KR20130110168A - 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment - Google Patents

Abstract

식 IProvided are selected imidazo [1,2-f] [1,2,4] triazinyl nucleosides, nucleoside phosphates and prodrugs thereof, wherein the 2 ′ position of the nucleoside sugar is a halogen and carbon substituent Is replaced by. Provided the compounds, compositions, and methods are useful for the Flaviviridae (flaviviridae) virus infections, particularly the treatment of hepatitis C infections caused by both wild type and mutant strains of HCV.

Equation I

Description

2'-FLUORO SUBSTITUTED CARBO-NUCLEOSIDE ANALOGS FOR ANTIVIRAL TREATMENT FOR 2-FLUORO-

The present invention relates generally to anti-viral activity with the compound, and more particularly to the Flaviviridae (flaviviridae) pressed in against the infection active nucleosides, and most particularly inhibitors of hepatitis C virus RNA- dependent RNA polymerase.

The virus of the Flaviviridae and comprises a (flaviviridae) comprises at least three distinguishable in comprising a pestivirus, flavivirus, and hepaciviruses (Calisher, meat al . , J. Gen. Virol., 1993, 70, 37-43). Pestiviruses cause many economically important animal diseases such as bovine viral diarrhea virus (BVDV), classic swine fever virus (CSFV, swine cholera) and sheep border disease (BDV), but their importance in human diseases is not well understood. (Moennig, V., et al . , Adv. Vir. Res. 1992, 48, 53-98). Flavivirus is Important human diseases are the cause of dengue and yellow fever and hepaciviruses cause hepatitis C virus infection in humans. Flaviviridae other important viral infections caused by the (flaviviridae) is West Nile virus (WNV) Japanese encephalitis virus (JEV), tick-borne encephalitis virus, forward (Junjin) virus, Murray Valley (Murray Valley) encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus and Zika virus. Plastic Composite infection BB Florida (flaviviridae) from the viral strain causes significant mortality, morbidity and economic losses throughout the world. Thus, there is a need to develop effective treatments for Flaviviridae (flaviviridae) virus infection.

Hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 32: 98-112, 2000). Considerable interest in current antiviral studies is the development of chronic HCV infection in humans. Towards the development of improved treatment methods (Di Besceglie, AM and Bacon, BR, Scientific American, Oct .: 80-85, (1999); Gordon, CP, et al., J. Med . Chem . 2005 , 48 , 1-20;.... Maradpour, D .; et al, Nat Rev Micro 2007, 5 (6), 453-463). Many HCV treatments are described by Bymock et al. in Antiviral Chemistry & Chemotherapy, 11: 2; 79-95 (2000).

RNA-dependent RNA polymerase (RdRp) is one of the best studied targets for the development of novel HCV therapeutics. NS5B polymerase is a target for inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2, US 2004/0006002 A1). These enzymes have been extensively identified at the biochemical and structural levels using screening assays for identifying selective inhibitors (De Clercq, E. (2001) J. Pharmacol. Exp.Ther. 297: 1-10; De Clercq, E. (2001) J. Clin. Virol. 22: 73-89). Biochemical targets such as NS5B are important in the development of HCV therapies because HCV does not replicate in the laboratory and has difficulty in developing cell-based assays and preclinical animal systems.

Currently, there are mainly two antiviral compounds used for the treatment of chronic HCV infection in humans, ribavirin, nucleoside analogues, and interferon-alpha (α) (IFN). Ribavirin alone is not effective in reducing viral RNA levels, has significant toxicity and is known to induce anemia. The combination of IFN and ribavirin has been reported to be effective in the management of chronic hepatitis C (Scott, LJ, et al. Drugs 2002 , 62 , 507-556) Less than half of patients infected with some genotypes continue to benefit when given treatment. Other patent applications that disclose the use of nucleoside analogs to treat hepatitis C virus include WO 01/32153, WO 01/60315, WO 02/057425, WO 02/057287, WO 02/032920, WO 02/18404. , WO 04/046331, WO2008 / 089105 and WO2008 / 141079, but additional treatments for HCV infection have not yet been available to patients.

Viral treatment of patients with chronic HCV infection is difficult to achieve due to the huge amount of daily virus production of chronically infected patients and the high natural mutagenicity of the HCV virus (Neumann, et al., Science 1998 , 282 , 103-7; Fukimoto, et al., Hepatology , 1996 , 24 , 1351-4; Domingo, et al., Gene , 1985 , 40 , 1-8; Martell, et al., J. Virol . 1992 , 66 , 3225-9. Experimental anti-viral nucleoside analogs have been shown to induce viable mutations in HCV virus both in vivo and in vitro (Migliaccio, et al., J. Biol . Chem . 2003 , 926; Carroll, et al. Antimicrobial Agents Chemotherapy 2009 , 926; Brown, AB, Expert Opin . Investig . Drugs 2009 , 18 , 709-725). Thus, improved antiviral properties, in particular increased activity against resistant strains of the virus; Improved oral bioavailability; There is an urgent need for drugs with fewer undesirable side effects and effective half-life in vivo (De Francesco, R. et al. (2003) Antiviral Research 58: 1-16).

Nucleobase pyrrolo [1,2-f] [1,2,4] triazine, imidazo [1,5-f] [1,2,4] triazine, imidazo [1,2-f] Certain ribosides of [1,2,4] triazine, and [1,2,4] triazolo [4,3-f] [1,2,4] triazine are carbohydrates Research 2001, 331 (1), 77-82; Nucleosides & Nucleotides (1996), 15 (1-3), 793-807; Tetrahedron Letters (1994), 35 (30), 5339-42; Heterocycles (1992), 34 (3), 569-74; J. Chem . Soc . Perkin Trans . 1 1985, 3, 621-30; J. Chem . Soc . Perkin Trans . 1 1984, 2, 229-38; WO 2000056734; Organic Letters (2001), 3 (6), 839-842; J. Chem . Soc . Perkin Trans. 1 1999, 20, 2929-2936; And J. Med . Chem . 1986, 29 (11), 2231-5. However, these compounds are not disclosed to be useful for the treatment of HCV.

Pyrrolo [1,2-f] [1,2,4] triazinyl, imidazo [1,5-f] [1,2,4] tria having antiviral, anti-HCV, and anti-RdRp activity Genyl, imidazo [1,2-f] [1,2,4] triazinyl, and [1,2,4] triazolo [4,3-f] [1,2,4] triazinyl nucleobases Ribosides of Babu, YS to WO2008 / 089105 and WO2008 / 141079; Cho, et al. WO2009 / 132123 and Francom, et al. WO2010 / 002877. Butler, et al. WO2009 / 132135 disclose antiviral pyrrolo [1,2-f] [1,2,4] triazinyl, imidazo [1,5-f, wherein the 1 'position of the nucleoside sugar is substituted. ] [1,2,4] triazinyl, imidazo [1,2-f] [1,2,4] triazinyl, and [1,2,4] triazolo [4,3-f] [1, 2,4] triazinyl nucleosides are disclosed.

Summary of the Invention

Provided are compounds that inhibit viruses of the Flaviviridae (flaviviridae). The invention also encompasses compounds of formula I or formula IV-VI that inhibit HCV RNA-dependent RNA polymerase (RdRp) rather than viral nucleic acid polymerase, in particular cellular nucleic acid polymerase. Compounds of formula I or formula IV-VI have been found to be effective against both wild type and S282T mutant strains of HCV virus. Thus, the compounds of Formula I or Formula IV-VI may be (Flaviviridae) Flaviviridae are useful for the treatment of infections.

In one embodiment, provided is a compound of Formula I:

Equation I

Or a pharmaceutically acceptable salt thereof;

here:

R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;

R ² is halogen;

Each R ³ , R ⁴ , or R ⁵ is independently H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , halogen, (C ₁ -C ₈ ) Alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;

Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms are —O (CO) O— when bonded together or form a double bond when bonded with the ring carbon atom to which they are attached;

R ⁶ is ^{H, OR a, N (R} a) 2, N 3, CN, NO 2, S (O) n R a, -C (= O) R 11, -C (= O) OR 11, - ^{C (= O) NR 11 R} 12, -C (= O) SR 11, -S (O) R 11, -S (O) 2 R 11, -S (O) (OR 11), -S (O ) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , halogen, (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈₎ alkynyl, (C ₂ -C ₈₎ substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

Each n is independently 0, 1, or 2;

Each R ^a is independently H, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, aryl (C ₁ -C ₈₎ alkyl, (C ₄ -C ₈₎ heterocyclyl-alkyl ^{carbonyl, -C (= O) R 11} , -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), or -SO ₂ NR ¹¹ R ¹² ;

R ⁷ is H, -C (= O) R 11, -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R 11 ^{_{, -S (O) 2 R 11}} , -S (O) (oR 11), -S (O) 2 (oR 11), -SO 2 NR 11 R 12, or

Each Y or Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;

When W ¹ and W ² are bonded together, -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; or One of W ¹ or W ² is -Y ³ -with one of R ³ or R ⁴ and the other of W ¹ or W ² is Formula Ia; Or W < ^{1 >} and W < ² > are each independently a group of formula Ia:

Formula Ia

here:

Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;

Each Y < ³ > is independently O, S, or NR;

M2 is 0,1 or 2;

Each R ^x is independently R ^y or a group of formula:

here:

Each M1a, M1c, and M1d is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Each R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y 1) R, -C (= Y 1) OR, -C (= Y 1) N (R) _{2, -N (R) 2,} - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) (OR), -S (O) 2 (OR), -OC (= Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) (N (R) 2), -SC (= Y 1) R, -SC (= ^{Y 1) OR, -SC (=} Y 1) (N (R) 2), -N (R) C (= Y 1) R, -N (R) C (= Y 1) OR, -N (R ^{) C (= Y 1) N} (R) 2, -SO 2 NR 2, -CN, -N 3, -NO 2, -OR, or W ^3; Or when taken together, two R ^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

Each R is independently selected from the group consisting of H, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) (C ₂ -C ₈₎ alkynyl, (C ₂ -C ₈₎ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocyclyl, C ₂ - C ₂₀ substituted heterocyclyl, arylalkyl or substituted arylalkyl;

W ³ is W ⁴ or W ⁵ ; W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y , or -SO ₂ W ⁵ ; And W < ⁵ > is a carbocycle or heterocycle, wherein W < ⁵ > is independently substituted with 0 to 3 R < ^{y &}

Each X ¹ or X ² is independently CR ¹⁰ or N;

Each R ⁸ is ^{halogen, NR 11 R 12, N (} R 11) OR 11, NR 11 NR 11 R 12, N 3, NO, NO 2, CHO, CN, -CH (= NR 11), -CH = ^{NNHR 11, -CH = N (OR} 11), -CH (OR 11) 2, -C (= O) NR 11 R 12, -C (= S) NR 11 R 12, -C (= O) OR 11 , (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, optionally substituted aryl, heteroaryl, -C (= O) (C 1 -C 8) _{alkyl, -S (O) n (C} 1 -C 8) alkyl, aryl (C ₁ -C ₈₎ alkyl, oR ¹¹ or SR ^11;

Each R ⁹ or R ¹⁰ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, ^{NR 11), -CH = NHNR 11} , -CH = N (OR 11), -CH (OR 11) 2, -C (= O) NR 11 R 12, -C (= S) NR 11 R 12, - C (= O) OR ¹¹ , R ¹¹ , OR ¹¹ or SR ¹¹ ;

Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl optionally substituted by _one or more substituents selected from the group consisting of ₈ ) alkyl; Or R < ¹¹ > and R < ¹² > are taken together with the nitrogen to which they are both attached to form a 3-7 membered heterocyclic ring in which any carbon atom of the heterocyclic ring is replaced by -O-, or -NR ^a - may be substituted with;

Where each of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , Each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of R ¹¹ or R ¹² is independently , one or more halo, hydroxy, CN, N _3, N (R ^a) ₂ or OR &^lt; a >; And wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl can optionally be replaced by -O-, -S-, or -NR ^a -.

In another embodiment, provided is a compound of Formula I or Formula IV-VI and a pharmaceutically acceptable salt thereof and all of its racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, and amorphous forms to be.

In yet another embodiment, provided is a compound of formula I or the novel formula IV-VI which is active against a (flaviviridae) virus infectious Flaviviridae. Without being bound by theory, the compounds of the present invention can inhibit viral RNA-dependent RNA polymerase and thus inhibit the replication of the virus. The compounds of the present invention are useful for treating human patients infected with human viruses such as hepatitis C.

In another embodiment, provided is a pharmaceutical composition comprising an effective amount of a Formula I or Formula IV-VI compound, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

In another embodiment, the present application provides a co-medicament comprising:

a) a compound of formula I or formula IV-VI; Or a pharmaceutically acceptable salt, solvate, or ester thereof; And

b) interferon, ribavirin or analogues thereof, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents , Endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophylline inhibitors, HCV IRES inhibitors, pharmacokinetics Enhancers and other drugs to treat HCV; Or at least one additional therapeutic agent selected from the group consisting of mixtures thereof.

In another embodiment, the present application provides a method of treating a cell infected with HCV with an effective amount of a compound of Formula I or Formula IV-VI; Or a method of inhibiting HCV polymerase comprising contacting with a pharmaceutically acceptable salt, solvate, and / or ester thereof.

In another embodiment, the present application provides a method of treating a cell infected with HCV with an effective amount of a compound of Formula I or Formula IV-VI; Or pharmaceutically acceptable salts, solvates, and / or esters thereof; And a method of inhibiting HCV polymerase comprising contacting at least one additional therapeutic agent.

In another embodiment, the present application is directed to administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or Formula IV-VI, or a pharmaceutically acceptable salt thereof; Provided are methods for treating and / or preventing diseases caused by viral infection, wherein the viral infection is dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-mediated encephalitis virus, Junjin virus, Murray Valley (Murray Valley) encephalitis virus, St Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and hepatitis C virus Caused by

In another embodiment, the present application provides a therapeutically effective amount of a compound of Formula I or Formula IV-VI; Or administering a pharmaceutically acceptable salt, solvate, and / or ester thereof to a patient.

In another embodiment, the present application provides a therapeutically effective amount of a compound of Formula I or Formula IV-VI; Or pharmaceutically acceptable salts, solvates, and / or esters thereof; And administering at least one additional therapeutic agent to the patient.

Another aspect of the invention provides a method of administering to an animal, ie treating an animal, a pharmaceutical combination composition or formulation comprising an effective amount of a Formula I compound or Formula IV-VI, and a second compound having anti-HCV properties. A method for the treatment or prevention of symptoms or effects of HCV infection in an infected animal is provided.

In another aspect, the invention also provides a method of inhibiting HCV, comprising administering to a mammal infected with HCV an amount of a Formula I or Formula IV-VI compound effective to inhibit replication of HCV in infected cells in a mammal. To provide.

In yet another aspect, provided are the Flaviviridae (flaviviridae) the use of a formula I or formula IV-VI for the preparation of pharmaceutical compounds for the treatment of viral infections. In yet another aspect, provided is a compound of the Flaviviridae (flaviviridae) expression for use in the treatment of viral infections formula I or IV-VI. In one embodiment, the Flaviviridae (flaviviridae) virus infection is an acute or chronic HCV infection. In one embodiment of each aspect of the use and compound, the treatment induces a reduction in one or more viral loads or clearance of RNA in the patient.

In another aspect, the invention also provides the processes and novel intermediates disclosed herein useful for the preparation of the compounds of Formula I or Formula IV-VI of the present invention.

In another aspect, novel methods are provided for the synthesis, analysis, separation, isolation, purification, characterization, and testing of the compounds of the present invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to specific embodiments of the invention, examples of which are illustrated in the accompanying descriptions, structures and formulas. While the present invention has been described in conjunction with the listed embodiments, it will be understood that this embodiment is not intended to limit the invention to such embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention.

In another aspect, the compound of formula I is formula II:

Expression II

Or pharmaceutically acceptable salts thereof;

here:

R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;

Each R ³ , R ⁴ , or R ⁵ is independently H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , halogen, (C ₁ -C ₈ ) Alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;

Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms are —O (CO) O— when bonded together or form a double bond when bonded with the ring carbon atom to which they are attached;

R ⁶ is ^{H, OR a, N (R} a) 2, N 3, CN, NO 2, S (O) n R a, -C (= O) R 11, -C (= O) OR 11, - ^{C (= O) NR 11 R} 12, -C (= O) SR 11, -S (O) R 11, -S (O) 2 R 11, -S (O) (OR 11), -S (O ) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , halogen, (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈₎ alkynyl, (C ₂ -C ₈₎ substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

Each n is independently 0, 1, or 2;

Each R ^a is independently H, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, aryl (C ₁ -C ₈₎ alkyl, (C ₄ -C ₈₎ heterocyclyl-alkyl ^{carbonyl, -C (= O) R 11} , -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), or -SO ₂ NR ¹¹ R ¹² ;

R ⁷ is H, -C (= O) R 11, -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R 11 ^{_{, -S (O) 2 R 11}} , -S (O) (oR 11), -S (O) 2 (oR 11), -SO 2 NR 11 R 12, or

Each Y or Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;

When W ¹ and W ² are bonded together, -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; or One of W ¹ or W ² is -Y ³ -with one of R ³ or R ⁴ and the other of W ¹ or W ² is Formula Ia; Or W < ^{1 >} and W < ² > are each independently a group of formula Ia:

Formula Ia

here:

Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;

Each Y < ³ > is independently O, S, or NR;

M2 is 0,1 or 2;

Each R ^x is independently R ^y or a group of formula:

here:

Each M1a, M1c, and M1d is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Each R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y 1) R, -C (= Y 1) OR, -C (= Y 1) N (R) _{2, -N (R) 2,} - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) (OR), -S (O) 2 (OR), -OC (= Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) (N (R) 2), -SC (= Y 1) R, -SC (= ^{Y 1) OR, -SC (=} Y 1) (N (R) 2), -N (R) C (= Y 1) R, -N (R) C (= Y 1) OR, -N (R ^{) C (= Y 1) N} (R) 2, -SO 2 NR 2, -CN, -N 3, -NO 2, -OR, or W ^3; Or when taken together, two R ^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

Each R is independently selected from the group consisting of H, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) (C ₂ -C ₈₎ alkynyl, (C ₂ -C ₈₎ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocyclyl, C ₂ - C ₂₀ substituted heterocyclyl, arylalkyl or substituted arylalkyl;

W ³ is W ⁴ or W ⁵ ; W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y , or -SO ₂ W ⁵ ; And W < ⁵ > is a carbocycle or heterocycle, wherein W < ⁵ > is independently substituted with 0 to 3 R < ^{y &}

Each X ¹ or X ² is independently CR ¹⁰ or N;

Each R ⁸ is ^{halogen, NR 11 R 12, N (} R 11) OR 11, NR 11 NR 11 R 12, N 3, NO, NO 2, CHO, CN, -CH (= NR 11), -CH = ^{NNHR 11, -CH = N (OR} 11), -CH (OR 11) 2, -C (= O) NR 11 R 12, -C (= S) NR 11 R 12, -C (= O) OR 11 , (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, optionally substituted aryl, heteroaryl, -C (= O) (C 1 -C 8) _{alkyl, -S (O) n (C} 1 -C 8) alkyl, aryl (C ₁ -C ₈₎ alkyl, oR ¹¹ or SR ^11;

Each R ⁹ or R ¹⁰ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, ^{NR 11), -CH = NHNR 11} , -CH = N (OR 11), -CH (OR 11) 2, -C (= O) NR 11 R 12, -C (= S) NR 11 R 12, - C (= O) OR ¹¹ , R ¹¹ , OR ¹¹ or SR ¹¹ ;

Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl optionally substituted by _one or more substituents selected from the group consisting of ₈ ) alkyl; Or R < ¹¹ > and R < ¹² > are taken together with the nitrogen to which they are both attached to form a 3-7 membered heterocyclic ring in which any carbon atom of the heterocyclic ring is replaced by -O-, or -NR ^a - may be substituted with;

Where each of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , Each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of R ¹¹ or R ¹² is independently , one or more halo, hydroxy, CN, N _3, N (R ^a) ₂ or OR &^lt; a >; And wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl can optionally be replaced by -O-, -S-, or -NR ^a -.

In one embodiment of the invention of Formula II, R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is H. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ .

In one embodiment of Formula II, R ³ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) Alkenyl or (C ₂ -C ₈ ) alkynyl. In one aspect of this embodiment, R ³ is H. In another aspect of this embodiment, R ³ is H and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ³ is H and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ³ is H and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ³ is H and R ¹ is methyl. In another aspect of this embodiment, R ³ is H, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ³ is H, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ³ is H, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ³ is H, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ³ is H, R ¹ is methyl and R ⁶ is H.

In one embodiment of Formula II, R ⁴ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) Alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In one embodiment of Formula II, R ⁵ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) Alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁵ is N ₃ .

In another embodiment of Formula II, R ⁵ is H. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula II, R ⁶ is H, CN, OR ^a or CH ₃ . In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula II, R ⁶ is CN, OR ^a or CH ₃ . In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ .

In one embodiment of Formula II, R ⁷ is H, -C (= 0) R ¹¹ , -C (= 0) OR ¹¹ , -C (= 0) SR ¹¹ or

이다. 이 구체예의 한 양상에서, R⁷는 H이다. 이 구체예의 또다른 양상에서, R⁷는 -C(=O)R¹¹이다. 이 구체예의 또다른 양상에서, R⁷는 -C(=O)R¹¹이며, 여기서 R¹¹는 (C₁-C₈)알킬이다. 이 구체예의 또다른 양상에서, R⁷는

to be. In one aspect of this embodiment, R ⁷ is H. In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ . In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ , wherein R ¹¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R < ⁷ > is

이다. 이 구체예의 또다른 양상에서 R⁶는 H이다. 이 구체예의 또다른 양상에서 R⁶는 CN이다. 이 구체예의 또다른 양상에서 R⁶는 OR^a이다. 이 구체예의 또다른 양상에서 R⁶는 OH이다. 이 구체예의 또다른 양상에서 R⁶는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 H 또는 OR^a이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a이고 R¹는 (C₁-C₈)알킬, (C₂-C₈) 알케닐 또는 (C₂-C₈)알키닐이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a이고 R¹는 (C₁-C₈)알킬이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a이고 R¹는 메틸이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 (C₁-C₈)알킬이고 X¹ 또는 X² 중 적어도 하나는 N이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 메틸이고 X¹ 또는 X² 중 적어도 하나는 N이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 (C₁-C₈)알킬이고 R⁶는 CN, OH, 또는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 메틸이고 R⁶는 CN, OH, 또는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 메틸이고 R⁶는 H이다. 이 구체예의 또다른 양상에서, R⁴는 OH이고 R¹는 메틸이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 (C₁-C₈)알킬이고 X¹ 또는 X² 중 적어도 하나는 N이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 메틸이고 X¹ 또는 X² 중 적어도 하나는 N이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 (C₁-C₈)알킬이고 R⁶는 CN, OH, 또는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 메틸이고 R⁶는 CN, OH, 또는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 메틸이고 R⁶는 H이다.

to be. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In one embodiment of Formula II, X ¹ is N or CR ¹⁰ . In another aspect of this embodiment, X ¹ is N. In another aspect of this embodiment, X ¹ is CR ¹⁰ . In another aspect of this embodiment, X ² is CH. In another aspect of this embodiment, X ¹ is N and X ² is CH. In another aspect of this embodiment, X ¹ is CR ¹⁰ and X ² is CH. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula II, each R ⁸ is independently halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ¹¹ or SR ¹¹ . In another aspect of this embodiment, R ¹ is methyl, CH ₂ F or ethynyl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl, CH ₂ F or ethynyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula II, each R ¹⁰ is independently H, halogen, CN or optionally substituted heteroaryl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ¹ is methyl, CH ₂ F or ethynyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl, CH ₂ F or ethynyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment, the compound of Formula I or Formula II is formula III:

Equation III

Or pharmaceutically acceptable salts thereof;

here:

R ¹ is CH ₃ , CH ₂ F, or ethynyl and all remaining variables are as defined for Formula I.

In one embodiment of Formula III, R ⁴ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) Alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is CH ₃ , CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula III, R ⁶ is H, CN, OR ^a or CH ₃ . In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula III, R ⁶ is CN, OR ^a or CH ₃ . In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ .

In one embodiment of Formula III, R ⁷ is H, -C (= 0) R ¹¹ , -C (= 0) OR ¹¹ , -C (= 0) SR ¹¹ or

이다. 이 구체예의 한 양상에서, R⁷는 H이다. 이 구체예의 또다른 양상에서, R⁷는 -C(=O)R¹¹이다. 이 구체예의 또다른 양상에서, R⁷는 -C(=O)R¹¹이며 여기서 R¹¹는 (C₁-C₈)알킬이다. 이 구체예의 또다른 양상에서, R⁷는

to be. In one aspect of this embodiment, R ⁷ is H. In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ . In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ wherein R ¹¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R < ⁷ > is

이다. 이 구체예의 또다른 양상에서 R⁶는 H이다. 이 구체예의 또다른 양상에서 R⁶는 CN이다. 이 구체예의 또다른 양상에서 R⁶는 OR^a이다. 이 구체예의 또다른 양상에서 R⁶는 OH이다. 이 구체예의 또다른 양상에서 R⁶는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 H 또는 OR^a이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a이고 R¹는 메틸이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 메틸이고 X¹ 또는 X² 중 적어도 하나는 N이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 메틸이고 R⁶는 CN, OH, 또는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 OR^a, R¹는 메틸이고 R⁶는 H이다. 이 구체예의 또다른 양상에서, R⁴는 OH이고 R¹는 메틸이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 메틸이고 X¹ 또는 X² 중 적어도 하나는 N이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 메틸이고 R⁶는 CN, OH, 또는 CH₃이다. 이 구체예의 또다른 양상에서, R⁴는 OH, R¹는 메틸이고 R⁶는 H이다.

to be. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In one embodiment of formula III, X ¹ is N or CR ¹⁰ . In another aspect of this embodiment, X ¹ is N. In another aspect of this embodiment, X ¹ is CR ¹⁰ . In another aspect of this embodiment, X ² is CH. In another aspect of this embodiment, X ¹ is N and X ² is CH. In another aspect of this embodiment, X ¹ is CR ¹⁰ and X ² is CH. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula III, each R ⁸ is independently halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ¹¹ or SR ¹¹ . In another aspect of this embodiment, R ¹ is methyl, CH ₂ F or ethynyl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl, CH ₂ F or ethynyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment of Formula III, each R ¹⁰ is, independently, H, halogen, CN or optionally substituted heteroaryl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment R ⁶ is H. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R ⁶ is OR ^a . In another aspect of this embodiment R ⁶ is OH. In another aspect of this embodiment R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl and R ⁶ is H.

In another embodiment, provided is a compound of Formula IV:

Equation IV

Or a pharmaceutically acceptable salt thereof;

here:

R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;

R ² is halogen;

R ³ , R ⁴ , and R ⁵ are each independently H, halogen, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , (C ₁ -C ₈ ) Alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;

Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms are —O (CO) O— when bonded together or form a double bond when bonded with the ring carbon atom to which they are attached;

Each n is independently 0, 1, or 2;

Each R ^a is independently H, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, aryl (C ₁ -C ₈₎ alkyl, (C ₄ -C ₈₎ heterocyclyl-alkyl ^{carbonyl, -C (= O) R 11} , -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), or -SO ₂ NR ¹¹ R ¹² ;

R ⁷ is H, -C (= O) R 11, -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R 11 ^{_{, -S (O) 2 R 11}} , -S (O) (oR 11), -S (O) 2 (oR 11), -SO 2 NR 11 R 12, or

Y is O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;

When W ¹ and W ² are bonded together, -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; or

One of W ¹ or W ² is —Y ³ — with either R ³ or R ⁴ and the other of W ¹ or W ² is Formula Ia; or

W ¹ and W ² are each, independently, a group of formula IVa:

Formula IVa

here:

Each Y ¹ is, independently, O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;

Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;

Each Y < ³ > is independently O, S, or NR;

M2 is 0,1 or 2;

Each R ^x is a group of formula IVb:

Formula IVb

here:

Each M1a, M1c, and M1d is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C ( = Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) ₂ R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R ) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, -N (R) C (= Y ¹ ) N (R) ₂ , -SO ₂ NR ₂ , -CN, -N ₃ , -NO ₂ , -OR, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ Heterocyclyl, arylalkyl, heteroarylalkyl;

Wherein each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R ²⁰ groups;

Or when taken together, two R ^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

Each R is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbo Cyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;

Each R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , OR ¹¹ or S (O) _n R ¹¹ ;

Each R ⁹ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, -CH (= NR ¹¹ ) , -CH = NHNR ¹¹ , -CH = N (OR ¹¹ ), -CH (OR ¹¹ ) ₂ , -C (= O) NR ¹¹ R ¹² , -C (= S) NR ¹¹ R ¹² , -C (= O) OR ¹¹ , R ¹¹ , OR ¹¹ or S (O) _n R ¹¹ ;

Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl optionally substituted by _one or more substituents selected from the group consisting of ₈ ) alkyl; Or R ¹¹ and R ¹² combine with the nitrogen to which they are both attached to form a 3-7 membered heterocyclic ring wherein one of the carbon atoms of the heterocyclic ring is -O-, -S- Or -NR ^b -can be optionally substituted;

Each R ¹³ is independently carbocycle or heterocycle optionally substituted with 1-3 R ²⁰ groups;

Each R ²⁰ is independently halogen, CN, N ₃ , N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= Y ¹ ) R, -C (= Y ¹ ) OR, or C (= Y ¹ ) N (R) ₂ ;

Where each of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , Each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of R ¹¹ or R ¹² is independently , One or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or Optionally substituted with OR ^b ; And wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl may be optionally substituted with —O—, —S— or —NR ^b ;

Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, -C (= 0) R ²¹ , -C (= 0) OR ²¹ , -C (= 0) NR ²¹ R ²² , -C (= 0) SR ²¹ , -S (O) R ²¹ , -S (O) ₂ R ²¹ , -S (O) (OR ²¹ ), -S (O) ₂ (OR ²¹ ), or —SO ₂ NR ²¹ R ²² ;

Each R ²¹ or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocycle Arylalkyl, -C (= 0) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl;

Provided that the optional clue is that compounds 1, 1d, 1e, 2, TP-1, A-1, 8, and 21 are excluded.

In another aspect of this embodiment Y and Y ¹ are O. In another aspect of this embodiment R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ¹¹ or S (O) _n R ¹¹ . In another aspect of this embodiment R ⁹ is H, halogen, S (O) _n R ¹¹ or NR ¹¹ R ¹² . In another aspect of this embodiment R ⁴ is OR ^a . In another aspect of this embodiment R ¹ is CH ₃ . In another aspect of this embodiment R ² is F. In another aspect of this embodiment R ⁷ is

Where Y is -O-; W ¹ is Formula Ia and W ² is —O— with R ⁴ . In another embodiment, the compound of Formula IV is formula V:

Equation V

Represented by

Wherein R ¹ is methyl or ethynyl and R ⁴ is OR ^a . In another aspect of this embodiment R ⁷ is H or

이다.

to be.

In another aspect of this embodiment, the compound of formula V is represented by the following structure:

In another embodiment, provided is a compound of Formula VI:

Expression VI

Or a pharmaceutically acceptable salt thereof;

here:

R ⁴ is OR ^a ;

Each n is independently 0, 1, or 2;

Each R ^a is independently H, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, aryl (C ₁ -C ₈₎ alkyl, (C ₄ -C ₈₎ heterocyclyl-alkyl ^{carbonyl, -C (= O) R 11} , -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), or -SO ₂ NR ¹¹ R ¹² ;

R ⁷ is H, -C (= O) R 11, -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R 11 ^{_{, -S (O) 2 R 11}} , -S (O) (oR 11), -S (O) 2 (oR 11), -SO 2 NR 11 R 12, or

;

;

Y is O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;

When W ¹ and W ² are bonded together, -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; or

One of W ¹ or W ² is -Y ³ -with R ⁴ and the other of W ¹ or W ² is A group of formula Ia; or

W ¹ and W ² are each, independently, a group of formula VIa:

Expression VIa

here:

Each Y ¹ is, independently, O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;

Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;

Each Y < ³ > is independently O, S, or NR;

M2 is 0,1 or 2;

Each R ^x is a group of the formula VIb:

Expression VIb

here:

Each M1a, M1c, and M1d is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C ( = Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) ₂ R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R ) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, -N (R) C (= Y ¹ ) N (R) ₂ , -SO ₂ NR ₂ , -CN, -N ₃ , -NO ₂ , -OR, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ Heterocyclyl, arylalkyl, heteroarylalkyl;

Wherein each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R ²⁰ groups;

Each R is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbo Cyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;

Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl optionally substituted by _one or more substituents selected from the group consisting of ₈ ) alkyl;

Each R ¹³ is independently carbocycle or heterocycle optionally substituted with 1-3 R ²⁰ groups;

Each R ²⁰ is independently halogen, CN, N ₃ , N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= Y ¹ ) R, -C (= Y ¹ ) OR, or C (= Y ¹ ) N (R) ₂ ;

Where each R ⁴ , Each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of R ¹¹ or R ¹² is independently , One or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or Optionally substituted with OR ^b ; And wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl may be optionally substituted with —O—, —S— or —NR ^b ;

Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, -C (= 0) R ²¹ , -C (= 0) OR ²¹ , -C (= 0) NR ²¹ R ²² , -C (= 0) SR ²¹ , -S (O) R ²¹ , -S (O) ₂ R ²¹ , -S (O) (OR ²¹ ), -S (O) ₂ (OR ²¹ ), or —SO ₂ NR ²¹ R ²² ;

Each R ²¹ or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocycle Arylalkyl, -C (= 0) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl;

Provided that the optional clue is that compounds 1, 1c, 1d, 1e, 2, TP-1, A-1, 8, and 21 are excluded.

In another aspect of this embodiment R ^a is H, (C ₁ -C ₈ ) alkyl, or —C (═O) (C ₁ -C ₆ ) alkyl; R ⁷ or R ⁴ and R ⁷ are together

, 또는

이고;

, or

ego;

here

a is the point of attachment to R ⁷ ;

b is the point of attachment to R ⁴ ;

Ar is phenyl or naphthyl, wherein said phenyl and naphthyl are optionally substituted with 1-3 R ²⁰ groups;

Each R ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, wherein said alkyl and carbocyclyl are optionally substituted with 1-3 R ²⁰ groups;

Each R is independently H, (C ₁ -C ₆ ) alkyl, or arylalkyl;

Each R ²⁰ is independently halogen, CN, N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= O) R, -C ( = O) OR, or C (= 0) N (R) ₂ .

In another embodiment, the compound of Formula IV-VI has the structure:

, 또는

, or

을 가지는 화합물;

Compound having;

Or pharmaceutically acceptable salts thereof.

In one embodiment of Formulas I-III and IV-VI, R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈₎ alkynyl, (C ₄ -C ₈₎ alkyl, heterocyclyl carbonyl, aryl, optionally substituted heteroaryl, -C (= O) (C 1 -C 8) alkyl, -S (O optionally substituted) _n ( C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl. In another embodiment, R ¹¹ and R ¹² are taken together with the nitrogen to which they are both attached to form a 3- to 7-membered heterocyclic ring, wherein any carbon atom of the heterocyclic ring is - O-, -S- or -NR < ^a > -. Thus, by way of example and not limitation, the moiety —NR ¹¹ R ¹² may have the following heterocycle:

And the like.

In another embodiment of Formulas I-III and IV-VI, each of R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² is independently (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) Wherein said (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) _{hydroxy, CN, N 3, N (} R a) 2 or OR &^lt; ^{a &} gt ;. Thus, by way of example and not limitation, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² is a moiety such as —CH (NH ₂ ) CH ₃ , —CH (OH) CH ₂ CH ₃ , —CH (NH ₂ ) CH (CH ₃ ) ₂ , —CH ₂ CF ₃ , — (CH ₂ ) ₂ CH (N ₃ ) CH ₃ ,-(CH ₂ ) ₆ NH _{2 And the} like.

In another embodiment of Formulas I-III and IV-VI, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² is (C ₁ -C ₈₎ alkyl wherein each of said (C ₁ -C ₈₎ one or more of the non-alkyl-optionally substituted with - the terminal carbon atom is -O-, -S- or -NR ^a Can be replaced. Thus, by way of example and not limitation, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² is a moiety such as —CH ₂ OCH ₃ , —CH ₂ OCH ₂ CH ₃ , —CH ₂ OCH (CH ₃ ) ₂ , —CH ₂ SCH ₃ , — (CH ₂ ) ₆ OCH ₃ ,-( CH ₂ ) ₆ N (CH ₃ ) ₂ , and the like.

In another embodiment, Formula I-III is selected from the group consisting of

;And

;

Or a pharmaceutically acceptable salt or ester thereof.

In another embodiment, provided is a compound of Formula I selected from the group consisting of, or compounds useful for the synthesis of salts or esters thereof:

및

.

And

.

Justice

Unless otherwise stated, the following terms and phrases used in this specification are intended to have the following meanings:

When a trademark is used in this specification, the applicant intends to independently include the trademark product and the active pharmaceutical ingredient (s) of the trademark product.

As used herein, "compound of the present invention" or "compound of formula I" means a compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, for isolable intermediates, the phrase "compound of formula (number)" means a compound of that formula and its pharmaceutically acceptable salts.

"Alkyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, the alkyl group of 1 to 20 carbon atoms (i.e., C ₁ -C ₂₀ alkyl), from 1 to 8 carbon atoms (i.e., C ₁ -C ₈ alkyl), or one to six carbon atoms (i.e., C ₁ - C ₆ alkyl). Examples of suitable alkyl groups include methyl (Me, -CH _3), ethyl _{(Et, -CH 2 CH 3)} , 1- propyl (n -Pr, n - _{propyl, -CH 2 CH 2 CH 3)} , 2- propyl (i -Pr, i - _{propyl, -CH (CH 3) 2)} , 1- butyl (n -Bu, n - _{butyl, -CH 2 CH 2 CH 2 CH} 3), 2- methyl-1-propyl (i -Bu, i - _{butyl, -CH 2 CH (CH 3)} 2), 2- butyl (s -Bu, s - _{butyl, -CH (CH 3) CH 2} CH 3), 2- methyl-2-propyl ( t -Bu, t - _{butyl, -C (CH 3) 3)} , 1- pentyl (n - _{pentyl, -CH 2 CH 2 CH 2 CH} 2 CH 3), 2- pentyl (-CH (CH ₃₎ CH ₂ CH ₂ CH _3), 3- pentyl _{(-CH (CH 2 CH 3)} 2), 2- methyl-2-butyl _{(-C (CH 3) 2 CH} 2 CH 3), 3- methyl-2-butyl ( _{-CH (CH 3) CH (CH} 3) 2), 3- methyl-1-butyl _{(-CH 2 CH 2 CH (CH} 3) 2), 2- methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH _3), 1- hexyl _{(-CH 2 CH 2 CH 2 CH} 2 CH 2 CH 3), 2- hexyl _{(-CH (CH 3) CH 2} CH 2 CH 2 CH 3), 3- hexyl ( _{-CH (CH 2 CH 3) (} CH 2 CH 2 CH 3)), 2- methyl-2-pentyl _{(-C (CH 3) 2 CH} 2 CH 2 CH 3), 3- methyl-2-pentyl (- _{CH (CH 3) CH (CH} 3) CH 2 CH 3), 4- methyl-2-pentyl _{(-CH (CH 3) CH 2} CH (CH 3) 2), 3- methyl-3 -Pentyl _{(-C (CH 3) (CH} 2 CH 3) 2), 2- methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl-2 butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3, and octyl (- (CH _{2) 7} CH ₃ ) _{. &} Lt _{; / RTI &} gt _;

"Alkoxy" means a group having formula-O-alkyl, wherein an alkyl group as defined above is attached to the parent molecule via an oxygen atom. The alkyl portion of the alkoxy group may have 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ alkoxy), 1 to 12 carbon atoms (ie, C ₁ -C ₁₂ alkoxy), or 1 to 6 carbon atoms (ie, C ₁ − C ₆ alkoxy). Examples of suitable alkoxy groups include methoxy (-O-CH ₃ or -OMe), ethoxy (-OCH ₂ CH ₃ or -OEt), t-butoxy (-OC (CH ₃ ) ₃ or -OtBu) But are not limited to,

"Haloalkyl" is an alkyl group as defined above wherein at least one hydrogen atom of the alkyl group is replaced by a halogen atom. The alkyl portion of the haloalkyl group may have 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ haloalkyl), 1 to 12 carbon atoms (ie, C ₁ -C ₁₂ haloalkyl), or 1 to 6 carbon atoms (ie, C ₁ -C ₆ alkyl). Examples of suitable haloalkyl groups include _{-CF 3, -CHF 2, -CFH 2} , -CH 2 CF 3, and so on, but are not limited to.

"Alkenyl" is a hydrocarbon containing at least one unsaturated site, ie, normal, secondary, tertiary or cyclic carbon atoms with carbon-carbon, sp ² double bonds. For example, an alkenyl group may have from 2 to 20 carbon atoms (i.e., C ₂ -C ₂₀ alkenyl), from 2 to 8 carbon atoms (i.e., C ₂ -C ₈ alkenyl), or from 2 to 6 carbon atoms C ₂ -C ₆ alkenyl). Examples of suitable alkenyl groups include ethylene or vinyl (-CH = CH _2), allyl _{(-CH 2 CH = CH 2)} , cyclopentenyl (-C ₅ H _7), and 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH = CH ₂ ).

"Alkynyl" is a hydrocarbon containing at least one unsaturated site, ie, normal, secondary, tertiary or cyclic carbon atoms with carbon-carbon, sp triple bonds. For example, the alkynyl group may have from 2 to 20 carbon atoms (i.e., C ₂ -C ₂₀ alkynyl), from 2 to 8 carbon atoms (i.e., C ₂ -C ₈ alkyne), or from 2 to 6 carbon atoms C ₂ -C ₆ alkynyl). Examples of suitable alkynyl groups include acetylenic (-C≡CH), propargyl (-CH ₂ C≡CH), but are not limited to.

"Alkylene" refers to saturated, branched or straight chain or cyclic hydrocarbon radicals having two monovalent radical centers by removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkylene radicals are methylene (-CH ₂ -), 1,1- ethyl _{(-CH (CH 3) -)} , 1,2- ethyl _{(-CH 2 CH 2 -),} 1,1- propyl (-CH (CH ₂ CH ₃ ) -), 1,2-propyl (-CH ₂ CH (CH ₃ ) -), 1,3-propyl (-CH ₂ CH ₂ CH ₂ -), ₂ CH ₂ CH ₂ CH ₂ -), and the like.

"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers by removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkene. For example, and the alkenylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Representative alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH = CH-).

"Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers by removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. For example, the alkynylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkynylene radicals include acetylene (-C≡C-), propargyl (-CH ₂ C≡C-), and 4-pentynyl _{(-CH 2 CH 2 CH 2 C≡C-} ) , but limited to, It does not.

"Amino" refers generally to nitrogen radicals which may be considered as derivatives of ammonia having the formula -N (X) ₂ , wherein each "X" is independently H, substituted or unsubstituted alkyl, substituted Substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, and the like. The hybridization of nitrogen is approximately sp ³ . Nonlimiting types of amino is -NH _2, -N (alkyl) _2, -NH (alkyl), -N (heterocyclyl carbonyl) _2, -NH (heterocyclyl carbonyl), -N (heterocyclyl) _2, - (Heterocyclyl), -N (aryl) ₂ , -NH (aryl), -N (alkyl) (aryl), -N (alkyl) (heterocyclyl), -N (carbocyclyl) (Aryl) (heteroaryl), -N (alkyl) (heteroaryl), and the like. The term "alkylamino" refers to an amino group substituted with at least one alkyl group. Non-limiting examples of amino groups include -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -NH (CH ₂ CH ₃ ), -N (CH ₂ CH ₃ ) ₂ , -NH , -N (phenyl) ₂ , -NH (benzyl), -N (benzyl) ₂ , and the like. Substituted alkylamino generally refers to an alkylamino group as defined above wherein at least one substituted alkyl as defined herein is attached to an amino nitrogen atom. Non-limiting examples of substituted alkylamino include -NH (alkylene-C (O) -OH), -NH (alkylene-C (O) OH) ₂ , -N (alkylene-C (O) -O-alkyl) ₂ , and the like.

"Aryl" means an aromatic hydrocarbon radical derived from the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Representative aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl,

"Arylalkyl" refers to a non-cyclic alkyl radical in which one of the carbon atoms, typically the hydrogen atoms bonded to the terminal or sp ³ carbon atoms, is replaced by an aryl radical. Representative arylalkyl groups include but are not limited to benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2- . The arylalkyl group may comprise 7 to 20 carbon atoms, for example, the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

"Arylalkenyl" refers to a non-cyclic alkenyl radical in which not only a carbon atom, typically a terminal or sp ³ carbon atom, but also one of the hydrogen atoms bonded to the sp ² carbon atom is replaced by an aryl radical . The aryl moiety of the arylalkenyl may include, for example, any of the aryl groups disclosed herein, and the alkenyl moiety of the arylalkenyl may be, for example, Or a benzyl group. The arylalkenyl group may comprise 8 to 20 carbon atoms, for example, the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

"Arylalkynyl" refers to a non-cyclic alkynyl radical in which not only a carbon atom, typically a terminal or sp ³ carbon atom, but also one of the hydrogen atoms attached to the sp carbon atom is replaced by an aryl radical. The aryl moiety of the arylalkynyl can include, for example, any of the aryl groups described herein, and the alkynyl moiety of the arylalkynyl can be, for example, Or a < / RTI > The arylalkynyl group may comprise from 8 to 20 carbon atoms, for example the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

With respect to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc. the term "substituted", for example "substituted alkyl", "substituted alkylene", " Substituted aryl "," substituted arylalkyl "," substituted heterocyclyl ", and" substituted carbocyclyl ", unless otherwise indicated, each of one or more hydrogen atoms is independently a non-hydrogen substituent; Refers to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl each replaced. Typical substituents include ^{-X, -R b, -O -,} = O, -OR b, -SR b, -S -, -NR b 2, -N + R b 3, = NR b, -CX 3, - CN, -OCN, -SCN, -N = C = O, -NCS, -NO, -NO 2, = N 2, -N 3, -NHC (= O) R b, -OC (= O) R b ^{, -NHC (= O) NR b} 2, -S (= O) 2 -, -S (= O) 2 OH, -S (= O) 2 R b, -OS (= O) 2 OR b, - S (═O) ₂ NR ^b ₂ , -S (═O) R ^b , -OP (═O) (OR ^b ) ₂ , ^{-P (= O) (OR b} ) 2, -P (= O) (O -) 2, -P (= O) (OH) 2, -P (O) (OR b) (O -), - ^{C (= O) R b,} -C (= O) X, -C (S) R b, -C (O) OR b, -C (O) O -, -C (S) OR b, -C ^{(O) SR b, -C (} S) SR b, -C (O) NR b 2, -C (S) NR b 2, -C (= NR b) NR ^b ₂ including and not limitation , Wherein each X is independently halogen: F, Cl, Br, or I; Each R ^b is independently H, alkyl, aryl, arylalkyl, heterocycle, or a protecting group or a prodrug moiety. Alkylene, alkenylene, and alkynylene rings may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used with an arylalkyl group having, for example, two or more moieties that can be substituted, the substituents are the aryl moiety, the alkyl moiety, or both It can be attached to everything.

The term “prodrug” as used herein refers to a drug as a result of spontaneous chemical reaction (s), enzyme catalyzed chemical reaction (s), photolysis, and / or metabolic chemical reaction (s) when administered to a biological system. A substance, ie, any compound that produces an active ingredient. Prodrugs are thus covalently modified analogues or latent forms of therapeutically active compounds.

Those skilled in the art will appreciate that substituents and other moieties of the compounds of Formulas I-III and IV-VI to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptable stable pharmaceutical compositions. It will be recognized that a tee should be selected. Definitions and substituents for the various genera and subclasses of the compounds are described and illustrated herein. Those skilled in the art naturally understand that no combination of the above-defined definitions and substituents should result in an inoperable species or compound. An “operable species or compound” refers to the isolation and formulation of a compound structure (eg, a carbon atom linking more than four covalent bonds) or a pharmaceutically acceptable dosage form in violation of the relevant scientific principles. It means a compound that is too unstable to tolerate.

