CROSS-REFERENCE TO RELATED APPLICATION

This is a division of U.S. Ser. No. 12/215,598, filed Jun. 26, 2008, which claims the benefit of U.S. Provisional Application No. 60/937,726, filed Jun. 29, 2007, and U.S. Provisional Application No. 60/959,714, filed Jul. 16, 2007, each of which is herein incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

This application relates generally to compounds and pharmaceutical compositions which selectively activates toll-like receptor 7 (TLR7), and methods of making and using them.

BACKGROUND OF THE INVENTION

The innate immune system provides the body with a first line defense against invading pathogens. In an innate immune response, an invading pathogen is recognized by a germline-encoded receptor, the activation of which initiates a signaling cascade that leads to the induction of cytokine expression. Innate immune system receptors have broad specificity, recognizing molecular structures that are highly conserved among different pathogens. One family of these receptors is known as Toll-like receptors (TLRs), due to their homology with receptors that were first identified and named in Drosophila, and are present in cells such as macrophages, dendritic cells, and epithelial cells.

There are at least ten different TLRs in mammals. Ligands and corresponding signaling cascades have been identified for some of these receptors. For example, TLR2 is activated by the lipoprotein of bacteria (e.g., E. coli), TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharide (i.e., LPS or endotoxin) of Gram-negative bacteria (e.g., Salmonella and E. coli O157:H7), TLR5 is activated by flagellin of motile bacteria (e.g., Listeria), TLR7 recognizes and responds to imiquimod and TLR9 is activated by unmethylated CpG sequences of pathogen DNA. The stimulation of each of these receptors leads to activation of the transcription factor NF-ÎºB, and other signaling molecules that are involved in regulating the expression of cytokine genes, including those encoding tumor necrosis factor-alpha (TNF-Î±), interleukin-1 (IL-1), and certain chemokines.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the discovery by the applicants that a number of small molecules can alter TLR-mediated immunostimulatory signaling. Accordingly, the present application is directed to compounds and pharmaceutical compositions, and methods for use in preventing or treating diseases or conditions associated with Toll-like receptor 7 (TLR7) activity in patients. In one embodiment, the invention comprises a compound of formula I or II:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- X¹is â€”NHâ€”, â€”Oâ€”, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, carbocyclylene, substituted carbocyclylene, heterocyclylene, or substituted heterocyclylene;
- D is carbocyclylene or heterocyclylene;
- each L¹is independently alkylene or substituted alkylene;
- each R¹is independently â€”NR⁴R⁵;
- m is 1 or 2;
- L²is a covalent bond, â€”NHâ€”, â€”Oâ€”, or â€”Sâ€”;
- R²is H, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl,
- â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)OR⁷, â€”S(O)NR⁷R⁸, â€”S(O)₂R⁷, â€”S(O)R⁷, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸;
- L³is â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, â€”N(R⁹)C(O)â€”, â€”S(O)₂â€”, â€”S(O)â€”, or a covalent bond;
- R³is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or
- R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;
- R⁶is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁷and R⁸are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or
- R⁷and R⁸, taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle;
- R⁹is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R¹⁰is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; and
  - n is an integer from 0 to 5; and
- with the following proviso:
- (a) When X¹is â€”CH₂â€”, D is 1,4-phenylene, R³-L³- is CH₃CH₂CH₂CH₂Oâ€” or CH₃â€”Oâ€”CH₂CH₂â€”O, n=0, m=1, then NR⁴R⁵is not: (1) a 4-substituted or 4,4-disubstituted piperidine or piperazine (2) â€”NHCH₃;
- (b) When X¹is â€”CH₂â€”, D is 1,4-phenylene or 1,4-piperidinylene, R³-L³- is CH₃CH₂CH₂CH₂Oâ€” or CH₃â€”Oâ€”CH₂CH₂â€”O, n=0, m=1, then neither R⁴nor R⁵are substituted alkyl, substituted heterocycyl, or substituted benzyl; and
- (c) When X¹is â€”CH₂â€”, D is 2,5-pyridylene, R³-L³- is CH₃CH₂CH₂CH₂Oâ€” or CH₃â€”Oâ€”CH₂CH₂â€”O, n=0, m=1, then NR⁴R⁵is not pyrrolyl, piperazyl, or N(CH₃)₂.

In another embodiment, Formula I can be represented by Formula Ia:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- R¹is â€”NR⁴R⁵;
- R²is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸;
- L³is â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, â€”N(R⁹)C(O)â€”, â€”S(O)₂â€”, â€”S(O)â€”, or a covalent bond;
- R³is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or
- R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;
- R⁶is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁷and R⁸are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or
- R⁷and R⁸, taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle;
- R⁹is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting group, or a prodrug moiety;
- R¹⁰is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; and
- n is an integer from 0 to 4.

In another embodiment, Formula II can be represented by Formula IIa:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- R¹is â€”NR⁴R⁵;
- R²is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸;
- L³is â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, â€”N(R⁹)C(O)â€”, â€”S(O)₂â€”, â€”S(O)â€”, or a covalent bond;
- R³is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or
- R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;
- R⁶is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁷and R⁸are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or
- R⁷and R⁸, taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle;
- R⁹is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting group, or a prodrug moiety;
- R¹⁰is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; and
- n is 0, 1, 2, or 3.

In another embodiment, the present application provides for a pharmaceutical composition comprising at least one compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof; and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present application provides for a pharmaceutical composition comprising at least one compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof; at least one additional active agent; and a pharmaceutically acceptable carrier or exipient.

In another embodiment, the present application provides for a method for treating or preventing a viral infection comprising administering, to a patient in need thereof, a therapeutically effective amount of at least one compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

In another embodiment, the present application provides for a combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional active agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the invention to those claims. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

All documents referenced herein are each incorporated by reference in their entirety for all purposes.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.

As used herein, â€œa compound of the inventionâ€ or â€œa compound of formula I or IIâ€ means a compound of formula I or II, or a pharmaceutically acceptable salt, solvate, ester or physiologically functional derivative thereof. Compounds of the invention also include tautomeric forms thereof, e.g., tautomeric â€œenolsâ€ as described herein. Similarly, with respect to isolatable intermediates such as for example, compounds of formula (2), the phrase â€œa compound of formula (number)â€ means a compound of that formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.

â€œAlkylâ€ is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e, C₁-C₂₀alkyl), 1 to 10 carbon atoms (i.e., C₁-C₁₀alkyl), or 1 to 6 carbon atoms (i.e., C₁-C₆alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, â€”CH₃), ethyl (Et, â€”CH₂CH₃), 1-propyl (n-Pr, n-propyl, â€”CH₂CH₂CH₃), 2-propyl (1-Pr, i-propyl, â€”CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, â€”CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (1-Bu, i-butyl, â€”CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, â€”CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (1-Bu, 1-butyl, â€”C(CH₃)₃), 1-pentyl (n-pentyl, â€”CH₂CH₂CH₂CH₂CH₃), 2-pentyl (â€”CH(CH₃)CH₂CH₂CH₃), 3-pentyl (â€”CH(CH₂CH₃)₂), 2-methyl-2-butyl (â€”C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (â€”CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (â€”CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (â€”CH₂CH(CH₃)CH₂CH₃), 1-hexyl (â€”CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (â€”CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (â€”CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (â€”C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (â€”CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (â€”CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (â€”C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (â€”CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (â€”C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (â€”CH(CH₃)C(CH₃)₃, and octyl (â€”(CH₂)₇CH₃).

â€œAlkoxyâ€ means a group having the formula â€”O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C₁-C₂₀alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (â€”Oâ€”CH₃or â€”OMe), ethoxy (â€”OCH₂CH₃or â€”OEt), t-butoxy (â€”Oâ€”C(CH₃)₃or â€”OtBu) and the like.

â€œHaloalkylâ€ is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C₁-C₂₀haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂haloalkyl), or 1 to 6 carbon atoms (i.e., C₁-C₆alkyl). Examples of suitable haloalkyl groups include, but are not limited to, â€”CF₃, â€”CHF₂, â€”CFH₂, â€”CH₂CF₃, and the like.

â€œAlkenylâ€ is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp²double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀alkenyl), 2 to 12 carbon atoms (i.e., C₂-C₁₂alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene, vinyl (â€”CHâ• CH₂), allyl (â€”CH₂CHâ• CH₂), cyclopentenyl (â€”C₅H₇), and 5-hexenyl (â€”CH₂CH₂CH₂CH₂CHâ• CH₂).

â€œAlkynylâ€ is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀alkynyl), 2 to 12 carbon atoms (i.e., C₂-C₁₂alkyne), or 2 to 6 carbon atoms (i.e., C₂-C₆alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (â€”Câ‰¡CH), propargyl (â€”CH₂Câ‰¡CH), and the like.

â€œAlkyleneâ€ refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (â€”CH₂â€”), 1,1-ethyl (â€”CH(CH₃)â€”), 1,2-ethyl (â€”CH₂CH₂â€”), 1,1-propyl (â€”CH(CH₂CH₃)â€”), 1,2-propyl (â€”CH₂CH(CH₃)â€”), 1,3-propyl (â€”CH₂CH₂CH₂â€”), 1,4-butyl (â€”CH₂CH₂CH₂CH₂â€”), and the like.

â€œAlkenyleneâ€ refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, and alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (â€”CHâ• CHâ€”).

â€œAlkynyleneâ€ refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (â€”Câ• Câ€”), propargyl (â€”CH₂Câ‰¡Câ€”), and 4-pentynyl (â€”CH₂CH₂CH₂Câ‰¡CHâ€”).

â€œAminoalkylâ€ refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an amino radical.

â€œAmidoalkylâ€ refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a â€”NR^aCOR^bgroup where R^ais hydrogen or alkyl and R^bis alkyl, substituted alkyl, aryl, or substituted aryl as defined herein, e.g., â€”(CH₂)₂â€”NHC(O)CH₃, â€”(CH₂)₃â€”NHâ€”C(O)â€”CH₃, and the like.

â€œArylâ€ means a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

â€œAryleneâ€ refers to an aryl as defined above having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent aryl. Typical arylene radicals include, but are not limited to, phenylene.

