WO2007058646A1 - Hiv integrase inhibitors: cyclic pyrimidinone compounds - Google Patents

Hiv integrase inhibitors: cyclic pyrimidinone compounds Download PDF

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Publication number
WO2007058646A1
WO2007058646A1 PCT/US2005/041283 US2005041283W WO2007058646A1 WO 2007058646 A1 WO2007058646 A1 WO 2007058646A1 US 2005041283 W US2005041283 W US 2005041283W WO 2007058646 A1 WO2007058646 A1 WO 2007058646A1
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Prior art keywords
methyl
oxo
carboxamide
spiro
hydroxy
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PCT/US2005/041283
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French (fr)
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B. Narasimhulu Naidu
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Bristol-Myers Squibb Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • Recent statistics 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.
  • 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, hi 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.
  • nevaripine, delavirdine and efavirenz are non-nucleoside reverse transcriptase inhibitors, which inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism.
  • these drugs When used alone these drugs are effective in reducing viral replication. The effect, however, is only temporary as the virus readily develops resistance to all known agents.
  • combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients, hi the US, where combination therapy is widely available, the number of HFV-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).
  • 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-I 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. Then Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
  • the invention encompasses a series of pyrimidinone compounds which inhibit HIV integrase and thereby prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS.
  • the invention also encompasses intermediates useful for making the pyrimidone compounds. Additionally, pharmaceutical compositions and methods for treating those infected with HIV are encompassed.
  • One aspect of the invention is a compound of Formula I
  • R 1 is Ci -6 (ArVIkVl;
  • R 2 is hydrogen, Ci -6 alkyl, or OR 6 ;
  • R 3 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, Ci -6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, CON(R 6 )(R 6 ), SOR 7 , SO 2 R 7 , SO 2 N(R 6 XR 6 ), or Ar 2 ;
  • R 4 is hydrogen, halo, hydroxy, cyano, Ci -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • R 5 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyL C 1 ⁇ aIkOXy, C 1-6 haloalkyl, or Ci -6 haloalkoxy;
  • R 6 is hydrogen or C 1-6 alkyl
  • R 7 is Ci -6 alkyl
  • R 8 and R 9 taken together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 , OCH 2 CH 2 , CH 2 OCH 2 , OCH 2 CH 2 CH 2 , CH 2 OCH 2 CH 2 , OCH 2 CH 2 CH 2 CH 2, CH 2 OCH 2 CH 2 CH 2, CH 2 CH 2 OCH 2 CH 2 , OCH 2 CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 OCH 2 CH 2 CH 2 , N(R 6 )CH 2 CH 2 , CH 2 N(R 6 )CH 2 , N(R 6 )CH 2 CH 2 CH 2 , CH 2 N(R 6 )CH 2 CH 2> N(R 6 )CH 2 CH 2 CH 2 CH 2 , CH 2 N(R 6 )CH 2 CH 2 CH 2 , CH 2 CH 2 N(R 6 )CH 2 CH
  • Ar 2 is tetrazolyl, triazolyl, imidazolyl, pyrazolyl, pyrrolyl, or dioxothiazinyl, and is substituted with 0-2 substituents selected from the group consisting of amino, oxo, halo, cyano, and C ⁇ alkyl; and
  • X-Y-Z is C(R 8 )(R 9 )CH 2 CH 2; C(R 8 )(R 9 )CH 2 CH 2 CH 2 , C(R 8 )(R 9 )CH 2 CH 2 CH 2 CH 2 , C(R 8 )(R 9 )OCH 2, C(R 8 )(R 9 )OCH 2 CH 2 , or C(R 8 )(R 9 )OCH 2 CH 2 CH 2 ;
  • Another aspect of the invention is a compound of Formula I where X-Y-Z is
  • Another aspect of the invention is a compound of Formula I according to the following structures.
  • Another aspect of the invention is a compound of Formula I where X-Y-Z is C(R 8 )(R 9 )OCH 2; C(R 8 )(R 9 )OCH 2 CH 2 , or C(R 8 )(R 9 )OCH 2 CH 2 CH 2 .
  • Another aspect of the invention is a compound of Formula I according to the following structures.
  • R 8 and R 9 taken together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2, CH 2 CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 CH 2, CH 2 N(R 6 )CH 2 CH 2) or CH 2 CH 2 N(R 6 )CH 2 CH 2 .
  • Another aspect of the invention is a compound of Formula I where R 1 is (Ar ⁇ methyl.
  • Another aspect of the invention is a compound of Formula I where R 2 is hydrogen.
  • Another aspect of the invention is a compound of Formula I where R 3 is fluoro, chloro, methyl, CON(R 6 )(R 6 ), or Ar 2 .
  • Another aspect of the invention is a compound of Formula I where R 4 is hydrogen, fluoro, chloro, or methyl.
  • Another aspect of the invention is a compound of Formula I where R 5 is hydrogen.
  • Another aspect of the invention is a compound of Formula I where Ar 1 is
  • any scope of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 taken together, and X-Y-Z can be used independently with any scope of any other substituent.
  • Another aspect of the invention is a compound of Formula II.
  • P is hydrogen, mesyl, tosyl, allyl, benzyl, fluorenylmethyl, allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, tri(C 1-6 alkyl)silyl, Ci -6 alkyl,
  • R 6a is hydrogen, C 1-6 alkyl, or Ci -6 (Ar I )alkyl
  • P is hydrogen, mesyl, tosyl, allyl, benzyl, fluorenylmethyl, allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, tri(Ci -6 alkyl)silyl Ci -6 alkyl, Ci -6 alkylcarbonyl, or C 1-6 alkoxycarbonyl.
  • Alkyl alkoxy
  • haloalkyl and related terms for other hydrocarbon and substituted hydrocarbon substituents include straight and branched isomeric configurations.
  • a term such as “C 1-6 (R)alkyl” means a straight or branched alkyl group of 1 to 6 carbons substituted with the substituent R.
  • Haloalkyl and related terms for halogenated substituents include all permutations of halogenation, from monohaloalkyl to perhaloalkyl.
  • Aryl means an aromatic ring system and includes carbocyclic and heterocyclic systems. Some substituents are divalent, for example, X-Y-Z. Divalent substituents which are asymmetric can be attached to the parent molecule in either of the configurations.
  • 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.
  • the invention also includes all solvated forms of the compounds, particularly hydrates. Solvates do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents.
  • Solvates may form in stoichiometric amounts or may form from adventitious solvent or a combination of both.
  • One type of solvate is hydrate, and some hydrated forms include monohydrate, hemiliydrate, and dihydrate.
  • the invention includes all tautomeric forms of the compounds.
  • An example of a tautomeric pair is shown below.
  • the invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. An example of enantiomers is shown below. Methods of making and separating stereoisomers are known in the art.
  • 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 schemes (for example, X, n, and P) are separate 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.
  • "X” and "n” include alkylene spacers which may contain ether or amino functionalities.
  • P may include an appropriate protecting group. Starting materials can be made using methods known in the art. Scheme 1.
  • HIV integrase inhibitors have been reported to prevent viral integration and inhibited HIV-I replication in cells (Hazuda et al. Science 2000, 257, 646). Recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Then Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
  • another aspect of the invention is a method for treating HIV infection in a patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating HIV infection in a patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate 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.
  • compositions comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
  • “Combination,” “coadministration,” “concurrent,” and similar terms referring to the administration of compounds 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.
  • 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 exipients.
  • 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 rng/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.
  • the dosing regimen will be similar to other antiretroviral agents used clinically.
  • the daily dose will be 1-100 mg/kg body weight daily.
  • more compound is required orally and less parenterally.
  • the specific dosing regime 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 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.
  • the compound 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 2 lists some agents useful in treating AIDS and HIV infection which are suitable for this method.
  • reaction mixture was quenched with saturated ammonium chloride (1 mL), diluted with EtOAc (100 mL), dried (MgSO 4 ), filtered and concentrated to give intermediate 1 as yellow oil which was used in the next step without further purification.
  • Tetrahydro ⁇ 2H-pyran-4-carbonitrile A solution of tetrahydro-4H r -pyran-4- one (25 g, 250 mmol) and toluenesulfonylmethyl cyanide (53.7 g, 275 mmol) dissolved in ethylene glycol dimethylether (1 L) was cooled to 0 °C. Added dropwise over 30 min was a solution of potassium t-butoxide (56 g, 500 mmol) dissolved in t-butanol (350 mL) and ethylene glycol dimethylether (150 mL).
  • reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the product intermediate 5 as a colorless liquid (3.737 g, 99%).
  • Nitrile 33 (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). Aqueous HCl (15 mL, IN) was added followed by 10% Pd/C (200 mg). The mixture was shaken under H 2 at 55 psi for 4 h., filtered over celite and concentrated. The residue was partitioned between EtOAc and water. The aqueous phase was lyophilized to give intermediate 35 as a white powder (2.96 g, 99%).
  • 4-Fluoro-2-methylsulfanyl-benzylamine 4-Fluoro-2-(methylthio)benzonitrile (prepared as in Anthony, N. J. et al. PCT Appl. WO 02/30931, 2002) (1.67 g, 0.1 mol) was dissolved in 20 mL THF and under N 2 treated with 10 mL 2M BH 3 -Me 2 S. This was heated at 60 °C for 2 hrs. Heating was discontinued and 5mL MeOH was cautiously added, followed by the cautious addition of 4 mL 6N HCl. Then 20 niL more H 2 O added and EtOAc and the layers were separated.
  • N-t-Butoxycarbonyl- (4-fluoro-2-(methylthio)phenyl)methanamine A stirred solution of intermediate 37 (5.1g, 0.03 mol) and 3.3g triethylamine in 10OmL CH 2 Cl 2 under N2 was treated with di-t-butyl dicarbonate (7.2g, 0.033 mol) portionwise and stirred at room temperature for 30 min. Then, the reaction mixture was washed with dil HCl and water. The organic layer was dried over MgSO 4 , filtered and concentrated to leave 8.1g (100%) of intermediate 38 as a clear oil.
  • diethyl-2-(benzyloxy)-3-hydroxyfumarate prepared from benzyloxy ethylacetate (2.91g, 0.015 mol) and diethyloxalate (2.19g, .015 mol) with an equivalent amount of sodium hydride in 40 mL THF and 2 drops EtOH by stirring for 30 min
  • 20 mL EtOH was added intermediate 54 in 10 mL EtOH and with stirring 60% NaH (300mg, 0.0075 mol) was added portionwise. This was stirred for 3 h at rt and concentrated. The residue was dissolved in CH 2 Cl 2 and washed with water. The CH2C12 layer was dried over MgSO 4 , filtered and concentrated.
  • 2-Azido-l-bromo-4-fluorobenzene 2-Bromo-5-fluoro aniline (2.00 g, 10.53 mtnol) was dissolved in concentrated HCl (10 mL) and water (10 mL) and cooled to 0 0 C. Aqueous NaNO 2 solution (1.09 g, 15.8 mmol OfNaNO 2 in 10 mL of water) was added dropwise at such a rate that the temperature did not exceed 5 0 C. This mixture was stirred at 0 0 C for 1.5 h.
  • the title compound can be prepared according to the procedure provided for l-(2- bromo-5-fluorophenyl)-4-(trimethylsilyl)-lH-l,2,3-triazole 1 H NMR (400 MHz, CDCl 3 ) ⁇ ppm: 7.73-7.69 (IH, m), 7.20-7.16 (2H, m), 2.22 (3H, s), 0.39 (9H, s); LCMS C ESI, M+H*) m/z 328/330.
  • ester 3 (0.146 g, .499 mmol), 4-fluorobenzylamine (0.156 g, 1.25 mmol, and triethylami ⁇ e (0.14 mL, 1 mmol) in 1:1 DMF/EtOH (2 mL) was heated at 110 °C for 1.5 h. Then, the reaction mixture was cooled and purified preparative HPLC using MeOH/water containing 0.1F TFA (gradient elution). The fractions containing the product were combined and evaporated to afforded the product as a white solid (0.0955g, 51.5%).
  • Ci 9 Hi 9 CI 2 N 3 O 3 C, 55.89; H, 4.69; N, 10.29; found: C, 55.66; H, 4.83; N, 10.27. Yield: 51 %.
  • example 18 52 mg, 0.124 mmol
  • mCPBA 64.2 mg, 0.372 mmol
  • example 89 26.2 mg, 47%) as a purple solid.
  • Example 90 was prepared according to the procedure for example 89 using example 39 to afford product in 38% as a purple solid.
  • HRMS M+H
  • the reaction was quenched with 1.0 N HCl solution (4 mL), and extracted into ethyl acetate (2 x 10 mL) and CH 2 Cl 2 (10 mL). The combined extracts were dried (Na 2 SO 4 ), filtered, and concentrated in-vacuo.
  • the crude material was dissolved in dimethylformamide (3 mL) and purified by C-18 reverse phase column chromatography, eluting with 10% - 30% acetonitrile in water. Product fractions were concentrated to dryness by rotary evaporator, or optionally reduced in volume and extracted with CH 2 Cl 2 . The product was then triturated with 95% ethanol or, optionally, AcCN.

Abstract

The invention encompasses a series of pyrimidinone compounds which inhibit HIV integrase and thereby prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses intermediates useful for making the pyrimidone compounds. Additionally, pharmaceutical compositions and methods for treating those infected with HIV are encompassed. Formula: (I).

Description

HIV INTEGRASE INHIBITORS: CYCLIC PYRIMIDINONE COMPOUNDS
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, hi 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. And nevaripine, delavirdine and efavirenz are non-nucleoside reverse transcriptase inhibitors, which inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. When used alone these drugs are effective in reducing viral replication. The effect, however, is only temporary as the virus readily develops resistance to all known agents. Currently, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients, hi the US, where combination therapy is widely available, the number of HFV-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-I 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 due 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-I 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. Then Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
DESCRIPTION OF THE INVENTION
The invention encompasses a series of pyrimidinone compounds which inhibit HIV integrase and thereby prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses intermediates useful for making the pyrimidone compounds. Additionally, pharmaceutical compositions and methods for treating those infected with HIV are encompassed. One aspect of the invention is a compound of Formula I
Figure imgf000005_0001
where:
R1 is Ci-6(ArVIkVl;
R2 is hydrogen, Ci-6alkyl, or OR6;
R3 is hydrogen, halo, hydroxy, cyano, C1-6alkyl, C3-7cycloalkyl, Ci-6haloalkyl, C1-6alkoxy, C1-6alkylthio, C1-6haloalkoxy, CON(R6)(R6), SOR7, SO2R7, SO2N(R6XR6), or Ar2;
R4 is hydrogen, halo, hydroxy, cyano, Ci-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy;
R5 is hydrogen, halo, hydroxy, cyano, C1-6alkyL C1^aIkOXy, C1-6haloalkyl, or Ci-6haloalkoxy;
R6 is hydrogen or C1-6alkyl; R7 is Ci-6alkyl;
R8 and R9 taken together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2, OCH2CH2, CH2OCH2, OCH2CH2CH2, CH2OCH2CH2, OCH2CH2CH2CH2, CH2OCH2CH2CH2, CH2CH2OCH2CH2, OCH2CH2CH2CH2CH2, CH2OCH2CH2CH2CH2, CH2CH2OCH2CH2CH2, N(R6)CH2CH2, CH2N(R6)CH2, N(R6)CH2CH2CH2, CH2N(R6)CH2CH2> N(R6)CH2CH2CH2CH2, CH2N(R6)CH2CH2CH2, CH2CH2N(R6)CH2CH2, N(R6)CH2CH2CH2CH2CH2, CH2N(R6)CH2CH2CH2CH2, or CH2CH2N(R6)CH2CH2CH2;
Figure imgf000006_0001
Ar2 is tetrazolyl, triazolyl, imidazolyl, pyrazolyl, pyrrolyl, or dioxothiazinyl, and is substituted with 0-2 substituents selected from the group consisting of amino, oxo, halo, cyano, and C^alkyl; and
X-Y-Z is C(R8)(R9)CH2CH2; C(R8)(R9)CH2CH2CH2, C(R8)(R9)CH2CH2CH2CH2, C(R8)(R9)OCH2, C(R8)(R9)OCH2CH2, or C(R8)(R9)OCH2CH2CH2;
or a pharmaceutically acceptable salt or solvate thereof.
Another aspect of the invention is a compound of Formula I where X-Y-Z is
C(R8)(R9)CH2CH2, C(R8)(R9)CH2CH2CH2, or C(R8)(R9)CH2CH2CH2CH2.
Another aspect of the invention is a compound of Formula I according to the following structures.
Figure imgf000006_0002
Another aspect of the invention is a compound of Formula I where X-Y-Z is C(R8)(R9)OCH2; C(R8)(R9)OCH2CH2, or C(R8)(R9)OCH2CH2CH2.
Another aspect of the invention is a compound of Formula I according to the following structures.
Figure imgf000007_0001
Another aspect of the invention is a compound of Formula I where R8 and R9 taken together are CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2CH2, CH2N(R6)CH2CH2) or CH2CH2N(R6)CH2CH2.
Another aspect of the invention is a compound of Formula I where R1 is (Ar^methyl.
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 fluoro, chloro, methyl, CON(R6)(R6), or Ar2.
Another aspect of the invention is a compound of Formula I where R4 is hydrogen, fluoro, chloro, or methyl.
Another aspect of the invention is a compound of Formula I where R5 is hydrogen.
Another aspect of the invention is a compound of Formula I where Ar1 is
Figure imgf000007_0002
For a compound of Formula I, any scope of R1, R2, R3, R4, R5, R6, R7, R8 and R9 taken together, and X-Y-Z can be used independently with any scope of any other substituent.
Another aspect of the invention is a compound of Formula II.
where
Figure imgf000008_0001
R6a is hydrogen, C1-6alkyl, Ci^Ar^alkyl, ArC1-6, C-(C=Qn-C, C1-6-O-Ci-6-O-C1-6, C1-6-O-Ci-6-Ar, C(Ar)2-3, CO(C1-6)1-3, or COAr; and
P is hydrogen, mesyl, tosyl, allyl, benzyl, fluorenylmethyl, allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, tri(C1-6alkyl)silyl, Ci-6alkyl,
C^βalkylcarbonyl, or C1-6alkoxycarbonyl, ArC1-6, C-(C=Qn-C, Ci-6-O-Ci-6-O-Ci-6, C1-6-O-C1-6-Ar, CO(C1-6)I-3, COAr, or C(Ar)2-3.
Another aspect of the invention is a compound of Formula II where R6a is hydrogen, C1-6alkyl, or Ci-6(ArI)alkyl; and P is hydrogen, mesyl, tosyl, allyl, benzyl, fluorenylmethyl, allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, tri(Ci-6alkyl)silyl Ci-6alkyl, Ci-6alkylcarbonyl, or C1-6alkoxycarbonyl.
