CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. Provisional Application Serial Number 61/528,384 filed August 29, 2011.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. In particular, the invention herein is directed to spiro bicyclic diamine derivatives as HIV attachment inhibitors that possess unique antiviral activity.

BACKGROUND OF THE INVENTION HIV-1 (human immunodeficiency virus -1) infection remains a major medical problem, with an estimated 45 million people infected worldwide at the end of 2007. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors zidovudine (or AZT or RETROVIR®), didanosine (or VIDEX®), stavudine (or ZERIT®), lamivudine (or 3TC or EPIVIR®), zalcitabine (or DDC or HIVID®), abacavir succinate (or ZIAGEN®), tenofovir disoproxil fumarate salt (or VIREAD®), emtricitabine (or FTC - EMTRIVA®); non- nucleoside reverse transcriptase inhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®), efavirenz (or SUSTIVA®), etravirine (INTELENCE ®) and rilpivirine (EDURANT ®), and peptidomimetic protease inhibitors or approved formulations:

saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ®) and tipranavir (APTIVUS®), and integrase inhibitors such as raltegravir (ISENTRESS ®), and entry inhibitors such as enfuvirtide (T-20) (FUZEON ®) and maraviroc (SELZENTRY ®). Several single pill combinations have been also approved, which include COMBIVIR® (contains lamivudine and zidovudine), TRIZIVIR® (contains abacavir, zidovudine, and lamivudine), Epzicom (contains abacavir and lamivudine), TRUVADA® (contains tenofovir disoproxil fumarate and emtricitabine), ATRIPLA® (contains efavirenz, emtricitabine and tenofovir disoproxil fumarate) and COMPLERA® (contains emtricitabine, rilpivirine, and tenofovir disoproxil fumarate).

Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients may ultimately fail combination drug therapies. Insufficient drug potency, non- compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g., most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV- 1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present. Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options. Improved HIV fusion inhibitors and HIV entry coreceptor antagonists are two examples of new classes of anti-HIV agents further being studied by a number of investigators.

HIV attachment inhibitors are a novel subclass of antiviral compounds that bind to the HIV surface glycoprotein gpl20, and interfere with the interaction between the surface protein gpl20 and the host cell receptor CD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, and block HIV replication in the first stage of the HIV life cycle. The properties of HIV attachment inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents. A disclosure describing indoles of which the structure shown below for BMS-705 is representative, has been disclosed (Antiviral Indoleoxoacetyl Piperazine Derivatives). groups

piperazine amide

BMS-705

Two other compounds, referred to in the literature as BMS-806 and BMS-043 have been described in both the academic and patent art:

azaindole oxo acetyl groups

BMS-806 BMS-043

Some description of their properties in human clinical trials has been disclosed in the literature.

It should be noted that in all three of these structures, a piperazine amide (in these three structures a piperazine phenyl amide) is present and this group is directly attached to an oxoacetyl moiety. The oxoacetyl group is attached at the 3 -position of 4-fluoro indole in BMS-705 and to the 3 position of substituted azaindoles in BMS-806 and BMS-043.

In an effort to obtain improved anti-HIV compounds, later publications described in part, modified substitution patterns on the indoles and azaindoles. Examples of such efforts include: (1) novel substituted indoleoxoacetic piperazine derivatives, (2) substituted piperazinyloxoacetylindole derivatives, and (3) substituted azaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substituted heteroaromatics or bicyclic hydrocarbons was also shown to be feasible. Examples include: (1) indole, azaindole and related heterocyclic amidopiperazine derivatives; (2) bicyclo 4.4.0 antiviral derivatives; and (3) diazaindole derivatives. A select few replacements for the piperazine amide portion of the molecules have also been described in the art and among these examples are (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) some N-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5) some carboline-containing compounds.

Method(s) for preparing prodrugs for this class of compounds are disclosed in

Prodrugs of Piperazine and Substituted Piperidine Antiviral Agents (Ueda et al, U.S. Publication No. 2005/0209246 or WO 2005/090367 Al).

A published PCT patent application WO 2003/103607 Al (June 1 1, 2003) disclosures an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies with piperazine benzamide inhibitors, for example, U.S. Publication No. 2005/0215543 (WO 2005/102328 Al), U.S. Publication No. 2005/0215544 (WO 2005/102391 Al), and U.S. Publication No. 2005/0215545 (WO 2005/102392 A2).

A publication on new compounds in this class of attachment inhibitors (Wang, J. et al, Org. Biol. Chem., 3: 1781-1786 (2005)) and a patent application on some more remotely related compounds have appeared WO 2005/016344 published on February 24, 2005.

Published patent applications WO 2005/016344 and WO 2005/121094 also describe piperazine derivatives which are HIV inhibitors. Other references in the HIV attachment area include U.S. Publication Nos. 2007/0155702, 2007/0078141 and

2007/0287712, WO 2007/103456, as well as U.S. Patent Nos. 7,348,337 and 7,354,924.

A literature reference is J. Med. Chem., 50:6535 (2007).

What is therefore needed in the art are new HIV attachment inhibitor compounds, and compositions thereof, which are efficacious against HIV infection.

Of particular interest are new spiro bicyclic diamines as HIV attachment inhibitor compounds, described herein. The compounds of the present invention are spiro bicyclic diamine deviratives, which are structurally distinct from the piperazine HIV attachment inhibitors disclosed in literature. SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, the

pharmaceutically acceptable salts and/or solvates (e.g., hydrates) thereof, their pharmaceutical formulations, and their use in patients suffering from or susceptible to a virus such as HIV. The compounds of Formula I, their pharmaceutically acceptable salts and/or solvates are effective antiviral agents, particularly as inhibitors of HIV. They are useful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound of Formula I, including pharmaceutically acceptable salts thereof:

I wherein A is selected from the group consisting of:

wherein

a, b, c, d and e are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR ⁵⁶ , XR ⁵⁷ , NA ^X A ² , C(0)R ⁷ , C(0)NR ⁵⁵ R ⁵⁶ , B, Q, and E;

B is selected from the group consisting of -C(=NR ⁴⁶ )(R ⁴⁷ ), C(O)NR ⁴⁰ R ⁴¹ , aryl, heteroaryl, heteroalicyclic, S(0) ₂ R ⁸ , S(O) ₂ NR ⁴⁰ R ⁴¹ , C(0)R ⁷ , XR ^8a , (Ci_ ₆ )alkylNR ⁴⁰ R ⁴¹ , (Ci_6)alkylCOOR ^8b ; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group F; wherein aryl is napthyl or substituted phenyl; wherein heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which may contain from 1 to 2 heteroatoms in the ring skeleton and which may be fused to a benzene or pyridine ring; Q is selected from the group consisting of (Ci_6)alkyl and (C2-6)alkenyl; wherein said (Ci_ 6)alkyl and (C2-6)alkenyl are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group consisting of C(0)NR ⁵⁵ R ⁵⁶ , hydroxy, cyano and XR ⁵⁷ ; E is selected from the group consisting of (Ci_6)alkyl and (C2-6)alkenyl; wherein said (Ci_ ₆ )alkyl and (C2-6)alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C(0)NR ⁵⁶ R ⁵⁷ , C(0)R ⁵⁷ , S02(Ci-6)alkyl and SO2PI1; wherein heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms;

F is selected from the group consisting of (Ci_ ₆ )alkyl, (C3_7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, aryloxy, (Ci_6)thioalkoxy, cyano, halogen, nitro, - C(0)R ⁵⁷ , benzyl, -NR ⁴² C(0)-(Ci_ ₆ )alkyl, -NR ⁴² C(0)-(C ₃ -6)cycloalkyl, -NR ⁴² C(0)-aryl, - NR ⁴² C(0)-heteroaryl, -NR ⁴² C(0)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N- lactam, -NR ⁴² S(0) ₂ -(Ci_ ₆ )alkyl, -NR ⁴² S(0) ₂ -(C ₃ -6)cycloalkyl, -NR ⁴² S(0)2-aryl, -

NR ⁴² S(0) ₂ -heteroaryl, -NR ⁴² S(0)2-heteroalicyclic, S(0) ₂ (Ci_ ₆ )alkyl, S(0) ₂ aryl, -S(0)2 NR ⁴² R ⁴³ , NR ⁴² R ⁴³ , (Ci_ ₆ )alkylC(0)NR ⁴² R ⁴³ , C(0)NR ⁴² R ⁴³ , NHC(0)NR ⁴² R ⁴³ ,

OC(0)NR ⁴² R ⁴³ , NHC(0)OR ⁵⁴ , (Ci_ ₆ )alkylNR ⁴² R ⁴³ , COOR ⁵⁴ and (Ci_ ₆ )alkylCOOR ⁵⁴ ; wherein said (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, (Ci-6)alkoxy, and aryloxy, are optionally substituted with one to nine same or different halogens or from one to five same or different substituents selected from the group G; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

G is selected from the group consisting of (Ci_6)alkyl, (C3_7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, aryloxy, cyano, halogen, nitro,-C(0)R ⁵⁷ , benzyl, - NR ⁴⁸ C(0)-(Ci_ ₆ )alkyl, -NR ⁴⁸ C(0)-(C ₃ -6)cycloalkyl,-NR ⁴⁸ C(0)-aryl, -NR ⁴⁸ C(0)- heteroaryl, -NR ⁴⁸ C(0)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam, - NR ⁴⁸ S(0) ₂ -(Ci_ ₆ )alkyl, -NR ⁴⁸ S(0) ₂ -(C ₃ - ₆ )cycloalkyl, -NR ⁴⁸ S(0)2-aryl, -NR ⁴⁸ S(0) ₂ - heteroaryl, -NR ⁴⁸ S(0)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR ⁴⁸ R ⁴⁹ , (Ci_ ₆ )alkyl C(0)NR ⁴⁸ R ⁴⁹ , C(0)NR ⁴⁸ R ⁴⁹ , NHC(0)NR ⁴⁸ R ⁴⁹ , OC(0)NR ⁴⁸ R ⁴⁹ , NHC(0)OR ^54' , (Ci_ ₆ )alkylNR ⁴⁸ R ⁴⁹ , COOR ⁵⁴ , and (Ci_ ₆ )alkylCOOR ⁵⁴ ; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