â€œArylalkylâ€ refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

â€œArylalkenylâ€ refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp²carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein. The arylalkenyl group can comprise 6 to 20 carbon atoms, e.g., the alkenyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

â€œArylalkynylâ€ refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or spa carbon atom, but also an sp carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein. The arylalkynyl group can comprise 6 to 20 carbon atoms, e.g., the alkynyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

The term â€œsubstitutedâ€ in reference to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, etc., for example, â€œsubstituted alkylâ€ , â€œsubstituted alkyleneâ€ , â€œsubstituted arylâ€ , â€œsubstituted arylalkylâ€ , â€œsubstituted heterocyclylâ€ , and â€œsubstituted carbocyclylâ€ means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include, but are not limited to, â€”X, â€”R, â€”O^âˆ’, â• O, â€”OR, â€”SR, â€”S^âˆ’, â€”NR₂, â€”N⁺R₃, â• NR, â€”CX₃, â€”CN, â€”OCN, â€”SCN, â€”Nâ• Câ• O, â€”NCS, â€”NO, â€”NO₂, â• N₂, â€”N₃, â€”NHC(â• O)R, â€”C(â• O)NRRâ€”S(â• O)₂O^âˆ’, â€”S(â• O)₂OH, â€”S(â• O)₂R, â€”OS(â• O)₂OR, â€”S(â• O)₂NR, â€”S(â• O)R, â€”OP(â• O)(OR)₂, â€”P(â• O)(OR)₂, â€”P(â• O)(O^âˆ’)₂, â€”P(â• O)(OH)₂, â€”P(O)(OR)(O), â€”C(â• O)R, â€”C(S)R, â€”C(O)OR, â€”C(O)O^âˆ’, â€”C(S)OR, â€”C(O)SR, â€”C(S)SR, â€”C(O)NRR, â€”C(S)NRR, â€”C(â• NR)NRR, where each X is independently a halogen: F, Cl, Br, or I; and each R is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted.

Those skilled in the art will recognize that when moieties such as â€œalkylâ€ , â€œarylâ€ , â€œheterocyclylâ€ , etc. are substituted with one or more substituents, they could alternatively be referred to as â€œalkyleneâ€ , â€œaryleneâ€ , â€œheterocyclyleneâ€ , etc. moieties (i.e., indicating that at least one of the hydrogen atoms of the parent â€œalkylâ€ , â€œarylâ€ , â€œheterocyclylâ€ moieties has been replaced with the indicated substituent(s)). When moieties such as â€œalkylâ€ , â€œarylâ€ , â€œheterocyclylâ€ , etc. are referred to herein as â€œsubstitutedâ€ or are shown diagrammatically to be substituted (or optionally substituted, e.g., when the number of substituents ranges from zero to a positive integer), then the terms â€œalkylâ€ , â€œarylâ€ , â€œheterocyclylâ€ , etc. are understood to be interchangeable with â€œalkyleneâ€ , â€œaryleneâ€ , â€œheterocyclyleneâ€ , etc.

The term â€œprodrugâ€ as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and other moieties of the compounds of Formula I or II should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of Formula I or II which have such stability are contemplated as falling within the scope of the present invention.

â€œHeteroalkylâ€ refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S. For example, if the carbon atom of the alkyl group which is attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., â€”OCH₃, etc.), an amine (e.g., â€”NHCH₃, â€”N(CH₃)₂, etc.), or a thioalkyl group (e.g., â€”SCH₃). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., â€”CH₂CH₂â€”Oâ€”CH₃, etc.), an alkyl amine (e.g., â€”CH₂NHCH₃, â€”CH₂N(CH₃)₂, etc.), or a thioalkyl ether (e.g., â€”CH₂â€”Sâ€”CH₃). If a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., â€”CH₂CH₂â€”OH), an aminoalkyl group (e.g., â€”CH₂NH₂), or an alkyl thiol group (e.g., â€”CH₂CH₂â€”SH). A heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C₁-C₆heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

â€œHeterocycleâ€ or â€œheterocyclylâ€ as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographsâ€ (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention â€œheterocycleâ€ includes a â€œcarbocycleâ€ as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). The terms â€œheterocycleâ€ or â€œheterocyclylâ€ includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups. A non-limiting example of a carbonyl substituted heterocyclyl is:

[Image Omitted]

Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, Î²-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

[Image Omitted]

By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or Î²-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

â€œHeterocyclyleneâ€ refers to a heterocyclyl, as defined herein, derived by replacing a hydrogen atom from a carbon atom or heteroatom of a heterocyclyl, with an open valence. Similarly, â€œheteroaryleneâ€ refers to an aromatic heterocyclylene.

â€œHeterocyclylalkylâ€ refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety). Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH₂â€”, 2-(heterocyclyl)ethan-1-yl, and the like, wherein the â€œheterocyclylâ€ portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkyl group comprises 2 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises 1 to 14 carbon atoms. Examples of heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

â€œHeterocyclylalkenylâ€ refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also a sp²carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). The heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkenyl group comprises 2 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises 1 to 14 carbon atoms.

â€œHeterocyclylalkynylâ€ refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or spa carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkynylene- moiety). The heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkynyl group comprises 2 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises 1 to 14 carbon atoms.

â€œHeteroarylâ€ refers to a monovalent aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of those listed in the definition of â€œheterocyclylâ€ , including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.

â€œCarbocycleâ€ or â€œcarbocyclylâ€ refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged as a bicyclo (5,6) or (6,6) system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, etc.

â€œCarbocyclyleneâ€ refers to a carbocyclyl or carbocycle as defined above having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent carbocyclyl. Typical carbocyclylene radicals include, but are not limited to, phenylene.

â€œArylheteroalkylâ€ refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein. The aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group can have the general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, any of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.

â€œHeteroarylalkylâ€ refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein. Non-limiting examples of heteroaryl alkyl include â€”CH₂-pyridinyl, â€”CH₂-pyrrolyl, â€”CH₂-oxazolyl, â€”CH₂-indolyl, â€”CH₂-isoindolyl, â€”CH₂-purinyl, â€”CH₂-furanyl, â€”CH₂-thienyl, â€”CH₂-benzofuranyl, â€”CH₂-benzothiophenyl, â€”CH₂-carbazolyl, â€”CH₂-imidazolyl, â€”CH₂-thiazolyl, â€”CH₂-isoxazolyl, â€”CH₂-pyrazolyl, â€”CH₂-isothiazolyl, â€”CH₂-quinolyl, â€”CH₂-isoquinolyl, â€”CH₂-pyridazyl, â€”CH₂-pyrimidyl, â€”CH₂-pyrazyl, â€”CH(CH₃)-pyridinyl, â€”CH(CH₃)-pyrrolyl, â€”CH(CH₃)-oxazolyl, â€”CH(CH₃)-indolyl, â€”CH(CH₃)-isoindolyl, â€”CH(CH₃)-purinyl, â€”CH(CH₃)-furanyl, â€”CH(CH₃)-thienyl, â€”CH(CH₃)-benzofuranyl, â€”CH(CH₃)-benzothiophenyl, â€”CH(CH₃)-carbazolyl, â€”CH(CH₃)-imidazolyl, â€”CH(CH₃)-thiazolyl, â€”CH(CH₃)-isoxazolyl, â€”CH(CH₃)-pyrazolyl, â€”CH(CH₃)-isothiazolyl, â€”CH(CH₃)-quinolyl, â€”CH(CH₃)-isoquinolyl, â€”CH(CH₃)-pyridazyl, â€”CH(CH₃)-pyrimidyl, â€”CH(CH₃)-pyrazyl, etc.

The term â€œoptionally substitutedâ€ in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more substituents.

â€œEster thereofâ€ means any ester of a compound in which any of the â€”COOH functions of the molecule is replaced by a â€”C(O)OR function, or in which any of the â€”OH functions of the molecule are replaced with a â€”OC(O)R function, in which the R moiety of the ester is any carbon-containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof. Esters can also include estersâ€”as described aboveâ€”of â€œtautomeric enolsâ€ , e.g. as shown below:

[Image Omitted]

The term â€œester thereofâ€ includes but is not limited to pharmaceutically acceptable esters thereof.

The term â€œchiralâ€ refers to molecules which have the property of non-superimposability of the mirror image partner, while the term â€œachiralâ€ refers to molecules which are superimposable on their mirror image partner.

The term â€œstereoisomersâ€ refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

â€œDiastereomerâ€ refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

â€œEnantiomersâ€ refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. 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 forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (âˆ’) are employed to designate the sign of rotation of plane-polarized light by the compound, with (âˆ’) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms â€œracemic mixtureâ€ and â€œracemateâ€ refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups include prodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group â€œPGâ€ will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.

Various functional groups of the compounds of the invention may be protected. For example, protecting groups for â€”OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) include â€œether- or ester-forming groupsâ€ . Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.

A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9) (â€œGreeneâ€ ). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfinate.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g., C¹⁴or H³) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no anti-infective activity of their own.

Compounds of Formula I or II

In one embodiment, the present application provides compounds according to Formula I or II, as described herein.

In each of the embodiments herein, the following provisos apply when applicable:

- (a) When X¹is â€”CH₂â€”, D is 1,4-phenylene, R³-L³- is CH₃CH₂CH₂CH₂Oâ€” or CH₃â€”Oâ€”CH₂CH₂â€”O, n=0, m=1, then NR⁴R⁵is not: (1) a 4-substituted or 4,4-disubstituted piperidine or piperazine (2) â€”NHCH₃;
- (b) When X¹is â€”CH₂â€”, D is 1,4-phenylene or 1,4-piperidinylene, R³-L³- is CH₃CH₂CH₂CH₂Oâ€” or CH₃â€”Oâ€”CH₂CH₂â€”O, n=0, m=1, then neither R⁴nor are substituted alkyl, substituted heterocycyl, or substituted benzyl; and
- (c) When X¹is â€”CH₂â€”, D is 2,5-pyridylene, R³-L³- is CH₃CH₂CH₂CH₂Oâ€” or CH₃â€”Oâ€”CH₂CH₂â€”O, n=0, m=1, then NR⁴R⁵is not pyrrolyl, piperazyl, or N(CH₃)₂.