Some compounds of the invention are
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-4'-oxo- spirotcyclopentane-ljPXό'^-^HJpyridofl^-ajpyriniidineJ^'-carboxarnide;
N-[(4-fluoro-3-methylphenyl)methyl]-7l,8t-dihydro-31-hydroxy-4'-oxo- spko[cyclopentane-l,9χ6Η)-[4H]pyrido[l,2-a]pyrimidine]-2'-carboxamide; N -[[2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3'-hydroxy-4'-oxo- spiro[cyclopentane- 1 ,9'(6H)-[4H]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N -[[4-fluoro-2-(1H-1,2,4-triazol-l-yl)phenyl]methyl]-7t,8'-dihydro-3'- hyα^oxy^'-oxo-spkotcyclopentaiie-l^'Cό'J^-^HJpyridotl^-^pyrimidine]-2'- carboxamide;
N -[[5-fluoro-2-(1H- 1,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(6'H)-[4H]pyrido[l ,2-α]pyrimidine]-2'- carboxamide;
N -[[4-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl]methyl]-7',8'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclopentane-1,9'(6'H)-[4H]pyrido[l,2-α]pyrimidine]-2t- carboxamide;
N -[[4-fluoro-2-(1H- imidazol-l-yl)plienyl]methyl]-7',8'-diliydro-3'-hydroxy-4'- oxo-spiro[cyclopentane-l,9t(6'H)-[4H]pyrido[l,2-α]pyrimidine]-2'-carboxamide;
N -[[2-(tetrahydro-l,l-dioxido-2H--l,2-thiazin-2-yl)phenyl]methyl]-7',8'- dihydro-3 '-hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(6'H)-[4HJpyrido[ 1 ,2- α]pyrimidήie]-2'-carboxamide;
N -[[4-fluoro-2-(tetrahydro-l,l-dioxido-2H-l,2-thiazin-2-yl)phenyl]methyl]- 7',8'-diliydro-3'-h.ydroxy-4'-oxo-spiro[cyclopentane-l,9'(6'H)-[4H]pyrido[1,2- α]pyrimidine]-2'-carboxamide;
N - [[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl] -7',8'-diliydro-3'- hydroxy-4'-oxo-spiro[cyclopentane-l^Xό'Hj-^HJpyridotl^-^pyrimidine]^'- carboxamide;
N -[[4-fluoro-2-(methylsulfonyl)ρhenyl]methyl]-7l,8t-dihydro-3'-hydroxy-4l- oxo-spiro[cyclopentane- 1 ,9'(6'H)-[4H]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide; N-[[3-fluoro-2-(1H- 1,2,4-triazol-l-yl)phenyl]methy]- 7',8'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclopentane-1,9'(6'H)-[4H]pyrido[1,2-α]pyrimidine]-2'- carboxamide;
N-(phenylmethyl)-7',8'-dihydro-3l-liydroxy-4'-oxo-spiro[cyclobutane-
1 ,9'(6'H)-[4H]ρyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N-[(4-methylphenyl)methyl]-7',8'-dihydro-3'-liydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(6'H)-[4H]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N-[(4-methoxyphenyl)methyl]-7',8'-dihydro-3'-liydroxy-4'-oxo- spiro[cyclobutane-1,9'(6'H)-[4H]pyrido[l,2-α]pyrimidine]-2'-carboxamide;
N-[(4-chlorophenyl)methyl]-7',8'-dihydro-3'- hydroxy-4'-oxo- spiro[cyclobutane-1[Xo'H^-^Hjpyridofl^-^pyrimidinej^'-carboxamide;
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(6'H) -[4H]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N-[(3-fluorophenyl)metliyl]-7l,8'-diliydro-3'-liydroxy-4'-oxo- spiro[cyclobutane-l,9'(6'7ϊ)-[4H]pyrido[l,2-βf]pyrimidine]-2'-carboxamide;
N -[(2-fluorophenyl)methyl]-7',8l-dihydro-3'-hydroxy-4'-oxo- spkofcyclobutane-l^Xo'/^-^HJpyridotl^-ajpyrimidineJ^'-carboxamide;
N-[(3,4-dimethylρhenyl)methyl]-7',8'-dib.ydro-3'-hydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(6'H)-[4H]pyrido[ 1 ,2-α]pyrimidine] -2'-carboxamide;
N- [(3 ,4-dichlorophenyl)methyl] -7',8 '-dib.ydro-3 '-hydroxy-4'-oxo- spkotcyclobutane-l^Xό'/^-^HJpyridofl^-αJpyrimidineJ^'-carboxamide;
N-[(2,4-dimethoxyphenyl)methyl]-7',8'-dihydro-3'-liydroxy-4'-oxo- spiro[cyclobutane-l,9'(6'H)-[4H ]pyrido[l,2-α]pyrimidine]-2'-carboxamide; N- [(4-fluoro-3-metliylphenyl)metliyl]-7!,8l-diliydro-3t-hydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(6'H)-[4H ]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N-[(3-fluoro-4-methylphenyl)methyl]-7l,8l-dihydro-3'-hydroxy-4'-oxo- spiro[cyclobutane-1,9'(6'H)-[4H]pyrido[1,2-a]pyrimidine]-2'- carboxamide;
N- [I -(4-fluorophenyl)ethyl]-7I,8'-dihydro-3'-hydroxy-4t-oxo- • spiro[cyclobutane-l,9χ6'J^-[4iϊ]pyrido[l,2-βr]pyrimidine]-2'-carboxamide;
N -[(2,5-difluorophenyl)metliyl]-7l,8l-dihydro-3'-hydroxy-4t-oxo- spiro[cyclobutane- 1 ,9'(6H)-[4H]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N -[(2,5-dichlorophenyl)methyl]-7',8'-diliydro-3'-liydroxy-4l-oxo- spiro[cyclobutane-l,9χ6'/iO-[4H]pyrido[l,2-α]pyrimidine]-2'-carboxamide;
N -[[5-fluoro-2-(l/f-1,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane-1,9'(6'H)-[4H]pyrido[l,2-α]pyriinidine]-2l- carboxamide;
N -[[4-fluoro-2-(liϊ-l,2,4-triazol-l-yl)plienyl]methyl]-7l,8t-dihydro-3t- hydroxy-4'-oxo-spiro[cyclobutane-l,9'(6'H)-[4Jjr|pyrido[l,2-α]pyrimidine]-2'- carboxamide;
N -[[4-fluoro-2-(tetrahydro- 1 , 1 -dioxido-2H-l ,2-thiazin-2-yl)phenyl]methyl]- 7',8'-dihydro-3l-liydroxy-4'-oxo-spiro[cyclobutane-l,9l(6l/i)-[4Ji]pyrido[l,2- α]pyrimidine]-2'-carboxamide;
N -[[2-(1H-l,2,4-triazol-l-yl)phenyl]methyl]-7t,8l-dib.ydro-31-liydroxy-4l-oxo- spiro[cyclobutane- 1 ,9'(6H)-[4H]pyrido[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N -[[4-fluoro-2-(methylsulfonyl)ρhenyl]methyl]-7',8'-diliydro-31-hydroxy-4l- oxo-spirofcyclobutane-ljθXθ'/^-^J^pyridotl^-αJpyrimidineJ^'-carboxamide; N-[[2-[(dimethylamino)sulfonyl]-4-fluoroρhenyl]methyl]-7t,8'-dihydro-3'- hydroxy^'-oxo-spirotcyclobutane-l^Xό'i^-^HJpyridotl^-αJpyrimidine]^'- carboxamide;
7',8t-diliydro-3'-liydroxy-4l-oxo-iV-[[2-(tetrahydro-l,l-dioxido-2Jf-l,2-thiazin-
2-yl)phenyl]methyl]-spko[cyclobutane-l,9X6'i^-[4/<lpyrido[l,2-α]pyrimidine]-2'- carboxamide;
iV-[(4-fluorophenyl)methyl]-6',7'-dihydro-3'-hydroxy-4t-oxo- spko[cyclopentane-l,8X4'iϊ)-pyrrolo[l,2-α]pyrimidine]-2t-carboxaiiiide;
7V-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6t 57t-dihydro-3t-hydroxy-4t- oxo-spiro[cyclopentane- 1 ,8'(4Η)-pyrrolo[ 1 ,2-α]pyrimidine]-2'-carboxamide;
N-[[2-[(dimethylamiiio)sulfonyl]-4-fluorophenyl3methyl]-6!,7'-dihydro-3 '- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,8'(4Η)-pyrrolo[ 1 ,2-α]pyrimidine]-2'- carboxamide;
iV-[[4-fluoro-2-(lH'-l,2,4-triazol-l-yl)phenyl]methyl]-61,7I-diliydro-3'- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,8'(4'H)-pyrrolo[ 1 ,2-α]pyrimidine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-2,3,5,6,7',81-hexahydro-3'-liydroxy-4l-oxo- spiro[4H-pyran-4,9'(6'H)-[4H]pyrido[l,2-a]pyrimidine]-2'-carboxamide;
N-(phenylmethyl)-6',7'-dihydro-3 '-hydroxy-4'-oxo- spiro[cyclopentane- 1 ,9'(4'H)-pyriinido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
N-[(4-fluorophenyl)methyl]-6',7'-dib.ydro-3'-hydroxy-4'-oxo- spiro[cyclopentane-l,9'(4'H)-pyriinido[2,l-c][l,4]oxazme]-2t-carboxamide;
N-[(4-fluoro-3-methylphenyl)methyl]-6!,7l-dihydro-3'-hydroxy-4'-oxo- spiro[cyclopentane-l,9'(4'H)-pyriπiido[2,l-c][l,4]oxazine]-2'-carboxamide; N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7'-dihydro-3!- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4] oxazine]-2'- carboxamide;
N-[[4-fluoro-2-(methylthio)pheiiyl]methyl]-6!,7'-dihydro-3'-hydroxy-4t-oxo- spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
6',7'-dihydro-3'-hydroxy-N-[(4-methylphenyl)methyl]-4'-oxo- spiro[cyclopentane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine] -2'-carboxamide;
N-[(4-chlorophenyl)methyl]-6',7'-dihydro-3'-hydroxy-4'-oxo- spiro[cyclopentane-l,9'(4'H)-pyriinido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-tCS^-dichloropheny^methylj-ό'^'-dihydro-S'-hydroxy^'-oxo- spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine]-2'-carboxamide;
N-tCS^-dimethylpheny^methylJ-ό'J'-diliydro-S'-hydroxy^'-oxo- spiro[cyclopentane-l,9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
6l,7'-dihydro-3'-hydroxy-N-[(4-methoxyplienyl)metliyl]-4t-oxo- spiro[cyclopentane-l,9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-[(2-fluorophenyl)methyl]-6',7'-dihydro-3'-hydroxy-4'-oxo- spiro[cyclopentane-l ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2l-carboxamide;
N-[(2,4-dimethoxyphenyl)methyl] -6',7'-dihydro-3 '-hydroxy-4'-oxo- spiro[cyclopentane-l ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
N-[(3-fluorophenyl)methyl]-6',7t-dihydro-3'-hydroxy-4'-oxo- spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'-carboxamide;
N-[(3-fluoro-4-methylphenyl)methyl]-6',7'-dihydro-3'-hydroxy-4'-oxo- spiro[cyclopentane-l ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide; N-[[(2-(dimethylamino)sulfonyl]-4-fluorophenyl)methyl]-6',7'-dihydro-3!- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4Joxazine]-2'- carboxamide;
iV-ttS-fluoro^-ClH-l^^-triazol-l-yOphenyljmethylJ-ό'J'-dihydro-S'- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine]-2'- carboxamide;
N-[2-(4-fluorophenyl)ethyl]-6',7!-dihydro-3'-hydroxy-4!-oxo- spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
7V-[3-(4-fluorophenyl)propyl]-6',7l-dihydro-3!-liydroxy-4'-oxo- spiro[cyclopentane-l ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-l/i-l,2,4-triazol-l-yl)phenyl3methyl]-6t,7'-dihydro-
3 '-hydroxy-4'-oxo-spiro [cyclopentane- 1 ,9'(4Η)-pyrimido [2, 1 -c] [ 1 ,4] oxazine] -T- carboxamide;
6t,71-dihydro-3'-hydroxy-4t-oxo-iV-[[2-(lH-l,2,4-triazol-l-yl)plienyl]metliyl]- spiro [cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
iV-[[4-fluoro-2-(tetrahydro-l,l-dioxido-2/f-l,2-thiazin-2-yl)plienyl]niethyl]-
6l,7'-dihydro-3'-hydroxy-4'-oxo-spiro[cyclopentane-l,9'(41H)-pyrimido[2,l- c] [ 1 ,4] oxazine] -2'-carboxamide;
6'57'-dihydro-3!-hydroxy-4'-oxo-iV-[[2-(tetrab.ydro-l,l-dioxido-2H-l,2-tliiazin- 2-yl)phenyl]methyl]-spiro[cyclopentane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-455,6',7'-tetrahydro-3'-hydroxy-4'-oxo- spiro[furan-3(2H),9'(4Η)-pyriinido[2,l-c][l,4]oxazine]-2'-carboxamide; N-[(4-fluoro-3-methylphenyl)methyl]-4,5,6',7'-tetraliydro-3'-liydroxy-4'-oxo- spiro[furan-3(2H),9'(4'H)-pyrimido[2,l-c][l,4]oxaziiie]-2'-carboxainide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl3-4,5,6',7'-tetrahydro-3'- hydroxy-4l-oxo-spiro[furan-3(2H),9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'- carboxamide;
N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,5,6',7'-tetrahydro-3'-hydroxy-4!- oxo-spiro[furan-3(2H),9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
N-[(4-fluorophenyl)methyl]-2,3,5,6,6',7'-hexahydro-3'-hydroxy-4t-oxo- spiro[4H-pyran-4,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-f^-fluoro^-ClH-l^^-triazol-l-yOphenylJmethyl]2,3,5,6,6',7'- hexahydro- 3'-hydroxy-4'-oxo-spiro[4H-pyran-4,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'- carboxamide;
N -[[4-fluoro-2-(tetrahydro- 1 , 1 -dioxido-2H- 1 ,2-thiazin-2-yl)phenyl]methyl]- 2,3,5,6,6t,7l-hexahydro-3'-hydroxy-4!-oxo-spiro[4H-pyran-4,9'(4'H)-pyrimido[2,l- c][l,4]oxazine]-2'-carboxamide;
N -[[2-(tetrahydro-l,l-dioxido-2H-l,2-thiazin-2-yl)phenyl]methyl]- 2,3,5,6,6^7t-hexahydro-3t-hydroxy-4t-oxo-spiro[4H-pyran-4,9'(4'H)-pyrimido[2,l- c] [ 1 ,4]oxazine]-2'-carboxamide;
N -[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,6t,7t-hexahydro-3l- hydroxy-4l-oxo-spiro[4H- pyran-4,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -T- carboxamide;
N -[(4-fluoro-3-methylphenyl)methyl]-2,3,5,6,6t,7'-hexahydro-3t-hydroxy-4'- oxo-spiro[4H-pyran-4,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine]-2'-carboxamide; N-[(l^-dimethoxyphenyOmethyll-l^^^^'J'-hexahyclro-3'-liydroxy^'-oxo- spiro[4//-pyran-4,9'(4'H)-pyrimido[2, 1 -c][ 1 ,4]oxazine]-2'-carboxamide;
1,9'(6'H)-1,9'(6'H)-NN-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-2,3,5,6,6',7'- hexahydro-3'-hydroxy-4'-oxo-spiro[4H-pyran-4,9'(4tH)-pyrimido[2,l- c] [ 1 ,4] oxazine]-2'-carboxamide
N-[(3,4-dimethylphenyl)methyl]-2,3,5,6,6t,7'-hexahydro-3'-liydroxy-4l-oxo- spiro[4H-pyran-4,9'(4'ijH)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
iV-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-2,3,5,6,6t,7I- hexahydro-3l- hydroxy-4'-oxo-spiro[4iϊ-pyran-4,9'(4'H)-pyrimido[2, 1 - c] [ 1 ,4] oxazine]-2'-carboxamide ;
N- [[4-fluoro-2-(3-metliyl-lH-l,2,4-triazol-l-yl)plienyl3metliyl]-2,3,5,6,6',7'- hexahydro-3'-hydroxy-4'-oxo-spiro[4H-pyran-4,9'(4'H)-pyrimido[2,l- c][l,4]oxazine]-2'-carboxamide;
N-[μ-fluoro-2-(1H- 1,2,4-triazol-l-y^phenyllmethyll-ό'J'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane-l ,9'(4Η)-ρyrimido[2, 1 -c] [ 1 ,4] oxazine] -2- carboxamide;
N-[(4-fluorophenyl)methyl]-6',7'-dihydro-3l-hydroxy-4'-oxo- spiro[cyclobutane-l,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6',71-dihydro-3'-hydroxy-4'- oxo-spiro[cyclobutane-l,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxainide;
N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-6',7'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane-l,9'(4'H)-pyrimido[2,l-c][1,4]oxazine]-2'- carboxamide; iV-[[4-fluoro-2-(tetrahydro-l,l-dioxido-2H-l,2-thiazin-2-yl)phenyl]methyl]- 6^7l-dihydro-3'-hydroxy-4'-oxo-spiro[cyclobutane-l,9l(4'H)-pyrimido[2,l- c] [ 1 A] oxazine] -2'-carboxamide;
7V-[[2-(tetrahydro-l,l-dioxido-2H-l,2-thiazin-2-yl)phenyl]metliyl]-6',7'- dihydro-3 '-hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] - 2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7t-dihydro- 3'-hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'- carboxamide;
N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-7',8'-dihydro-3'-hydroxy-4t- oxo-spiro[cyclobutane- 1 , 10'(4'H)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-7',8'-diliydro-3'-hydroxy-4'-oxo- spiro[cyclobutane-l,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7t,8'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane- 1 , 10'(4'H)-[6H]pyrimido[2, 1 -c] [1 ,4]oxazepine]-2'- carboxamide;
N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-7',8'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane-l , 10'(4Η)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepine]-2'- carboxamide;
7V-[(4-fluorophenyl)methyl]-6',7l-diliydro-3l-hydroxy-4l-oxo-spiro[piperidine- 4,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'-carboxamide
N-[[4-fluoro-2-(methylsulfonyl)ρhenyl]methyl]-6',7!-diliydro-3'-hydroxy-4'- oxo-spiro[cyclopentane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide; N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,5,6l,7'-tetrahydro-3'- hydroxy-4t-oxo-spiro[furan-3(2H),9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-21- carboxamide; and
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-6',7'-dihydro-3l- hydroxy-4'-oxo-spiro[cyclobutane-l,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'- carboxamide;
and salts and solvates of these compounds.
Some other compounds of Formula I include
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-8'-methyl-4'-oxo- spiro[cyclopentane- 1 ,9'(6'H)-[4H]pyrazmo[ 1 ,2-a]pyrimidine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3'- hydroxy-8'-metliyl-4'-oxo-spiro[cyclopentane-l,9'(6Η)-[4H]pyrazino[l,2- a]pyrimidine]-2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7t,8'-dihydro-
3!-hydroxy-8l-metliyl-4'-oxo-spiro[cyclopentane-l,9'(6'H)-[4H]pyrazino[l,2- a]pyrimidine]-2'-carboxamide;
N-[(4-fluorophenyl)methyl]-7l,8'-dihydro-3'-hydroxy-8t-methyl-4'-oxo- spiro[cyclohexane- 1 ,9'(6Η)-[4H]pyrazino[ 1 ,2-a]pyrimidine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7t,8'-dihydro-3l- hydroxy-8'-methyl-4'-oxo-spiro[cyclohexane- 1 ,9'(6Η)-[4H]pyrazino[ 1 ,2- ajpyrimidine] -2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro- 3'-hydroxy-8'-methyl-4'-oxo-spiro[cyclohexane-l,9l(6Η)-[4H]pyrazino[l,2- a]pyrimidine]-2'-carboxamide; N-[(4-fluorophenyl)methyl]-7t,8t-dihydro-3'-hydroxy-8'-methyl-4'-oxo- spkofcyclobutane-l^Xό^-^Hjpyrazinotl^-aJpyrimidineJ-l'-carboxamide;
N-[[4-fluoro-2-(lH-l52,4-triazol-l-yl)phenyl]methyl]-7',8!-diliydro-3'- hydroxy-8'-methyl-4'-oxo-spiro[cyclobutane-l,9t(6'H)-[4H]pyrazino[l,2- a]pyrimidine] -2'-carboxamide;
N-[[4-fluoro-2-(5-metliyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dUiydro- 3'-hydroxy-8'-methyl-4'-oxo-spiro[cyclobutane-l,9'(6'H)-[4H]pyrazino[l,2- a]pyrimidine]-2'-carboxamide;
N-Cμ-fluoro^-ClH-l^^-triazol-l-yOphenyηmethylj-β'J'-dihydro-S'- hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -T- carboxamide;
N-[[2-(4,5-dimethyl-lH-l,2,3-triazol-l-yl)-4-fluorophenyl]methyl]-6',71- dihydro-3'-hydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 - c] [ 1 ,4] oxazine] -2'-carboxamide;
N-[[2-[4-(l , 1 -dimethylethyl)- 1 H- 1 ,2,3-triazol- 1 -yl]-4-fluorophenyl]methyl]-
6',7'-dilαydro-3 '-hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 - c] [ 1 ,4] oxazine] -2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,2,3-triazol-l-yl)plienyl]methyl]-6',7'-dihydro- 3'-hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'- carboxamide;
N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-6':>7'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'- carboxamide;
N-[[4-fluoro-2-(2-oxo-l-azetidinyl)phenyl]methyl]-6',7'-diliydro-3'-hydroxy- 4'-oxo-spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide; N-[[2-(4,5-dimethyl-lH-l,2,3-triazol-l-yl)-4-fluorophenyl]methyl]-7t,8'- dihydro-3'-hydroxy-4'-oxo-spiro[cyclobutane-l,10'(4Η)-[6H]pyrimido[2,l- c] [1 ,4]oxazepine]-2'-carboxamide;
N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7'-diliydro-
3'-hydroxy-4'-oxo-spiro[oxetane-3,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-6l,7'-dihydro-3t-hydroxy-4t-oxo-spiro[oxetane- 3,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7'-dihydro-3'- hydroxy-4'-oxo-spiro[oxetane-3,9'(4'H)-pyrimido[2,l-c][l,4]oxazme]-2'- carboxamide;
N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6',7'-dihydro-3'-hydroxy-4'- oxo-spiro[oxetane-3,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-tμ-fluoro^-ClH-l^^-triazol-l-yOphenyηmethyl]-2,3,5,6,6',7'-hexahydro- 3l-hydroxy-4'-oxo-spiro[4H-ρyran-4,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'- carboxamide;
N-t^-fluoro^-ClH-l^^-triazol-l-yOphenyηmethyll-ό'J'-dihydro-S'- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-2,3,5,6,7',8t-hexahydro-3'- hydroxy-4'-oxo- spiro[4H-pyran-4, 10'(4'H)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepine]-2'-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-2,3,5,6,7',8'- hexahydro-3l-liydroxy-4l-oxo-spiro[4H-pyran-4,10!(4Η)-[6H]pyrimido[2,l- c] [ 1 ,4] oxazepine]-2'-carboxamide; N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,7',8'-hexahydro-3'- hydroxy-4'-oxo-spiro[4H-pyran-4, 10'(4Η)-[6H]pyriinido[2, 1 -c] [1 ,4] oxazepine] -2'- carboxamide;
[5-fluoro-2-[[[(2,3,5,6,7',8'-hexahydro-3'-liydroxy-4'-oxospiro[4H-pyran-
4, 10'(4'H)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepin]-2'-yl)carbonyl]amino]metliyl]phenyl]- phosphonic acid, dimethyl ester;
N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methy]-2,3,5,6,7',8'-hexahydro- 3'-hydroxy-4'-oxo-spiro[4H-pyran-4, 10'(4'H)-[6H]pyrimido[2, 1 -c] [ 1 ,4] oxazepine] -2'- carboxamide;
N-C^-fluoro^-CS-methyl-lH-l^^-triazol-l-yOphenyηmethylJ^^^^,?'^1- hexahydro-3'-hydroxy-4'-oxo-spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l- c] [ 1 ,4]oxazepine]-2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-2,3,5,6,7',8'- hexahydro-3'-hydroxy-4'-oxo-spiro[4H-pyran-4,10'(4Η)-[6H]pyrimido[2,l- c] [ 1 ,4] oxazepine] -2'-carboxamide;
2,3,5,6,7t,8t-hexahydro-3'-hydroxy-N-[[2-(3-methyl-lH-l,2,4-triazol-l- yl)phenyl]methyl]-4'-oxo-spiro[4H-pyran-4, 10'(4Η)-[6H]pyrimido[2, 1 - c] [ 1 ,4]oxazepine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl]methyl]-2,3,5,6,7',8'-hexahydro-
3'-hydroxy-4'-oxo-spiro[4H-pyran-4, 10'(4Η)-[6H]pyrimido[2, 1 -c] [ 1 ,4] oxazepine] -2'- carboxamide;
N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8l-dihydro- 3 '-hydroxy-4'-oxo-spiro [cyclobutane- 1 , 10'(4'H)- [ 6H]pyrimido [2, 1 -c] [ 1 ,4] oxazepine] - 2'-carboxamide; N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7t-dihydro- 3 '-hydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -T- carboxaniide;
6',7'-dihydro-3'-liydroxy-4'-oxo-N-[[2-(2-oxo-l-azetidinyl)plienyl]metliyl]- spiro[cyclobutane-l,9l(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxaniide;
6',7l-dihydro-3'-hydroxy-4l-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]metb.yl]- spiro[cyclobutane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'-carboxamide;
N-[[2-(3 ,5-dimethyl- 1 H- 1 ,2,4-triazol- 1 -yl)-4-fluorophenyl]methyl]-6',7'- dihydro-3l-hydroxy-4'-oxo-spiro[cyclobutane-l,9'(4'H)-pyriinido[2,l-c][l,4]oxazine]- 2'-carboxamide;
N-[[2-(3 ,5-dimethyl- 1 H- 1 ,2,4-triazol- 1 -yl)-4-fluorophenyl]methyl]-7',8 '- dihydro-3'-hydroxy-4'-oxo-spiro[cyclobutane-l,10'(4Η)-[6H]pyrimido[2,l- c] [ 1 ,4] oxazepine] -2'-carboxamide;
N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6t,7l-dihydro- 3'-hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -T- carboxamide;
N-[[2-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-4-fluoroρhenyl]methyl]-6t,7t- dihydro-3'-hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4Η)-pyrimido[2, 1 - c][l,4]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3l- hydroxy-4'-oxo-spiro[cyclobutane-l,9'(6Η)-[4H]pyrazino[l,2-a]pyrimidine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(6Η)-[4H]pyrazino[ 1 ,2-a]pyrimidine]-2'-carboxamide; and pharmaceutically acceptable salts and solvates of these compounds.
"Alkyl," "alkoxy," "haloalkyl," and related terms for other hydrocarbon and substituted hydrocarbon substituents include straight and branched isomeric configurations. A term such as "C1-6(R)alkyl" means a straight or branched alkyl group of 1 to 6 carbons substituted with the substituent R. "Haloalkyl" and related terms for halogenated substituents include all permutations of halogenation, from monohaloalkyl to perhaloalkyl. "Aryl" means an aromatic ring system and includes carbocyclic and heterocyclic systems. Some substituents are divalent, for example, X-Y-Z. Divalent substituents which are asymmetric can be attached to the parent molecule in either of the configurations.
;'Dioxothiazinyl" means
Figure imgf000023_0001
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.
The invention also includes all solvated forms of the compounds, particularly hydrates. Solvates do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents.
Solvates may form in stoichiometric amounts or may form from adventitious solvent or a combination of both. One type of solvate is hydrate, and some hydrated forms include monohydrate, hemiliydrate, and dihydrate.
The invention includes all tautomeric forms of the compounds. An example of a tautomeric pair is shown below.
Figure imgf000024_0001
Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. An example of enantiomers is shown below. Methods of making and separating stereoisomers are known in the art.
Figure imgf000024_0002
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 schemes (for example, X, n, and P) are separate 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. "X" and "n" include alkylene spacers which may contain ether or amino functionalities. "P" may include an appropriate protecting group. Starting materials can be made using methods known in the art. Scheme 1.
Figure imgf000025_0001
Figure imgf000025_0002
Scheme 2.
Figure imgf000025_0003
Figure imgf000025_0004
Scheme 3.
Figure imgf000026_0001
Scheme 4.
Figure imgf000026_0002
Biological Methods
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 niM. Samples were counted in TopCountNXT (Packard) and the CPM was used as a measure of integration. The reaction condition was as described in Engelman, A. and Craigie, R. J. Virol. 1995, 69, 5908. The sequences of substrate and target DNA were described in Nucleic Acid Research 1994, 22, 1121. Using this assay, the compounds of this invention were found to have an ICs0 from less than 0.1 μM (see Tables 1 and Ia).