R ⁷ is selected from the group consisting of aryl, heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with from one to three same or different substituents selected from the group F ; wherein for R 7 , R 8 , R 8a , R 8b aryl is phenyl; heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for mono cyclic systems and up to 10 atoms in a bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,

tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

R ⁸ is selected from the group consisting of hydrogen, (Ci-6)alkyl, (C3_7)cycloalkyl, (C ₂ -6)alkenyl, (C3-7)cycloalkenyl, (C ₂ -6)alkynyl, aryl, heteroaryl, and heteroalicyclic; wherein said (Ci_6)alkyl, (C3_7)cycloalkyl, (C ₂ _6)alkenyl, (C3_7)cycloalkenyl,

(C ₂ _6)alkynyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F or (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl;

R ^8a is a member selected from the group consisting of aryl, heteroaryl, and

heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F;

8b

R is selected from the group consisting of hydrogen, (Ci_6)alkyl and phenyl; X is selected from the group consisting of NH or NCH ₃ , O, and S;

R ⁴⁰ and R ⁴¹ are independently selected from the group consisting of (a) hydrogen; (b) (Ci_ ₆ )alkyl or (C3_7)cycloalkyl substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F or different functional groups: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (Ci_6)alkoxy, aryl, heteroaryl or heteroalicyclic; or R ⁴⁰ and R ⁴¹ taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl, and

heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F; wherein for R and R ⁴¹ aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine; provided when B is C(O)NR ⁴⁰ R ⁴¹ , at least one of R ⁴⁰ and R ⁴¹ is not selected from groups (a) or (b);

R ⁴² and R ⁴³ are independently selected from the group consisting of hydrogen,

(Ci_6)alkyl, allyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R ⁴² and R ⁴³ taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said (Ci_6)alkyl, (Ci_ ₆ )alkoxy, (C3_7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group G or different functional groups: (Ci_6)alkyl, (C _3- 6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; wherein for R ⁴² and R ⁴³ aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,

tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

R ⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryl and (Ci_6)alkyl, OR ⁵⁷ , and NR ⁵⁵ R ⁵⁶ ; R is selected from the group consisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and (Ci-6)alkyl;

R ⁴⁸ and R ⁴⁹ are independently selected from the group consisting of hydrogen,

(Ci_6)alkyl, phenyl, aryl and heteroaryl;

R ⁵⁰ is selected from the group consisting of H, (Ci_6)alkyl, (C3-6)cycloalkyl, and benzyl; wherein each of said (Ci_6)alkyl, (C3_7)cycloalkyl and benzyl are optionally substituted with one to three same or different (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl

R ⁵⁴ is selected from the group consisting of hydrogen and (Ci_6)alkyl; R ⁵⁴ is (Ci_ ₆ )alkyl; R ⁵⁵ and R ⁵⁶ are independently selected from the group consisting of hydrogen and (Ci_ ₆ )alkyl; and

R ⁵⁷ is selected from the group consisting of hydrogen, (Ci_6)alkyl, aryl, heteroaryl; and A ¹ and A ² are independently selected from hydrogen, (Ci_6)alkyl, aryl, heteroaryl, S02D , S02ND ² D ³ , COD ⁴ , COCOD ⁴ , COOD ⁴ , COND ⁵ D ⁶ , COCOND ⁵ D ⁶ , COCOOD ⁴ ,

C(=ND ⁷ )D ⁸ , C(=ND ⁹ )ND ¹⁰ D ⁿ ; A ¹ and A ² can either never connect with each other, or they can conjoin to form structure;

D ¹ , D ² , D ³ , D ⁴ , D ⁵ , D ⁶ , D ⁷ , D ⁸ , D ⁹ , D ¹⁰ , and D ¹¹ are each independently selected from the group consisting of H, C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, phenyl, heteroaryl, C3-C50 amide and C3-C50 ether; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, lH-imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin- 2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbon atoms which comprise the carbon-carbon double bond of said C3-C2 ₀ alkenyl or the carbon-carbon triple bond of said C3-C2 ₀ alkynyl are not the point of attachment to the nitrogen to which D ² , D ³ , D ⁵ , D ⁶ , D ⁷ , D ⁹ , D ¹⁰ , and D ¹¹ is attached; wherein said C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, aryl, phenyl, heteroaryl, C3-C50 amide and C3-C50 ether is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide and steroid, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; selected from the group of:

P is selecited form Ar or J; Ar is selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are each independently optionally substituted with one to three same or different members selected from the group Ar-I; and heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, lH-imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl;

Ar-I is selected from the group consisting of (Ci_ ₆ )alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, primary amine, secondary amine, tertiary amine, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, oxime and hydrazine, among which ether, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; wherein said (Ci_6)alkyl, (Ci-6)alkyl, (C3-6)cycloalkyl is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, oxime and hydrazine, among which ether, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic;

J is selected from the group consisting of H, C1-C30 alkyl, C3-C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C30 urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine; aryl or heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H- imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl, triazolyl, naphthalenyl, quinolinyl,

isoquinolinyl, quinoxalinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl, azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein said C1-C30 alkyl, C3- C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C3o urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci-6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, and peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic;

Z is selected from the group consisting of phenyl, C5-C7 monocyclic heteroaryl, C9-C1 ₀ bicyclic aryl, C9-C10 bicyclic heteroaryl, C4-C7 heteroalicyclic, and C5-C7 cycloalkyl wherein said heteroaryl or heteroalicyclic contains from 1 to 4 heteroatoms selected from O, N, and S and with the proviso when Z is a bicyclic heteroaryl both R and Z are attached to a common ring wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from oxo, hydroxyl, Ci-C ₆ alkyl, -NR ¹⁰¹ R ¹⁰² , - OC1-C3 alkyl, -S-Ri,-S(0) ₂ Ri, CF ₃ , CN,; wherein said d-C ₆ alkyl can be optionally substituted with Group B;

R is selected from the group of:

Ii, , I3, 14, 15, , I7, 1 ₈ , ¾, I10, In and I ₁₂ are each independently selected from the group consisting of H, (Ci_6)alkyl, (C _3- 6) cycloalkyl, (C _2- 6) alkenyl, (C4-6) cycloalkenyl, (C _2- 6) alkynyl, CR ⁸¹ R ⁸² OR ⁸³ , COR ⁸⁴ , COOR ⁸⁵ , or CONR ⁸⁶ R ⁸⁷ ; wherein each of said alkyl and cycloalkyl being optionally substituted with one to three same or different cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl;

R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ , R ⁸⁵ , R ⁸⁶ and R ⁸⁷ are each independently selected from the group consisting of H, (Ci_6)alkyl, (C _3- 6) cycloalkyl, (C _2- 6) alkenyl, (C4-6) cycloalkenyl, (C _2- 6) alkynyl; and

R ¹⁰¹ and R ¹⁰² are selected from the group consisting of H, C1-C ₃₀ alkyl, C ₃ -C ₃₀ cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C30 tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C ₃₀ bicycloalkenyl, C7-C ₃₀ tricycloalkenyl, C9-C ₃₀ tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C30 urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine; aryl or heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H- imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl, triazolyl, naphthalenyl, quinolinyl,

isoquinolinyl, quinoxalinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl, azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein said C1-C30 alkyl, C3- C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C3o urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, and peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic.

Another embodiment of the present invention is directed to a method for treating mammals infected with a virus, especially wherein the virus is HIV, comprising administering to said mammal an antiviral effective amount of a compound of Formula I above, and one or more pharmaceutically acceptable carriers, excipients or diluents. Optionally, the compound of Formula I can be administered in combination with an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator; and (d) other HIV entry inhibitors. Another embodiment of the present invention is a pharmaceutical composition comprising an antiviral effective amount of a compound of Formula I and one or more pharmaceutically acceptable carriers, excipients, diluents and optionally in combination with an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an

immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or more methods for making the compounds of Formula I.

The present invention is directed to these, as well as other important ends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds of the present invention may possess asymmetric centers and therefore occur as mixtures of diastereomers and enantiomers, the present disclosure includes the individual diastereoisomeric and enantiomeric forms of the compounds of Formula I in addition to the mixtures thereof.

Definitions

Unless otherwise specifically set forth elsewhere in the application, one or more of the following terms may be used herein, and shall have the following meanings:

The term "H" refers to hydrogen, including its isotopes, such as deuterium.

The term "Ci_ ₆ alkyl" as used herein and in the claims (unless specified otherwise) mean straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ?-butyl, amyl, hexyl and the like.

"Ci -C ₄ fluoroalkyl" refers to F-substituted Ci -C ₄ alkyl wherein at least one H atom is substituted with F atom, and each H atom can be independently substituted by F atom.

"Halogen" refers to chlorine, bromine, iodine or fluorine.

An "aryl" or "Ar" group refers to an all carbon monocyclic or fused-ring polycyclic(z.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NR ^x R ^y , wherein R ^x and R ^y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- or six-member heteroalicyclic ring.

As used herein, a "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Unless otherwise indicated, the heteroaryl group may be attached at either a carbon or nitrogen atom within the heteroaryl group. It should be noted that the term heteroaryl is intended to encompass an N-oxide of the parent heteroaryl if such an N-oxide is chemically feasible as is known in the art. Examples, without limitation, of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine, triazinyl, tetrazinyl, and tetrazolyl. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino, and -NR ^x R ^y , wherein R ^x and R ^y are as defined above.

