CROSS REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of U.S. provisional patent application no. 61/421,919 filed December 10, 2010.

BACKGROUND OF THE INVENTION The disclosure generally relates to the novel compounds of formula I, including their salts, which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics (UNAIDS: Report on the Global HIV/AIDS Epidemic, December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.

There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into four classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir atazanavir darunavir, amprenavir, fosamprenavir, lopinavir and tipranavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine, emtricitibine, tenofovir and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevirapine, delavirdine, efavirenz and etravirine inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Enfuvirtide and maraviroc inhibit the entry of the virus into the host cell. Used alone these drugs are effective in reducing viral replication. There are also peptidomimetic protease inhibitors including saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, darunavir, atazanavir, and tipranavir, and integrase inhibitors such as raltegravir. The effect is only temporary as the virus readily develops resistance to all known agents.

However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HlV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853- 860). Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV- 1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drug potency, poor compliance to the complicated drug regiment as well as intrinsic pharmacological barriers to exposure provides fertile ground for resistance to emerge. More disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (< 50 copies/ml) (Carpenter, C. C; Cooper, D. A.; Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.;

Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. S.; Schechter, M.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381-390). Clearly, there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further. HIV expresses three enzymes, reverse transcriptase, an aspartyl protease, and integrase. All three are targets for treating AIDS and HIV infection. HIV integrase is a component of the pre-integration complex of the virus that is assembled in the cell shortly after infection (Chiu, T.K.; Davies, D.R. Curr. Top. Med. Chem. 2004, 4, 965- 977). This enzyme catalyzes the integration of proviral DNA into the host genome and is absolutely required for viral infectivity. Early experiments showed that mutating the active site of integrase within a proviral clone produces virus unable to replicate due to its inability to insert into the host chromosome (Englund, G.;

Theodore, T.S.; Freed, E.O.; Engleman, A.; Martin, M.A. J. Virol. 1995, 69, 3216- 3219). Selective HIV integrase inhibitors have been shown to possess effective anti- HIV activity in cell culture (Hazuda, D.J.; Felock, P.; Witmer, M.; Wolfe, A;

Stillmock, K.; Grobler, J.A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C; Miller, M.D. Science, 2000, 287, 646-650), and it is clear that this class of inhibitors is very effective as part of a combination regimen containing HIV inhibitors of different classes. An HIV integrase inhibitor, raltegravir (Isentress ), has been approved for use in treatment experienced patients based upon 48 week trial results (Cooper, D.A.; Gatell, J.; Rockstroh, J.; Katlama, C; Yeni, P.; Lazzarin, A.;, Xu, X.;, Isaacs, R.; Teppler, H.; Nguyen, B.Y. 15th Conference on Retroviruses and

Opportunistic Infections, Boston, MA., Feb 3-6, 2008 Abst. 105LB: Evering, T.H.; Markowitz, M. Drugs Today, 2007, 43, 865-877). In addition, a second integrase inhibitor, elvitegravir (GS-9137), completed a successful Phase II trial in

combination with ritonavir boosting in naive and treatment experienced patients (Zolopa, A. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA. Feb 25-28, 2007 Abst. 143LB). Thus, HIV-1 integrase is a promising target for novel anti-HIV-1 therapeutics.

HIV integrase inhibitors have been disclosed. See, for example, PCT patent application publications WO05/061501 and WO2010/088167.

The invention provides technical advantages, for example, the compounds are novel and inhibit HIV integrase. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, including

pharmaceutically acceptable salts, their pharmaceutical compositions, and their inhibiting HIV integrase and treating those infected with HIV or AIDS.

One aspect of the invention are compounds of Formula I

where:

R ¹ is hydrogen, alkyl, alkylCO, (tetrahydropyranyl)CO, ((Ar ² )alkyl)CO,

((Ar ² )cycloalkyl)CO, (Ar ² )CO, C0 ₂ R ⁴ , CON(R ⁵ )(R ⁶ ), COC0 ₂ R ⁴ , or

COCON(R ⁵ )(R ⁶ );

R ² is hydrogen or alkyl;

R ³ is hydrogen; R ⁴ is hydrogen, alkyl, or benzyl;

R ⁵ is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or alkylCO; R ⁶ is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or alkylCO; or N(R ⁵ )(R ⁶ ) taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo and alkyl;

Ar ¹ is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, or pyrrolyl; Ar ¹ is substituted with 1 benzyl moiety which is further substituted with 0-3 substituents selected from halo and alkyl; and Ar ¹ is substituted with 0-2 alkyl substituents; and

Ar ² is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or hydroxypyridinyl, and is substituted with 0-3 substituents selected from the group consisting of oxo, halo, cyano, benzyl, alkyl, alkoxy, N(R ⁵ )(R ⁶ ), C0 ₂ R ⁴ , and CON(R ⁵ )(R ⁶ ); or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula I where

R ¹ is hydrogen, ((Ar ² )alkyl)CO, ((Ar ² )cycloalkyl)CO, (Ar ² )CO, or COCON(R ⁵ )(R ⁶ );

R ² is hydrogen or alkyl;

R ³ is hydrogen;

R ⁵ is hydrogen, alkyl, or alkylCO; R ⁶ is hydrogen or alkyl; or N(R ⁵ )(R ⁶ ) taken together is pyrrolidinyl; Ar ¹ is triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, oxazolyl, or thiazolyl; Ar ¹ is substituted with 1 benzyl moiety which is further substituted with 1 halo substituent; and Ar ² is triazolyl, pyrazolyl, isoxazolyl, pyridinyl, or pyridazinyl, and is substituted with 0-1 alkyl substituents; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula I where R ¹ is hydrogen, ((Ar ² )(dimethyl)methyl)CO, ((Ar ² )cyclopropyl)CO, (Ar ² )CO, or

COCON(R ⁵ )(R ⁶ ); R ² is hydrogen or methyl; R ³ is hydrogen; R ⁵ is methylor acetyl; R ⁶ is methyl; or N(R ⁵ )(R ⁶ ) taken together is pyrrolidinyl; Ar ¹ is triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, oxazolyl, or thiazolyl; Ar ¹ is substituted with 1 p- fluorobenzyl; and Ar ² is triazolyl, methylpyrazolyl, methylisoxazolyl, pyridinyl, or pyridazinyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where

R ¹ is ((Ar ² )alkyl)CO, ((Ar ² )cycloalkyl)CO, (Ar ² )CO, or COCON(R ⁵ )(R ⁶ ).

Another aspect of the invention is a compound of formula I where R ¹ is ((Ar ² )alkyl)CO, ((Ar ² )cycloalkyl)CO, (Ar ² )CO, or COCON(R ⁵ )(R ⁶ ).

Another aspect of the invention is a compound of formula I where R ¹ is COCON(R ⁵ )(R ⁶ ).

Another aspect of the invention is a compound of formula I where R ¹ is COCONMe ₂ . Another aspect of the invention is a compound of formula I where Ar ¹ is triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, oxazolyl, or thiazolyl, and Ar ¹ is substituted with 1 benzyl moiety which is further substituted with 0-3 substituents selected from halo and alkyl. Another aspect of the invention is a compound of formula I where Ar ² is pyrazolyl or isoxazolyl, and is substituted with 0-1 alkyl substituents.

For a compound of Formula I, the scope of any instance of a variable substituent, including R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Ar ¹ , and Ar ² , can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.

Unless specified otherwise, these terms have the following meanings. "Halo" means fluoro, chloro, bromo, or iodo. "Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. "Hydroxy alkyl," "alkoxy" and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. "Halo" includes all halogenated isomers from monohalo substituted to perhalo substituted in substituents defined with halo, for example, "Haloalkyl" and "haloalkoxy",

"halophenyl", "halophenoxy." "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. "Heteroaryl" means a 5 to 7 membered monocyclic or 8 to 1 1 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system (for example a bicyclic ring system) are intended to bond to the ring where they are drawn to append. For example, substituents R ¹ and R ² of formula IV are intended to bond to the benzene ring of formula IV and not to the thiophene ring. "Dioxothiazinyl" means

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. An example of a tautomeric pair is shown below.