Table
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Activity. A: 0.001-0.01 μM; B: 0.01-0.1 μM.
Table Ia. HIV Integrase Inhibition
Figure imgf000029_0002
Figure imgf000030_0001
Activity. A: 0.001-0.01 μM; B: 0.01-0.1 μM Pharmaceutical Composition and Methods of Use
The compounds of this invention inhibit HIV integrase. HIV integrase inhibitors have been reported to prevent viral integration and inhibited HIV-I replication in cells (Hazuda et al. Science 2000, 257, 646). Recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Then 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 patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
Another aspect of the invention is a method for treating HIV infection in a patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate 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 comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
"Combination," "coadministration," "concurrent," and similar terms referring to the administration of compounds 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 exipients. 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 rng/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 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 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 2 lists some agents useful in treating AIDS and HIV infection which are suitable for this method.
Table 2. ANTΓVIRALS
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
P 58646
34
Figure imgf000036_0001
Figure imgf000037_0001
IMMUNOMODULATORS
Figure imgf000037_0002
Figure imgf000038_0001
ANTI-ΓNFECTIVES
Figure imgf000038_0002
Figure imgf000039_0002
DESCRIPTION OF SPECIFIC EMBODIMENTS
Intermediate 1
Figure imgf000039_0001
l-(3-chloropropyl)cyclopentanecarbonitrile. To a stirred solution of cyclopentanecarbonitrile (1.04 mL, 10 mmol) in THF (20 mL) at -78 °C was added LiHMDS (IM in THF, 11 mL) via syringe. After 30 min, l-chloro-3-iodopropane (1.6 mL, 15 mmol) was added at once and slowly warmed to room temperature. After 20 h, the reaction mixture was quenched with saturated ammonium chloride (1 mL), diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated to give intermediate 1 as yellow oil which was used in the next step without further purification.
Intermediate 2
Figure imgf000040_0001
To a stirred mixture of intermediate 1 from previous experiment and hydroxylamine hydrochloride (1.39 g, 20 mmol) in 1:1 EtOH/water (30 mL) was added sodium carbonate (1.6 g, 15 mmol) over 5 min. Then, the reaction mixture was stirred to 80 0C for 15 h and concentrated to dryness. The resulting white residue was re-dissolved into 1:1 EtOH/water (30 mL) and diethyl acetylenedicarboxylate (2.4 mL, 15 mmol) was added. After Ih, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 X 50 mL). The combined EtOAc extracts dried (Na2SO4), filtered and concentrated to give brown oil. Flash chromatography using 9:1, 4:1 and 7:1 Hexanes/EtOAc mixtures afforded intermediate 2 as pale yellow oil (1.03 g, 30%). 1H NMR (500 MHz, CDCl3) δ: 4.34- 4.11 (4H, m), 3.50-3.46 (IH, m), 3.38-3.34 (IH, m), 3.31 (IH, d, J = 16.2 Hz), 2.91 (IH, d, J = 16.2 Hz), 2.23-2.13 (2H, m), 1.95-1.89 (2H, m), 1.74-1.69 (2H, m), 1.62 (2H, t, J = 5.9 Hz), 1.54-1.48 (2H, m), 1.34-1.23 (8H, m). HRMS (M+H) calcd for C17H27N2O5: 339.1920; found: 339.1923. Intermediate 3
Figure imgf000041_0001
A solution of intermediate 2 (1.0 g, 2.955 mmol) in 3, 4-dichlorotoluene (10 mL) was heated at 210 0C for 15 h. Then, the reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC using MeOH/water containing 0.1% TFA (gradient elution). The fractions containing the product were combined and concentrated to afford intermediate 3 as a dark paste (0.8639 g, 28.6%). 1H NMR (500 MHz, CDCl3) 6: 10.75 (IH, br s), 4.43 (2H5 q, J = 7.0 Hz), 4.03 (2H, t, J = 5.8 Hz), 2.25-2.20 (2H, m), 1.99-1.93 (4H3 m), 1.79-1.64 (6H, m), 1.42 (3H, t, J = 7.0 Hz), . HRMS (M+H) calcd for C15H2jN2O4: 293.1501; found: 293.1513.
Intermediate 4
Figure imgf000041_0002
Tetrahydro~2H-pyran-4-carbonitrile. A solution of tetrahydro-4Hr-pyran-4- one (25 g, 250 mmol) and toluenesulfonylmethyl cyanide (53.7 g, 275 mmol) dissolved in ethylene glycol dimethylether (1 L) was cooled to 0 °C. Added dropwise over 30 min was a solution of potassium t-butoxide (56 g, 500 mmol) dissolved in t-butanol (350 mL) and ethylene glycol dimethylether (150 mL). After stirring the resulting mixture for 3 h at room temp, diethyl ether (1 L) was added and the organic phase was washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4) and concentrated. The residue was distilled at 39 °C 1.7 mm Hg to give the title compound as a colorless oil (10.87 g, 39% yield). 1H NMR (300 MHz, CDCl3) δ: 3.91-3.83 (2H, m), 3.61-3.54 (2H, m), 2.89-2.80 (IH, m), 1.97-1.78 (4H, m).
Intermediate 5
Figure imgf000042_0001
4-(3~chloropropyl)-tetrahydro-2H-pyran-4-carbonitrile. To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at -78 0C was added dropwise a solution of intermediate 4 (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, l-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at -78 °C for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the product intermediate 5 as a colorless liquid (3.737 g, 99%). 1H NMR (500 MHz, CDCl3) δ: 3.97 (2H, dd, J = 11.3, 3.7 Hz), 3.71 (2H, td, J = 12.2, 1.8 Hz), 3.61 (2H, t, J = 6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J = 13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m).
Intermediate 6
Figure imgf000042_0002
A mixture of intermediate 5 (1.83 "g, 9.75 mmol) and NaI (3.0 g, 20 mmol) was stirred at ambient temperature for Ih. To this reaction mixture was added 50% aqueous hydroxylamine (1 mL, 10.87 mmol mmol) and stirred for three-days at ambient temperature. To this was added diethyl acetylenedicarboxylate (1.6 mL, 10 mmol) and stirred for 1 h. Then, the reaction mixture was diluted with EtOAc (100 mL) washed with water (50 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow oil. Flash chromatography using 10-50% EtOAc/Hexanes afforded the desired intermediate 6 as pale yellow oil (0.627 g, 18%%). 1H NMR (500 MHz, CDCl3) δ:. HRMS (M+H) calcd for C17H27N2O5:; found. 1E NMR (500 MHz, CDCl3) 5: 4.32-4.20 (2H, m), 4.14 (2H5 q, J = 7.0 Hz), 3.86 (IH, td, J = 11.0, 2.7 Hz), 3.79-3.70 (3H, m), 3.52-3.46 (IH, m), 3.38-3.34 (IH, m), 3.26 (IH, d, JAB = 16.2 Hz), 2.97 (IH, d, JAB = 16.2 Hz), 2.06-1.89 (4H, m), 1.66- 1.66 (2H, m), 1.60-1.53 (2H, m), 1.30 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.0 Hz).
Intermediate 7
Figure imgf000043_0001
A solution of intermediate 6 (1.0 g, 2.955 mmol) in cyclohexylbenzene (25 mL) was heated at 200 °C for 15 h. Then, the reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC using MeOH/water containing 0.1% TFA (gradient elution). The fractions containing the product were combined and concentrated to afford intermediate 7 as an off-white solid (0.1263 g, 23%). 1H NMR (500 MHz, CDCl3) δ: 10.35 (IH, br s), 4.45 (2H, q, J = 7.0 Hz), 4.09- 4.05 (2H, m), 4.01-3.99 (2H, m), 3.74-3.69 (2H, m), 2.35-2.29 (2H, m), 2.02-1.93 (4H, m), 1.59-1.54 (2H, m), 1.44 (3H, t, J = 7.0 Hz). HRMS (M+H) calcd for C15H21N2O4: 309.1451; found: 309.1463. Intermediate 8
Figure imgf000044_0001
(E)-2-{[l-(2-Hydroxyethoxy)cyclopentanecarboximidoyl]-aminooxy}but-2- enedioic acid diethyl ester. A stirred mixture of cyclopentanone ethylene ketal
(12.82 g, 100 mmol) and ZnI2 (45 mg, catalytic) was placed in water bath and to this was added trimethylsilyl cyanide (13.35 mL, 100 mmol) via syringe over 10 min. After 16 h, EtOH (100 mL) followed by 50% aqueous hydroxylamine (6.43 mL, 100 mmol) was added and stirred at 80 0C for 2 h. Then, the reaction mixture was cooled in ice-water bath and diethyl acetylenedicarboxylate (16 mL, 100 mmol) was added over 5 min. Then, cooled bath removed, stirred for 4 h at room temperature and concentrated to give intermediate 8 as a dark-brown oil which was used in the next step without purification. LRMS (M+H) calcd for C16H27N2O7: 359.2; found: 359.2.
Intermediate 9
Figure imgf000044_0002
5-Hydroxy-2-[3-(2-hydroxy-ethoxy)tetrahydrofuran-3-yl] -6-oxo-l, 6- dϊhydropyrimidine-4-carboxylic acid ethyl ester. A xylenes (200 ml) solution of crude intermediate 8 (100 mmol) was heated at reflux for 24 h, cooled and concentrated. The resulting dark-residue was stirred with 0.5 M Na2CO3 (150 mL) for 30 min and extracted with EtOAc (3 X 50 mL). The combined organic phases were re-extracted with 0.5 M Na2CO3 (50 mL) and EtOAc extracts discarded. The combined aqueous layers was carefully acidified with cone. HCl (20 rnL) and extracted with CH2Cl2 (4 X 50 ml). The combined CH2Cl2 layers dried (Na2Sθ4/actvated charcoal), filtered and concentrated to give brown solid which triturated with ether and filtered to afford intermediate 9 as a light brown powder (11.81 g, 38%). This material is contaminated with about 15% of an identified impurity whose M+l = 295. LRMS (M+H) calcd for C14H21N2O6: 313.32; found: 313.27.
Intermediate 10
Figure imgf000045_0001
To a stirred solution of crude intermediate 9 (11.67 g) in THF (100 mL) at 5 °C was added MsCl (8.7 mL, 112.4 mmol) followed by Et3N (15.8 mL, 112.5 mmol). The resulting turbid reaction mixture was stirred for 4 h while allowing it to warm to room temperature. Then diluted with EtOAc (200 mL), washed with water (2 X 50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to give viscous yellow oil. This oil was re-dissolved in anhydrous EtOH (100 mL) and stirred with K2CO3 (4.15 g, 30 mmol). After 4 h, the viscous slurry was diluted with EtOAc (150 mL) and continued stirring for additional 1 h. Then, the reaction mixture was filtered and concentrated to give white solid which was triturated with ether, and filtered to afford intermediate 10 as a white fluffy solid (8.284 g, 64%). 1H NMR (500 MHz, CDCl3) δ: 4.43 (2H, q, J = 7.0 Hz), 3.99 (4H, s), 3.53 (3H, s), 2.33- 2.28 (2H, m), 2.09-2.05 (2H, m), 1.93-1.82 (4H, m), 1.40 (3H, U = 7.0 Hz). HRMS (M+H) calcd for C15H21N2O7S: 373.1069; found: 373.1053. Intermediate 11
Figure imgf000046_0001
To a stirred suspension of intermediate 10 (0.6861 g, 1.84 mmol) in THF (50 mL) was added IM EtONaZEtOH (IO mL). After Ih, the resulting yellow solution was concentrated, acidified with 1 M aq. HCl (20 mL), extracted with CH2Cl2 (3 X 35 mL). The combined organic layers dried (Na2SO4), filtered and concentrated to give intermediate 11 as a brown solid (0.4668 g, 86%). 1H NMR (500 MHz, CDCl3) δ: 10.49 (IH, s), 4.44 (2H, q, J = 7.0 Hz), 4.03-3.97 (4H, m), 2.28-2.22 (2H, m), 2.06-2.01 (2H, m), 1.93-1.81 (4H, m), 1.42 (3H, t, J = 7.0 Hz). HRMS (M+H) calcd for C14Hi9N2O5: 295.1294; found: 295.1293.
Intermediate 12
Figure imgf000046_0002
Dihydrofuran-3(2H)-one . A mixture of 3-hydroxyfuran (24 g, 272 mmol) and TEMPO (0.86 g, 5.5 mmol) in CH2Cl2 (175 mL) and KBr (7.141 g, 60 mmol) in water was vigorously stirred and cooled in an ice- water bath. The pH of NaOCl (commercial grade bleach, 600 mL, 806 mmol) was adjusted to 9.5 by dissolving NaHCO3 (8.632 g, 102.75 mmol) immediately before use. This NaOCl solution was added over 40 min while keeping the internal temperature of the reaction mixture between 0 0C and 5 °C. After 2 h, the greenish-yellow organic phase was separated and aqueous phase was saturated with NaCl and extracted with CH2Cl2 (4 X 100 mL). The combined organic phases was washed with 10% HCl aq. (1 X 300 mL) containing KI (12 g) and 10% aq. Na2CO3 (2 X 150 mL). The organic layer dried (Na2SO4), filtered and concentrated to give intermediate 12 as a pale yellow liquid (15.79 g, 67%) which was used without purification. 1H NMR (500 MHz, CDCl3) δ: 4.24 (2H, t, J = 7.3 Hz), 3.86 (2H, s), 2.49 (2H, t, J = 7.3 Hz).
Intermediate 13
Figure imgf000047_0001
l,4, 7~Trioxaspiro[4.4]nonane. A mixture of intermediate 12 (15.79 g, 183.5 mmol), ethylene glycol (16.7 mL, 300 mmol) and cat. TsOH*H2O (100 mg) in benzene (100 mL) was heated at reflux using Dean-Stark trap. After 17 h, the reaction mixture was cooled, diluted with ether (150 mL), washed with sat. Na2CO3 and brine (50 mL each), dried (Na2SO4), filtered and concentrated to give yellow liquid. Distillation under reduced pressure afforded intermediate 13 as a yellow liquid (19.13 g, 80%). 1H NMR (500 MHz, CDCl3) δ: 3.9.4 (2H, t, J = 7.0 Hz), 3.94- 3.90 (4H, m), 3.68 (2H, s), 2.09 (2H, t, J = 7.0 Hz).
Intermediate 14
Figure imgf000047_0002
(E)-2-{[3-(2-Hydroxy-ethoxy)tetrahydrofuran-3-carboximidoyl]- aminooxy}but-2-enedioic acid diethyl ester. Prepared according to the procedure for intermediate 8. Yield: 38%; viscous yellow paste. 1H NMR (500 MHz, CDCl3) δ: 5.78 (IH, d, J = 7.6 Hz), 5.59 (IH, br s), 5.38 (IH, s), 4.37-4.27 (2H, m), 4.20-4.13 (2H, m), 4.03-3.87 (4H, m), 3.79-3.75 (2H, m), 3.53-3.45 (2H5 m), 1.60 (IH, br s), 1.38-1.23 (6H, m). HRMS (M+H) calcd for C15H25N2O8: 361.1611; found: 361.1620. Intermediate 15
Figure imgf000048_0001
Prepared according to the procedure for intermediate 11. Yield: 29%; brown solid. 1H NMR (500 MHz, CDCl3) δ: 10.63 (IH, br s), 4.44 (2H, q, J = 7.0 Hz), 4.18-4.11 (4H, m), 4.08-4.01 (4H, m), 2.66-2.60 (IH, m), 2.35-2.30 (IH, m), 1.41 (3H, t, J = 7.0 Hz). HRMS (M+H) calcd for C13H17N2O6: 297.1087; found: 297.1071.
Intermediate 16
Figure imgf000048_0002
1 ,4,8-Trioxa-spiro[4.5] decane. A mixture of tetrahydro-4-pyranone (10 g, 99.9 mmol), ethylene glycol (20 mL, 150 mmol) and catalytic toluene sulfonic acid was refluxed in benzene (120 mL) for 5 h. After cooling to room temp, the benzene layer was decanted from the dark oil in the bottom of the flask and was concentrated. The resulting oil was taken up in methylene chloride and shaken in a separatory funnel. The CH2Cl2 layer was decanted from the insoluble oil. The CH2Cl2 layer was concentrated to give the intermediate 16 as a pale yellow oil (11.62 g, 81% yield). 1H-NMR (300 MHz, CDCl3) 5: 3.91 (4H, s), 3.71 (4H, t, J= 5.5 Hz), 1.68 (4H, t, J= 5.7 Hz). Intermediate 17
Figure imgf000049_0001
(E^-2- {[4- (2-Hydroxyethoxy)tetrahydropyran-4-carboximidoyl]- aminooxyJbut-2-enedioic acid diethyl ester. Prepared according to the procedure for intermediate 8. Yield: 60%; yellow oil. 1H-NMR (300 MHz, CDCl3) δ: 5.72 (IH, d, J= 22.7 Hz), 5.50 (IH, bs), 5.29 (IH, bs), 4.33-4.23 (2H, m), 4.19-4.04 (2H, m), 3.95-3.87 (IH, m), 3.79-3.63 (6H, m), 3.43-3.39 (2H, m), 2.15-1.74 (4H, m), 1.35- 1.19 (6H, m). LCMS [M+H]+ calcd for C16H27N2O8: 375.17; found: 375.19.
Intermediate 18
Figure imgf000049_0002
5-Hydroxy-2-[4-(2-hydroxyethoxy)tetrahydropyran-4-yl] -6-oxo-l, 6- dihydropyrimidine-4-carboxylic acid ethyl ester. A solution of an intermediate 17 (9.3 g, 25 mmol) in xylenes (150 niL) was refluxed for 18 h. After cooling to room temp, the mixture was shaken with 0.2 M Na2CO3. The aqueous phase was washed with EtOAc, made acidic with conc'd HCl and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated. The resulting residue was triturated with ether to give the intermediate 18 as a brown solid (0.87 g, 10% yield) and impure product (2.36 g). LCMS [M+H]+ calcd for C14H21N2O7: 329.13; found: 329.15. Intermediate 19
Figure imgf000050_0001
A solution of intermediate 18 (0.86 g, 2.6 mmol) in THF (10 mL) was cooled to 0 °C. Added to this was methanesulfonyl chloride (0.613 mL, 7.9 mmol) followed by slow addition of triethylamine (1.07 mL, 7.9 mmol). The mixture stirred for 4 h while gradually warming to room temp, before diluting with EtOAc. The mixture was washed with water and brine and dried (Na2SO4) before concentrating to give a dark oil. This was dissolved in EtOH (20 mL) and THF (10 mL) and added potassium carbonate (0.56 g, 4.04 mmol). The mixture was stirred at room temp for 18 h, diluted with EtOAc (200 mL) and the solids were removed by filtration. The solution was concentrated and the residue was triturated with methanol. Filtration gave the intermediate 19 as a white solid (0.23 g, 23 %). 1H-NMR (300 MHz, CDCl3) 5: 4.41 (2H, q, J= 7.2 Hz), 4.03-3.98 (4H, m), 3.88-3.82 (2H, m), 3.74 (2H, t, J= 11.2 Hz), 3.50 (3H, s), 2.44 (2H, dt, J= 13.1, 4.9 Hz), 1.76 (2H, d, J= 13.9 Hz), 1.38 (3H, t, J= 7.1 Hz). LCMS [M+H]+ calcd for C15H2IN2O8S3: 389.10; found: 389.13.
Intermediate 20
Figure imgf000050_0002
l-Hydroxycyclobutanecarbonitrile. To a flask containing cyclobutanone (13.41 g, 191 mmol) was added a solution of potassium phosphate monobasic (29.10 g, 214 mmol) in water (50 mL), followed by a solution of sodium cyanide (10.39 g, 210 mmol) in water (50 mL), and the reaction was stirred for 16 hours. The reaction was treated with diethyl ether (100 mL) and stirred for 30 minutes. The separated aqueous layer was washed with ether (2 x 100 mL), and the combined extracts were concentrated to an oil. The oil was dissolved in dichloromethane, dried (sodium sulfate), filtered, and concentrated to give an amber oil (15.10 g), which contained approximately 15% of intermediate 20. The intermediate was used without further purification or treatment. 1H NMR (500 MHz, CDCl3) δ: 3.15 (IH, br s), 2.60 - 2.68 (2H, m), 2.29 - 2.38 (2H, m), 1.89 - 2.03 (2H, m).
Intermediate 21
Figure imgf000051_0001
l-(2-Ch!oroethoxy)cyclobutanecarbonitrile. Zinc chloride (36.03 g, 264 mmol) was fused using a propane torch while under vacuum. The molten zinc was cooled and the evacuated flask was flushed with nitrogen. The flask was loaded with intermediate 2 (15.10 g,) and 2-chloroethanol (17.7 g, 218 mmol) and stirred with heating (900C) for 20 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (1 x 150 mL, 4 x 100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to an oil in-vacuo. The crude product was purified by vacuum distillation (b.p.12 85°C) to give intermediate 21 (5.0Og, 31.3 mmol, 16.4% over two steps) as a clear liquid. 1H NMR (500 MHz, CDCl3) 5: 3.75 (2H, t, J=5.5 Hz), 3.65 (2H, t, J=5.6 Hz), 2.52 - 2.61 (2H, m), 2.31 - 2.43 (2H, m), 1.91 - 2.06 (2H, m).
Intermediate 22
Figure imgf000052_0001
A solution of intermediate 21 (2.64 g, 16.5 mmol) in ethanol (10 mL) was treated with a 50 weight-percent aqueous solution of hydroxylamine (3.34 g, 50 mmol), and stirred with heating (60 °C) for 16 hours. The solvent was removed in vacuo, and the residue was dried from ethanol- water (1:1, 10 mL) twice, to give as an oily solid. This was used immediately in the following step.
A cold (0 °C) solution of the above oily solid in. ethanol (5 mL) and water (10 mL) was treated with a solution of diethyl acetylenedicarboxylate (4.22 g, 25 mmol) in ethanol (50 mL). The reaction was stirred for 5 minutes, then warmed to room temperature, and stirred for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried (sodium sulfate), filtered, and concentrated in vacuo. The crude was partially purified by flash silica gel column chromatography, eluting with 10% to 35% ethyl acetate in hexanes. Product fractions were pooled and concentrated in vacuo to give intermediate 22 (2.58 g, 48%) as a yellow oil, which was used immediately in the following step. LC/MS [M+H]+ = 327.14.
Intermediate 23
Figure imgf000052_0002
A solution of intermediate 22 (2.51 g, 7.7 mmol) in 1,2,4-trimethyl benzene (25 niL) was heated at reflux (180 0C) for 3 hours, then cooled to room temperature. The solvent was removed in vacuo, and the crude was dissolved in ethyl acetate (75 mL) and extracted with a saturated aqueous solution of sodium bicarbonate (4 x 75 mL). The combined extracts were brought to pH 1-2 using 6N hydrochloric acid, and the resultant solid was extracted with ethyl acetate (4 x 50 mL). The combined extract was dried (sodium sulfate), filtered, and concentrated in vacuo to give intermediate 23 (0.235 g, 5.2% over two steps) as a brown solid. 1H NMR (500 MHz, CDCl3) δ: 10.54 (IH, s), 4.46 (2H, q, ./=7.1 Hz), 3.95 - 4.00 (4H, m), 2.67 - 2.74 (2H, m), 2.30 (2H, ddd, J=IlA, 9.9, 7.3 Hz), 2.09 - 2.19 (IH, m), 1.97 - 2.06 (IH, m), 1.44 (3H, t, J=7.2 Hz). LC/MS [M+H]+ = 281.11.
Alternative preparation of intermediate 23 from cyclobutanone.
