell Viability Assay (Promega)

Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free+PS+2 mM glutamine; 100 ul/well). The compounds to be tested for inhibition of cell viability are added to the experimental wells (10 μl/well at 10× assay concentration) and the cells are then incubated (5% CO₂, 37° C.) for 48 h.

Day 2, Reagent Preparation and Assay: The CellTiter-Glo Buffer is thawed and equilibrated to room temperature prior to use. The lyophilized CellTiter-Glo Substrate is equilibrated to room temperature prior to use. 10 ml of CeliTiter-Glo Buffer is transferred to 1 vial of CellTiter-Glo Substrate and mixed by gently with a Vortex. 100 μl of CellTiter-Glo Assay reagent (CellTiter-Glo Buffer+CellTiter-Glo Substrate Mixture) is added to each well. The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.

TABLE 1
			Toxicity		Toxicity
			% Inhibition		% Inhibition
		Luciferase	at 100 um	TaqMan	at 50 uM
comp. #	Structure	IC50	(1 dose)	IC50	(2 doses)
VQ_31729		3.53	3.0	0.36	5.1
VQ_31734		3.84	4.3	0.67	0.7
VQ_31711		5.16	4.6	0.12	4.3
VQ_31738		5.44	23.6	0.21	6.1
VQ_31748		5.38	10.0	1.97	4.9
VQ_31754		5.45	2.5	5.35	1.9
VQ_31758		6.16	14.7	5.24	2.6
VQ_31763		8.29	4.6	0.43	6.5
VQ_31712		4.92	16.6	>30	10.0
VQ_31715		2.80	53.4	0.55	13.4
VQ_31744		4.50	10.9	0.28	7.0
VQ_32806		5.57	16.5	1.40	8.3
VQ_36312		3.06	5.0	0.89	40.8
VQ_36341		0.28	14.6	0.40	31.2
VQ_36343		0.13	21.1	0.16	37.9
VQ_36467		51.13	22.8	0.46	13.9
VQ_36468		43.30	40.7	0.71	16.3
VQ_36469		53.64	14.7	4.16	3.3
VQ_36470		59.94	12.5	4.08	−2.7
VQ_36471		0.04	9.8	1.78	15.2
VQ_36472		0.03	5.9	0.85	6.5
VQ_36473		0.02	4.3	1.71	10.7
VQ_36594		0.74	9.1	>30	13.7
VQ_32833		2.89	34.6	0.58	20.7
VQ_33645		2.33	21.5	>30	17.2
VQ_34453		8.5	24.6	1.97	12.2
VQ_35027		2.1	4.6	Inactive	12.5
VQ_35018		1.0	10.0	Inactive	12.3

Claims

1. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of Formula I:

2. The method of claim 1, comprising administering a compound of the formula II:

3. The method of claim 2, comprising administering a compound of the formula III:

4. The method of claim 3, comprising administering a compound of the formula IV:

5. The method of claim 4, comprising administering a compound of the formula IV, wherein R7 is selected to be an aryl or heteroaryl group.

6. The method of claim 3, comprising administering a compound of the formula V:

7. The method of claim 4, comprising administering a compound of the formula VI:

8. The method of claim 2, comprising administering a compound of the formula VII:

9. The method of claim 8, comprising administering a compound of the formula VIIa:

10. The method of claim 9, comprising administering a compound of the formula VIIa wherein R2 is selected from the group consisting of aryl and heteroaryl.

11. The method of claim 10, comprising administering a compound of the formula VIIa wherein R2 is selected from the group consisting of aryl and heteroaryl, and R4is H.

12. The method of claim 8, comprising administering a compound of the formula VIII:

13. The method of claim 12, comprising administering a compound of the formula VIII wherein R7 is selected from the group consisting of aryl and heteroaryl groups.

14. The method of claim 8, comprising administering a compound of the formula IX:

15. The method of claim 12, comprising administering a compound of the formula X:

16. The method of claim 1, comprising administering a compound of the formula XI:

17. The method of claim 16, comprising administering a compound of the formula XII:

18. The method of claim 17, comprising administering a compound of the formula XIII:

19. The method of claim 18, comprising administering a compound of the formula XIII wherein R6 is selected from the group consisting of aryl and heteroaryl groups.

20. The method of claim 17, comprising administering a compound of the formula XIV:

21. The method of claim 18, comprising administering a compound of the formula XV:

22. The method of claim 16, comprising administering a compound of the formula XVI:

23. The method of claim 22, comprising administering a compound of the formula XVII:

24. The method of claim 23, comprising administering a compound of the formula XVII wherein R6 is selected from the group consisting of aryl or heteroaryl groups.