The compounds of the present invention do not include any of the compounds disclosed in WO 07/034,817, WO 07/034,917, U.S. Patent Application Publication 2006/0052403, JP 2005/089334, or U.S. Pat. No. 6,329,381, each of which is incorporated by reference in its entirety.

The definitions and substituents for various genus and subgenus of the present compounds are described and illustrated herein. It should be understood by one skilled in the art that any combination of the definitions and substituents described above should not result in an inoperable species or compound. â€œInoperable species or compoundsâ€ means compound structures that violates relevant scientific principles (such as, for example, a carbon atom connecting to more than four covalent bonds) or compounds too unstable to permit isolation and formulation into pharmaceutically acceptable dosage forms. For example, it is understood to one skilled in the art that the definition of L²as a covalent bond only applies to Formula I, and not to Formula II.

Similarly, the skilled artisan will understand that when L²is â€”NHâ€”, â€”Oâ€”, or â€”Sâ€”, in Formula II, L²defines a â• NH (imine), â• O (carbonyl), or â• S (thiocarbonyl) group.

In one embodiment of Formula I or II, X¹is alkylene or substituted alkylene; wherein the substituted alkylene comprises an alkylene substituted with one or more substituents selected from the group consisting of halo, hydroxyl, amino, heteroalkyl, substituted heteroalkyl, cyano, azido, nitro, alkyl, substituted alkyl, and combinations thereof.

In another embodiment of Formula I or II, m is 1.

In another embodiment of Formula I or II, L¹is â€”CH₂â€” or â€”CH₂CH₂â€”.

In another embodiment of Formula I or II, R¹is independently â€”NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; wherein the heterocycle is a 4- to 8-membered monocyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S; or a 8- to 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

In another embodiment of Formula I or II, R¹is independently â€”NR⁴R⁵; and R⁴is H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and R⁵is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸.

In another embodiment of Formula I or II, R¹is independently â€”NR⁴R⁵; R⁴is H or carbocyclylalkyl; and R⁵is alkyl, substituted alkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In another embodiment of Formula I or II, D is arylene or heteroarylene.

In another embodiment of Formula I or II, L²is â€”Oâ€”.

In one embodiment of Formula I, -L²-R²is â€”OH.

In another embodiment of Formula I or II, L²is â€”Oâ€”; and R²is â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)OR⁷, â€”S(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸.

In another embodiment of Formula I or II, R²is â€”C(O)OCH₃, â€”C(O)OCH₂CH₃, â€”C(O)OCH(CH₃)₂, â€”C(O)NHCH₃, â€”C(O)NHCH₂CH₃, â€”C(O)NHCH(CH₃)₂.

In another embodiment of Formula I or II, L²is â€”Oâ€”; and R²is alkyl, substituted alkyl, cyclylalkyl, substituted cyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

In another embodiment of Formula I or II, R²is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, methylcyclopropyl, cyclopropylmethylene, benzyl, or methoxybezyl.

In another embodiment of Formula I or II, L³is â€”Oâ€”.

In another embodiment of Formula I or II, R³is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

In another embodiment of Formula I or II, -L³-R³is â€”O-alkyl or â€”O-alkylene-O-alkyl.

In another embodiment of Formula I or II, -L³-R³is â€”OCH₂CH₂OCH₃or â€”OCH₂CH₂CH₂CH₃.

In another embodiment of Formula I, R⁴and R⁵are not each simultaneously H or alkyl.

In another embodiment of the present invention, Formula I is represented by Formula Ia:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- R¹is â€”NR⁴R⁵;
- R²is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸;
- L³is â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, â€”N(R⁹)C(O)â€”, â€”S(O)₂â€”, â€”S(O)â€”, or a covalent bond;
- R³is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or
- R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;
- R⁶is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁷and R⁸are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or
- R⁷and R⁸, taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle;
- R⁹is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting group, or a prodrug moiety;
- R¹⁰is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; and
- n is an integer from 0 to 4.

In one embodiment of Formula Ia, R¹is NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

In another embodiment of Formula Ia, R¹is NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; wherein the heterocycle is a 4- to 8-membered monocyclic fully saturated, partially unsaturated, or heteroaryl ring containing at least one hetero atom selected from N, O, and S; or a 8- to 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

In another embodiment of Formula Ia, the heterocycle is selected from the group consisting of:

[Image Omitted]

In another embodiment of Formula Ia, R¹is NR⁴R⁵; R⁴is H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and R⁵is carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸.

In another embodiment of Formula Ia, R⁴is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, cyclopropyl, or cyclopropylmethylenyl, R⁵is phenyl, pyridinyl, â€”C(O)CH₃, â€”C(O)OCH₃, â€”C(O)CH₂CH₃, or â€”C(O)OCH₂CH₃.

In another embodiment of Formula Ia, R¹is NR⁴R⁵; R⁴is H; and R⁵is alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl.

In another embodiment of Formula Ia, R¹is independently â€”NR⁴R⁵; R⁴is H; and R⁵is alkyl, substituted alkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In another embodiment of Formula Ia, R¹is independently â€”NR⁴R⁵; R⁴is H; and R⁵is selected from the group consisting of

[Image Omitted]

In another embodiment of Formula Ia, R²is H.

In another embodiment of Formula Ia, R²is â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)OR⁷, â€”S(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸.

In another embodiment of Formula Ia, R²is â€”C(O)OCH₃, â€”C(O)OCH₂CH₃, â€”C(O)OCH(CH₃)₂, â€”C(O)NHCH₃, â€”C(O)NHCH₂CH₃, â€”C(O)NHCH(CH₃)₂.

In another embodiment of Formula Ia, R²is alkyl, substituted alkyl, cyclylalkyl, substituted cyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

In another embodiment of Formula Ia, R²is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, methylcyclopropyl, cyclopropylmethylene, benzyl, or methoxybezyl.

In another embodiment of Formula Ia, L³is â€”Oâ€”.

In another embodiment of Formula Ia, -L³-R³is â€”O-alkyl, â€”O-(substituted alkyl), â€”O-carbocyclyl, â€”O-heterocyclyl, â€”O-carbocyclylalkyl, â€”O-heterocyclylalkyl, or â€”O-alkylene-O-alkyl. In this embodiment, it is preferred that R²is H. It is further preferred that R¹is NR⁴R⁵and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

[Image Omitted]

In another embodiment of Formula Ia, -L³-R³is â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CH₂CH₃, â€”OCH₂CH₂CF₃, â€”OCH₂CF₂CF₃, â€”OCH₂CH(CH₃)₂, â€”OCH₂CF₃,

[Image Omitted]

In this embodiment, it is preferred that R²is H. It is further preferred that R¹is NR⁴R⁵and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

[Image Omitted]

In another embodiment of Formula Ia, R¹is â€”NR⁴R⁵; R²is H, â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸; L³is â€”Oâ€”; R³is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl; and R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

In another embodiment of Formula Ia, R⁴and R⁵are not each simultaneously H or alkyl.

In another embodiment of Formula Ia, -L³-R³

is â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CH₃, â€”OCH₂CH₂CH₂CH₃, â€”Oc-butyl, â€”Oc-butyl, â€”Oc-pentyl, â€”OCH₂c-propyl, â€”OCH₂c-butyl, â€”OCH₂CH₂c-propyl, â€”OCH₂CH₂CH₂CH₂OH, â€”OCH₂CF₃, â€”OCH₂CH₂CF₃, â€”OCH₂CH₂CH₂CF₃, or (tetrahydrofuran-2-yl)methoxy.

In another embodiment of Formula Ia, -L³-R³is â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CH₂CH₃, â€”OCH₂CH₂CF₃, â€”OCH₂CH₂CH₂CH₂OH, â€”Oi-butyl, â€”OCH₂CH₂c-propyl, or â€”OCH₂c-propyl. In still another embodiment, -L³-R³is as defined immediately previously, R²is H, and R¹is NR⁴R⁵and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

[Image Omitted]

In another embodiment of Formula Ia, -L³-R³is â€”OCH₂CH₂CH₂CH₃, â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CF₃, â€”OCH₂CH₂CH₂CH₂OH, or â€”OCH₂c-propyl. In still another embodiment, -L³-R³is as defined immediately previously, R²is H, and R¹is NR⁴R⁵and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

[Image Omitted]

In a further embodiment -L³-R³is â€”OCH₂CH₂CH₂CH₃.

In one embodiment of the present invention, Formula II is represented by Formula IIa:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

- R¹is â€”NR⁴R⁵;
- R²is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸;
- L³is â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, â€”N(R⁹)C(O)â€”, â€”S(O)₂â€”, â€”S(O)â€”, or a covalent bond;
- R³is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or
- R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;
- R⁶is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁷and R⁸are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or
- R⁷and R⁸, taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle;
- R⁹is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting group, or a prodrug moiety;
- R¹⁰is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; and
- n is 0, 1, 2, or 3.

In one embodiment of Formula IIa, R¹is NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

In another embodiment of Formula IIa, R¹is NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; wherein the heterocycle is a 4- to 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S; or a 10- to 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

In another embodiment of Formula IIa, the heterocycle is selected from the group consisting of:

[Image Omitted]

In another embodiment of Formula IIa, R¹is NR⁴R⁵; R⁴is H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and R⁵is carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸.

In another embodiment of Formula IIa, R²is â€”C(O)R⁶, â€”C(O)OR⁶, â€”C(O)NR⁷R⁸, â€”S(O)OR⁷, â€”S(O)NR⁷R⁸, â€”S(O)₂OR⁷, or â€”S(O)₂NR⁷R⁸.

In another embodiment of Formula IIa, R⁴is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, cyclopropyl, or cyclopropylmethylenyl, R⁵is phenyl, pyridinyl, â€”C(O)CH₃, â€”C(O)OCH₃, â€”C(O)CH₂CH₃, or â€”C(O)OCH₂CH₃.

In another embodiment of Formula IIa, R²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

In another embodiment of Formula IIa, R²is methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, cyclopropyl, methylcyclopropyl, cyclopropylmethylene, benzyl, or methoxybezyl.

In another embodiment of Formula IIa, L³is â€”Oâ€”.

In another embodiment of Formula IIa, -L³-R³is â€”O-alkyl or â€”O-alkylene-O-alkyl.