Intermediate 24
Figure imgf000053_0001
5,8-Dioxa-spiro[3.4]octane. A solution of cyclobutanone (7.7 g, 0.11 mol), ethylene glycol (6.82 g, 0.11 mol) and p-toluenesulfonic acid mono hydrate (200 mg, 1 mmol) in benzene (200 mL) was heated at reflux with a Dean-Stark trap for 14 hrs. After cooling, the mixture was washed with aqueous sodium bicarbonate solution (saturated, 15 mL), then with brine and dried (magnesium sulfate), filtered and concentrated to obtain 9.37 g (82%) of intermediate 24 as a colorless liquid: 1H NMR (CDCl3, 500 MHz) δppm 3.87 (4H, s, CH2), 2.31 (4H, t, J = 8 Hz, CH2), 1.67 (2H, qt, J = 8 Hz, CH2); 13C NMR (CDCl3, 125.77 Hz) δ: 109.08 (C), 63.87 (CH2), 35.58 (CH2), 11.42 (CH2). Intermediate 25
Figure imgf000054_0001
2-{[l-(2-hydroxyethoxy)cyclobutanecarboximidoyl]-caninooxy}but-2-enedioic acid diethyl ester. To a mixture of intermediate 24 (5.70 g> 50 mmol) and trimethylsilyl cyanide (5.05 g, 50 mmol) was added a catalytic amount of ZnI2 (12 mg) in a cool water bath of ~10°C and the mixture stirred at room temperature for 5 hrs to obtain 10.7 g of l-(2-trimethylsilanyloxyethoxy)cyclobutanecarbonitrile as a mobile oil: 1H NMR (CDCl3, 500 MHz) δ: 3.75 (2H, t, J = 5 Hz, OCH2), 3.55 (2H, t, J = 5 Hz, OCH2), 2.51-2.56 (2H, m, CH2), 2.30-2.37 (2H, m, CH2), 1.91-1.98 (2H, m, CH2), 0.124 (9H, s, SiCH3); 13C NMR (CDCl3, 125.77 Hz) δppm 120.43 (CN), 72.05 (C), 67.71 (CH2), 61.49 (CH2), 34.02 (CH2), 12.91 (CH2), -0.29 (CH3). LC/MS m/z 142 (M+H-SiMe3).
A solution of l-(2-trimethylsilanyloxyethoxy)cyclobutanecarbonitrile (3.5 g,
16.4 mmol) and 50 % aqueous hydroxylamine (1.08 g, 16.4 mmol) in EtOH (16 mL) was stirred in an oil bath heated at 80°C for 2.5 hrs and then cooled to room temperature. To a solution was added drop-wise diethyl acetylenedicarboxylate (2.93 g, 17.2 mmol) in an ice-bath and the mixture stirred at room temperature for 5 hrs. This mixture was concentrated in vacuo to obtain 6.16 g of a crude brownish oil containing intermediate 25: 1H NMR (500 MHz, CDCl3) 6: 1.19-1.38 (6 H, m) 1.72- 1.86 (2 H, m) 2.06-2.24 (2 H, m) 2.29-2.49 (2 H, m) 3.26-3.38 (2 H, m) 3.65-3.76 (2 H, m) 4.11-4.19 (2 H, m) 4.24-4.38 (2 H, m) 5.67 (0.25 H, s) 5.85 (0.5 H, s). HRMS (M+H) calcd for C15H25N2O7 345.1662, found 345.1648. Intermediate 26
Figure imgf000055_0001
5-hydroxy-2-[l-(2-hydroxy-ethoxy)-cyclobutyl] -6-oxo-l, 6-dihydro- pyrimidine-4-carboxylic acid ethyl ester. A solution of a crude intermediate 25 (5.9 g) in xylenes (30 mL) was heated at 150-155 0C for 20 li. The mixture was concentrated in vacuo and the residue re-dissolved in EtOAc (30 mL) was extracted with IM aq. sodium carbonate solution (3x20 mL). The aqueous extracts were acidified with careful addition of concentrated HCl, and this mixture was extracted with CH2Cl2 (2x20 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated to obtain intermediate 26 (1.19 g, 24% over three steps) as brownish oil: LC/MS m/z 299 (M+H).
Intermediate 27
Figure imgf000055_0002
Ethyl 1 - (methylsulfonyl)-5- (methylsulfonyloxy)-2- (1 - (2-
(methylsulfonyloxy)ethoxy)cyclobutyl)-6-oxo-l,6-dihydropyrimidine-4-carboxylate (27): A cold (0°C) solution of intermediate 26 (7.23 g, 25 mmol) in anhydrous tetrahydrofuran was treated with methanesulfonylchloride (Aldrich) by dropwise addition. The solution was warmed to room temperature and stirred for 4 hrs. The reaction was concentrated in- vacuo, and the crude product was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution. The organic solution was dried (sodium sulfate), filtered to remove solids, and concentrated in vacuo to give intermediate 27 as a brown oil. This was used in the subsequent reaction without further purification. 1H NMR (500 MHz, CDCl3) δ:4.49 (2H, q, J= 7.0 Hz), 4.35-4.38 (2H, m), 3.93-4.00 (IH, m), 3.66-3.67 (3H, s), 3.62-3.65 (2H, m), 3.44-3.46 (3H, s), 3.05-3.07 (3H, s), 2.74-2.82 (IH, m), 2.60-2.67 (2H, m), 2.41-2.49 (2H, m). 1.43 (3H, t, J= 7.0 Hz). LCMS (M+H): 532.94.
Intermediate 28
Figure imgf000056_0001
To a solution of intermediate 27 obtained above in absolute ethanol (50 mL) and anhydrous tetrahydrofuran (75 mL) was added anhydrous potassium carbonate (3.46 g, 25 mmol), and the reaction was stirred with heating (65°C) for 20 hrs. Solvent was removed in- vacuo and the crude product was dissolved in water (150 mL) and extracted with ethyl acetate (2 x 100 mL). The aqueous layer was made acidic (pH ~ 1-2) using 6.0 N hydrochloric acid, and the resulting solid was extracted with ethyl acetate (2 x 75 mL). The combined extract was dried (sodium sulfate), filtered to remove solids, and concentrated to give intermediate 28 (4.30 g, 61%) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ: 10.57 (IH, s), 4.46 (2H, q, J= 7.2 Hz), 3.97 (4H, s), 2.67-2.73 (2H, m), 2.27-2.33 (2H, m), 2.10-2.18 (IH, m), 1.98-2.06 (IH, m), 1.44 (3H, t, J= 7.2 Hz). 13C NMR (126 MHz, CDCl3) δ: 169.56, 157.68, 150.41, 148.19, 125.24, 79.09, 62.63, 58.52, 42.66, 34.72, 14.18, 13.87; LC/MS (M+H): 281.13. Intermediate 29
Figure imgf000057_0001
Intermediate 29 was prepared (50% yield) according to the procedure for intermediate 24. 1H NMR (500 MHz, C6D6) 6: 3.49 (4H, t, J=5.5 Hz), 2.23 (4H, t, J=8 Hz), 1.63 (2H, qt, J=8 Hz), 1.24 (2H, qt, J=5.5 Hz).
Intermediate 30
Figure imgf000057_0002
Intermediate 30 was prepared (52% yield) according to the procedure for intermediate 25. 1H NMR (500 MHz, C6D6) 6: 3.54 (2H, t, J=6.1 Hz), 3.45 (2H, t, J=6.1 Hz), 2.06 - 2.12 (2H, m), 1.87 (2H, dq, J=9.7, 2.6 Hz), 1.68 (2H, qt, J=6.1 Hz), 1.43 - 1.51 (IH, m), 1.26 - 1.34 (IH, m), 0.10 (9H, s). LC/MS [M+H]+ = 359.20
Intermediate 31
Figure imgf000057_0003
Intermediate 31 was prepared (69% yield) according to the procedure for intermediate 26. 1B. NMR (500 MHz, CDCl3) δ: 4.46 (2H, q, J=7.0 Hz), 3.84 (2H5 1, J=5.5 Hz), 3.41 (2H, t, J=5.5 Hz), 2.51 - 2.58 (2H, m), 2.29 - 2.38 (2H5 m), 1.89 - 1.99 (2H, m), 1.82 - 1.90 (3H, m), 1.45 (3H, t, J=7.0 Hz), 1.31 - 1.41 (IH, m). LC/MS (ESI) [M+H]+ = 313.05.
Intermediate 32
Figure imgf000058_0001
A cold (0°C) solution of intermediate 31 (3.0 g, 9.6 mmol) in tetrahydrofuran (25 mL) was treated with methanesulfony chloride (3.30 g, 29 mmol) followed by dropwise addition of triethylamine (4.7 mL, 33.6 mmol). The reaction was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the mixture was dissolved in ethanol (50 mL) and dimethylformamide (25 mL). To the slurry was added potassium carbonate (1.36 g, 9.7 mmol) and the reaction was stirred at room temperature for 16 hours, followed by heating (80 °C) for 3 hours. The solvent was removed in vacuo. The crude product was diluted with ethyl acetate (50 mL) and washed with IN hydrochloric acid (2 x 50 mL), extracted with ethyl acetate (2 x 25 mL) then brine ((50 mL). The solution was then dried (sodium sulfate), filtered and concentrated to give intermediate 32 (0.534 g, 19%) as a brown solid. 1H NMR (500 MHz, CDCl3) 5: 10.64 (IH, br s), 4.45 (2H, q, J=7.0 Hz), 4.38 (2H, br), 3.91 (2H, t, J=5.0 Hz), 2.81 (2H, br), 2.36 - 2.44 (2H, m), 1.87 - 1.97 (IH, m), 1.82 - 1.86 (2H, m), 1.67 - 1.75 (IH5 m), 1.43 (3H, t, J=7.2 Hz). Intermediates 33 and 34
Figure imgf000059_0001
4-Fluoro-2-(lH-l,2,4-triazol-l-yl)benzonitrile (33) and 4-(lH-l,2,4-triazol-l- yl)-2-fluorobenzonit}"ile. To a solution of 2,4-difluorobenzonitrile (10 g, 72 mmol) dissolved in THF (20 mL), and DMF (40 mL) was added 1,2,4-triazole sodium derivative (6.3 g, 70 mmol) and the mixture was stirred at 90 °C for 3 h, filtered and concentrated. The residue was adsorbed onto Silica gel and purified by flash chromatography eluting with 0%-10%-30% EtOAc/hexanes to give intermediate 33 as colorless needles (2.46 g, 18%) and intermediate 34 was obtained as a white solid (0.7455 g, 6%).
intermediate 33: 1H NMR (500 MHz, CDCl3) 6: 8.89 (IH, s), 8.19 (IH, s), 7.85 (IH, dd, J= 8.7, 5.6 Hz), 7.60 (IH, dd, J= 8.8, 2.4 Hz), 7.28-7.24 (IH, m). LCMS (M+H) calcd for C9H6N4F: 189.05; found: 189.13.
Intermediate 34: 1H NMR (500 MHz, CDCl3) δ: 8.66 (IH, s), 8.15 (IH, s), 7.79 (IH, dd, J= 8.5, 6.7 Hz), 7.69 (IH, dd, J= 9.5, 1.8 Hz), 7.65-7.63 (IH, m). LCMS (M+H) calcd for C9H6N4F: 189.05; found: 189.13.
Intermediate 35
Figure imgf000059_0002
(4-Fluoro-2~(lH-l,2,4-triazol-l-yl)phenyl)methanamine hydrochloride. Nitrile 33 (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). Aqueous HCl (15 mL, IN) was added followed by 10% Pd/C (200 mg). The mixture was shaken under H2 at 55 psi for 4 h., filtered over celite and concentrated. The residue was partitioned between EtOAc and water. The aqueous phase was lyophilized to give intermediate 35 as a white powder (2.96 g, 99%). 1H NMR (500 MHz, CD3OD) δ: 9.51 (IH, s), 8.63 (IH, s), 7.85 (IH3 dd, J= 8.5, 5.8 Hz), 7.68 (IH, dd, J= 8.8, 2.4 Hz), 7.49 (IH, td, J= 8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08; found: 193.16.
Intermediate 36
Figure imgf000060_0001
(4-Fluoro-2-(lH-l , 2, 4-triazol-l-yl)phenyl)methanamine hydrochloride. Intermediate 36 was prepared (79% yield) following the procedure for intermediate 35 using intermediate 34. 1H NMR (500 MHz, CD3OD) δ: 9.25 (IH, s), 8.46 (IH, s), 7.80 (IH, dd, J= 8.6, 5.8 Hz), 7.64 (IH, dd, J- 8.8, 2.4 Hz), 7.44 (IH, td, J= 8.3, 2.6 Hz), 4.17 (2H, s). LCMS (M+H) calcd for C9Hi0N4F: 193.08; found: 193.16.
Intermediate 37
Figure imgf000060_0002
4-Fluoro-2-methylsulfanyl-benzylamine. 4-Fluoro-2-(methylthio)benzonitrile (prepared as in Anthony, N. J. et al. PCT Appl. WO 02/30931, 2002) (1.67 g, 0.1 mol) was dissolved in 20 mL THF and under N2 treated with 10 mL 2M BH3-Me2S. This was heated at 60 °C for 2 hrs. Heating was discontinued and 5mL MeOH was cautiously added, followed by the cautious addition of 4 mL 6N HCl. Then 20 niL more H2O added and EtOAc and the layers were separated. The aqueous layer was made basic with IN NaOH and extracted with CH2Cl2. The extracts were dried (MgSO4), filtered, concentrated and dried in vacuum to give intermediate 37 (1.3g, 76%)as a solid. 1H NMR (500 MHz, CDCl3) δ: 7.20 - 7.31 (1 H, m) 6.90 (1 H, dd, J=2.4 Hz) 6.75 - 6.86 (1 H, m) 3.86 (2 H, s) 2.47 (3 H, s). LC/MS (M+H): 172.
Intermediate 38
Figure imgf000061_0001
N-t-Butoxycarbonyl- (4-fluoro-2-(methylthio)phenyl)methanamine. A stirred solution of intermediate 37 (5.1g, 0.03 mol) and 3.3g triethylamine in 10OmL CH2Cl2 under N2 was treated with di-t-butyl dicarbonate (7.2g, 0.033 mol) portionwise and stirred at room temperature for 30 min. Then, the reaction mixture was washed with dil HCl and water. The organic layer was dried over MgSO4, filtered and concentrated to leave 8.1g (100%) of intermediate 38 as a clear oil. 1H NMR (500 MHz, CDCl3) 5: 7.22 - 7.29 (1 H, m) 6.89 (1 H, dd, J=9.61, 2.29 Hz) 6.75 - 6.83 (1 H, m) 4.93 (1 H, s) 4.31 (2 H, d, J=5.49 Hz) 2.47 (3 H, s) 1.44 (9 H, s). LC/MS (M+H): 272.
Intermediate 39
Figure imgf000061_0002
(4-Fluoro-2-(methylsulfonyl)pherryl)methanamine hydrochloride. A solution of intermediate 38 (8.1g, 0.03 mol) in 10OmL acetone and 5OmL water was treated with oxone (18.5g, 0.03 mol) and stirred for 10 min. Then an additional 18.5g oxone was added and the mixture was warmed at 60 °C for 1.5 hrs. This was cooled, concentrated to remove acetone and extracted with CH2Cl2. This was concentrated to an oil, dissolved in 20 mL ethanol and treated with 10 mL 6N HCl and warmed at 60 °C for 2h. Removal of solvents gave a gum which was crystallized from ethanol to give intermediate 39 (2.Og) as crystals. The aqueous layer was made basic with ammonium hydroxide and extracted further with CHaCl2 and concentration of the extracts gave a gum which was treated with HCl in ethanol to give an additional 0.9g of intermediate 39. 1H NMR (500 MHz, DMSO-D6) δ: 8.54 (3 H, s) 7.89 (1 H, dd, J=8.54, 5.19 Hz) 7.67 - 7.85 (2 H, m) 4.40 (2 H, s) 3.41 (3 H, s). LC/MS (M+H) = 204.
Intermediate 40
Figure imgf000062_0001
5-Fluoro-2,N,N-trimethyl-benzenesulfonamide. To a solution of 5-fluoro-2- methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in THF (25 mL) was added drop- wise in 15 min a solution of dimethylamine in THF (2M, 25 mL, 50 mmol) under nitrogen and the mixture stirred for 5 min. The insoluble materials formed were filtered and the filtrate concentrated. The residue was purified by column chromatography (SiO2, 5 % Et2O in CH2Cl2) to obtain intermediate 40 (4.3 g, 90 %) as a clear oil. 1HNMR (500 MHz, CDCl3) δ: 2.57 (3 H, s) 2.82 (3 H, s) 2.82 (3 H, s) 7.12 - 7.18 (1 H, m) 7.28 (1 H, dd, J=8.2, 5.5 Hz) 7.59 (1 H, dd, J=8.2, 2.1 Hz). LC/MC (M+H): 218. Intermediate 41
2-Bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide. A mixture of intermediate 40 (435 mg, 2.0 mmol) and N-bromosuccinimide (391 mg, 2.2 rnmol) in CCl4 (20 mL) was stirred in an oil bath heated at 80-90 0C under nitrogen for 5 min. To this mixture was added 2,2'-azobisisobutyronitrile (AIBN5IOO mg) and the mixture continued to heat at 80-90 0C for 30 min. After cooling, the insoluble precipitates were filtered and the filtrate concentrated and purified by column chromatography (SiO2, CH2Cl2) to obtain intermediate 41 (440 mg, 74 %). 1HNMR (500 MHz, CDCl3) δ: 2.87 (6 H, s) 4.86 (2 H, s) 7.28 (1 H, dd, J=8.55, 2.75 Hz) 7.61 - 7.65 (2 H, m). LC/MC (M+H): 296/298.
Intermediate 42
Figure imgf000063_0002
2-Azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide. A mixture of intermediate 41 (880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) in DMF (4 mL) was stirred under nitrogen in an oil bath heated at 55-60 0C for 30 min and the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic phase was washed with water, dried (Na2SO4), filtered and concentrated to obtain intermediate 42 (670 mg, 87 %) of as a yellow oil. 1HNMR (500 MHz, CDCl3) δ: 2.84 (6 H5 s) 4.78 (2 H, s) 7.29 - 7.34 (1 H, m) 7.59 - 7.64 (2 H, m). Intermediate 43
Figure imgf000064_0001
2-(aminomethyl)-5-fluoro-N,N-dimethylhenzenesulfonamide hydrochloride. To a solution of intermediate 42 (660 mg, 2.6 mmol) in THF (10 mL) and water (2 mL) was added triphenylpliosphine (740 mg, 2.8 mmol), and the mixture stirred under nitrogen for 1 h. The THF was evaporated in vacuo and a mixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated in an oil bath at 80 °C for 20 h. This was washed with CH2Cl2, and the aqueous phase basifϊed with dilute NH4OH and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and concentrated to obtain free amine 43 (210 mg, 35 %) as an oil. 1H NMR (500 MHz, CDCl3) δ: 2.84 (6 H, s) 4.10 (2 H, s) 7.23 - 7.29 (1 H, m) 7.53 - 7.60 (2 H, m); LC/MS (M+H): 233.
Alternatively, a solution of intermediate 42 (23.6 g, 91.37 mmOl) in EtOH
(100 mL) and 5M aq. HCl (22 mL) was degassed by bubbling N2 through it for 5 min. and 10%Pd/carbon (2.0 g) was added. This mixture was evacuated and vented to H2 (repeated three times) and left on Parr shaker for 20 h under H2 (40 psi) atmosphere. The reaction mixture was filtered, concentrated and resulting residue was taken up in water (200 mL). This was extracted with EtOAc (3 X 50 mL). The organic layer discarded and aqueous layer freeze dried to afford 43 (16.3 g, 66%) as pale yellow powder.
Intermediate 44
Figure imgf000065_0001
To a solution of intermediate 28 (0.103 g, 0.367 mmol) in anhydrous dimethylformamide (4 mL) was added anhydrous potassium carbonate (0.206 g, 1.47 mmol) and benzyl bromide (0.071 g, 0.39 mmol), and the reaction was stirred with heating (60 0C) for 18 hours under nitrogen atmosphere. To the reaction mixture was added lithium hydroxide (0.024 g, 0.92 mmol), water (5 mL) and ethanol (5 mL). The reaction was stirred (60 °C) for 2 hours, after which HPLC indicated reaction was complete. The solvent was removed in vacuo, and the crude product was dissolved in water (~10 mL) and brought to pH 1-2 using 6 N hydrochloric acid. The product was extracted with ethyl acetate (3 x 30 mL), dried (Na2SO4), filtered and concentrated to give 0.13 g (100%) of intermediate 44 as an oil which solidified upon standing. The intermediate was used in the following reaction without further purification: 1R NMR (500 MHz, CDCl3) δ: 7.54 (2H, d, J=7.3 Hz), 7.30 - 7.38 (3H, m), 5.49 (2H3 s), 3.95 - 4.01 (4H, m), 2.67 - 2.74 (2H, m), 2.33 - 2.41 (2H, m), 2.06 - 2.14 (2H, m).
Intermediate 45
Figure imgf000065_0002
To a solution of intermediate 44 (obtained above) in dimethylformamide (3 mL) was added <9-(7-azabenzotriazol-l-yl)-ΛζiV)N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.167 g, 0.44 mmol) and the mixture was stirred for 20 minutes. To this was added 2-(aminomethyl)-5-fluoro-N-metliylbenzamide hydrochloride (prepared according to M. Egbertson et al PCT Appl. WO 03077850 ) and ΛζN-dimethylaminopyridine (0.068 g, 0.55 mmol) and the reaction was stirred for 16 hours. The solvent was removed in vacuo and the crude product in ethyl acetate (25 niL) was washed with 1.0 N hydrochloric acid (25 mL), then dried (Na2SO4), filtered, and concentrated to give an orange-brown solid. This was purified by flash silica gel column chromatography, eluting with 30% to 60% ethyl acetate in hexanes, to give a colorless oil. The oil was triturated with diethyl ether and dried in- vacuo to give intermediate 45 (0.101 g, 54% over two steps) as a white glassy solid: 1H NMR (500 MHz, CDCl3) δ: 8.62 (IH, t, J=6.1 Hz), 7.44-7.51 (3H, m), 7.27-7.33 (3H, m), 7.13 (IH, dd, J=8.9, 2.7 Hz), 7.08 (IH, dt, J=8.2, 2.7 Hz), 6.49-6.58 (IH, m), 5.28 (2H, s), 4.56 (2H, d, J=6.4 Hz), 3.90-4.00 (4H, m), 2.98 (3H, d, J=4.9 Hz), 2.71-2.79 (2H, m), 2.26-2.36 (2H, m), 2.14-2.24 (IH, m), 2.04-2.11 (IH, m). LC/MS (M+H) 507.13.
Intermediate 46
Figure imgf000066_0001
' 2-(lH-l,2,4-triazol-l-yl)benzonitrile: A suspension of 2-fluorobenzylnitrile
(3.0 g, 25 mmol) and 1,2,4-triazole sodium complex (2.4 g, 27 mmol) were stirred in THF (7 mL) and DMF (14 mL) at 95° C for 18 h. After cooling and concentrating, the product was crystallized from hot CH2Cl2/hexane (1:1) to give the title compound as a white solid (4.25 g, 100% yield). 1H-NMR (300 MHz, CDCl3) δ: 8.74 (IH, s), 8.16 (IH, s), 7.82 (IH, dd, J= 4.9,1.3 Hz), 7.77-7.25 (2H, m), 7.57-7.51 (IH, m). LCMS [M+H]+ calcd for C9H7N4: 171.06; found: 171.12. Intermediate 47
Figure imgf000067_0001
2-(1H-1, 2,4-triazol-l-yl)phenyI)methanamine hydrochloride: Intermediate 46
(4.25 g, 25 mmol) was dissolved in EtOH (50 mL) and IN HCl (25 mL). Added Pd/C (1 g) and mixture was shaken under H2 for 2 h at 50 psi. After filtration over celite and concentration, the residue was triturated with diethyl ether and the title compound was collected as a white solid (3.94 g, 75% yield). 1H-NMR (300 MHz, CD3OD) δ: 9.01 (IH, s), 8.32 (IH, s), 7.78-7.64 (4H, m), 4.15 (2H, s). LCMS [M+H]+ calcd for C9HnN4: 175.09; found: 175.17.