The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

Synthetic Methods The compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention. Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: "NaHMDS" for sodium bis(trimethylsilyl)amide; "DMF" for ,N- dimethylformamide; "MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl; "TFA" for trifluoroacetic acid; "LAH" for lithium aluminum hydride;

"BOC", "DMSO" for dimethylsulfoxide; "h" for hours; "rt" for room temperature or retention time (context will dictate); "min" for minutes; "EtOAc" for ethyl acetate; "THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic acid; "Et ₂ 0" for diethyl ether; "DMAP" for 4-dimethylaminopyridine; "DCE" for 1,2-dichloroethane; "ACN" for acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for 1- hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine, "Nf ' for

CF ₃ (CF ₂ ) ₃ S0 ₂ -; and "TMOF" for trimethylorthoformate. Scheme 1

11 Scheme 4

Biological Methods

HIV-Integrase Inhibition Activity. Radiolabeled integrase inhibitor, BMS- 641493 was used as a known reference ligand to determine the binding constants towards the integrase enzyme of the compounds described in this invention using a method similar to that described in; Dicker et al. J. Biological Chem. 2007, 282, 31 186-31 196; Dicker et al. J. Biol. Chem. 2008, 283, 23599-23609 and Dicker et al. Biochemistry 2008, 47, 13481-13488. BMS-641493 is a known active-site binding inhibitor as it can be competed off the Kd values for [3HJBMS-641493 were determined from fitting data to a saturation binding curve using Graphpad Prism, V4.01. The Ki measurement toward integrase was made by measuring the inhibition of binding of [3HJBMS-641493 to enzyme-SPA bead complexes in the presence of serial dilutions of the test compounds. The Ki value was determined from the [3HJBMS-641493 Kd and the inhibition binding curve using Graphpad Prism, V4.03. Results are shown in the Table 1.

Table 1.

Inhibition of HIV replication. A recombinant NL-Rluc virus was constructed in which a section of the nef gene from NL4-3 was replaced with the Renilla

Luciferase gene. The NL-RLuc virus was prepared by co-transfection of two plasmids, pNLRLuc and pVSVenv. The pNLRLuc contains the NL-Rluc DNA cloned into pUC18 at the Pvull site, while the pVSVenv contains the gene for VSV G protein linked to an LTR promoter. Transfections were performed at a 1 :3 ratio of pNLRLuc to pVSVenv on 293T cells using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, CA) according to manufactures instruction, and the pseudotype virus generated was titered in MT-2 cells. Susceptibility of viruses to compounds was determined by incubation in the presence of serial dilutions of the compound. The 50% effective concentration (EC ₅ 0) was calculated by using the exponential form of the median effect equation where (Fa) = 1/[1+ (ED ₅ o/drug conc.) ^m ] (Johnson VA, Byington RT. Infectivity Assay. In Techniques in HIV Research, ed. Aldovini A, Walker BD. 71-76. New York: Stockton Press.1990). the results from at least 2 experiments were used to calculate the EC5 ₀ values. Results are shown in the Table 2.

Table 2.

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV integrase. HIV integrase inhibitors belonging to a class of diketo acid compounds prevented viral integration and inhibited HIV-1 replication in cells (Hazuda et al. Science 2000, 287, 646). Recently reltegravir, an HIV integrase inhibitor, has been approved by the FDA for treating AIDS and HIV infection.

Accordingly, another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of AIDS or HIV infection.

Another aspect of the invention is a method for treating HIV infection in a human patient comprising the administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.

Another aspect of the invention is a method wherein the agent is a nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method wherein the agent is a non- nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the non-nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable thereof.

Another aspect of the invention is a method wherein the agent is an HIV protease inhibitor.

Another aspect of the invention is a method wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is an HIV fusion inhibitor.

Another aspect of the invention is a method wherein the HIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is an HIV attachment inhibitor. Another aspect of the invention is a method wherein the agent is a CCR5 inhibitor.

Another aspect of the invention is a method wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO- 140, and UK- 427,857, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor. Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is an HIV budding or maturation inhibitor.

Another aspect of the invention is a method wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method wherein the agent is an HIV integrase inhibitor.

Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.

Another aspect of the invention is the composition wherein the agent is a nucleoside HIV reverse transcriptase inhibitor. Another aspect of the invention is the composition wherein the nucleoside

HIV transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt thereof. Another aspect of the invention is the composition wherein the agent is a non- nucleoside HIV reverse transcriptase inhibitor. Another aspect of the invention is the composition wherein the non- nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent is an HIV protease inhibitor.

Another aspect of the invention is the composition wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent is an HIV fusion inhibitor.

Another aspect of the invention is the composition method wherein the HIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent is an HIV attachment inhibitor.

Another aspect of the invention is the composition wherein the agent is a CCR5 inhibitor.

Another aspect of the invention is the composition wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO- 140, and UK-427,857, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor. Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100 or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent is an HIV budding or maturation inhibitor.

Another aspect of the invention is the composition wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt thereof. Another aspect of the invention is the composition wherein the agent is an

HIV integrase inhibitor.

"Combination," "coadministration," "concurrent," and similar terms referring to the administration of a compound of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.

"Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality. "Patient" means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.

"Treatment," "therapy," "regimen," "HIV infection," "ARC," "AIDS" and related terms are used as understood by practitioners in the field of AIDS and HIV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example,

Remington 's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA (1985).

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL. The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection. Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti- infectives. In these combination methods, the compound of Formula I will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement. A partial list of such agents is shown in the table below.

ANTIVIRALS

Drug Name Manufacturer Indication 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

K I-272 Nat'l Cancer Institute HIV-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 ^J (Emtricitabine) 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 ^J Bristol-Myers Squibb HIV infection

(or atazanavir) AIDs, protease

inhibitor

Fuzeon^ 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-Ploug 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®) and Emtriva® (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 GS 1349572 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 (aides lukin)

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 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; R5121 1 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 DESCRIPTION OF SPECIFIC EMBODIMENTS

Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and Examples are defined as follows: "NaHMDS" for sodium bis(trimethylsilyl)amide; "DMF" for N,N- dimethylformamide; "MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl; "TFA" for trifluoroacetic acid; "LAH" for lithium aluminum hydride;

"BOC", "DMSO" for dimethylsulfoxide; "h" for hours; "rt" for room temperature or retention time (context will dictate); "min" for minutes; "EtOAc" for ethyl acetate; "THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic acid; "Et ₂ 0" for diethyl ether; "DMAP" for 4-dimethylaminopyridine; "DCE" for 1,2-dichloroethane; "ACN" for acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for 1- hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine, "Nf ' for

CF ₃ (CF ₂ ) ₃ S0 ₂ -; and "TMOF" for trimethylorthoformate.