As used herein, a "heteroalicyclic" group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. Rings are selected from those which provide stable arrangements of bonds and are not intended to encompass systems which would not exist. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of

heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3- pyrrolidin-l-yl, morpholinyl, thiomorpholinyl and tetrahydropyranyl. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and -NR ^x R ^y , wherein R ^x and R ^y are as defined above.

An "alkyl" group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., "1-20", is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from trihaloalkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,

heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy,

thioheteroalicycloxy, cyano, halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O- carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,

trihalomethanesulfonyl, and combined, a five- or six-member heteroalicyclic ring.

A "cycloalkyl" group refers to an all-carbon monocyclic or fused ring (i.e., rings which share and adjacent pair of carbon atoms) group wherein one or more rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C- thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and -NR ^x R ^y with R ^x and R ^y as defined above.

An "alkenyl" group refers to an alkyl group, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond.

An "alkynyl" group refers to an alkyl group, as defined herein, having at least two carbon atoms and at least one carbon-carbon triple bond.

A "hydroxy" group refers to an -OH group.

An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group as defined herein.

An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.

A "heteroaryloxy" group refers to a heteroaryl-O- group with heteroaryl as defined herein.

A "heteroalicycloxy" group refers to a heteroalicyclic-O- group with

heteroalicyclic as defined herein.

A "thiohydroxy" group refers to an -SH group.

A "thioalkoxy" group refers to both an S-alkyl and an -S-cycloalkyl group, as defined herein.

A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.

A "thioheteroaryloxy" group refers to a heteroaryl-S- group with heteroaryl as defined herein.

A "thioheteroalicycloxy" group refers to a heteroalicyclic-S- group with heteroalicyclic as defined herein.

A "carbonyl" group refers to a -C(=0)-R" group, where R" is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), as each is defined herein.

An "aldehyde" group refers to a carbonyl group where R" is hydrogen.

A "thiocarbonyl" group refers to a -C(=S)-R" group, with R" as defined herein.

A "Keto" group refers to a -CC(=0)C- group wherein the carbon on either or both sides of the C=0 may be alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroalicyclic group. A "trihalomethanecarbonyl" group refers to a Z ₃ CC(=0)- group with said Z being a halogen.

A "C-carboxy" group refers to a -C(=0)0-R" groups, with R" as defined herein. An "O-carboxy" group refers to a R"C(-0)0-group, with R" as defined herein. A "carboxylic acid" group refers to a C-carboxy group in which R" is hydrogen.

A "trihalomethyl" group refers to a -CZ ₃ , group wherein Z is a halogen group as defined herein.

A "trihalomethanesulfonyl" group refers to an groups with Z as defined above.

A "trihalomethanesulfonamido" group refers to a group with Z as defined above and R ^x being H or (Ci-6)alkyl.

A "sulfinyl" group refers to a -S(=0)-R" group, with R" being (Ci_6)alkyl.

A "sulfonyl" group refers to a -S(=0)2R" group with R" being (Ci_6)alkyl.

A "S-sulfonamido" group refers to a -S(=0) ₂ NR ^x R ^Y , with R ^x and R ^Y independently being H or (Ci-6)alkyl.

A "N-Sulfonamido" group refers to a R"S(=0)2NRx- group, with R _x being H or (Ci _-6 )alkyl.

A "O-carbamyl" group refers to a -OC(=0)NR ^x R ^y group, with R ^x and R ^Y independently being H or (Ci_6)alkyl.

A "N-carbamyl" group refers to a R ^x OC(=0)NR ^y group, with R ^x and R ^y independently being H or (Ci_6)alkyl.

A "O-thiocarbamyl" group refers to a -OC(=S)NR ^x R ^y group, with R ^x and R ^y independently being H or (Ci_6)alkyl.

A "N-thiocarbamyl" group refers to a R ^x OC(=S)NR ^y - group, with R ^x and R ^y independently being H or (Ci-6)alkyl.

An "amino" group refers to an -NH ₂ group.

A "C-amido" group refers to a -C(=0)NR ^x R ^y group, with R ^x and R ^y

independently being H or (Ci_6)alkyl.

A "C-thioamido" group refers to a -C(=S)NR ^x R ^y group, with R ^x and R ^y independently being H or (Ci-6)alkyl.

A "N-amido" group refers to a R ^x C(=0)NR ^y - group, with R ^x and R ^y

independently being H or (Ci_6)alkyl. An "ureido" group refers to a -NR ^x C(=0)NR ^y R ^y2 group, with R ^x , R ^y , and R ^y2 independently being H or (Ci-6)alkyl.

A "guanidino" group refers to a -R ^x NC(=N)NR ^y R ^y2 group, with R ^x , R ^y , and R ^y2 independently being H or (Ci_6)alkyl.

A "guanyl" group refers to a R ^x R ^y NC(=N)- group, with R ^x and R ^y independently being H or (Ci_6)alkyl.

A "cyano" group refers to a -CN group.

A "silyl" group refers to a -Si(R")3, with R" being (Ci-6)alkyl or phenyl.

A "phosphonyl" group refers to a P(=0)(OR ^x ) ₂ with R ^x being (C _1-6 )alkyl.

A "hydrazino" group refers to a -NR ^x NR ^y R ^y2 group, with R ^x , R ^y , and R ^y2 independently being H or (Ci_6)alkyl.

A "4, 5, or 6 membered ring cyclic N-lactam" group refers to

Any two adjacent R groups may combine to form an additional aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initially bearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be

"participating in a heteroaryl ring double bond", and this refers to the form of double bonds in the two tautomeric structures which comprise five-member ring heteroaryl groups. This dictates whether nitrogens can be substituted as well understood by chemists in the art. The disclosure and claims of the present disclosure are based on the known general principles of chemical bonding. It is understood that the claims do not encompass structures known to be unstable or not able to exist based on the literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosed herein are within the scope of this disclosure. The term "pharmaceutically acceptable salt" as used herein and in the claims is intended to include nontoxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. The term "pharmaceutically acceptable salt" as used herein is also intended to include salts of acidic groups, such as a carboxylate, with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines

(methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g., hydroxyl-substituted alkylamines such as diethanolamine,

triethanolamine or tris(hydroxymethyl)- aminomethane), or with bases such as piperidine or morpholine.

As stated above, the compounds of the invention also include "prodrugs". The term "prodrug" as used herein encompasses both the term "prodrug esters" and the term "prodrug ethers". The term "prodrug esters" as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of Formula I with either alkyl, alkoxy, or aryl substituted acylating agents or phosphorylating agent employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates, amino acid esters, phosphates, half acid esters such as malonates, succinates or glutarates, and the like. In certain embodiments, amino acid esters may be especially preferred.

Examples of such prodrug esters include

The term "prodrug ethers" include both phosphate acetals and O-glucosides. Representative examples of such prodrug ethers include

Prodrug derivatives in which the prodrug moiety is attached to the indole N atom are also considered part of this invention. These prodrugs can be prepared by substitution of the indole N with a moiety that modifies the physical properties of the compound and can be unmasked either by chemical or enzymatic degradation. Examples of R3 include acyl derivatives similar to those described above. A preferred prodrug is the

phosphonoxymethyl moiety which can be introduced using methods previously described and converted to pharmaceutically acceptable salt forms that confer chemical stability and advantageous physical properties:

As set forth above, the invention is directed to compounds of Formula I, including pharmaceutically acceptable salts thereof:

I wherein A is selected from the group consisting

wherein a, b, c, d and e are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR ⁵⁶ , XR ⁵⁷ , NA ^X A ² , C(0)R ⁷ , C(0)NR ⁵⁵ R ⁵⁶ , B, Q, and E;

B is selected from the group consisting of -C(=NR ⁴⁶ )(R ⁴⁷ ), C(O)NR ⁴⁰ R ⁴¹ , aryl, heteroaryl, heteroalicyclic, S(0) ₂ R ⁸ , S(O) ₂ NR ⁴⁰ R ⁴¹ , C(0)R ⁷ , XR ^8a , (Ci_ ₆ )alkylNR ⁴⁰ R ⁴¹ , (Ci_6)alkylCOOR ^8b ; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group F; wherein aryl is napthyl or substituted phenyl; wherein heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which may contain from 1 to 2 heteroatoms in the ring skeleton and which may be fused to a benzene or pyridine ring; Q is selected from the group consisting of (Ci_6)alkyl and (C2-6)alkenyl; wherein said (Ci- 6)alkyl and (C2-6)alkenyl are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group consisting of C(0)NR ⁵⁵ R ⁵⁶ , hydroxy, cyano and XR ⁵⁷ ; E is selected from the group consisting of (Ci_6)alkyl and (C2-6)alkenyl; wherein said (Ci_ ₆ )alkyl and (C2-6)alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh,

-C(0)NR ⁵⁶ R ⁵⁷ , C(0)R ⁵⁷ , S0 ₂ (Ci_ ₆ )alkyl and S0 ₂ Ph; wherein heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms;

F is selected from the group consisting of (Ci_6)alkyl, (C3_7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, aryloxy, (Ci_6)thioalkoxy, cyano, halogen, nitro, - C(0)R ⁵⁷ , benzyl, -NR ⁴² C(0)-(Ci_ ₆ )alkyl, -NR ⁴² C(0)-(C ₃ - ₆ )cycloalkyl, -NR ⁴² C(0)-aryl, - NR ⁴² C(0)-heteroaryl, -NR ⁴² C(0)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N- lactam, -NR ⁴² S(0) ₂ -(Ci_ ₆ )alkyl, -NR ⁴² S(0) ₂ -(C ₃ -6)cycloalkyl, -NR ⁴² S(0)2-aryl, -