Intermediate 48
Figure imgf000067_0002
4-Fluoro-2(2H-l,2,3-triazol-2-yl)benzonitrile: To a solution of l/i-1,2,3- triazole (3.5 g, 50.7 mmol) in THF (10 mL) and DMF (20 mL) was added portionwise, NaH (1.3 g, 51 mmol, 95%). The mixture was stirred at room temp for 30 min. Added to this was 2,4-difiuorobenzonitrile (7.6 g, 55 mmol) and the mixture was stirred at 85° C for 3 h. The white mixture was concentrated and purified by flash chromatography eluting with 0%-5%-10% EtOAc/hexane to give the title compound as white needles (0.34 g, 3% yield). 1H-NMR (300 MHz, CDCl3) δ: 7.92 (2H, s), 7.88-7.79 (2H, m), 7.19-7.12 (IH, m). LCMS [M+H]+ calcd for C9H6N4F: 189.05; found: 189.12. Intermediate 49
Figure imgf000068_0001
4-Fluoro-2-(2H-l, 2, 3-triazol-2-yl)phenyl)methanamine hydrochloride:
Intermediate 48 (0.34 g, 1.8 mmol) was dissolved in EtOH (50 mL). Added to this solution was IN HCl (10 mL) and catalytic Pd/C. The mixture was shaken under H2 at 55 psi for 4 h, filtered over celite and concentrated to give the title compound as a yellow solid (0.4021 g, 98 % yield). 1H-NMR (500 MHz, CD3OD) δ: 8.13 (2H, s), 7.87 (IH, dd, J= 4.9, 2.6 Hz), 7.73 (IH, dd, J= 4.9, 2.6 Hz), 7.34 (IH, td5 J= 8.2, 2.7 Hz), 4.35 (2H, s). LCMS [M+H]+ calcd for C9H10N4F: 193.08; found: 193.16.
Intermediate 50
Figure imgf000068_0002
2 -(l,l-dioxo-lλ6-[l,2]thiazinan-2-yl)benonitrile: Added to a solution of 1,1- dioxo[l,2]thiazinane (3.37 g, 25 mmol) in DMF (35 mL) was sodium hydride (0.675 g, 25 mmol, 95%) and the mixture was stirred at room temp for 15 min. 2- Fluόrobenzonitrile (3.37 mL, 31.3 mmol) was added and the micture was stirred at 80° C for 18 h. The mixture was cooled, diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography eluting with 10%- 100% EtOAc/hexane. The isolated solid was recrystalized from hot EtOAc/hexane (2:1) to give the title compound as white crystals (4.15 g, 70% yield). 1H-NMR (300 MHz, CDCl3) δ: 7.70 (IH, dd, J= 7.7,1.1 Hz), 7.64-7.53 (2H, m), 7.41 (IH, td, J= 7.3, 1.6 Hz), 3.72 (2H, t, J= 5.5 Hz), 3.32 (2H, t, J= 6.0 Hz), 2.40-2.32 (2H, m), 2.05-1.97 (2H, m). LCMS [M+H]+ calcd for C11H12N2O2S: 237.06; found: 237.10.
Intermediate 51
Figure imgf000069_0001
2-(l,l-dioxo-lλ6-[l,2]thiazinan-2-yl)benzylamine hydrochloride: Intermediate 50 (2.63 g, 11.14 mmol) was dissolved in EtOH (150 mL) and IN HCl (13 mL). Added to this was Pd/C (0.5 g) and the mixture was shaken under H2 at 55 psi for 24 h. Filtration over celite and concentration gave the title compound as a white solid (2.93 g, 95% yield). 1H-NMR (300 MHz, CD3OD) δ: 7.61-7.47 (4H, m), 4.30 (2H, q, J= 13.7 Hz), 3.96-3.87 (IH, m), 3.49-3.36 (3H, m), 2.40-2.31 (2H, m), 2.05-1.96 (2H, m). LCMS [M+H]+ calcd for CHHI7N2SO2: 241.10; found: 241.10.
Intermediate 52
Figure imgf000069_0002
4-Fluoro- 2-(l,l-dioxo-lλ6-[l,2]thiazinan-2-yl)benzonitrile: To a solution of l,l-dioxo[l,2]thiazinane (8.84 g, 65.4 mmol) in DMF (20 mL) and THF (10 mL) was added portion-wise sodium hydride (1.65 g, 65.5 mmol, 95%). After stirring for 30 min, 2,4-difluorobenzonitrile (10.0 g, 72 mmol) was added and the mixture was stirred at 90° C for 2.5 h. The mixture was cooled and concentrated and the residue was purified by flash chromatography eluting with 0%-l 0% EtOAc/hexane to give the title compound as white needles (1.37 g, 8% yield). 1H-NMR (500 MHz, CDCl3) δ: 7.70 (IH, dd, J= 8.8, 5.8 Hz), 7.30 (IH, dd, J= 8.8, 2.4 Hz), 7.15-7.12 (IH, m), 3.72 (2H, t, J= 5.3 Hz), 3.33 (2H, t, J= 6.1 Hz), 2.40-2.35 (2H, m), 2.05-2.01 (2H, m). LCMS [M+H]+ calcd for C11H12N2FO2S: 255.06; found: 255.19.
Intermediate 53
Figure imgf000070_0001
4-Fluoro- 2-(l,l-dioxo-l λ6-[l ,2] thiazinan-2-yl)benzylamine hydrochloride: Following the procedure for Intermediate 51 using Intermediate 52 (1.37 g, 5.4 mmol) gave the title compound as a white solid (1.58 g, 100 % yield). 1H-NMR (300 MHz, CD3OD) 5: 7.61 (IH, dd, J= 8.4, 6.2 Hz), 7.38 (IH, dd, J= 9.3, 2.7 Hz), 7.28 (IH, td, J= 8.2, 2.7 Hz), 7.26 (2H, dd, J= 21.4, 13.7 Hz), 3.93-3.84 (IH, m), 3.50- 3.41 (3H, m), 2.40-2.31 (2H, m), 2.04-1.96 (2H, m). LCMS [M+H]+ calcd for CnH16N2FO2S: 259.09; found: 259.24.
Intermediate 54
Figure imgf000070_0002
To a solution of l-(2-chloroethyl)cyclopentanecarbonitrile (1.38g, 8.73 mmol; prepared according to R. M. Burk et al Heterocycles 1993, 35, 205) in 40 mL MeOH was added 1 mmol sodium iodide and the solution was saturated with ammonia. The reaction bottle was sealed and warmed at 900C with stirring for 20 h. After cooling the reaction bottle was opened and solvents were evaporated under vacuum. LC/MS (M+H): 139. 1H NMR (500 MHz, CDCl3) δ: 1.50-2.33 (1OH, m), 3.53-3.78 (2H, m). Intermediate 55
Figure imgf000071_0001
To a solution of diethyl-2-(benzyloxy)-3-hydroxyfumarate [prepared from benzyloxy ethylacetate (2.91g, 0.015 mol) and diethyloxalate (2.19g, .015 mol) with an equivalent amount of sodium hydride in 40 mL THF and 2 drops EtOH by stirring for 30 min] in 20 mL EtOH was added intermediate 54 in 10 mL EtOH and with stirring 60% NaH (300mg, 0.0075 mol) was added portionwise. This was stirred for 3 h at rt and concentrated. The residue was dissolved in CH2Cl2 and washed with water. The CH2C12 layer was dried over MgSO4, filtered and concentrated. Chromatography on silica and elution with 9:1 CH2Cl2:Et20 gave 600mg of the title compound 55 (Yield = 19%). LC/MS (M+H): 369. 1H NMR (500 MHz, CDCl3) δ: 1.29 (3H, t, J= 7.2 Hz)5 1.56 (IH, s), 1.68-1.80 (3H, m), 1.85-1.96 (IH, m), 2.04- 2.17 (3H, m), 4.03-4.08 (IH, m), 4.03-4.10 (2H, m), 4.22 (IH, q, J- 7.0 Hz), 4.32 (IH, q, J= 7.0 Hz), 4.63 (IH, s), 5.24 (2H, s), 7.28-7.40 (3H, m), 7.47 (2H, d, J= 6.7 Hz).
Intermediate 56
Figure imgf000071_0002
Intermediate 55 was dissolved in 15 mL TFA and stirred at rt for 16h. The TFA was removed and the crude chromatographed on Cl 8 using 10% CH3CN/ H2O initially as eluant. Product eluted with 20% CH3CN. Pure fractions were concentrated and extracted with CH2Cl2. Evaporation of the solvent left 300 mg (Yield = 51%) of the title compound 56. LC/MS (M+H): 279. 1H NMR (300 MHz, CDCl3) δ: 1.41 (3H, t, J= 7.1 Hz), 1.65-1.79 (4H, m), 1.84-1.97 (2H, m), 2.00-2.12 (4H, m), 3.98-4.08 (2H, m), 4.44 (2H5 q, J= 7.0 Hz), 10.78 (IH, s).
Intermediate 57
Figure imgf000072_0001
To a solution of l,4-dioxa-8-azaspiro[4,5]decane (10.0 g, 70 mmol) and triethylamine (20 mL, 142 mmol) in diethylether (50 mL) cooled to 0° C was added dropwise tosyl chloride (13.5 g, 71 mmol) dissolved in CH2Cl2. The resulting suspension was stirred at room temperature 5 h. and washed with saturated aqueous NaHCO3, water and dried (Na2SO4). Concentration gave the Intermediate 57 as a white solid (20.20 g, 97%). 1H-NMR (300 MHz, CDCl3) δ: 7.61 (2H, d, J= 8.0 Hz), 7.28 (2H, d, J= 8.0 Hz), 3.86 (4H, s), 3.11 (4H, t, J= 5.8 Hz), 2.40 (3H, s), 1.75 (4H, t, J = 5.8 Hz). LCMS (M+H) calcd for C14H20NO4S: 298.11; found: 298.16.
Intermediate 58
Figure imgf000072_0002
To a stirred solution of zinc iodide (2.05 g, 6.26 mmol) and Intermediate 57 (9.3 g, 31.3 mmol) in dichloromethane (10 mL) was added trimethylsilylcyanide (4.29 mL, 31.3 mmol) with water bath cooling. The resulting mixture was stirred at room temp for 2 h and concentrated. The amber oil was used in the next step without purification.
To solution of above crude in EtOH (60 mL) was added hydroxylamine (2.1 mL, 31.3 mmol, 50wt% in water) and the resulting mixture was stirred at room temperature. After 18 h diethylacetylenedicarboxylate (6.0 mL, 37.5 mmol) was added and stirred for additional 3 days and concentrated. The residue was purified by flash chromatography eluting with 0%-25%-50% EtOAc/Hexane to give the Intermediate 58 as a yellow foam (11.72 g, 71%). 1H-NMR (300 MHz, CDCl3) δ: 7.62 (2H, t, J= 7.7 Hz), 7.30 (2H, t, J= 8.2, 2.0 Hz), 5.27 (IH, s), 4.34-4.23 (2H, m), 4.19-4.05 (2H, m), 3.68-3.66 (2H, m), 3.54-3.49 (2H, m), 3.34-3.28 (2H, m), 2.72 (IH, dt, J= 11.4, 2.5 Hz), 2.66-2.57 (IH, m), 2.40 (3H5 d, J= 1.6 Hz), 2.05-1.89 (4H, m), 1.35-1.22 (6H, m). LCMS (M+H) calcd for C23H34N3O9S: 528.20; found: 528.13.
Intermediate 59
Figure imgf000073_0001
1,2,4-trimethylbenzene (100 mL) was added to Intermediate 58 (11.7 g, 22 mmol) and the mixture was stirred at 140° C for 3 h. The mixture was cooled to room temp and concentrated. Residue dissolved in CH2Cl2 and insoluble solids removed by filtration and discarded. Concentration gave the Intermediate 59 as a brown foam (5.02 g, 47% yield). LCMS (M+H) calcd for C21H28N3O8S: 482.16; found: 482.11. Intermediate 60
Figure imgf000074_0001
A solution of Intermediate 59 (3.0 g, 6.2 mmol) and triethylamine (2.5 mL,
18.7 mmol) in CH2Cl2 (8 mL) was cooled to 0° C. To this was added to methanesulfonylchloride (0.47 mL), 6.3 mmol) and the resulting mixture was stirred while gradually warming to room temperature for 18 h. The mixture was washed with water and the organic phase was dried (Na2SO4) to give a brown foam that was purified by flash chromatography eluting with 10%-50% EtOAc/hexane to give the Intermediate 60 as a yellow foam (0.477 g, 14% yield). 1H-NMR (300 MHz, CDCl3) 6: 7.63 (2H, d, J= 8.4 Hz), 7.31 (2H, d, J= 8.0 Hz), 4.41 (2H, q, J= 7.3 Hz), 3.92- 3.89 (2H, m), 3.73-3.68 (IH, m), 3.49 (3H, s), 3.49-3.42 (IH, m), 2.63-2.48 (2H, m), 2.43-2.41 (4H, m), 1.94-1.90 (2H, d, J= 13.5 Hz), 1.39 (3H, t, J= 7.1 Hz). LCMS (M+H) calcd for C22H28N3O9S2: 542.12; found: 542.03.
Intermediate 61
Figure imgf000074_0002
To a stirred solution of Intermediate 60 (0.411 g, 0.76 mmol) in THF (10 mL) at cooled to -78° C was added dropwise a freshly prepared mixture of sodium (0.42 g, 20 mmol) dissolved in Naphthaline (2.56 g, 20 mmol) and THF (20 mL) until the blue color persisted. The resulting mixture stirred an additional 1 h and was quenched with IN HCl. The aqueous layer was washed with EtOAc and freeze dried. The solids were purified by preparative HPLC (YMC Combiprep ODS-A, 30mm x 50mm, MeOH/H2O/0.1% TFA), to give the Intermediate 61 as a white solid (0.024 g, 10% yield). LCMS (M+H) calcd for CJ4H20N3O5: 310.14; found: 310.10.
Intermediate 62
Figure imgf000075_0001
(4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl)methanamine hydrochloride: Intermediate 62 was prepared according to procedure for intermediate 35. LCMS (M+H): 207.2.
Intermediate 63
Figure imgf000075_0002
(4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl)methanamine hydrochloride: Intermediate 63 was prepared according to procedure for intermediate 35. LCMS (M+H): 207.2. Intermediate 64 and 65
Figure imgf000076_0001
4-Fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)benzonitrile and 4-fluoro-2-(5- methyl-lH-l,2,4-triazol-l-yl)benzonitrile. A solution of 2,4-difluorobenzonitrile (7.07 g, 50.8 mmol) and 3-methyl-lH-l,2,4-triazole (4.22 g, 50.8 mmol) in N5N- dimethylformamide (45 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was stirred at 22 0C for 18h. The solid was then filtered and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The mixture containing the 2 and 4-triazolyl-benzonitriles was purified by a combination of chromatography on silica gel ( elution gradient of ethyl acetate in hexane) and on reversed phase silica gel to give 1.86 g (18 % yield) of Intermediate 64 and 0.526 g (5 % yield) of Intermediate 65.
4-Fluoro-2-(3-methyl-lH-l ,2,4-triazol-l -yl)benzonitrile. white crystals (ethyl acetate - hexane) ; mp 117 - 1180C. 1HNMR 400 MHz (CDCl3) δ (ppm) : 2.54 (3H5 S5 CH3), 7.24 (IH5 m5 CH)5 7.62 (IH5 dd5 J = 2.5 Hz and J = 9.1 Hz5 CH)5 7.84 (IH5 dd, J = 5.6 Hz and J = 8.6 Hz5 CH)5 8.82 (IH, s, CH). Anal. Calcd for Ci0H7FN4: C 59.40, H 3.49, N 27.71; Found: C 59.25, H 3.32, N 27.81.
4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)benzonitrile. white crystals (ethyl acetate -hexane); mp 120 - 121 0C. 1HNMR 400 MHz (CDCl3) δ (ppm) : 2.56 (3H, s, CH3), 7.30 (IH, dd, J = 2.5 Hz and J = 8.1 Hz5 CH)5 7.39 (IH5 m, CH), 7.91 (IH, dd5 J = 5.5 Hz and J = 8.6 Hz, CH), 8.06 (IH5 s, CH). Anal. Calcd for Ci0H7FN4: C 59.40, H 3.49, N 27.71; Found: C 59.35, H 3.70, N 27.77. Intermediate 66
Figure imgf000077_0001
(4-Fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yJ)phenyl)methanamine hydrochloride salt. Hydrogenation of 4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l- yl)benzonitrile (0.680 g, 3.36 mmol) gave 0.720 g (88 % yield) of the title hydrochloride salt as a white solid. 1HNMR 400 MHz (DMSOd6) δ (ppm) : 2.40 (3H5 s, CH3), 4.02 (2H, m, NCH2), 7.50 (IH, m, CH), 7.62 (IH, dd, J = 2.8 Hz and J = 9.3 Hz, CH), 7.84 (IH, dd, J = 6.1 Hz and J = 9.1 Hz, CH), 9.00 (IH, s, CH). HRMS (ESI+) calculated for Ci0Hi2FN4 [M+H +] : 207.1046 ; found : 207.1047.
Intermediate 67
Figure imgf000077_0002
(4-Fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl)methanamine hydrochloride salt. Hydrogenation of 4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l- yl)benzonitrile (0.244 g, 1.20 mmol) gave 0.290 g (100 % yield) of the title hydrochloride salt as a white solid. 1HNMR 400 MHz (DMSOd6) δ (ppm) : 2.42 (3H, s, CH3), 3.78 (2H, m, NCH2), 7.58 (IH, m, CH), 7.67 (IH, dd, J = 2.8 Hz and J = 9.3 Hz, CH), 7.90 (IH, dd, J = 6.0 Hz and J = 8.6 Hz, CH), 8.22 (IH, s, CH). HRMS (ESI+) calculated for Ci0Hi2FN4 [M+H +] : 207.1046 ; found : 207.1041.
Intermediate 68
Figure imgf000077_0003
2-Azido-l-bromo-4-fluorobenzene. 2-Bromo-5-fluoro aniline (2.00 g, 10.53 mtnol) was dissolved in concentrated HCl (10 mL) and water (10 mL) and cooled to 0 0C. Aqueous NaNO2 solution (1.09 g, 15.8 mmol OfNaNO2 in 10 mL of water) was added dropwise at such a rate that the temperature did not exceed 5 0C. This mixture was stirred at 0 0C for 1.5 h. A solution OfNaN3 (1.027 g, 15.8 mmol) and NaOAc (12.95 g, 158 mmol) in water (50 mL) was then added at 0-5 0C and the mixture was stirred for an additional Ih at this temperature. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na2SO4. The filtrate was concentrated to afford the title compound as a tan solid (2.19 g, 96% yield): 1H NMR (400 MHz, CDCl3): 7.53 (1 H, dd, J=8.8, 5.6 Hz), 6.94 (1 H, dd, J=8.8, 2.8 Hz), 6.79 (1 H, ddd, J=8.8, 7.6, 2.8 Hz).
Intermediate 69
Figure imgf000078_0001
l-(2-Bromo-5-fluorophenyl)-4-(trimethylsilyl)-lH-l,2J-Mazole. A rώx\mQ of 2-azido-l-bromo-4-fluorobenzene (1.047 g, 4.85 mmol) and trimethylsilylacetylene (2.01 mL, 14.54 mmol) in toluene (5 mL) was heated in a pressure vessel at 110 0C for 21.5 h. The reaction mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes: ethyl acetate (9:1) gradient as the eluent to afford the title compound as a colorless oil (1.451 g, 95% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.97 (1 H, s), 7.74 (1 H, dd, J=9.0, 5.4 Hz), 7.37 (1 H, dd, J=8.5, 2.9 Hz), 7.16 (1 H, ddd, J=8.8, 7.6, 3.0 Hz), 0.40 (9 H, s), LCMS C ESI, M+H+) m/z 314/316. Intermediate 70
Figure imgf000079_0001
l-(2-Bromo-5-fluorophenyl)-5-methyl-4-(trimethylsilyl)-lH-l,2,3-triazole.
The title compound can be prepared according to the procedure provided for l-(2- bromo-5-fluorophenyl)-4-(trimethylsilyl)-lH-l,2,3-triazole 1H NMR (400 MHz, CDCl3) δ ppm: 7.73-7.69 (IH, m), 7.20-7.16 (2H, m), 2.22 (3H, s), 0.39 (9H, s); LCMS C ESI, M+H*) m/z 328/330.
Intermediate 71
Figure imgf000079_0002
l-(2-Bromo-5-fluorophenyl)-4-tert-butyl-lH-l,2,3-triazole. The title compound can be prepared according to the procedure provided for l-(2-bromo-5- fluorophenyl)-4-(trimethylsilyl)-lH-l,2,3-triazole 1H NMR (400 MHz, CDCl3) δ ppm: 7.68 - 7.75 (2 H, m), 7.38 (1 H, dd, J=8.5, 2.9 Hz), 7.14 (1 H, ddd, J=8.8, 7.6, 3.0 Hz), 1.43 (9 H, s), LCMS (+ESI, M+H+) m/z 298/300. Intermediate 72
Figure imgf000080_0001
l-(2-Bromo-5-fluorophenyl)-4-((tert-butyldimethylsilyloxy)methyl)-lH-l, 2, 3- triazole. The title compound can be prepared according to the procedure provided for l-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-lH-l,2,3-triazole 1H NMR (400 MHz, CDCl3) δ ppm: 7.95 (1 H5 s), 7.75 (1 H, dd, J=9.0, 5.4 Hz), 7.38 (1 H, dd, J=8.3, 3.0 Hz), 7.17 (1 H, ddd, J=9.0, 7.5, 2.8 Hz), 4.96 (2 H, s), 0.93 (9 H, s), 0.13 (6 H, s), LCMS C+ESL M+H+) m/z 386/388.
Intermediate 73
Figure imgf000080_0002
l-(2-Bromo-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)-lH-l,2,3- triazole. The title compound can be prepared according to the procedure provided for l-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-lH-l,2,3-triazole 1H NMR (400 MHz, CDCl3) δppm: 7.70 - 7.78 (2 H, m), 7.19 - 7.30 (2 H, m), 4.67 (2 H5 s), 0.82 (9 H, s)5 -0.03 (6 H, s), LCMS C ESI5 M+H+) m/z 386/388. Intermediate 74
Figure imgf000081_0001
l-(2-Bromo-5-fluorophenyl)-lH-l,2, 3-triazole. 1 -(2-Bromo-5-fluorophenyl)-
4-(trimethylsilyl)-lH-l,2,3-triazole (0.80 g, 2.55 mmol) was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (2.8 mL, 2.80 mmol, 1.0 M in tetrahydrofuran) was added dropwise and the reaction mixture was stirred at 25 0C for 4h. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (8:2 to 7:3) gradient as the eluent to afford the title compound as a white solid (0.36 g, 58% yield): 1H NMR (400 MHz, CDCl3) 6 ppm: 8.06 (1 H, d, J=LO Hz), 7.90 (1 H, d, J=I.3 Hz), 7.76 (1 H, dd, J=8.8, 5.3 Hz), 7.39 (1 H, dd, J=8.3, 2.8 Hz), 7.19 (1 H, ddd, J=8.9, 7.5, 3.0 Hz), LCMS ('"ESI, M+H+) m/z 242/244.