Abbreviations as used herein, are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, "°C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "μΕ" for microliter or microliters, "N" for normal, "M" for molar, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "sat" or "sat'd " for saturated, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "FIRMS" for high resolution mass spectrometry , "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tic" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, for proton, "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art. Intermediate 1

2-(Diphenylmethyleneamino)-3-(4-fluorophenyl)propanenitrile (procedure adapted from J. Org. Chem. 2003, 68, 50-54). To a solution of 2- (diphenylmethyleneamino)acetonitrile (1.21 g, 5.47 mmol, 1.0 equiv) in CH ₂ CI ₂ (9.12 mL) was added 4-fluorobenzyl bromide (0.75 mL, 6.02 mmol, 1.1 equiv), benzyltrimethylammomum chloride (0.10g, 0.547 mmol, 0.1 equiv), and aOH (0.99 mL of a 10 M aqueous solution, 9.85 mmol, 1.8 equiv). The reaction was stirred vigorously for 18 h, at which time TLC analysis indicated complete consumption of the starting nitrile. The reaction was added to water and extracted with CH ₂ CI ₂ (x3). The combined CH2CI2 extracts were dried ( a2S0 ₄ ) and concentrated in vacuo. The crude product was purified by silica gel chromatography (5-30% ethyl

acetate/hexane) to provide the title compound (1.65 g, 92% yield) as a viscous yellow oil. ^X H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.54 - 7.65 (m, 2 H), 7.38 - 7.48 (m, 4 H), 7.31 - 7.38 (m, 2 H), 7.00 - 7.09 (m, 2 H), 6.89 - 6.97 (m, 2 H), 6.84 (d, J=6.30 Hz, 2 H), 4.35 (dd, J=7.81, 6.04 Hz, 1 H), 3.10 - 3.29 (m, 2 H); LCMS (ES+, (M+H) ⁺ ) m/z 329.25.

Intermediate 2

2-Amino-3-(4-fluorophenyl)propanenitrile hydrochloride. To a solution of 2- (diphenylmethyleneamino)-3-(4-fluorophenyl)propanenitrile, intermediate 1 (1.65 g, 5.02 mmol, 1.0 equiv) in THF (20.1 mL) was added HC1 (5.53 mL of a 1 M aqueous solution, 5.53 mmol, 1.1 equiv). After stirring 3 h, the reaction was poured into water and washed with ether (x3). The aqueous layer was neutralized by the addition of 10 M NaOH and extracted with CH2CI2 (x3). The combined CH2CI2 extracts were dried ( a ₂ S0 ₄ ) and then concentrated in vacuo to provide the title compound (0.77 g, 93% yield) as a colorless oil. For convenience, the amine could be converted into the hydrochloride salt by dissolution in ether, treating with 2 M HC1 in ether, and filtering the resulting white solid: ^X H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.24 - 7.29 (m, 2 H), 7.01 - 7.08 (m, 2 H), 3.85 - 3.96 (m, 1 H), 2.92 - 3.07 (m, 2 H), 1.60 (d, J=7.55 Hz, 2 H).

Intermediate 3

Ethyl 3-(benzyloxy)-10-( ( (benzyloxy)carbonyl) amino) -4-oxo-4, 6, 7, 8, 9, 10- hexahydro-7, 10-ethanopyrimido[l ,2-aJ azepine-2-carboxyiate. To a solution of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9, 10-hexahydro- 7, 10-ethanopyrimido[l,2-a]azepine-2-carboxylate (prepared according to the procedure in WO2009117540) (500 mg, 1.170 mmol) in DMF (20 mL) was added K2CO ₃ (323 mg, 2.339 mmol) followed by benzyl bromide (0.208 mL, 1.755 mmol) and the resulting mixture was heated at 50° C for 16 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, dried ( a ₂ S0 ₄ ), filtered and concentrated. The crude product was purified by silica gel

chromatography (20 -100% ethyl acetate/hexane to afford the title compound (250 mg, 42% yield) as a light yellow liquid. ^X H NMR (500 MHz, CDC1 ₃ ) δ: 7.47 (d, 2H, J = 7.02 Hz), 7.32-7.39 (m, 8H), 7.19 (brs, 1H), 5.26 (s, 2H), 5.08 (s, 2H), 4.31 (q, 2H, J = 7.02 Hz), 4.13 (d, 2H, J = 3.97 Hz), 2.87-2.96 (m, 2H), 2.46 (brs, 1H), 1.94- 2.03 (m, 2H), 1.80-1.89 (m, 2H), 1.65-1.75 (m, 2H), 1.29 (t, 3H, J = 7.32 Hz).

LCMS (M+H) = 518.28. Intermediate 4

3-(Benzyloxy)-10-( ( (benzyloxy)carbonyl)amino)-4-oxo-4, 6, 7, 8, 9,10- hexahydro-7, 10-ethanopyrimido[ 1 ,2-a] ^' azepine-2-carboxylic acid. To a solution of ethyl 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8, 9,10-hexahydro- 7,10-ethanopyrimido[l,2-a]azepine-2-carboxylate, Intermediate 3 (250 mg, 0.483 mmol) in EtOH (5 mL) was added water (1.250 mL) followed by LiOH-H ₂ 0 (20.27 mg, 0.483 mmol) and the mixture was stirred at room temp for 16 h. Water (10 mL) was then added and the mixture was extracted with ether (100 mL). The aqueous layer was then acidified with IN HC1 and then extracted with ethyl acetate (2X 100 mL), washed with brine, dried (Na ₂ S0 ₄ ), filtered and concentrated to afford the title compound (180 mg, 76% yield) as a light yellow solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ: 7.51 (d, 2H, J = 6.71 Hz), 7.30-7.40 (m, 9H), 5.46 (s, 2H), 5.06 (s, 2H), 4.10-4.15 (m, 2H), 2.47-2.61 (m, 3H), 2.03-2.11 (m, 2H), 1.91-2.01 (m, 2H), 1.63-1.73 (m, 2H). LCMS (M+H) = 490.23.

Intermediate 5

Benzyl (3-(benzyloxy)-2-((l-cyano-2-(4-fluorophenyl)ethyl)carbamoyl )-4-oxo- 6, 7,8,9-tetrahydro-7, 10-ethanopyrimido[l ,2-a] azepin-10(4H)-yl)carbamate. To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8, 9,10- hexahydro-7,10-ethanopyrimido[l,2-a]azepine-2-carboxylic acid, Intermediate 4 (180 mg, 0.368 mmol) in CH ₂ C1 ₂ (2 mL) was added oxalyl chloride (0.051 mL, 0.588 mmol) followed by 1 drop of DMF. After stirring for 2 h, the mixture was concentrated under reduced pressure. The crude acid chloride was then diluted with dichloromethane (2 mL) and added to a stirred solution of 2-amino-3-(4- fluorophenyl)propanenitrile HC1 (81 mg, 0.404 mmol) and triethylamine (0.205 mL, 1.471 mmol) in (¾(¾ (2 mL) and the resulting solution was stirred at room temperature. After 16 h at room temperature, the reaction mixture was poured into sat. aHC03 and extracted with dichloromethane (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50 -100% EtOAc/hexane) to afford the title compound (145 mg, 62% yield) as a light yellow solid. ¾ NMR (500 MHz, CDC1 ₃ ) δ: 7.82 (brs, 1H), 7.28-7.49 (m, 10H), 7.06-7.17 (m, 2H), 6.96 (t, 2H, J = 8.39 Hz), 6.63 (brs, 1H), 5.27-5.40 (m, 2H), 5.00-5.14 (m, 2H), 4.07-4.14 (m, 3H), 2.77-2.92 (m, 2H), 2.64-2.78 (m, 2H), 2.49 (brs, 1H), 1.87-2.02 (m, 4H), 1.63-1.75 (m, 2H). LCMS (M+H) = 636.19.