"Heteroalkyl" refers to an alkyl group in which one or more carbon atoms is replaced by a heteroatom, such as O, N, or S. For example, if the carbon atom of the alkyl group attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), then each resulting heteroalkyl group may be substituted with an alkoxy group, _3, and the like), amines (e.g., -NHCH _3, -N (CH _{3) 2,} etc.), or a thioalkyl group (e.g., -SCH _3). If the non-terminal carbon atoms of an alkyl group not attached to the parent molecule are replaced by a heteroatom (eg O, N, or S), the resulting heteroalkyl group is each an alkyl ether (e.g.- CH ₂ CH ₂ -O-CH ₃ , etc., alkyl amines (eg -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ) ₂ , etc.), or thioalkyl ethers (eg -CH ₂ -S-CH ₃ ). If the terminal carbon atom of the alkyl group is replaced by a heteroatom (e.g., O, N, or S), then the resulting heteroalkyl group may each be substituted with a hydroxyalkyl group (e.g., -CH ₂ CH ₂ - OH), an aminoalkyl group (e.g., -CH ₂ NH _2), or an alkyl thiol group (e.g., -CH ₂ CH ₂ -SH). Heteroalkyl groups may have, for example, from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. C ₁ -C ₆ heteroalkyl group means a heteroalkyl group having from 1 to 6 carbon atoms.

As used herein, "heterocycle" or "heterocyclyl" includes, by way of example and not limitation, Paquette, Leo A .; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds , A Series of Monographs " (John Wiley & Sons, New York, 1950 to present), in particular the volumes described in volumes 13, 14, 16, 19, and 28; and J. Am . Chem . S oc . (1960) 82: 5566 In one particular embodiment of the invention “heterocycle” includes “carbocycle” as defined herein, wherein one or more (eg 1, 2, 3, or 4) ) Carbon atoms are replaced with heteroatoms (eg, O, N, or S. The term “heterocycle” or “heterocyclyl” refers to saturated rings, partially unsaturated rings, and aromatic rings (ie, Heteroaromatic ring) Substituted heterocyclyl includes heterocyclic rings substituted with any of the substituents disclosed herein including, for example, carbonyl groups. Non-limiting examples of the following are:

Illustrative examples of heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, Wherein the heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, Pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, Thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofura Pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, Pyridazinyl, indolinyl, isoindolinyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnaolinyl , Pterridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenantridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, iso Chromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotria Zolyl, benzisoxazolyl, oxindolinyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

을 포함한다.

.

Illustratively and non-limitingly, the carbon-bonded heterocycle may be substituted at the 2, 3, 4, 5, or 6 positions of the pyridine, at the 3, 4, 5, or 6 positions of the pyridazine, Or 6 position of the pyrazine, 2,3, 4,5 or 6 position of the pyrazine, furan, tetrahydrofuran, thiophene, thiophene, pyrrole or tetrahydropyrrole, oxazole, imidazole or Position 2, 3, or 4 of the azetidine, position 3, 4, or 5 of the aziridine, position 2, 3, or 4 of the azetidine, position 3, 4, or 5 of the isothiazole, 5, 6, 7, or 8 position of the isoquinoline or at 1, 3, 4, 5, 6, 7, or 8 positions of the isoquinoline. Still more typically, the carbon bonded heterocycle is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6- pyridyl, 3- pyridazinyl, Pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2- pyrazinyl, 3- pyrazinyl, - pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

Illustratively and non-limitingly, the nitrogen-linked heterocycle is selected from the group consisting of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, Isoindole, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, isoindoline, 2 position, 4 position of morpholine, and carbazole, or 9 position of? -Carboline. Still more typically, the nitrogen bonded heterocycle includes 1-aziridyl, 1-azetadyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” is a non-cyclic alkyl radical (ie, heterocyclyl-alkylene, in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced by a heterocyclyl radical) Moieties). Representative heterocyclyl alkyl groups heterocyclyl, -CH ₂ -, 2- (heterocyclyl) ethane-1-yl, and the like and not limitation, wherein "heterocyclyl" portion Principles of Including those described in Modern Heterocyclic Chemistry, it includes any of the heterocyclyl groups described above. The skilled artisan will also appreciate that the heterocyclyl group may be attached to the alkyl portion of the heterocyclylalkyl by a carbon-carbon bond or a carbon-heteroatom bond, with the only proviso that the resulting group is chemically stable will be. Said heterocyclylalkyl group comprises 3 to 20 carbon atoms, for example the alkyl portion of said arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms. Illustrative and non-limiting examples of heterocyclylalkyl include 5-membered sulfur, oxygen, and / or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, Methyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and / or nitrogen containing heterocycle such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl , Pyrazinylmethyl, and the like.

"Heterocyclylalkenyl" is a non-cyclic alkenyl radical in which one of the hydrogen atoms attached to the sp ² carbon atom as well as the carbon atom, typically the terminal or sp ³ carbon atom, is replaced by a heterocyclyl radical. (Ie, heterocyclyl-alkenylene-moiety). The heterocyclyl portion of the heterocyclyl alkenyl group is represented by Principles of Modern Heterocyclic Includes any of the heterocyclyl groups described herein, including those described in Chemistry , wherein the alkenyl portion of the heterocyclylalkenyl group includes any of the alkenyl groups disclosed herein . The skilled artisan will also appreciate that the heterocyclyl group may be attached to the alkenyl portion of the heterocyclylalkenyl by a carbon-carbon bond or a carbon-heteroatom bond, with the only proviso that the resulting group is chemically stable I will understand. The heterocyclyl alkenyl group contains 4 to 20 carbon atoms, for example, the alkenyl portion of the heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms .

"Heterocyclylalkynyl" is a non-cyclic alkynyl radical in which one of the carbon atoms, typically terminal or sp ³ carbon atoms, as well as one of the hydrogen atoms bonded to the sp carbon atom is replaced by a heterocyclyl radical (Ie, heterocyclyl-alkynylene-moiety). The heterocyclyl moiety of the heterocyclyl alkynyl group is represented by Principles of Modern Heterocyclic Any of the heterocyclyl groups described herein, including those described in Chemistry , and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein. The skilled artisan will recognize that the heterocyclyl group may be attached to the alkynyl moiety of the heterocyclylalkynyl by a carbon-carbon bond or a carbon-heteroatom bond, with the only proviso that the resulting group is chemically stable It will also understand that. The heterocyclylalkynyl group contains from 4 to 20 carbon atoms, for example, the alkynyl portion of the heterocyclylalkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms .

"Heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included within the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all aromatic rings listed within the definition of "heterocyclyl" and include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl , Benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, and the like .

"Carbocycles" or "carbocyclyl" refers to saturated (i. E., Cycloalkyl), partially (i. E., Cyclic) alkyl groups having from 3 to 7 carbon atoms as the monocycle, from 7 to 12 carbon atoms as the bicycle, Refers to an unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) or aromatic ring. The monocyclic carbocycle has 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles are, for example, 7 to 12 ring atoms arranged as bicyclo [4,5], [5,5], [5,6] or [6,6] , 6] or [6, 6] systems, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclocarbocycles include naphthyl, tetrahydronaphthalene, and decalin.

"Carbocyclylalkyl" refers to a non-cyclic alkyl radical in which one of the hydrogen atoms attached to the carbon atom is replaced by a carbocyclyl radical as described herein. Representative, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

"Arylheteroalkyl" refers to a heteroalkyl as defined herein, wherein a hydrogen atom (which may be attached to a carbon atom or a heteroatom) is replaced with an aryl group as defined herein. The aryl group may be attached to the carbon atom of the heteroalkyl group, or to the heteroatom of the heteroalkyl group, with the only proviso that the resulting aryl heteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group is a group of the formula -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, S-aryl, -alkylene-S-alkylene-aryl, and the like. In addition, any of the alkylene moieties in the above general formula may be further substituted with any of the substituents defined or exemplified herein.

"Heteroarylalkyl" refers to an alkyl group as defined herein wherein a hydrogen atom is replaced with a heteroaryl group as defined herein. Non-limiting examples of heteroaryl alkyl include -CH ₂ - pyridinyl, -CH ₂ - pyrrolyl, -CH ₂ - oxazolyl, -CH ₂ - indolyl, -CH ₂ - isoindolyl, -CH ₂ - Purifying carbonyl , -CH ₂ -furanyl, -CH ₂ -thienyl, -CH ₂ -benzofuranyl, -CH ₂ -benzothiophenyl, -CH ₂ -carbazolyl, -CH ₂ -imidazolyl, -CH ₂ - Thiazolyl, -CH ₂ -isoxazolyl, -CH ₂ -pyrazolyl, -CH ₂ -isothiazolyl, -CH ₂ -quinolyl, -CH ₂ -isoquinolyl, -CH ₂ -pyridazyl, -CH _2-pyrimidyl, -CH ₂ - pyrazyl, -CH (CH ₃₎ - pyridinyl, -CH (CH ₃₎ - pyrrolyl, -CH (CH ₃₎ - oxazolyl, -CH (CH ₃₎ - indole Reel, -CH (CH ₃₎ - isoindolyl, -CH (CH ₃₎ - Fourier carbonyl, -CH (CH ₃₎ - furanyl, -CH (CH ₃₎ - thienyl, -CH (CH ₃₎ - benzofuranyl, -CH (CH ₃₎ - benzo thiophenyl, -CH (CH ₃₎ - carbazolyl, -CH (CH ₃₎ - imidazolyl, -CH (CH ₃₎ - thiazolyl, -CH (CH ₃₎ isoxazolyl, -CH (CH ₃₎ - pyrazolyl, -CH (CH ₃₎ - isothiazolyl, -CH (CH ₃₎ - quinolyl, -CH (CH ₃₎ - isoquinolyl, - CH (CH ₃₎ - pyrido multiple material, -CH (CH ₃₎ - pyrimidine Includes pyrazyl, etc.-pyridyl, -CH (CH _3).

With respect to certain moieties of the compounds of Formulas I-III and IV-VI, the term “optionally substituted” (eg, optionally substituted aryl group) refers to all substituents being hydrogen or one or more hydrogen of the moiety to a substituent Refers to a moiety that is listed, for example, under the definition of “substituted” or that may be replaced by ones as indicated elsewhere.

With respect to certain moieties of the compounds of formulas I-III and IV-VI, the term “optionally substituted” (eg, the carbon atoms of said (C ₁ -C ₈ ) alkyl are -O-, -S-, Or -NR ^a -may be optionally substituted with one or more methylene groups of (C ₁ -C ₈ ) alkyl wherein 0, 1, 2, or more specified groups (eg, -O-, -S- It means that) can be replaced by a -, or -NR ^a.

In the context of an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety, the term “non-terminal carbon atom (s)” is defined between the first carbon atom in the moiety and the last carbon atom in the moiety. Refers to carbon atoms in the moiety that intervene. Thus, illustratively and without limitation, the alkyl moiety ^{_{-CH 2 (C *) H 2}} (C *) H 2 CH 3 or alkylene moiety ^{_{-CH 2 (C *) H 2}} (C *) H 2 Within the CH ₂ -, the C ^* atom is considered a non-terminal carbon atom.

또는

, 각각에 의해 또한 나타내어질 수 있고, 본 발명을 기술하는 목적에 대해 상기한 표현과 동등한 것으로 의도된다.Certain Y and Y ¹ alternatives are nitrogen oxides such as ⁺ N (O) (R) or ⁺ N (O) (OR). As shown herein, these nitrogen oxides attached to carbon atoms are charged separated groups such as

or

, Respectively, and is intended to be equivalent to the above description for the purpose of describing the present invention.

"Linker" or "link" means a chemical moiety containing a covalent bond or chain of atoms. The linker is preferably a polymer comprising repeating units of alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine ™; and succinate, succinamide, diglycolate, , And diacid esters and amides including caproamides.

The term "oxygen-linked", "nitrogen-linked", "carbon-linked", "sulfur-linked", or " , Then the bond formed between the moieties means through the specified atom. For example, nitrogen-linked amino acids are bound through the nitrogen atom of an amino acid rather than through the oxygen or carbon atom of the amino acid.

Unless otherwise specified, carbon atoms of compounds of Formulas I-III and IV-VI are intended to have four valences. In some chemical structure expressions where the carbon atom has a number of attached variables that are not sufficient to produce four valences, the remaining carbon substituents necessary to provide the four valences must be assumed to be hydrogen. For example,

는

The

과 동일한 의미를 가진다.

.

 "Protecting group" refers to the moiety of a compound that conceals or alters the properties of the functional group or the properties of the compound as a whole. The chemical substructure of the protecting group varies widely. One function of the protecting group is to act as an intermediate in the synthesis of the parent drug substance. Chemical protectors and strategies for protection / deprotection are well known in the art. (Protective Groups in Organic Chemistry ", Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups can be used to produce certain chemical reactions such as, for example, The protection of the functional groups of the compound is dependent on other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilic (hydrophobic) , And other properties that can be measured by conventional analytical tools. The chemically protected intermediate may itself be biologically active or inactive.

Protected compounds may also exhibit altered in vitro and in vivo, and in some cases optimized properties, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this role, a protected compound having an intended therapeutic effect may be referred to as a prodrug. Another function of the protecting group is to convert the parent drug to a prodrug whereby the parent drug is released by conversion of the prodrug in vivo. Since prodrugs that are active can be more effectively absorbed than the parent drug, prodrugs may have greater in vivo efficacy than the parent drug. Protecting groups are removed in vitro for chemical intermediates or in vivo for prodrugs. In chemical intermediates, it is generally preferred that the resulting products after deprotection, e. G., Alcohols, are pharmacologically harmless, although the physiologically acceptable product is not particularly critical.

"Prodrug moiety" means an unstable functional group that is released from an inhibitory compound that is active during metabolism systemically in cells by hydrolysis, enzymatic degradation, or some other process (Bundgaard, Hans, Textbook). of Drug Design and Development (1991) in "Design and Application of Prodrugs", P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes that are capable of enzymatic activation mechanisms with the phosphonate prodrug compounds of the present invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to optimize drug delivery, bioavailability, and efficacy by increasing solubility, absorbency and lipophilicity.

The prodrug moiety may comprise the active metabolite or the drug itself.

Exemplary prodrug moieties include hydrolytically sensitive or labile acyloxymethyl esters -CH ₂ OC (= O) R ³⁰ and acyloxymethyl carbonate -CH ₂ OC (= O) OR ³⁰ wherein R ³⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl. The acyloxyalkyl esters are used as prodrug strategies for carboxylic acids and are described in Farquhar et al (1983) J. Pharm . Sci . 72: 324; Also applied as phosphates and phosphonates by U.S. Patent Nos. 4816570, 4968788, 5663159 and 5792756. In certain compounds of the invention, the prodrug moiety is part of a phosphate group. The acyloxyalkyl esters can be used to transfer phosphoric acid through the cell membrane and to increase oral bioavailability. Alkoxycarbonyloxyalkyl esters (carbonates), which are close variants of acyloxyalkyl esters, can also increase oral bioavailability as a prodrug moiety within the compounds of the combination of the present invention. An exemplary acyloxymethyl ester is methyl _{a-methoxy-yl-oxy, (POM) -CH 2 OC (} = O) C (CH 3) 3 feet blood. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethyl carbonate (POC) -CH ₂ OC (= O) OC (CH ₃ ) ₃ .

The phosphate group may be a phosphate prodrug moiety. The prodrug moiety may be susceptible to hydrolysis, including, but not limited to, those containing pivaloyloxymethyl carbonate (POC) or a POM group. Alternatively, the prodrug moiety may be sensitive to enzymatically enhanced degradation, such as a lactate ester or a phosphonamidate-ester group.

Aryl esters, especially phenyl esters, of the phosphorous group have been reported to enhance oral bioavailability (DeLambert et al (1994) J. Med . Chem . 37: 498). A phenyl ester containing an ortho carboxylic acid ester to a phosphate has also been described (Khamnei and Torrence, (1996) J. Med . Chem . 39: 4109-4115). Benzyl esters have been reported to generate mophosphonic acid. In some cases, substituents in the ortho -or para- position can accelerate the hydrolysis. Benzyl analogs with acylated phenols or alkylated phenols can generate phenolic compounds through the action of enzymes such as esterase, oxydase, etc., and this phenolic compound eventually leads to benzylic CO-linkages Decomposition to generate phosphoric acid and quinone methide intermediates. An example of this class of prodrugs is described by Mitchell et al (1992) J. Chem . Soc . Perkin Trans . I 2345; WO 91/19721 to Brook et al. Still other benzyl prodrugs have been described containing carboxylic ester-containing groups attached to benzyl methylene (Wla 91/19721 to Glazier et al.). It has been reported that thio-containing prodrugs are useful for intracellular delivery of phosphonate drugs. These pro-esters contain an ethylthio group in which the thiol group is esterified with an acyl group or in combination with another thiol group to form a disulfide. Deesterification or reduction of the disulfide produces a free thio intermediate which is subsequently degraded to phosphoric acid and episulfide (Puech et al (1993) Antiviral Res ., 22: 155-174; Benzaria et al (1996) J. Med . Chem . 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (US Pat. No. 6312662 to Erion et al.).

All enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudos, of compounds within the range of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI and pharmaceutically acceptable salts thereof It should be noted that polymorphs are included in the present invention. All mixtures of such enantiomers and diastereoisomers are within the scope of the present invention.

The compounds of formulas I-III and IV-VI and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, a crystalline polymorph refers to the ability of a crystalline compound to exist in a different crystalline structure. The crystalline polymorphism can arise from differences in crystal packing (packing polymorphism) or differences in packing between different variants of the same molecule (steric pyramidal polymorphism). As used herein, crystalline pseudopolymorph means the ability of a hydrate or solvate of a compound to exist in a different crystalline structure. Pseudopolymorphs of the invention may exist due to crystal packing differences (packing pseudopolymorphs) or due to packing differences (stereoscopic pseudopolymorphisms) between different isoforms of the same molecule. The present invention includes all polymorphs and pseudopolymorphs of the compounds of Formulas I-III and IV-VI and their pharmaceutically acceptable salts.

The compounds of formulas I-III and IV-VI and their pharmaceutically acceptable salts may also exist as amorphous solids. Amorphous solids, as used herein, are solids without long-range order of position of atoms within a solid. This definition also applies when the crystal size is less than 2 nanometers. Additives, including solvents, can be used to produce the amorphous form of the present invention. The present invention includes all amorphous forms of the compounds of Formulas I-III and IV-VI and their pharmaceutically acceptable salts.

Selected substituents, including compounds of Formulas I-III and IV-VI, are present at repeatable levels. In this context, "repetitive substituent" means that the substituent can refer to another instance of itself. Due to the repetitive nature of such substituents, theoretically, a large number of compounds may be present in any given embodiment. For example, R ^x comprises an R ^y substituent. R ^y can be R. R can be W < ³ >. W ³ is W ^4, and W ⁴ may be may include a substituent which may be R or R ^y include. Those of ordinary skill in the art of pharmaceutical chemistry understand that the total number of such substituents is reasonably limited by the desired properties of the intended compound. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application characteristics such as activity against the intended target, and practical properties, such as ease of synthesis.

Illustratively and non-limiting, W ³ and R ^y are, in certain embodiments, repetitive substituents. Typically, each repetitive substituent is independently selected from the group consisting of 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 2, 1, or 0 times. More typically, each repetitive substituent can independently occur in a given embodiment at a frequency of 12 or less. Even more typically, each repetitive substituent can independently occur in a given embodiment at a frequency of 3 or less. For example, in a given embodiment W ³ will occur from 0 to 8 times, and R ^y will occur from 0 to 6 times. Even more typically, in a given embodiment, W ³ will occur from 0 to 6 times and R ^y will occur from 0 to 4 times.

Repeated substituents are intended aspects of the present invention. Those of ordinary skill in the art of pharmaceutical chemistry understand the diversity of such substituents. To the extent that repeating substituents are present in embodiments of the present invention, the total number will be determined as specified above.

The modifier "about" used with respect to quantity (Including, for example, the degree of error associated with a particular amount of measurement) for the stated value.

일 수 있고 여기서 각각의 Y 또는 Y¹는, 독립적으로, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), 또는 N-NR₂; W¹ 및 W²는 함께 결합될 때 -Y³(C(R^y)₂)₃Y³-; 또는 W¹ 또는 W² 중 하나는 R³ 또는 R⁴와 함께 -Y³-이고 W¹ 또는 W²의 다른 하나는 식 Ia; 또는 W¹ 및 W²는 각각, 독립적으로, 식 Ia의 기이고: Compounds of formulas I-III and IV-VI are as R ⁷ A phosphate group, and the phosphate group may include a prodrug moiety

, Wherein each Y or Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ; When W ¹ and W ² are bonded together, -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; Or one of W ¹ or W ² is -Y ³ - together with R ³ or R ⁴ and the other of W ¹ or W ² is of formula Ia; Or W < ^{1 >} and W < ² > are each independently a group of formula Ia:

here:

Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;

Each Y < ³ > is independently O, S, or NR;

M2 is 0,1 or 2;

Each R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y 1) R, -C (= Y 1) OR, -C (= Y 1) N (R) _{2, -N (R) 2,} - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) (OR), -S (O) 2 (OR), -OC (= Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) (N (R) 2), -SC (= Y 1) R, -SC (= ^{Y 1) oR, -SC (=} Y 1) (N (R) 2), -N (R) C (= Y 1) R, -N (R) C (= Y 1) oR, or -N ( ^{R) C (= Y 1)} N (R) 2, -SO 2 NR 2, -CN, -N 3, -NO 2, -OR, protecting group or W ^3; Or when taken together, two R ^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

Each R ^x is independently R ^y , a protecting group, or a group of formula:

;

;

here:

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Each R is H, halogen, (C ₁ -C ₈₎ alkyl, (C ₁ -C ₈₎ substituted alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocyclyl, arylalkyl, substituted arylalkyl or a protecting group;

W ³ is W ⁴ or W ⁵ ; W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y , or -SO ₂ W ⁵ ; And W < ⁵ > is a carbocycle or a heterocycle, wherein W < ⁵ > is independently substituted with 0 to 3 R < ^y >

W ⁵ carbocycle and W ⁵ heterocycle may be independently substituted with 0 to 3 R ^y groups. W < ⁵ > can be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. W ⁵ may have 3 to 10 ring atoms, for example 3 to 7 ring atoms. The W ⁵ ring is saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated when containing 5 ring atoms, mono- or di-unsaturated, Mono- or di-unsaturated when containing an atom, or aromatic.

W ⁵ heterocycle is a monocycle having 7 to 10 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a 7 to 10 ring member (4 to 9 carbon atoms And 1 to 3 heteroatoms selected from N, O, P, and S). W ⁵ heterocyclic monocycle is a heterocyclic monocycle having 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); Or 5 or 6 ring atoms (1 to 2 heteroatoms selected from 3 to 5 carbon atoms and N and S). The W ⁵ heterocyclic bicycles contain 7 to 10 ring atoms (6 to 9 carbon atoms and 6 to 10 ring atoms) arranged as a bicyclo [4,5], [5,5], [5,6], or [ 1 to 2 heteroatoms selected from N, O, and S); Or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S) arranged as a [5,6] or [6,6] system as a bicyclic. The W ⁵ The heterocycle may be bonded to Y ² via carbon, nitrogen, sulfur or other atoms by stable covalent bonding.

W ⁵ heterocycle may be, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, Morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, and morpholinyl. W ⁵ also includes, but is not limited to, the following examples:

및

And

W < ⁵ > carbocycle and heterocycle may be independently substituted with 0 to 3 R groups as defined above. For example, substituted W ⁵ carbocycles include:

Examples of substituted phenylcarbocycles include:

Embodiments of R ⁷ together with R ⁷ or R ⁴ include the following structures:

또는

or

here

a is the point of attachment to R ⁷ ;

b is the point of attachment to R ⁴ ;

Ar is phenyl or naphthyl, wherein said phenyl and naphthyl are optionally substituted with 1-3 R ²⁰ groups;

Each R ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, wherein said alkyl and carbocyclyl are optionally substituted with 1-3 R ²⁰ groups;

Each R is independently H, (C ₁ -C ₆ ) alkyl, or arylalkyl;

Each R ²⁰ is independently halogen, CN, N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= O) R, -C ( = O) OR, or C (= 0) N (R) ₂ .

의 구체예는 하위구조 가령:Of the compounds of formulas I-III and IV-VI

A sub-structure, for example:

을 포함하고

And

Wherein each Y ^2b is independently O or N (R). In yet another aspect of this embodiment, each Y ^2b is O and each R ^x is Independently:

Wherein M12c is 1, 2 or 3 and each Y ² is a bond independently, O, CR _2, or S. In another aspect of this embodiment, one Y ^2b -R ^x is NH (R) and the other Y ^2b -R ^x is OR ^x , wherein R ^x is:

Where M12c is 2. In yet another aspect of this embodiment, each Y ^2b is O and each R ^x is independently:

Where M12c is 2. In yet another aspect of this embodiment, each Y ^2b is O and each R ^x is independently:

Wherein M12c is 1 and Y ² is a bond, O, or CR _2.