Intermediate 75
Figure imgf000081_0002
l-(2-Bromo-5-fluorophenyl)-5-methyl-lH-l,2,3-tria∑ole. The title compound can be prepared according to the procedure provided for l-(2-bromo-5-fluorophenyl)- lH-l,2,3-triazole 1H NMR (400 MHz, CDCl3) 6 ppm: 7.76 (1 H, dd, J=9.1, 5.3 Hz), 7.62 (1 H, s), 7.19 - 7.26 (2 H, m), 2.25 (3 H, s), LCMS ^ESI, M+H+) m/z 256/258. Intermediate 76
Figure imgf000082_0001
(l-(2-Bromo-5-fluorophenyl)-lH-l,2,3-triazol-4-yl)methanol. The title compound can be prepared according to the procedure provided for l-(2-bromo-5- fluorophenyl)-lH-l,2,3-triazole 1H NMR (400 MHz, CDCl3) δ ppm: 8.02 (1 H, s), 7.75 (1 H5 dd, J=8.8, 5.3 Hz), 7.38 (1 H, dd, J=8.2, 2.9 Hz), 7.19 (1 H, ddd, J=8.9, 7.5, 3.0 Hz), 4.94 (2 H, s), LCMS (^ ESL M+H+) m/z 270/272.
Intermediate 77
Figure imgf000082_0002
4-Fluoro-2-(lH-l,2,3-triazol-l-yl)benzonitrile. A mixture of l-(2-bromo-5- fluorophenyl)-lH-l,2,3-triazole (0.603 g, 2.49 mmol) , CuCN (0.245 g, 2.74 mmol), and 15 niL of NMP was subjected to microwave irradiation at 150 0C for 0.5 h. The brown mixture was filtered over celite and washed with dimethylformamide. This solution was treated with 10% aqueous NH4OH (28-30% solution) and extracted with ethyl acetate. The combined organic layers were successively washed with 10% aqueous NH4OH (28-30% solution), sat. NH4Cl aq., water, brine and dried over Na2SO4. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (7:3 to 6:4) gradient as the eluent to afford the title compound as a light yellow solid (0.285 g, 61% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 8.40 (1 H, d, J=LO Hz), 7.96 (1 H, s), 7.91 (1 H, dd, J=S.6, 5.6 Hz), 7.77 (1 H, dd, J=ZJ, 2.4 Hz), 7.31 - 7.39 (1 H, m). Intermediate 78
Figure imgf000083_0001
4-Fluoro-2-(5-methyl-lH-l,2,3-triazol-l-yl)benzonitrile. The title compound can be prepared according to the procedure provided for 4-fluoro-2-(lH-l,2,3-triazol~ l-yl)benzonitrile 1H NMR (400 MHz, CDCl3) 5 ppm: 7.93 (1 H, dd, J=8.7, 5.4 Hz)3 7.67 (1 H, s), 7.44 (1 H, ddd, J=8.6, 7.6, 2.5 Hz), 7.35 (1 H, dd, J=8.1, 2.5 Hz), 2.39 (3 H, s), LCMS (4ESL M+H+) m/z 203.
Intermediate 79
Figure imgf000083_0002
2-(4-tert-Butyl-lH-l,2,3-triazol-l-yl)-4-fluorobenzonitrile. The title compound can be prepared according to the procedure provided for 4-fluoro-2-(lH- l,2,3-triazol-l-yl)benzonitrile 1H NMR (400 MHz, CDCl3) δ ppm: 8.07 (1 H, s), 7.87 (1 H, dd, J=8.8, 5.6 Hz), 7.74 (1 H, dd, J=8.8, 2.5 Hz), 7.25 - 7.33 (1 H, m), 1.45 (9 H, s), LCMS (""ESI, M+H+) m/z 245. Intermediate 80
Figure imgf000084_0001
4-Fluoro-2-(4-(hydroxymethyl)-lH-l,2,3-triazol-l-yl)benzonitrile. The title compound can be prepared according to the procedure provided for 4-fluoro-2-(lH- l,2,3-triazol-l-yl)benzonitrile 1H NMR (400 MHz, CDCl3) δ ppm: 8.34 (1 H, s), 7.91 (1 H, dd, J=8.7, 5.4 Hz), 7.74 (1 H, dd, J=8.6, 2.5 Hz), 7.35 (1 H, ddd, J=8.8, 7.3, 2.5 Hz), 4.96 (2 H, s), LCMS C+ESI, M+ϊt) m/z 219.
Intermediate 81
Figure imgf000084_0002
(4-Fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl)methanamine hydrochloride. 1H
NMR (400 MHz, DMSO-D6) 6 ppm: 8.73 (1 H, d, J=I.0 Hz), 8.53 (3 H, brs), 8.07 (1 H, d, J=1.0 Hz), 7.91 (1 H, dd, J=8.7, 5.9 Hz), 7.66 (1 H, dd, J=9.2, 2.7 Hz), 7.60 (1 H, td, J=8.5, 2.7 Hz), 3.92 (2 H, q, J=5.6 Hz), LCMS C ESI, M+H+) m/z 193.
Intermediate 82
Figure imgf000084_0003
(4-Fluoro-2-(5-methyl-lH-l,2,3-triazol-l-yl)phenyl)methanamine hydrochloride. 1E NMR (400 MHz, DMSO-D6) δ ppm: 8.61 (2 H, s), 7.98 (1 H5 dd, J=9.5, 6.2 Hz), 7.80 (1 H, s), 7.61 - 7.67 (2 H, m), 3.66 (2 H, q, J=5.7 Hz), 2.26 (3 H, s), LCMS C ESI, M+H+) m/z 206.
Intermediate 83
Figure imgf000085_0001
(2-(4-tert-Butyl-lH~l,2,3-triazol-l-yl)-4-fluorophenyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm: 8.55 (2 H, brs), 8.52 (1 H, s), 7.89 (1 H, dd, J=8.8, 6.1 Hz), 7.65 (1 H, dd, J=9.3, 2.5 Hz), 7.55 (1 H, td, J=8.5, 2.5 Hz), 3.95 (2 H, q, J=5.6 Hz), 1.36 (9 H, s), LCMS f ESI, M+H+) m/z 249.
Intermediate 84
Figure imgf000085_0002
(l-(2-(aminomethyl)-5-fluorophenyl)-lH-l,2,3-triazol-4-yl)methanol hydrochloride. 1E NMR (400 MHz, DMSO-D6) δ ppm: 8.56 (1 H, s), 8.50 (2 H, s), 7.89 (1 H, dd, J=8.7, 5.9 Hz), 7.63 (1 H, dd, J=9.2, 2.7 Hz), 7.58 (1 H, td, J=8.5, 2.8 Hz), 4.65 (2 H, s), 3.94 (2 H, q, J=5.4 Hz), LCMS C ESI, M+H+) m/z 223. Intermediate 85
Figure imgf000086_0001
(2-(Chloromethyl)-l,3-dioxolan-2-yl)methyl acetate. A solution of 1-acetoxy-
3-chloroacetone (20.0 g, 133 mmol, TCI America) and 1,2- bis(trimethylsilyloxy)ethane (30.2 g, 146 mmol, Aldrich) in anhydrous CH2Cl2 and under N2 atmosphere was cooled (-78°C, dry ice/acetone) and trimethylsilyl trifluoromethanesulfonate (1.2 mL, 6.6 mmol, Aldrich) was added. The reaction was warmed to room temperature and stirred for 5 days, with monitoring by 1H-NMR. The crude reaction solution was separated by silica gel column, and eluted with CH2Cl2, then 5% Et2O in CH2Cl2. Product fractions were pooled and concentrated in- vacuo giving the title compound (19.05 g) as a yellow oil, contaminated with 1- acetoxy-3-chloroacetone (2.93 g) and CH2Cl2 (1.0 g): 1H NMR (500 MHz, CDCl3) δ ppm 4.17 (2H, s), 4.03 - 4.11 (4H, m), 3.60 (2H, s), 2.09 (3H, s).
Intermediate 86
Figure imgf000086_0002
3-Chloro-2-cyano-2-(2-hydroxyethoxy)propyl acetate. A mixture of (2- (chloromethyl)-l,3-dioxolan-2-yl)methyl acetate (67.8 mmol), trimethylsilyl cyanide (20.29 g, 204 mmol, TCI America) and zinc iodide (3.65 g, 11.4 mmol) was heated (400C, oil bath) for 6 hrs, then at ambient temperature for 16 hrs. The mixture was diluted with CH2Cl2 (100 mL) and stirred with silica gel (50 g) for several hours. The mixture was loaded onto a flash silica gel column (350 g silica) and eluted with CH2Cl2 then increasing amounts OfEt2O to a final eluent of 30% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo to give the title compound as an amber oil: 1H NMR (500 MHz, CDCl3) δ ppm 4.44 (IH, d, J=I 1.90 Hz), 4.35 (IH, d, J=I 1.90 Hz), 3.83 - 3.88 (2H, m), 3.79 - 3.84 (4H, m), 2.13 - 2.16 (3H, m); LC/MS m/z 222.16 (M+H).
Intermediate 87
Figure imgf000087_0001
2-(Chloromethyl)-3-(ltydroxyamino)-2-(2-hydroxyethoxy)-3-iminopropyl acetate. A solution of 3-chloro-2-cyano-2-(2-hydroxyethoxy)propyl acetate (9.40 g, 42.4 mmol) in ethanol (150 mL) was treated with 50% aqueous hydroxylamhie solution (2.94 g, 44.5 mmol, Aldrich) and the reaction was heated (65°C) for 1.5 hrs. The solution was cooled to room temperature and the product was used as-is in the subsequent reaction: LC/MS m/z 255.20 (M+H).
Intermediate 88
Figure imgf000087_0002
2-{[3-Acetoxy-2-chloromethyl-2-(2-hydroxy-ethoxy)-propionimidoyl]- aminooxy}-but-2-enedioic acid diethyl ester. The ethanol solution of 2- (chloromethyl)-3-(hydroxyamino)-2-(2-hydroxyethoxy)-3-iminopropyl acetate, obtained above, was treated with diethyl acetylenedicarboxylate (46.6 mmol, Alfa Aesar) and stirred 16 hrs. Solvent was removed in- vacuo and the resultant amber oil was dissolved in ethyl acetate (100 mL) and washed with water (2 x 100 mL).. The organic layer was dried (Na2SO4), filtered and concentrated in- vacuo. The crude product was purified by flash column chromatography, eluting with 30%-50% ethyl acetate in hexanes. Product fractions were pooled and concentrated in- vacuo to give the title compound (11.1 g) as a viscous amber oil: LC/MS m/z 425.19 (M+H).
Intermediate 89
Figure imgf000088_0001
Ethyl 2- (3-acetoxy-l -chloro-2- (2-hydroxyethoxy)propan-2-yl)-5-hydroxy- 6- oxo-1, 6-dihydropyrimidine~4-carboxyJate. A solution of 2-{[3-acetoxy-2- chloromethyl-2-(2-hydroxy-ethoxy)-propionimidoyl]-aminooxy}-but-2-enedioic acid diethyl ester (11.1 g, 26.13 mmol) in 1,2,4-trimethyl benzene (260 mL, Aldrich) was heated at reflux (160°C, oil bath) for 90 minutes. The reaction was cooled and the solvent was removed in- vacuo. The crude product was dissolved in ethyl acetate (100 mL) and extracted into saturated NaHCO3 aqueous solution (4 x 50 mL). The combined extracts were brought to pH~l using 6.0 N HCl, and re-extracted into ethyl acetate (3 x 75 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated in- vacuo to give a pale yellow solid This was triturated with Et2O, and solids were collected by filtration, followed by drying in- vacuo, to give the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3) δ ppm 12.13 (IH, br), 10.86 (IH, br), 4.76 (IH, d, J=I 1.90 Hz), 4.44 (2H5 q, J=7.02 Hz ), 4.32 (IH, d, J=I 1.90 Hz), 4.08 (IH, d, J=12.5), 4.00 (IH, d, J=12.5), 3.83 - 3.95 (2H, m), 3.66 - 3.78 (2H, m), 2.02 (3H, s), 1.42 (3H, t, J=7.17 Hz); 13C NMR (126 MHz, CDCl3) δ ppm 170.23, 168.97, 159.39, 150.15, 147.87, 126.88, 79.86, 65.94, 63.91, 62.86, 61.37, 44.33, 20.78, 14.20; HRMS (ESI) calcd for C14H20N2O8Cl (M+H) 379.0908; found 379.0896. Intermediate 90
Figure imgf000089_0001
Ethyl 9-(acetoxymethyl)-9-(chloromethyl)-3-(methylsulfonyloxy)-4-oxo-
4,6, 7,9-tetrahydropyrimido[2,l-c][l,4]oxazine-2-carboxylate. A solution of ethyl 2- (3-acetoxy-l-chloro-2-(2-hydroxyethoxy)propan-2-yl)-5-hydroxy-6-oxo-l,6- dihydropyrimidine-4-carboxylate (2.322 g, 6.13 mmol) in tetrahydrofuran (100 mL) was treated with methane sulfonylchloride (2.11 g, 18.4 mmol) and Et3N (2.25 g, 22 mmol) and then heated (600C, oil bath) for 3 hrs. Solvent was removed in- vacuo and the crude product was dissolved in ethyl acetate (100 mL), then washed with water (2 x 50 mL). The organic solution was dried (Na2SO4), filtered and concentrated in- vacuo to give the title compound as a viscous amber oil which was used immediately in the following reaction.
Intermediate 91
Figure imgf000089_0002
Ethyl 9- (acetoxymethyl)-9- (chloromethyl)-3-hydroxy-4-oxo-4, 6, 7, 9- tetrahydropyrimido[2,l-c] [1 ,4] oxazine-2-carboxylate. A solution of ethyl 9- (acetoxymethyl)-9-(chloromethyl)-3-(methylsulfonyloxy)-4-oxo-4,6,7,9- tetrahydropyrimido[2,l-c][l,4]oxazine-2-carboxylate, obtained above, hi absolute ethanol (120 mL) was treated with solid sodium ethoxide (0.440 g, 6.13 mmol, 95%, Aldrich) and stirred for 30 min. The reaction was monitored by HPLC, and additional sodium ethoxide in ethanol (0.5 mL, 1.34 mmol, 21 wt%, Aldrich) was added. The reaction was stirred 20 minutes and then concentrated in-vacuo. The crude material was dissolved in ethyl acetate (20 mL) and washed with 0.05 N HCl aqueous solution (40 mL). The organic solution was dried (Na2SO4), filtered, and concentrated in- vacuo to give the title compound (2.05 g) as an amber oil: LC/MS m/z 361.19 (M+H)
Intermediate 92
Figure imgf000090_0001
Ethyl 9-(acetoxymethyl)-3-(benzyloxy)-9-(chloromethyl)-4-oxo-4, 6, 7,9- tetrahydropyrimido[2,l-c] [l,4]oxazine-2-carboxylate. A solution of ethyl 9- (acetoxymethyl)-9-(chloromethyl)-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,l- c][l,4]oxazine-2-carboxylate (2.05 g, 5.68 mmol) in dimethylformamide (60 mL) was treated with benzyl bromide (1.46 g, 8.5 mmol, Aldrich) and K2CO3 (1.26 g, 9.1 mmol) and stirred for 16 hrs. Solvent was removed in-vacuo and the crude material was dissolved in ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic solution was dried (Na2SO4), filtered, and concentrated to give an amber oil. This was purified by flash column chromatography, eluting with 5% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo to give the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (2H, d, J=7.32 Hz), 7.29 - 7.39 (3H, m), 4.68 (IH, d, J=I 1.90 Hz), 4.37 (IH, d, J=I 1.90 Hz), 4.31 (2H, q, J=7.22 Hz), 4.16 - 4.24 (2H, m), 4.09 - 4.16 (IH, m), 4.06 (IH, d, J=I 1.29 Hz), 3.95 - 4.03 (IH, m), 3.89 (IH, d, J=I 1.29 Hz), 2.06 (3H, s), 1.56 (2H, s), 1.29 (3H, t, J=7.17 Hz); 13C NMR (126 MHz, CDCl3) 5 ppm 170.16, 164.04, 158.67, 150.65, 141.94, 141.67, 136.51, 128.59 128.52, 128.45, 79.57, 74.51, 65.90, 62.11, 60.59, 49.08, 42.16, 20.83, 14.16; HRMS (ESI) calcd for C21H24N2O7Cl (M+H) 451.1272; found 451.1274. Intermediate 93
Figure imgf000091_0001
N-(4-Fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)benzyl)-9-(chloromethyl)-3- hydroxy-9-(hydroxymethyl)-4-oxo-4,6, 7,9-tetrahydropyrimido[2,l-c][l,4]oxazine-2- carboxamide. A solution of ethyl 9-(acetoxymethyl)-3-(benzyloxy)-9-(chloromethyl)- 4-oxo-4,6,7,9-tetrahydropyrimido[2,l-c][l,4]oxazine-2-carboxylate (1.0 g) in trifluoroacetic acid (5 mL) CH2Cl2 (5 niL) was stirred for 2 hrs. An aliquot was transferred to a separate reaction flask and concentrated to give des-OBn intermediate (0.363 g, 1.01 mmol). This was immediately dissolved in dimethylformamide (2 mL) and ethanol (2 mL) and treated with (4-fluoro-2-(3 -methyl- 1 H- 1,2,4-triazol-l- yl)benzylamine hydrochloride (0.320 g, 1.31 mmol) and triethyl amine (0.75 mL, 5.2 mmol), and heated (90°C) for 5 hrs. To the reaction was added Cs2CO3 (0.340 g, 1.1 mmol) and water (1 mL) and the reaction stirred for 2.5 hrs. The reaction was concentrated in-vacuo and the resultant crude material was suspended in water (10 mL) and extracted into CH2Cl2 (2 x 10 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give a solid which was then triturated with a small volume of 95% ethanol. The resultant precipitate was collected by filtration and dried in-vacuo to give the title compound as a white crystalline solid: 1H NMR (500 MHz5 CDCl3) 6 ppm 12.18 - 12.31 (IH, m), 8.49 (IH, t, J=6.26 Hz)5 8.32 (IH5 s)5 7.67 (IH, dd, J=8.39, 5.95 Hz), 7.19 (IH5 dt, J=8.16, 2.29 Hz)5 7.08 (IH, dd, J=8.395 2.29 Hz)5 5.29 (2H5 s), 4.54 (IH5 dd, J=14.19, 6.87 Hz)5 4.19 - 4.27 (IH5 m)5 4.12 - 4.18 (IH5 m)5 4.10 (2H, t, J=4.58 Hz), 4.00 (2H5 1, J=12.21 Hz), 3.90 - 3.96 (2H5 m), 2.55 (3H, s); 13C NMR (126 MHz5 CDCl3) δ ppm 167.69, 163.26, 162.49, 157.34, 147.41, 146.32, 144.26, 134.31, 134.24, 128.45, 128.42, 125.59, 116.93, 116.76, 112.41, 112.21, 80.41, 66.93, 60.79, 53.52, 48.62, 42.47, 39.41, 14.12; HRMS ESI) calcd for C20H21N6O5FCl (M+H) 479.1246, found 479.1224; Elem. Anal, calcd for C20H20N6O5FCl: C 49.79, H 4.26, N 17.42, found: C 50.11, H 4.10, N 17.28.
Intermediate 94
Figure imgf000092_0001
2-(3-Methyl-lH-l,2,4-triazol-l-yl)benzonitrile. White crystals; mp 109 - 110 0C (ethyl acetate - hexane).1HNMR 400 MHz (CDCl3) 6 (ppm) : 2.54 (3H, s, CH3), 7.5 -7.58 (IH, m, aromatic), 7.75 -7.8 (2H, m, aromatics), 7.82 -7.86 (IH, m, aromatic), 8.68 (IH, s, CH). Anal. Calcd for Ci0H8N4: C 65.20, H 4.37, N 30.41; Found: C 64.99, H 4.09, N 30.50.
Intermediate 95
Figure imgf000092_0002
(2-(3-Methyl-lH-l,2,4-triazol-l-yl)phenyl)methanamine hydrochloride. White solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm) : 2.41 (3H, s, CH3), 4.01 (2H, m, CH2), 7.6 (3H, m, aromatics), 7.78 (IH, m, aromatic), 8.5 (broad, NH), 8.98 (IH, s, CH). MS (ESI+) m/e 189 [M+H +]. Intermediate 96
Figure imgf000093_0001
2-(5-Methyl-lH-l,2,4-triazol-l-yI)benzonitrile. White crystals; mp 119 - 120 0C (ethyl acetate - hexane).1HNMR 400 MHz (CDCl3) δ (ppm) : 2.52 (3H, s, CH3), 7.55 (IH, m, aromatic), 7.67 (IH, m, aromatic), 7.82 (IH, m, aromatic), 7.89 (IH, m, aromatic), 8.05 (IH, s, CH). Anal. Calcd for Ci0H8N4: C 65.20, H 4.37, N 30.41; Found: C 64.97, H 4.07, N 30.42.
Intermediate 97
Figure imgf000093_0002
(2-(5-Methyl-lH-l,2,4-triazol-l-yl)phenyl)methanamine hydrochloride.
White solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm) : 2.38 (3H, s, CH3), 3.80 (2H, m, CH2), 7.56 - 7.7 (3H, m, aromatics), 7.8 - 7.82 (IH, m, aromatic), 8.17 (IH, s, CH), 8.44 (broad, NH). MS (ESI+) m/e 189 [M+H %
Intermediate 98
Figure imgf000093_0003
Ethyl 5-hydroxy-2-(4-(3-hydroxypropoxy)-tetrahydro-2H-pyran-4-yl)-6-oxo- l,6-dihydropyrimidine-4-carboxylate. Clear yellow OiL1HNMR 400 MHz (CDCl3) δ (ppm) : 1.43 (3H, t, J = 7.1 Hz, CH3), 1.8 - 2.3 (6H, m, 3 x CH2), 3.44 (2H, t, J = 5.5 Hz, CH2), 3.6 -4.0 (6H, m, 3 x CH2), 4.44 (2H, q, J = 7.1 Hz, OCH2), 10.8 (IH, broad, OH). HRMS (ESI+) calculated for C15H23N2O7 [M+H +] : 343.1505 ; found : 343.1499.
Intermediate 88
Figure imgf000094_0001
White crystals; mp 140 - 142 0C (ethyl acetate).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.46 (3H, t, J = 7.1 Hz, CH3), 1.86 (2H, m, CH2), 2.02 (2H, m, CH2), 2.43 (2H, m, CH2), 3.75 (2H, m, CH2), 3.83 -3.91 (4H, m, 2 x CH2), 4.46 (2H, q, J = 7.1 Hz, OCH2), 4.6 (2H, broad m, CH2), 10.62 (IH, broad, OH). Anal. Calcd for C15H20N2O6: C 55.55, H 6.21, N 8.63; Found: C 55.56, H 6.22, N 8.55.
Intermediate 100
Figure imgf000094_0002
Clear OiL1HNMR 400 MHz (CDCl3) δ (ppm) : 1.33 (3H, t, J = 7.1 Hz, CH3), 1.86 (2H, m, CH2), 2.03 (2H, m, CH2), 2.42 (2H, m, CH2), 3.77 (2H, m, CH2), 3.8 - 3.9 (4H5 m, 2 x CH2), 4.36 (2H, q, J = 7.1 Hz, OCH2), 4.55 (2H, broad m, CH2), 5.28 (2H, s, OCH2), 7.3 - 7.4 (3H, m , aromatics), 7.5 (2H, m , aromatics). MS (ESI+) m/e 415 [M+H +].
Intermediate 101
Figure imgf000095_0001
White crystals; mp 185 - 186 0C (ethyl acetate).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.89 (2H, m, CH2), 2.06 (2H, m, CH2), 2.34 (2H, m, CH2), 3.77 (2H, m, CH2), 3.8 -3.92 (4H, m, 2 x CH2), 4.58 (2H, broad m, CH2), 5.50 (2H, s, OCH2), 7.3 - 7.4 (3H, m , aromatics), 7.56 (2H, m , aromatics). Anal. Calcd for C20H22N2O6: C 62.16, H 5.73, N 7.25; Found: C 62.29, H 5.78, N 7.17.