Intermediate 6

Benzyl (3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-lH-imidazol-2- yl)-4- oxo-6, 7, 8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)ca rbamate. To a solution of benzyl (3 -(benzyloxy)-2-(( 1 -cyano-2-(4-fluorophenyl)ethyl)carbamoyl)- 4-oxo-6,7, 8, 9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carb amate, Intermediate 5 (140 mg, 0.220 mmol) in acetonitrile (4 mL) was added carbon tetrachloride (0.053 mL, 0.551 mmol), followed by triphenylphosphine (144 mg, 0.551 mmol) and the mixture was heated at 45° C. After stirring for 16 h, the mixture was cooled to room temp and concentrated in vacuo. The residue was then treated with dichloromethane (10 mL) and 0.5 N NaOH (20 mL). The mixture was then poured into water and extracted with dichloromethane (x4), dried ( a ₂ S0 ₄ ), filtered and concentrated. The crude product was then purified by silica gel chromatography (40-100% EtOAc/hexane) to afford the title compound (90 mg, 42% yield) as a yellow solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 1.65 - 1.74 (m, 2 H) 1.92 - 2.03 (m, 4 H) 2.47 (br. s., 1 H) 2.71 - 2.86 (m, 2 H) 3.74 (s, 2 H) 4.13 (d, J=3.66 Hz, 2 H) 5.12 (s, 2 H) 5.29 (s, 2 H) 6.92 (d, J=7.63 Hz, 4 H) 7.08 (br. s., 1 H) 7.29 - 7.37 (m, 8 H) 7.39 - 7.46 (m, 2 H) 10.08 (br. s., 1 H). (M+H) = 654.28.

Intermediate 7

Benzyl (3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl) -4-oxo- 6, 7,8,9-tetrahydro-7, 10-ethanopyrimido[l ,2-aJ azepin-10(4H)-yl) carbamate. To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8, 9, 10- hexahydro-7, 10-ethanopyrimido[l,2-a]azepine-2-carboxylic acid, Intermediate 4 (400 mg, 0.817 mmol) in CH ₂ C1 ₂ (8 mL) was added oxalyl chloride (0.114 mL, 1.307 mmol) followed by 1 drop of DMF. After stirring for 2 h, the mixture was concentrated under reduced pressure. The crude acid chloride was then diluted with dichloromethane (5 mL)) and added to a stirred solution of l-amino-3-(4- fluorophenyl)propan-2-one HCl (183 mg, 0.899 mmol) and triethylamine (0.456 mL, 3.27 mmol) in CH ₂ C1 ₂ (8.00 mL) and the resulting solution stirred at room temperature. After 16 h the reaction mixture was poured into sat. aHC0 ₃ and extracted with dichloromethane (50 mL x 3), dried ( a ₂ S0 ₄ ), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50-100% EtOAc/ hexane) to afford the title compound (400 mg, 0.626 mmol, 77 % yield) as a light yellow solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 7.99 (1 H, br. s.), 7.49 (2 H, d, J=5.80 Hz), 7.28 - 7.37 (8 H, m), 7.15 (2 H, dd, J=8.55, 5.49 Hz), 7.01 - 7.04 (2 H, m), 6.79 (1 H, br. s.), 5.32 (2 H, s), 5.06 (2 H, s), 4.17 (2 H, d, J=4.88 Hz), 4.12 (2 H, d, J=3.66 Hz), 3.69 (2 H, s), 2.67 - 2.78 (2 H, m), 2.47 (1 H, br. s.), 1.89 - 2.01 (4 H, m), 1.64 - 1.72 (2 H, m). LCMS (M+H) = 640.04.

Intermediate 8

Benzyl (3-(benzyloxy)-2-(5-(4-fluorobenzyl)-l,3-thiazol-2-yl)-4-oxo -6, 7,8,9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbam ate. To a solution of benzyl (3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl) -4-oxo- 6,7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-y l)carbamate,

Intermediate 7 (120 mg, 0.188 mmol) in toluene was added Lawesson's Reagent (76 mg, 0.188 mmol) and stirred for 15 min at room temperature, 30 min at 60°C and 2h at 100° C. The resulting clear yellow mixture was then cooled, concentrated and purified by preparative HPLC to provide the title compound (60 mg, 0.094 mmol, 50.2 % yield) as a yellow solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.79 (1 H, s), 7.47 - 7.52 (2 H, m), 7.29 - 7.39 (8 H, m), 7.17 (2 H, dd, J=8.28, 5.27 Hz), 6.94 - 7.07 (3 H, m), 5.38 (2 H, s), 5.09 (2 H, s), 4.09 - 4.19 (4 H, m), 2.69 - 2.84 (2 H, m), 2.49 (1 H, br. s.), 1.94 - 2.04 (4 H, m), 1.65 - 1.76 (2 H, m). LCMS (M+H) = 637.27. Intermediate 9

Benzyl (3-(benzyloxy)-2-(hydrazinylcarbonyl)-4-oxo-6, 7,8,9-tetrahydro-7,10- ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate. To a solution of 3-(benzyloxy)- 10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9, 10-hexahydro-7, 10- ethanopyrimido[l,2-a]azepine-2-carboxylic acid, Intermediate 4 (1 g, 2.043 mmol) in CH2CI2 (20 mL) was added oxalyl chloride (0.286 mL, 3.27 mmol). A few drops of DMF were added and the mixture stirred at room temperature for 2h. Solvent was then removed under reduced pressure. The crude acid chloride was then diluted with dichloromethane (10 mL)) and added to a stirred solution of hydrazine (0.641 mL, 20.43 mmol) and triethylamine (2.85 mL, 20.43 mmol) in CH ₂ C1 ₂ (20 mL) and the resulting solution stirred at room temperature. After 16 h the reaction mixture was poured into sat. aHC0 ₃ and extracted with dichloromethane (50 mL x 3), dried ( a ₂ S04), filtered and concentrated to give a yellow oil which was used in the next step without further purification. LCMS (M+H) = 504.10.

Intermediate 10

Benzyl (3-(benzyloxy)-2-((2-((4-fluorophenyl)acetyl)hydrazinyl)carb onyl)-4- oxo-6, 7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl) carbamate. To a solution of benzyl (3-(benzyloxy)-2-(hydrazinylcarbonyl)-4-oxo-6,7,8,9-tetrahyd ro- 7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate, Intermediate 9 (400 mg, 0.794 mmol) in CH ₂ C1 ₂ (15 mL) at 0 °C was added triethylamine (0.221 mL, 1.589 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (0.098 mL, 0.715 mmol) and the resulting mixture stirred for lh. The mixture was allowed to warm to room temp and stirred for 3h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (70 mg, 0.109 mmol, 13.78 % yield) as a white solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 10.00 (1 H, br. s.), 8.35 (1 H, br. s.), 7.48 - 7.53 (2 H, m), 7.27 - 7.38 (10 H, m), 7.00 - 7.07 (2 H, m), 6.55 (1 H, br. s.), 5.39 (2 H, s), 5.05 (2 H, s), 4.10 (2 H, d, J=3.36 Hz), 3.60 (2 H, s), 2.56 - 2.70 (2 H, m), 2.47 (1 H, br. s.), 1.88 - 2.04 (4 H, m), 1.59 - 1.71 (2 H, m). LCMS (M+H) = 640.35.

Intermediate 11

Benzyl (3-(benzyloxy)-2-(5-(4-fluorobenzyl)-l,3,4-oxadiazol-2-yl)-4 -oxo- 6, 7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl) carbamate. To a stirred solution of benzyl (3-(benzyloxy)-2-((2-((4- fluorophenyl)acetyl)hydrazinyl)carbonyl)-4-oxo-6,7,8,9-tetra hydro-7,10- ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate, Intermediate 10 (70 mg, 0.109 mmol), Ph ₃ P (51.7 mg, 0.197 mmol), N,N-diisopropylethylamine (0.115 mL, 0.657 mmol) in acetonitrile (3 mL) was added hexachloroethane (0.016 mL, 0.142 mmol). After 16h the resulting mixture was purified by preparative HPLC to afford the title compound (30 mg, 0.048 mmol, 44.1 % yield) as an off-white solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 7.45 - 7.48 (2 H, m), 7.32 - 7.41 (8 H, m), 7.21 - 7.26 (2 H, m), 7.09 (1 H, br. s.), 6.95 (2 H, t, J=8.55 Hz), 5.40 (2 H, s), 5.13 (2 H, s), 4.19 (2 H, s), 4.18 (2 H, d, J=3.66 Hz), 2.87 - 2.96 (2 H, m), 2.52 (1 H, br. s.), 1.98 - 2.08 (2 H, m), 1.87 - 1.95 (2 H, m), 1.69 - 1.78 (2 H, m). LCMS (M+H) = 622.33.