NR ⁴² S(0) ₂ -heteroaryl, -NR ⁴² S(0)2-heteroalicyclic, S(0) ₂ (Ci_ ₆ )alkyl, S(0) ₂ aryl, -S(0)2 NR ⁴² R ⁴³ , NR ⁴² R ⁴³ , (Ci_ ₆ )alkylC(0)NR ⁴² R ⁴³ , C(0)NR ⁴² R ⁴³ , NHC(0)NR ⁴² R ⁴³ ,

OC(0)NR ⁴² R ⁴³ , NHC(0)OR ⁵⁴ , (Ci_ ₆ )alkylNR ⁴² R ⁴³ , COOR ⁵⁴ , and (Ci_ ₆ )alkylCOOR ⁵⁴ ; wherein said (Ci_6)alkyl, (C3_7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, (Ci_6)alkoxy, and aryloxy, are optionally substituted with one to nine same or different halogens or from one to five same or different substituents selected from the group G; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

G is selected from the group consisting of (Ci_ ₆ )alkyl, (C3_7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, aryloxy, cyano, halogen, nitro,-C(0)R ⁵⁷ , benzyl, - NR ⁴⁸ C(0)-(Ci_ ₆ )alkyl, -NR ⁴⁸ C(0)-(C ₃ -6)cycloalkyl,-NR ⁴⁸ C(0)-aryl, -NR ⁴⁸ C(0)- heteroaryl, -NR ⁴⁸ C(0)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam, - NR ⁴⁸ S(0) ₂ -(Ci_ ₆ )alkyl, -NR ⁴⁸ S(0) ₂ -(C ₃ -6)cycloalkyl, -NR ⁴⁸ S(0)2-aryl, -NR ⁴⁸ S(0) ₂ - heteroaryl, -NR ⁴⁸ S(0)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR ⁴⁸ R ⁴⁹ , (Ci_ ₆ )alkyl C(0)NR ⁴⁸ R ⁴⁹ , C(0)NR ⁴⁸ R ⁴⁹ , NHC(0)NR ⁴⁸ R ⁴⁹ , OC(0)NR ⁴⁸ R ⁴⁹ , NHC(0)OR ^54' , (Ci_ ₆ )alkylNR ⁴⁸ R ⁴⁹ , COOR ⁵⁴ , and (Ci_ ₆ )alkylCOOR ⁵⁴ ; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

R ⁷ is selected from the group consisting of aryl, heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with from one to three same or different substituents selected from the group F; wherein for R 7 , R 8 , R 8a , R 8b aryl is phenyl; heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for mono cyclic systems and up to 10 atoms in a bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,

tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

R ⁸ is selected from the group consisting of hydrogen, (Ci-6)alkyl, (C3_7)cycloalkyl, (C2-6)alkenyl, (C3_7)cycloalkenyl, (C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic; wherein said (Ci-6)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (C3-7)cycloalkenyl,

(C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F or (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl;

R ^8a is a member selected from the group consisting of aryl, heteroaryl, and

heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F;

R ^8b is selected from the group consisting of hydrogen, (Ci_6)alkyl and phenyl;

X is selected from the group consisting of NH or NCH3, O, and S;

R ⁴⁰ and R ⁴¹ are independently selected from the group consisting of

(a) hydrogen; (b) (Ci_6)alkyl or (C3_7)cycloalkyl substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F or different functional groups: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (Ci_6)alkoxy, aryl, heteroaryl or heteroalicyclic; or R ⁴⁰ and R ⁴¹ taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F; wherein for R ⁴⁰ and R ⁴¹ aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine; provided when B is C(O)NR ⁴⁰ R ⁴¹ , at least one of R ⁴⁰ and R ⁴¹ is not selected from groups (a) or (b);

R ⁴² and R ⁴³ are independently selected from the group consisting of hydrogen,

(Ci_6)alkyl, allyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R ⁴² and R ⁴³ taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said (Ci_6)alkyl, (Ci_ ₆ )alkoxy, (C3_7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group G or different functional groups: (Ci_6)alkyl, (C ₃ _ 6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; wherein for R ⁴² and R ⁴³ aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,

tetrahydrofuran, tetrahydropyran, azepine, and morpholine;

R ⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryl and (Ci_6)alkyl, OR ⁵⁷ , and NR ⁵⁵ R ⁵⁶ ;

R ⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and (Ci_6)alkyl;

R ⁴⁸ and R ⁴⁹ are independently selected from the group consisting of hydrogen,

(Ci-6)alkyl, phenyl, aryl and heteroaryl;

R ⁵⁰ is selected from the group consisting of H, (Ci_6)alkyl, (C3-6)cycloalkyl, and benzyl; wherein each of said (Ci_6)alkyl, (C3_7)cycloalkyl and benzyl are optionally substituted with one to three same or different (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl

R ⁵⁴ is selected from the group consisting of hydrogen and (Ci_6)alkyl;

R ⁵⁴ is (Ci_ ₆ )alkyl; R and R are independently selected from the group consisting of hydrogen and (Ci- ₆ )alkyl; and R ⁵⁷ is selected from the group consisting of hydrogen, (Ci_6)alkyl, aryl, heteroaryl; and

A ¹ and A ² are independently selected from hydrogen, (Ci_6)alkyl, aryl, heteroaryl, S02D ¹ , S02ND ² D ³ , COD ⁴ , COCOD ⁴ , COOD ⁴ , COND ⁵ D ⁶ , COCOND ⁵ D ⁶ , COCOOD ⁴ ,

C(=ND ⁷ )D ⁸ , C(=ND ⁹ )ND ¹⁰ D ⁿ ;

A ¹ and A ² can either never connect with each other, or they can conjoin to form a ring structure;

D ¹ , D ² , D ³ , D ⁴ , D ⁵ , D ⁶ , D ⁷ , D ⁸ , D ⁹ , D ¹⁰ , and D ¹¹ are each independently selected from the group consisting of H, C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, phenyl, heteroaryl, C ₃ -C50 amide and C ₃ -C50 ether; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, lH-imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin- 2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbon atoms which comprise the carbon-carbon double bond of said C ₃ -C2 ₀ alkenyl or the carbon-carbon triple bond of said C ₃ -C2 ₀ alkynyl are not the point of attachment to the nitrogen to which D ² , D ³ , D ⁵ , D ⁶ , D ⁷ , D ⁹ , D ¹⁰ , and D ¹¹ is attached; wherein said C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, aryl, phenyl, heteroaryl, C ₃ -C50 amide and C ₃ -C50 ether is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C ₃ _6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide and steroid, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; selected from the group of:

P is selecited form Ar or J; Ar is selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are each independently optionally substituted with one to three same or different members selected from the group Ar-I; and heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, lH-imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl;

Ar-I is selected from the group consisting of (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, primary amine, secondary amine, tertiary amine, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, oxime and hydrazine, among which ether, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; wherein said (Ci-6)alkyl, (Ci_6)alkyl, (C3_6)cycloalkyl is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, oxime and hydrazine, among which ether, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; J is selected from the group consisting of H, C1-C30 alkyl, C3-C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C30 urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C ₃ -C30 cyclic guanidine; aryl or heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H- imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl, triazolyl, naphthalenyl, quinolinyl,

isoquinolinyl, quinoxalinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl, azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein said C1-C30 alkyl, C3- C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C3o urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, and peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; Z is selected from the group consisting of phenyl, C5-C7 monocyclic heteroaryl, C9-C1 ₀ bicyclic aryl, C9-C10 bicyclic heteroaryl, C4-C7 heteroalicyclic, and C5-C7 cycloalkyl wherein said heteroaryl or heteroalicyclic contains from 1 to 4 heteroatoms selected from O, N, and S and with the proviso when Z is a bicyclic heteroaryl both R and Z are attached to a common ring wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from oxo, hydroxyl, Ci-C ₆ alkyl, -NR ¹⁰¹ R ¹⁰² , - OC1-C3 alkyl, -S-Ri,-S(0) ₂ Ri, CF ₃ , CN,; wherein said d-C ₆ alkyl can be optionally substituted with Group B;

R is selected from the group of:

Ii, , I3, 14, 15, , I7, 1 ₈ , ¾, I10, In and I12 are each independently selected from the group consisting of H, (Ci-6)alkyl, (C3-6) cycloalkyl, (C2-6) alkenyl, (C4-6) cycloalkenyl, (C2-6) alkynyl, CR ⁸¹ R ⁸² OR ⁸³ , COR ⁸⁴ , COOR ⁸⁵ , or CONR ⁸⁶ R ⁸⁷ ; wherein each of said alkyl and cycloalkyl being optionally substituted with one to three same or different cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; R , R , R , R , R , R ^8b and R ^{8 /} are each independently selected from the group consisting of H, (Ci-6)alkyl, (C3-6) cycloalkyl, (C2-6) alkenyl, (C4-6) cycloalkenyl, (C2-6) alkynyl; and R ¹⁰¹ and R ¹⁰² are selected from the group consisting of H, C1-C30 alkyl, C3-C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C30 urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine; aryl or heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H- imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl, triazolyl, naphthalenyl, quinolinyl,

isoquinolinyl, quinoxalinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl, azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein said C1-C30 alkyl, C3- C30 cycloalkyl, C4-C30 bicycloalkyl, C5-C ₃ o tricycloalkyl, C6-C ₃₀ tetracycloalkyl, C3-C30 alkenyl, C4-C30 cycloalkenyl, C5-C30 bicycloalkenyl, C7-C30 tricycloalkenyl, C9-C30 tetracycloalkyl, phenyl, aryl, heteroaryl, C1-C30 amide, C3-C30 cyclic amide, C1-C30 amine, C3-C30 cyclic amine, C2-C30 ester, C3-C30 cyclic ester, C2-C30 ether, C3-C30 cyclic ether, C1-C30 sulfonamide, C3-C30 cyclic sulfonamide, C2-C30 sulfone, C3-C30 cyclic sulfone, C2-C30 sulfamide , C3-C30 cyclic sulfamide, C2-C30 acyl sulfamide, C3-C30 acyl sulfamide, C2-C3o urea, C3-C30 cyclic urea, C2-C30 amidine, C3-C30 cyclic amidine, C2-C30 guainidine, and C3-C30 cyclic guanidine is optionally substituted with one to three same or different of the following functionalities: (Ci_6)alkyl, (C3_6)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (Ci_6)alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, and peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic or cyclic.