In another embodiment of Formula IIa, -L³-R³is â€”OCH₂CH₂OCH₃or â€”OCH₂CH₂CH₂CH₃.

In another embodiment of Formula IIa, R¹is â€”NR⁴R⁵; R²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cyclylalkyl, substituted cyclylalkyl, cyclylalkylalkyl, substituted cyclylalkylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl; L³is â€”Oâ€”; R³is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

In one embodiment of Formula I, L²is a covalent bond, and R²is hydrogen or halogen. That is, Formula I is represented by Formula Ib:

[Image Omitted]

wherein:

- R¹is â€”NR⁴R⁵;
- R²is H or halo;
- L³is â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, â€”N(R⁹)C(O)â€”, â€”S(O)₂â€”, â€”S(O)â€”, or a covalent bond;
- R³is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁴and R⁵are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, â€”C(O)H, â€”C(O)R³, â€”S(O)R³, â€”S(O)₂R³, â€”C(O)OR³, or â€”C(O)NR⁷R⁸; or
- R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;
- R⁶is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
- R⁷and R⁸are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or
- R⁷and R⁸, taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle;
- R⁹is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting group, or a prodrug moiety;
- R¹⁰is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; and
- n is an integer from 0 to 4; and

In one embodiment of Formula Ib, R¹is NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; wherein the heterocycle is a 4- to 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S. In this embodiment, the heterocycle can be selected from the group consisting of:

[Image Omitted]

In one embodiment of Formula Ib, -L³-R³is â€”O-alkyl or â€”O-alkylene-O-alkyl. It is preferred that -L³-R³is â€”OCH₂CH₂OCH₃or â€”OCH₂CH₂CH₂CH₃.

In one embodiment of Formula Ib, R¹is NR⁴R⁵; -L³-R³is â€”O-alkyl or â€”O-alkylene-O-alkyl; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; wherein the heterocycle is a 4- to 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

In another embodiment of formula (I) or (II), the compound is selected from the group consisting of:

[Image Omitted]

or pharmaceutically acceptable salts, solvates, and/or esters thereof.

In one embodiment, the present application provides compounds according to Formula Ia:

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein:

- -L³-R³is â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CH₃, â€”OCH₂CH₂CH₂CH₃, â€”Oi-butyl, â€”Oc-butyl, â€”Oc-pentyl, â€”OCH₂c-propyl, â€”OCH₂c-butyl, â€”OCH₂CH₂c-propyl, â€”OCH₂CH₂CH₂CH₂OH, â€”OCH₂CF₃, â€”OCH₂CH₂CF₃, â€”OCH₂CH₂CH₂CF₃, or (tetrahydrofuran-2-yl)methoxy;
- R²is H;
- n is 0;
- R¹is â€”NR⁴R⁵; and R⁴and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

[Image Omitted]

In one embodiment of Formula Ia, -L³-R³is â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CH₂CH₃, â€”OCH₂CH₂CF₃, â€”OCH₂CH₂CH₂CH₂OH, â€”Oi-butyl, â€”OCH₂CH₂c-propyl, or â€”OCH₂c-propyl.

In one embodiment of Formula Ia, -L³-R³

is â€”OCH₂CH₂CH₂CH₃, â€”OCH₂CH₂OCH₃, â€”OCH₂CH₂CF₃, â€”OCH₂CH₂CH₂CH₂OH, or â€”OCH₂c-propyl.

In one embodiment of Formula Ia, -L³-R³is â€”OCH₂CH₂CH₂CH₃.

In one embodiment of Formula Ia, R⁴and R⁵, taken together with the nitrogen to which they are both attached form a heterocycle selected from the group consisting of:

[Image Omitted]

In still yet another embodiment, the compounds of Formula I and II are named below in tabular format (Table 5) as compounds of general Formula III:

[Image Omitted]

Compounds of general Formula III are depicted as four moieties T1, T2, T3 and T4 attached in the manner shown above. Tables A-D show, respectively, the structures of the T1, T2, T3 and T4 moieties, with the point(s) of attachment to neighboring moieties. Each moiety T1, T2, T3 and T4 in Tables A-D is represented by a â€œcodeâ€ comprising letters and numbers. Each structure of a compound of Formula III can be designated in tabular form by combining the â€œcodeâ€ representing each structural moiety using the following syntax: T1.T2.T3.T4. Thus, for example, T1A.T2A.T3A.T4A represents the following structure:

[Image Omitted]

wherein the terms â€œalkyleneâ€ , â€œaryleneâ€ , â€œalkylâ€ , â€œcycloalkylalkylâ€ , â€œheteroaryleneâ€ , â€œcarboxcyclyleneâ€ , â€œcarbocyclylâ€ , â€œheterocyclylâ€ , etc. are as defined herein.

TABLE 1T1 StructuresLabelT1 StructureT1Aâ€”O-alkylT1Bâ€”O-alkylene-O-alkylT1Câ€”S-alkylT1Dâ€”NH-alkyl (alkyl is substituted or unsubstituted)T1EalkylT1F(cycloalkyl)alkyl-Oâ€”T1GCycloalkyl-Oâ€”

TABLE 2T2 StructuresLabelT2 StructureT2A [Image Omitted]

T2B

T2C

T2D

TABLE 3T3 StructuresLabelT3 StructureT3A-alkylene-arylene-alkylene-T4(substituted or unsubstituted)T3B-alkylene-carbocyclylene-alkylene-T4(substituted or unsubstituted)T3C-alkylene-heteroarylene-alkylene-T4(substituted or unsubstituted)T3D-alkylene-heterocyclene-alkylene-T4(substituted or unsubstituted)

TABLE 4T4 StructuresLabelT4 StructureT4Aâ€”N(alkyl)S(O)₂-alkylT4Bâ€”N(cycloalkylalkyl)C(O)O-alkylT4Câ€”N(cycloalkylalkyl)C(O)N(alkyl)₂T4Dâ€”N(cycloalkylalkyl)₂T4Eâ€”NH(cycloalkylalkyl)T4Fâ€”NH(carbocyclyl)T4Gâ€”NH(heterocyclyl)T4HNitrogen containing heterocycleattached at nitrogen