25. The method of claim 22, comprising administering a compound of the formula XVIII:

26. The method of claim 17, comprising administering a compound of the formula XIX:

27. The method of claim 7, comprising administering a compound of the formula

28. The method of claim 7, comprising administering a compound of the formula

29. The method of claim 7, comprising administering a compound of the formula

30. The method of claim 7, comprising administering a compound of the formula

31. The method of claim 7, comprising administering a compound of the formula

32. The method of claim 7, comprising administering a compound of the formula

33. The method of claim 7, comprising administering a compound of the formula

34. The method of claim 7, comprising administering a compound of the formula

35. The method of claim 7, comprising administering a compound of the formula

36. The method of claim 7, comprising administering a compound of the formula

37. The method of claim 7, comprising administering a compound of the formula

38. The method of claim 7, comprising administering a compound of the formula

39. The method of claim 6, comprising administering a compound of the formula

40. The method of claim 8, comprising administering a compound of the formula

41. The method of claim 8, comprising administering a compound of the formula

42. The method of claim 9, comprising administering a compound of the formula

43. The method of claim 9, comprising administering a compound of the formula

44. The method of claim 9, comprising administering a compound of the formula

45. The method of claim 9, comprising administering a compound of the formula

46. The method of claim 9, comprising administering a compound of the formula

47. The method of claim 9, comprising administering a compound of the formula

48. The method of claim 9, comprising administering a compound of the formula

49. The method of claim 21, comprising administering a compound of the formula

50. The method of claim 21, comprising administering a compound of the formula

51. The method of claim 21, comprising administering a compound of the formula

52. The method of claim 21, comprising administering a compound of the formula

53. The method of claim 21, comprising administering a compound of the formula

54. The method of claim 21, comprising administering a compound of the formula

55. The method of claim 1, comprising administering a therapeutically effective amount of a combination of the compound having the formula I, or a therapeutically acceptable salt or hydrate thereof, and at least one additional agent selected from an interferon, ribavirin, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV IRES inhibitor, an HCV Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an HCV NS2 inhibitor.

56. The method of claim 55, wherein the at least one additional agent is an interferon.

57. The method of claim 56, wherein the at least one additional agent is α-interferon.

58. The method of claim 55, wherein the at least one additional agent is an interferon and ribavirin.

59. A compound having the formula II:

60. The compound of claim 59, having the formula III:

61. The compound of claim 60, having the formula IV:

62. The compound of claim 61, wherein R7 is selected to be an aryl or heteroaryl group.

63. The compound of claim 60, having the formula V:

64. The compound of claim 61, having the formula VI:

65. The compound of claim 59, having the formula VII:

66. The compound of claim 65, having the formula VIIa:

67. The compound of claim 66, wherein R2 is selected from the group consisting of aryl and heteroaryl.

68. The compound of claim 67, wherein R4 is H.

69. The compound of claim 65, having the formula VIII:

70. The compound of claim 69, wherein, R7 is selected from the group consisting of aryl and heteroaryl groups.

71. The compound of claim 65, having the formula IX:

72. The compound of claim 69, having the formula X:

73. A compound having the formula XIII:

74. The compound of claim 73, wherein R6 is selected from the group consisting of aryl and heteroaryl groups.

75. The compound of claim 73, having the formula XV:

76. A compound having the formula XIV:

77. A compound having the formula XVI:

78. The compound of claim 77, having the formula XVII:

79. The compound of claim 78, wherein R6 is selected from the group consisting of aryl or heteroaryl groups.

80. The compound of claim 77, having the formula XVIII:

81. The compound of claim 78, having the formula XIX:

82. The compound of claim 64, having the formula

83. The compound of claim 64, having the formula

84. The compound of claim 64, having the formula

85. The compound of claim 64, having the formula

86. The compound of claim 64, having the formula

87. The compound of claim 64, having the formula

88. The compound of claim 64, having the formula

89. The compound of claim 64, having the formula

90. The compound of claim 64, having the formula

91. The compound of claim 64, having the formula

92. The compound of claim 64, having the formula

93. The compound of claim 64, having the formula

94. The compound of claim 63, having the formula

95. The compound of claim 65, having the formula

96. The compound of claim 65, having the formula

97. The compound of claim 66, having the formula

98. The compound of claim 66, having the formula

99. The compound of claim 66, having the formula

100. The compound of claim 66, having the formula

101. The compound of claim 66, having the formula

102. The compound of claim 66, having the formula

103. The compound of claim 66, having the formula

104. The compound of claim 75, having the formula

105. The compound of claim 75, having the formula

106. The compound of claim 75, having the formula

107. The compound of claim 75, having the formula

108. The compound of claim 75, having the formula

109. The compound of claim 75, having the formula