In a further embodiment of Formula I above, there is the proviso that at least one of a-e is selected from B or E.

Also preferred are compounds wherein A is

More preferred compounds of Formula I include those which are selected from the group consisting of:

Of the foregoing,

are even more preferred.

The compounds of the present invention, according to all the various embodiments described above, may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques), by inhalation spray, or rectally, and by other means, in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, excipients and diluents available to the skilled artisan. One or more adjuvants may also be included. Thus, in accordance with the present disclosure, there is further provided a method of treatment, and a pharmaceutical composition, for treating viral infections such as HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition which contains an antiviral effective amount of one or more of the compounds of Formula I, together with one or more pharmaceutically acceptable carriers, excipients or diluents. As used herein, the term "antiviral effective amount" means the total amount of each active component of the composition and method that is sufficient to show a meaningful patient benefit, i.e., inhibiting, ameliorating, or healing of acute conditions characterized by inhibition of the HIV infection. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The terms "treat, treating, treatment" as used herein and in the claims means preventing, ameliorating or healing diseases associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form of orally administrable suspensions or tablets; as well as nasal sprays, sterile injectable

preparations, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories. Pharmaceutically acceptable carriers, excipients or diluents may be utilized in the pharmaceutical compositions, and are those utilized in the art of pharmaceutical preparations.

When administered orally as a suspension, these compositions are prepared according to techniques typically known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art.

The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses, usually over an extended period, such as days, weeks, months, or even years. One preferred dosage range is 1 to 10 mg/kg body weight orally in divided doses. Another preferred dosage range is 1 to 20 mg/kg body weight in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula I herein set forth, together with one or more agents useful in the treatment of AIDS. For example, the compounds of this disclosure may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines, such as those in the following non-limiting table:

ANTIVIRALS

Drug Name Manufacturer Indication

Rilpivirine Tibotec HIV infection, AIDS, ARC

(non-nucleoside

reverse transcriptase inhibitor)

Complera ® Gilead HIV infection, AIDS,

ARC; combination

with emtricitabine, rilpivirine, and tenofovir disoproxil fumarate 097 Hoechst/Bayer HIV infection,

AIDS, ARC

(non-nucleoside

reverse transcriptase (RT)

inhibitor)

Amprenavir Glaxo Wellcome HIV infection,

141 W94 AIDS, ARC

GW 141 (protease inhibitor)

Abacavir (1592U89) Glaxo Wellcome HIV infection,

GW 1592 AIDS, ARC

(RT inhibitor)

Acemannan Carrington Labs ARC

(Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS,

ARC

AD-439 Tanox Biosystems HIV infection, AIDS,

ARC

AD-519 Tanox Biosystems HIV infection, AIDS,

ARC

Adefovir dipivoxil Gilead Sciences HIV infection

AL-721 Ethigen ARC, PGL

(Los Angeles, CA) HIV positive, AIDS

Alpha Interferon Glaxo Wellcome Kaposi's sarcoma,

HIV in combination w/Retrovir

Ansamycin Adria Laboratories ARC

LM 427 (Dublin, OH)

Erbamont

(Stamford, CT)

Antibody which Advanced Biotherapy AIDS, ARC

Neutralizes pH Concepts

Labile alpha aberrant (Rockville, MD)

Interferon AR177 Aronex Pharm HIV infection, AIDS,

ARC

Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated

diseases

BMS-234475 Bristol-Myers Squibb/ HIV infection,

(CGP-61755) Novartis AIDS, ARC

(protease inhibitor)

CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis,

herpes, papillomavirus

Curdlan sulfate AJI Pharma USA HIV infection

Cytomegalovirus Medlmmune CMV retinitis

Immune globin

Cytovene Syntex Sight threatening Ganciclovir CMV

peripheral CMV retinitis

Darunavir Tibotec- J & J HIV infection, AIDS, ARC

(protease inhibitor) Delaviridine Pharmacia-Upj ohn HIV infection,

AIDS, ARC

(RT inhibitor)

Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV

Ind. Ltd. (Osaka, positive

Japan) asymptomatic ddC Hoffman-La Roche HIV infection, AIDS,

Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV infection, AIDS,

Dideoxyinosine ARC; combination

with AZT/d4T DMP-450 AVID HIV infection,

(Camden, NJ) AIDS, ARC

(protease inhibitor)

Efavirenz Bristol Myers Squibb HIV infection,

(DMP 266, Sustiva ^® ) AIDS, ARC

(-)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor)

4(S)-trifluoro- methyl- 1 ,4-dihydro- 2H-3, 1 -benzoxazin- 2-one, STOCRI E EL10 Elan Corp, PLC HIV infection

(Gainesville, GA)

Etravirine Tibotec/ J & J HIV infection, AIDS, ARC

(non-nucleoside reverse transcriptase inhibitor)

Famciclovir Smith Kline herpes zoster,

herpes simplex

GS 840 Gilead HIV infection,

AIDS, ARC

(reverse transcriptase inhibitor)

HBY097 Hoechst Marion HIV infection,

Roussel AIDS, ARC

(non-nucleoside reverse transcriptase inhibitor)

Hypericin VIMRx Pharm. HIV infection, AIDS,

ARC

Recombinant Human Triton Biosciences AIDS, Kaposi's

Interferon Beta (Almeda, CA) sarcoma, ARC

Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS,

ARC, asymptomatic HIV positive, also in combination with AZT/ddl/ddC

ISIS 2922 ISIS Pharmaceuticals CMV retinitis

KNI-272 Nat'l Cancer Institute HlV-assoc. diseases

Lamivudine, 3TC Glaxo Wellcome HIV infection,

AIDS, ARC

(reverse

transcriptase inhibitor); also with AZT

Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,

Pharmaceuticals AIDS, ARC

(protease inhibitor)

Nevirapine Boeheringer HIV infection,

Ingleheim AIDS, ARC

(RT inhibitor)

Novapren Novaferon Labs, Inc. HIV inhibitor

(Akron, OH)

Peptide T Peninsula Labs AIDS

Octapeptide (Belmont, CA)

Sequence Trisodium Astra Pharm. CMV retinitis, HIV

Phosphonoformate Products, Inc. infection, other CMV infections

PNU- 140690 Pharmacia Upjohn HIV infection,

AIDS, ARC

(protease inhibitor)

Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection,

Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,

AIDS, ARC

(protease inhibitor)

Saquinavir Hoffmann- HIV infection,

LaRoche AIDS, ARC

(protease inhibitor)

Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS,

Didehydrodeoxy- ARC

Thymidine

Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC

(protease inhibitor)

Valaciclovir Glaxo Wellcome Genital HSV & CMV

Infections

Virazole Viratek/ICN asymptomatic HIV

Ribavirin (Costa Mesa, CA) positive, LAS, ARC

VX-478 Vertex HIV infection, AIDS,

ARC

Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,

ARC, with AZT

Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS,

ARC, Kaposi's

sarcoma, in combination with other therapies

Tenofovir disoproxil, HIV infection,

fumarate salt (Viread ^® ) AIDS,

(reverse transcriptase inhibitor)

Emtriva" (Emtricitabine) Gilead HIV infection,

(FTC) AIDS,

(reverse transcriptase inhibitor) Combivir GSK HIV infection,

AIDS,

(reverse transcriptase inhibitor)

Abacavir succinate GSK HIV infection,

(or Ziagen ^® ) AIDS,

(reverse transcriptase inhibitor)

Reyataz Bristol-Myers Squibb HIV infection

(or atazanavir) AIDs, protease

inhibitor

Fuzeon ^J Roche / Trimeris HIV infection

(Enfuvirtide or T-20) AIDs, viral Fusion

inhibitor Lexiva GSK/Vertex HIV infection

(or Fosamprenavir calcium) AIDs, viral protease

inhibitor

Selzentry

Maraviroc; (UK 427857) Pfizer HIV infection

AIDs, (CCR5 antagonist, in development)

Trizivir GSK HIV infection

AIDs, (three drug combination)

Sch-417690 (vicriviroc) Schering-Plough HIV infection

AIDs, (CCR5 antagonist, in development)

TAK-652 Takeda HIV infection

AIDs, (CCR5 antagonist, in development)

GSK 873140 GSK/ONO HIV infection

(ONO-4128) AIDs, (CCR5 antagonist, in development)

Integrase Inhibitor Merck HIV infection

MK-0518 AIDs

Raltegravir ®

Truvada Gilead Combination of Tenofovir disoproxil fumarate salt (Viread ^R ) and Emtriva ^R (Emtricitabine)

Integrase Inhibitor Gilead/Japan Tobacco HIV Infection

GS917/JTK-303 AIDs

Elvitegravir in development

Triple drug combination Gilead/Bristol-Myers Squibb Combination of Tenofovir

®

Atripla disoproxil fumarate salt

(Viread®), Emtriva® (Emtricitabine), and

®

Sustiva (Efavirenz)

Festinavir Oncolys BioPharma HIV infection

AIDs

in development

CMX-157 Chimerix HIV infection

Lipid conjugate of AIDs

nucleotide tenofovir

GSK1349572 GSK HIV infection

Integrase inhibitor AIDs

IMMUNOMODULATORS

Drug Name Manufacturer Indication

AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS

Acemannan Carrington Labs, Inc. AIDS, ARC

(Irving, TX) CL246,738 Wyeth AIDS, Kaposi's Lederle Labs sarcoma

FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells

Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor)