TABLE 5List of Compound Structures of Formula IIIT1A.T2A.T3A.T4A, T1A.T2A.T3A.T4B, T1A.T2A.T3A.T4C,T1A.T2A.T3A.T4D, T1A.T2A.T3A.T4E, T1A.T2A.T3A.T4F,T1A.T2A.T3A.T4G, T1A.T2A.T3A.T4H, T1A.T2A.T3B.T4A,T1A.T2A.T3B.T4B, T1A.T2A.T3B.T4C, T1A.T2A.T3B.T4D,T1A.T2A.T3B.T4E, T1A.T2A.T3B.T4F, T1A.T2A.T3B.T4G,T1A.T2A.T3B.T4H, T1A.T2A.T3C.T4A, T1A.T2A.T3C.T4B,T1A.T2A.T3C.T4C, T1A.T2A.T3C.T4D, T1A.T2A.T3C.T4E,T1A.T2A.T3C.T4F, T1A.T2A.T3C.T4G, T1A.T2A.T3C.T4H,T1A.T2A.T3D.T4A, T1A.T2A.T3D.T4B, T1A.T2A.T3D.T4C,T1A.T2A.T3D.T4D, T1A.T2A.T3D.T4E, T1A.T2A.T3D.T4F,T1A.T2A.T3D.T4G, T1A.T2A.T3D.T4H, T1A.T2B.T3A.T4A,T1A.T2B.T3A.T4B, T1A.T2B.T3A.T4C, T1A.T2B.T3A.T4D,T1A.T2B.T3A.T4E, T1A.T2B.T3A.T4F, T1A.T2B.T3A.T4G,T1A.T2B.T3A.T4H, T1A.T2B.T3B.T4A, T1A.T2B.T3B.T4B,T1A.T2B.T3B.T4C, T1A.T2B.T3B.T4D, T1A.T2B.T3B.T4E,T1A.T2B.T3B.T4F, T1A.T2B.T3B.T4G, T1A.T2B.T3B.T4H,T1A.T2B.T3C.T4A, T1A.T2B.T3C.T4B, T1A.T2B.T3C.T4C,T1A.T2B.T3C.T4D, T1A.T2B.T3C.T4E, T1A.T2B.T3C.T4F,T1A.T2B.T3C.T4G, T1A.T2B.T3C.T4H, T1A.T2B.T3D.T4A,T1A.T2B.T3D.T4B, T1A.T2B.T3D.T4C, T1A.T2B.T3D.T4D,T1A.T2B.T3D.T4E, T1A.T2B.T3D.T4F, T1A.T2B.T3D.T4G,T1A.T2B.T3D.T4H, T1A.T2C.T3A.T4A, T1A.T2C.T3A.T4B,T1A.T2C.T3A.T4C, T1A.T2C.T3A.T4D, T1A.T2C.T3A.T4E,T1A.T2C.T3A.T4F, T1A.T2C.T3A.T4G, T1A.T2C.T3A.T4H,T1A.T2C.T3B.T4A, T1A.T2C.T3B.T4B, T1A.T2C.T3B.T4C,T1A.T2C.T3B.T4D, T1A.T2C.T3B.T4E, T1A.T2C.T3B.T4F,T1A.T2C.T3B.T4G, T1A.T2C.T3B.T4H, T1A.T2C.T3C.T4A,T1A.T2C.T3C.T4B, T1A.T2C.T3C.T4C, T1A.T2C.T3C.T4D,T1A.T2C.T3C.T4E, T1A.T2C.T3C.T4F, T1A.T2C.T3C.T4G,T1A.T2C.T3C.T4H, T1A.T2C.T3D.T4A, T1A.T2C.T3D.T4B,T1A.T2C.T3D.T4C, T1A.T2C.T3D.T4D, T1A.T2C.T3D.T4E,T1A.T2C.T3D.T4F, T1A.T2C.T3D.T4G, T1A.T2C.T3D.T4H,T1A.T2D.T3A.T4A, T1A.T2D.T3A.T4B, T1A.T2D.T3A.T4C,T1A.T2D.T3A.T4D, T1A.T2D.T3A.T4E, T1A.T2D.T3A.T4F,T1A.T2D.T3A.T4G, T1A.T2D.T3A.T4H, T1A.T2D.T3B.T4A,T1A.T2D.T3B.T4B, T1A.T2D.T3B.T4C, T1A.T2D.T3B.T4D,T1A.T2D.T3B.T4E, T1A.T2D.T3B.T4F, T1A.T2D.T3B.T4G,T1A.T2D.T3B.T4H, T1A.T2D.T3C.T4A, T1A.T2D.T3C.T4B,T1A.T2D.T3C.T4C, T1A.T2D.T3C.T4D, T1A.T2D.T3C.T4E,T1A.T2D.T3C.T4F, T1A.T2D.T3C.T4G, T1A.T2D.T3C.T4H,T1A.T2D.T3D.T4A, T1A.T2D.T3D.T4B, T1A.T2D.T3D.T4C,T1A.T2D.T3D.T4D, T1A.T2D.T3D.T4E, T1A.T2D.T3D.T4F,T1A.T2D.T3D.T4G, T1A.T2D.T3D.T4H, T1B.T2A.T3A.T4A,T1B.T2A.T3A.T4B, T1B.T2A.T3A.T4C, T1B.T2A.T3A.T4D,T1B.T2A.T3A.T4E, T1B.T2A.T3A.T4F, T1B.T2A.T3A.T4G,T1B.T2A.T3A.T4H, T1B.T2A.T3B.T4A, T1B.T2A.T3B.T4B,T1B.T2A.T3B.T4C, T1B.T2A.T3B.T4D, T1B.T2A.T3B.T4E,T1B.T2A.T3B.T4F, T1B.T2A.T3B.T4G, T1B.T2A.T3B.T4H,T1B.T2A.T3C.T4A, T1B.T2A.T3C.T4B, T1B.T2A.T3C.T4C,T1B.T2A.T3C.T4D, T1B.T2A.T3C.T4E, T1B.T2A.T3C.T4F,T1B.T2A.T3C.T4G, T1B.T2A.T3C.T4H, T1B.T2A.T3D.T4A,T1B.T2A.T3D.T4B, T1B.T2A.T3D.T4C, T1B.T2A.T3D.T4D,T1B.T2A.T3D.T4E, T1B.T2A.T3D.T4F, T1B.T2A.T3D.T4G,T1B.T2A.T3D.T4H, T1B.T2B.T3A.T4A, T1B.T2B.T3A.T4B,T1B.T2B.T3A.T4C, T1B.T2B.T3A.T4D, T1B.T2B.T3A.T4E,T1B.T2B.T3A.T4F, T1B.T2B.T3A.T4G, T1B.T2B.T3A.T4H,T1B.T2B.T3B.T4A, T1B.T2B.T3B.T4B, T1B.T2B.T3B.T4C,T1B.T2B.T3B.T4D, T1B.T2B.T3B.T4E, T1B.T2B.T3B.T4F,T1B.T2B.T3B.T4G, T1B.T2B.T3B.T4H, T1B.T2B.T3C.T4A,T1B.T2B.T3C.T4B, T1B.T2B.T3C.T4C, T1B.T2B.T3C.T4D,T1B.T2B.T3C.T4E, T1B.T2B.T3C.T4F, T1B.T2B.T3C.T4G,T1B.T2B.T3C.T4H, T1B.T2B.T3D.T4A, T1B.T2B.T3D.T4B,T1B.T2B.T3D.T4C, T1B.T2B.T3D.T4D, T1B.T2B.T3D.T4E,T1B.T2B.T3D.T4F, T1B.T2B.T3D.T4G, T1B.T2B.T3D.T4H,T1B.T2C.T3A.T4A, T1B.T2C.T3A.T4B, T1B.T2C.T3A.T4C,T1B.T2C.T3A.T4D, T1B.T2C.T3A.T4E, T1B.T2C.T3A.T4F,T1B.T2C.T3A.T4G, T1B.T2C.T3A.T4H, T1B.T2C.T3B.T4A,T1B.T2C.T3B.T4B, T1B.T2C.T3B.T4C, T1B.T2C.T3B.T4D,T1B.T2C.T3B.T4E, T1B.T2C.T3B.T4F, T1B.T2C.T3B.T4G,T1B.T2C.T3B.T4H, T1B.T2C.T3C.T4A, T1B.T2C.T3C.T4B,T1B.T2C.T3C.T4C, T1B.T2C.T3C.T4D, T1B.T2C.T3C.T4E,T1B.T2C.T3C.T4F, T1B.T2C.T3C.T4G, T1B.T2C.T3C.T4H,T1B.T2C.T3D.T4A, T1B.T2C.T3D.T4B, T1B.T2C.T3D.T4C,T1B.T2C.T3D.T4D, T1B.T2C.T3D.T4E, T1B.T2C.T3D.T4F,T1B.T2C.T3D.T4G, T1B.T2C.T3D.T4H, T1B.T2D.T3A.T4A,T1B.T2D.T3A.T4B, T1B.T2D.T3A.T4C, T1B.T2D.T3A.T4D,T1B.T2D.T3A.T4E, T1B.T2D.T3A.T4F, T1B.T2D.T3A.T4G,T1B.T2D.T3A.T4H, T1B.T2D.T3B.T4A, T1B.T2D.T3B.T4B,T1B.T2D.T3B.T4C, T1B.T2D.T3B.T4D, T1B.T2D.T3B.T4E,T1B.T2D.T3B.T4F, T1B.T2D.T3B.T4G, T1B.T2D.T3B.T4H,T1B.T2D.T3C.T4A, T1B.T2D.T3C.T4B, T1B.T2D.T3C.T4C,T1B.T2D.T3C.T4D, T1B.T2D.T3C.T4E, T1B.T2D.T3C.T4F,T1B.T2D.T3C.T4G, T1B.T2D.T3C.T4H, T1B.T2D.T3D.T4A,T1B.T2D.T3D.T4B, T1B.T2D.T3D.T4C, T1B.T2D.T3D.T4D,T1B.T2D.T3D.T4E, T1B.T2D.T3D.T4F, T1B.T2D.T3D.T4G,T1B.T2D.T3D.T4H, T1C.T2A.T3A.T4A, T1C.T2A.T3A.T4B,T1C.T2A.T3A.T4C, T1C.T2A.T3A.T4D, T1C.T2A.T3A.T4E,T1C.T2A.T3A.T4F, T1C.T2A.T3A.T4G, T1C.T2A.T3A.T4H,T1C.T2A.T3B.T4A, T1C.T2A.T3B.T4B, T1C.T2A.T3B.T4C,T1C.T2A.T3B.T4D, T1C.T2A.T3B.T4E, T1C.T2A.T3B.T4F,T1C.T2A.T3B.T4G, T1C.T2A.T3B.T4H, T1C.T2A.T3C.T4A,T1C.T2A.T3C.T4B, T1C.T2A.T3C.T4C, T1C.T2A.T3C.T4D,T1C.T2A.T3C.T4E, T1C.T2A.T3C.T4F, T1C.T2A.T3C.T4G,T1C.T2A.T3C.T4H, T1C.T2A.T3D.T4A, T1C.T2A.T3D.T4B,T1C.T2A.T3D.T4C, T1C.T2A.T3D.T4D, T1C.T2A.T3D.T4E,T1C.T2A.T3D.T4F, T1C.T2A.T3D.T4G, T1C.T2A.T3D.T4H,T1C.T2B.T3A.T4A, T1C.T2B.T3A.T4B, T1C.T2B.T3A.T4C,T1C.T2B.T3A.T4D, T1C.T2B.T3A.T4E, T1C.T2B.T3A.T4F,T1C.T2B.T3A.T4G, T1C.T2B.T3A.T4H, T1C.T2B.T3B.T4A,T1C.T2B.T3B.T4B, T1C.T2B.T3B.T4C, T1C.T2B.T3B.T4D,T1C.T2B.T3B.T4E, T1C.T2B.T3B.T4F, T1C.T2B.T3B.T4G,T1C.T2B.T3B.T4H, T1C.T2B.T3C.T4A, T1C.T2B.T3C.T4B,T1C.T2B.T3C.T4C, T1C.T2B.T3C.T4D, T1C.T2B.T3C.T4E,T1C.T2B.T3C.T4F, T1C.T2B.T3C.T4G, T1C.T2B.T3C.T4H,T1C.T2B.T3D.T4A, T1C.T2B.T3D.T4B, T1C.T2B.T3D.T4C,T1C.T2B.T3D.T4D, T1C.T2B.T3D.T4E, T1C.T2B.T3D.T4F,T1C.T2B.T3D.T4G, T1C.T2B.T3D.T4H, T1C.T2C.T3A.T4A,T1C.T2C.T3A.T4B, T1C.T2C.T3A.T4C, T1C.T2C.T3A.T4D,T1C.T2C.T3A.T4E, T1C.T2C.T3A.T4F, T1C.T2C.T3A.T4G,T1C.T2C.T3A.T4H, T1