의 다른 구체예는 하위구조 가령:Of the compounds of formulas I-III and IV-VI

Other embodiments of the sub-structure include:

을 포함하고

And

Wherein each Y < ³ > is independently O or N (R). In yet another aspect of this embodiment, each Y < ³ > In yet another aspect of this embodiment, the substructure comprises:

Wherein R ^y is W ⁵ as defined herein.

의 또다른 구체예는 다음 하위구조를 포함하고:Of formulas I-III and IV-VI

Another embodiment of the invention includes the following sub-structure:

Wherein each Y ^2c is independently O, N (R ^y ), or S.

의 또다른 구체예는 W¹ 또는 W² 중 하나는 R³ 또는 R⁴ 중 하나와 함께 -Y³-이고 W¹ 또는 W²의 다른 하나는 식 Ia인 하위구조를 포함한다. 그러한 구체예는 다음으로부터 선택되는 식 Ib의 화합물에 의해 나타내어진다:Of the compounds of formulas I-III and IV-VI

Another embodiment is of one of the W ¹ or W ² is R ³ or R ⁴ -Y ³ with one - and the other of W ¹ or W ² and comprises a sub-structure formula Ia. Such embodiments are represented by compounds of formula Ib selected from:

또는

or

Expression Ib

In yet another aspect of embodiments of formula Ib, each of Y and Y < ³ > In yet another aspect of embodiments of formula Ib, W ¹ or W ² is Y ^2b -R ^x ; Each Y, Y ³ and Y ^2b is O and R ^x is:

Wherein M12c is 1, 2 or 3 and each Y ² is a bond independently, O, CR _2, or S. In yet another aspect of embodiments of formula Ib, W ¹ or W ² is Y ^2b -R ^x ; Each Y, Y ³ and Y ^2b is O and R ^x is:

Where M12c is 2. In yet another aspect of embodiments of formula Ib, W ¹ or W ² is Y ^2b -R ^x ; Each Y, Y ³ and Y ^2b is O and R ^x is:

Wherein M12c is 1 and Y ² is a bond, O, or CR _2.

의 또다른 구체예는 다음 하위구조:Of the compounds of formulas I-III and IV-VI

≪ / RTI > Another embodiment of the < RTI ID = 0.0 &

을 포함하고

And

Where W < ⁵ > is a carbocycle such as phenyl or substituted phenyl. In yet another aspect of this embodiment, the substructure comprises:

Wherein Y ^2b is O or N (R) and the phenyl carbocycle is substituted with 0 to 3 R groups. In yet another aspect of this sub-structure of this embodiment, R ^x is:

Wherein M12c is 1, 2 or 3 and each Y ² is a bond independently, O, CR _2, or S.

의 또다른 구체예는 하위구조:Of formulas I-III and IV-VI

Another embodiment of the sub structure:

또는

을 포함한다.

or

.

The chiral carbon of the amino acid and the lactate moiety may be in the R or S configuration or a racemic mixture.

의 또다른 구체예는 하위구조Of formulas I-III and IV-VI

Another embodiment of < RTI ID = 0.0 >

이고

ego

Wherein each Y ² is, independently, -O- or -NH-. In this embodiment a further aspect, R ^y is a (C ₁ -C ₈₎ alkyl, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈₎ alkynyl or a (C ₂ -C ₈₎ substituted alkynyl. In this embodiment a further aspect, R ^y is a (C ₁ -C ₈₎ alkyl, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈₎ alkynyl or (C ₂ -C ₈₎ substituted alkynyl; R is CH _3. In this embodiment a further aspect, R ^y is a (C ₁ -C ₈₎ alkyl, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈₎ alkynyl or (C ₂ -C ₈₎ substituted alkynyl; R is CH _3, and; Each Y < ² > is -NH-. In one aspect of this embodiment, W ¹ and W ² are, independently, nitrogen-linked, naturally-occurring amino acids or naturally-occurring amino acid esters. In another aspect of this embodiment, W ¹ and W ² are independently a naturally occurring 2-hydroxy carboxylic acid or a naturally occurring 2-hydroxy carboxylic acid ester wherein the acid or ester is a 2-hydroxy group Is connected to P.

의 또다른 구체예는 하위구조:Expression I, expression II, expression III, expression IV, expression V, or expression VI

Another embodiment of the sub structure:

이다.

to be.

In one aspect of this embodiment, each R ^x is, independently, (C ₁ -C ₈ ) alkyl. In yet another aspect of this embodiment, each R ^x is independently C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl.

는 다음으로부터 선택된다: In a preferred embodiment,

Is selected from the following:

또는

or

의 또다른 구체예는 하위구조 Of formulas I-III and IV-VI

Another embodiment of < RTI ID = 0.0 >

이고

ego

Where W ¹ and W ² are independently selected from one of the formulas in Tables 20.1-20.37 and Table 30.1 below. The variables used in tables 20.1-20.37 (for example, W ²³ , R ²¹ , etc.) refer only to tables 20.1-20.37 unless otherwise indicated.

The variables used in Tables 20.1 to 20.37 have the following definitions:

Each R ²¹ is H or (C ₁ -C ₈₎ independently alkyl;

Each R ²² is independently H, R ²¹ , R ²³ or R ²⁴ wherein each R ²⁴ is independently substituted with 0 to 3 R ²³ ;

Each R ²³ is independently R ^23a , R ^23b , R ^23c or R ^23d , provided that when R ²³ is bonded to a heteroatom then R ²³ is R ^23c or R ^23d ;

Each R ^23a is independently selected from F, Cl, Br, I, -CN, N 3 or -NO _2;

Each R ^23b is independently selected from the group consisting of Y ²¹ ;

Each R ^23c is independently -R ^2x , -N (R ^2x ) (R ^2x ), -SR ^2x , -S (O) R ^2x , -S (O) ₂ R ^2x , -S (O) (OR ^2x ), -S (O) ₂ (OR ^2x ), -OC (= Y ²¹ ) R ^2x , -OC (= Y ²¹ ) OR ^2x , -OC (= Y ²¹ ) (N (R ^2x ) (R ^2x )), -SC (= Y ²¹ ) R ^2x , -SC (= Y ²¹ ) OR ^2x , -SC (= Y ²¹ ) (N (R ^2x ) (R ^2x )), -N (R ^2x ) C ( = Y ²¹ ) R ^2x , -N (R ^2x ) C (= Y ²¹ ) OR ^2x , or -N (R ^2x ) C (= Y ²¹ ) (N (R ^2x ) (R ^2x ));

Each R ^23d is independently -C (= Y ²¹ ) R ^2x , -C (= Y ²¹ ) OR ^2x or -C (= Y ²¹ ) (N (R ^2x ) (R ^2x ));

Each R ^2x is independently selected from the group consisting of H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl, heteroaryl; Or two R < ^2x > are taken together with the nitrogen to which they are both attached to form a 3- to 7-membered heterocyclic ring wherein either carbon atom of the heterocyclic ring is replaced by -O-, -S-, or Lt; ²¹ >-; And wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl can be optionally replaced by -O-, -S- or -NR ²¹ -;

Each R ²⁴ is independently (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, or (C ₂ -C ₈ ) alkynyl;

Each R ²⁵ is independently R ²⁴ wherein each R ²⁴ is substituted with 0 to 3 R ²³ groups;

Each R < ^25a > Independently represent (C ₁ -C ₈₎ alkylene, (C ₂ -C ₈₎ alkenylene, or (C ₂ -C ₈₎ alkynylene wherein the (C ₁ -C ₈₎ alkylene, (C ₂ -C ₈ ) Alkenylene, or (C ₂ -C ₈ ) alkynylene is substituted with a 0-3 R ²³ group;

Each W ²³ is independently W ²⁴ or W ²⁵ ;

Each W ²⁴ is independently selected from the group consisting of R ²⁵ , -C (= Y ²¹ ) R ²⁵ , -C (= Y ²¹ ) W ²⁵ , -SO ₂ R ²⁵ , or -SO ₂ W ²⁵ ;

Each W ²⁵ is independently a carbocycle or a heterocycle wherein W ²⁵ is independently substituted with 0 to 3 R ²² groups; And

Each Y ²¹ is independently O or S;

Table 20.1

Table 20.2

Table 20.3

Table 20.4

Table 20.5

Table 20.6

Table 20.7

Table 20.8

Table 20.9

Table 20.10

Table 20.11

Table 20.12

Table 20.13

Table 20.14

Table 20.15

Table 20.16

Table 20.17

Table 20.18

Table 20.19

Table 20.20

Table 20.21

Table 20.22

Table 20.23

Table 20.24

Table 20.25

Table 20.26

Table 20.27

Table 20.28

Table 20.29

Table 20.30

Table 20.31

Table 20.32

Table 20.33

Table 20.34

Table 20.35

Table 20.36

Table 20.37

Table 30.1

.

Specific examples of R ^x include esters, carbamates, carbonates, thioesters, amides, thioamides, and ureas:

및

을 포함한다.

And

.

Any reference to a compound of the invention described herein also includes reference to a physiologically acceptable salt thereof. Physiologically acceptable salts of the exemplified compounds of the present invention is a suitable base, for example alkali metal or alkaline earth metal (e.g., Na ^+, Li ^+, K ^+, Ca ⁺² and Mg ^+2), ammonium and NR ₄ ⁺ (Wherein R is defined herein). Physiologically acceptable salts of the nitrogen atom or amino group include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) an organic acid such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, But are not limited to, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, Salicylic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and salts formed with salicylic acid, salicylic acid, salicylic acid, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, And (c) salts formed from elemental anions such as chlorine, bromine, and iodine. Physiologically acceptable salts of the compounds of the hydroxy group include the anions of such compounds in combination with suitable cations such as Na ^< ⁺ & gt ^; and NR < ₄ ⁺ >.

For therapeutic use, the salts of the active ingredients of the compounds of this invention are physiologically acceptable, i. E. Salts derived from physiologically acceptable acids or bases. However, salts of acids or bases which are not physiologically acceptable can also be used, for example, in the manufacture or purification of physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the present invention.

Finally, it is to be understood that the compositions herein comprise the compounds of the invention in their non-ionized, also zwitterionic form, and in combination with stoichiometric amounts of water as in the case of hydrates.

The compounds of the invention exemplified by formulas I-III and IV-VI may have a chiral center, such as a chiral carbon or phosphorus atom. The compounds of the present invention thus encompass racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropoisomers. In addition, the compounds of the present invention encompass optical isomers enriched or fractionated at any or all asymmetric, chiral atoms. In other words, the apparent chiral center from the figure is provided as a chiral isomer or racemic mixture. Both the racemic and diastereomeric mixtures, as well as the isolated or synthesized individual optical isomers substantially free of their enantiomeric or diastereomeric partners are all within the scope of the present invention. The racemic mixture can be separated and purified by well-known techniques such as, for example, separation of an optically active auxiliary, such as an acid or base, and a formed diastereomeric salt, followed by conversion to the optically active material Are separated into their individual, substantially optically pure isomers. In most cases, the desired optical isomer is synthesized by stereospecific reaction, starting with the appropriate stereoisomer of the desired starting material.

The term "chiral" refers to a molecule having non-overlapping properties of a mirror partner, and the term "achiral " refers to a molecule that can overlap on their mirror partner.

The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.

"Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. The diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereoisomers can be separated under high resolution analytical procedures, such as electrophoresis and chromatography.

"Enantiomer" refers to two stereoisomers of a mirror image compound that can not overlap with each other.

Stereochemistry definitions and conventions commonly used herein are described in SP Parker, Ed., McGraw - Hill. Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active form, i. E. They have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute arrangement of molecules with respect to their chiral center (s). The prefixes d and l, D and L, or (+) and (-) are used by the compound to indicate the sign of rotation of planar polarization, and S, (-), or l is the compound is left turnable, Compounds with a prefix of R, (+), or d mean right turn. For a given chemical structure, these stereoisomers are identical except that they are mirrored to each other. Certain stereoisomers may also be referred to as enantiomers and mixtures of such isomers are often referred to as enantiomer mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in the absence of stereoselection or stereospecificity in a chemical reaction or process. The terms " racemic mixture "and" racemic "refer to a mixture of equivalent moles of two enantiomeric species that are not optically active.

는 결합하는 하위구조, 기, 모이어티, 또는 원자에 대한 공유적 결합 부착의 부위를 나타낸다.Whenever a compound described herein is substituted with more than one and the same designated group, for example, "R" or "R ^{1 &} quot ;, the groups may be the same or different, i.e. each group is independently selected Should be understood. Wavy lines,

Represents a moiety of a covalent bond to a joining substructure, group, moiety, or atom.

The compounds of the present invention may also exist in certain instances as tautomers. Although only one non-resonant resonance structure can be described, all such forms are contemplated within the scope of the present invention. For example, ene-amine tautomers can exist for purines, pyrimidines, imidazoles, guanidines, amidines, and tetrazole systems, and all of their possible tautomeric forms are within the scope of this invention.

One skilled in the art would be pyrrolo [1,2-f] [1,2,4] triazine, imidazo [1,5-f] [1,2,4] triazine, imidazo [1,2 -f] [1,2,4] triazine, and [1,2,4] triazolo [4,3-f] [1,2,4] triazine nucleoside may exist in tautomeric form Will recognize. For example, but not by way of limitation, structures (a) and (b) may have the equivalent tautomeric forms shown below:

In all embodiments disclosed herein all possible tautomeric forms of the heterocycle are within the scope of the present invention.

HCV Polymerase  Inhibition method

Another aspect of the invention relates to a method for inhibiting the activity of HCV polymerase comprising treating a sample suspected of containing HCV with a composition of the invention.

The compositions of the present invention can act as inhibitors of HCV polymerase, act as intermediates for such inhibitors, or have other uses as described below. The inhibitor will bind to a position on or in the cavity of the HCV polymerase having a geometry inherent to the HCV polymerase. Compositions that bind HCV polymerase can bind to varying degrees of reversibility. Compounds that bind substantially irreversibly are ideal candidates for use in the methods of the invention. Once labeled, the substantially irreversible binding composition is useful as a probe for detection of HCV polymerase. Accordingly, the present invention relates to a method for detecting HCV polymerase in a sample suspected of containing HCV polymerase, comprising the following steps: A compound of the invention bound to a label containing a sample suspected of containing HCV polymerase. Treatment with a composition comprising; And observing the effect of the sample on the activity of the label. Suitable labels are well known in the field of diagnostics and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. Compounds herein are labeled in a conventional manner using functional groups such as hydroxyl, carboxyl, sulfidyl or amino.

Within the context of the present invention, samples suspected of containing HCV polymerase include natural or artificial substances such as living organisms; Tissue or cell culture; Biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, bile, saliva, tissue samples, etc.); Laboratory samples; Food, water, or air samples; Biological product samples such as extracts of cells, in particular recombinant cells that synthesize certain glycoproteins; And the like. Typically the sample will be suspected to contain organisms that produce HCV polymerase, frequently pathogenic organisms such as HCV. The sample can be contained in any medium comprising water and an organic solvent / water mixture. Samples include living organisms such as humans, and artificial materials such as cell cultures.

The process steps of the present invention include adding a composition of the present invention to a sample or adding a precursor of the composition to the sample. The additional step includes any of the methods of administration as described above.

If desired, the activity of HCV polymerase after application of the composition can be observed by any method including direct and indirect methods of detecting HCV polymerase activity. Both quantitative, qualitative, and semiquantitative methods of determining HCV polymerase activity are contemplated. Typically one of the above screening methods described above applies, however, any other method such as the observation of the physiological properties of living organisms is also applicable.

Organisms containing HCV polymerase include the HCV virus. Compounds of the invention are useful in the treatment or prevention of HCV infection in animals or in humans.

However, it should be borne in mind that in the screening of compounds capable of inhibiting human immunodeficiency virus, the results of the enzyme assay may not be correlated with the cell culture assay. Thus, cell based assays should only be primary screening tools.

HCV Polymerase  Screening for Inhibitors.

The composition of the present invention is screened for inhibitory activity against HCV polymerase by any conventional technique for assessing enzyme activity. Within the context of the present invention, a composition is first screened for inhibition of HCV polymerase, typically in vitro, and a composition that exhibits inhibitory activity is then screened for in vivo activity. Compositions having an in vitro Ki (inhibitory constant) of less than about 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M and preferably less than about 5 × 10 ⁻⁸ M are preferred for in vivo use. Do.

Useful in vitro screenings have been described in detail and are not described in detail herein. However, the examples describe suitable in vitro assays.

Pharmaceutical formulation

The compounds of the present invention are formulated as conventional carriers and excipients, and conventional carriers and excipients will be selected according to conventional practice. Tablets may contain excipients, lubricants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery other than oral administration. All formulations will optionally contain excipients such as those specified in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, but usually about 7 to 10.

The active ingredient may be administered alone, but is preferably presented as a pharmaceutical formulation. The formulation of the present invention, which is both animal and human, comprises at least one active ingredient as defined above together with one or more acceptable carriers and optionally other therapeutic ingredients therefor. The carrier (s) must be "acceptable" in the sense of conformity with the other ingredients of the formulation and physiologically harmless to its recipient.

Such formulations include those suitable for the intended route of administration. Such formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts. Techniques and formulations are generally found in Remington ' s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with a carrier which constitutes one or more ancillary ingredients. Formulations are generally prepared by uniformly and densely associating the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of active ingredient; As powders or granules; As a solution or suspension in an aqueous or non-aqueous liquid; Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, soft or paste.

Optionally, the tablets are made by compression or molding with one or more ancillary ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in suitable equipment, optionally in admixture with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent. The shaped tablet can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in the appropriate equipment. The tablets may optionally be coated or salted and optionally formulated to provide delayed or controlled release of the active ingredient.

For infections of the eye or other external tissues such as mouth and skin, the preparation is preferably administered, for example, at a concentration of 0.075 to 20% w / w (0.1% w / w of active ingredient (s) w / w, and most preferably 0.5 to 10% w / w), preferably in an amount ranging from 0.5% w / w to 0.6% w / w, As a topical ointment or cream containing the active ingredient (s). When formulated in ointments, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

If desired, the cream base water phase may comprise, for example, a polyhydric alcohol of at least 30% w / w, ie an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol , Mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical agent may preferably comprise a compound that enhances absorption or permeation of the active ingredient through the skin or other areas of invasion. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.

The oily phase of the emulsion of the present invention can be constituted from known components in a known manner. The phase may comprise only an emulsifier (otherwise known as an emulgent), but preferably comprises a mixture of at least one emulsifier together with either a fat or an oil or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oils and fats. Together, the emulsifier (s) constitute a so-called emulsifying wax with or without stabilizer (s), which constitutes a so-called emulsifying ointment base which together with the oil and fat forms an oily disperse phase in the cream formulation.

Suitable emulsion and emulsion stabilizers for use in the formulations of the invention are Tween ^® 60, Span ^® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate It includes.

The choice of a suitable oil or fat for the formulation is based on achieving certain cosmetic properties. The cream should preferably be a non-oily, non-dyed and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadiate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate Combinations of branched chain chain esters known as 2-ethylhexyl palmitate or Crodamol CAP can be used, the last three being the preferred esters. They may be used alone or in combination depending on the required properties. Alternatively, a high melting point liquid such as white soft paraffin and / or liquid paraffin or other mineral oil is used.

Pharmaceutical formulations according to the invention comprise combinations according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended mode of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the preparation of such pharmaceutical compositions, and such compositions may include sweetening agents, flavoring agents, coloring agents, and preservatives to provide formulations suitable for the mouth. It may contain one or more agents. Tablets containing the active ingredient in admixture with suitable non-toxic pharmaceutically acceptable excipients for the manufacture of tablets are acceptable. These excipients include, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; Granulating and disintegrating agents, such as corn starch, or alginic acid; Binders, such as starch, gelatin or acacia; And a lubricant, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation, which slows disintegration and adsorption in the gastrointestinal tract and thereby provides long-term delayed action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with the wax.

Formulations for oral use also include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. It may be presented as a soft gelatin capsule.

The aqueous suspensions of the present invention contain the active materials mixed with the appropriate excipients for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally occurring phosphates Tide (eg lecithin), condensation products of fatty acids with alkylene oxides (eg polyoxyethylene stearate), condensation products of long chain aliphatic alcohols with ethylene oxide (eg heptadecaethyleneoxycetanol) Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (eg polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavors and one or more sweeteners, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oral suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those specified above, and flavoring agents, may be added to provide mouth-compatible oral preparations. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules of the present invention suitable for the manufacture of aqueous suspensions by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients such as sweetening agents, flavoring agents and coloring agents may also be present.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or peanut oil, mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers are naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphites, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, And condensation products of ethylene oxide with these partial esters, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives, flavors or coloring agents.

The pharmaceutical compositions of this invention may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be prepared as a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane-diol, or as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Sterile nonvolatile oils can also be used conventionally as solvents or suspending media. For this purpose, any non-irritating nonvolatile oil containing synthetic mono- or diglycerides may be used. In addition, fatty acids such as oleic acid may be similarly used in the production of injectables.

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, time-release formulations intended for oral administration to humans may contain from about 1% to about 5%, preferably from about 1% to about 5%, of a combined, appropriate and convenient amount of carrier material, 1000 mg of active substance compound. The pharmaceutical composition may be formulated to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 [mu] g of active ingredient per milliliter of solution to allow injection of the appropriate volume at a rate of about 30 mL / hour.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and especially about 1.5% w / w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; Pastilles comprising an inert base such as gelatin and glycerin, or sucrose and an active ingredient in acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

Preparations for rectal administration may be presented as suppositories with suitable bases including, for example, cocoa butter or salicylate.

Formulations suitable for intrapulmonary or nasal administration may have a particle size in the range of, for example, 0.1 to 500 micrometers, such as 0.5, 1, 30, 35, etc., by rapid inhalation by nasal passage or inhalation through the mouth to reach the alveoli. Administered. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as the compounds used so far in the treatment or prevention of HCV infection, as described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations which contain, in addition to the active ingredient, carriers known in the art as suitable.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacterial growth inhibitors and solutes which are made into the blood of the intended recipient and isotonic agents; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

Such formulations may be present in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, Lt; / RTI > Instant injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing the daily dose or unit daily sub-dose of the active ingredient as referred to hereinabove, or a suitable fraction thereof.

In addition to the abovementioned components specifically mentioned above, the formulations of the present invention may include other agents conventional in the art for the type of formulation in question, for example those suitable for oral administration may include flavoring agents. It should be understood.

The invention further provides an animal composition comprising at least one active ingredient as defined above together with an animal carrier therefor.

Animal carrier is a substance useful for the purpose of administering the composition and may be a solid, liquid or gaseous substance inert or acceptable in the animal industry and is compatible with the active ingredient. These animal compositions can be administered orally, parenterally or by any other desired route.

Compounds of the invention are used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the invention as active ingredients, wherein the release of the active ingredients in such formulations allows for less frequent administration or Controlled and regulated to improve the pharmacokinetic or toxicity profile of a given active ingredient.

The effective dosage of the active ingredient depends at least on the nature of the condition to be treated, the toxicity, whether the compound is used prophylactically (low dose) or against active viral infection, the method of delivery and the pharmaceutical preparation, and according to conventional dose escalation studies Using will be determined by the doctor. An effective dose of the active ingredient is from about 0.0001 to about 100 mg / kg body weight per day; Typically, about 0.01 to about 10 mg / kg body weight per day; More typically about 0.01 to about 5 mg / kg body weight per day; Most typically from about 0.05 to about 0.5 mg / kg body weight per day. For example, a daily candidate dose for an adult of about 70 kg body weight is between 1 mg and 1000 mg, preferably between 5 mg and 500 mg, and may take the form of the single or multiple administrations described above.

Route of administration

One or more compounds of the invention (referred to herein as active ingredients) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), intravaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may depend, for example, on the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

Combination therapy

Combinations of compounds of formulas I-III and IV-VI are typically selected based on the condition to be treated, the cross-reactivity of the components and the pharmacological-characteristics of the combination. For example, when treating an infection (eg, HCV), the compositions of the present invention are combined with other active therapeutic agents (such as those described herein).

The compositions of the present invention are also used in combination with one or more other active ingredients. Preferably, the other active therapeutic ingredient or agent is an interferon, ribavirin or analogue thereof, an HCV NS3 protease inhibitor, an NS5a inhibitor, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a mevalonate decarboxylase antagonist, renin Antagonists of the angiotensin system, other anti-fibrillating agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, Cyclophylline inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers or other drugs for treating HCV; Or mixtures thereof.