Intermediate 12

10-Amino-2-(5-(4-fluorobenzyl)-l,3,4-oxadiazol-2-yl)-3-hy droxy-7,8,9,10- tetrahydro-7 , 10-ethanopyrimido[l ,2-aJ azepin-4(6H)-one. To a mixture of benzyl (3- (benzyloxy)-2-(5-(4-fluorobenzyl)-l,3,4-oxadiazol-2-yl)-4-ox o-6,7,8,9-tetrahydro- 7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate, Intermediate 11 (30 mg, 0.048 mmol) in CH ₂ C1 ₂ (2 mL) was added HBr in acetic acid (0.218 mL, 1.206 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated and dried under high vacuum to afford the title compound (18 mg, 0.038 mmol, 78 % yield) as a brown solid. ¾ NMR (500 MHz, MeOD) δ ppm 7.39 - 7.46 (2 H, m), 7.08 - 7.14 (2 H, m), 4.38 (2 H, s), 4.20 (2 H, d, J=3.66 Hz), 2.60 (1 H, br. s.), 2.22 - 2.31 (2 H, m), 2.05 - 2.18 (4 H, m), 1.85 - 1.94 (2 H, m). LCMS (M+H) = 398.18. Intermediate 13

Benzyl (3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl) -4-oxo-

6, 7,8,9-tetrahydro-7, 10-ethanopyrimido[l ,2-aJ azepin-10(4H)-yl)carbamate. To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8, 9,10- hexahydro-7,10-ethanopyrimido[l,2-a]azepine-2-carboxylic acid, Intermediate 4 (1 g, 2.043 mmol) in CH ₂ C1 ₂ (20 mL) was added oxalyl chloride (0.286 mL, 3.27 mmol). A few drops of DMF was then added and the mixture stirred at room temperature for 2h. Solvent was removed under reduced pressure and the crude acid chloride was diluted with dichloromethane (10 mL) and added to a stirred solution of l-amino-3-(4-fluorophenyl)propan-2-one HC1 (0.458 g, 2.247 mmol) and triethylamine (1.139 mL, 8.17 mmol) in CH2CI2 (20 mL). The resulting solution was stirred at room temperature for 16 h then poured into sat. aHC03 and extracted with dichloromethane (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50 - 100% EtOAc/ hexane) to afford the title compound (770 mg, 1.206 mmol, 59.0 % yield) as a light yellow solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 7.99 (1 H, br. s.), 7.49 (2 H, d, J=5.80 Hz), 7.28 - 7.37 (8 H, m), 7.15 (2 H, dd, J=8.55, 5.49 Hz), 7.01 - 7.04 (2 H, m), 6.79 (1 H, br. s.), 5.32 (2 H, s), 5.06 (2 H, s), 4.17 (2 H, d, J=4.88 Hz), 4.12 (2 H, d, J=3.66 Hz), 3.69 (2 H, s), 2.67 - 2.78 (2 H, m), 2.47 (1 H, br. s.), 1.89 - 2.01 (4 H, m), 1.64 - 1.72 (2 H, m). LCMS (M+H)= 640.04. Intermediate 14

10-Amino-N-(3-(4-fluorophenyl)-2-oxopropyl)-3-hydroxy-4-o xo-4,6, 7,8,9,10- hexahydro-7,10-ethanopyrimido[l,2-a]azepine-2-carboxamide. To a mixture of benzyl (3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl) -4-oxo- 6,7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-y l)carbamate, Intermediate 13 (540 mg, 0.845 mmol) in MeOH (8 mL) was added IN HC1 (0.930 mL, 0.930 mmol) followed by 10% Pd/C (90 mg, 0.085 mmol) and the mixture stirred under a hydrogen atmosphere for 2 h. The mixture was then filtered and thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo and dried under high vacuum overnight to afford the title compound (318 mg, 0.705 mmol, 83 % yield) as an off-white solid. ^X H NMR (500 MHz, DMSO-i/ ₆ ) δ ppm 12.07 (1 H, br. s.), 9.61 (1 H, t, J=5.95 Hz), 7.24 - 7.30 (2 H, m), 7.13 - 7.20 (2 H, m), 4.33 (2 H, d, J=6.10 Hz), 4.00 (2 H, d, J=3.66 Hz), 3.92 (2 H, s), 2.46 (1 H, br. s.), 2.01 - 2.13 (4 H, m), 1.79 - 1.88 (2 H, m), 1.68 - 1.77 (2 H, m). LCMS (M+H) 415.15.

Intermediate 15

N'-(2-((3-(4-Fluorophenyl)-2-oxopropyl)carbamoyl)-3-hydroxy- 4-oxo-

6, 7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl) -N,N- dimethylethanediamide. To a solution of 10-amino-N-(3-(4-fluorophenyl)-2- oxopropyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethan opyrimido[l,2- a]azepine-2-carboxamide, Intermediate 14 (318 mg, 0.705 mmol) in DMF (8 mL) were added 2-(dimethylamino)-2-oxoacetic acid (165 mg, 1.411 mmol), N,N- diisopropylethylamine (0.739 mL, 4.23 mmol), HATU (536 mg, 1.411 mmol) and DMAP (17.23 mg, 0.141 mmol) and the resulting mixture was stirred at room temperature for 3 h. The mixture was then purified by preparative HPLC to afford the title compound (210 mg, 0.409 mmol, 58.0 % yield) as an off- white solid.

^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 11.67 (1 H, br. s.), 8.54 (1 H, t, J=5.49 Hz), 8.03 (1 H, s), 7.19 (2 H, dd, J=8.55, 5.19 Hz), 6.99 - 7.05 (2 H, m), 4.26 (2 H, d, J=5.49 Hz), 4.17 (2 H, d, J=3.97 Hz), 3.77 (2 H, s), 3.28 (3 H, s), 2.92 (3 H, s), 2.46 - 2.57 (5 H, m), 2.09 - 2.17 (2 H, m), 1.91 - 2.01 (2 H, m), 1.67 - 1.77 (2 H, m). LCMS (M+H) = 514.26.

Intermediate 16

N'-(3-(Benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carb amoyl)-4-oxo-

6, 7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl) -N,N- dimethylethanediamide. To a mixture of N'-(2-((3-(4-fluorophenyl)-2- oxopropyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10 -ethanopyrimido[l,2- a]azepin-10(4H)-yl)-N,N-dimethylethanediamide, Intermediate 15 (140 mg, 0.273 mmol) in DMF (5 mL) was added K2CO ₃ (67.8 mg, 0.491 mmol) followed by (bromomethyl)benzene (0.049 mL, 0.409 mmol) and the resulting mixture stirred at room temp for 16h. Water was then added and the mixture was extracted with ethyl acetate (2 x 50 mL), dried ( a2S0 ₄ ), filtered and concentrated. The crude product was purified by silica gel chromatography to afford the title compound (140 mg, 0.162 mmol, 59.5 % yield) as a yellow oil. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 8.73 (1 H, s), 8.31 (1 H, s), 7.53 - 7.59 (2 H, m), 7.31 - 7.38 (3 H, m), 7.18 - 7.24 (2 H, m), 7.02 - 7.07 (2 H, m), 5.35 (2 H, s), 4.73 (2 H, s), 4.29 (2 H, d, J=5.49 Hz), 4.16 (2 H, d, J=3.66 Hz), 2.94 (3 H, s), 2.91 (3 H, s), 2.70 - 2.79 (2 H, m), 2.53 (1 H, br. s.), 1.98 - 2.12 (4 H, m), 1.70 - 1.80 (2 H, m). LCMS (M+H) = 604.31.