C.T2C.T3B.T4A, T1C.T2C.T3B.T4B,T1C.T2C.T3B.T4C, T1C.T2C.T3B.T4D, T1C.T2C.T3B.T4E,T1C.T2C.T3B.T4F, T1C.T2C.T3B.T4G, T1C.T2C.T3B.T4H,T1C.T2C.T3C.T4A, T1C.T2C.T3C.T4B, T1C.T2C.T3C.T4C,T1C.T2C.T3C.T4D, T1C.T2C.T3C.T4E, T1C.T2C.T3C.T4F,T1C.T2C.T3C.T4G, T1C.T2C.T3C.T4H, T1C.T2C.T3D.T4A,T1C.T2C.T3D.T4B, T1C.T2C.T3D.T4C, T1C.T2C.T3D.T4D,T1C.T2C.T3D.T4E, T1C.T2C.T3D.T4F, T1C.T2C.T3D.T4G,T1C.T2C.T3D.T4H, T1C.T2D.T3A.T4A, T1C.T2D.T3A.T4B,T1C.T2D.T3A.T4C, T1C.T2D.T3A.T4D, T1C.T2D.T3A.T4E,T1C.T2D.T3A.T4F, T1C.T2D.T3A.T4G, T1C.T2D.T3A.T4H,T1C.T2D.T3B.T4A, T1C.T2D.T3B.T4B, T1C.T2D.T3B.T4C,T1C.T2D.T3B.T4D, T1C.T2D.T3B.T4E, T1C.T2D.T3B.T4F,T1C.T2D.T3B.T4G, T1C.T2D.T3B.T4H, T1C.T2D.T3C.T4A,T1C.T2D.T3C.T4B, T1C.T2D.T3C.T4C, T1C.T2D.T3C.T4D,T1C.T2D.T3C.T4E, T1C.T2D.T3C.T4F, T1C.T2D.T3C.T4G,T1C.T2D.T3C.T4H, T1C.T2D.T3D.T4A, T1C.T2D.T3D.T4B,T1C.T2D.T3D.T4C, T1C.T2D.T3D.T4D, T1C.T2D.T3D.T4E,T1C.T2D.T3D.T4F, T1C.T2D.T3D.T4G, T1C.T2D.T3D.T4H,T1D.T2A.T3A.T4A, T1D.T2A.T3A.T4B, T1D.T2A.T3A.T4C,T1D.T2A.T3A.T4D, T1D.T2A.T3A.T4E, T1D.T2A.T3A.T4F,T1D.T2A.T3A.T4G, T1D.T2A.T3A.T4H, T1D.T2A.T3B.T4A,T1D.T2A.T3B.T4B, T1D.T2A.T3B.T4C, T1D.T2A.T3B.T4D,T1D.T2A.T3B.T4E, T1D.T2A.T3B.T4F, T1D.T2A.T3B.T4G,T1D.T2A.T3B.T4H, T1D.T2A.T3C.T4A, T1D.T2A.T3C.T4B,T1D.T2A.T3C.T4C, T1D.T2A.T3C.T4D, T1D.T2A.T3C.T4E,T1D.T2A.T3C.T4F, T1D.T2A.T3C.T4G, T1D.T2A.T3C.T4H,T1D.T2A.T3D.T4A, T1D.T2A.T3D.T4B, T1D.T2A.T3D.T4C,T1D.T2A.T3D.T4D, T1D.T2A.T3D.T4E, T1D.T2A.T3D.T4F,T1D.T2A.T3D.T4G, T1D.T2A.T3D.T4H, T1D.T2B.T3A.T4A,T1D.T2B.T3A.T4B, T1D.T2B.T3A.T4C, T1D.T2B.T3A.T4D,T1D.T2B.T3A.T4E, T1D.T2B.T3A.T4F, T1D.T2B.T3A.T4G,T1D.T2B.T3A.T4H, T1D.T2B.T3B.T4A, T1D.T2B.T3B.T4B,T1D.T2B.T3B.T4C, T1D.T2B.T3B.T4D, T1D.T2B.T3B.T4E,T1D.T2B.T3B.T4F, T1D.T2B.T3B.T4G, T1D.T2B.T3B.T4H,T1D.T2B.T3C.T4A, T1D.T2B.T3C.T4B, T1D.T2B.T3C.T4C,T1D.T2B.T3C.T4D, T1D.T2B.T3C.T4E, T1D.T2B.T3C.T4F,T1D.T2B.T3C.T4G, T1D.T2B.T3C.T4H, T1D.T2B.T3D.T4A,T1D.T2B.T3D.T4B, T1D.T2B.T3D.T4C, T1D.T2B.T3D.T4D,T1D.T2B.T3D.T4E, T1D.T2B.T3D.T4F, T1D.T2B.T3D.T4G,T1D.T2B.T3D.T4H, T1D.T2C.T3A.T4A, T1D.T2C.T3A.T4B,T1D.T2C.T3A.T4C, T1D.T2C.T3A.T4D, T1D.T2C.T3A.T4E,T1D.T2C.T3A.T4F, T1D.T2C.T3A.T4G, T1D.T2C.T3A.T4H,T1D.T2C.T3B.T4A, T1D.T2C.T3B.T4B, T1D.T2C.T3B.T4C,T1D.T2C.T3B.T4D, T1D.T2C.T3B.T4E, T1D.T2C.T3B.T4F,T1D.T2C.T3B.T4G, T1D.T2C.T3B.T4H, T1D.T2C.T3C.T4A,T1D.T2C.T3C.T4B, T1D.T2C.T3C.T4C, T1D.T2C.T3C.T4D,T1D.T2C.T3C.T4E, T1D.T2C.T3C.T4F, T1D.T2C.T3C.T4G,T1D.T2C.T3C.T4H, T1D.T2C.T3D.T4A, T1D.T2C.T3D.T4B,T1D.T2C.T3D.T4C, T1D.T2C.T3D.T4D, 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T1F.T2C.T3B.T4E,T1F.T2C.T3B.T4F, T1F.T2C.T3B.T4G, T1F.T2C.T3B.T4H,T1F.T2C.T3C.T4A, T1F.T2C.T3C.T4B, T1F.T2C.T3C.T4C,T1F.T2C.T3C.T4D, T1F.T2C.T3C.T4E, T1F.T2C.T3C.T4F,T1F.T2C.T3C.T4G, T1F.T2C.T3C.T4H, T1F.T2C.T3D.T4A,T1F.T2C.T3D.T4B, T1F.T2C.T3D.T4C, T1F.T2C.T3D.T4D,T1F.T2C.T3D.T4E, T1F.T2C.T3D.T4F, T1F.T2C.T3D.T4G,T1F.T2C.T3D.T4H, T1F.T2D.T3A.T4A, T1F.T2D.T3A.T4B,T1F.T2D.T3A.T4C, T1F.T2D.T3A.T4D, T1F.T2D.T3A.T4E,T1F.T2D.T3A.T4F, T1F.T2D.T3A.T4G, T1F.T2D.T3A.T4H,T1F.T2D.T3B.T4A, T1F.T2D.T3B.T4B, T1F.T2D.T3B.T4C,T1F.T2D.T3B.T4D, T1F.T2D.T3B.T4E, T1F.T2D.T3B.T4F,T1F.T2D.T3B.T4G, T1F.T2D.T3B.T4H, T1F.T2D.T3C.T4A,T1F.T2D.T3C.T4B, T1F.T2D.T3C.T4C, T1F.T2D.T3C.T4D,T1F.T2D.T3C.T4E, T1F.T2D.T3C.T4F, T1F.T2D.T3C.T4G,T1F.T2D.T3C.T4H, T1F.T2D.T3D.T4A, T1F.T2D.T3D.T4B,T1F.T2D.T3D.T4C, T1F.T2D.T3D.T4D, T1F.T2D.T3D.T4E,T1F.T2D.T3D.T4F, T1F.T2D.T3D.T4G, T1F.T2D.T3D.T4H,T1G.T2A.T3A.T4A, T1G.T2A.T3A.T4B, T1G.T2A.T3A.T4C,T1G.T2A.T3A.T4D, T1G.T2A.T3A.T4E, T1G.T2A.T3A.T4F,T1G.T2A.T3A.T4G, T1G.T2A.T3A.T4H, T1G.T2A.T3B.T4A,T1G.T2A.T3B.T4B, T1G.T2A.T3B.T4C, T1G.T2A.T3B.T4D,T1G.T2A.T3B.T4E, T1G.T2A.T3B.T4F, T1G.T2A.T3B.T4G,T1G.T2A.T3B.T4H, T1G.T2A.T3C.T4A, T1G.T2A.T3C.T4B,T1G.T2A.T3C.T4C, T1G.T2A.T3C.T4D, T1G.T2A.T3C.T4E,T1G.T2A.T3C.T4F, T1G.T2A.T3C.T4G, T1G.T2A.T3C.T4H,T1G.T2A.T3D.T4A, T1G.T2A.T3D.T4B, T1G.T2A.T3D.T4C,T1G.T2A.T3D.T4D, T1G.T2A.T3D.T4E, T1G.T2A.T3D.T4F,T1G.T2A.T3D.T4G, T1G.T2A.T3D.T4H, T1G.T2B.T3A.T4A,T1G.T2B.T3A.T4B, T1G.T2B.T3A.T4C, T1G.T2B.T3A.T4D,T1G.T2B.T3A.T4E, T1G.T2B.T3A.T4F, T1G.T2B.T3A.T4G,T1G.T2B.T3A.T4H, T1G.T2B.T3B.T4A, T1G.T2B.T3B.T4B,T1G.T2B.T3B.T4C, T1G.T2B.T3B.T4D, T1G.T2B.T3B.T4E,T1G.T2B.T3B.T4F, T1G.T2B.T3B.T4G, T1G.T2B.T3B.T4H,T1G.T2B.T3C.T4A, T1G.T2B.T3C.T4B, T1G.T2B.T3C.T4C,T1G.T2B.T3C.T4D, T1G.T2B.T3C.T4E, T1G.T2B.T3C.T4F,T1G.T2B.T3C.T4G, T1G.T2B.T3C.T4H, T1G.T2B.T3D.T4A,T1G.T2B.T3D.T4B, T1G.T2B.T3D.T4C, T1G.T2B.T3D.T4D,T1G.T2B.T3D.T4E, T1G.T2B.T3D.T4F, T1G.T2B.T3D.T4G,T1G.T2B.T3D.T4H, T1G.T2C.T3A.T4A, T1G.T2C.T3A.T4B,T1G.T2C.T3A.T4C, T1G.T2C.T3A.T4D, T1G.T2C.T3A.T4E,T1G.T2C.T3A.T4F, T1G.T2C.T3A.T4G, T1G.T2C.T3A.T4H,T1G.T2C.T3B.T4A, T1G.T2C.T3B.T4B, T1G.T2C.T3B.T4C,T1G.T2C.T3B.T4D, T1G.T2C.T3B.T4E, T1G.T2C.T3B.T4F,T1G.T2C.T3B.T4G, T1G.T2C.T3B.T4H, T1G.T2C.T3C.T4A,T1G.T2C.T3C.T4B, T1G.T2C.T3C.T4C, T1G.T2C.T3C.T4D,T1G.T2C.T3C.T4E, T1G.T2C.T3C.T4F, T1G.T2C.T3C.T4G,T1G.T2C.T3C.T4H, T1G.T2C.T3D.T4A, T1G.T2C.T3D.T4B,T1G.T2C.T3D.T4C, T1G.T2C.T3D.T4D, T1G.T2C.T3D.T4E,T1G.T2C.T3D.T4F, T1G.T2C.T3D.T4G, T1G.T2C.T3D.T4H,T1G.T2D.T3A.T4A, T1G.T2D.T3A.T4B, T1G.T2D.T3A.T4C,T1G.T2D.T3A.T4D, T1G.T2D.T3A.T4E, T1G.T2D.T3A.T4F,T1G.T2D.T3A.T4G, T1G.T2D.T3A.T4H, T1G.T2D.T3B.T4A,T1G.T2D.T3B.T4B, T1G.T2D.T3B.T4C, T1G.T2D.T3B.T4D,T1G.T2D.T3B.T4E, T1G.T2D.T3B.T4F, T1G.T2D.T3B.T4G,T1G.T2D.T3B.T4H, T1G.T2D.T3C.T4A, T1G.T2D.T3C.T4B,T1G.T2D.T3C.T4C, T1G.T2D.T3C.T4D, T1G.T2D.T3C.T4E,T1G.T2D.T3C.T4F, T1G.T2D.T3C.T4G, T1G.T2D.T3C.T4H,T1G.T2D.T3D.T4A, T1G.T2D.T3D.T4B, T1G.T2D.T3D.T4C,T1G.T2D.T3D.T4D, T1G.T2D.T3D.T4E, T1G.T2D.T3D.T4F,T1G.T2D.T3D.T4G, T1G.T2D.T3D.T4H,