More specifically, one or more compounds of the present invention may be used in combination with one or more compounds selected from the group consisting of:

1) interferons such as PEGylated rIFN-alpha 2b (PEG-Intron), PEGylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon Alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, Suvaline), Interferon Alphacon-1 (Infergen), Interferon Alpha-n1 (Wellferon), Interferon Alpha-n3 (Alferon), Interferon-beta (Avonex , DL-8234), interferon-omega (omega DUROS, Biomed 510), Albu Interferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI- 005), PEG-Infergen, PEGylated Interferon Lambda (PEGylated IL-29), and Velerophone,

2) ribavirin and its analogues, such as ribavirin (Rebetol, Copegus), and taravivirin (Viramidine),

3) HCV NS3 protease inhibitors, such as bonded preverber (SCH-503034, SCH-7), telaprever (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-1230, MK-7009, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS-790052, BMS-605339, PHX-1766, AS-101, YH- 5258, YH5530, YH5531, and ITMN-191 (R-7227),

4) alpha-glucosidase 1 inhibitors, for example Celgosib (MX-3253), Miglitol, and UT-231B,

5) hepatoprotectants such as emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silybine, and MitoQ,

6) nucleotide or nucleotide inhibitors of HCV NS5B polymerase, For example, R1626, R7128 (R4048), IDX184, IDX-102, PSI-7851, BCX-4678, Valophytabin (NM-283), and MK-0608,

7) of the HCV NS5B polymerase, non-nucleoside inhibitors, e.g., Philippe Buber (PF-868554), ABT- 333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (Nesbuber), GSK625433, BILN- 1941, XTL-2125, and GS-9190,

8) HCV NS5A inhibitors such as AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,

9) TLR-7 agonists such as imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320,

10) cyclophylline inhibitors such as DEBIO-025, SCY-635, and NIM811,

11) HCV IRES inhibitors, for example MCI-067,

12) pharmacokinetic enhancers such as BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and Loxythromycin,

13) Other drugs for the treatment of HCV, for example, thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (birostat), PYN-17 (Altilex), KPE02003002, ill Tilon (CPG-10101), GS-9525, KRN-7000, Cibasir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, Tarbasin, EHC- 18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, and VX-497 (Marymethodive)

14) mevalonate decarboxylase antagonists such as statins, HMGCoA synthase inhibitors (eg himegluzin), squalene synthesis inhibitors (eg zaragozic acid);

15) angiotensin II receptor antagonists such as losaltan, irbesaltan, olmesaltan, candesaltan, valsaltan, telmisaltan, eprosaltan;

16) angiotensin-converting enzyme inhibitors, such as captopril, jofenopril, enalapril, ramipril, quinapril, perindopril, risinopril, benazepril, fosinopril;

17) other anti-fibrillating agents, for example amyloid and

18) endothelin antagonists, such as bosentan and ambrisentan.

In yet another embodiment, the present application relates to a compound of the invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient. Disclosed is a pharmaceutical composition comprising in combination.

According to the present invention, the therapeutic agent used in combination with the compound or composition of the present invention may be any agent having a therapeutic effect when used in combination with the compound of the present invention. For example, the therapeutic agent used in combination with a compound or composition of the invention may be an interferon, ribavirin or analogue thereof, an HCV NS3 protease inhibitor, an NS5a inhibitor, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a mevalonate dekar Carboxylase antagonists, antagonists of the Lenin-Angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR -7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers or other drugs to treat HCV; Or mixtures thereof.

More specifically, the compositions of one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of:

1) interferons such as PEGylated rIFN-alpha 2b (PEG-Intron), PEGylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon Alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, Suvaline), Interferon Alphacon-1 (Infergen), Interferon Alpha-n1 (Wellferon), Interferon Alpha-n3 (Alferon), Interferon-beta (Avonex , DL-8234), interferon-omega (omega DUROS, Biomed 510), Albu Interferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI- 005), PEG-Infergen, PEGylated Interferon Lambda (PEGylated IL-29), and Velerophone,

2) ribavirin and its analogues, such as ribavirin (Rebetol, Copegus), and taravivirin (Viramidine),

3) HCV NS3 protease inhibitors, such as bonded preverber (SCH-503034, SCH-7), telaprever (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-1230, MK-7009, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS-790052, BMS-605339, PHX-1766, AS-101, YH- 5258, YH5530, YH5531, and ITMN-191 (R-7227),

4) alpha-glucosidase 1 inhibitors, for example Celgosib (MX-3253), Miglitol, and UT-231B,

5) hepatoprotectants such as emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silybine, and MitoQ,

6) nucleotide or nucleotide inhibitors of HCV NS5B polymerase, For example, R1626, R7128 (R4048), IDX184, IDX-102, PSI-7851, BCX-4678, Balopidisitibine (NM-283), and MK-0608,

7) of the HCV NS5B polymerase, non-nucleoside inhibitors, e.g., Philippe Buber (PF-868554), ABT- 333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (Nesbuber), GSK625433, BILN- 1941, XTL-2125, and GS-9190,

8) HCV NS5A inhibitors such as AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,

9) TLR-7 agonists such as imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320,

10) cyclophylline inhibitors such as DEBIO-025, SCY-635, and NIM811,

11) HCV IRES inhibitors, for example MCI-067,

12) pharmacokinetic enhancers such as BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and Loxythromycin,

13) Other drugs for the treatment of HCV, for example, thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (birostat), PYN-17 (Altilex), KPE02003002, ill Tilon (CPG-10101), GS-9525, KRN-7000, Cibasir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, Tarbasin, EHC- 18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, and VX-497 (Marymethodive)

14) mevalonate decarboxylase antagonists such as statins, HMGCoA synthase inhibitors (eg himegluzine), squalene synthesis inhibitors (eg Zaragoza acid);

15) angiotensin II receptor antagonists such as losaltan, irbesaltan, olmesaltan, candesaltan, valsaltan, telmisaltan, eprosaltan;

16) angiotensin-converting enzyme inhibitors, such as captopril, jofenopril, enalapril, ramipril, quinapril, perindopril, risinopril, benazepril, fosinopril;

17) other anti-fibrillating agents, for example amyloid and

18) endothelin antagonists, such as bosentan and ambrisentan.

In yet another embodiment, the present application provides a combination medicament comprising:

a) a first pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, or ester thereof; And

b) HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogues, NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophylline inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs to treat HCV, And at least one additional therapeutic agent selected from the group consisting of a combination thereof.

Combinations of the compounds of Formulas I-III and IV-VI and additional active therapeutic agents may be selected to treat patients infected with HCV and other conditions such as HIV infection. Thus, the compounds of formulas I-III and IV-VI may include one or more compounds useful for the treatment of HIV, such as HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptases, HIV nucleosides of reverse transcriptases. Inhibitors, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 prothiase inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin Inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs to treat HCV.

More specifically, one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of: 1) HIV protease inhibitors such as amprenab, atazanaber, force cancer Prenaber, Indiana, Lopinaber, Ritonaber, Lopinaber + Litonaber, Nelpinaber, Saquinaber, Tipranaber, Brecanaver, Darunabern, TMC-126, TMC-114, Mozena (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100, 2) HIV non-nucleoside inhibitors, e.g., Capra fishy, emitter fishy, DE irregularities Dean, efavirenz, nevirapine, (+) color play leads a, Et la fishy, GW5634, DPC-083, DPC -961 , DPC-963, MIV-150, and TMC-120, TMC-278 (Lilfivirin), Epavirens, BILR 355 BS, VRX 840773, UK-453,061, RDEA806, 3) HIV nucleoside inhibitors of reverse transcriptases, For example , leadership Dean, Emtricitabine, Didanosine, Stavudine, Jalcitabine, Lamivudine, Avacarver, Amdoxosorber, Elbusitabine, Allobudine, MIV-210, Receiver (± FTC), D-d4FC, Emtricitabine, Phosphazide, pozivudine tidoxyl, posalvudine tidoxyl, apricyvin (AVX754), amtoxosorber, KP-1461, abacaber + lamivudine, abacaber + lamivudine + zidovudine, zidobudine + lamivudine, 4) reverse transcription HIV nucleotide inhibitors of the enzyme, for example, tenofovir member, tenofovir member disoproxil fumarate + emtricitabine, tenofovir member disoproxil fumarate + M tricyclic efavirenz the turbine +, and O depot member, 5 ) HIV integrase inhibitors , for example curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicafeoylquinic acid, derivatives of 3,5-dicafeoylquinic acid, aurintricarboxylic acid , Derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, phenethyl caffeic acid Derivatives of esters, tripostin, derivatives of tripostin, quercetin, derivatives of quercetin, S-1360, Gintheber (AR-177), L-870812, and L-870810, MK-0518 (raltegravir), BMS- 707035, MK-2048, BA-011, BMS-538158, GSK364735C, 6) gp41 inhibitors, such as Enfuvertide, Cifuvertide, FB006M, TRI-1144, SPC3, DES6, Locus gp41, CovX, and REP 9, 7) CXCR4 inhibitors such as AMD-070, 8) entry inhibitors such as SP01A, TNX-355, 9) gp120 inhibitors such as BMS-488043 and BlockAide / CR, 10) G6PD and NADH- oxidase inhibitors, e.g., a Municipal tin, 10) CCR5 inhibitors, e.g., Oh although Plastic, non-Cri though, INCB9471, PRO-140, INCB15050, PF-232798, CCR5mAb004, and do though, 11) interferons such as PEGylated rIFN-alpha 2b, PEGylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, inferzen, levif, lacteron , AVI-005, PEG-Infergen, PEGylated IFN-beta, light Old interferon alpha, peron, leaferon, intermax alpha, r-IFN-beta, infergen + actinib, IFN-omega with DUROS, and albuferon, 12) ribavirin analogs, such as levitol, cofe Goose, VX-497, and viramidine (taribavirin) 13) NS5a inhibitors such as A-831, A-689 and BMS-790052, 14) NS5b polymerase inhibitors such as NM-283, Valophytibine, R1626, PSI-6130 (R1656), IDX184, PSI-7851, HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, and XTL- 2125, 15) NS3 protease inhibitors, for example SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN-2065, 16) alpha-glucosidase 1 inhibitors, eg For example, MX-3253 (Cellgossie) and UT-231B, 17) hepatoprotectants such as IDN-6556, ME 3738, MitoQ, and LB-84451, 18) non-nucleoside inhibitors of HCV, For example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives, 19) HCV Other drugs for treatment, for example, Jaxin, Nitasoxanide (Alinea), BIVN-401 (Virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Babituximab, o Glupanide, PYN-17, KPE02003002, Actilon (CPG-10101), KRN-7000, Cibasir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, Tarvacin, EHC-18 And NIM811, 19) pharmacokinetic enhancers such as BAS-100 and SPI452, 20) RNAse H inhibitors such as ODN-93 and ODN-112, 21) other anti-HIV agonists such as , VGV-1, PA-457 (Baby Rimat), Ampligen, HRG214, Cytoline, Polymoon, VGX-410, KD247, AMZ 0026, CYT 99007, A-221 HIV, BAY 50-4798, MDX010 ( Iplimumab), PBS119, ALG889, and PA-1050040.

It is also possible to combine any of the compounds of the invention into a unit dosage form for simultaneous or sequential administration to a patient with one or more other active therapeutic agents. The combination therapy may be administered as a simultaneous or sequential administration schedule. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration of a compound of the present invention with a therapeutic agent that is one or more other active agents generally provides a therapeutically effective amount of a compound of the present invention and one or more other active therapeutic agents, Refers to simultaneous or sequential administration of a compound and one or more other active therapeutic agents.

Co-administration is seen within seconds, minutes or hours of administration of a unit dose of a compound of the invention, eg, administration of one or more other active therapeutic agents, before or after administration of a unit dose of one or more other active therapeutic agents. Administration of a compound of the invention. For example, a unit dose of a compound of the invention is administered first, followed by administration of a unit dose of one or more other active agents within a few seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present invention within a few seconds or a few minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed by a unit dose of one or more other active therapeutic agents after a period of several hours (e.g., 1-12 hours) have. In other cases, it may be desirable to first administer a unit dose of one or more other active therapeutic agents, and thereafter administer a unit dose of a compound of the invention after a period of several hours (e.g., 1-12 hours) .

The combination therapy may provide "synergism" and "synergy", ie, the effect achieved when the active ingredients are used together is greater than the sum of the effects of using the compounds individually. The synergistic effect can be obtained when the active ingredient is: (1) co-formulated in the combined preparation and administered or delivered at the same time; (2) delivered alternately or simultaneously as separate agents; Or (3) by any other dosage regimen. When delivered in an alternation therapy, a synergistic effect can be obtained when the compound is administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during an alternation therapy, the effective dose of each active ingredient is administered sequentially, i. E., Serially, while in combination therapy an effective dosage of two or more active ingredients is administered together. The synergistic anti-viral effect refers to an antiviral effect greater than the predicted pure additive effect of the individual compounds of the combination.

In yet another embodiment, the present application provides a method of inhibiting HCV polymerase in a cell, comprising: an effective amount of a compound of formulas I-III and IV-VI, or a cell infected with HCV, or Contacting with pharmaceutically acceptable salts, solvates, and / or esters thereof thereby inhibiting HCV polymerase.

In yet another embodiment, the present application provides a method of inhibiting HCV polymerase in a cell, comprising: an effective amount of a compound of formulas I-III and IV-VI, or a cell infected with HCV, or Contacting with a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional active therapeutic agent thereby inhibiting HCV polymerase.

In yet another embodiment, the present application provides a method of inhibiting HCV polymerase in a cell, comprising: an effective amount of a compound of formulas I-III and IV-VI, or a cell infected with HCV, or Pharmaceutically acceptable salts, solvates, and / or esters thereof, and one or more interferons, ribavirin or analogs thereof, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonates Decarboxylase antagonists, antagonists of the Lenin-Angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophylline inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs to treat HCV; Or contacting with at least one additional active therapeutic agent selected from the group consisting of mixtures thereof.

In yet another embodiment, the present application provides a method of treating HCV in a patient, comprising: a therapeutically effective amount of a compound of Formulas I-III and IV-VI, or a pharmaceutically acceptable thereof Administering possible salts, solvates, and / or esters to the patient.

In yet another embodiment, the present application provides a method of treating HCV in a patient, comprising: a therapeutically effective amount of a compound of Formulas I-III and IV-VI, or a pharmaceutically acceptable thereof Possible salts, solvates, and / or esters, and at least one additional active therapeutic agent to the patient, thereby inhibiting HCV polymerase.

In yet another embodiment, the present application provides a method of treating HCV in a patient, comprising: a therapeutically effective amount of a compound of Formulas I-III and IV-VI, or a pharmaceutically acceptable thereof Possible salts, solvates, and / or esters, and one or more interferons, ribavirin or analogs thereof, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, Antagonists of the Lenin-Angiotensin System, Other Anti-Fiberizing Agents, Endothelin Antagonists, Nucleoside or Nucleoside Inhibitors of HCV NS5B Polymerase, Non-Nucleoside Inhibitors of HCV NS5B Polymerase, HCV NS5A Inhibitors, TLR-7 Agonists , Cyclophylline inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs to treat HCV; Or administering to the patient at least one additional active therapeutic agent selected from the group consisting of mixtures thereof.

In yet another embodiment, the present application provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for the manufacture of a medicament for treating HCV infection in a patient. .

Compounds of the invention Metabolism

In addition, the in vivo metabolic products of the compounds described herein are within the scope of the present invention to the extent that such products are novel and unobvious compared to the prior art. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of compounds administered primarily by enzymatic processes. Accordingly, the present invention includes new and untouchable compounds produced by processes comprising contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof. Such products are typically isotopically labeled (e.g. ¹⁴ C or ³ H) to produce a compound of the invention, which can be used in animals such as parenterally detectable doses (e.g. greater than about 0.5 mg / kg). Administering to rats, mice, guinea pigs, monkeys or humans, leaving sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion product from urine, blood or other biological sample Confirmed by the process. These products are labeled and are readily isolated (others are isolated by the use of antibodies capable of binding to the epitope remaining in the metabolism). The metabolite structure is determined by conventional methods, such as MS or NMR analysis. In general, analysis of metabolites is done in the same manner as conventional drug metabolism studies widely known to those skilled in the art. Such conversion products are useful in diagnostic assays for the therapeutic administration of a compound of the invention, even if they do not have HCV polymerase inhibitory activity, unless they are found in vivo.

Prescriptions and methods for determining the stability of a compound in a surrogate gastrointestinal tract secretion are known. A compound is defined herein as stable in the gastrointestinal tract when less than about 50 mole percent of the protected group is deprotected in an alternative gastrointestinal tract or gastric juice by incubation at 37 占 폚 for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean it can not be hydrolyzed in vivo. The prodrugs of the present invention are typically stable in the digestive tract but can be substantially hydrolyzed into the parent drug, liver, or other metabolic organs, generally within the cell.

Example

Specific abbreviations and acronyms are used in describing the experimental details. Although most of these are understood by those skilled in the art, Table 1 includes a list of many acronyms and acronyms.

Table 1. List of abbreviations and acronyms.

Preparation of compounds

Compound 1

7-Bromo-2,4-bis-methylsulfanyl-imidazo [2,1-f] [1,2,4] triazine in dry THF (5 mL) To a suspension of (prepared according to WO2008116064, 500 mg, 1.72 mmol), BuLi (1.6 M in hexanes, 1.61 mL, 2.41 mmol) was added dropwise at -78 ° C. The suspension became a reddish brown solution after 5 minutes, after which a mixture of 1a (prepared according to WO 200631725, 675 mg, 1.81 mmol) and boron trifluoride etherate (2.40 mL, 1.89 mmol) in THF (5 mL) Dropwise to the mixture was added. After stirring at −78 ° C. for 2 h, saturated NH ₄ Cl was added to quench the reaction. The mixture is diluted with ethyl acetate; The organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give 1b as a rich yellow foam. (650 mg, 67%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (d, 2H), 8.03 (d, 2H), 7.81 (d, 1H), 7.59 (t, 1H), 7.45 (m, 3H), 7.36 (t , 2H), 6.40 (brs, 1H), 6.01 (dd, 1H), 4.78 (m, 2H), 4.60 (dd, 1H), 2.68 (s, 3H), 2.45 (s, 3H), 1.62 (d, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -167.5. MS = 585.1 (M + H ⁺ ).

To a solution of 1b (820 mg, 1.40 mmol) in dichloromethane (20 mL) was added boron trifluoride etherate (2 mL) and triethylsilane (2 mL) and stirred at rt for 16 h. Additional boron trifluoride etherate (1 mL) and triethylsilane (1 mL) were added and stirred for 7 days. The mixture was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was washed sequentially with water, saturated ammonium chloride and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give (EtOAc / hexane) to give 1c . (605 mg, 76%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.10 (d, J = 7.2 Hz, 2H), 8.00 (d, J = 7.2 Hz, 2H), 7.66 (s, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 5.78 (m, 2H), 4.80 ( dd, 1H), 4.68 (m, 1H), 4.60 (dd, 1H), 2.68 (s, 3H), 2.65 (s, 3H), 1.32 (d, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ −149.9. MS = 569.1 (M + H ⁺ ).

Compound 1c (635 mg, 1.12 mmol) was placed in a steel bomb reactor. Liquid ammonia (˜30 mL) was charged and the bomb reactor was tightly sealed. The mixture was stirred at 50 ° C. for 16 h. After cooling to room temperature, ammonia was evaporated and the solid residue was dissolved in THF (10 mL) and MeOH (10 mL). Sodium ethoxide (25% wt. 0.63 mL) was added and stirred at 60 ° C. for 40 minutes. The mixture was neutralized with AcOH and concentrated. The residue was purified by RP HPLC to give product 1d (175 mg, 48%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.21 (brs, 2H), 7.60 (s, 1H), 5.45 (brs, 1H), 5.43 (d, 1H), 4.91 (t, 1H), 3.92 (m, 1H), 3.76 (m, 2H), 3.57 (m, 1H), 2.44 (s, 3H), 1.09 (d, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ): δ −153.5. MS = 330.1 (M + H ⁺ ).

To a solution of 1d (175 mg, 0.53 mmol) in dichloromethane (11 mL) was added MCPBA (370 mg, ˜1.5 mmol) and stirred at rt for 16 h. The mixture was concentrated to give crude 1e which was used without purification for the next reaction. MS = 362.0 (M + H ⁺ ).

Compound 1e (obtained from the previous reaction) was placed in a steel bomb reactor. Liquid ammonia (˜30 mL) was charged and the bomb reactor was tightly sealed. The mixture was stirred at 115 ° C. for 3 days. After cooling to room temperature, ammonia was evaporated. The solid residue was purified by RP HPLC to give compound 1 (105 mg, 66% in two steps). ¹ H NMR (400 MHz, D ₂ O): δ 7.31 (s, 1H), 5.43 (d, J = 25.2 Hz, 1H), 4.07 (dd, J = 9.6, 23.2, 1H), 3.89 (m, 1H ), 3.83 (dd, J = 2.4, 12.8 Hz, 1H), 3.67 (dd, J = 4.8, 12.8 Hz, 1H), 1.05 (d, J = 22.8 Hz, 3H). ¹⁹ F NMR (376 MHz, D ₂ O): δ -153.5. MS = 299.2 (M + H ⁺ ).

Compound 2

To a solution of compound 1 (82 mg, 0.28 mmol) in water (340 mL) add adenosine deaminase (A5168 bovine spleen type IX from Sigma-Aldrich, 0.125 units per mL of water) and stir at 37 ° C. for 4 h It was. The mixture was concentrated and purified by RP HPLC to give compound 2 (56 mg, 68%). ¹ H NMR (400 MHz, D ₂ O): δ 7.35 (s, 1H), 5.46 (d, J = 25.2 Hz, 1H), 4.08 (dd, J = 9.6, 22.6, 1H), 3.93 (m, 1H ), 3.87 (dd, J = 2.4, 12.8 Hz, 1H), 3.71 (dd, J = 4.8, 12.8 Hz, 1H), 1.12 (d, J = 23.2 Hz, 3H). ¹⁹ F NMR (376 MHz, D ₂ O): δ -153.4. MS = 300.2 (M + H ⁺ ).

Compound 3

TMSCl in a suspension of 7-bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-ylamine (prepared according to WO2007056170, 2.13 g, 10 mmol) in THF (20 mL) (2.66 mL, 21 mmol) was added and stirred under argon at rt for 16 h. After cooling to −78 ° C., a solution of BuLi in hexanes (1.6 M, 21 mL, 33 mmol) was added dropwise. The mixture was stirred at the same temperature for 1 hour. A solution of 1a (prepared according to WO 200631725, 4.46 g, 12 mmol) in THF (10 mL) was then added. After stirring at −78 ° C. for 2 h, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 3b as a yellow solid (1.6 g, 32%). MS = 507.1 (M + H ⁺ ).

Chlorotrimethylsilane  1,2- Vis - [( Chlorodimethyl ) Silanyl ] Alternative Procedure for Compound 3b Using Ethane

In a suspension of 7-bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-ylamine (500 mg, 2.35 mmol) in THF (6.5 mL), BuLi ( 1.6 M in hexanes, 1.6 mL) was added. After 30 minutes, a solution of 1,2-bis-[(chlorodimethyl) silanyl] ethane (538 mg, 2.4 mmol) in THF (1.2 mL) was added. After 45 minutes, BuLi (1.6 mL) was added. After an additional 30 minutes, BuLi (1.5 mL) was added. After 30 minutes, a solution of 1a (610 mg, 1.64 mmol) in THF (2 mL) was then added dropwise. The resulting mixture was stirred at -78 ° C for 2 hours under argon. Acetic acid (0.7 mL) was added dropwise to quench the reaction, followed by addition of saturated ammonium chloride. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 3b (320 mg, 40%). The starting la was also recovered from the chromatography (350 mg).

To a solution of compound 3b (50 mg, 0.1 mmol) and TMSCN (67 uL, 0.5 mmol) in acetonitrile (2.0 mL) was added TMSOTf (91 uL, 0.5 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then at 65 ° C. for 3 days. The reaction was quenched with saturated NaHCO ₃ at room temperature and diluted with CH ₃ CO ₂ Et. The organic phase was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC (acetonitrile / water) to afford the desired compound 3c (28 mg, 54%). MS = 516.1 (M + H ⁺ ).

To a solution of 3c (56 mg, 0.11 mmol) in methanol (1.2 mL) was added ammonium hydroxide (28% in water, 0.8 mL) and stirred at rt for 16 h. The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile) to give compound 3 (20 mg, 60%). ¹ H NMR (500 MHz, D ₂ O): δ 7.88 (s, 1H), 7.07 (d, 1H), 6.92 (d, 1H), 4.17 (m, 2H), 4.04 (dd, 1H), 3.87 ( dd, 1 H), 1.15 (d, 3 H). MS = 308.1 (M + H ⁺ ).