Intermediate 17

N'-(3-(Benzyloxy)-2-(5-(4-fluorobenzyl)-l,3-oxazol-2-yl)- 4-oxo-6, 7,8,9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-N,N- dimethylethanediamide. To a mixture of N'-(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2- oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyr imido[l,2-a]azepin- 10(4H)-yl)-N,N-dimethylethanediamide, Intermediate 16 (125 mg, 0.207 mmol) in THF (8 mL) was added Burgess Reagent (345 mg, 1.450 mmol) and the mixture heated to reflux for 5h. The mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound (65 mg, 0.111 mmol, 53.6 % yield) as a white solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 9.24 (1 H, s), 7.38 - 7.42 (2 H, m), 7.30 - 7.34 (3 H, m), 7.18 - 7.23 (2 H, m), 7.11 (1 H, s), 6.99 - 7.04 (2 H, m), 5.38 (2 H, s), 4.18 (2 H, d, J=3.66 Hz), 4.02 (2 H, s), 3.30 (3 H, s), 3.03 (3 H, s), 2.88 - 2.96 (2 H, m), 2.54 (1 H, br. s.), 1.94 - 2.10 (4 H, m), 1.71 - 1.80 (2 H, m). LCMS (M+H) = 586.31.

Example 1

10-Amino-2-[4-[(4-fluorophenyl)methyl] -lH-imidazol-2-yl] -7,8,9, 10- tetrahydro-3-hydroxy-7,10-ethanopyrimido[l,2-a]azepin-4(6H)- one. To a solution of benzyl (3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-lH-imidazol-2- yl)-4-oxo- 6,7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-y l)carbamate,

Intermediate 6 (60 mg, 0.092 mmol) in MeOH (3 mL) was added formic acid (0.100 mL, 2.65 mmol) followed by 10% Pd/C (98 mg, 0.092 mmol) and the mixture stirred at 40°C for 3h. After cooling to room temperature, the mixture was filtered through a pad of celite and concentrated. The mixture was then treated with sat. aHC03, extracted with dichloromethnae (x4), dried ( a2S0 ₄ ), filtered and concentrated to afford the title compound (30 mg, 83% yield) as a light purple solid. ^X H NMR (500 MHz, DMSO-i¾) δ ppm 1.53 - 1.60 (m, 2 H), 1.73 - 1.81 (m, 6 H), 2.37 (br. s., 1 H), 2.51 - 2.54 (m, 2 H), 3.93 - 3.99 (m, 2 H), 4.01 (d, J=3.66 Hz, 2 H), 7.10 - 7.17 (m, 3 H), 7.30 (dd, J=8.24, 5.80 Hz, 2 H). LCMS (M+H) = 396.13.

Example 2

N'-(2-( 4-( 4-Fluorobenzyl)-lH-imidazol-2-yl)-3-hydroxy-4-oxo-6, 7, 8, 9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-N,N- dimethylethanediamide. To a stirred solution of 10-amino-2-(4-(4-fluorobenzyl)-lH- imidazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyri mido[l,2-a]azepin- 4(6H)-one, Example 1 (27 mg, 0.068 mmol) and 2-(dimethylamino)-2-oxoacetic acid (11.99 mg, 0.102 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine

(0.061 mL, 0.35 mmol), DMAP (1.668 mg, 0.014 mmol) and HATU (38.9 mg, 0.102 mmol) and the resulting mixture stirred at room temp for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (6 mg, 8% yield) as an off-white solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 1.63 - 1.77 (m, 2 H), 1.93-1.98 (m, 2 H), 2.29 - 2.38 (m, 4 H), 2.50 (br. s., 1 H), 3.00 (s, 3 H), 3.17 (s, 3 H), 4.03 (s, 2 H), 4.14 (s, 2 H), 6.82 (br. s., 1 H), 7.00 (t, J=8.39 Hz, 1 H), 7.21 - 7.27 (m, 3 H), 7.70 (s, 1 H). LCMS (M+H) = 495.20.

Example 3

N-(2-(4-( 4-Fluorobenzyl)-lH-imidazol-2-yl)-3-hydroxy-4-oxo-6, 7, 8, 9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-2-oxo -2-(pyrrolidin-l- yl)acetamide. white solid (20 mg,38% yield). ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 9.0 (1 H, br. s.), 7.1 - 7.2 (3 H, m), 7.0 (3 H, t, J=8.55 Hz), 4.1 (4 H, br. s.), 3.4 - 3.6 (3 H, m), 2.5 (1 H, br. s.), 2.2 - 2.4 (2 H, m), 2.1 - 2.2 (2 H, m), 2.0 - 2.1 (3 H, m), 1.8 - 1.9 (3 H, m), 1.5 - 1.7 (3 H, m). LCMS (M+H) = 521.53.

Example 4

N-(2-(4-(4-Fluorobenzyl)-lH-imidazol-2-yl)-3-hydroxy-4-ox o-6, 7,8,9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-5-met hyl-l,2-oxazole-3- carboxamide. To a solution of 10-amino-2-(4-(4-fluorobenzyl)-lH-imidazol-2-yl)-3- hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin -4(6H)-one, Example 1 (30 mg, 0.076 mmol) in CH ₂ C1 ₂ (3 mL) was added triethylamine (0.063 mL, 0.455 mmol) followed by 5-methylisoxazole-3-carbonyl chloride (55.2 mg, 0.379 mmol) and the resulting mixture stirred at room temperature. After 16 h the reaction mixture was concentrated to give the crude product which was treated with 2M

dimethylamine/MeOH (0.5 mL) in MeOH (2 mL) at 60°C for 2 h. The mixture was then cooled and purified by preparative HPLC to afford the title compound (15 mg, 39 %) as a white solid. ^X H NMR (500 MHz, DMSO-i¾) δ ppm 13.4 (1 H, br. s.), 9.0 (1 H, s), 7.4 (1 H, br. s.), 7.4 (2 H, dd, J=8.24, 5.80 Hz), 7.2 (2 H, t, J=8.85 Hz), 6.6 (1 H, s), 4.1 (2 H, d, J=3.36 Hz), 4.1 (2 H, s), 2.7 - 2.8 (2 H, m), 2.5 (1 H, br. s.), 2.0 - 2.0 (2 H, m), 1.9 - 1.9 (2 H, m), 1.7 - 1.8 (2 H, m). LCMS (M+H) = 505.49.

Example 5

10-Amino-3-(benzyloxy)-2-(5-(4-fluorobenzyl)- l,3-thiazol-2-yl)-7, 8,9,10- tetrahydro-7 , 10-ethanopyrimido[l ,2-aJ azepin-4(6H)-one. To a solution of benzyl (3-(benzyloxy)-2-(5-(4-fluorobenzyl)-l,3-thiazol-2-yl)-4-oxo -6,7,8,9-tetrahydro- 7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate Intermediate 8 (60 mg, 0.094 mmol) in methanol (3 mL) was added IN HC1 (0.104 mL, 0.104 mmol) followed by Pd/C (10.03 mg, 9.42 μιηοΐ) and the resulting mixture was stirred under a hydrogen atmosphere for 3h. The catalyst was removed by filtration and the mixture concentrated then diluted with dichloromethane (3 mL), treated with 48% HBr (0.2 mL) and stirred at room temperature for 16h. The mixture was concentrated and the crude product was triturated with ethyl acetate/hexane, filtered and dried under high vacuum to afford the title compound HBr salt 0.102 mL, 1.885 mmol) as a dark brown solid. ^X H NMR (500 MHz, DMSO-i¾) δ ppm 7.97 (1 H, s), 7.36 (2 H, dd, J=8.70, 5.65 Hz), 7.16 - 7.20 (2 H, m), 4.32 (2 H, s), 4.05 (2 H, d, J=3.36 Hz), 2.46 (1 H, br. s.), 2.08 - 2.16 (2 H, m), 1.96 - 2.04 (2 H, m), 1.81 - 1.89 (2 H, m), 1.70 - 1.79 (2 H, m). LCMS (M+H) = 414.18. Example 6

