# Patent

## Title
Substituted imidazo[1,2-a]pyrimidines as HIV viral DNA integrase inhibitors

## Abstract

The invention encompasses a series of bicyclic heterocyclic compounds of Formula I which are inhibitors of 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.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. No. 60/713,080, filed Aug. 31, 2005.


BACKGROUND OF THE INVENTION
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 three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfmavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavirdine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. 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 HIV-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 catalyzes insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. 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). And recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
DESCRIPTION OF THE INVENTION
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and methods for inhibiting HIV integrase and treating those infected with HIV.
One aspect of the invention is a compound of Formula I




    wherein:
    R1 is (Ar1)alkyl;
    R2 is hydrogen, hydroxy, alkyl, or alkoxy;
    R3 is hydrogen, halo, hydroxy, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, C4-6lactamyl, N(R6)SO2R7, N(R6)COR7, N(R6)CO2R7, OCOR7, OCO2R7, OCON(R6)(R6), COR7, CO2R6, CON(R6)(R6), SOR7, SO2R7, SO2N(R6)(R6), P(O)(OR6)2, or Ar2;
    R4 is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy;
    R5 is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy;
    R6is hydrogen, alkyl, or cycloalkyl;
    R7 is alkyl or cycloalkyl;
    R8 is hydrogen or alkyl;
    R9 is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, (alkoxy)alkyl, phenyl, or benzyl, wherein phenyl and benzyl are substituted with 0-2 substituents selected from the group consisting of halo, cyano, alkyl, alkoxy, halolkyl, and haloalkoxy;
    Ar1 is






    Ar2 is tetrazolyl, triazolyl, pyrazolyl, imidazolyl, pyrrolyl, or dioxothiazinyl, and is substituted with 0-2 substituents selected from the group consisting of amino, oxo, halo, and alkyl; and
    X—Y-Z is N(R9)C(R8)2C(R8)2, N(R9)C(R8)2C(R8)2C(R8)2, or N(R9)C(R8)2C(R8)2C(R8)2C(R8)2;

or a pharmaceutically acceptable salt thereof.



Another aspect of the invention is a compound of Formula I where R1 is




Another aspect of the invention is a compound of Formula I where R1 is




provided that R3 is not hydrogen.

Another aspect of the invention is a compound of Formula I 1 where R1 is




and R3 is C4-6lactamyl, N(R6)SO2R7, N(R6)COR7, N(R6)CO2R7, OCOR7, OCO2R7, OCON(R6)(R6), COR7, CO2R6, CON(R6)(R6), SOR7, SO2R7, SO2N(R6)(R6), or Ar2.

Another aspect of the invention is a compound of Formula I where R2 is hydrogen.
Another aspect of the invention is a compound of Formula I where R3 is triazinyl substituted with 0-1 methyl groups; R4 is hydrogen, chloro, fluoro, or methyl; and R5 is hydrogen.
Another aspect of the invention is a compound of Formula I where R6 is hydrogen or alkyl.
Another aspect of the invention is a compound of Formula I where R7is alkyl.
Another aspect of the invention is a compound of Formula I where R8 is hydrogen or methyl.
Another aspect of the invention is a compound of Formula I where X—Y-Z is N(R9)CH2CH2, N(R9)CH2CH2CH2, or N(R9)CH2CH2CH2CH2.
Another aspect of the invention is a compound according to one of the following structures:




Another aspect of the invention is a compound according to the following structure




Another aspect of the invention is a compound of Formula I where R9 is alkyl, cycloalkyl, hydroxyalkyl (alkoxy)alkyl, phenyl, or benzyl.
For a compound of Formula I, any scope of R1, R2, R3, R4, R5, R6, R7, R8, R9, Ar1, Ar2, and X—Y-Z can be used independently with any scope of any other variable.
“C4-6lactamyl” means a lactam of 4 to 6 carbons, for example caprolactam.
“Dioxothiazinyl” means




Unless specified otherwise, these terms have the following meanings. “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. “Alkynyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7 carbons. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo to perhalo. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion. “Aryl” includes carbocyclic and heterocyclic aromatic substituents. 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.
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.




Synthetic Methods
The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The variables shown in the synthetic schemes are distinct from and should not be confused with the variables in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.
Some formula I compounds can be synthesized from an appropriately substituted heterocycle I-1 according to Scheme I, where Ra and P can serve as protecting groups (see Greene, T. W. and Wutz, P. G. M. Protective Groups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons, New York). When P is benzyl or substituted benzyl it can be removed by hydrogenolysis (H2—Pd/C) or acid hydrolysis (trifluoroacetic acid) to yield intermediate I-2. I-2 can be transaminated to I-4 by reaction with amine I-3. When Ra is a lower alkyl group, Ra can be removed under ester hydrolysis conditions, such as treatment with NaOH, LiOH, or KOH to deliver the corresponding carboxylic acid I-5. Alternatively, Ra can be removed by nucleophilic displacement using NaI. When Ra is benzyl and substituted benzyl, Ra can be removed by hydrogenolysis. Intermediate I-5 can be coupled using amide bond forming reagents such as DCC, PyBOP, BOP or other reagents (see March, J. Advanced Organic Chemistry, Fourth Edition 1992 John Wiley & Sons, New York). The resulting intermediate I-6 can be deprotected as described for intermediate I-1.




Some bicyclic heterocycles can be synthesized according to a variety of methods, some examples of which are illustrated in Scheme II. Using methods similar to that described in Sunderland, J. S.; Botta, M.; Aime, S.; Raymond, K. N. Inorg. Chem. 2001, 40, 6756-6756, II-1 and II-2 can be condensed to provide intermediate II-3. Intermediate II-3 can be reacted with thiourea to yield pyrimidinone II-4. Pyrimidinone II-4 can be transformed to II-5 by addition of an appropriately substituted ethylamine to the N-3 of the pyrimidinone. The sulfide of II-4 can be activated for nucleophilic displacement by treating with an appropriate oxidizing agent such as mCPBA to form the sulfone II-6. The sulfone can be displaced by the appropriately functionalized amino group to yield II-7. This compound can be carried on to the final product according to the methods described in Scheme I.




In Scheme III, the intermediate II-3 is prepared in the same manner as in Scheme II. Condensation with a cyclic guanidine, such as III-2 provides the bicyclic intermediate III-3, which in turn is carried on to final compound as described in Scheme I.




Biological Methods
Another aspect of the invention is a method for inhibiting HIV integrase comprising contacting a compound of Formula I with HIV integrase.
Another aspect of the invention is a method for inhibiting HIV viral cDNA integration into human DNA comprising administering an effective amount of a compound of Formula I to a human cell infected with HIV.
HIV-Integrase Inhibition Activity. To evaluate in-vitro activity against HIV-integrase, 5 pmole of biotin labeled substrate DNA was bound to 100 μg of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech). Recombinant integrase (0.26 ng) was incubated with the beads for 90 min at 37° C. Unbound enzyme was removed by washing the complex followed by addition of inhibitors and 0.1 fmol of P33 labeled target DNA. The reaction was stopped by adding EDTA to a final concentration of 10 mM. Samples were counted in TopCountNXT (Packard) and the CPM was used as a measure of integration. The reaction condition was as described in A. Engelman and R. Craigie, J. Virol. 69, 5908-5911 (1995). The sequences of substrate and target DNA were described in Nucleic Acid Research 22,1121-1122 (1994). Results shown in the Table 1. Activity equal to A refers to a compound having IC50=0.005 to 0.010 μM while B and C denote compounds having IC50=0.010 to 0.030 μM and IC50>0.030 μM respectively.










TABLE 1







Example
Activity



















1
B



2
B



3
B



4
B



5
B



6
B



7
B



8
A



9
B



10
C



11
A



12
B



13
B



14
B



15
A



16
C



17
B



18
B



19
B



20
A



21
A



22
B



23
A



24
A



25
B



26
B



27
B



28
A



29
B



30
B



31
B



32
A



33
A



34
A



35
B



36
B



37
B



38
C



39
C



40
A



41
B



42










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 PvuII 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, Calif.) 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 (EC50) was calculated by using the exponential form of the median effect equation where (Fa)=1/[1+(ED50/drug conc.)m] (Johnson V A, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed. Aldovini A, Walker B D. 71-76. New York: Stockton Press. 1990). The anti-viral activity of compounds was evaluated under three serum conditions, 10% FBS, 15 mg/ml human serum albumin/10% FBS or 40% human serum/5% FBS, and the results from at least 2 experiments were used to calculate the EC50 values. Results are shown in the Table 2. Activity equal to A refers to a compound having EC50=0.004 to 0.030 μM while B and C denote compounds with EC50=0.030 to 0.1 μM and EC50>0.1 μM respectively.










TABLE 2







Example
Activity



















1
C



2
C



3
C



4
C



5
C



6
C



7
C



8
C



9
A



10
A



11
C



12
C



13
C



14
A



15
A



16
B



17
B



18
B



19
B



20
B



21
A



22
A



23
A



24
A



25
A



26
A



27
A



28
A



29
C



30
C



31
C



32
C



33
C



34
A



35
B



36
C



37
C



38
C










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, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
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 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 therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection. Some suitable agents are 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 composition 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.
“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.
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 judgment.
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 judgment.
Table 3 lists some agents useful in treating AIDS and HIV infection which are suitable for this invention.