Compound 4

To a solution of compound 3b (60 mg, 0.12 mmol) in methanol (0.5 mL) was added ammonium hydroxide (28% in water, 0.5 mL) and stirred at rt for 16 h. The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile) to give compound 4 (25 mg, 70%). MS = 299.1 (M + H ⁺ ).

Compound 5

1b to 1c Compound 3b was converted to compound 5a by a procedure similar to the conversion. Compound 5a was then converted to compound 5 by a procedure similar to the conversion of 3c to 3 . ¹ H NMR (300 MHz, D ₂ O): δ 7.68 (s, 1H), 6.75 (d, J = 4.5 Hz, 1H), 6.65 (d, J = 4.5 Hz, 1H), 5.65 (d, J = 25.2 Hz, 1H), 3.95 (m, 3H), 3.74 (dd, 1H), 0.98 (d, J = 22.8 Hz, 3H). ¹⁹ F NMR (282 MHz, D ₂ O): δ -154.2. MS = 283.2 (M + H ⁺ ).

Nucleoside Triphosphate  General procedure for manufacturing:

Fill a pear-shaped flask (5-15 mL) with nucleosides (˜20 mg). Trimethyl phosphate (0.5-1.0 mL) is added. The solution is cooled in an ice-water bath. POCl ₃ (40-45 mg) is added and stirred at 0 ° C. until the reaction is complete (1-4 hours; reaction progress is monitored by ion-exchange HPLC; take ˜3 μL of reaction mixture and give 1.0 Analytical samples are prepared by dilution with M Et ₃ NH ₂ CO ₃ (30-50 μL)). A solution of pyrophosphate-Bu ₃ N (250 mg) and Bu ₃ N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) is then added. The mixture is stirred at 0 ° C. for 0.3-2.5 hours, after which the reaction is quenched with 1.0 M Et ₃ NH ₂ CO ₃ (˜5 mL). The resulting mixture is stirred while warming to room temperature for an additional 0.5-1 hour. The mixture is concentrated to dryness, re-dissolved in water (4 mL) and purified by ion exchange HPLC. Fractions containing the desired product are concentrated to dryness, dissolved in water (˜5 mL), concentrated to dryness and again dissolved in water (˜5 mL). NaHCO ₃ (30-50 mg) is added and concentrated to dryness. The residue is dissolved in water and concentrated again to dryness. This process is repeated 2-5 times. The residue is then treated with C-18 HPLC purification to afford the desired product as sodium or salt. Alternatively, the crude reaction mixture is first treated with C-18 HPLC and then by ion exchange HPLC purification to afford the desired product as triethylammonium salt.

compound TP -One

Compound TP- 1 was prepared by the above general method using compound 2 as starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.44 (s, 1H), 5.45 (d, J = 25.5 Hz, 1H), 4.0-4.4 (m, 4H), 3.05 (m, N CH ₂ CH ₃ ), 1.10 (m, NCH ₂ CH ₃ and 2′- C — CH ₃ ). ³¹ P NMR (121.4 MHz, D ₂ O): δ -9.5 (d, J = 22.1 Hz), -11.0 (d, J = 19.9 Hz), -23.2 (t, J = 23.0 Hz). ¹⁹ F NMR (282 MHz, D ₂ O): δ -153.9.

compound TP -2

Compound TP- 2 was prepared by the above general method using compound 3 as starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.82 (s, 1H), 7.03 (d, 1H), 6.90 (d, 1H), 4.1-4.4 (m, 4H), 3.05 (m, N CH ₂ CH ₃ ), 1.10 (m, NCH ₂ CH ₃ and 2′- C — CH ₃ ). ³¹ P NMR (121.4 MHz, D ₂ O): δ -10.7 (d, J = 19.5 Hz), -11.3 (d, J = 19.8 Hz), -23.1 (t, J = 19.8 Hz).

compound TP -3

Compound TP- 3 was prepared by the above general method using compound 5 as starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.73 (s, 1H), 6.87 (d, 1H), 6.82 (d, 1H), 5.71 (d, J = 24.6 Hz, 1H), 4.0-4.4 ( m, 4H), 3.05 (m , N CH 2 CH 3), 1.14 (m, NCH 2 CH 3), 1.00 (d, J = 22.8 Hz, 3H, 2'- C - CH 3). ³¹ P NMR (121.4 MHz, D ₂ O): δ -8.1 (d, J = 22.1 Hz), -11.1 (d, J = 19.9 Hz), -22.7 (t, J = 23.0 Hz). ¹⁹ F NMR (282 MHz, D ₂ O): δ -155.6. MS = 520.9 (M-H ⁺ ).

compound TP -8a

Compound TP- 8a was prepared by the above general method using compound 8 as starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.95 (s, 1 H), 7.68 (s, 1 H), 5.63 (d, J = 25.5 Hz, 1 H), 4.0-4.4 (m, 4H), 3.05 ( m, N CH ₂ CH ₃ ), 1.10 (m, NCH ₂ CH ₃ and 2′- C — CH ₃ ). ³¹ P NMR (121.4 MHz, D ₂ O): δ -9.20 (d, J = 22.1 Hz), -11.07 (d, J = 19.9 Hz), -23.82 (t, J = 23.0 Hz). ¹⁹ F NMR (282 MHz, D ₂ O): δ -155.9. MS = 521.6 (M-H ⁺ ).

Nucleoside Prodrug  General Procedure for Manufacturing (Method A):

To a solution of nucleoside (0.1 mmol) in trimethylphosphite (1.0 mL) was added 1H -tetrazole (42 mg, 0.6 mmol) and then 2,2-dimethyl-thiopropionic acid S- (2- { Diisopropylamino- [2- (2,2-dimethyl-propionylsulfanyl) -ethoxy] -phosphanyloxy} -ethyl) ester (Made according to J. Med . Chem ., 1985 , 38 , 3941, 90 mg, 0.2 mmol) was added. After stirring for 2 hours, 30% hydrogen peroxide in H ₂ O (140 μL) was added to the mixture. The mixture was then allowed to warm up to room temperature. After stirring for 30 minutes, the reaction was quenched by the addition of 1 M Na ₂ S ₂ O ₃ in H ₂ O (5 mL). The organic layer was washed with saturated aqueous Na ₂ CO ₃ (10 mL × 2), brine and concentrated in vacuo. The residue was purified by RP-HPLC (MeCN-H ₂ O gradient) to give prodrug A.

Compound A-1

Compound A-1 was prepared by Method A using Compound 1 as starting material. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.42 (s, 1H), 5.47 (d, J = 26.4 Hz, 1H), 4.95 (brs, 2H), 4.59 (m, 2H), 4.35 (m, 1H , 4'-H), 4.18 (m, 2H, 5'-H), 4.10 (m, 4H), 3.13 (m, 4H), 1.24 (d, 3H), 1.22 (s, 9H), 1.19 (d , 9H). ³¹ P NMR (161.9 MHz, CDCl ₃ ): δ −1.26. MS = 667.1 (M + H ⁺ ).

Nucleoside Prodrug  General Procedure for Manufacturing (Method B):

Non-limiting examples of mono-phosphoamidate prodrugs comprising the present invention can be prepared according to General Scheme 1.

Scheme 1

The general procedure involves the reaction of an amino acid ester salt 19b , eg, HCl salt, with aryl dichlorophosphate 19a in the presence of about 2 to 10 equivalents of a suitable base to obtain the phosphoramidate 19c . Suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DABCO, and substituted amidines such as DBN and DBU. Tertiary amines are particularly preferred. Preferably, the product of each step is used directly in subsequent steps without recrystallization or chromatography. Examples of specific, but non-limiting, 19a , 19b , and 19c can be found in WO 2006/121820, which is incorporated herein by reference in its entirety. Nucleoside base 19d reacts with the phosphoramidate 19c in the presence of a suitable base. Suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DABCO, and substituted amidines such as DBN and DBU. Product B can be isolated by recrystallization and / or chromatography.

Compound B-1

Phenyl ethoxyalaninyl phosphorochlorate (124 mg, 0.42 mmol; prepared according to McGuigan et al, J. Med . Chem . 1993 , 36 , 1048-1052) was prepared in compound 3 in anhydrous trimethyl phosphate (0.8 mL). (20 mg, 0.065 mmol) and N -methylimidazole (42 μL, 0.52 mmol) are added to the mixture. The reaction mixture was stirred for 3 hours at room temperature, after which the reaction was quenched by addition of methanol. The methanol solvent is removed under reduced pressure. The residue was purified by reverse-phase HPLC and then by silica gel column chromatography (100% ethyl acetate) to give compound B- 1. (10 mg, 27%). ³¹ P NMR (121.4 MHz, CDCl ₃ ): δ -3.42, 3.77. MS = 563.0 (M + H ⁺ ), 561.0 (M-H ⁺ ).

Compound b-2

About 3.1 mmol of 4-chlorophenyl 2-propyloxyalaninyl phosphorochlorate (prepared according to McGuigan et al, J. Med . Chem . 1993 , 36 , 1048-1052) in about 3 mL anhydrous trimethyl phosphate To about 0.5 mmol of compound 3 and about 3.8 mmol of N -methylimidazole. The reaction mixture is stirred at room temperature for 1 to 24 hours and methanol is added to quench the reaction. The methanol solvent is removed under reduced pressure. The residue is purified by reverse-phase HPLC to give compound B-2 .

Compound b-3

Compound B- 3 was obtained by a similar procedure used for compound B-1 . ³¹ P NMR (121.4 MHz, CDCl ₃ ): δ -3.50, 3.76. MS = 577.2 (M + H ⁺ ).

Compound b-4

Compound B- 4 was obtained by a similar procedure used for compound B-1 . ³¹ P NMR (162 MHz, CD ₃ OD): δ 2.2. MS = 633.4 (M + H ⁺ ).

Compound B-5

B-5

Compound B- 5 was obtained by a similar procedure used for compound B-1 . ³¹ P NMR (162 MHz, CDCl ₃ ): δ 4.15, 4.27. MS = 549.3 (M + H ⁺ ).

Compound b-6

Compound B- 6 was obtained by a similar procedure used for compound B-1 . ³¹ P NMR (162 MHz, CDCl ₃ ): δ 3.50, 4.07. MS = 613.1 (M + H ⁺ ).

Compound b-7

Compound B-7 was obtained by a similar procedure used for compound B-1 using compound 5 as parent nucleoside. ³¹ P NMR (162 MHz, CDCl ₃ ): δ 3.37, 3.97. MS = 538.1 (M + H ⁺ ).

Compound B-8

Compound B-8 was obtained by a similar procedure used for compound B-1 using compound 5 as parent nucleoside. ³¹ P NMR (162 MHz, CDCl ₃ ): δ 3.69, 4.39. MS = 588.1 (M + H ⁺ ).

Nucleoside Prodrug  Alternative Procedures for Manufacturing (Method C):

CH ₂ Cl ₂ (46 mL, 0.3 M) and phenyl dichlorophosphate (2.1 mL, 13.8 mmoL, into a flask containing ethyl L -valine hydrochloride (2.5 g, 13.8 mmoL, 1 equiv) before cooling to −10 ° C. 1 equivalent) was added. After 10 minutes, TEA (3.8 mL, 13.8 mmoL, 1 equiv) was slowly added to the reaction mixture over 5 minutes. The reaction was allowed to proceed for 1 hour before adding p -nitrophenol (1.9 g, 13.8 mmoL, 1 equiv) to the reaction mixture followed by addition of TEA (3.8 mL, 13.8 mmoL, 1 equiv) over 5 minutes. The reaction was allowed to warm up and run for another 2 hours. The reaction was concentrated in vacuo and dissolved in diethyl ether (200 mL). Insoluble salts were filtered off and the filtrate was concentrated in vacuo. Flash column chromatography was performed using 4/1 Hex / EtOAc to provide a clear oil as C-1a .

¹ H NMR (400 MHz, CDCl ₃ ): d 8.21 (s, 2H), 7.41-7.20 (m, 7H), 4.22 -4.05 (m, 3H), 2.46 (s, 2H), 1.99 ( dd, J = 23.0, 20.1 Hz, 2H), 1.68 (s, 1H), 1.20 -1.05 (m, 8H).

³¹ P NMR (162 MHz, CDCl ₃ ): d -2.79 (dd, J = 28.0, 4.2 Hz).

LC MS m / z 422.99 [M + H ⁺ ].

Compound C-1

THF (1 mL, 0.2 M) and NMP (1 mL, 0.2 M) were added into a flask containing compound 3 (70 mg, 0.23 mmoL, 1 equiv) before cooling to 0 ° C. t- BuMgCl (560 μL, 2.5 equiv, 1M THF) was added slowly and stirred for 5 minutes before adding the phenolate C-1a (207 mg, 0.46 mmoL, dissolved in 2 equiv 500 μL THF). It was. The reaction mixture was warmed to 50 ° C. The reaction was monitored by LCMS. Once the reaction was complete, the mixture was then concentrated in vacuo and the residue was purified by HPLC to give compound C-1 .

¹ H NMR (400 MHz, CDCl ₃ ) d 7.87 (s, 1 H), 7.24-7.10 (m, 4H), 7.03 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 4.6 Hz, 1 H), 6.52 (d, J = 4.7 Hz, 1 H), 5.61 (s, 2H), 4.46 (dd, J = 24.0, 11.4 Hz, 2 H), 4.33-4.14 (m, 2H), 4.06 (dt, J = 7.2, 4.2 Hz, 2H), 3.82-3.70 (m, 1H), 3.63 (t, J = 10.6 Hz, 2H), 1.98 (s, 1H), 1.17 (dd, J = 14.8, 7.6 Hz, 3 H), 0.82 (dd, J = 22.8, 6.8 Hz, 6 H).

³¹ P NMR (162 MHz, CDCl ₃ ): d 5.11.

¹⁹ F NMR (376 MHz, CDCl ₃ ): d -152.28.

LC MS m / z 591.21 [M + H ⁺ ].

In a similar procedure to that exemplified for compound C-1a However, compound C-2a was obtained using methionine ester.

¹ H NMR (400 MHz, CDCl ₃ ) d 8.19 (s, 2 H), 7.44-7.03 (m, 7 H), 4.11 (s, 2 H), 3.81 (d, J = 44.5 Hz, 1H), 2.04 (s, 3H), 1.61 (s, 2H), 1.21 (d, J = 6.1 Hz, 2H), 1.01-0.65 (m, 4H).

³¹ P NMR (162 MHz, CDCl ₃ ) d −2.00 (d, J = 12.9 Hz).

LC MS m / z 455.03 [M + H ⁺ ].

Compound C-2

Compound C- 2 was obtained using compounds 3 and C-2a in a similar procedure to that exemplified for compound C-1 .

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (d, J = 15.8 Hz, 1H), 7.40-7.06 (m, 13H), 6.93 (d, J = 6.7 Hz, 1H), 6.70 (s, 1H) , 5.98 (s, 1H), 4.54 (dd, J = 21.6, 11.7 Hz, 2H), 4.32 (d, J = 12.0 Hz, 2H), 4.14 (dt, J = 13.0, 6.4 Hz, 4H), 2.44 ( d, J = 7.5 Hz, 2H), 2.00 (d, J = 16.2 Hz, 5H), 1.89 (s, 2H), 1.35-1.13 (m, 7H).

³¹ P NMR (162 MHz, CDCl ₃ ) d 4.12, 3.58.

¹⁹ F NMR (376 MHz, CDCl ₃ ) d -152.28 (s).

LC MS m / z 623.27 [M + H ⁺ ].

Compound C- 3a was obtained in a procedure similar to that exemplified for compound C-1a but with tryptophan esters.

¹ H NMR (400 MHz, CDCl ₃ ) d 8.18-8.03 (m, 3 H), 7.29-7.08 (m, 8 H), 7.36-6.98 (m, 3 H), 4.41-4.11 (m, 1 H) , 4.15-3.95 (m 2 H), 3.68-3.80 (m, 1 H), 3.33-3.04 (m, 2H), 1.06 -1.17 (m, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) d -2.87, -2.99.

LC MS m / z 510.03 [M + H ⁺ ].

Compound c-3

Compound C- 3 was obtained using compound 3 and C-3a in a similar procedure to that exemplified for compound C-1 .

¹ H NMR (400 MHz, CDCl ₃ ) d 8.27 (s, 1H), 7.84 (s, 1H), 7.47 (s, 1H), 7.36-6.77 (m, 11H), 6.57 (s, 1H), 4.40-3.96 (m, 6H), 3.20 (s, 4H), 2.60 (s, 1H), 1.30-1.04 (m, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) d 4.02, 3.75

¹⁹ F NMR (376 MHz, CDCl ₃ ) d -152.13.

LC MS m / z 678.32 [M + H ⁺ ].

Compound C- 4a was obtained by replacing the phenylalanine ester in a similar procedure to that exemplified for compound C-1a .

¹ H NMR (400 MHz, CDCl ₃ ) d 8.15 (t, J = 8.7 Hz, 2H), 7.43-7.11 (m, 10H), 7.04 (ddd, J = 11.4, 6.7, 2.9 Hz, 2H), 4.32 (ddd, J = 15.3, 11.3, 6.1 Hz, 4 H), 4.15-3.99 (m, 7 H), 3.74 (td, J = 11.0, 5.0 Hz, 8 H), 3.01 (d, J = 5.7 Hz , 2H), 1.17 (td, J = 7.1, 5.2 Hz, 2H).

³¹ P NMR (162 MHz, CDCl ₃ ) d -2.97, -2.99.

LC MS m / z 471.03 [M + H ⁺ ].

Compound C-4

Compound C- 4 was obtained using compounds 3 and C-4a in a similar procedure to that exemplified for compound C-1 .

¹ H NMR (400 MHz, CDCl ₃ ) d 7.92 (d, J = 13.2 Hz, 1H), 7.46-6.97 (m, 17H), 6.91 (s, 1H), 6.75 (s, 1H), 4.10 (dd, J = 29.6, 19.2 Hz, 8H), 2.97 (s, 3H), 1.32-1.05 (m, 7H).

³¹ P NMR (162 MHz, CDCl ₃ ) d 5.11.

¹⁹ F NMR (376 MHz, CDCl ₃ ) d -152.34 (s).

LC MS m / z 639.24 [M + H ⁺ ].

In a similar procedure to that exemplified for compound C-1a However, proline ester was used to give compound C-5a .

¹ H NMR (400 MHz, CDCl ₃ ) d 8.20 (d, J = 7.8 Hz, 2H), 7.45-7.08 (m, 7H), 4.37 (td, J = 8.0, 3.8 Hz, 2H), 4.17 -3.98 (m, 2H), 3.61-3.34 (m, 2H), 2.21-1.77 (m, 3H), 1.19 (td, J = 7.1, 3.8 Hz, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) d -3.92, -3.96.

LC MS m / z 420.98 [M + H ⁺ ].

Compound C-5

Compound C- 5 was obtained using compounds 3 and C-5a in a similar procedure to that exemplified for compound C-1 .

¹ H NMR (400 MHz, CDCl ₃ ) d 7.95 (d, J = 4.5 Hz, 1 H), 7.39-7.10 (m, 4 H), 6.92 (dd, J = 16.0, 4.6 Hz, 1 H), 6.69 (s, 1H), 6.03 (bs, 2H), 4.46-4.36 (m, 1H), 4.36-3.96 (m, 4H), 3.37 (d, J = 58.9 Hz, 2H), 2.26-1.66 (m, 4H), 1.39-1.12 (m, 8H).

³¹ P NMR (162 MHz, CDCl ₃ ) d 3.47, 2.75.

¹⁹ F NMR (376 MHz, CDCl ₃ ) d -152.36.

LC MS m / z 589.14 [M + H ⁺ ].

Compound C-6

Compound C- 6 was obtained using sulfone analogs of compounds 3 and C-1a in a similar procedure to that exemplified for compound C-1 .

¹ H NMR (400 MHz, CDCl ₃ ) d 7.93 (s, 1 H), 7.89 (s, 1 H), 7.35-7.01 (m, 5 H), 6.93 (d, J = 2.8 Hz, 1 H) , 6.58 (d, J = 2.8 Hz, 1H), 5.79 (bs, 2H), 4.30 (s, 6H), 4.11 (d, J = 7.0 Hz, 6H), 3.10-2.84 (m, 3H) , 2.75 (s, 3H), 2.54 (s, 6H), 1.31 -1.15 (m, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) d 3.39, 3.33.

¹⁹ F NMR (376 MHz, CDCl ₃ ) d -152.40

LC MS m / z 655.24 [M + H ⁺ ].

compound PD -A-8b

To a solution of compound 8 (200 mg, 0.71 mmol) in THF (1 mL) and NMP (1 mL) was added tert-butyl magnesium chloride (1.0 M in THF, 1.06 mL, 1.06 mmol) at 0 ° C. under an atmosphere of argon. It was. After 15 minutes, compound 30d-1 (280 mg, 0.71 mmol) was added as a solution in THF. After 5 minutes, the reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C., quenched with MeOH and concentrated. The reaction was purified by silica gel chromatography and then RP HPLC to give PD -A-8b (225 mg, 59%). ¹ H NMR (400 MHz, CDCl ₃ ): d 8.09 (two s, 1H), 7.54 (two s, 1H), 7.31-7.12 (m, 5H), 5.66 (dd, 1H), 4.52-4.45 ( m, 2H), 4.19-4.03 (m, 4H), 3.87-3.69 (m, 1H), 1.35-1.15 (m, 9H). ³¹ P NMR (161 MHz, CDCl ₃ ): d 4.14 (s), 3.55 (s).

LC / MS = 539 (M + H ⁺ ).

Retention time: 1.94 minutes

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX mass spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid

Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5% -100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100% -5% ACN, 3.55 min-4 min 5 % ACN.

Preparation of 30d-1

Compound 30d-1 was prepared from 30a by replacing alanine isopropyl ester hydrochloric acid with alanine ethyl ester hydrochloric acid with a material similar to 30d-2 .

Compound (S)- PD -A-8c

Substituted with 30d-1 to the (S) -30d-2 with similar materials and PD -A-8b to the compound (S) - to prepare a PD -A-8c. ¹ H NMR (400 MHz, CDCl ₃ ): d 8.14 (s, 1H), 7.60 (s, 1H), 7.1-7.3 (m, 5H), 5.66 (dd, 1H), 5.02 (m, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.1-4.3 (m, 2H), 3.98 (m, 1H), 3.78 (m, 1H), 3.18 (brs, 1H), 1.15-1.4 (m, 12H ). ³¹ P NMR (161 MHz, CDCl ₃ ): d 3.70 (s).

LC / MS = 553 (M + H ⁺ ).

Preparation of (S) -30d-2

Alanine isopropyl ester hydrochloride (7.95 g, 47.4 mmol) was suspended in dichloromethane (100 mL). Compound 31a (10 g, 47.4 mmol) was added. Triethylamine (13.2 mL, 95 mmol) was then added dropwise over a period of 15 minutes (internal reaction temperature; -10 ° C to -3 ° C). When the reaction was almost complete (by phosphorus NMR), p -nitrophenol (6.29 g, 45.0 mmol) was added in one portion as a solid. Triethylamine (6.28 mL, 45 mmol) was added to the resulting slurry over a period of 15 minutes. The mixture was then warmed up to room temperature. When the reaction was complete, MTBE (100 mL) was added. The white precipitate was removed by filtration. The filter cake was washed with MTBE (3 x 50 mL). The filtrate and washes were combined and concentrated. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexanes) to give compound 30d-2 as a 1: 1 ratio of diastereomeric mixture (14.1 g, 77%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.22 (2d, 2H), 7.2-7.4 (m, 7H), 5.0 (m, 1H), 4.09 (m, 1H), 3.96 (m, 1H), 1.39 (2d, 3 H), 1.22 (m, 6 H). MS = 409.0 (M + H ⁺ ), 407.2 (M-H ⁺ ).

compound 30d-2 of Separation of Two Diastereomers

The two diastereomers were separated by chiral column chromatography under the following conditions;

Column: Chiralpak IC, 2 x 25 cm

Solvent System: 70% Heptane and 30% Isopropanol (IPA)

Flow rate: 6 mL / min

Loading volume per run: 1.0 mL

Concentration of loading sample: 150 mg / mL in 70% heptane and 30% IPA

(S) -Compound 30d-2 : retention time 43 minutes ³¹ P NMR (162.1 MHz, CDCl ₃ ): δ -2.99 (s).

(R) -Compound 30d-2 : retention time 62 minutes ³¹ P NMR (162.1 MHz, CDCl ₃ ): δ -3.02 (s).

Alternatively, the two diastereomers were separated by crystallization under the following procedure;

Compound 30d-2 was dissolved in diethyl ether ( ˜10 mL / gram). With stirring, hexane was then added until the solution became cloudy. Seed crystals (˜10 mg / gram of compound 30d-2 ) were added to promote crystallization. The resulting suspension was gently stirred for 16 hours, cooled to ˜0 ° C., stirred for an additional 2 hours and filtered to collect crystalline material (35% -35% recovery yield of the crystalline material). The crystalline material contains ˜95% of (S) -compound 30d-2 and ˜5 % of (R) -compound 30d-2 . Re-crystallization gave 99% diastereomerically pure (S) -isomer.

By way of example, the following PD -A compounds are prepared by the above general procedure:

compound PD -A-8d

compound PD -A-8e

compound PD -A-8f

compound PD -A-8g

및

And

compound PD -A-8h

Nucleoside Prodrug  General Procedure for Manufacturing (Method D):

Non-limiting examples of 3′-O-acylated mono-phosphoamidate prodrugs comprising the present invention can be prepared according to General Scheme 2.

Scheme 2

The general procedure is PD -A (R ⁴ = OH) and carboxylic acid or the carboxylate, for example, acyl includes the reaction of a chloride or an acid anhydride, and this activation is well known in general to those skilled in the industry (Journal of Medicinal Chemistry , 2006 , 49, 6614 and Organic Letters , 2003 , 6, 807). When R ⁸ = NH ₂ , protection of the amino group may be necessary. Briefly, N, N -dimethylformamide dimethyl acetal (˜1.1 eq.) Is added to a solution of compound PD- A in acetonitrile (2 mL) and stirred at room temperature for 1 hour. After the protection of the 6-amino group is complete, the mixture is then concentrated to dryness. To the residue is added a dehydrating agent such as DCC (-4 eq.), Acetonitrile and carboxylic acid (-2 eq.). The mixture is stirred at room temperature for 24-48 hours. Water (0.2 mL) and trifluoroacetic acid (0.1 mL) are added at 0 ° C. and stirred at room temperature for 64 hours. Sodium bicarbonate is added at 0 ° C. The mixture is stirred at room temperature for 0.5 hours and filtered. The filtrate is concentrated and the residue is purified by silica gel column chromatography to give compound PD- B . If acyl chloride or acid anhydride is used, a suitable base such as triethylamine is added in place of the dehydrating agent.

compound PD -B-8i

In DCM (1.0 mL) To a solution of PD- A-8b (100 mg, 0.19 mmol) was added N, N -dimethylformamide-dimethylacetal (25 μL, 0.19 mmol) at room temperature under an atmosphere of argon. After 30 minutes, the reaction mixture was concentrated. The reaction was dissolved in DCM and concentrated. This process was repeated twice. The resulting residue was dissolved in THF (1.0 mL) and cooled to 0 ° C. under an atmosphere of argon. Triethylamine (79 μL, 0.57 mmol) and DMAP (5 mg, 0.04 mmol) were added to the solution. After 5 minutes, isobutyryl chloride (60 μL, 0.57 mmol) was added. After 10 minutes, the reaction was allowed to warm up to room temperature and stirred for 3 hours. The mixture was cooled to 0 ° C., quenched with 5% TFA solution in water and then allowed to stir at room temperature for 4 hours. The resulting mixture was extracted with ethyl acetate (3 ×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by RP HPLC (acetonitrile / water) to give PD -B-8i (71 mg, 61%). ¹ H NMR (400 MHz, CDCl ₃ ): d 8.17 (two s, 1H), 7.66 (two s, 1H), 7.34-7.14 (m, 5H), 5.69 (dd, 1H), 5.56-5.43 ( m, 1H), 4.55-4.01 (m, 5H), 3.79-3.69 (m, 1H), 2.70-2.64 (m, 1H), 1.37-1.17 (m, 15H). ³¹ P NMR (161 MHz, CDCl ₃ ): d 2.99 (s), 2.88 (s).

LC / MS = 609 (M + H ⁺ ).

Retention time: 2.21 minutes

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX mass spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid

Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5% -100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100% -5% ACN, 3.55 min-4 min 5 % ACN.

By way of example, the following PD -B compounds are prepared by the above general procedure:

compound PD -B-8j

compound PD -B-8k

compound PD -B-8l

compound PD -B-8m

compound PD -B-8n

, 및

, And

compound PD -B-8o

Nucleoside Prodrug  General Procedure for Manufacturing (Method E):

Non-limiting examples of 3 ', 5'-cyclic mono-phosphoamidate prodrugs comprising the present invention can be prepared according to General Scheme 3.

Scheme 3

Scheme 3 illustrates a chemical process that may be useful for the preparation of compound PD- C . Therefore, PD -A1 When Ar is substituted with an electron withdrawing group such as p -nitro or p -chloro group it is converted to PD- C in the presence of a base ( European Journal of Medicinal Chemistry , 2009 , 44, 3769). Alternatively, Compound 40 is Bioorganic and Is converted to Compound 41 according to Medicinal Chemistry Letters , 2007 , 17, 2452, which is then coupled with an amino acid ester salt to form PD- C .

compound PD -C-8q

Within DMSO The solution of PD- A-8p was treated with potassium t -butoxide (˜1 eq.) At room temperature and the resulting mixture was stirred for about 10 minutes to about 2 hours. The mixture was then cooled to 0 ° C. and neutralized with 1N HCl to pH 6. The mixture was purified by HPLC to give compound PD- C-8q .

Additionally, by way of example, the following PD -C compounds are prepared by the above general procedure:

compound PD -C-8r

compound PD -C-8s

및

And

compound PD -C-8t

.

.

compound PD -D-8u

Compound 8 is dissolved in PO (OMe) ₃ (0.1-0.5 M solution) and cooled to 0 ° C. under argon. POCl ₃ in this stirred solution (1.0-5.0 eq.) Is added dropwise and the reaction mixture is allowed to warm to room temperature for about 2-16 hours. The resulting solution is added dropwise to a rapidly stirred solution of acetonitrile and 0.05-0.5 M aqueous KOH. When the addition is complete, the solvent is removed under reduced pressure. The resulting residue is dissolved in water and purified by HPLC to give compound 41-1 .

A solution of compound 41-1 in DCM and PO (OMe) ₃ was prepared. Prepare and cool to 0 ° C. To this solution oxalyl chloride (1.0-5.0 eq.) Is added followed by the catalytic amount of DMF. The mixture is allowed to stir for about 10 minutes to about 1 hour. When activation is complete, a large volume of 2-propanol is added to the reaction mixture, allowed to stir and warmed to room temperature. The solvent is removed under reduced pressure and the resulting crude is purified by preparative HPLC to give compound PD- D-8u .

compound PD -E-8v

Compound PD- E-8v is prepared from compound 41-1 with a substance similar to compound PD- D-8u by replacing 2-propanol with 2-aminopropane.

compound PD -F-8w

compound PD -F-8w

Compound 18 is substituted with compound 8 to produce compound PD- F-8w , with a substance similar to compound 20 .

compound PD -G-8x

compound PD -G-8x

About 90 mM Compound 8 in THF Cool to about −78 ° C. and add about 2.2 to about 5 equivalents of t -butylmagnesium chloride (1 M in about THF). The mixture is warmed to about 0 ° C. for about 30 minutes and cooled back to about −78 ° C. A solution of ( 2S ) -2-{[chloro (1-phenoxy) phosphoryl] amino} ethyl isobutyrate (WO2008085508) (1 M in THF, about 2 equivalents) is added dropwise. Cooling is removed and the reaction is stirred for about 1 to about 24 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The extract is dried, evaporated and the residue is purified by chromatography to give compound PD-G-8x .

Compound 6

Compound 4 (about 0.04 mmol) and anhydrous MeOH (about 5 mL) are treated with acetic acid (about 5 mL) and the reaction is stirred overnight at room temperature. Saturated NaHCO ₃ is added to neutralize the reaction mixture and the crude material is purified using HPLC system (acetonitrile-H ₂ O) to give 6 .

Compound 7

To a dry, argon purged round bottom flask (50 mL) is added compound 3b (about 0.39 mmol) and anhydrous dichloromethane (about 10 mL). The flask is placed in a dry ice / acetone bath (˜-78 ° C.) and the solution is stirred for about 10 minutes. Add BF ₃ -Et ₂ O (about 0.10 mL) dropwise and stir the reaction for about 10 minutes. AlMe ₃ (about 1.16 mmol, 2.0 M in toluene) is then added. After a few minutes, the dry ice / acetone bath is removed and the reaction mixture is stirred at room temperature to about 45 ° C. over about 4 hours to about 4 days. A solution of pyridine (about 2 mL) in MeOH (about 10 mL) is added and the solvent is removed under reduced pressure. The crude material is purified by chromatography and treated with ammonium hydroxide in methanol at about room temperature for about 16 hours. The mixture is concentrated and the residue is purified by HPLC to give 7 .

Compound 8

7-bromoimidazo [1,2-f] [1,2,4] triazine-4-amine in THF ( ACS Medicinal Chemistry Obtained according to Letters , 2010 , 1, 286; 375 mg, 1.75 mmol) was added 1,2-bis-[(chlorodimethyl) silanyl] ethane (452 mg, 2.10 mmol) under an atmosphere of argon. After 60 minutes, the reaction was cooled to -78 ° C and BuLi (1.6 M in THF, 3.8 mL, 6.10 mmol) was added. After 10 min at −78 ° C., a solution of (1.0 mL) 1a (obtained according to WO 200631725, 782 mg, 2.10 mmol) in THF was added dropwise. The resulting mixture was stirred at -78 ° C for 1 hour. Saturated aqueous ammonium chloride was added and allowed to warm to 0 ° C. Water was added until all solids were soluble. The mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 8b (606 mg, 59%) as a yellow solid.

LC / MS = 508 (M + H ⁺ )

Retention time: 2.17-2.26 minutes

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX mass spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid

Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5% -100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100% -5% ACN, 3.55 min-4 min 5 % ACN.

Dichloroethane (10.0 mL) under my compound 8b (510 mg, 1.39 mmol) under argon atmosphere at 0 ℃ To a solution of triethylsilane added (1.77 mL, 11.09 mmol) and after _{BF 3 · Et 2 O (1.41} mL , 11.09 mmol) was added. The reaction mixture was stirred at 55 ° C. for 16 h. The reaction was cooled to 0 ° C. and quenched with saturated NaHCO ₃ (aq). The reaction was extracted with DCM and then extracted with EtOAc. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 8c . (453 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ): d 8.10-7.94 (m, 5H), 7.6-7.33 (m, 7H), 5.91 (dd, 1H), 5.78 (d, J = 24.6 Hz, 1H), 4.87 (dd, 1H), 4.70 (m, 1H), 4.58 (dd, 1H), 1.31 (d, J = 22.4 Hz, 3H).

LC / MS = 491 (M ⁺ ).

Retention time: 2.36 minutes

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX mass spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid

Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5% -100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100% -5% ACN, 3.55 min-4 min 5 % ACN.

To a solution of 8c (500 mg, 01.02 mmol) in (5.0 mL) THF was added lithium hydroxide (122 mg, 5.09 mmol) as a solution in H ₂ O (5.0 mL) and stirred at rt for 1 h. The reaction was cooled to 0 ° C. and neutralized with 1N HCl in water (5.1 mL). The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile) to give compound 8 (185 mg, 64%). ¹ H NMR (400 MHz, CD ₃ OD): d 7.97 (s, 1 H), 7.63 (s, 1 H), 5.54 (d, J = 24.8 Hz, 1 H), 4.03 (dd, 1H), 3.88 (m, 1H), 3.71 (dd, 1H), 1.80 (d, J = 22.1 Hz, 3H).

LC / MS = 284 (M + H ⁺ ).

Retention time: 1.06 minutes

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX mass spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid

Gradient: 0 min -0.1 min 5% ACN, 0.1 min -1.95 min 5% -100% ACN, 1.95 min -3.5 min 100% ACN, 3.5 min -3.55 min 100% -5% ACN, 3.55 min -4 min 5 % ACN.

Alternative Procedure for Compound 8

Compound 1e (crude obtained from the previous reaction step) was dissolved in EtOH. When the reaction was almost complete, excess sodium borohydride was added in portions. The mixture was neutralized with acetic acid. The mixture was concentrated and the solid residue was purified by silica gel column chromatography (0-10% MeOH / dichloromethane) to give compound 27 (210 mg, 50% in two steps).

Additional Alternative Procedures for Compound 8

Raney Ni (about 500 mg) was neutralized by washing with H ₂ O and added to a solution of 1d (about 100 mg) in ethanol (about 10 mL). The mixture was then heated to 80 ° C. until the reaction was complete. The catalyst was removed by filtration and the solution was concentrated in vacuo. The mixture was concentrated and the residue was purified by HPLC to give 8 .

Compound 9

PO (OMe) ₃ (1.5 mL, 0.25 M) was added to a flask containing Compound 3 (120 mg, 0.39 mmoL, 1 equiv) and cooled to 0 ° C. before addition of POCl ₃ (125 μL, 1.37 mmoL, 3.5 equiv) I was. The reaction mixture was allowed to stir for 5 hours before quenching the reaction with water. This was purified directly by HPLC to give the monophosphate compound 9 .

LC MS m / z 387.95 [M + H ⁺ ].

Compound 10

Add NMP (0.8 mL, 0.1 M) to a flask containing compound 9 (30 mg, 0.078 mmoL, 1 equiv) and then add TEA (43 μL) before adding chloromethylisopropyl carbonate (60 μL, 0.38 mmoL, 5 equiv) , 0.31 mmoL, 4 equiv), tetrabutylammonium bromide (25 mg, 0.078 mmoL, 1 equiv) was added. The reaction mixture was heated to 50 ° C. and allowed to stir overnight. This was purified directly by HPLC to give compound 10 .

¹ H NMR (400 MHz, CDCl ₃ ) d 7.98 (s, 1 H), 7.01 (d, J = 4.7 Hz, 1 H), 6.72 (d, J = 4.7 Hz, 1 H), 6.04 (bs, 2 H), 5.74-5.61 (m, 4H), 4.91 (ddt, J = 12.6, 9.4, 6.3 Hz, 2H), 4.64-4.28 (m, 4H), 1.37-1.19 (m, 15H).

³¹ P NMR (162 MHz, CDCl ₃ ) d -4.06.

¹⁹ F NMR (376 MHz, CDCl ₃ ) d -76.58, -151.95 TFA salt.

LC MS m / z 620.03 [M + H ⁺ ].

Compound 11

The solution of compound B-2 in DMSO is treated with about 3 molar equivalents of potassium t- butoxide for about 15 minutes to 24 hours. The reaction is quenched with 1N HCl and compound 11 is isolated by reverse-phase HPLC.

Compound 12

Compound 1b (about 1 mmol) is placed in a steel bomb reactor. The reactor is charged with liquid ammonia (about 30 mL) and the mixture is stirred at about 0 ° C. to 50 ° C. for about 16 hours. The ammonia is evaporated and the residue is purified to give 12a . A solution of 12a (about 100 mg) in ethanol (about 10 mL) is treated with Raney Ni (about 500 mg) neutralized by washing with H ₂ O. The mixture is then heated to about 35 to about 80 ° C. until the reaction is complete. The catalyst is removed by filtration and the solution is concentrated in vacuo. The mixture is concentrated and the residue is purified by HPLC to give 12b . TMSOTf (about 0.5 mmol) is added to a solution of compound 12b (about 50 mg) and TMSCN (about 0.5 mmol) in acetonitrile (about 2.0 mL) at about 0 ° C. The reaction mixture is stirred at room temperature for about 1 hour and then at 65 ° C. for about 3 days. The reaction is quenched with saturated NaHCO ₃ at room temperature and diluted with CH ₃ CO ₂ Et. The organic phase is separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by RP-HPLC and then dissolved in methanol (about 1 mL). Ammonium hydroxide (28% in water, about 0.8 mL) is added and the mixture is stirred at about room temperature for 16 hours. The mixture is concentrated and the residue is purified by RP HPLC to give 12 .

Compound 13

Compound 13 is prepared in the same manner as Compound 9 using compound 12 as starting material.

Compound 14

Compound 14 is prepared by treating Compound 13 with about 1 to about 5 equivalents of DCC in pyridine and heating the reaction to reflux for about 1 to about 24 hours. Compound 14 is isolated by conventional ion exchange and reverse-phase HPLC.

Compound 15

A solution of about 0.4 mmol of compound 14 in about 10 mL of DMF is treated with about 0.8 mmol of DIPEA and about 0.8 mmol of chloromethyl isopropyl carbonate (WO2007 / 027248). The reaction is heated to about 25 to about 80 ° C. for about 15 minutes to about 24 hours. The solvent is removed under vacuum and the residue is purified by HPLC to give compound 15 .

Compound 16

Compound 3 (about 0.22 mmoL) is dissolved in anhydrous pyridine (about 2 mL) and chlorotrimethylsilane (about 0.17 mL) is added. About 0 Stir at from about 1 to about 24 hours. Additional chlorotrimethylsilane (about 0.1 mL) is added and the reaction is stirred for about 1 to about 24 hours. 4.4'-dimethoxytrityl chloride (about 0.66 mmol) and DMAP (about 0.11 to about 0.22 mmol) are added sequentially. The mixture is stirred for about 1 to about 24 hours. A solution of TBAF (1.0 M, about 0.22 mL) in THF is added and the reaction is stirred for about 1 to about 24 hours. The mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is dried and concentrated. The residue is purified by chromatography to give compound 16 .

Compound 17

A mixture of about 1.25 mmol of compound 16 and about 1.9 mmol of triethylammonium 2- (2,2-dimethyl-3- (trityloxy) propanoylthio) ethyl phosphinate (WO2008082601) was added to anhydrous pyridine (about 19 mL). Pivaloyl chloride (about 2.5 mmol) from about -30 to about 0 Add dropwise at ° C and stir the solution for about 30 minutes to about 24 hours. The reaction is diluted with methylene chloride and neutralized with aqueous ammonium chloride (about 0.5 M). The methylene chloride phase is evaporated and the residue is dried and purified by chromatography to give compound 17 .

Compound 18

To a solution of about 0.49 mmol of compound 17 in anhydrous carbon tetrachloride (about 5 mL) is added dropwise benzylamine (about 2.45 mmol). The reaction mixture is stirred for about 1 to about 24 hours. The solvent is evaporated and the residue is purified by chromatography to give compound 18 .

Compound 20

A solution of about 2 mmol of compound 18 in methylene chloride (about 10 mL) is treated with a solution of aqueous trifluoroacetic acid (90%, about 10 mL). The reaction mixture is from about 25 to about 60 Stir at about 1 hour to about 24 hours. The reaction mixture is diluted with ethanol, the volatiles are evaporated and the residue is purified by chromatography to give 20 .

Compound 21

About 90 mM Compound 2 in THF About -78 Cool to C and add about 2.2 to about 5 equivalents of t -butylmagnesium chloride (about 1 M in THF). About 0 Warm at ca. for 30 min and again cool to ca.

A solution of ( 2S ) -2-{[chloro (1-phenoxy) phosphoryl] amino} propyl pivalate (WO2008085508) (1 M in THF, about 2 equivalents) is added dropwise. The cooling is removed and the reaction is stirred for about 1 to about 24 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The extract is dried, evaporated and the residue is purified by chromatography to give compound 21 .

Compound 22

22a

Compound 22a was obtained in a procedure similar to the procedure for the preparation of C-1a .

¹ H NMR (400 MHz, CDCl ₃ ) d 8.11 (d, J = 9.0 Hz, 2H), 8.02 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.42-7.25 (m , 4H), 7.21 (dt, J = 14.9, 5.5 Hz, 2H), 7.08 (t, J = 7.3 Hz, 2H), 5.17-5.03 (m, 2H), 4.99 (dd, J = 16.5 , 9.7 Hz, 2H), 3.44 (s, 1H), 3.35-3.21 (m, 2H), 3.19 (d, J = 9.2 Hz, 1H), 3.00-2.80 (m, 2H).

³¹ P NMR (162 MHz, CDCl ₃ ) d 4.27.

LC MS m / z 452.09 [M + H ⁺ ].

Compound 22b was obtained using compounds 3 and 22a in a procedure similar to the procedure for the preparation of C-1 .

¹ H NMR (400 MHz, CD ₃ OD) d 7.76 (d, J = 6.3 Hz, 1H), 7.38 (t, J = 8.2 Hz, 1H), 7.27-7.12 (m, 4H), 7.06-6.81 (m, 3H), 6.74 (dd, J = 4.6, 3.5 Hz, 1H), 4.95-4.79 (m, 1H), 4.35-3.90 (m, 4H), 3.23 (dt, J = 3.2, 1.6 Hz, 3H), 3.18-3.05 (m, 2H), 2.82 (dt, J = 14.7, 7.3 Hz, 2H), 1.15 (d, J = 22.4 Hz, 3H).

³¹ P NMR (162 MHz, CD ₃ OD) d 10.76, 10.71.

LC MS m / z 620.05 [M + H ⁺ ].

Compound 22

Ethanol (4 mL) was added to the flask containing 22b (50 mg, 0.08 mmoL, 1 equiv) followed by Pd (OH) ₂ (56 mg, 0.08 mmoL, 1 equiv) and ammonium formate (42 mg, 0.64 mmoL, 8 equivalents) was added. The reaction was heated to 80 ° C. for about 1 hour. Solids were removed by filtration and the material was purified by HPLC.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 10.72 (s, 1H), 7.91 (s, 1 H), 7.95-7.89 (bs, 2 H), 7.41 (d, J = 7.7 Hz, 1 H) , 7.26 (d, J = 8.1 Hz, 1H), 7.19-6.66 (m, 3H), 4.20-3.75 (m, 3H), 2.99 (dd, J = 16.5, 9.6 Hz, 2H), 2.89 -2.70 (m, 2H), 2.48-2.58 (m, 8H), 1.10 (d, J = 22.3 Hz, 3H).

³¹ P NMR (162 MHz, DMSO-d ₆ ) d 7.49.

¹⁹ F NMR (376 MHz, DMSO-d ₆ ) d -154.89.

LC MS m / z 530.21 [M + H ⁺ ].

Compound 23

Compound 3 (250 mg, 0.82 mmol) was dissolved in PO (OMe) ₃ (5 mL, 0.16 M) and cooled under argon to 0 ° C. POCl ₃ in this stirred solution (0.32 mL, 4.1 mmol) was slowly added dropwise and the reaction mixture was allowed to warm to room temperature for 16 h. The resulting solution was added dropwise to a rapidly stirred solution of acetonitrile (400 mL) and 0.08M aqueous KOH (300 mL). When the addition was complete, the reaction progress was confirmed by LCMS. When the reaction was complete, the solvent was removed under reduced pressure. The resulting solid residue was dissolved in water and purified by HPLC to give 140 mg of compound 23 (yield; 47%).

¹ H-NMR (400 MHz; CD ₃ OD) : d 8.15 (s, 1H), 7.40 (d, 1H; J = 4.8 Hz), 7.09 (d, 1H; J = 4.8 Hz), 4.64 (dd, 1H; J = 24 Hz, 7.2 Hz), 4.50-4.36 (m, 3H), 1.32 (d, 3H; J = 22 Hz).

¹⁹ F-NMR (376 MHz; CD ₃ OD) : d -153.11.

³¹ P-NMR (162 MHz; CD ₃ OD) : d -2.20.

MS [M + H ⁺ ] = 370.2.

Compound 24

A solution of compound 23 (7 mg, 0.02 mmol) and PO (OMe) ₃ (1 mL) in DCM (2 mL) was prepared and cooled to 0 ° C. Oxalyl-Cl (10 μL) was added to this solution followed by DMF (2 μL). The mixture was allowed to stir for 1 minute and then aliquots were removed and quenched in MeOH and subsequently confirmed by LCMS for activation. Continuous amounts of oxalyl-Cl (10 μL) and DMF (2 μL) were added until activation was complete. At this point, a large volume of 2-propanol (5 mL) was added to the reaction mixture, allowed to stir and warmed to room temperature. Once the reaction was complete, the solvent was removed under reduced pressure and the resulting crude was purified by preparative HPLC to give 5.5 mg of compound 24 . (Yield 70%).

¹ H-NMR (400 MHz; DMSO-d ₆ ) d 8.26 (br, 1H), 8.15 (br, 1H), 7.97 (s, 1H), 7.00 (d, 1H; J = 4.4 Hz), 6.88 (d, 1H; J = 4.4 Hz), 4.59-4.51 (m, 2H), 4.37-4.25 (m, 2H), 1.23 (d, 3H; J = 22.8 Hz).