Example 1
Figure imgf000095_0002
A mixture of ester 3 (0.146 g, .499 mmol), 4-fluorobenzylamine (0.156 g, 1.25 mmol, and triethylamiαe (0.14 mL, 1 mmol) in 1:1 DMF/EtOH (2 mL) was heated at 110 °C for 1.5 h. Then, the reaction mixture was cooled and purified preparative HPLC using MeOH/water containing 0.1F TFA (gradient elution). The fractions containing the product were combined and evaporated to afforded the product as a white solid (0.0955g, 51.5%). 1H NMR (500 MHz, CDCl3) δ: 11.70 (IH, s), 7.86 (IH, br t), 7.32-7.29 (2H, m), 7.05 (2H, t, J = 8.6 Hz), 4.59 (2H, d, J = 6.4 Hz), 4.01 (2H, t, J = 6.4 Hz), 2.16-2.11 (2H, m), 1.99-1.94 (2H3 m), 1.82-1.65 (8H, m). HRMS (M+H) calcd for C20H23FN3O3: 372.1724; found: 371.1714. Anal cald for C20H22FN3O3: C, 64.67; H, 5.97; N, 11.31. Found: C, 64.58; H, 6.24; N, 11.11.
Other examples made by similar methods using amine (2-10 equiv), Et3N (2- 10 equiv.) and appropriate ester in DMF, DMF/EtOH, or other solvent system at 60 0C-140 °C are listed in Table 3.
Table 3.
Ex. Structure Data
Yield: 43%. 1H NMR (500 MHz, CDCI3) δ: 11.72 (1 H, s), 7.84 (1 H1 br t), 7.15-7.09 (2H, m), 6.99 (1 H, t, J = 8.9 Hz), 4.55 (2H, d, J = 6.1 Hz), 4.01 (2H, t, J = 6.4 Hz), 2.28 (3H1 s), 2.17-2.12 (2H, m), 1.99-1.94 (2H, m), 1.83-1.65 (8H, m). HRMS (M+H) calcd
Figure imgf000096_0001
for C21 H25FN3O3: 386.188; found: 386.1875. Anal cald for C2-ιH24FN3O3«0.03 H2O»0.05 CH2CI2: C, 64.79; H1 6.24; N, 10.77; found: C, 64.71; H, 6.31; N, 10.71.
Ex. Structure Data
Yield: 65%. 1H NMR (500 MHz, CDCI3) δ: 11.82 (1 H, s), 8.80 (1H1 1, J = 6.1 Hz), 8.43 (1H, s), 8.15 (1H1 s), 7.73 (1H, dd, J = 7.3, 1.5 Hz), 7.52-7.44 (2H, m), 7.36 (1H1 dd, J = 7.6, 1.2 Hz), 4.48 (2H, d, J = 6.7 Hz), 3.99 (2H, t, J = 6.4 Hz), 2.28-2.23 (2H, m), 1.99-1.91 (4H, m), 1.79-1.66 (6H, m). HRMS (M+H) calcd for C22H25N6O3:
Figure imgf000097_0001
421.1988; found: 421.2001. Anal cald for C22H24N6O3: C1 62.84; H1 5.75; N1 19.98; found: C1 62.55; H, 5.68; N1 20.03. Yield: 70%. 1H NMR (500 MHz, CDCI3) δ: 11.76 (0.6H1 s), 11.69 (0.4H1 s), 8.77 (0.6H1 t, J = 6.4 HZ)1 8.68 (0.4H1 t, J = 6.4 Hz)1 8.44 (0.6H1 S)1 8.39 (0.4H1 s), 8.16 (0.6H1 s), 8.15 (0.4H1 S)1 7.73 (0.H1 dd, J = 8.6, 6.1 Hz)1 7.43 (0.4H1 dd, J = 8.6, 2.8 Hz)1 7.34 (0.4H1 dd, J = 8.5, 4.9 Hz),7.21 (0.6H, td, J = 8.2, 2.4 Hz), 7.15 (0.4H, td, J = 8.5 , 3.0 Hz)1 7.11 (0.6H1 dd, J = 8.6 2.4 Hz), 4.45 (0.6H1 d, J = 6.7 Hz), 4.43 (0.4H1 d, J = 7.0
Figure imgf000097_0002
Hz)1 4.04-3.98 (2H, m), 2.27-2.22 (2H, m), 1.98-1.91 (4H, m), 1.81-1.66 (6H, m). HRMS (M+H) calcd for C22H24FN6O3: 439.1894; found: 439.1887. Anal cald for C22H23FN6O3: C1 60.26; H1 5.28; N1 19.16; found: C1 60.10; H1 5.42; N, 19.25. Ex. Structure Data
Yield: 71 %. 1H NMR (500 MHz, CDCI3) δ: 11.77 (0.6H, s), 11.70 (0.4H, s), 8.80 (0.6H, t, J = 6.7 Hz), 8.70 (0.4H, t, J = 6.4 Hz),
8.44 (0.6H, s), 8.39 (0.4H, s), 8.16 (0.6H, s), 8.15 (0.4H, s), 7.73 (0.6H, dd, J = 8.5, 6.1 Hz), 7.43 (0.4H, dd, J = 8.6, 2.8 Hz), 7.34 (0.4H, dd, J = 8.9, 4.9 Hz), 7.21 (0.6H, td, J = 8.2, 2.7 Hz), 7.15 (0.4H, td, J = 8.6, 2.8 Hz), 7.11 (0.6H, dd, J = 8.4, 2.6 Hz),
4.45 (0.6H, d, J = 6.7 Hz), 4.43 (0.4H, d, J
Figure imgf000098_0001
= 6.7 Hz)1 4.01-3.98 (2H, m), 2.27-2.22 (2H, m), 1.98-1.92 (4H, m), 1.80-1.66 (6H, m). HRMS (M+H) calcd for C22H24FN6O3: 439.1894; found: 439.1875. Anal cald for C22H23FN6O3: C, 60.26; H, 5.28; N, 19.16; found: C, 60.14; H, 5.38; N, 19.25. Yield:73%. 1H NMR (500 MHz, CDCI3) δ: 11.87 (1 H, s), 8.91 (1 H, t, J = 6.7 Hz), 7.91 (2H, s), 7.69 (1 H, dd, J = 8.5, 5.8 Hz), 7.63 (1 H, dd, J = 9.3, 2.6 Hz), 7.13 (1 H, td, J = 8.2, 2.6 Hz), 4.64 (2H, d, J = 7.0 Hz), 3.99 (2H, t, J = 6.4 Hz), 2.23-2.17 (2H, m), 1.97- 1.85 (4H, m), 1.78-1.63 (6H, m). HRMS
Figure imgf000098_0002
(M+H) calcd for C22H24FN6O3: 439.1894; found: 439.1912. Anal cald for
C22H23FN6O3: C, 60.26; H, 5.28; N, 19.16; found: C, 59.97; H, 4.99; N, 19.03. Ex. Structure Data
Yield: 63%. 1H NMR (500 MHz, CDCI3) δ: 13.02 (1 H, br s), 8.82 (1 H1 s), 7.98 (1 H1 t, J = 5.2 Hz), 7.60-7.57 (2H, m), 7.47 (1 H, s), 7.33 (1 H, td, J = 7.6, 1.8 Hz), 7.13 (1 H, d, J = 7.3 Hz), 4.39 (2H, d, J = 5.8 Hz)1 3.99 (2H, t, J = 6.4 Hz), 2.16-2.10 (2H, m), 1.99- 1.94 (2H, m), 1.86-1.67 (8H, m). HRMS (M+H) calcd for C23H25FN5O3: 438.1941 ;
Figure imgf000099_0001
found: 438.1954. Anal cald for
C23H24FN5O3»0.3 EtOAc: C, 50.92; H, 4.37; N, 10.84; found: C, 50.59; H, 4.14; N, 10.95.
Yield: 77%. 1H NMR (500 MHz, CDCI3) δ: 11.90 (1 H, s), 8.22-8.20 (1 H, m), 7.47-7.43 (2H, m), 7.36-7.32 (2H, m), 4.98 (1 H, dd, J = 14.3, 8.5 Hz), 4.46 (1 H, dd, J = 14.3, 4.0 Hz), 3.99 (2H, td, J = 6.2, 1.8 Hz), 3.90- 3.85 (1H, m), 3.44-3.39 (1 H, m), 3.25-3.22 (2H, m), 2.44-2.30 (2H, m), 2.23-2.15 (2H, m), 1.97-1.89 (4H, m), 1.85-1.80 (2H, m), 1.73-1.58 (6H, m). HRMS (M+H) calcd for
Figure imgf000099_0002
C24H31N4O5S: 487.2015; found: 487.2030. Anal cald for C24H30N4O5S: C, 59.24; H, 6.21; N, 11.51 ; found: C, 58.94; H, 6.47; N, 11.43. Ex. Structure Data
-Yield: 70%. 1H NMR (500 MHz, CDCI3) δ: 11.85 (1 H, s), 8.22-8.19 (1H, m), 7.46 (1 H, dd, J = 8.6, 6.4 Hz)1 7.16 (1H, dd, J = 9.2, 2.5 Hz), 7.06 (1H, td, J = 8.2, 2.8 Hz), 4.95 (1 H, dd, J = 14.3, 8.9 Hz), 4.39 (1H, dd, J = 14.3, 4.0 Hz),3.99 (2H, td, J = 6.4, 1.8 Hz), 3.86-3.81 (1H, m), 3.43-3.39 (1H, m), 3.25- 3.23 (2H, m), 2.44-2.30 (2H, m), 2.22-2.14
(2H, m), 1.98-1.90 (4H, m), 1.85-1.80 (2H,
Figure imgf000100_0001
m), 1.74-1.58 (6H, m). HRMS (M+H) calcd for C24H30FN4O5S: 505.1921 ; found: 505.1942. Anal cald for C24H29FN4O5S: C, 57.13; H, 5.79; N, 11.10; found: C, 57.01; H, 5.98; N, 11.02.
Yield: 66%. 1H NMR (500 MHz, CDCI3) δ: 11.65 (1 H, br s), 8.60 (1 H, t, J = 6.7 Hz), 7.69 (1H, dd, J = 8.4, 5.4 Hz), 7.49 (1 H, dd, J = 8.4, 2.6 Hz), 7.28-7.24 (1H, m), 4.81 (2H, d, J = 6.7 Hz), 3.98 (2H, t, J = 6.4 Hz),
10 2.89 (6H, s), 2.22-2.16 (2H, m), 1.96-1.91 (4H, m), 1.76-1.61 (6H, m). HRMS (M+H)
Figure imgf000100_0002
calcd for C22H28FN4O5S: 479.1764; found: 479.1788. Anal cald for C22H27FN4O5S* 0.8 H2O: C, 53.60; H, 5.85; N1 11.37; found: C, 53.48; H, 5.50; N, 10.98. Ex. Structure Data
Yield: 53%. 1H NMR (500 MHz, CDCI3) δ: 11.54 (1 H, s), 8.56 (1H, t, J = 6.4 Hz), 7.74 (1 H1 dd, J = 8.1, 2.6 Hz), 7.71 (1 H, dd, J = 8.6, 5.2 Hz), 7.33 (1 H, td, J = 8.1 , 2.8 Hz), 4.83 (2H, d, J = 7.0 Hz), 3.97 (2H, t, J = 6.4
Hz), 3.16 (3H, s), 2.20-2.15 (2H, m), 1.96- 1.91 (4H, m), 1.76-1.62 (6H, m). HRMS
Figure imgf000101_0001
(M+H) calcd for C2IH25FN3O5S: 450.1499; found: 450.1479. Anal cald for
C2IH24FN3O5S: C, 56.11 ; H1 5.38; N1 9.34; found: C1 55.89; H, 5.39; N1 9.19. Yield: 66%. 1H NMR (500 MHz1 CDCI3) δ: 11.73 (1 H1 s), 8.71 (1H1 t, J = 6.4 Hz)1 8.45 (1 H1 d, J = 3.4 Hz)1 8.18 (1 H1 s), 7.51 (1 H1 d, J = 7.6 Hz)1 7.48-7.43 (1 H1 m), 7.27-7.23 (1 H1 m), 4.43 (2H, d, J = 6.7 Hz)1 3.99 (2H1 t, J = 6.4 Hz)1 2.28-2.22 (2H, m), 2.00-1.92 (4H, m), 1.81-1.74 (4H, m), 1.72-1.67 (2H1 m). HRMS (M+H) calcd for C22H24FN6O3:
Figure imgf000101_0002
439.1894; found: 439.1883. Anal cald for C22H23FN6O3: C1 60.26; H1 5.28; N1 19.16; found: C1 60.06; H1 5.22; N1 19.09.
Ex. Structure Data
Yield: 59%. 1H NMR (500 MHz, CDCl3) δ: 11.90 (1H, s), 7.93 (1H, br t), 7.34-7.32 (2H, m), 7.05 (2H, t, J = 8.5 Hz), 4.60 (2H, d, J = 6.4 Hz)1 3.99 (2H, t, J = 6.4 Hz), 3.90-3.90 (2H, m), 3.65 (2H, dt = 11.9, 1.5 Hz), 2.38 (2H1 dt, J = 13.5, 3.7 Hz), 2.03- 1.94 (4H, m), 1.52 (2H1 d, J = 13.7 Hz). HRMS (M-H) calcd for C20H2IFN3O4:
Figure imgf000102_0001
386.1516; found: 386.1499. Anal cald for C20H22FN3O4-0.04 H2O»0.2 TFA: C1 64.79; H, 6.24; N1 10.77; found: C1 64.71; H1 6.31; N1 10.71.
Yield: 79%. 1H NMR (500 MHz, CDCI3) δ: 12.01 (1H1 s), 7.78 (1H1 br t), 7.39-7.30 (5H1 m), 4.63 (2H1 d, J = 6.4 Hz), 4.03-3.96 (4H1 m), 2.16-2.04 (4H1 m), 1.86-1.79 (4H, m). HRMS (M+H) calcd for Ci9H22N3O4: 356.1610; found: 356.1616. Anal cald for
Figure imgf000102_0002
C19H21N3O4: C1 64.21; H, 5.95; N, 11.82; found: C, 63.98; H, 5.81; N, 11.71. Yield: 85%. 1H NMR (500 MHz, CDCl3) δ: 11.92 (1H, s), 7.75 (1H, br t), 7.30 (2H, dd, J = 8.5, 5.5 Hz)1 7.04 (2H1 t, J = 8.5 Hz)1 4.58 (2H1 d, J = 6.4 Hz)1 4.02-3.95 (4H, m),
2.15-2.04 (4H1 m), 1.88-1.79 (4H, m). HRMS (M+H) calcd for C19H2I FN3O4: 374.1516; found: 374.1506. Anal cald for
Figure imgf000102_0003
C19H20FN3O4-0.15 H2O: C1 60.09; H, 5.37; N, 11.01; F, 5.72; found: C, 59.87; H1 5.24; N, 10.90; F, 5.53. Ex. Structure Data
Yield: 67%. 1H NMR (500 MHz, CDCI3) δ: 11.95 (1 H, s), 7.72 (1 H, br t), 7.14 (1 H, d, J = 7.0 Hz), 7.11-7.08 (1 H, m), 6.98 (1 H, t, J = 9.0 Hz), 4.54 (2H, d, J = 6.4 Hz), 4.03- 3.95 (4H1 m), 2.27 (3H, s), 2.16-2.03 (4H1
Figure imgf000103_0001
m), 1.88-1.79 (4H, m). HRMS (M+H) calcd for C20H23FN3O4: 388.1673; found: 388.1661.
Yield: 51 %. 1H NMR (500 MHz, CDCI3) δ: 11.90 (1 H, s), 8.76 (1 H1 t, J = 6.4 Hz), 8.44 (1 H1 s), 8.13 (1 H, s), 7.70 (1 H, dd, J = 8.5, 6.1 Hz), 7.21 (1H1 td, J = 8.2, 2.4 Hz), 7.11 (1 H, dd, J = 8.4, 2.6 Hz), 4.44 (2H, d, J =
17 6.7 Hz), 4.01-3.94 (4H, m), 2.27-2.21 (2H1 m), 2.09-2.04 (2H, m), 1.93-1.88 (4H1 m).
Figure imgf000103_0002
HRMS (M+H) calcd for C2IH22FN6O4: 441.1687; found: 441.1691. Anal cald for C21H2IFN6O4: N1 19.08; F, 4.31; found: N1 19.37; F1 4.56.
Yield: 77%. 1H NMR (500 MHz1 CDCI3) δ: 11.84 (1 H1 s), 8.08 (1 H1 t, J = 5.2 Hz)1 7.30 (1H, dd, J =8.4, 6.0 Hz), 6.95 (1H, dd, J = 9.5, 2.7 Hz)1 6.83 (1 H, td, J = 8.2, 2.8 Hz), 4.60 (2H, d, J = 6.4 Hz), 4.01-3.94 (4H, m),
18 2.51 (3H, s), 2.20-2.14 (2H, m), 2.08-2.03
Figure imgf000103_0003
(2H, m), 1.88-1.82 (4H, m). HRMS (M+H) calcd for C20H23FN3O4S: 420.1393; found: 420.1383. Anal cald for C20H22FN3O4S: C, 57.26; H, 5.28; N, 10.01 ; F, 4.52; found: C, 57.27; H, 5.31 ; N, 10.01 ; F, 4.49. Ex. Structure Data
Yield: 83%. 1H NMR (500 MHz, CDCI3) δ: 12.04 (1H, s) 7.74 (1H1 br t), 7.22 (2H1 d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz)1 4.58 (2H1 d, J = 6.1 Hz), 4.03-3.95 (4H, m), 2.35 (3H, s), 2.15-2.03 (4H1 m), 1.87-1.79 (4H, m). HRMS (M+H) calcd for C20H24N3O4:
Figure imgf000104_0001
370.1767; found: 370.1778. Anal cald for C20H23N3O4: C1 65.02; H1 6.27; N1 11.37; found: C1 64.93; H, 6.44; N1 11.32. Yield: 75%. 1H NMR (500 MHz1 CDCI3) δ: 11.90 (1H1 S)1 7.76 (1H1 t, J = 5.4 Hz)1 7.34 (2H1 d, J = 7.9 Hz)1 7.26 (2H1 d, J = 7.9 Hz)1 .59 (2H1 d, J = 6.4 Hz)1 4.03-3.96 (4H1 m), .16-2.04 (4H1 m), 1.89-1.79 (4H1 m). RMS (M+H) caicd for C19H21CIN3O4:
Figure imgf000104_0002
901221 ; found: 390-1216. Anal cald for C19H20CIN3O4: C1 58.54; H1 5.17; N1 10.77; found: C1 58.34; H1 5.24; N1 10.59. Yield: 73%. 1H NMR (500 MHz1 CDCI3) δ: 11.81 (1H1 S)1 7.79 (1H, t, J = 5.4 Hz)1 7.43 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 1.5 Hz)1 7.17 (1 H1 dd, J = 8.2, 1. 5 Hz)1 4.57 (2H1 d, J = 6.4 Hz), 4.03-3.96 (4H1 m), 2.17-2.05 (4H1 m), 1.90-1.81 (4H1 m). HRMS (M+H)
Figure imgf000104_0003
calcd for C19H20CI2N3O4: 424.0831; found: 424.0811. Ex. Structure Data
Yield: 85%. 1H NMR (500 MHz, CDCI3) δ: 12.06 (1 H, s), 7.74 (1 H, br t), 7.13 (1 H, d, J = 7.6 Hz), 7.09 (1 H, s), 7.05 (1 H, d, J = 7.6 Hz), 4.56 (2H, d, J = 6.1 Hz), 4.03-3.95 (4H, m), 2.26 (6H, s), 2.16-2.03 (4H, m), 1.87-1.80 (4H, m). HRMS (M+H) calcd for C2IH26N3O4: 384.1923; found: 384.1937.
Figure imgf000105_0001
Anal cald for C21H25N3O4: C, 65.78; H, 6.57; N, 10.95; found: C, 65.58; H, 6.58; N, 10.89.
Yield: 84%. 1H NMR (500 MHz, CDCI3) δ: 12.04 (1 H, s), 7.71 (1H, br t), 7.26 (2H, d, J = 8.6 Hz), 6.90 (2H, d, J = 8.6 Hz)1 4.55 (2H1 d, J = 6.4 Hz), 4.03-3.95 (4H, m), 3.81 (3H, s), 2.15-2.03 (4H1 m), 1.87-1.79 (4H, m). HRMS (M+H) calcd for C20H24N3O5: 386.1716; found: 386.1697. Anal cald for
Figure imgf000105_0002
C20H23N3O5-0.11 CH2CI2: C, 61.19; H, 5.93; N, 10.64; found: C, 60.86; H, 5.98; N.10.55 .
Yield: 78%. 1H NMR (500 MHz, CDCI3) δ: 11.89 (1H, s), 7.88 (1H, t, J = 5.2 Hz)1 7.37 (1H1 td, J = 7.6 1.2 Hz)1 7.33-7.28 (1H1 m), 7.14 (1H, t, J = 7.6 Hz)1 7.09 (1H, t, J = 9.3 Hz)1 4.66 (2H1 d, J = 6.4 Hz), 4.03-3.95 (4H1 m), 2.19-2.13 (2H1 m), 2.09-2.04 (2H1 m), 1.89-1.83 (4H1 m). HRMS (M+H) calcd for Ci9H2I FN3O4: 374.1516; found:
Figure imgf000105_0003
374.1532. Anal cald for Ci9H20FN3O4»0.05 Et2O »0.05 CH2CI2: C, 60.63; H, 5.45; N, 11.02; found: C, 60.58; H1 5.33; N1 11.03. Ex. Structure Data
Yield: 88%. 1H NMR (500 MHz, CDCI3) δ: 12.10 (1 H1 s), 8.06 (1 H, t, J = 5.6 Hz), 7.20 (1H, d, J = 8.2 Hz), 6.48 (1H, d, J = 2.4 Hz), 6.45 (1 H, dd, J = 8.2, 2.4 Hz), 4.51 (2H, d, J = 6.4 Hz), 4.01-3.95 (4H1 m), 3.85 (3H, s),
25 3.80 (3H, s), 2.20-2.14 (2H, m), 2.09-2.04 (2H, m), 1.91-1.83 (4H, m). HRMS (M+H)
Figure imgf000106_0001
calcd for C2IH26N3O6: 416.1822; found: 416.1837. Anal cald for C21H25N3O6: C, 60.71 ; H, 6.06; N, 10.11; found: C, 60.47; H, 6.10; N, 9.97.
Yield: 86%. 1H NMR (500 MHz, CDCI3) δ: 11.89 (1 H, s), 7.80 (1 H, br t), 7.34 (1 H, q, J = 7.6 Hz), 7.10 (1H, d, J = 7.6 Hz), 7.03- 6.98 (2H, m), 4.62 (2H, d, J = 6.4 Hz), 4.04- 3.96 (4H, m), 2.17-2.05 (4H, m), 1.88-1.81 (4H1 m). HRMS (M+H) calcd for
Figure imgf000106_0002
C19H2IFN3O4: 374.1516; found: 374.1504. Anal cald for C19H20FN3O4-0.1 CH2CI2: C, 60.07; H, 5.33; N, 11.00; found: C, 60.06; H, 5.39; N, 10.94.