N'-(2-( 5-( 4-Fluorobenzyl)-l, 3-thiazol-2-yl)-3-hydroxy-4-oxo-6, 7, 8, 9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-N,N- dimethylethanediamide. To a stirred solution of 10-amino-3-(benzyloxy)-2-(5-(4- fluorobenzyl)- 1 ,3-thiazol-2-yl)-7,8,9, 10-tetrahydro-7, 10-ethanopyrimido[ 1 ,2- a]azepin-4(6H)-one, Example 5 (35 mg, 0.085 mmol) in DMF (2 mL) was added 2- (dimethylamino)-2-oxoacetic acid (19.87 mg, 0.170 mmol), N,N- diisoproplylethylamine (0.119 mL, 0.679 mmol), HATU (64.5 mg, 0.170 mmol) and DMAP (5.18 mg, 0.042 mmol) and the resulting mixture stirred at room temperature for 16h. The mixture was purified by preparative HPLC to afford the title compound (7mg, 0.013 mmol, 15.32 % yield) as a light green solid. ^X H NMR (400 MHz, DMSO-i¾) δ ppm 11.17 (1 H, br. s.), 9.04 (1 H, br. s.), 7.87 (1 H, br. s.), 7.36 (2 H, dd, J=8.16, 5.65 Hz), 7.19 (2 H, t, J=8.78 Hz), 4.29 (2 H, s), 4.06 (2 H, d, J=3.51 Hz), 3.04 (3 H, s), 2.87 (3 H, s), 2.33 - 2.45 (3 H, m), 2.03 - 2.14 (2 H, m), 1.79 - 1.90 (2 H, m), 1.60 - 1.71 (2 H, m). LCMS (M+H) = 512.01.

Example 7

N'-(2-( 5-( 4-Fluorobenzyl)-l, 3, 4-oxadiazol-2-yl)-3-hydroxy-4-oxo-6, 7, 8, 9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-N,N- dimethylethanediamide. To a solution of 10-amino-2-(5-(4-fluorobenzyl)-l,3,4- oxadiazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyr imido[l,2-a]azepin- 4(6H)-one, Intermediate 12 (20 mg, 0.042 mmol) in DMF (1.5 mL) was added 2- (dimethylamino)-2-oxoacetic acid (9.79 mg, 0.084 mmol), N,N- dissopropylethylamine (0.044 mL, 0.251 mmol), HATU (31.8 mg, 0.084 mmol) and DMAP (5.11 mg, 0.042 mmol) and the resulting mixture stirred at room temp for 3h and then purified by preparative HPLC to afford the title compound (5 mg, 9.47 μιηοΐ, 22.64 % yield) as a purple solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 11.10 (1 H, br. s.), 9.60 (1 H, s), 7.54 (2 H, dd, J=8.39, 5.34 Hz), 7.10 (2 H, t, J=8.55 Hz),

4.35 (2 H, s), 4.24 (2 H, br. s.), 3.44 (3 H, s), 3.13 (3 H, s), 2.99 - 3.08 (3 H, m), 2.54 (1 H, br. s.), 2.03 - 2.13 (2 H, m), 1.85 - 1.94 (2 H, m), 1.72 - 1.81 (2 H, m). LCMS (M+H)+= 497.18.

Example 8

N'-(4-( 5-( 4-Fluorobenzyl)- 1 , 3-oxazol-2-yl)-3-hydroxy-4-oxo-6, 7, 8, 9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-N,N- dimethylethanediamide. To a solution of N'-(3-(benzyloxy)-2-(5-(4-fluorobenzyl)- l,3-oxazol-2-yl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimid o[l,2-a]azepin-10(4H)- yl)-N,N-dimethylethanediamide, Intermediate 17 (60 mg, 0.102 mmol) in CH2CI2 (3 mL) was added TFA (1 mL, 12.98 mmol) and the resulting mixture heated at 40°C for 16h. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the title compound (23 mg, 0.046 mmol, 45.3 % yield) as a white solid. ^X H NMR (500 MHz, CDC1 ₃ ) δ ppm 10.84 (1 H, br. s.), 9.74 (1 H, s), 7.45 (2 H, dd, J=8.55, 5.49 Hz), 7.08 (2 H, t, J=8.70 Hz), 6.97 (1 H, s), 4.23 (2 H, d, J=3.66 Hz), 4.13 (2 H, s), 3.43 (3 H, s), 3.11 (3 H, s), 3.01 - 3.09 (2 H, m), 2.52 (1 H, br. s.), 2.02 - 2.12 (2 H, m), 1.84 - 1.92 (2 H, m), 1.72 - 1.80 (2 H, m). LCMS (M+H)= 496.28.

Example 9

N'-[2-[l-[(4-Fluorophenyl)methyl] -lH-1 ,2,4-triazol-3-yl] -6, 7,8,9-tetrahydro-

3-hydroxy-4-oxo-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-y l]-N,N-dimethyl- ethanediamide. ¾ NMR (400 MHz, CDC1 ₃ ) δ ppm 9.61 (1 H, br. s.), 8.25 (1 H, br. s.), 7.45 (2 H, br. s.), 7.13 (2 H, t, J=7.7 Hz), 5.46 (2 H, br. s.), 4.22 (2 H, br. s.), 3.35 (3 H, s), 3.06 (3 H, br. s.), 2.97 (2 H, br. s.), 2.52 (1 H, br. s.), 2.05 (2 H, br. s.), 1.94 (2 H, br. s.), 1.75 (2 H, br. s.); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm -111.90 (1 F, s); LCMS (ES+, (M+H) ⁺ ) m/z 496.1.

Example 10

N'-[2-[ 4-f ( 4-Fluoro-3-methylphenyl)methyl] -lH-imidazol-2-yl] -6, 7, 8, 9- tetrahydro-3-hydroxy-4-oxo- 7,10-ethanopyrimido[ 1, 2-a]azepin-10( 4H)-yl]-N,N- dimethyl- ethanediamide trifluoroacetate salt. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 7.60 (br. s., 1 H), 7.03 - 7.14 (m, 2 H), 6.95 (t, J=8.78 Hz, 1 H), 6.87 (s, 1 H), 4.15 (d, J=3.01 Hz, 2 H), 4.03 (s, 2 H), 3.18 (s, 3 H), 3.03 (s, 3 H), 2.53 (br. s., 1 H), 2.37 - 2.47 (m, 2 H), 2.27 - 2.37 (m, 2 H), 2.25 (s, 3 H), 1.91 - 2.04 (m, 2 H), 1.73 (br. s., 2 H); ^iy F NMR (376 MHz, CDC1 ₃ ) δ ppm -75.65 (s, 3 F), -119.63 (s, 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 509.16.

Example 11

N-[2-[ 4-[ (4-Fluoro-3-methylphenyl)methyl] - lH-imidazol-2-yl] -6, 7, 8,9- tetrahydro-3-hydroxy-4-oxo-7, 10-ethanopyrimido[l ,2-aJ azepin-10(4H)-yl]- 3- pyridinecarboxamide trifluoroacetate salt. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 11.42 (br. s., 1 H), 9.34 (d, J=3.76 Hz, 1 H), 8.39 (d, J=8.03 Hz, 1 H), 7.78 (dd, J=8.41, 5.14 Hz, 1 H), 7.09 - 7.19 (m, 2 H), 7.08 (s, 1 H), 6.96 (t, J=8.91 Hz, 1 H), 4.25 (br. s., 2 H), 4.17 (br. s., 2 H), 3.07 - 3.27 (m, 2 H), 2.56 (br. s., 1 H), 2.25 (s, 3 H), 2.09 - 2.21 (m, 2 H), 1.92 - 2.04 (m, 2 H), 1.78 - 1.91 (m, 2 H); ¹⁹ F NMR (376 MHz, CDCI3) δ ppm -75.40 (s, 3 F), -119.20 (s, 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 515.1.