Granulocyte Genetics Institute AIDS

Macrophage Colony Sandoz

Stimulating Factor Granulocyte Hoechst-Roussel AIDS

Macrophage Colony Immunex

Stimulating Factor

Granulocyte Schering-Plough AIDS,

Macrophage Colony combination

Stimulating Factor w/AZT

HIV Core Particle Rorer Seropositive HIV Immunostimulant

IL-2 Cetus AIDS, in combination

Interleukin-2 w/AZT

IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in

Interleukin-2 CD4 cell counts (aldeslukin)

Immune Globulin Cutter Biological Pediatric AIDS, in

Intravenous (Berkeley, CA) combination w/AZT

(human)

IMREG-1 Imreg AIDS, Kaposi's

(New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's

(New Orleans, LA) sarcoma, ARC, PGL

Imuthiol Diethyl Merieux Institute AIDS, ARC

Dithio Carbamate

Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS

Methionine- TNI Pharmaceutical AIDS, ARC

Enkephalin (Chicago, IL)

MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma

Muramyl-Tripeptide

Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT

Factor

Remune Immune Response Immunotherapeutic

Corp. rCD4 Genentech AIDS, ARC

Recombinant

Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids

Recombinant Biogen AIDS, ARC

Soluble Human CD4

Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC,

in combination w/AZT

SK&F 106528 Smith Kline HIV infection Soluble T4

Thymopentin Immunobiology HIV infection

Research Institute

(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon

ANTI-INFECTIVES

Drug Name Manufacturer Indication

Clindamycin Pharmacia Upjohn PCP

Primaquine

Fluconazole Pfizer Cryptococcal

meningitis, candidiasis

Pastille Squibb Corp. Prevention of

Nystatin Pastille oral candidiasis

Ornidyl Merrell Dow PCP

Eflornithine

Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL)

Trimethoprim Antibacterial

Trimethoprim/ sulfa Antibacterial

Piritrexim Burroughs Wellcome PCP treatment

Pentamidine Fisons Corporation PCP prophylaxis Isethionate for

Inhalation

Spiramycin Rhone-Poulenc Cryptosporidia! diarrhea

Intraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcal

meningitis Trimetrexate Warner-Lambert PCP

Daunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemia

Erythropoietin assoc. with AZT

therapy

Recombinant Human Serono AIDS-related

Growth Hormone wasting, cachexia

Megestrol Acetate Bristol-Myers Squibb Treatment of

anorexia assoc.

W/AIDS

Testosterone Alza, Smith Kline AIDS-related wasting

Total Enteral Norwich Eaton Diarrhea and

Nutrition Pharmaceuticals malabsorption

related to AIDS

Additionally, the compounds of the disclosure herein set forth may be used in combination with other HIV entry inhibitors. Examples of such HIV entry inhibitors are discussed in Drugs of the Future, 24(12): 1355-1362 (1999); Cell, 9:243-246 (Oct. 29, 1999); and Drug Discovery Today, 5(5): 183-194 (May 2000) and Meanwell, N.A. et al, "Inhibitors of the entry of HIV into host cells", Curr. Op. Drug Disc. Dev, 6(4):451-461 (2003). Specifically the compounds can be utilized in combination with other attachment inhibitors, fusion inhibitors, and chemokine receptor antagonists aimed at either the CCR5 or CXCR4 coreceptor.

It will be understood that the scope of combinations of the compounds of this disclosure with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines is not limited to the list in the above Table but includes, in principle, any combination with any pharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with a compound of the present disclosure and an inhibitor of HIV protease and/or a non- nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir). Typically a dose of 300 to 600mg is administered once a day. This may be co-administered with a low dose of Ritonavir (50 to 500mgs). Another preferred inhibitor of HIV protease is KALETRA®. Another useful inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl- 4-(S)-hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcar boxamido)-piperazinyl))- pentaneamide ethanolate, and is synthesized according to U.S. Patent No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine. (The preparation of ddC, ddl and AZT are also described in EP 0 484 071.)

In such combinations the compound of the present disclosure and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

GENERAL CHEMISTRY (METHODS OF SYNTHESIS)

The present invention comprises compounds of Formula I, their pharmaceutical formulations, and their use in patients suffering from or susceptible to HIV infection. The compounds of Formula I include pharmaceutically acceptable salts thereof. General procedures to construct compounds of Formula I and intermediates useful for their synthesis are described in the following Schemes (after the Abbreviations).

Abbreviations One or more of the following abbreviations, most of which are conventional abbreviations well known to those skilled in the art, may be used throughout the description of the disclosure and the examples: h = hour(s)

rt = room temperature

mol = mole(s)

mmol = millimole(s)

g = gram(s)

mg = milligram(s)

mL = milliliter(s)

TFA = trifluoroacetic Acid

DCE = 1,2-Dichloroethane

CH2CI2 = dichloromethane

TPAP = tetrapropylammonium perruthenate

THF = tetrahydrofuran

DEPBT = 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one

DMAP = 4-dimethylaminopyridine

P-EDC = polymer supported l-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDC = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMF = N,N-dimethylformamide

Hunig's Base = N,N-diisopropylethylamine

MCPBA = meto-chloroperbenzoic acid

azaindole = lH-pyrrolo-pyridine

4-azaindole = lH-pyrrolo[3,2-/?]pyridine

5- azaindole = lH-pyrrolo[3,2-c]pyridine

6- azaindole = lH-pyrrolo[2,3-c]pyridine

7- azaindole = lH-pyrrolo[2,3-6]pyridine

PMB = 4-methoxybenzyl

DDQ = 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

OTf = trifluoromethanesulfonoxy

ΝΜΜ = 4-methylmorpholine

PIP-COPh = 1-benzoylpiperazine NaHMDS = sodium hexamethyldisilazide

EDAC = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide

TMS = trimethylsilyl

DCM = dichloromethane

DCE = dichloroethane

MeOH = methanol

THF = tetrahydrofuran

EtOAc = ethyl acetate

LDA = lithium diisopropylamide

TMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium

DME = dimethoxyethane

DIBALH = diisobutylaluminum hydride

HOBT = 1-hydroxybenzotriazole

CBZ = benzyloxycarbonyl

PCC = pyridinium chlorochromate

TBTU = 0-(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

DEBPT = 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one

BOP = benzotriazole- 1 -yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

Chemistry

The present invention comprises compounds of Formula I, their pharmaceutical formulations, and their use in patients suffering from or susceptible to HIV infection. The compounds of Formula I include pharmaceutically acceptable salts thereof. General procedures to construct compounds of Formula I and intermediates useful for their synthesis are described in the following Schemes.

Preparation of Compounds of Formula I

Preparaion of template A-CO-CO-C1 and A-CO-CO-OH has been described in detail in WO-00076521, WO-00162255, WO-00204440, WO-02062423, WO-02085301, WO-03068221 and US-2004/0063744. Standard conditions such as reacting amine with acyl halide 1 (Scheme la) and carboxyl acid 4 (Scheme lb) can be used to convert the ketone to the desired amide products. Some general references of these methodologies and directions for use are contained in "Comprehensive Organic Transformation" by Richard C. Larock, Wiley - VCH, New York, 1989, 972 (Carboxylic acids to amides), 979 (Acid halides to amides).

Scheme la

Scheme la depicts a general method for forming an amide from N- monosubstituted spiro diamine 2 and acyl chloride 1. An appropriate base (from catalytic to an excess amount) selected from sodium hydride, potassium carbonate, triethylamine, DBU, pyridine, DMAP or di-isopropyl ethyl amine was added into a solution of spiro diamine derivative 2 and acyl chloride 1 in an appropriate solvent selected from dichloromethane, chloroform, benzene, toluene, THF, diethyl ether, dioxane, acetone, Ν,Ν-dimethylformamide or pyridine at room temperature. Then reaction was carried out at either room temperature or evaluated temperature up to 150°C over a period of time (30 minutes to 16 hours) to afford amidine 3, the structure of Formula I. Some selected references involving such reactions include a) Indian J. Chem., Sect B 1990, 29, 1077; 2) Chem. Sci. 1998, 53, 1216; 3) Chem. Pharm. Bull. 1992, 40, 1481; 4) Chem. Heterocycl. Compd. 2002, 38, 539.

Scheme lb

Alternatively, as shown in Scheme lb, a N-monosubstituted spiro diamine 2 can be coupled with an acid 4 using standard amide bond or peptide bond forming coupling reagents. Many reagents for amide bond couplings are known by an organic chemist skilled in the art and nearly all of these are applicable for realizing coupled amide products. The combination of EDAC and triethylamine in tetrahydrofuran or BOPCl and diisopropyl ethyl amine in chloroform have been utilized most frequently but DEPBT, or other coupling reagents such as PyBop could be utilized. Another useful coupling condition employs HATU ((a) J. Chem.Soc. Chem Comm. 1994, 201; (b) J. Am. Chem. Soc. 1994, 116, 1 1580). Additionally, DEPBT (3 -(diethoxyphosphoryloxy)- 1,2,3 - benzotriazin-4(3H)-one) and N,N-diisopropylethylamine, commonly known as Hunig's base, represents another efficient method to form the amide bond and provide compounds of Formula I. DEPBT is either purchased from Adrich or prepared according to the procedure described in Organic Lett., 1999, 1, 91. Typically an inert solvent such as DMF or THF is used but other aprotic solvents could be used.

In Schemes 2-8, the spiro diamines H-R-H is expressed as the drawing in Figure

1.

Figure 1

The N-monosubstituted spiro diamines 2 used in Scheme la and Scheme lb may be prepared by methods described in the Schemes 2-8. Scheme 2

The N-monoaroylation of spiro diamine can be carried out by reacting the dianion 6 of a spiro diamine 5 with aroyl chloride. A procedure was described in J. Org. Chem. 1999, 64, 7661 to prepare mono-aroyl diamine by treatmeant diamine with 2 equivalents of M-butyllithium, followed by the addition of aroyl chloride at room temperature.

Correspondingly, in this invention by appling the same procedure in using a spiro diamine 5 instead, N-monoaroylated spiro diamine can be prepared by treating spiro diamine 5 with 2 equivalents of w-butyllithium, prior to the addition of aroyl chloride.

Scheme 3

A spiro diamine 5 can also be pretreated with 1 eq. of 9-BBN to form a complex 8 at room temperature in THF, ether, hexane, benzene or CH2CI2. Subsequent reaction between the complex 8 and acyl chloride leads to formation of structure 9 after aqueous workup. A general procedure for the selective mono-acylation of symmetrical diamines via prior pomplexation with boron can be found in Org. Lett. 2003, 5, 3399.

Alternatively, a N-Boc spiro diamine 10 can react with either acyl halide or caboxylic acid via the processes described in Scheme la and Scheme lb to acylate the free nitrogen of compound 10, which affords compound 11. A well established deprotection of Boc group of compound 11 under acidic solution could provide acyl spiro diamine 9. TFA and HC1 are the typical acids used for this deprotection, while the most commonly used solvents are ether and dichloromethane or the TFA itself, but other acidic agents and solvents could be used. Some selected references involving such reactions include 1) Bioorg. Med. Chem. Lett. 1996, 6, 2777; 2) Zh. Org. Khim. 1996, 32, 1010; 3) J. Fluorine Chem. 1996, 76, 177; 4) Synth. Commun. 1996, 26, 3549; 5) J. Heterocycl. Chem. 1994, 31, 841; 6) J. Org. Chem. 1964, 29, 794.

Scheme 5

X = F, CI, Br, I

An excess of spiro diamine 5 (5-10 eq.) canbe added to a solution of halo electrophile 12 (e.g., 5-chloro-l -phenyl- lH-tetrazole) in THF, dioxane, benzene, toluenen, DMSO or DMF. The reaction can be run for 2 to 120 hours at room temperature or 150°C to furnish structure 13. The reactions can be carried out with or without base or catalyst. A base can be selected from Et ₃ N, iPr ₂ NEt, NaH, KH, BuLi, Li ₂ C0 ₃ , Na ₂ C0 ₃ , K ₂ C0 ₃ , Cs ₂ C0 ₃ , K ₃ P0 ₄ , K ₂ HP0 ₄ , KH ₂ P0 ₄ , LiHMDS, NaHMDS, KHMDS. A catalyst can be a species containing a metal such as Cu, Pd, Ni or Pt.

Scheme 6

10 12 14 13

X = F, CI, Br, I Structure 13 can be also synthesized from a N-Boc spiro diamine 10. By using the same procedure of Scheme 5, N-Boc spiro diamine 10 reacts with halide 12 to give N,N- disubstituted spiro diamine 14. Final de-Boc of compound 14 using the condition described in Scheme 4 gives N-mono-substitiuted spiro diamine 13. Scheme 7

The N-Boc spiro diamine 10 can also react with a Ν,Ν-disubstituted carbamic chloride 16 with or without a base at room temperature or 150°C to provide structure 16. The solvent can be selected from THF, dioxane, DMF, benzene, ether, and CH2CI2. The base can be selected from Et ₃ N, iPr ₂ NEt, NaH, KH, BuLi, Li ₂ C0 ₃ , Na ₂ C0 ₃ , K ₂ C0 ₃ , Cs ₂ C0 ₃ , K ₃ P0 ₄ , K ₂ HP0 ₄ , KH ₂ P0 ₄ , LiHMDS, NaHMDS, and KHMDS. Sequential removal of Boc group from structure 16, applying the condition described in Scheme 4, leads to the formation of structure 17. In Scheme 7, R ¹⁰¹ and R ¹⁰² can not be hydrogen.

Scheme 8

17

The structure 10 can also react with di(lH-imidazol-l-yl)methanone 18, followed by an addition of amine 19 to give intermediate 16. Then, de-Boc reaction will give the desired N-mono substituted spiro diamine 17. In Scheme 8, R ¹⁰¹ or R ¹⁰² or both can be hydrogen. Reaction conditions and methods given in the specific examples are broadly applicable to compounds with other substitution and to other tranformations in this application.

Examples

The following examples illustrate typical syntheses of the compounds of Formula I as described generally above. These examples are illustrative only and are not intended to limit the disclosure in any way. The reagents and starting materials are readily available to one of ordinary skill in the art.

Chemistry Experimental

Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly as obtained from commercial sources, and reactions were performed under a nitrogen atmosphere. Flash chromatography was conducted on Silica gel 60 (0.040-0.063 particle size; EM Science supply). ^X H NMR spectra were recorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or Varian Gemini 300 at 300 MHz as stated). The chemical shifts were reported in ppm on the δ scale relative to 6TMS = 0. The following internal references were used for the residual protons in the following solvents: CDCI ₃ (¾ 7.26), CD ₃ OD (¾ 3.30), and DMSO-i/6 (¾ 2.50). Standard acronyms were employed to describe the multiplicity patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b (broad), app (apparent). The coupling constant (J) is in Hertz. All Liquid

Chromatography (LC) data were recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector with Mass Spectrometry (MS) data determined using a Micromass Platform for LC in electrospray mode.

HPLC Method fi.e., compound isolation) Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) and purified using a Shimadzu LC-8A or LC-IOA automated preparative HPLC system. Preparation of intermediates

Synthesis of 2-(l -phenyl- lH-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane:

Step 1: Et ₃ (5 mL) was added into a solution of tert-butyl 2,7-diazaspiro[4.4]nonane-2- carboxylate (1 g) and 5-chloro-l-phenyl-lH-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115°C for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over MgS0 ₄ and concentrated to give a residue which was purified by silica gel chromatography to givetert-butyl 7-(l-phenyl-lH-tetrazol-5-yl)-2,7- diazaspiro [4.4] nonane-2 -carboxy late.

Step 2: tert-butyl 7-(l-phenyl-lH-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane-2-ca rboxylate (100 mg) was dissolved in 10% TFA solution in CH2CI2 (10 mL). The reaction was stirred at room temperature for 24 hous. After removal of solvents, the residue, crdue 2- (1 -phenyl- lH-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane, was used in the further reactions without purification.

Synthesis of phenyl(2,7-diazaspiro[4.4]nonan-2-yl)methanone:

Step 1 : Et ₃ N (0.5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate (0.2 g) and benzoyl chloride (0.1 mL) in THF (10 mL). The mixture was heated to 1 15°C for 24 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgS0 ₄ and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 7-benzoyl-2,7-diazaspiro[4.4]nonane-2- carboxylate.

Solvent Pair Water - Methanol- TFA

Column PHENOMENEX-LU A 4.6 x 30mm S5

Step 2: tert-butyl 7-benzoyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2CI2 (10 mL). The reaction was stirred at room temperature for 24 hous. After removal of solvents, the residue, phenyl(2,7- diazaspiro[4.4]nonan-2-yl)methanone, was used in the further reactions without purification.

Synthesis of Main Compounds Preparation of Compound 1001, l-(4-fluoro-7-(lH-l,2,3-triazol-l-yl)-lH- pyrrolo[2,3-c]pyridin-3-yl)-2-(7-(l-phenyl-lH-tetrazol-5-yl) -2,7- diazaspiro[4.4]nonan-2-yl)ethane-l,2-dione and Compound 1002, l-(4-methoxy-7-(3- methyl-lH-l,2,4-triazol-l-yl)-lH-pyrrolo[2,3-c]pyridin-3-yl) -2-(7-(l-phenyl-lH- tetrazol-5-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethane-l,2-dion e:

2-Keto acid (1 eq.), sprio bicyclic diamine agent (1 - 5 eq.), 3-(diethoxyphosphoryloxy)- l,2,3-benzotriazin-4(3H)-one (DEPBT) or 0-(lH-benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU) (1 - 5 eq.) or (2-(7-Aza-lH-benzotriazole- l-yl)-l, l,3,3-tetramethyluronium hexafluorophosphate) (HATU) (1 - 5 eq.) and Hunig's Base or N-methyl morpholine (1- 100 eq.) were combined in THF or DMF. The mixture was stirred at room temperature or 115°C for 17 hours. THF or DMF was removed via evaporation at reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCC>3 aqueous solution. The aqueous layer was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous MgS0 ₄ . Concentration in vacuo provided a crude product, which was purified by tritaration, or recrystallization, or silica gel column chromatography, or Shimadzu automated preparative HPLC System.

Column PHENOMENEX-LUNA 4.6 x 50mm S10 MS (M+H) ⁺ Observ. 554.5

Retention Time 1.70 min

LC Condition

Solvent A 90% Water -10% Methanol-0.1% TFA

Solvent B 10% Water -90% Methanol-0.1% TFA

Start % B 0

Final % B 100

Gradient Time 2 min

Flow Rate 4 mL/min

Wavelength 220

Solvent Pair Water - Methanol- TFA

Column PHENOMENEX-LU A 4.6 x 50mm S10

The following methods were used to prepare Compounds 2001 - 2004. Analytical HPLC method: Waters Xbridge 2.1x50mm 5 urn CI 8, A = 5:95 ACN:Water; B = 95:5 ACN:Water; Modifier = 10 mM NH ₄ OAc. 0.00 min = 0% B, 2.0 min = 100% B, 3.0 min = 100% B, 3.05 min = 0%B, 3.5 min = 0% B, Flow rate = 1 mL/min

The general procedures below pertain to the experimental procedure for library compounds.