In still another embodiment, selected compounds of Formula I and II are named below in tabular format (Table 10) as compounds of general Formula IV (below):

X-A-Yâ€”Zâ€ƒâ€ƒFormula IV

where X, A, Y, and Z are defined in Tables 6-9, below. Each compound is designated in tabular form by combining the â€œcodeâ€ representing each structural moiety using the following syntax: X.A.Y.Z. Thus, for example, X1.A1.Y1.Z1 represents the following structure:

[Image Omitted]

TABLE 6â€œAâ€ StructuresCodeâ€œAâ€ StructureA1 [Image Omitted]

TABLE 7â€œXâ€ StructuresCodeâ€œXâ€ StructureX1 [Image Omitted]

TABLE 8â€œYâ€ StructuresCodeâ€œYâ€ StructureY1 [Image Omitted]

TABLE 9â€œZâ€ StructuresCodeâ€œZâ€ StructureZ1 [Image Omitted]

TABLE 10List of Compound Structures of Formula IIIX1.A1.Y1.Z1, X1.A1.Y1.Z2, X1.A1.Y1.Z3, X1.A1.Y1.Z4,X1.A1.Y1.Z5, X1.A1.Y1.Z6, X1.A1.Y1.Z7, X1.A1.Y1.Z8,X1.A1.Y2.Z1, X1.A1.Y2.Z2, X1.A1.Y2.Z3, X1.A1.Y2.Z4,X1.A1.Y2.Z5, X1.A1.Y2.Z6, X1.A1.Y2.Z7, X1.A1.Y2.Z8,X1.A1.Y3.Z1, X1.A1.Y3.Z2, X1.A1.Y3.Z3, X1.A1.Y3.Z4,X1.A1.Y3.Z5, X1.A1.Y3.Z6, X1.A1.Y3.Z7, X1.A1.Y3.Z8,X1.A1.Y4.Z1, X1.A1.Y4.Z2, X1.A1.Y4.Z3, X1.A1.Y4.Z4,X1.A1.Y4.Z5, X1.A1.Y4.Z6, X1.A1.Y4.Z7, X1.A1.Y4.Z8,X1.A2.Y1.Z1, X1.A2.Y1.Z2, X1.A2.Y1.Z3, X1.A2.Y1.Z4,X1.A2.Y1.Z5, X1.A2.Y1.Z6, X1.A2.Y1.Z7, X1.A2.Y1.Z8,X1.A2.Y2.Z1, X1.A2.Y2.Z2, X1.A2.Y2.Z3, X1.A2.Y2.Z4,X1.A2.Y2.Z5, X1.A2.Y2.Z6, X1.A2.Y2.Z7, X1.A2.Y2.Z8,X1.A2.Y3.Z1, X1.A2.Y3.Z2, X1.A2.Y3.Z3, X1.A2.Y3.Z4,X1.A2.Y3.Z5, X1.A2.Y3.Z6, X1.A2.Y3.Z7, X1.A2.Y3.Z8,X1.A2.Y4.Z1, X1.A2.Y4.Z2, X1.A2.Y4.Z3, X1.A2.Y4.Z4,X1.A2.Y4.Z5, X1.A2.Y4.Z6, X1.A2.Y4.Z7, X1.A2.Y4.Z8,X1.A3.Y1.Z1, X1.A3.Y1.Z2, X1.A3.Y1.Z3, X1.A3.Y1.Z4,X1.A3.Y1.Z5, X1.A3.Y1.Z6, X1.A3.Y1.Z7, X1.A3.Y1.Z8,X1.A3.Y2.Z1, X1.A3.Y2.Z2, X1.A3.Y2.Z3, X1.A3.Y2.Z4,X1.A3.Y2.Z5, X1.A3.Y2.Z6, X1.A3.Y2.Z7, X1.A3.Y2.Z8,X1.A3.Y3.Z1, X1.A3.Y3.Z2, X1.A3.Y3.Z3, X1.A3.Y3.Z4,X1.A3.Y3.Z5, X1.A3.Y3.Z6, X1.A3.Y3.Z7, X1.A3.Y3.Z8,X1.A3.Y4.Z1, X1.A3.Y4.Z2, X1.A3.Y4.Z3, X1.A3.Y4.Z4,X1.A3.Y4.Z5, X1.A3.Y4.Z6, X1.A3.Y4.Z7, X1.A3.Y4.Z8,X1.A4.Y1.Z1, X1.A4.Y1.Z2, X1.A4.Y1.Z3, X1.A4.Y1.Z4,X1.A4.Y1.Z5, X1.A4.Y1.Z6, X1.A4.Y1.Z7, X1.A4.Y1.Z8,X1.A4.Y2.Z1, X1.A4.Y2.Z2, X1.A4.Y2.Z3, X1.A4.Y2.Z4,X1.A4.Y2.Z5, X1.A4.Y2.Z6, X1.A4.Y2.Z7, X1.A4.Y2.Z8,X1.A4.Y3.Z1, X1.A4.Y3.Z2, X1.A4.Y3.Z3, X1.A4.Y3.Z4,X1.A4.Y3.Z5, X1.A4.Y3.Z6, X1.A4.Y3.Z7, X1.A4.Y3.Z8,X1.A4.Y4.Z1, X1.A4.Y4.Z2, X1.A4.Y4.Z3, X1.A4.Y4.Z4,X1.A4.Y4.Z5, X1.A4.Y4.Z6, X1.A4.Y4.Z7, X1.A4.Y4.Z8,X2.A1.Y1.Z1, X2.A1.Y1.Z2, X2.A1.Y1.Z3, X2.A1.Y1.Z4,X2.A1.Y1.Z5, X2.A1.Y1.Z6, X2.A1.Y1.Z7, X2.A1.Y1.Z8,X2.A1.Y2.Z1, X2.A1.Y2.Z2, X2.A1.Y2.Z3, X2.A1.Y2.Z4,X2.A1.Y2.Z5, X2.A1.Y2.Z6, X2.A1.Y2.Z7, X2.A1.Y2.Z8,X2.A1.Y3.Z1, X2.A1.Y3.Z2, X2.A1.Y3.Z3, X2.A1.Y3.Z4,X2.A1.Y3.Z5, X2.A1.Y3.Z6, X2.A1.Y3.Z7, X2.A1.Y3.Z8,X2.A1.Y4.Z1, X2.A1.Y4.Z2, X2.A1.Y4.Z3, X2.A1.Y4.Z4,X2.A1.Y4.Z5, X2.A1.Y4.Z6, X2.A1.Y4.Z7, X2.A1.Y4.Z8,X2.A2.Y1.Z1, X2.A2.Y1.Z2, X2.A2.Y1.Z3, X2.A2.Y1.Z4,X2.A2.Y1.Z5, X2.A2.Y1.Z6, X2.A2.Y1.Z7, X2.A2.Y1.Z8,X2.A2.Y2.Z1, X2.A2.Y2.Z2, X2.A2.Y2.Z3, X2.A2.Y2.Z4,X2.A2.Y2.Z5, X2.A2.Y2.Z6, X2.A2.Y2.Z7, X2.A2.Y2.Z8,X2.A2.Y3.Z1, X2.A2.Y3.Z2, X2.A2.Y3.Z3, X2.A2.Y3.Z4,X2.A2.Y3.Z5, X2.A2.Y3.Z6, X2.A2.Y3.Z7, X2.A2.Y3.Z8,X2.A2.Y4.Z1, X2.A2.Y4.Z2, X2.A2.Y4.Z3, X2.A2.Y4.Z4,X2.A2.Y4.Z5, X2.A2.Y4.Z6, X2.A2.Y4.Z7, X2.A2.Y4.Z8,X2.A3.Y1.Z1, X2.A3.Y1.Z2, X2.A3.Y1.Z3, X2.A3.Y1.Z4,X2.A3.Y1.Z5, X2.A3.Y1.Z6, X2.A3.Y1.Z7, X2.A3.Y1.Z8,X2.A3.Y2.Z1, X2.A3.Y2.Z2, X2.A3.Y2.Z3, X2.A3.Y2.Z4,X2.A3.Y2.Z5, X2.A3.Y2.Z6, X2.A3.Y2.Z7, X2.A3.Y2.Z8,X2.A3.Y3.Z1, X2.A3.Y3.Z2, X2.A3.Y3.Z3, X2.A3.Y3.Z4,X2.A3.Y3.Z5, X2.A3.Y3.Z6, X2.A3.Y3.Z7, X2.A3.Y3.Z8,X2.A3.Y4.Z1, X2.A3.Y4.Z2, X2.A3.Y4.Z3, X2.A3.Y4.Z4,X2.A3.Y4.Z5, X2.A3.Y4.Z6, X2.A3.Y4.Z7, X2.A3.Y4.Z8,X2.A4.Y1.Z1, X2.A4.Y1.Z2, X2.A4.Y1.Z3, X2.A4.Y1.Z4,X2.A4.Y1.Z5, X2.A4.Y1.Z6, X2.A4.Y1.Z7, X2.A4.Y1.Z8,X2.A4.Y2.Z1, X2.A4.Y2.Z2, X2.A4.Y2.Z3, X2.A4.Y2.Z4,X2.A4.Y2.Z5, X2.A4.Y2.Z6, X2.A4.Y2.Z7, X2.A4.Y2.Z8,X2.A4.Y3.Z1, X2.A4.Y3.Z2, X2.A4.Y3.Z3, X2.A4.Y3.Z4,X2.A4.Y3.Z5, X2.A4.Y3.Z6, X2.A4.Y3.Z7, X2.A4.Y3.Z8,X2.A4.Y4.Z1, X2.A4.Y4.Z2, X2.A4.Y4.Z3, X2.A4.Y4.Z4,X2.A4.Y4.Z5, X2.A4.Y4.Z6, X2.A4.Y4.Z7, X2.A4.Y4.Z8,X3.A1.Y1.Z1, X3.A1.Y1.Z2, X3.A1.Y1.Z3, X3.A1.Y1.Z4,X3.A1.Y1.Z5, X3.A1.Y1.Z6, X3.A1.Y1.Z7, X3.A1.Y1.Z8,X3.A1.Y2.Z1, X3.A1.Y2.Z2, X3.A1.Y2.Z3, X3.A1.Y2.Z4,X3.A1.Y2.Z5, X3.A1.Y2.Z6, X3.A1.Y2.Z7, X3.A1.Y2.Z8,X3.A1.Y3.Z1, X3.A1.Y3.Z2, X3.A1.Y3.Z3, X3.A1.Y3.Z4,X3.A1.Y3.Z5, X3.A1.Y3.Z6, X3.A1.Y3.Z7, X3.A1.Y3.Z8,X3.A1.Y4.Z1, X3.A1.Y4.Z2, X3.A1.Y4.Z3, X3.A1.Y4.Z4,X3.A1.Y4.Z5, X3.A1.Y4.Z6, X3.A1.Y4.Z7, X3.A1.Y4.Z8,X3.A2.Y1.Z1, X3.A2.Y1.Z2, X3.A2.Y1.Z3, X3.A2.Y1.Z4,X3.A2.Y1.Z5, X3.A2.Y1.Z6, X3.A2.Y1.Z7, X3.A2.Y1.Z8,X3.A2.Y2.Z1, X3.A2.Y2.Z2, X3.A2.Y2.Z3, X3.A2.Y2.Z4,X3.A2.Y2.Z5, X3.A2.Y2.Z6, X3.A2.Y2.Z7, X3.A2.Y2.Z8,X3.A2.Y3.Z1, X3.A2.Y3.Z2, X3.A2.Y3.Z3, X3.A2.Y3.Z4,X3.A2.Y3.Z5, X3.A2.Y3.Z6, X3.A2.Y3.Z7, X3.A2.Y3.Z8,X3.A2.Y4.Z1, X3.A2.Y4.Z2, X3.A2.Y4.Z3, X3.A2.Y4.Z4,X3.A2.Y4.Z5, X3.A2.Y4.Z6, X3.A2.Y4.Z7, X3.A2.Y4.Z8,X3.A3.Y1.Z1, X3.A3.Y1.Z2, X3.A3.Y1.Z3, X3.A3.Y1.Z4,X3.A3.Y1.Z5, X3.A3.Y1.Z6, X3.A3.Y1.Z7, X3.A3.Y1.Z8,X3.A3.Y2.Z1, X3.A3.Y2.Z2, X3.A3.Y2.Z3, X3.A3.Y2.Z4,X3.A3.Y2.Z5, X3.A3.Y2.Z6, X3.A3.Y2.Z7, X3.A3.Y2.Z8,X3.A3.Y3.Z1, X3.A3.Y3.Z2, X3.A3.Y3.Z3, X3.A3.Y3.Z4,X3.A3.Y3.Z5, X3.A3.Y3.Z6, X3.A3.Y3.Z7, X3.A3.Y3.Z8,X3.A3.Y4.Z1, X3.A3.Y4.Z2, X3.A3.Y4.Z3, X3.A3.Y4.Z4,X3.A3.Y4.Z5, X3.A3.Y4.Z6, X3.A3.Y4.Z7, X3.A3.Y4.Z8,X3.A4.Y1.Z1, X3.A4.Y1.Z2, X3.A4.Y1.Z3, X3.A4.Y1.Z4,X3.A4.Y1.Z5, X3.A4.Y1.Z6, X3.A4.Y1.Z7, X3.A4.Y1.Z8,X3.A4.Y2.Z1, X3.A4.Y2.Z2, X3.A4.Y2.Z3, X3.A4.Y2.Z4,X3.A4.Y2.Z5, X3.A4.Y2.Z6, X3.A4.Y2.Z7, X3.A4.Y2.Z8,X3.A4.Y3.Z1, X3.A4.Y3.Z2, X3.A4.Y3.Z3, X3.A4.Y3.Z4,X3.A4.Y3.Z5, X3.A4.Y3.Z6, X3.A4.Y3.Z7, X3.A4.Y3.Z8,X3.A4.Y4.Z1, X3.A4.Y4.Z2, X3.A4.Y4.Z3, X3.A4.Y4.Z4,X3.A4.Y4.Z5, X3.A4.Y4.Z6, X3.A4.Y4.Z7, X3.A4.Y4.Z8,X4.A1.Y1.Z1, 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Pharmaceutical Formulations