Example 12

N-[2-[ 4-[ (4-Fluoro-3-methylphenyl)methyl] -lH-imidazol-2-yl] -6, 7, 8,9- tetrahydro-3-hydroxy-4-oxo-7, 10-ethanopyrimido[l ,2-aJ azepin-10(4H)-yl]- 3- pyridazinecarboxamide trifluoroacetate salt. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 10.95 (br. s., 1 H), 9.55 (s, 1 H), 8.76 (d, J=7.78 Hz, 1 H), 8.66 (d, J=5.52 Hz, 1 H), 7.82 - 7.91 (m, 1 H), 6.79 - 6.97 (m, 3 H), 6.44 (s, 1 H), 4.17 (br. s., 2 H), 3.78 (br. s., 2 H), 2.79 - 2.94 (m, 2 H), 2.59 (br. s., 1 H), 2.30 - 2.45 (m, 2 H), 2.22 (s, 3 H), 1.96 - 2.10 (m, 2 H), 1.69 - 1.84 (m, 2 H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm -75.81 (br. S. , 3 F), -120.29 (br. s., 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 516.0.

Example 13

N-[2-[4-[(4-Fluorophenyl)methyl]-lH-imidazol-2-yl]-6, 7,8,9-tetrahydro-3- hydroxy-4-oxo-7, 10-ethanopyrimido[ 1, 2-a]azepin-10( 4H)-yl] -Ν,Ν',Ν'-trimethyl- ethanediamide trifluoroacetate salt. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 7.23 - 7.33 (m, 2 H), 6.96 - 7.07 (m, 3 H), 4.10 (s, 2 H), 3.69 (br. s., 1 H), 3.41 (br. s., 1 H), 3.08 (s, 3 H), 3.05 (s, 3 H), 3.01 (s, 3 H), 2.53 (br. s., 1 H), 1.99 - 2.17 (m, 4 H), 1.83 (br. s., 2 H), 1.60 (br. s., 2 H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm -75.70 (br. s., 3 F), - 115.73 (br. s., 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 509.0.

Example 14

N-[2-[ 4-[ (4-Fluoro-3-methylphenyl)methyl] - lH-imidazol-2-yl] -6, 7, 8,9- tetrahydro-3-hydroxy-4-oxo- 7, 10-ethanopyrimidof 1 ,2-aj 'azepin-10( 4H)-yl ]- alpha,alpha-dimethyl-lH-l,2,4-triazole-l-acetamide trifluoroacetate salt. ^X H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.48 (s, 1 H), 7.97 (s, 1 H), 7.34 (s, 1 H), 7.10 (s, 1 H), 7.05 (d, J=7.03 Hz, 1 H), 6.98 - 7.03 (m, 1 H), 6.95 (t, J=8.78 Hz, 1 H), 4.16 (d, J=3.51 Hz, 2 H), 4.07 (s, 2 H), 2.43 - 2.55 (m, 3 H), 2.24 (d, J=1.51 Hz, 3 H), 1.86 - 1.98 (m, 4 H), 1.87 (br. s., 6 H), 1.60 - 1.73 (m, 2 H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm -75.78 (br. s., 3 F), -119.54 (s, 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 547.2.

Example 15

l-(Acetylmethylamino)-N-[2-[4-[(4-fluoro-3-methylphenyl)meth yl]-lH- imidazol-2-yl J -6, 7, 8, 9-tetrahydro-3-hydroxy-4-oxo- 7, 10-ethanopyrimidof 1,2- a]azepin-10(4H)-yl]- cyclopropanecarboxamide trifluoroacetate salt. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 8.49 (s, 1 H), 7.05 - 7.14 (m, 2 H), 7.02 (s, 1 H), 6.94 (q, J=8.55 Hz, 1 H), 4.29 - 4.43 (m, 1 H), 3.99 - 4.20 (m, 3 H), 3.00 (s, 3 H), 2.41 - 2.54 (m, 1 H), 2.24 (s, 6 H), 1.97 (br. s., 4 H), 1.77 (br. s., 2 H), 1.60 (br. s., 4 H), 1.15 - 1.40 (m, 1 H), 0.80 - 0.92 (m, 1 H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm -76.28 (br. s., 3 F), - 120.63 (s, 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 549.1.

Example 16

N'-[2-[5-[ (4-Fluorophenyl)methyl] - 1 ,3,4-thiadiazol-2-yl] -6, 7,8,9-tetrahydro- 3-hydroxy-4-oxo-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl]- N,N-dimethyl- ethanediamide. ¾ NMR (400 MHz, CDC1 ₃ ) δ ppm 9.40 (1 H, s), 7.30 - 7.38 (2 H, m), 7.07 (2 H, t, J=8.5 Hz), 4.48 (2 H, s), 4.22 (2 H, d, J=3.8 Hz), 3.40 (3 H, s), 3.05 (3 H, s), 2.94 (2 H, ddd, J=14.2, 9.4, 5.3 Hz), 2.52 (1 H, br. s.), 1.98 - 2.09 (2 H, m), 1.82 - 1.93 (2 H, m), 1.76 (2 H, d, J=14.1 Hz); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm - 114.62 (1 F, s); LCMS (ES+, (M+H) ⁺ ) m/z 513.1.

Example 17

N-[2-[ 4-f (4-Fluoro-3-methylphenyl)methyl] -lH-imidazol-2-yl] -6, 7, 8,9- tetrahydro-3-hydroxy-4-oxo-7,10-ethanopyrimido[l,2-a]azepin- 10(4H)-yl]-N,N',N'- trimethyl- ethanediamide trifluoroacetate salt. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 6.89 - 7.17 (m, 4 H), 4.07 (s, 2 H), 3.66 (br. s., 1 H), 3.41 (br. s., 1 H), 3.09 (s, 3 H), 3.06 (s, 3 H), 3.01 (s, 3 H), 2.54 (br. s., 1 H), 2.25 (s, 3 H), 2.09 (br. s., 4 H), 1.83 (br s., 2 H), 1.61 (br. s., 2 H); ^iy F NMR (376 MHz, CDC1 ₃ ) δ ppm -75.75 (br. s., 3 F), - 119.93 (s, 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 523.17.

Example 18

N-[2-[ 4-[ (4-Fluoro-3-methylphenyl)methyl] - lH-imidazol-2-yl] -6, 7, 8,9- tetrahydro-3-hydroxy-4-oxo-7 0-ethanopyrimido[l,2-a]azepin-10(4H)-yl]-l-methyl- lH-pyrazole-3-carboxamide. TFA salt. ^X H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.92 (br. s., 1 H), 7.40 (d, J=2.01 Hz, 1 H), 7.03 - 7.14 (m, 2 H), 6.96 (t, J=8.78 Hz, 1 H), 6.76 (d, J=2.26 Hz, 1 H), 6.63 (br. s., 1 H), 4.03 (br. s., 5 H), 3.94 (br. s., 2 H), 2.54 - 2.68 (m, 2 H), 2.47 - 2.54 (m, 1 H), 2.27 (br. s., 5 H), 2.01 (br. s., 2 H), 1.64 (br. s., 2 H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ ppm -75.69 (br. s., 3 F), -1 19.87 (br. s., 1 F); LCMS (ES+, (M+H) ⁺ ) m/z 518.1.

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.