¹⁹ F-NMR (376 MHz; CD ₃ OD) : d -151.72.

³¹ P-NMR (162 MHz; CD ₃ OD) : d -5.69.

MS [M + H ⁺ ] = 412.0.

Compound 25

Compound 25 was substituted with compound 24 from compound 23 . A similar material was prepared by substituting 2-propanol with heptyl ester of alanine (yield 5.3%).

^OneH-NMR (400 MHz; CD₃OD) d: 7.91 (s, 1H), 6.98 (d, 1H; J = 4.8 Hz), 6.92 (d, 1H; J = 4.8 Hz), 5.29 (dd, 1H; J = 24.4 Hz, 8.8 Hz), 4.66- 4.60 (m, 2H), 4.48-4.40 (m, 1H), 4.15-4.11 (m, 3H), 3.92 (dd, 1H; J = 9.6 Hz, 7.2 Hz), 1.67-1.64 (m, 3H), 1.40 -1.27 (m, 15H), 0.91-0.87 (m, 6H).

¹⁹ F-NMR (376 MHz; CD ₃ OD) : d -151.46.

³¹ P-NMR (162 MHz; CD ₃ OD) d 7.36.

MS [M + H ⁺ ] = 539.4.

Compound 26

Compound 26

Compound 26 is prepared from a compound 22 similar to the preparation of compound 10 .

Antiviral activity

Another aspect of the present invention is a method for inhibiting a viral infection, Comprising the step of treating a sample or individual suspected of requiring such inhibition with a composition of the invention.

Samples suspected of containing the virus within the context of the present invention Natural or anthropogenic substances such as living organisms; Tissue or cell culture; Biological samples such as blood, serum, urine, cerebrospinal fluid, tears, follicles, saliva, tissue samples, etc.; Laboratory samples; Food, water, or air samples; A biological product sample, such as an extract of a cell, particularly a recombinant cell that synthesizes a desired glycoprotein; And the like. Typically, the sample will be suspected of containing a virus infection, an organism that frequently leads to a pathogenic organism, such as a tumor virus. The sample may be contained in any medium including water and an organic solvent / water mixture. Samples include living organisms such as humans, and artificial materials, such as cell cultures.

If desired, the anti-viral activity of the compounds of the invention following application of the composition can be observed by any method, including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semi-quantitative methods that determine such activity are all considered. Representatively, one of the screening methods described above is applied, but any other method, such as observing the physiological characteristics of a living organism, is also applicable.

Antiviral activity of the compounds of the present invention can be measured using known standard screening protocols. For example, the antiviral activity of a compound can be measured using the following general protocol.

Cell-based Flavivirus  Immunodetection Assay

2x10 in Hams F-12 medium (A549 cells) or RPMI-1640 medium (BHK21 cells) trypsinized, counting BHK21 or A549 cells and supplemented with 2% fetal bovine serum (FBS) and 1% penicillin / streptomycin Dilute to ⁵ cells / mL. 2 × 10 ⁴ cells per well are dispensed in clear 96-well tissue culture plates and placed overnight at 37 ° C., 5% CO ₂ . The following day, the cells are infected with the virus again for 48 hours at 37 ° C. and 5% CO ₂ for 1 hour in the presence of various concentrations of test compound at an infection multiplicity (MOI) of 0.3. The cells are washed once with PBS and fixed with cold methanol for 10 minutes. After washing twice with PBS, the fixed cells are blocked with PBS containing 1% FBS and 0.05% Tween-20 for 1 hour at room temperature. The primary antibody solution (4G2) is then added for 3 hours at a concentration of 1:20 to 1: 100 in PBS containing 1% FBS and 0.05% Tween-20. The cells are washed three times with PBS and then incubated with horseradish peroxidase (HRP) -conjugated anti-mouse IgG (Sigma, 1: 2000 dilution) for 1 hour. After washing three times with PBS, 50 microliters of 3,3 ', 5,5'-tetramethylbenzidine (TMB) substrate solution (Sigma) is added to each well for 2 minutes. The reaction is stopped by adding 0.5 M sulfuric acid. The plate is read for viral load quantitation at 450 nm absorbance. After the measurement, the cells are washed three times with PBS and then incubated with propidium iodide for 5 minutes. The plates are read for cell number quantification in a Tecan Safire ^™ reader (here 537 nm, emission 617 nm). Dose response curves are plotted from the log of mean absorbance versus concentration of test compound. EC ₅₀ is calculated by non-linear regression. Positive controls such as N-nonyl-deoxynojirimycin can be used.

Cell-based Flavivirus  Cytopathic effect Assay

For testing for West Nile virus or Japanese encephalitis virus, BHK21 cells are trypsinized and diluted to a concentration of 4 × 10 ⁵ cells / mL in RPMI-1640 medium supplemented with 2% FBS and 1% penicillin / streptomycin. For testing for dengue virus, Huh7 cells are trypsinized and diluted to 4 × 10 ⁵ cells / mL concentration in DMEM medium supplemented with 5% FBS and 1% penicillin / streptomycin. 50 microliters of cell suspension (2 × 10 ⁴ cells) are dispensed per well in a 96-well optical bottom PIT polymer-based plate (Nunc). Cells are grown overnight at 37 ° C., 5% CO ₂ in culture medium, then West Nile virus (eg B956 strain) or Japanese encephalitis virus (eg Nakayama) at MOI = 0.3 in the presence of different concentrations of test compound Strain), or with dengue virus (eg DEN-2 NGC strain) at MOI = 1. The plate containing the virus and the compound is further incubated at 37 ° C., 5% CO ₂ for 72 hours. At the end of the incubation, 100 microliters of CellTiter-Glo ^™ reagent is added to each well. The contents are mixed for 2 minutes on an orbital shaker to induce cell degradation. The plate is incubated at room temperature for 10 minutes to stabilize the luminescence signal. Record the luminescence reading using a plate reader. Positive controls such as N-nonyl-deoxynojirimycin can be used.

Dengue  Antiviral Activity in Mouse Models of Infection.

Compounds are tested in vivo in a mouse model of dengue virus infection (Schul et al . J. Infectious Dis. 2007; 195: 665-74). 6 to 10 week old AG129 mice (B & K Universal Ltd, Hll, UK) are housed in individually ventilated cages. Mice are injected intraperitoneally with 0.4 mL TSV01 dengue virus 2 suspension. Blood samples are taken by retro orbital puncture under isoflurane anesthesia. Blood samples are collected to a final concentration of 0.4% in a tube containing sodium citrate and immediately centrifuged at 6000 g for 3 minutes to obtain plasma. Plasma (20 microliters) is diluted in 780 microliters RPMI-1640 medium and snap frozen in liquid nitrogen for plaque assay analysis. The remaining plasma is preserved for cytokine and NS1 protein level determination. Mice develop dengue virus hyperemia over several days and peak three days after infection.

For testing of antiviral activity, the compounds of the present invention may be used in vehicle fluids such as 10% ethanol, 30% PEG 300 and 60% D5W (5% dextrose in water; or 6N HCl (1.5 eq): 1N NaOH ( PH adjusted to 3.5): dissolved in 100 mM citrate buffer pH 3.5 (0.9% v / v: 2.5% v / v: 96.6% v / v) 36 6-10 week old AG129 mice Divide into 6 groups All mice are infected with dengue virus as described above (day 0) Group 1 starts twice day with 0.2 mg / kg of the compound of the invention twice a day (morning) on day 0 Once early and late in the evening) by oral co-administration of 200 mL / mouse (first dose just prior to dengue infection) Groups 2, 3 and 4 show 1 mg / kg, 5 mg / kg and 25 mg of the compound. / kg are each administered in the same manner Positive controls, such as (2R, 3R, 4R, 5R) -2- (2-amino-6-hydroxy-purin-9-yl) -5-hydroxymethyl-3 -Methyl-te La dihydro-furan-3,4-diol may be used, it is administered by oral administration of a force of 200 microliters / mouse the same way as the previous group and add the group treated with only vehicle fluid.

Approximately 100 microliter blood samples (anticoagulated with sodium citrate) are taken from the mice by retro-orbital puncture under isoflurane anesthesia on day 3 post infection. Plasma is obtained from each blood sample by centrifugation and snap frozen in liquid nitrogen for plaque assay analysis. Collected plasma samples are analyzed by plaque assay as described in Schul et al. Cytokines are also analyzed as described in Schul. NS1 protein levels are analyzed using the Platelia ^™ kit (BioRad Laboratories). Antiviral effects are shown by reduction of cytokine levels and / or NS1 protein levels.

Typically, a reduction of about 5-100 fold, more typically 10-60 fold, most typically 20-30 fold, of viremia is obtained with 5-50 mg / kg twice daily administration of a compound of the invention.

HCV IC ₅₀  decision

Assay Protocol: Following wild type or S282T (Migliaccio, et al, J. Biol . Chem . 2003 , 49164-49170; Klumpp, et al., J. Biol . Chem . 2006 , 3793-3799) mutant polymerase enzymes Used in Say. NS5b polymerase assay (40 μL) was added to 28 μL polymerase mixture (final concentration: 50 mM Tris-HCl, 10 mM KCL, 5 mM MgCl ₂ , 1 mM DTT, 10 mM EDTA, 4 ng / μL at pH 7.5). RNA template, and 75 nM HCV Δ21 NS5b polymerase) were added to the assay plate and then assembled by adding 4 μL of compound dilution. The polymerases and compounds were pre-incubated at 35 ° C. for 10 minutes prior to the addition of 8 μL of nucleotide substrate mixture (33 P-α-labeled competitive nucleotides at K _M and the remaining three nucleotides of 0.5 mM). The assay plate was covered and incubated at 35 ° C. for 90 minutes. The reaction was then filtered through a 96-well DEAE-81 filter plate via vacuum. The filter plate was then washed with multiple volumes of 0.125 M NaHPO ₄ , water, and ethanol under vacuum to remove unincorporated labels. Plates were then counted on TopCount to assess the level of product synthesis compared to background control. IC50 values are determined using the Prism fitting program.

Preferably, the compounds described herein inhibited NS5b polymerase with an IC ₅₀ of less than 1000 μM, more preferably less than 100 μM, and most preferably less than 10 μM _. For example, compound TP- 1 has an IC ₅₀ of 0.15 μM against both wild type HCV polymerase and the S282T mutant enzyme. Table II below shows triphosphate of 2'-methyl guanidine and (2R, 3R, 4R, 5R) -2- (4-aminopyrrolo [1,2-f] [1,2,4] triazine-7 -Yl) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyl-tetrahydrofuran-2-carbonitrile compared to both the wild type and the S282T mutant enzyme as compared to the activity obtained with triphosphate. Show the activity of TP- 1 and TP- 2 against. It was unexpected to replace the 2 'OH of the pyrrolo [1,2-f] [1,2,4] triazin-7-yl nucleoside with 2' F against the resistant S282T HCV mutant strain of the virus. To demonstrate activity.

HCV EC ₅₀  decision

Replicon cells were seeded in 96-well plates at a density of 8 × 10 ³ cells per well in 100 μL of culture medium excluding Geneticin. Compounds were serially diluted in 100% DMSO and then added to the cells at 1: 200 dilution to achieve a final concentration of 0.5% DMSO and a total volume of 200 μL. Plates were incubated at 37 ° C. for 3 days, then the culture medium was removed and cells were lysed in lysis buffer provided by Promega's Luciferase Assay System. According to the manufacturer's instructions, 100 μL of luciferase substrate was added to the lysed cells and luciferase activity was measured in the TopCount photometer. Preferably, the compounds described herein have an EC50 of less than 1000 μM, more preferably less than 100 μM, and most preferably less than 10 μM. The activity of representative compounds of Formula I is shown in Table III below.

Cytotoxicity of the compounds of the present invention can be determined using the following general protocol.

Metabolic Research:

Applicant has observed the monophosphate prodrug of a nucleoside analog having a nitrogen at position X ¹ can have an increased activity compared to the counterpart with the carbon in the X ¹ position. This difference in activity correlates with the amount of triphosphate analog that is active in the compound in the cell. This can be quantified by metabolic studies that quantify the intracellular concentration of the triphosphate analog. Higher intracellular concentrations of the triphosphate metabolite correlate with the prodrug with increased activity.

For example, with the prodrug compound PD- A-8b Comparison of the prodrug compound B-7 It shows increased activity when the X ¹ position is nitrogen. This can be observed in Table III, where the HCV EC ₅₀ for the compound (Compound PD- A-8b ) where the X ¹ position is nitrogen is given for Compound B-7 0.68 μM compared to 63-73 μM. Of the prodrug analog PD- A-8b Activation (to its triphosphate analog TP- 8a ) is 100 times greater than its prodrug counterpart B-7 (to its triphosphate analog TP- 3 ), wherein the X ¹ position is carbon, as can be seen in Table IV. It was found to be more effective in size.

Experiment:

Huh-luc / neo replicon cells containing HCV genotype 1b subgenomic replicon contain glutamax supplemented with 10% heat inactivated fetal bovine serum, penicillin-streptomycin, and G418 disulfate salt solution Was maintained in Dulbecco's modified Eagle's medium. Cells were transferred to 12 well tissue culture plates by trypsinization and grown to front culture (0.88 × 10 ⁶ cells / well). Cells were treated with 10 μM nucleosides, or 10 μM prodrug for 24 hours. After 24 hours, cells were washed twice with 2.0 mL very cold 0.9% sodium chloride saline. The cells were then scraped into 0.5 mL 70% methanol (MeOH) and frozen overnight to facilitate extraction of nucleotide metabolites. Cell material extracted in 70% MeOH was transferred to a tube and dried. After drying, the samples were resuspended in 1 mM ammonium phosphate pH 8.5 containing an internal standard (100 nM ClATP). Intracellular levels of the nucleoside triphosphate were quantified based on the rated standard curve by liquid chromatography coupled to tandem mass spectrometry.

result

Table IV: Huh-luc / neo replicon cells after 24 hour incubation with 10 μM PD- A-8b and B-7 Formed within Intracellular triphosphate analog concentration.

Cytotoxic Cell Culture Assay  ( CC50 Decision):

The assay is based on the evaluation of the cytotoxic effects of the compounds tested using metabolic substrates.

CC50  For decision Assay  protocol:

1. Maintain MT-2 cells in RPMI-1640 medium supplemented with 5% fetal bovine serum and antibiotics.

2. Distribute the cells into 96-well plates (20,000 cells in 100 μL medium per well) and add various concentrations of the test compound in triplicates (100 μL / well). Include untreated controls.

3. Incubate the cells at 37 ° C. for 5 days.

4. Prepare XTT solution (6 ml per assay plate) at a concentration of 2 mg / ml in phosphate-buffered saline pH 7.4 in the dark. Heat the solution in a water-bath at 55 ° C. for 5 minutes. Add 50 μL of N-methylphenazonium metasulfate (5 μg / mL) per 6 mL of XTT solution.

5. Remove 100 μL medium from each well on the assay plate and add 100 μL of the XTT substrate solution per well. Incubate in CO ₂ incubator at 37 ° C. for 45-60 minutes.

6. Add 20 μL of 2% Triton X-100 per well to stop the metabolic conversion of XTT.

7. Read the absorbance at 450 nm, subtracting the background at 650 nm.

8. Plot the percent absorbance versus untreated control and estimate the CC50 value as drug concentration that induces 50% inhibition of cell growth. Consider that the absorbance is directly proportional to cell growth.

All publications, patents, and patent documents referred to herein are incorporated herein by reference as if individually incorporated by reference. The present invention has been described in terms of various specific and preferred embodiments and techniques. However, those skilled in the art will understand that many modifications and variations can be made within the spirit and scope of the invention.

Claims (20)

A compound of formula IV or a pharmaceutically acceptable salt thereof.

Equation IV
here:
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
R ² is halogen;
R ³ , R ⁴ , and R ⁵ are each independently H, halogen, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , (C ₁ -C ₈ ) Alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms are —O (CO) O— when bonded together or form a double bond when bonded with the ring carbon atom to which they are attached;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, aryl (C ₁ -C ₈₎ alkyl, (C ₄ -C ₈₎ heterocyclyl-alkyl ^{carbonyl, -C (= O) R 11} , -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), or -SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, -C (= 0) R ¹¹ , -C (= 0) OR ¹¹ , -C (= 0) NR ¹¹ R ¹² , -C (= 0) SR ¹¹ , -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

ego;
Y is ^{O, S, NR, + N} (O) (R), N (OR), + N (O) (OR), or N-NR ₂ a;
W ¹ and W ² , when taken together, are -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; or
One of W ¹ or W ² is —Y ³ — with R ³ or R ⁴ and the other of W ¹ or W ² is Lt; / RTI > or
W ¹ and W ² are each, independently, a group of formula IVa:

Formula IVa
here:
Each Y ¹ is, independently, O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;
Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^x is a group of formula IVb:

Formula IVb
here:
Each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C ( = Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) ₂ R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R ) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, -N (R) C (= Y ¹ ) N (R) ₂ , -SO ₂ NR ₂ , -CN, -N ₃ , -NO ₂ , -OR, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ Heterocyclyl, arylalkyl, heteroarylalkyl;
Wherein each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R ²⁰ groups;
Or when taken together, two R ^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;
Each R is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbo Cyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;
Each R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , OR ¹¹ or S (O) _n R ¹¹ ;
Each R ⁹ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, -CH (= NR ¹¹ ) , -CH = NHNR ¹¹ , -CH = N (OR ¹¹ ), -CH (OR ¹¹ ) ₂ , -C (= O) NR ¹¹ R ¹² , -C (= S) NR ¹¹ R ¹² , -C (= O) OR ¹¹ , R ¹¹ , OR ¹¹ or S (O) _n R ¹¹ ;
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl optionally substituted by _one or more substituents selected from the group consisting of ₈ ) alkyl; Or R ¹¹ and R ¹² combine with the nitrogen to which they are both attached to form a 3-7 membered heterocyclic ring, wherein one carbon atom of the heterocyclic ring is -O-, -S -Or -NR ^b -can be optionally substituted;
Each R ¹³ is independently carbocycle or heterocycle optionally substituted with 1-3 R ²⁰ groups;
Each R ²⁰ is, independently, halogen, CN, N ₃ , N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= Y ¹ ) R, -C (= Y ¹ ) OR, or C (= Y ¹ ) N (R) ₂ ;
Where each of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , Each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of R ¹¹ or R ¹² is independently , One or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or Optionally substituted with OR ^b ; Wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl may be optionally substituted with —O—, —S— or —NR ^b ;
Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, -C (= 0) R ²¹ , -C (= 0) OR ²¹ , -C (= 0) NR ²¹ R ²² , -C (= 0) SR ²¹ , -S (O) R ²¹ , -S (O) ₂ R ²¹ , -S (O) (OR ²¹ ), -S (O) ₂ (OR ²¹ ), or —SO ₂ NR ²¹ R ²² ;
Each R ²¹ or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocycle Arylalkyl, —C (═O) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl. The compound of claim 1, wherein each Y and Y ¹ is O. 7. The compound of claim 2, wherein R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ¹¹ or S (O) _n R ¹¹ . The compound of claim 3, wherein R ⁹ is H, halogen, S (O) _n R ¹¹ or NR ¹¹ R ¹² . The compound of claim 4, wherein R ⁴ is OR ^a . The compound of claim 5, wherein R ¹ is CH ₃ . The compound of claim 6, wherein R ² is F. 8. 8. The compound of claim 7, wherein R ⁷ is

ego;
Wherein Y is -O-; W ¹ is A compound of formula Ia, wherein W ² is —O— together with R ⁴ . The compound of claim 1 represented by formula V.

Expression V
Wherein R ¹ is methyl or ethynyl and R ⁴ is OR ^a . The compound of claim 9, wherein R ⁷ is H or

/ RTI > The structure of claim 1 wherein:

Compound having a. A compound of Formula VI or a pharmaceutically acceptable salt thereof.

Expression VI
here:
R ⁴ is OR ^a ;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, aryl (C ₁ -C ₈₎ alkyl, (C ₄ -C ₈₎ heterocyclyl-alkyl ^{carbonyl, -C (= O) R 11} , -C (= O) OR 11, -C (= O) NR 11 R 12, -C (= O) SR 11, -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), or -SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, -C (= 0) R ¹¹ , -C (= 0) OR ¹¹ , -C (= 0) NR ¹¹ R ¹² , -C (= 0) SR ¹¹ , -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

ego;
Y is ^{O, S, NR, + N} (O) (R), N (OR), + N (O) (OR), or N-NR ₂ a;
W ¹ and W ² , when taken together, are -Y ³ (C (R ^y ) ₂ ) ₃ Y ³ -; or
One of W ¹ or W ² is -Y ³ -with R ⁴ and the other of W ¹ or W ² is Lt; / RTI > or
W ¹ and W ² are each, independently, a group of formula VIa:

Expression VIa
here:
Each Y ¹ is, independently, O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ;
Each Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^x is a group of formula VIb:

Expression VIb
here:
Each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C ( = Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) ₂ R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R ) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, -N (R) C (= Y ¹ ) N (R) ₂ , -SO ₂ NR ₂ , -CN, -N ₃ , -NO ₂ , -OR, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ Heterocyclyl, arylalkyl, heteroarylalkyl;
Wherein each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R ²⁰ groups;
Each R is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbo Cyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocycle Arylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C (= 0) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl;
Each R ¹³ is independently carbocycle or heterocycle optionally substituted with 1-3 R ²⁰ groups;
Each R ²⁰ is, independently, halogen, CN, N ₃ , N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= Y ¹ ) R, -C (= Y ¹ ) OR, or C (= Y ¹ ) N (R) ₂ ;
Where each R ⁴ , Each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of R ¹¹ or R ¹² is independently , One or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or Optionally substituted with OR ^b ; Wherein at least one non-terminal carbon atom of each of said (C ₁ -C ₈ ) alkyl may be optionally substituted with —O—, —S— or —NR ^b ;
Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, -C (= 0) R ²¹ , -C (= 0) OR ²¹ , -C (= 0) NR ²¹ R ²² , -C (= 0) SR ²¹ , -S (O) R ²¹ , -S (O) ₂ R ²¹ , -S (O) (OR ²¹ ), -S (O) ₂ (OR ²¹ ), or —SO ₂ NR ²¹ R ²² ;
Each R ²¹ or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocycle Arylalkyl, —C (═O) (C ₁ -C ₈ ) alkyl, -S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl. The method of claim 12 wherein:
R ^a is H, (C ₁ -C ₈ ) alkyl, or —C (═O) (C ₁ -C ₆ ) alkyl;
R ⁷ or R ⁴ and R ⁷ are together

or

ego;
here
a is the point of attachment to R ⁷ ;
b is the point of attachment to R ⁴ ;
Ar is phenyl or naphthyl, wherein said phenyl and naphthyl are optionally substituted with 1-3 R ²⁰ groups;
Each R ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, wherein said alkyl and carbocyclyl are optionally substituted with 1-3 R ²⁰ groups;
Each R is independently H, (C ₁ -C ₆ ) alkyl, or arylalkyl;
Each R ²⁰ is independently halogen, CN, N (R) ₂ , OR, -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -C (= O) R, -C ( ═O) OR, or C (═O) N (R) ₂ . Compounds having the following structure:

, or

Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 16. The method of claim 15, wherein the interferon, ribavirin or analog thereof, HCV NS3 protease inhibitor, NS5a inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, mevalonate decarboxylase antagonist, antagonist of the renin-angiotensin system, endo Tellin antagonists, other anti-fibrotic agents, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophylline inhibitors, HCV IRES inhibitors Pharmacokinetic enhancers and other drugs to treat HCV; Or at least one additional therapeutic agent selected from the group consisting of mixtures thereof. A therapeutically effective amount of a method for treating, (flaviviridae) virus Flaviviridae comprising administering to a mammal in need of (flaviviridae) treatment of a viral infection a compound of claim 1 Flaviviridae. 18. The method of claim 17, wherein the viral infection is hepatitis C virus infection. 19. The method of claim 18, wherein the viral infection is caused by S282T mutation of hepatitis C virus. 18. The method according to claim 17, wherein the interferon, ribavirin or analog thereof, HCV NS3 protease inhibitor, NS5a inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, mevalonate decarboxylase antagonist, antagonist of renin- angiotensin system, endo Tellin antagonists, other anti-fibrotic agents, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophylline inhibitors, HCV IRES inhibitors Pharmacokinetic enhancers and other drugs to treat HCV; Or administering at least one additional therapeutic agent selected from the group consisting of mixtures thereof.