2-(4-fluoro-7-(lH-l,2,3-triazol-l-yl)-lH-pyrrolo[2,3-c]py ridin-3-yl)-2-oxoacetic acid (1 eq.) was dissolved in DMF and followed by addin DIPEA (3 eq.) and TBTU or HATU (1.1 eq) in DMF (1 mL). The solution then was added into a pre-weighed amine (1 eq.). Initial analysis by LC-MS after 3 hours indicated that reactions were nearly complete. Reactions were allowed to remain on the shaker overnight at room temperature. All samples were transferred into a plate and purified by HPLC.

2-(4-Methoxy-7-(3 -methyl- 1 H- 1 ,2,4-triazol- 1 -yl)- 1 H-pyrrolo[2,3 -c]pyridin-3 -yl)-2- oxoacetic acid (1 eq.) was dissolved in DMF and followed by addin DIPEA (3 eq.) and TBTU or HATU (1.1 eq) in DMF (1 mL). The solution then was added into a pre- weighed amine (1 eq.). Initial analysis by LC-MS after 3 hours indicated that reactions were nearly complete. Reactions were allowed to remain on the shaker overnight at room temperature. All samples were transferred into a plate and purified by HPLC.

Cmpd Structure MS MS RT

# (M+H) ⁺ (M+H) ⁺ (min)

Preparation of Compound 3001, 5-(2-(4-fluoro-7-(lH-l,2,3-triazol-l-yl)-lH- pyrrolo [2,3-c] pyridin-3-yl)-2-oxoacetyl)-N,N-dimethylhexahydropyrrolo [3,4- c]pyrrole-2(lH)-carboxamide:

2-Keto amide (1 eq.), carbamyl chloride (1 - 5 eq.) and Hunig's Base or Et ₃ N (1- 100 eq.) were combined in THF or DMF. The mixture was stirred at room temperature or 115°C for 17 hours. THF or DMF was removed via evaporation at reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCCh aqueous solution. The aqueous layer was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous MgS0 ₄ . Concentration in vacuo provided a crude product, which was purified by tritaration, or recrystallization, or silica gel column

chromatography, or Shimadzu automated preparative HPLC System.

Solvent B 10% Water -90% Methanol-0.1% TFA

Start % B 0

Final % B 100

Gradient Time 2 min

Flow Rate 4 mL/min

Wavelength 220

Solvent Pair Water - Methanol- TFA

Column PHENOMENEX-LU A 4.6 x 50mm S10

Synthesis of Compound 4001, l-(4-methoxy-7-(3-methyl-lH-l,2,4-triazol-l-yl)-lH- pyrrolo[2,3-c]pyridin-3-yl)-2-(6-(l-phenyl-lH-tetrazol-5-yl) -2,6- diazaspiro[3.3]heptan-2-yl)ethane-l,2-dione

Step 1 : To a stirred solution of pentaerythritol (0.5 g) in dry acetonitrile (25 mL) added trifluoromethane sulfonic anhydride (2.6 mL) slowly under nitrogen atmosphere at -30°C (Internal temperature below -10°C) fallowed by diisopropyl ethyl amine (3.2 mL) was added slowly (internal temperature below -10°C). The reaction mixture was stirred at - 30°C for about 45 minutes and diisopropyl ethyl amine (3.2 mL) was added fallowed by diphenyl amino methane (2.55 g).The reaction mixture was heated to reflux for about

2hrs and cooled to room temperature. Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using ethyl acetate\ hexane (5%) as eluent to afford 2,6-dibenzhydryl-2,6-diazaspiro[3.3]heptane (1 g). ^Χ Η NMR (300 MHz, DMSO - d ₆ ): δ ppm 3.30-3.40 (bs, 4H), 3.54 - 3.72 (bs, 4H), 5.7 (s, 2H), 7.38 - 7.45 (m, 20H). LCMS MS (M+H) ⁺ Calcd.: 431, Observ.: 431.

Step 2: 2,6-dibenzhydryl-2,6-diazaspiro[3.3]heptane (1 g) was taken in ethanol (50 mL), trifluoro acetic acid (0.3 mL) was added under nitrogen atmosphere. To this added palladium hydroxide (500 mg, 50mol %). The reaction mixture was then allowed to stir under hydrogen atmosphere 5 kg pressure for 16 hours. After the completion of the reaction, the reaction mixture was filtered through celite bed and washed repeatedly with methanol (100 mL). The filtrate was concentrated under reduced pressure to afford the desired 2,6-diazaspiro[3.3]heptane (0.2 g). ^X H NMR (300 MHz, DMSO - d ₆ ): δ ppm 4.11 (s, 8H), 8.79 (bs, 2H). LCMS MS (M+H) ⁺ Calcd.: 99, Observ.: 99.

Step 3: To potassium carbonate (76 mg) taken in ethanol (2.0 mL), a solution of 2,6- diazaspiro[3.3]heptane (220 mg in 2.0ml of ethanol) was added at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and a solution of 5- chloro-1 -phenyl tetrazole (0.1 g) in ethanol (2.0 mL) was added very slowly. The reaction mixture was allowed to stir for 5 hours at room temperature. The reaction mixture was evaporated to give a residue which was partitioned between water (10 mL) and EtOAc (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure gave crude product which was purified by column chromatography using

methanol\dichloromethane (1 :9) as eluent to afford 2-(l-phenyl-lH-tetrazol-5-yl)-2,6- diazaspiro[3.3]heptane (50 mg).

¾ NMR (400 MHz, DMSO - d ₆ ): δ ppm 3.85-3.90 (s, 4H), 4.01 - 4.04 (s, 4H), 7.51 - 7.60 (m, 5H). LCMS MS (M+H) ⁺ Calcd.: 243, Observ.: 243.

Step 4: 2-(4-methoxy-7-(3-methyl-lH-l,2,4-triazol-l-yl)-lH-pyrrolo[2 ,3-c]pyridin-3-yl)- 2-oxoacetic acid (0.050 g), 2-(l-phenyl-lH-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptane (0.044 g), BOP reagent (0.080 g) and Hunig's base (0.2 mL) were mixed in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with methanol (10 mL) and volatiles were removed under reduced pressure. The resulting oil was diluted with ethyl acetate (50 mL), washed with 10% NaHC03 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The resulting crude was purified by silica gel column chromatography using MeOH/CHCi3 (1 :9) as an eluent to afford 1 -(4-methoxy-7- (3 -methyl- 1 H- 1 ,2,4-triazol- 1 -yl)- 1 H-pyrrolo [2,3 -c]pyridin-3 -yl)-2-(6-( 1 -phenyl- 1 H- tetrazol-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-l,2-dio ne (30 mg). ^X H NMR (400 MHz, DMSO - d ₆ ): δ ppm 2.47-2.49(s, 3H), 3.93 (s, 4H), 4.08 - 4.13 (m, 2H), 4.20-4.36 (d, 2H), 7.54 - 7.62 (m, 5H), 7.84 (s, 1H), 8.30-8.32 (s, 1H), 9.22 (s, 1H), 12.26 (bs, 1H). LCMS MS (M+H) ⁺ Calcd.: 526, Observ.: 526.

Biology Data for the Examples

• "μΜ" means micromolar;

• "mL" means milliliter;

• "μΐ" means microliter;

• "mg" means milligram;

The materials and experimental procedures used to obtain the results reported in Table 1 are described below.

Cells: · Virus production-Human embryonic Kidney cell line, 293T (HEK 293T), was

propagated in Dulbecco's Modified Eagle Medium (Invitrogen, Carlsbad, CA) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis , MO). The human T-cell leukemia cell MT2 (AIDS Research and Reference Reagent Program, Cat. 237) was propagated in RPMI 1640 (Invitrogen, Carlsbad, CA) containing 10% fetal bovine serum (FBS, Hyclone, Logan , UT)

• Virus infection- Single-round infectious reporter virus was produced by co- transfecting HEK 293T cells with plasmide expressing the HIV-1 LAI envelope along with a plasmid containing an HIV- 1 LAI proviral cDNA with the envelope gene replaced by a firefly luciferase reporter gene (Chen et al, Ref. 41). Transfections were performed using lipofectAMTNE PLUS reagent as described by the manufacturer

(Invitrogen, Carlsbad, CA). Experimental Procedure

1. MT2 cells were plated in black, 384 well plates at a cell density of 5 X 10 ³ cells per well in 25 μΐ RPMI 1640 containing 10% FBS.

2. Compound (diluted in dimethylsulfoxide and growth medium) was added to cells at 12.5 μΐ/well, so that the final assay concentration would be <50 nM.

3. 12.5 μΐ of single-round infectious reporter virus in Dulbecco's Modified Eagle

Medium was added to the plated cells and compound at an approximate multiplicity of infection (MOI) of 0.01, resulting in a final volume of 50 μΐ per well.

4. Virus-infected cells were incubated at 37 degrees Celsius, in a CO ₂ incubator, and harvested 72 h after infection.

5. Viral infection was monitored by measuring luciferase expression in the infected cells using a luciferase reporter gene assay kit (Steady-Glo, Promega, Madison, WI) as described by the manufacturer. Luciferase activity was then quantified by measuring luminescence using an EnVision Multilabel Plate Readers (PerkinElmer, Waltham, MA).

6. The percent inhibition for each compound was calculated by quantifying the level of luciferase expression in cells infected in the presence of each compound as a percentage of that observed for cells infected in the absence of compound and subtracting such a determined value from 100.

7. An EC5 ₀ provides a method for comparing the antiviral potency of the compounds of this disclosure. The effective concentration for fifty percent inhibition (EC5 ₀ ) was calculated with the Microsoft Excel Xlfit curve fitting software. For each compound, curves were generated from percent inhibition calculated at 10 different concentrations by using a four paramenter logistic model (model 205). The EC ₅₀ data for the compounds is shown in Table 2. Table 1 is the key for the data in Table 2.

Table 1. Biological Data Key for EC ₅₀ s

Table 2 able 1

The foregoing description is merely illustrative and should not be understood to limit the scope or underlying principles of the invention in any way. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.