TABLE 3





DRUG NAME
MANUFACTURER
INDICATION















ANTIVIRALS









097
Hoechst/Bayer
HIV infection, AIDS,


(non-nucleoside reverse

ARC


transcriptase inhibitor)


Amprenavir
Glaxo Wellcome
HIV infection, AIDS,


141 W94

ARC


GW 141


(protease inhibitor)


Abacavir (1592U89)
Glaxo Wellcome
HIV infection, AIDS,


GW 1592

ARC


(RT inhibitor)


Acemannan
Carrington Labs
ARC



(Irving, TX)


Acyclovir
Burroughs Wellcome
HIV infection, AIDS,




ARC, in combination




with AZT


AD-439
Tanox Biosystems
HIV infection, AIDS,




ARC


AD-519
Tanox Biosystems
HIV infection, AIDS,




ARC


Adefovir dipivoxil
Gilead Sciences
HIV infection, ARC,


AL-721
Ethigen
PGL HIV positive, AIDS



(Los Angeles, CA)


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-232623
Bristol-Myers Squibb/
HIV infection, AIDS,


(CGP-73547)
Novartis
ARC


(protease inhibitor)


BMS-234475
Bristol-Myers Squibb/
HIV infection, AIDS,


(CGP-61755)
Novartis
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
MedImmune
CMV retinitis


Immune globin


Cytovene
Syntex
Sight threatening


Ganciclovir

CMV peripheral, CMV




retinitis


Delaviridine
Pharmacia-Upjohn
HIV infection, AIDS,


(RT inhibitor)

ARC


Dextran Sulfate
Ueno Fine Chem.
AIDS, ARC, HIV



Ind. Ltd. (Osaka,
positive asymptomatic



Japan)


ddC
Hoffman-La Roche
HIV infection, AIDS,


Dideoxycytidine

ARC


ddI
Bristol-Myers Squibb
HIV infection, AIDS,


Dideoxyinosine

ARC; combination with




AZT/d4T


DMP-450
AVID
HIV infection, AIDS,


(protease inhibitor)
(Camden, NJ)
ARC


Efavirenz
DuPont Merck
HIV infection, AIDS,


(DMP 266)

ARC


(−)6-Chloro-4-(S)-


cyclopropylethynyl-


4(S)-trifluoro-


methyl-1,4-dihydro-


2H-3,1-benzoxazin-


2-one, STOCRINE


(non-nucleoside RT


inhibitor)


EL10
Elan Corp, PLC
HIV infection



(Gainesville, GA)


Famciclovir
Smith Kline
herpes zoster, herpes




simplex


FTC
Emory University
HIV infection, AIDS,


(reverse transcriptase

ARC


inhibitor)


GS 840
Gilead
HIV infection, AIDS,


(reverse transcriptase

ARC


inhibitor)


HBY097
Hoechst Marion
HIV infection, AIDS,


(non-nucleoside reverse
Roussel
ARC


transcriptaseinhibitor)


Hypericin
VIMRx Pharm.
HIV infection, AIDS,




ARC


Recombinant Human
Triton Biosciences
AIDS, Kaposi's sarcoma,


Interferon Beta
(Almeda, CA)
ARC


Interferon alfa-n3
Interferon Sciences
ARC, AIDS


Indinavir
Merck
HIV infection, AIDS,




ARC, asymptomatic HIV




positive, also in




combination with




AZT/ddI/ddC


ISIS 2922
ISIS Pharmaceuticals
CMV retinitis


KNI-272
Nat'l Cancer Institute
HIV-associated diseases


Lamivudine, 3TC
Glaxo Wellcome
HIV infection, AIDS,


(reverse transcriptase

ARC, also with AZT


inhibitor)


Lobucavir
Bristol-Myers Squibb
CMV infection


Nelfinavir
Agouron
HIV infection, AIDS,


(protease inhibitor)
Pharmaceuticals
ARC


Nevirapine
Boeheringer
HIV infection, AIDS,


(RT inhibitor)
Ingleheim
ARC


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,


(protease inhibitor)

ARC


Probucol
Vyrex
HIV infection, AIDS


RBC-CD4
Sheffield Med.
HIV infection, AIDS,



Tech (Houston, TX)
ARC


Ritonavir
Abbott
HIV infection, AIDS,


(protease inhibitor)

ARC


Saquinavir
Hoffmann-
HIV infection, AIDS,


(protease inhibitor)
LaRoche
ARC


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


Didehydrodeoxy-

ARC


thymidine


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,
Gilead
HIV infection, AIDS


fumarate salt (Viread ®)


(reverse transcriptase


inhibitor)


Combivir ®
GSK
HIV infection, AIDS


(reverse transcriptase


inhibitor)


abacavir succinate
GSK
HIV infection, AIDS


(or Ziagen ®)


(reverse transcriptase


inhibitor)


Reyataz ®
Bristol-Myers Squibb
HIV infection, AIDS


(atazanavir)


Fuzeon
Roche/Trimeris
HIV infection, AIDS,


(Enfuvirtide, T-20)

viral fusion inhibitor


Trizivir ®

HIV infection, AIDS


Kaletra ®
Abbott
HIV infection, AIDS




ARC







IMMUNOMODULATORS









AS-101
Wyeth-Ayerst
AIDS


Bropirimine
Pharmacia Upjohn
Advanced AIDS


Acemannan
Carrington Labs, Inc.
AIDS, ARC



(Irving, TX)


CL246,738
American Cyanamid
AIDS, Kaposi's sarcoma



Lederle Labs


EL10
Elan Corp, PLC
HIV infection



(Gainesville, GA)


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, combination


Macrophage Colony

w/AZT


Stimulating Factor


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 CD4


Interleukin-2

cell counts


(aldeslukin)


Immune Globulin
Cutter Biological
Pediatric AIDS, in


Intravenous
(Berkeley, CA)
combination w/AZT


(human)


IMREG-1
Imreg
AIDS, Kaposi's sarcoma,



(New Orleans, LA)
ARC, PGL


IMREG-2
Imreg
AIDS, Kaposi's sarcoma,



(New Orleans, LA)
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 AIDS,


Muramyl-Tripeptide
Amgen
in combination w/AZT


Granulocyte


Colony Stimulating


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, AIDS,


Alfa 2a
in combination w/AZT
ARC


SK&F106528
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









Clindamycin with
Pharmacia Upjohn
PCP


Primaquine


Fluconazole
Pfizer
Cryptococcal meningitis,




candidiasis


Pastille
Squibb Corp.
Prevention of oral


Nystatin Pastille

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
Cryptosporidial



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 assoc.


Erythropoietin

with AZT therapy


Recombinant Human Growth
Serono
AIDS-related wasting,


Hormone

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




Ethyl 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Diethyl oxalate (7.66 g, 52.4 mmol) and ethyl benzyloxyacetate (10.2 g, 52.5 mmol) in dry tetrahydrofuran (70 ml) were treated at 22° C. with sodium hydride (2.31 g of a 60% dispersion in mineral oil, 57.7 mmol). Ethanol (40 μl) was then added and the mixture was stirred under argon for 16 h. The tetrahydrofuran was then concentrated under reduced pressure and the residue was treated with a mixture of 1-methyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (9.45 g, 52.5 mmol) (J. V. Grennhill et al. J. Chem. Soc. Perkin Trans.II, 1985, 1255-1264) in a solution of sodium ethoxide (26.0 mmol, prepared from 0.60 g of sodium) in ethanol (70 ml) and the resulting mixture was heated at 60° C. for 3 h. Acetic acid (2 ml) was added and the ethanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate washed successively with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (elution gradient of ethanol 0-20% in ethyl acetate) gave 5.33 g (30% yield) of intermediate 1 as white crystals; mp 135-137° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH3), 3.03 (3H, s, NCH3), 3.71 (2H, t, J=9.1 Hz, CH2), 4.15 (2H, t, J=9.1 Hz, CH2), 4.33 (2H, q, J=7.1 Hz, OCH2), 5.10 (2H, s, OCH2), 7.3-7.51 (5H, m, aromatics). Anal. Calcd for C17H19N3O4: C, 61.99, H 5.81; N, 12.75. Found: C, 61.73; H, 5.78; N, 12.73.




6-(Benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic Acid
A solution of ethyl 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.971 g, 2.95 mmol) in a mixture tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with 15 ml of 1 N sodium hydroxide and the mixture was stirred at 40° C. for 30 min. The solvent was then concentrated under reduced pressure and the residue was acidified with 1 N hydrochloric acid (20 ml). The precipitate formed was filtered, washed with water and dried in vacuo to give 0.874 g (98% yield) of the title acid as a white solid; mp 203° C. (dec; ethyl acetate). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.87 (3H, s, NCH3), 3.66 (2H, t, J=9 Hz, CH2), 4.01 (2H, t, J=9 Hz, CH2), 4.91 (2H, s, OCH2), 7.3-7.45 (5H, m, aromatics). HRMS (ESI+) calculated for C15H16N3O4 [M+H+]: 302.1141. found: 302.1127.




N-(4-Fluorobenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
A mixture of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.393 g, 1.30 mmol) and 4-fluorobenzylamine (0.163 g, 1.30 mmol) in acetonitrile (15 ml) was treated at 25° C. with triethylamine (0.42 ml, 2.5 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.662 g, 1.49 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethyl acetate gave 0.407 g (76% yield) of the title amide as white cubes; mp 189-191° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.02 (3H, s, NCH3), 3.70 (2H, t, J=9 Hz, CH2), 4.15 (2H, t, J=9 Hz, CH2), 4.50 (2H, d, J=5.6 Hz, NCH2), 5.11 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.24 (2H, m, aromatics), 7.3-7.45 (SH, m, aromatics), 7.71 (1H, broad t, NH). Anal. Calcd for C22H21FN4O3: C, 64.69; H, 5.18; N, 13.71. Found: C, 64.41; H, 5.10; N, 13.72.
EXAMPLE 1




N-(4Fluorobenzyl)-6-hydroxy-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
A solution of N-(4-fluorobenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.202 g, 0.495 mmol) in a mixture of ethyl acetate (150 ml) and ethanol (20 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (50 mg) and under one atmosphere of hydrogen for one hour to give 0.130 g (83% yield) of the title compound as white needles; mp 212° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.93 (3H, s, CH3), 3.63 (2H, t, J=8.6 Hz, CH2), 4.14 (2H, t, J=8.6 Hz, CH2), 4.59 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.89 (1H, broad t, NH), 11.57 (1H, s, OH). HRMS (ESI+) calculated for C15H16FN4O3 [M+H+]: 319.1206. found: 319.1191.




N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydromidazo[1,2-a]pyrimidine-7-carboxylic acid (0.439 g, 1.46 mmol) and 4-fluoro-3-methylbenzylamine (0.203 g, 1.46 mmol) as described for the synthesis of intermediate 3 gave 0.372 g (60% yield) of the title amide as white crystals; mp 182-184° C. (ethyl acetate). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.12 (3H, s, CH3), 2.90 (3H, s, NCH3), 3.66 (2H, t, J=8.6 Hz, CH2), 4.02 (2H, t, J=8.6 Hz, CH2), 4.33 (2H, d, J=6.0 Hz, NCH2), 4.88 (2H, s, OCH2), 6.97 (1H, m, aromatic), 7.11-7.2 (2H, m, aromatics), 7.3-7.4 (5H, m, aromatics), 8.81 (1H, broad t, NH). HRMS (ESI+) calculated for C23H24FN4O3 [M+H+]: 423.1832. found: 423.1827.
EXAMPLE 2




N-(4-Fluoro-3-methylbenzyl)-6-hydroxy-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-fluoro-3-methylbenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.338 g, 0.80 mmol) as described for example 1 gave 0.191 g (72% yield) of the title compound as white crystals; mp 187-189° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.30 (3H, s, CH3), 2.93 (3H, s, CH3), 3.63 (2H, t, J=8.6 Hz, CH2), 4.14 (2H, t, J=8.6 Hz, CH2), 4.54 (2H, d, J=6.2 Hz, NCH2), 7.0 (1H, m, aromatic), 7.12-7.18 (2H, m, aromatics), 7.87 (1H, broad t, NH), 11.59 (1H, s, OH). Anal. Calcd for C16H17FN4O3: C, 57.82; H, 5.15; N, 16.85. Found: C, 57.51; H, 5.27; N, 16.69.




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 1.0 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.295 g, 1.0 mmol) as described for the synthesis of intermediate 3 gave 0.253 g (54% yield) of the title amide as white crystals; mp 184° C. (ethyl acetate-hexane). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.78 (3H, d, J=4.5 Hz, NCH3), 2.91 (3H, s, NCH3), 3.66 (2H, t, J=8.9 Hz, CH2), 4.02 (2H, t, J=8.9 Hz, CH2), 4.46 (2H, d, J=6.2 Hz, NCH2), 4.90 (2H, s, OCH2), 7.04 (1H, m, aromatic), 7.25 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.29-7.46 (6H, m, aromatics), 8.49 (1H, broad q, NH), 8.78 (l H, broad t, NH). HRMS (ESI+) calculated for C24H25FN5O4 [M+H+]: 466.1891. found: 466.1899.
EXAMPLE 3




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-hydroxy-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.223 g, 0.48 mmol) as described for example 1 gave 0.048 g (27% yield) of the title compound a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.80 (3H, d, J=4.5 Hz, CH3), 2.89 (3H, s, NCH3), 3.56 (2H, t, J=8.6 Hz, CH2), 3.97 (2H, t, J=8.6 Hz, CH2), 4.53 (2H, d, J=6.5 Hz, NCH2), 7.27-7.4 (3H, m, aromatics), 8.54 (1H, broad q, NH), 9.18 (1H, broad t, NH), 11.60 (1H, s, OH). HRMS (ESI+) calculated for C17H19FN5O4 [M+H+]: 376.1421. found: 376.1410.




1-Isopropyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide
A solution of N-isopropylethylenediamine (10.0 g, 0.097 mol) in methanol (10 ml) was cooled to 0° C. and treated dropwise with a solution of cyanogen bromide (10.37 g, 0.098 mol) in methanol (25 ml) while maintaining the temperature below 10° C. The reaction mixture was then heated to 80° C. for 45 min, cooled and concentrated under reduced pressure. Crystallization of the residue from cold ethanol gave 10.4 g (50% yield) of the title product as white crystals; mp 154-155° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (6H, d, J=6.6 Hz, 2×CH3), 3.57-3.75 (4H, m, 2×CH2), 4.41 (1H, m, CH).




Ethyl 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Reaction of the adduct of diethyl oxalate (7.26 g, 49.7 mmol), ethyl benzyloxyacetate (9.65 g, 49.7 mmol) and sodium hydride (2.19 g of a 60% dispersion in mineral oil, 54.7 mmol) with 1-isopropyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (10.33 g, 49.7 mmol) as described for intermediate 1 gave 6.79 g (38% yield) of the title ester as white crystals; mp 131-132° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.22 (6H, d, J=6.8 Hz, 2×CH3), 1.31 (3H, t, J=7.1 Hz, CH3), 3.66 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.31 (2H, q, J=7.1 Hz, OCH2), 4.40 (1H, m, CH), 5.08 (2H, s, OCH2), 7.3-7.39 (3H, m, aromatics), 7.49 (2H, m, aromatics). Anal. Calcd for C19H23N3O4: C, 63.85; H, 6.48, N 11.75. Found: C, 63.57; H, 6.76; N, 11.98.




6-(Benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid
Saponification of ethyl 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (2.00 g, 5.60 mmol) as described for intermediate 2 gave 1.84 g (100% yield) of the title acid as a white solid; mp 163-165° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.7 Hz, 2×CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.14 (2H, t, J=9 Hz, CH2), 4.34 (1H, m, CH), 5.23 (2H, s, OCH2), 7.3-7.39 (3H, m, aromatics), 7.57 (2H, m, aromatics). HRMS (ESI+) calculated for C17H20N3O4 [M+H+]: 330.1454. found: 330.1458.




N-(4-Fluorobenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.385 g (96% yield) of the title amide as white crystals; mp 166-167° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.14 (2H, t, J=9 Hz, CH2), 4.42 (1H, m, CH), 4.50 (2H, d, J=6.0 Hz, NCH2), 5.09 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.3-7.37 (3H, m, aromatics), 7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). Anal. Calcd for C24H25FN4O3: C, 66.04; H, 5.77, N 12.83. Found: C, 65.84; H, 5.85; N, 12.58.
EXAMPLE 4




N-(4-Fluorobenzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-fluorobenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.46 mmol) as described for example 1 gave 0.134 g (84% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.21 (6H, d, J=6.8 Hz, 2×CH3), 3.60 (2H, t, J=8.6 Hz, CH2), 4.13 (2H, t, J=8.6 Hz, CH2), 4.22 (1H, m, CH), 4.59 (2H, d, J=6.3 Hz, NCH2), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.88 (1H, broad t, NH),11.51 (1H, broad, OH). HRMS (ESI+) calculated for C17H20FN4O3 [M+H+]: 347.1519. found: 347.1520.




N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy) 1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluoro-3-methylbenzylamine (0.133 g, 0.95 mmol) as described for the synthesis of intermediate 3 gave 0.384 g (93% yield) of the title amide as white crystals (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH3), 2.25 (3H, broad d, J=1.8 Hz, CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (1H, m, CH), 4.46 (2H, d, J=5.8 Hz, NCH2), 5.08 (2H, s, OCH2), 6.94 (1H, m, aromatic), 7.04-7.08 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.3-7.36 (3H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI+) calculated for C25H28FN4O3 [M+H+]: 451.2145. found: 451.2141.
EXAMPLE 5




N-(4-Fluoro-3-methylbenzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-fluoro-3-methylbenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.44 mmol) as described for example 1 gave 0.130 g (81% yield) of the title compound a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.21 (6H, d, J=6.8 Hz, 2×CH3), 2.29 (3H, d, J=1.7 Hz, CH3), 3.60 (2H, t, J=8.5 Hz, CH2), 4.13 (2H, t, J=8.5 Hz, CH2), 4.22 (1H, m, CH), 4.55 (2H, d, J=6.4 Hz, NCH2), 7.0 (1H, m, aromatic), 7.15 (2H, m, aromatics), 7.86 (1H, broad t, NH), 11.54 (1H, broad, OH). HRMS (ESI+) calculated for C18H22FN4O3 [M+H+]: 361.1676. found: 361.1691.




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.328 g (72% yield) of the title amide as white crystals; mp 197-198° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH3), 2.98 (3H, d, J=5 Hz, NCH3), 3.66 (2H, t, J=9 Hz, CH2), 4.12 (2H, t, J=9 Hz, CH2), 4.43 (1H, m, CH), 4.48 (2H, d, J=6.3 Hz, NCH2), 5.09 (2H, s, OCH2), 7.05 (1H, m, aromatic), 7.13-7.17 (2H, m, aromatics), 7.3-7.35 (4H, m, NH and aromatics), 7.43-7.46 (2H, m, aromatics), 8.35 (1H, broad t, NH). Anal. Calcd for C26H28FN5O4: C, 63.27; H, 5.71; N, 14.19. Found: C, 63.06; H, 5.65; N, 14.02.
EXAMPLE 6




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.40 mmol) as described for example 1 gave 0.125 g (77% yield) of the title compound white crystals; mp 205° C. (dec) (dichloromethane-ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.24 (6H, d, J=6.6 Hz, 2×CH3), 3.04 (3H, d, J=5.0 Hz, NCH3), 3.59 (2H, t, J=8.5 Hz, CH2),4.09 (2H, t, J=8.5 Hz, CH2),4.31 (1H, m, CH), 4.61 (2H, d, J=6.6 Hz, NCH2), 6.42 (1H, broad, NH), 7.10-7.20 (2H, m, aromatics), 7.49 (1H, dd, J=5.5 Hz and J=8.5 Hz, aromatic), 8.65 (1H, broad t, NH), 11.45 (1H, broad, OH). Anal. Calcd for C19H22FN5O4: C, 56.57; H, 5.49; N, 17.36. Found: C 56.34; H, 5.24; N, 17.26.




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (76% yield) of the title amide as white crystals; mp 171-172° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.24 (6H, d, J=6.8 Hz, 2×CH3), 3.66 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (2H, d, J=6.3 Hz, NCH2), 4.43 (1H, m, CH), 5.10 (2H, s, OCH2), 7.06 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.17 (1H, m, aromatic), 7.29-7.31 (3H, m, aromatics), 7.45-7.48 (2H, m, aromatics), 7.71 (1H, dd, J=5.9 Hz and J=8.6 Hz, aromatic), 8.0 (1H, s, CH), 8.36 (1H, broad t, NH), 8.39 (1H, s, CH). Anal. Calcd for C26H26FN7O3: C, 62.01; H, 5.20; N, 19.47. Found: C, 62.00; H, 5.20; N, 19.50.
EXAMPLE 7




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.40 mmol) as described for example 1 gave 0.134 g (82% yield) of the title compound white crystals (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (6H, d, J=6.5 Hz, 2×CH3), 3.60 (2H, t, J=8.5 Hz, CH2), 4.12 (2H, t, J=8.5 Hz, CH2), 4.25 (1H, m, CH), 4.48 (2H, d, J=6.8 Hz, NCH2), 7.13 (1H, dd, J=2.5 Hz and J=8.4 Hz, aromatic), 7.24 (1H, m, aromatic), 7.69 (1H, dd, J=5.8 Hz and J=8.6 Hz, aromatic), 8.18 (1H, s, CH), 8.46 (1H, s, CH), 8.66 (1H, broad t, NH), 11.41 (1H, broad, OH). HRMS (ESI+) calculated for C19H21FN7O3 [M+H+]: 414.1690. found: 414.1677.




N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-benzyloxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.150 g, 0.45 mmol) and 4-fluoro-2-(N,N-dimethylsulfamoyl)benzylamine hydrochloride (0.147 g, 0.55 mmol) as described for the synthesis of intermediate 3 gave 0.190 g (75% yield) of the title amide as white crystals; mp 161-163° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.9 Hz, 2×CH3), 2.85 (6H, s, 2×NCH3), 3.65 (2H, t, J=9 Hz, CH2),4.12 (2H, t, J=9 Hz, CH2),4.40 (1H, m, CH), 4.81 (2H, d, J=6.6 Hz, NCH2), 5.13 (2H, s, OCH2), 7.22 (1H, m, aromatic), 7.28-7.34 (3H, m, aromatics), 7.49-7.52 (2H, m, aromatics), 7.55 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.71 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.26 (1H, broad t, NH). Anal. Calcd for C26H30FN5O5S: C, 57.44; H, 5.56; N, 12.88. Found: C, 57.40; H, 5.46; N, 12.85.
EXAMPLE 8




N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
A solution of N-(4-fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-benzyloxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.155 g, 0.28 mmol) in trifluoroacetic acid (10 ml) was stirred at 25° C. for 72 h. The solvent was then evaporated under reduced pressure and the residue was purified by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) to give 0.105 g (81% yield) of the title amide as a white solid.
1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH3), 2.91 (6H, s, 2×NCH3), 3.59 (2H, t, J=8.5 Hz, CH2), 4.11 (2H, t, J=8.5 Hz, CH2), 4.24 (1H, m, CH), 4.84 (2H, d, J=6.8 Hz, NCH2), 7.30 (1H, m, aromatic), 7.56 (1H, dd, J=2.8 Hz and J=8.3 Hz, aromatic), 7.70 (1H, dd, J=5.3 Hz and J=8.6 Hz, aromatic), 8.52 (1H, broad t, NH), 11.4 (1H, broad, OH). MS (ESI+) m/e 454 [M+H+].




N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate-hexane). (75% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.9 Hz, 2×CH3), 2.46 (3H, s, CH3), 3.66 (2H, t, J=8.9 Hz, CH2), 4.13 (2H, t, J=8.9 Hz, CH2), 4.43 (1H, m, CH), 4.44 (2H, d, J=6.3 Hz, NCH2), 5.10 (2H, s, OCH2), 7.05 (1H, dd, J=2.7 Hz and J=8.6 Hz, aromatic), 7.14 (1H, m, aromatic), 7.27-7.28 (3H, m, aromatics), 7.42-7.45 (2H, m, aromatics), 7.69 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.26 (1H, broad t, NH), 8.26 (1H, s, CH). MS (ESI+) m/e 518 [M+H+].
EXAMPLE 9




N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid (100% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.24 (6H, d, J=6.6 Hz, 2×CH3), 2.55 (3H, s, CH3), 3.60 (2H, t, J=8.5 Hz, CH2), 4.12 (2H, t, J=8.5 Hz, CH2), 4.31 (1H, m, CH), 4.49 (2H, d, J=6.6 Hz, NCH2), 7.10 (1H, dd, J=2.5 Hz and J=8.3 Hz, aromatic), 7.20 (1H, m, aromatic), 7.70 (1H, dd, J=6.0 Hz and J=8.7 Hz, aromatic), 8.35 (1H, s, CH), 8.61 (1H, broad t, NH), 11.56 (1H, s, OH). MS (ESI+) m/e 428 [M+H+].




N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 158-159° C. (ethyl acetate). (71% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.24 (6H, d, J=6.5 Hz, 2×CH3), 2.44 (3H, s, CH3), 3.66 (2H, t, J=8.8 Hz, CH2), 4.13 (2H, t, J=8.8 Hz, CH2), 4.23 (2H, d, J=6.3 Hz, NCH2), 4.44 (1H, m, CH), 5.11 (2H, s, OCH2), 6.99 (1H, dd, J=2.5 Hz and J=8.3 Hz, aromatic), 7.18 (1H, m, aromatic), 7.29-7.34 (3H, m, aromatics), 7.48-7.50 (2H, m, aromatics), 7.66 (1H, dd, J=6.0 Hz and J=8.7 Hz, aromatic), 7.89 (1H, s, CH), 8.10 (1H, broad t, NH). MS (ESI+) m/e 518 [M+H+].
EXAMPLE 10




N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 212° C. (ethyl acetate). (61% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (6H, d, J=6.8 Hz, 2×CH3), 2.47 (3H, s, CH3), 3.60 (2H, t, J=8.6 Hz, CH2), 4.11 (2H, t, J=8.6 Hz, CH2), 4.28 (1H, m, CH), 4.31 (2H, d, J=6.5 Hz, NCH2), 7.03 (1H, dd, J=2.8 Hz and J=8.3 Hz, aromatic), 7.26 (1H, m, aromatic), 7.67 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.00 (1H, s, CH), 8.35 (1H, broad t, NH), 11.35 (1H, s, OH). MS (ESI+) m/e 428 [M+H+].




1-Butyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide
Reaction of N-butylethylenediamine (10.7 g, 0.092 mol) with cyanogen bromide (9.76 g, 0.092 mol) as described in the preparation of intermediate 6 gave 11.77 g (57% yield) of the title compound as white crystals (ether-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.96 (3H, t, J=7.2 Hz, CH3), 1.41 (2H, m, CH2), 1.60 (2H, m, CH2), 3.52 (2H, t, J=7.3 Hz, CH2), 3.64-3.74 (4H, m, 2×CH2), 7.58 and 7.7 (broad s, NH). MS (ESI+) m/e 142 [M+H+].




Ethyl 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Reaction of the adduct of diethyl oxalate (5.71 g, 39.1 mmol), ethyl benzyloxyacetate (7.59 g, 39.1 mmol) and sodium hydride (1.71 g of a 60% dispersion in mineral oil, 42.7 mmol) with 1-butyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (8.68 g, 39.1 mmol) as described for intermediate 1 gave 5.55 g (38% yield) of the title ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (3H, t, J=7.5 Hz, CH3), 1.31 (3H, t, J=7.1 Hz, CH3), 1.39 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 3.41 (2H, t, J=7.4 Hz, CH2), 3.69 (2H, t, J=8.9 Hz, CH2), 4.12 (2H, t, J=8.9 Hz, CH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.09 (2H, s, OCH2), 7.3-7.4 (3H, m, aromatics), 7.49 (2H, m, aromatics). MS (ESI+) m/e 372 [M+H+].




6-(Benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic Acid
Saponification of ethyl 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (5.50 g, 14.8 mmol) as described for intermediate 2 gave 5.08 g (100% yield) of the title acid as a white solid; mp 132-135° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (3H, t, J=7.3 Hz, CH3), 1.34-1.44 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 3.39 (2H, t, J=7.4 Hz, CH2), 3.71 (2H, t, J=8.9 Hz, CH2), 4.15 (2H, t, J=8.9 Hz, CH2), 5.23 (2H, s, OCH2), 7.3-7.4 (3H, m, aromatics), 7.58 (2H, m, aromatics). MS (ESI+) m/e 344 [M+H+].




N-(4-Fluorobenzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Coupling of 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.87 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (88% yield) of the title amide as white crystals; mp 107-109° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH3), 1.33-1.43 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 3.41 (2H, t, J=7.4 Hz, CH2), 3.70 (2H, t, J=8.9 Hz, CH2), 4.13 (2H, t, J=8.9 Hz, CH2), 4.50 (2H, d, J=5.8 Hz, NCH2), 5.10 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.33-7.37 (3H, m, aromatics), 7.46-7.48 (2H, m, aromatics), 7.68 (1H, broad t, NH). MS (ESI+) m/e 451 [M+H+].
EXAMPLE 11




N-(4-Fluorobenzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
Hydrogenolysis of N-(4-fluorobenzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.350 g, 0.77 mmol) as described for example 1 gave 0.278 g (99% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 0.95 (3H, t, J=7.3 Hz, CH3), 1.33-1.42 (2H, m, CH2),1.54-1.67 (2H, m, CH2), 3.31 (2H, t, J=7.2 Hz, CH2), 3.63 (2H, t, J=8.9 Hz, CH2),4.14 (2H, t, J=8.9 Hz, CH2), 4.59 (2H, d, J=6.3 Hz, NCH2), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.86 (1H, broad t, NH), 11.52 (1H, s, OH). MS (ESI+) m/e 361 [M+H+].




N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid, (90% yield).
1HNMR 400 MHz (CDCl3) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH3), 1.35-1.43 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 2.25 (3H, d, J=1.8 Hz, CH3), 3.41 (2H, t, J=7.5 Hz, CH2), 3.70 (2H, t, J=8.9 Hz, CH2), 4.15 (2H, t, J=8.9 Hz, CH2), 4.46 (2H, d, J=5.8 Hz, NCH2), 5.09 (2H, s, OCH2), 6.94 (1H, m, aromatic), 7.04-7.07 (1H, m, aromatic), 7.10 (1H, d, J=7.2 Hz, aromatic), 7.30-7.36 (3H, m, aromatics), 7.44-7.47 (2H, m, aromatics), 7.67 (1H, broad t, NH). MS (ESI+) m/e 465 [M+H+].
EXAMPLE 12




N-(4-Fluoro-3-methylbenzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid (94% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.95 (3H, t, J=7.3 Hz, CH3), 1.28-1.42 (2H, m, CH2), 1.54-1.63 (2H, m, CH2), 2.29 (3H, d, J=1.8 Hz, CH3), 3.31 (2H, t, J=7.3 Hz, CH2), 3.63 (2H, t, J=8.9 Hz, CH2), 4.14 (2H, t, J=8.9 Hz, CH2), 4.54 (2H, d, J=6.4 Hz, NCH2), 7.0 (1H, m, aromatic), 7.11-7.17 (2H, m, aromatics), 7.84 (1H, broad t, NH), 11.55 (1H, s, OH). MS (ESI+) m/e 375 [M+H+].




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid, (87% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.97 (3H, t, J=7.3 Hz, CH3), 1.37-1.44 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 2.98 (3H, d, J=4.8 Hz, CH3), 3.42 (2H, t, J=7.4 Hz, CH2), 3.68 (2H, t, J=8.7 Hz, CH2), 4.12 (2H, t, J=8.7 Hz, CH2), 4.48 (2H, d, J=6.3 Hz, NCH2), 5.10 (2H, s, OCH2), 7.02-7.09 (2H, m, aromatic and NH), 7.14 (1H, dd, J=2.8 Hz and J=8.9 Hz, aromatic), 7.30-7.37 (4H, m, aromatics), 7.44-7.49 (2H, m, aromatics), 8.42 (1H, broad t, NH). MS (ESI+) m/e 508 [M+H+].
EXAMPLE 13




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 175-177° C. (ethyl acetate). (92% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.99 (3H, t, J=7.3 Hz, CH3), 1.40-1.45 (2H, m, CH2), 1.58-1.64 (2H, m, CH2), 3.03 (3H, d, J=5.0 Hz, CH3), 3.38 (2H, t, J=7.4 Hz, CH2), 3.61 (2H, t, J=8.5 Hz, CH2), 4.10 (2H, t, J=8.5 Hz, CH2), 4.59 (2H, d, J=6.5 Hz, NCH2), 6.40 (1H, broad q, NH), 7.11-7.15 (1H, m, aromatic), 7.18 (1H, dd, J=2.7 Hz and J=8.8 Hz, aromatic), 7.48 (1H, dd, J=5.4 Hz and J=8.5 Hz, aromatic), 8.81 (1H, broad t, NH), 11.48 (1H, s, OH). MS (ESI+) m/e 418 [M+H+].




N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid, (95% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH3), 1.34-1.44 (2H, m, CH2), 1.55-1.66 (2H, m, CH2), 2.85 (6H, s, 2×NCH3), 3.41 (2H, t, J=7.4 Hz, CH2), 3.68 (2H, t, J=8.7 Hz, CH2), 4.12 (2H, t, J=8.7 Hz, CH2), 4.80 (2H, d, J=6.6 Hz, NCH2), 5.12 (2H, s, OCH2), 7.2-7.25 (1H, m, aromatic), 7.27-7.34 (3H, m, aromatics), 7.50-7.52 (2H, m, aromatics), 7.55 (1H, dd, J=2.7 Hz and J=8.5 Hz, aromatic), 7.71 (1H, dd, J=5.3 Hz and J=8.6 Hz, aromatic), 8.30 (1H, broad t, NH). MS (ESI+) m/e 558 [M+H+].
EXAMPLE 14




N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid (91% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (3H, t, J=7.3 Hz, CH3), 1.30-1.44 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 2.91 (6H, s, 2×NCH3), 3.34 (2H, t, J=7.2 Hz, CH2), 3.62 (2H, t, J=8.4 Hz, CH2), 4.12 (2H, t, J=8.4 Hz, CH2), 4.83 (2H, d, J=6.8 Hz, NCH2), 7.26-7.31 (1H, m, aromatic), 7.55 (1H, dd, J=2.6 Hz and J=8.4 Hz, aromatic), 7.69 (1H, dd, J=5.3 Hz and J=8.6 Hz, aromatic), 8.55 (1H, broad t, NH), 11.40 (1H, s, OH). MS (ESI+) m/e 468 [M+H+].




N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 172-173° C. (ethyl acetate-hexane). (64% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.94 (3H, t, J=7.3 Hz, CH3), 1.33-1.42 (2H, m, CH2), 1.55-1.63 (2H, m, CH2), 2.47 (3H, s, CH3), 3.42 (2H, t, J=7.4 Hz, CH2), 3.69 (2H, t, J=8.8 Hz, CH2), 4.14 (2H, t, J=8.8 Hz, CH2), 4.42 (2H, d, J=6.3 Hz, NCH2), 5.11 (2H, s, OCH2), 7.05 (1H, dd, J=2.7 Hz and J=8.5 Hz, aromatic), 7.11-7.16 (1H, m, aromatic), 7.24-7.28 (3H, m, aromatics), 7.41-7.44 (2H, m, aromatics), 7.68 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.24 (1H, broad t, NH), 8.29 (1H, s, CH). MS (ESI+) m/e 532 [M+H+]. Anal. Calcd for C28H30FN7O3: C, 63.26; H, 5.68; N, 18.44. Found: C, 63.18; H, 5.79; N, 18.32.
EXAMPLE 15




N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 214° C. (ethyl acetate). (93% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.95 (3H, t, J=7.4 Hz, CH3), 1.33-1.43 (2H, m, CH2), 1.56-1.64 (2H, m, CH2), 2.55 (3H, s, CH3), 3.38 (2H, t, J=7.2 Hz, CH2), 3.62 (2H, t, J=8.5 Hz, CH2), 4.13 (2H, t, J=8.5 Hz, CH2), 4.49 (2H, d, J=6.5 Hz, NCH2), 7.09 (1H, dd, J=2.6 Hz and J=8.4 Hz, aromatic), 7.17-7.22 (1H, m, aromatic), 7.69 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.32 (1H, s, CH), 8.57 (1H, broad t, NH), 11.60 (1H, s, OH). MS (ESI+) m/e 442 [M+H+].




1-Benzyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide
Reaction of N-benzylethylenediamine (15.02 g, 0.10 mol) with cyanogen bromide (10.6 g, 0.10 mol) as described in the preparation of intermediate 6 gave 23.82 g (93% yield) of the title product as white crystals; mp 202-204° C. (ethanol). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.48-3.56 (4H, m, 2×CH2), 4.57 (2H, m, NCH2), 7.30-7.44 (5H, m, aromatics), 7.92 and 8.18 (broad s, NH). Anal. Calcd for ClOH13N3.HBr: C, 46.89, H 5.50; N, 16.40. Found: C, 47.03; H, 5.49; N, 16.24.




Ethyl 1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Reaction of the adduct of diethyl oxalate (7.66 g, 52.4 mmol), ethyl benzyloxyacetate (10.2 g, 52.5 mmol) and sodium hydride (2.31 g of a 60% dispersion in mineral oil, 57.9 mmol) with 1-benzyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (13.39 g, 52.5 mmol) as described for intermediate 1 gave 3.98 g (18% yield) of the title ester as white crystals; mp 93° C. (ethyl acetate-hexane).
1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH3), 3.56 (2H, t, J=9.1 Hz, CH2), 4.12 (2H, t, J=9.1 Hz, CH2), 4.35 (2H, q, J=7.1 Hz, OCH2), 4.60 (2H, s, NCH2), 5.12 (2H, s, OCH2), 7.3-7.52 (10H, m, aromatics). Anal. Calcd for C23H23N3O4: C, 68.13; H, 5.71; N, 10.36. Found: C, 67.98; H, 5.70; N, 10.40.




1-Benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid
Saponification of ethyl 1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (2.04 g, 5.04 mmol) as described for intermediate 2 gave 1.90 g (100% yield) of the title acid as white crystals; mp 191° C. (dec), (ethyl acetate). 1HNMR 400 MHz (DMSO-d,) δ (ppm): 3.58 (2H, t, J=8.8 Hz, CH2), 4.05 (2H, t, J=8.8 Hz, CH2), 4.53 (2H, s, NCH2), 4.93 (2H, s, OCH2), 7.32-7.45 (10H, m, aromatics), 13.41 (1H, s, OH). Anal. Calcd for C21H19N3O4: C 66.83; H, 5.07; N, 11.13. Found: C, 66.73; H, 5.16; N, 10.97.




N-(4-Fluorobenzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 125° C. (ethyl acetate-hexane). (88% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.58 (2H, t, J=8.7 Hz, CH2), 4.13 (2H, t, J=8.7 Hz, CH2), 4.51 (2H, d, J=6.1 Hz, NCH2), 4.60 (2H, s, NCH2), 5.13 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.24-7.38 (10H, m, aromatics), 7.47-7.49 (2H, m, aromatics), 7.71 (1H, broad t, NH). HRMS (ESI+) calculated for C28H26FN4O3 [M+H+]: 485.1989. found: 485.1993.
EXAMPLE 16




N-(4-Fluorobenzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 225° C. (ethyl acetate-hexane). (97% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.53 (2H, t, J=8.6 Hz, CH2), 4.13 (2H, t, J=8.6 Hz, CH2), 4.50 (2H, s, NCH2),4.59 (2H, d, J=6.1 Hz, NCH2), 7.06 (2H, m, aromatics), 7.25-7.4 (7H, m, aromatics), 7.87 (1H, broad t, NH), 11.60 (1H, s, OH). HRMS (ESI+) calculated for C21H20FN4O3 [M+H+]: 395.1519. found: 395.1508.




N-(4-Fluoro-3-methylbenzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals. (81% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.24 (3H, s, CH3), 3.57 (2H, t, J=8.7 Hz, CH2), 4.12 (2H, t, J=8.7 Hz, CH2), 4.47 (2H, d, J=5.6 Hz, NCH2), 4.58 (2H, s, NCH2), 5.12 (2H, s, OCH2), 6.93 (1H, m, aromatic), 7.05-7.12 (2H, m, aromatics), 7.28-7.40 (8H, m, aromatics), 7.47-7.49 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI+) calculated for C29H28FN4O3 [M+H+]: 499.2145. found: 499.2132.
EXAMPLE 17




N-(4-Fluoro-3-methylbenzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 204° C. (dec) (ethyl acetate). (78% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.29 (3H, s, CH3), 3.53 (2H, t, J=8.5 Hz, CH2), 4.13 (2H, t, J=8.5 Hz, CH2), 4.50 (2H, s, NCH2),4.54 (2H, d, J=6.0 Hz, NCH2), 7.02 (1H, m, aromatics), 7.1-7.4 (7H, m, aromatics), 7.84 (1H, broad t, NH), 11.63 (1H, s, OH). Anal. Calcd for C22H2,FN4O3: C, 64.69; H, 5.18; N, 13.71. Found: C, 64.42; H, 5.26; N, 13.55.




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid (95% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.97 (3H, d, J=5.14 Hz, CH3), 3.55 (2H, t, J=8.8 Hz, CH2), 4.09 (2H, t, J=8.8 Hz, CH2), 4.50 (2H, d, J=6.28 Hz, NCH2), 4.60 (2H, s, NCH2), 5.12 (2H, s, OCH2), 7.03-7.08 (2H, m, aromatics), 7.14 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.28-7.48 (9H, m, NH and aromatics), 7.54-7.57 (2H, m, aromatics), 8.46 (1H, broad t, NH). HRMS (ESI+) calculated for C30H29FN5O4 [M+H+]: 542.2204. found: 542.2214.
EXAMPLE 18




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 206° C. (dec) (ethyl acetate). (72% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.75 (3H, d, J=4.4 Hz, NCH3), 3.49 (2H, t, J=8.3 Hz, CH2), 3.99 (2H, t, J=8.3 Hz, CH2), 4.54 (2H, d, J=6.0 Hz, NCH2), 4.57 (2H, s, NCH2), 7.25-7.4 (8H, m, aromatics), 8.53 (1H, broad, NH), 9.31 (1H, broad, NH), 11.64 (1H, s, OH). HRMS (ESI+) calculated for C23H23FN5O4 [M+H+]: 452.1734. found: 452.1720.




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid (91% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.57 (2H, t, J=8.7 Hz, CH2), 4.04 (2H, t, J=8.7 Hz, CH2), 4.30 (2H, d, J=6.05 Hz, NCH2), 4.57 (2H, s, NCH2), 4.91 (2H, s, OCH2), 7.16 (1H, m, aromatic), 7.29-7.53 (12H, m, aromatics), 8.23 (1H, s, CH), 8.88 (1H, broad t, NH), 8.99 (1H, s, CH). HRMS (ESI+) calculated for C30H27FN7O3 [M+H+]: 552.2159. found: 552.2173.
EXAMPLE 19




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 242° C. (dec) (ethyl acetate). (74% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.49 (2H, t, J=8.4 Hz, CH2), 4.00 (2H, t, J=8.4 Hz, CH2), 4.41 (2H, d, J=6.2 Hz, NCH2), 4.61 (2H, s, NCH2), 7.3-7.56 (8H, m, aromatics), 8.24 (1H, s, CH), 9.03 (1H, s, CH), 9.28 (1H, broad t, NH), 11.49 (1H, s, OH). HRMS (ESI+) calculated for C23H21FN7O3 [M+H+]: 462.1690. found: 462.1682.




1-Phenyl-4, 5-dihydro-1H-imidazol-2-amine hydrobromide
Reaction of N-phenylethylenediamine (9.80 g, 0.072 mol) with cyanogen bromide (7.62 g, 0.072 mol) as described in the preparation of intermediate 6 gave 11.76 g (67% yield) of the title product as white crystals from ethanol. 1HNMR 400 MHz (DMSO-d,) δ (ppm): 3.68 (2H, t, J=8.7 Hz, CH2), 4.08 (2H, t, J=8.7 Hz, CH2), 7.40-7.54 (5H, m, aromatics), 8.08 (broad s, NH). MS (ESI+) m/e 162 [M+H+].




Ethyl 6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Reaction of the adduct of diethyl oxalate (7.06 g, 48.3 mmol), ethyl benzyloxyacetate (9.38 g, 48.3 mmol) and sodium hydride (2.12 g of a 60% dispersion in mineral oil, 53.1 mmol) with 1-phenyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (11.70 g, 48.3 mmol) as described for intermediate 1 gave 1.99 g (11% yield) of the title ester as white crystals; mp 132-134° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH3), 4.23-4.29 (4H, m, 2×CH2), 4.35 (2H, q, J=7.1 Hz, OCH2), 5.18 (2H, s, OCH2), 7.16 (1H, m, aromatic), 7.3-7.53 (7H, m, aromatics), 7.73 (2H, m, aromatics). Anal. Calcd for C22H21N3O4: C, 67.50; H, 5.40; N, 10.73. Found: C, 67.44; H, 5.68; N, 10.73.




6-(Benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic Acid
Saponification of ethyl 6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.94 g, 4.95 mmol) as described for intermediate 2 gave 1.78 g (98% yield) of the title acid as white crystals. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.17-4.20 (4H, m, 2×CH2), 5.00 (2H, s, OCH2), 7.13 (1H, m, aromatic), 7.35-7.46 (7H, m, aromatics), 7.78 (2H, m, aromatics), 13.52 (1H, s, OH). HRMS (ESI+) calculated for C20H18N3O4 [M+H+]: 364.1297. found: 364.1292.




N-(4-Fluorobenzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 199-200° C. (dichloromethane-ethyl acetate). (85% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 4.22-4.31 (4H, m, 2×CH2), 4.51 (2H, d, J=6.1 Hz, NCH2), 5.19 (2H, s, OCH2), 7.02 (2H, m, aromatics), 7.14-7.5 (10H, m, aromatics), 7.62 (1H, broad t, NH), 7.67-7.71 (2H, m, aromatics). HRMS (ESI+) calculated for C27H24FN4O3 [M+H+]: 471.1832. found: 471.1833.
EXAMPLE 20




N-(4-Fluorobenzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (dichloromethane-hexane). (81% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 4.16 (2H, m, CH2), 4.28 (2H, m, CH2), 4.56 (2H, d, J=6.0 Hz, NCH2), 7.05 (2H, m, aromatics), 7.15 (1H, m, aromatic), 7.30 (2H, m, aromatics), 7.37 (2H, m, aromatics), 7.50 (2H, m, aromatics), 7.72 (1H, broad t, NH),11.69 (1H, s, OH). HRMS (ESI+) calculated for C20H18FN4O3 [M+H+]: 381.1363. found: 381.1378.




N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 147° C. (ethyl acetate). (86% yield). 1HNMR 400 MHz (DMSO-dr) δ (ppm): 2.12 (3H, s, CH3), 4.12-4.25 (4H, m, 2×CH2), 4.38 (2H, d, J=6.1 Hz, NCH2), 4.97 (2H, s, OCH2), 6.99 (1H, m, aromatic), 7.12-7.21 (3H, m, aromatics), 7.33-7.43 (7H, m, aromatics), 7.81 (2H, m, aromatics), 8.82 (1H, broad t, NH). HRMS (ESI+) calculated for C28H26FN4O3 [M+H+]: 485.1989. found: 485.1976.
EXAMPLE 21




N-(4-Fluoro-3-methylbenzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate). (61% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.22 (3H, s, CH3), 4.14 (4H, broad s, 2×CH2), 4.50 (2H, d, J=5.6 Hz, NCH2), 7.11 (2H, m, aromatics), 7.20 (2H, m, aromatics), 7.4 (2H, m, aromatics), 7.8 (2H, m, aromatics), 8.83 (1H, broad t, NH), 1 2.06 (1H, s, OH). HRMS (ESI+) calculated for C21H20FN4O3 [M+H+]: 95.1519. found: 395.1521.




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 194-195° C. (ethyl acetate). (76% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.79 (3H, d, J=4.52 Hz, NCH3), 4.14-4.25 (4H, m, 2×CH2), 4.49 (2H, d, J=6.5 Hz, NCH2), 5.0 (2H, s, OCH2), 7.08 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.29 (1H, dd, J=2.7 Hz and J=9.3 Hz, aromatic), 7.33-7.45 (8H, m, aromatics), 7.82 (2H, m, aromatics), 8.52 (1H, broad q, NH), 8.80 (1H, broad t, NH). Anal. Calcd for C29H26FN5O4: C, 66.02; H, 4.96; N, 13.27. Found: C, 65.77; H, 5.19; N, 13.28.
EXAMPLE 22




N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate). (60% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.88 (3H, d, J=4.5 Hz, NCH3), 4.12 (4H, broad s, 2×CH2), 4.54 (2H, d, J=6.6 Hz, NCH2), 7.11 (1H, m, aromatic), 7.3-7.5 (5H, m, aromatics), 7.86 (2H, m, aromatics), 8.68 (H, broad q, NH), 9.18 (1H, broad, NH), 12.0 (11H, s, OH). HRMS (ESI+) calculated for C22H21FN5O4 [M+H+]: 438.1578. found: 438.1576.




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 187-190° C. (ethyl acetate). (74% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.13-4.25 (4H, m, 2×CH2), 4.33 (2H, d, J=6.08 Hz, NCH2), 5.0 (2H, s, OCH2), 7.11-7.17 (2H, m, aromatics), 7.32-7.43 (7H, m, aromatics), 7.47-7.58 (2H, m, aromatics), 7.76-7.81 (2H, m, aromatics), 8.29 (1H, s, CH), 8.80 (1H, broad t, NH), 9.0 (1H, s, CH). HRMS (ESI+) calculated for C29H25FN7O3 [M+H+]: 538.2003 found: 538.1993.
EXAMPLE 23




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (dichloromethane-ethanol). (53% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.13 (4H, s, 2×CH2), 4.46 (2H, d, J=6.1 Hz, NCH2), 711 (1H, m, aromatic), 7.34-7.45 (3H, m, aromatics), 7.61 (2H, m, aromatics), 7.77 (2H, m, aromatics), 8.29 (1H, s, CH), 8.81 (1H, broad t, NH), 9.09 (1H, s, CH), 11.89 (1H, s, OH). HRMS (ESI+) calculated for C22H19FN7O3 [M+H+]: 448.1533. found: 448.1550.




N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 147-148° C. (ethyl acetate). (84% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.33 (3H, s, CH3),4.20-4.32 (4H, m, 2×CH2), 4.46 (2H, d, J=6.5 Hz, NCH2), 5.21 (2H, s, OCH2), 7.07 (1H ,dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.10-7.18 (2H, m, aromatics), 7.27-7.35 (5H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69-7.73 (3H, m, aromatics), 8.26 (1H, s, CH), 8.29 (1H, broad t, NH). MS (ESI+) m/e 552 [M+H+].
EXAMPLE 24




N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate). (71% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.23 (3H, s, CH3), 4.18 (2H, m, CH2), 4.29 (2H, m, CH2), 4.49 (2H, d, J=6.6 Hz, NCH2), 7.09-7.15 (2H, m, aromatics), 7.18-7.23 (1H, m, aromatic), 7.28-7.32 (2H, m, aromatics), 7.6-7.7 (3H, m, aromatics), 8.33 (1H, s, CH), 8.62 (1H, broad t, NH), 11.91 (1H, s, OH). MS (ESI+) m/e 462 [M+H+].




N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 181° C. (ethyl acetate). (72% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.44 (3H, s, CH3),4.23-4.32 (6H, m, 2×CH2 and NCH2), 5.22 (2H, s, OCH2), 7.00 (1H , dd, J=2.7 Hz and J=8.5 Hz, aromatic), 7.16-7.22 (2H, m, aromatics), 7.28-7.33 (3H, m, aromatics), 7.39-7.43 (2H, m, aromatics), 7.49-7.51 (2H, m, aromatics), 7.69-7.73 (3H, m, aromatics), 7.81 (1H, s, CH), 8.05 (1H, broad t, NH). Anal. Calcd for C30H26FN7O3: C, 65.32; H, 4.75; N, 17.77. Found: C, 65.03; H, 4.56; N, 17.49.
EXAMPLE 25




N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (65% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.50 (3H, s, CH3), 4.19 (2H, m, CH2), 4.28 (4H, m, 2×CH2), 7.04 (1H, dd, J=2.5 Hz and J=8.3 Hz, aromatic), 7.15-7.27 (2H, m, aromatics), 7.44 (2H, m, aromatics), 7.65-7.75 (2H, m, aromatics), 7.90 (1H, s, CH), 8.42 (1H, broad t, NH), 11.87 (1H, s, OH). MS (ESI+) m/e 462 [M+H+].




N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (acetonitrile). (75% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.80 (6H, s, 2×NCH3), 4.16-4.26 (4H, m, 2×CH2), 4.72 (2H, d, J=6.4 Hz, NCH2), 5.03 (2H, s, OCH2), 7.13-7.23 (2H, m, aromatics), 7.32-7.46 (7H, m, aromatics), 7.57-7.63 (2H, m, aromatics), 7.80-7.82 (2H, m, aromatics), 8.83 (1H, broad t, NH). HRMS (ESI+) calculated for C29H29FN5O5S [M+H+]: 578.1873. found: 578.1852.
EXAMPLE 26




N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate). (90% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.85 (6H, s, 2×NCH3), 4.13 (4H, s, 2×CH2), 4.82 (2H, d, J=6.6 Hz, NCH2), 7.11 (1H, m, aromatic), 7.42 (2H, m, aromatics), 7.55-7.65 (3H, m, aromatics), 7.78 (2H, m, aromatics), 8.77 (1H, broad t, NH), 11.76 (1H, s, OH). HRMS (ESI+) calculated for C22H23FN5O5S [M+H+]: 488.1404. found: 488.1419.




N-(4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate). (58% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.23 (2H, m, CH2), 2.58 (2H, t, J=8.0 Hz, CH2), 3.79 (2H, t, J=7.0 Hz, CH2), 4.15-4.30 (4H, m, 2×CH2), 4.46 (2H, d, J=6.0 Hz, NCH2), 5.22 (2H, s, OCH2), 6.91 (1H, dd, J=2.6 Hz and J=9.4 Hz, aromatic), 6.99 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.30-7.46 (5H, m, aromatics), 7.44 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.50-7.52 (2H, m, aromatics), 7.69-7.71 (2H, m, aromatics), 7.95 (1H, broad t, NH). MS (ESI+) m/e 554 [M+H+].
EXAMPLE 27




N-(4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (78% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.15 (2H, m, CH2), 2.55 (2H, t, J=7.9 Hz, CH2), 3.81 (2H, t, J=6.9 Hz, CH2), 4.13 (4H, broad s, 2×CH2), 4.41 (2H, d, J=6.4 Hz, NCH2), 7.07 (1H, m, aromatic), 7.18 (1H, m, aromatic), 7.28 (1H, dd, J=2.5 Hz and J=10 Hz, aromatic), 7.36-7.40 (2H, m, aromatics), 7.45 (1H, dd, J=6.5 Hz and J=8.6 Hz, aromatic), 7.82-7.84 (2H, m, aromatics), 8.87 (1H, broad t, NH), 12.10 (1H, s, OH). MS (ESI+) m/e 464 [M+H+].




N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (ethyl acetate). (22% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.10 (2H, t, J=4.4 Hz, CH2), 3.73 (2H, t, J=4.4 Hz, CH2), 4.19-4.31 (4H, m, 2×CH2), 4.60 (2H, d, J=6.3 Hz, NCH2), 5.21 (2H, s, OCH2), 6.88 (1H, m, aromatic), 6.93 (1H, dd, J=2.4 Hz and J=9.7 Hz, aromatic), 7.16 (1H, m, aromatic), 7.29-7.31 (3H, m, aromatics), 7.39-7.43 (2H, m, aromatics), 7.47-7.48 (2H, m, aromatics), 7.54 (1H, dd, J=6.3 Hz and J=8.3 Hz, aromatic), 7.70-7.72 (2H, m, aromatics), 8.25 (1H, broad t, NH). MS (ESI+) m/e 540 [M+H+].
EXAMPLE 28




N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals (dichloromethane). (67% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.17 (2H, t, J=4.4 Hz, CH2), 3.82 (2H, t, J=4.4 Hz, CH2), 4.13 (4H, broad s, 2×CH2),4.59 (2H, d, J=6.6 Hz, NCH2), 7.07-7.11 (2H, m, aromatics), 7.23 (1H, dd, J=2.5 Hz and J=10.4 Hz, aromatic), 7.37-7.41 (2H, m, aromatics), 7.45 (1H, dd, J=6.6 Hz and J=8.6 Hz, aromatic), 7.82-7.84 (2H, m, aromatics), 9.04 (1H, broad t, NH), 12.03 (1H, s, OH). MS (ESI+) m/e 450 [M+H+].




1-(2-Methoxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide
Reaction of N-(2-methoxyethyl)ethylenediamine (16.0 g, 0.135 mol) (R. C. F. Jones and J. R. Nichols, Tetrahedron Lett., 1990, 31, 1767-1770) with cyanogen bromide (14.34 g, 0.135 mol) as described in the preparation of intermediate 6 gave 26.86 g (88% yield) of the title product as large white prisms (ethanol); mp 143-145° C.
1HNMR 400.1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.28 (3H, s, OCH3), 3.48 (4H, s, 2×CH2), 3.52 (2H, m, CH2), 3.67 (2H, m, CH2), 7.87 (broad s, NH). Anal. Calcd for C6H13N3O. HBr: C, 32.15; H, 6.29; N, 18.75. Found: C, 32.23; H, 6.14; N, 18.85.




Ethyl 6-(benzyloxy)-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Reaction of the adduct of diethyl oxalate (16.95 g, 0.116 mol), ethyl benzyloxyacetate (22.53 g, 0.116 mol) and sodium hydride (5.10 g of a 60% dispersion in mineral oil, 0.127 mol) with 1-(2-methoxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide (26.0 g, 0.116 mol) as described for intermediate 1 gave 5.37 g (12% yield) of the title ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.1 Hz, CH3), 3.38 (3H, s, OCH3), 3.61 (4H, s, 2×CH2), 3.84 (2H, t, J=8.9 Hz, CH2), 4.14 (2H, t, J=8.9 Hz, CH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.09 (2H, s, OCH2), 7.3-7.38 (3H, m, aromatics), 7.49 (2H, m, aromatics). MS (ESI+) m/e 374 [M+H+].




6-(Benzyloxy)-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid
White crystals; mp 125-126° C. (ethyl acetate). (97% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.38 (3H, s, OCH3), 3.61 (4H, s, 2×CH2), 3.86 (2H, t, J=9.0 Hz, CH2), 4.16 (2H, t, J=9.0 Hz, CH2), 5.26 (2H, s, OCH2), 7.35-7.40 (3H, m, aromatics), 7.57 (2H, m, aromatics). Anal. Calcd for C17H19N3O5: C, 59.12; H, 5.54; N, 12.16. Found: C, 59.04; H, 5.55; N, 12.10.




N-(4-Fluorobenzyl)-6-(benzyloxy)-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 150° C. (ethyl acetate). (79% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.38 (3H, s, OCH3), 3.61 (4H, s, 2×CH2), 3.84 (2H, t, J=8.9 Hz, CH2), 4.14 (2H, t, J=8.9 Hz, CH2), 4.49 (2H, d, J=6.1 Hz, NCH2), 5.10 (2H, s, OCH2), 6.99 (2H, m, aromatics), 7.24 (2H, m, aromatics), 7.33-7.36 (3H, m, aromatics), 7.43-7.45 (2H, m, aromatics), 7.67 (1H, broad t, NH). Anal. Calcd for C24H25FN4O4: C, 63.70; H, 5.56; N, 12.38; Found: C, 64.00; H, 5.41; N, 12.10.
EXAMPLE 29




N-(4-Fluorobenzyl)-6-hydroxy-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 166° C. (ethanol). (96% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.38 (3H, s, OCH3), 3.51 (2H, m, CH2), 3.59 (2H, m, CH2), 3.76 (2H, t, J=8.6 Hz, CH2), 4.14 (2H, t, J=8.6 Hz, CH2), 4.58 (2H, d, J=6.6 Hz, NCH2), 7.07 (2H, m, aromatics), 7.32 (2H, m, aromatics), 7.85 (1H, broad t, NH), 11.57 (1H, s, OH). Anal. Calcd for C17H19FN4O4: C, 56.34; H, 5.28; N, 15.46. Found: C, 56.39; H, 5.37; N, 15.27.




1-(2-Hydroxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide
Reaction of 2-(2-aminoethylamino)ethanol (8.0 g, 76.8 mmol) with cyanogen bromide (8.13 g, 76.8 mmol) as described in the preparation of intermediate 6 gave 13.27 g (82% yield) of the title product as large white prisms (ethanol); mp 112-115° C. 1HNMR 400.1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.36 (2H, t, J=5.3 Hz, CH2), 3.50-3.58 (4H, m, 2×CH2), 3.69 (2H, m, CH2), 4.97 (1H, t, J=5.0 Hz, OH), 7.73 and 7.85 (broad s, NH). Anal. Calcd for C5H11N30.HBr: C, 28.58; H, 5.75, N 20.00. Found: C, 28.79; H, 5.58; N, 20.12.




Ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
Reaction of the adduct of diethyl oxalate (14.61 g, 0.10 mol), ethyl benzyloxyacetate (19.42 g, 0.10 mol) and sodium hydride (4.40 g of a 60% dispersion in mineral oil, 0.11 mol) with 1-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide (21.0 g, 0.10 mol) as described for intermediate 1 gave 3.37 g (9% yield) of the title ester as white crystals; mp 104-106° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH3), 3.53 (2H, m, CH2), 3.83 (2H, t, J=8.9 Hz, CH2), 3.90 (2H, m, CH2), 4.19 (2H, t, J=8.9 Hz, CH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.11 (2H, s, OCH2), 7.35-7.40 (3H, m, aromatics), 7.51 (2H, m, aromatics). Anal. Calcd for C18H21N3O5: C, 60.16; H, 5.89, N 11.69. Found: C, 60.24; H, 5.89; N, 11.77.




6-(Benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid
White crystals (ethyl acetate). (80% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.36 (2H, t, J=5.8 Hz, CH2), 3.58 (2H, broad t, CH2), 3.76 (2H, t, J=9.1 Hz, CH2), 4.02 (2H, t, J=9.1 Hz, CH2), 4.85 (1H, broad, OH), 4.90 (2H, s, OCH2), 7.34-7.43 (SH, m, aromatics), 13.3 (H, broad, OH). MS (ESI+) m/e 332 [M+H+].




Ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate
A solution of ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.40 g, 3.89 mmol) in a mixture of ethyl acetate (300 ml) and ethanol (75 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (200 mg) and under one atmosphere of hydrogen for four hours to give 1.05 g (100% yield) of the title compound as light yellow needles; mp 155-156° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH3), 3.46 (2H, m, CH2), 3.75 (2H, t, J=8.3 Hz, CH2), 3.92 (2H, m, CH2), 4.20 (2H, t, J=8.3 Hz, CH2), 4.43 (2H, q, J=7.1 Hz, OCH2), 10.20 (1H, s, OH). Anal. Calcd for C11H15N3O5: C, 49.06; H, 5.61; N, 15.60. Found: C, 49.09, H, 5.73; N, 15.58.
EXAMPLE 30




N-(4-Fluorobenzyl)-6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
A solution of ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.110 g, 0.408 mmol) and 4-fluorobenzylamine (0.200 g, 1.6 mmol) in anhydrous ethanol (5 ml) was heated under reflux for 6 h. The reaction mixture was then diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethanol gave 0.116 g (82% yield) of the title amide as white cubes; mp 203° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.54 (2H, t, J=5.0 Hz, CH2), 3.80 (2H, t, J=8.5 Hz, CH2), 3.89 (2H, t, J=5.0 Hz, CH2), 4.15 (2H, t, J=8.5 Hz, CH2), 4.57 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.92 (1H, broad t, NH), 11.68 (1H, s, OH). Anal. Calcd for C16H17FN4O4: C, 55.17; H, 4.92; N, 16.08. Found: C, 55.22; H, 5.06; N, 15.89.




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White solid (67% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.55 (2H, t, J=5.0 Hz, CH2), 3.81 (2H, t, J=8.7 Hz, CH2), 3.88 (2H, t, J=5.0 Hz, CH2), 4.17 (2H, t, J=8.7 Hz, CH2), 4.42 (2H, d, J=6.1 Hz, NCH2), 5.13 (2H, s, OCH2), 7.06 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.18 (1H, m, aromatic), 7.25-7.31 (3H, m, aromatics), 7.39-7.41 (2H, m, aromatics), 7.69 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.98 (1H, s, CH), 8.27 (1H, broad t, NH), 8.38 (1H, s, CH). MS (ESI+) m/e 506 [M+H+].
EXAMPLE 31




N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide
White crystals; mp 220-222° C. (ethanol). (86% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.42 (2H, t, J=5.8 Hz, CH2), 3.62 (2H, m, CH2), 3.68 (2H, t, J=8.5 Hz, CH2), 3.98 (2H, t, J=8.5 Hz, CH2), 4.41 (2H, d, J=6.0 Hz, NCH2), 4.79 (1H, t, J=5.6 Hz, OH), 7.42 (1H, m, aromatic), 7.53 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.57 (1H, dd, J=2.7 Hz and J=9.3 Hz, aromatic), 8.34 (1H, s, CH), 9.06 (1H, s, CH), 9.16 (1H, broad t, NH), 11.43 (1H, s, OH). MS (ESI+) m/e 416 [M+H+].
Some other examples of formula I compounds are listed in table 4.










TABLE 4







Example
Structure



















32







 



33







 



34







 



35







 



36







 



37







 



38







 



39







 



40







 



41







 



42







 



43

## Claims

1. A compound of Formula I



wherein:
R1 is (Ar1)alkyl;
R2 is hydrogen, hydroxy, alkyl, or alkoxy;
R3 is hydrogen, halo, hydroxy, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, C4-6lactamyl, N(R6)SO2R7, N(R6)COR7, N(R6)CO2R7, OCOR7, OCO2R7, OCON(R6)(R6), COR7, CO2R6, CON(R6)(R6), SOR7, SO2R7, SO2N(R6)(R6), P(O)(OR6)2, or Ar2;
R4 is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy;
R5 is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy;
R6 is hydrogen, alkyl, or cycloalkyl;
R7 is alkyl or cycloalkyl;
R8 is hydrogen or alkyl;
R9 is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, (alkoxy)alkyl, phenyl, or benzyl, wherein phenyl and benzyl are substituted with 0-2 substituents selected from the group consisting of halo, cyano, alkyl, alkoxy, halolkyl, and haloalkoxy;
Ar1 is




Ar2 is tetrazolyl, triazolyl, pyrazolyl, imidazolyl, pyrrolyl, or dioxothiazinyl, and is substituted with 0-2 substituents selected from the group consisting of amino, oxo, halo, and alkyl; and
X—Y-Z is N(R9)C(R8)2C(R8)2;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where R1 is

3. A compound of claim 1 where R1 is




provided that R3 is not hydrogen.

4. A compound of claim 1 where R1 is




and R3 is C4-6lactamyl, N(R6)SO2R7, N(R6)COR7, N(R6)CO2R7, OCOR7, OCO2R7, OCON(R6)(R6), COR7, CO2R6, CON(R6)(R6), SOR7, SO2R7, SO2N(R6)(R6), or Ar2.

5. A compound of claim 1 where R2 is hydrogen.

6. A compound of claim 1 where R3 is triazolyl substituted with 0-1 methyl groups; R4 is hydrogen, chloro, flouro, or methyl; and R5 is hydrogen.

7. A compound of claim 1 where R6 is hydrogen or alkyl.

8. A compound of claim 1 where R7 is alkyl.

9. A compound of claim 1 where X—Y-Z is N(R9)CH2CH2.

10. A compound of claim 1 where R9 is alkyl, cycloalkyl, hydroxyalkyl, (alkoxy)alkyl, phenyl, or benzyl.

11. A compound selected from the group consisting of
N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-methyl-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-methyl-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-methyl-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-hydroxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-butyl-N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-butyl-N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-butyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-butyl-N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-cyclohexyl-N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-cyclohexyl-N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-cyclohexyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-butyl-N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-cyclohexyl-N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-hydroxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(2-oxo-1-pyrrolidinyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide;
1-butyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide;
N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; and
[5-fluoro-2-[[[(1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenylimidazo[1,2-a]pyrimidin-7-yl)carbonyl]amino]methyl]phenyl]-phosphonic acid, dimethyl ester;

or a pharmaceutically acceptable salt thereof.

12. A composition comprising a therapeutic amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

13. A method for treating HIV infection comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

14. The method of claim 13, further comprising a therapeutically effective amount of one or more other HIV treatment agents selected from the group consisting of HIV protease inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV-entry inhibitors, HIV integrase inhibitors, immunomodulators, or a combination thereof.