The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986), herein incorporated by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.

While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations of the invention, both for veterinary and for human use, comprise at least one active ingredient, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be â€œacceptableâ€ in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by reference in its entirety. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a 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, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.

For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. 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 formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include TweenÂ® 60, SpanÂ® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining 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-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprise one or more compounds of 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 method 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 to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

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

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the 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, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, 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 a demulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may 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, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 Î¼g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye 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 in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly 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 the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 Î¼m (including particle sizes in a range between 0.1 and 500 Î¼m in increments such as 0.5 Î¼m, 1 Î¼m, 30 Î¼m, 35 Î¼m, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. 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 compounds heretofore used in the treatment or prophylaxis of infections as described herein.

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

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.

The effective dose of an active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. The effective dose can be expected to be from about 0.0001 to about 10 mg/kg body weight per day, typically from about 0.001 to about 1 mg/kg body weight per day, more typically from about 0.01 to about 1 mg/kg body weight per day, even more typically from about 0.05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from about 0.05 mg to about 100 mg, or between about 0.1 mg and about 25 mg, or between about 0.4 mg and about 4 mg, and may take the form of single or multiple doses.

In yet another embodiment, the present application discloses pharmaceutical compositions comprising a compound of Formula I, Ia, Ib, II, IIa, III, or IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional active agent, and a pharmaceutically acceptable carrier or exipient. Examples of the additional active agent also include, but are not limited to interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

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) interferons selected from the group consisting of 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, subalin), interferon alfacon-1 (Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29), belerofon, and mixtures thereof;

(2) ribavirin and its analogs selected from the group consisting of ribavirin (Rebetol, Copegus), taribavirin (Viramidine), and mixtures thereof;

(3) HCV NS3 protease inhibitors selected from the group consisting of boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191, and mixtures thereof;

(4) alpha-glucosidase 1 inhibitors selected from the group consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures thereof;

(5) hepatoprotectants selected from the group consisting of IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures thereof;

(6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase selected from the group consisting of R1626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283), MK-0608, and mixtures thereof;

(7) non-nucleoside inhibitors of HCV NS5B polymerase selected from the group consisting of PF-868554, 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 (nesbuvir), GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;

(8) HCV NS5A inhibitors selected from the group consisting of AZD-2836 (A-831), A-689, and mixtures thereof;

(9) TLR-7 agonists selected from the group consisting of ANA-975, SM-360320, and mixtures thereof;

(10) cyclophillin inhibitors selected from the group consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;

(11) HCV IRES inhibitors selected from the group consisting of MCI-067,

(12) pharmacokinetic enhancers selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, roxythromycin, and mixtures thereof; and

(13) other drugs for treating HCV selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures thereof.

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

a) a first pharmaceutical composition comprising a compound of Formula I, Ia, Ib, II, IIa, III, or IV, or a pharmaceutically acceptable salt, solvate, or ester thereof; and

Routes of Administration

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

Combination Therapy

In one embodiment, the compounds of the present invention are used in combination with other active therapeutic ingredients or agents. Combinations of the compounds of Formula I, Ia, Ib, II, IIa, III, or IV, and additional active agents may be selected to treat patients with a viral infection, e.g., HBV, HCV, or HIV infection.

Preferably, the other active therapeutic ingredients or agents are interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

Combinations of the compounds of Formula I, Ia, Ib, II, IIa, III, or IV, are typically selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. For example, when treating an infection (e.g., HCV), the compositions of the invention are combined with other active agents (such as those described herein).

Suitable active agents or ingredients which can be combined with the compounds of Formula I, Ia, Ib, II, IIa, III, or IV, can include one or more compounds selected from the group consisting of:

(2) ribavirin and its analogs selected from the group consisting of ribavirin (Rebetol, Copegus), taribavirin (Viramidine), and mixtures thereof;

(4) alpha-glucosidase 1 inhibitors selected from the group consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures thereof;

(5) hepatoprotectants selected from the group consisting of IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures thereof;

(6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase selected from the group consisting of 81626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283), MK-0608, and mixtures thereof;

(8) HCV NS5A inhibitors selected from the group consisting of AZD-2836 (A-831), A-689, and mixtures thereof;

(9) TLR-7 agonists selected from the group consisting of ANA-975, SM-360320, and mixtures thereof;

(10) cyclophillin inhibitors selected from the group consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;

(11) HCV IRES inhibitors selected from the group consisting of MCI-067,

(12) pharmacokinetic enhancers selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, roxythromycin, and mixtures thereof; and

In yet another embodiment, the present application discloses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional active agent, and a pharmaceutically acceptable carrier or exipient.

According to the present invention, the active agent used in combination with the compound of the present invention can be any agent having a therapeutic effect when used in combination with the compound of the present invention. For example, the active agent used in combination with the compound of the present invention can be interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

In another embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional active agent selected from the group consisting of: