Patent Grant
7494984
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).
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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+].
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.
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+].
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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+].
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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+].
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+].
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.
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+].
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.
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.
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+].
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+].
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+].
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+].
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.
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+].
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.
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.
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.
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.
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.
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+].
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.
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.
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+].
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.
This application claims the benefit of U.S. Provisional Application Ser. No. 60/713,080, filed Aug. 31, 2005.
| Number | Name | Date | Kind |
|---|---|---|---|
| 20050256109 | Naidu | Nov 2005 | A1 |
| 20050261322 | Naidu | Nov 2005 | A1 |
| 20050267105 | Naidu | Dec 2005 | A1 |
| 20050267131 | Naidu | Dec 2005 | A1 |
| 20050267132 | Banville | Dec 2005 | A1 |
| 20060046985 | Crescenzi | Mar 2006 | A1 |
| Number | Date | Country |
|---|---|---|
| 1698628 | Sep 2006 | EP |
| 2004 244320 | Feb 2004 | JP |
| WO 2005061490 | Jul 2005 | WO |
| WO 2005061501 | Jul 2005 | WO |
| WO 2006103399 | Oct 2006 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20070049606 A1 | Mar 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60713080 | Aug 2005 | US |