Yield: 65%. 1H NMR (500 MHz, CDCI3) δ: 11.93 (1 H, s), 7.76 (1 H, br t), 7.17 (1H, t, J = 7.9 Hz), 6.99 (1H, d, J = 7.9 Hz), 6.97 (1H, d, J = 10.4 Hz), 4.57 (2H, d, J = 6.4 Hz), 4.03-3.96 (4H, m), 2.26 (3H, s), 2.17- 2.05 (4H, m), 1.88-1.80 (4H, m). HRMS
Figure imgf000106_0003
(M+H) calcd for C20H23FN3O4: 388.1673; found: 388.1665. Anal cald for
C20H22FN3O4: C, 62.00; H, 5.72; N, 10.84; found: C, 61.73; H, 7.72; N1 10.66. Ex. Structure Data
Yield: 44%. 1H NMR (500 MHz, CDCI3) δ: 11.80 (1H1 br s), 8.61 (1H, t, J = 6.7 Hz), 7.68 (1H, dd, J = 8.6, 5.2 Hz), 7.48 (1H, dd, J = 8.4, 2.6 Hz), 7.28-7.24 (1 H1 m), 4.80 (2H, d, J = 7.0 Hz), 4.00-3.94 (4H, m), 2.90 (6H, s), 2.24-2.18 (2H, m), 2.06-2.00 (2H1 m), 1.96-1.80 (4H, m). HRMS (M+H) calcd for C2IH26FN4O6S: 481.1557; found:
Figure imgf000107_0001
481.1561. Anal cald for C2IH25FN4O6S* 0.35 CF3CO2H* 0.1 C4H10O: C, 50.29; H, 5.03; N, 10.61 ; found: C, 50.06; H1 4.70; N, 10.51.
Yield: 51%. 1H NMR (500 MHz, CDCI3) δ: 11.84 (1H, s), 8.67 (1H1 1, J = 5.8 Hz), 8.39 (1H, s), 8.13 (s, 1H), 7.42 (1H, dd, J = 8.4, 2.9 Hz) 7.34 (1H, dd, J = 8.7, 4.2 Hz), 7.16 (1H, td, J = 8.1, 2.8 Hz), 4.42 (2H, d, J = 6.7 Hz), 4.02-3.96 (4H, m), 2.28-2.22 (2H, m), 2.10-2.05 (2H1 m), 1.94-1.88 (4H1 m). HRMS (M+H) calcd for C2IH22FN6O4:
Figure imgf000107_0002
441.1687; found: 441.1697. Anal cald for C2-IH2IFN6O4: C, 57.26; H, 4.80; N, 19.08; found: C, 57.27; H1 4.85; N, 19.07.
Ex. Structure Data
Yield: 87%. 1H NMR (500 MHz, CDCI3) δ: 11.92 (1 H, s), 7.41 (1 H, br t), 7.20-7.17 (2H, m), 7.03-7.00 (2H, m), 4.01-3.99 (2H, m), 3.96-3.94 (2H, m),3.68 (2H1 q, J = 6.7 Hz), 2.89 (2H, t, J = 6.7 Hz)1 2.06-1.97 (4H1 m), 1.88-1.80 (2H, m), 1.77-1.69 (2H, m). HRMS (M+H) caicd for C20H23FN3O4:
Figure imgf000108_0001
388.1673; found: 388.1680. Anal cald for C20H22FN3O4«0.8 H2O: C, 60.05; H, 5.90; N, 10.50; found: C, 60.14; H, 5.60; N, 10.51.
Yield: 80%. 1H NMR (500 MHz, CDCI3) δ: 12.03 (1 H, s), 7.44 (1 H, br t), 7.16-7.13 (2H, m), 6.99-6.95 (2H, m), 4.03-4.01 (2H, m), 3.98-3.96 (2H, m), 3.44 (2H, q, J = 6.7 Hz), 2.68 (2H1 1, J = 7.6 Hz), 2.18-2.06 (4H, m), 1.97-1.84 (6H, m). HRMS (M+H) calcd
Figure imgf000108_0002
for C2IH25FN3O4: 402.1829; found: 402.1840. Anal cald for C21H24FN3O4: C, 62.83; H1 6.02; N, 10.46; found: C, 62.46; H, 6.26; N, 10.52.
Ex. Structure Data
Yield: 73%. 1H NMR (500 MHz1 CDCI3) δ: 12.10 (1H, s), 8.55 (1H, t, J = 6.4 Hz), 8.29 (1H, s), 7.68 (1H1 dd, J = 8.6, 6.1 Hz), 7.17 (1 H, td, J = 8.6, 2.8 Hz), 7.08 (1 H, dd, J = 8.6, 2.8 Hz), 4.47 (2H, d, J = 6.7 Hz), 4.02- 4.00 (2H, m), 3.96-3.94 (2H, m), 2.52 (3H, s), 2.23-2.16 (2H, m), 2.09-2.04 (2H, m), 1.88-1.83 (4H, m). HRMS (M+H) calcd for
Figure imgf000109_0001
C22H24FN6O4: 455.1843; found: 455.1850. Anal cald for C22H23FN6O4: C, 58.14; H, 5.10; N, 18.49; found: C, 58.04; H, 4.98; N, 18.53.
Yield: 10%. 1H-NMR (300 MHz, CDCI3) δ: 11.95 (1 H, s), 8.84-8.79 (1 H, m), 8.41 (1 H, s), 8.11 (1H1 s), 7.68 (1H1 dd, J = 6.8, 2.0 Hz), 7.51-7.42 (2H1 m), 7.33 (1H1 dd, J = 7.3, 1.8 Hz), 4.44 (2H, d, J = 7.0 Hz), 3.99- 3.92 (4H, m), 2.27-2.18 (2H1 m), 2.08-2.00 (2H1 m), 1.92-1.85 (4H1 m). HRMS [M+H]+
Figure imgf000109_0002
calcd for C21H23N6O4: 423.1781; found: 423.1773.
Ex. Structure Data
Yield: 59% yield. 1H-NMR (300 MHz1 CDCI3) δ: 11.83 (1 H1 br s), 8.26-8.22 (1 H, m), 7.43 (1H, dd, J = 8.8, 6,2 Hz), 7.15 (1 H, dd, J = 9.1 ,2.6 Hz), 7.04 (1 H, dt, J = 8.2, 2.6 Hz), 4.91 (1 H1 dd, J = 14.1 , 9.0 Hz), 4.34 (1 H, dd, J = 14.3, 3.7 Hz), 3.99-3.89 (4H, m), 3.86-3.77 (1H, m), 3.44-3.36 (1 H, m), 3.23-3.19 (2H, m), 2.40-2.30 (2H, m), 2.21-2.10 (2H, m), 2.01-1.89 (4H, m), 1.83-
Figure imgf000110_0001
1.74 (4H, m). HRMS [M+H]+ calcd for C23H28N4O6FS: 507.1714; found: 507.1735. Anal cald for C23H27N4O6FS: C, 54.54; H, 5.37; N, 11.06; S, 6.33; F, 3.75; found: C, 54.27; H, 5.22; N, 11.01 ; S, 6.14; F, 3.81. Yield: 81 % yield. 1H-NMR (300 MHz, CDCI3) δ: 12.08 (1 H, s), 8.27-8.23 (1 H, m), 7.46-7.41 (2H, m), 7.35-7.32 (2H, m), 4.93 (1H, dd, J = 14.1 , 9.0 Hz), 4.40 (1H, dd, J = 14.1, 3.5 Hz), 4.00-3.96 (2H, m), 3.93-3.88 (2H, m), 3.86-3.81 (1 H, m), 3.44-3.36 (1 H,
35 m), 3.22-3.18 (2H, m), 2.41-2.28 (2H, m), 2.21-2.11 (2H, m), 2.02-1.89 (4H, m), 1.84- 1.74 (4H, m). HRMS [M+H]+ calcd for
Figure imgf000110_0002
C23H29N4O6S: 489.1808; found: 489.1801. Anal cald for C23H28N4O6S: C, 56.54; H, 5.78; N, 11.47; found: C, 56.63; H, 5.48; N, 11.37. Ex. Structure Data
Yield: 65%. 1H NMR (500 MHz, CDCI3) δ: 12.10 (1 H, s), 7.74 (1 H, br t), 7.30 (2H1 dd, J = 8.5, 5.2 Hz), 7.04 (2H, t, J = 8.5 Hz), 4.62-4.53 (2H1 m), 4.14-3.99 (8H, m), 2.51- 2.45 (1H, m), 2.36-2.31 (1H, m). HRMS (M+H) calcd for C18H19FN3O5:; found:.
Figure imgf000111_0001
Anal cald for C18H18FN3O5: C, 57.59; H, 4.83; N, 11.19; F, 5.06; found: C, 57.95; H, 4.96; N, 10.95; F, 5.43. Yield: 68%. 1H NMR (500 MHz1 CDCI3) δ: 12.13 (1H, s), 7.71 (1H,br t), 7.14-7.08 (2H, m), 6.97 (1H, t, J = 8.8 Hz), 4.57-4.49 (2H, m), 4.14-3.99 (8H1 m), 2.51-2.44 (1H1 m),
2.36-2.31 (1H, m), 2.27 (3H1 s). HRMS (M+H) calcd for C19H21FN3O5: 390.1465;
Figure imgf000111_0002
found: 390.1451. Anal cald for
C19H20FN3O5: C, 58.60; H1 5.17; N1 10.79; F1 4.87; found: C1 58.62; H1 5.36; N1 10.77; F1 4.95.
Yield: 52%. 1H NMR (500 MHz1 CDCI3) δ: 11.908 (1H, S)1 8.92 (1H1 br t), 8.43 (1 H1 s), 8.26 (1H1 s), 7.69 (1H1 dd, J = 8.5, 5.8 Hz)1 7.21 (1H1 td, J = 8.2, 2.4 Hz)1 7.10 (1H1 dd, J = 8.5, 2.4 Hz)1 4.51-4.35 (2H1 m), 4.26- 3.97 (8H, m), 2.59-2.53 (1 H1 m), 2.36-2.31 (1H1 m). HRMS (M+H) calcd for
Figure imgf000111_0003
C20H20FN6O5: 443.1479; found: 443.1495. Anal cald for C20H19FN6O5: C1 54.29; H1 4.32; N, 18.99; F, 4.29; found: C1 54.26; H, 4.44; N, 19.01; F, 4.38. Ex. Structure Data
Yield: 63%. 1H NMR (500 MHz, CDCI3) δ: 12.01 (1H, s), 8.03 (1H, br t), 7.30-7.24 (1 H, m), 6.99-6.94 (1H, m), 6.87-6.81 (1H, rn), 4.64-4.59 (2H1 m), 4.14-3.99 (8H, m), 2.55-2.51 (1 H, m), 2.51 (3H, s), 2.38-2.31 (1 H, m). HRMS (M+H) calcd for C19H2IFN3O5S: 422.1186; found: 422.1165.
Figure imgf000112_0001
Anal cald for C19H2IFN3O5S: C, 54.14; H, 4.78; N, 9.97; found: C, 54.22; H, 5.07; N, 9.90.
Yield: 28%. 1H-NMR (500 MHz1 CDCI3) δ: 12.07 (1 H1 s), 7.81 (1 H, t, J = 6.0 Hz), 7.32 (2H, dd, J = 8.5, 5.5 Hz), 7.06 (2H, t, J = 8.7 Hz), 4.58 (2H1 d, J = 6.4 Hz), 4.05-4.01 (4H, m), 3.84 (2H, dd, J = 11.4, 5.3 Hz), 3.77 (2H, t, J = 11.3 Hz), 2.30 (2H, dt, J = 13.3, 5.2 Hz), 1.79 (2H, d, J = 13.7 Hz). ). HRMS [M+H] calcd for C19H21N3O5F:
Figure imgf000112_0002
390.14653; found: 390.1465. Anal clad for C19H20N3O5F: C, 58.60; H, 5.17; N, 10.79; F, 4.87; found: C, 58.70; H, 5.26; N, 10.80; F, 4.99.
Ex. Structure Data
Yield: 30%. 1H-NMR (500 MHz, CDCI3) δ: 11.86 (1 H, s), 9.12 (1H, t, J = 5.6 Hz)1 8.46 (1H1 s), 8.39 (1 H, s), 7.68 (1 H1 dd, J = 8.2, 6.1 Hz), 7.21 (1 H, dt, J = 8.2, 2.1 Hz), 7.10 (1 H, dd, J = 8.4, 2.0 Hz), 4.45 (2H, dd, J = 6.7 Hz), 4.02 (4H, s), 3.90 (2H, dd, J = 11.3, 4.6 Hz), 3.79 (2H, t, J = 11.7 Hz), 2.44 (2H, dt, J = 13.1 , 4.9 Hz), 1.80 (2H, d,
Figure imgf000113_0001
J = 13.4 Hz). HRMS (M+H) calcd for C2IH22N6O5F: 457.16358; found: 457.1639. Anal cald for C2iH2i N6O5F: C, 55.26; H, 4.63; N, 18.41 ; F, 4.16; found: C, 54.99; H, 4.54; N, 18.38; F, 4.08. Yield: 53%. 1H-NMR (500 MHz, CDCI3) δ: 12.12 (1 H, s), 8.25-8.23 (1 H, m), 7.48 (1 H, q, J = 8.5, 6.1 Hz), 7.21 (1 H, dd, J = 9.0, 2.6 Hz), 7.08 (1 H, dt, J = 8.2, 2.5 Hz), 4.90 (1H, dd, J = 14.2, 8.4 Hz), 4.43 (1 H, dd, J = 14.0, 4.3 Hz), 4.01 (4H, s), 3.86-3.71 (4H, m), 3.45-3.42 (1 H, m), 3.32 (1 H, dt, J= 13.2, 4.4 Hz), 3.28-3.22 (1 H, m), 2.47-2.29 (4H, m), 2.00-1.93 (2H, m), 1.72 (2H, t, J = 15.2 Hz). HRMS [M+H]+ calcd for
Figure imgf000113_0002
C23H28N6O7FS: 523.1663; found: 523.1666. Anal cald for C23H27N6O7FS* 0.5 H2O: C, 51.97; H, 5.31 ; N1 10.54; F, 3.57; S, 6.03; found: C, 51.84; H, 4.96; N, 10.28; F, 3.62; S, 6.01. Ex. Structure Data
Yield: 65%. 1H-NMR (300 MHz, CDCI3/1drop MeOD) δ: 8.28-8.24 (1H, m), 7.46-7.43 (2H, m), 7.35-7.32 (2H, m), 4.89 (1 H, dd, J = 14.3, 8.4 Hz), 4.45 (1 H, dd, J = 14.3, 4.4 Hz), 3.97 (4H1 s), 3.89-3.65 (5H, m), 3.43-3.36 (1H, m), 3.33-3.16 (2H, m), 2.46-2.24 (4H, m), 1.96-1.88 (2H, m), 1.73- 1.65 (2H, m). HRMS [M+H]+ calcd for C23H29N4O7S: 505.1757; found: 505.1761.
Figure imgf000114_0001
Anal cald for C23H28N4O7S: C, 54.75; H, 5.59; N, 11.10; S, 6.35; found: C, 55.03; H, 5.29; N, 11.06; S1 6.18. Yield: 70%. 1H-NMR (300 MHz, CDCI3) δ: 11.80 (1 H1 S)1 8.50 (1 H1 W = 6.6 Hz)1 7.74 (1H1 dd J = 8.1, 2.9 Hz), 7.65 (1H, dd, J = 8.6, 5.3 Hz), 7.31 (1 H, dt, J = 8.0, 3.2 H), 4.82 (2H1 d, J = 6.9 Hz), 3.99 (4H, S)1 3.84 (2H, dd, J = 11.5, 4.9 Hz), 3.74 (2H, td, J = 11.6, 1.3 Hz), 3.18 (3H, s), 2.31 (2H, td, J = 13.2, 5.5 Hz), 1.74 (2H, d, J = 13.2 Hz). HRMS [M+H]+ calcd for C20H23N3O7SF:
Figure imgf000114_0002
468.1241 ; found: 468.1237. Anal cald for C20H22N3O7SF: C, 51.38; H, 4.74; N, 8.98; S, 6.86; F, 4.06; found: C, 51.25; H1 4.62; N, 8.81; S, 6.82; F, 4.18. Ex. Structure Data
Yield: 19%. 1H-NMR (300 MHz, CDCI3) δ: 12.08 (1H, s), 7.75 (1 H, s, J = 5.8 Hz), 7.15-7.08 (2H, m), 6.96 (1H, t, J = 9.0 Hz), 4.51 (2H, d, J = 6.2 Hz), 4.00 (4H, s), 3.85- 3.70 (4H, m), 2.32-2.22 (2H, m), 2.26 (3H,
Figure imgf000115_0001
d, J = 1.8 Hz), 1.76 (2H, d, J = 13.5 Hz). HRMS [M+H]+ calcd for C20H23N3O5F: 404.1622; found: 404.1615. Yield: 39%. 1H-NMR (300 MHz, CDCI3) δ: 12.18 (1H, s), 8.12 (1H, t, J = 6.0 Hz), 7.19 (1 H, d, J = 8.0 Hz), 6.48-6.41 (2H, m), 4.50 (2H, d, J = 6.2 Hz), 3.99 (3H, s), 3.88 (3H, s), 3.86-3.71 (4H, m), 3.78 (4H, s), 2.27
46 (2H, td, J = 13.0, 5.6 Hz), 1.76 (2H, d, J = 12.8 Hz). HRMS [M+H]+ calcd for
Figure imgf000115_0002
C21H26N3O7: 432.1771 ; found: 432.1771. Anal cald for C2i H25N3O7: C, 58.46; H, 5.84; N, 9.74; found: C, 58.22; H, 5.89; N, 9.69.
Yield: 44%. 1H-NMR (300 MHz, CDCI3) δ: 11.91 (1 H, s), 8.52 (1 H, t, J = 6.6 Hz), 7.63 (1 H, dd, J = 8.4, 5.5 Hz), 7.47 (1H, dd, J = 8.4, 2.9 Hz), 7.27-7.22 (1 H1 m), 4.81 (2H, d, J = 6.9 Hz), 3.98 (4H1 s), 3.85-3.70 (4H, m), 2.90 (6H, s), 2.31 (2H1 td, J = 13.0, 5.2 Hz), 1.73 (2H, d, J = 13.5 Hz). HRMS [M+H]+ calcd for C2iH26N4O7FS: 497.1506; found:
Figure imgf000115_0003
497.1497. Anal cald for C2iH25N4O7FS: C, 50.80; H, 5.07; N, 11.28; S, 6.45; F, 3.82; found: C, 50.59; H, 4.99; N, 11.01; S, 6.19; F, 4.03. Ex. Structure Data
Yield: 54%. 1H-NMR (500 MHz, CDCI3) δ: 12.20 (1H, s), 7.76 (1H1 1, J = 5.3 Hz), 7.14- 7.11 (2H, m), 7.08 (1 H, d, J = 7.6 Hz), 4.54 (2H, d, J = 6.1 Hz), 4.04-4.01 (4H1 m), 3.83 (2H, dd, J = 11.4, 5.0 Hz), 3,77 (2H, t, J =
48 11.4 Hz), 2.32-2.28 (2H, m), 2.26 (6H, d, J = 5.8 Hz), 1.78 (2H, d, J = 13.4 Hz). HRMS
Figure imgf000116_0001
[M+H]+ calcd for C2IH26N3O5: 400.1872; found: 400.1869. Anal cald for C2IH25N3O5 C, 63.14; H, 6.30; N, 10.52; found: C, 62.39; H, 6.01 ; N, 10.23. Yield: 59%. 1H-NMR (300 MHz, CDCI3) δ: 11.80 (1H1 s), 8.83 (1H, t, J = 6.2 Hz) 8.20 (1 H, s), 7.63 (1 H, dd, J = 8.6, 6.0 Hz), 7.20 (1 H, dd, J = 8.6, 2.4 Hz), 6.99 (1 H, dd, J 8.4, 2.6 Hz), 4.27 (2H, d, J = 6.6 Hz), 3.99 (4H, s), 3.87 (2H, dd, J = 11.3, 4.4 Hz), 9 3.76 (2H, t, J = 11.7 Hz), 2.45 (3H, s), 2.48- 2.38 (2H1 m), 1.78 (2H1 d, J = 13.5 Hz).
Figure imgf000116_0002
HRMS [M+H]+ calcd for C22H24N6O5F: 471.1792; found: 471.1786. Anal cald for C22H23N6O5F: C1 56.16; H1 4.92; N1 17.86; F1 4.03; found: C1 55.88; H1 5.02; N, 17.74; F, 3.79.
Ex. Structure Data
Yield: 35%. 1H-NMR (300 MHz, CDCI3) δ: 12.11 (1 H, s), 8.78 (1H1 t, J = 7.3 Hz), 8.28 (1H1 s), 7.66 (1H, dd, J = 8.6, 6.0 Hz), 7.14 (1H1 td, J = 8.2, 2.7 Hz), 7.06 (1H, dd, J = 8.4, 2.6 Hz), 4.45 (2H, d, J = 6.6 Hz), 3.99 (4H1 s), 3.82-3.71 (4H, m), 2.59 (3H, s), 2.39-2.29 (2H, m), 1.75 (2H, d, J = 14.3 Hz). HRMS (M+H) calcd for C22H24N6O5F: 471.1792; found: 471.1812. Anal cald for
Figure imgf000117_0001
C22H24N6O5F • 0.2 H2O: C1 55.74; H1 4.98; N1 17.73; F1 4.01; found: C, 55.60; H, 4.92; N1 17.85; F, 3.84.
Yield: 34%. 1H NMR (500 MHz1 CDCI3) δ: 12.01 (1 H1 s), 8.95 (1H1 1, J = 6.3 Hz)1 8.46 (1H, s), 8.15 (1H1 s), 7.73 (1H1 dd, J = 8.6, 6.1 Hz)1 7.21 (1H1 td, J = 8.2, 2.6 Hz), 7.12 (1H, dd, J = 8.6, 2.4 Hz), 4.47 (2H, d, J = 6.7 Hz), 3.96 (4H, s), 2.67-2.75 (2H, m), 2.32-2.40 (2H, m), 2.15-2.24 (1H1 m), 2.08
Figure imgf000117_0002
(1H, m). HRMS (M+H) calcd for C20H20N6O4F: 427.1530; found: 427.1540.
Ex. Structure Data
Yield: 27%. 1H NMR (500 MHz, CDCI3) δ: 12.00 (1H1 s), 7.82-7.90 (1H, m), 7.32 (2H, del, 9, 5 Hz), 7.02-7.08 (2H, m), 4.61 (2H, d, 6 Hz), 3.97 (4H1 ddd, 14, 8, 3 Hz), 2.60- 2.66 (2H, m), 2.29-2.36 (2H, m), 2.01-2.10 (1 H, m), 1.90-1.99 (1 H1 m). 13C NMR (126
MHz1 CDCI3) 6: 168.39, 163.46, 161.50,
Figure imgf000118_0001
157.66, 150.60, 146.85, 133.20, 133.17, 129.42, 129.36, 125.4O1 116.02, 115.84, 78.73, 58.62, 42.53, 34.74, 14.13. HRMS (M+H) calcd for C18H19N3O4F: 360.1360; found: 360.1350.
Yield: 43%. 1H NMR (500 MHz, CDCI3) δ: 11.81 (1H, s), 8.68 (1H1 t, J = 7 Hz)1 7.71- 7.77 (2H, m), 7.35 (1H, td, 8, 3 Hz)1 4.84 (2H1 d, 7 Hz), 3.93-3.95 (4H, m), 3.18 (3H1 s), 2.62-2.68 (2H, m), 2.29-2.36 (2H, m), 2.13-2.19 (1 H, m), 2.01-2.08 (1H, m). 13C
53 NMR (126 MHz, CDCI3) δ: 168.22, 163.16,
161.14, 157J0, 150.86, 146.63, 140.77,
Figure imgf000118_0002
140.72, 135.31 , 135.25, 132.83, 132.80, 125.57, 121.69, 121.53, 117.65, 117.45, 78.69, 58.51, 45.18, 42.53, 40.34, 34.84, 13.59. HRMS (M+H) calcd for
C19H2IFN3O6S: 438.1135, found 438.1149. Ex. Structure Data
Yield: 56%. 1H NMR (500 MHz, CDCI3) δ: 11.91 (1 H, s), 8.73 (1 H, t, J = 6.7 Hz), 7.71 (1H, dd, J = 8.4, 5.3 Hz), 7.49 (1H, dd, J = 8.4, 2.6 Hz), 7.25-7.29 (1 H, m), 4.83 (2H1 d, J = 7.0 Hz), 3.94 (4H, s), 2.90 (6H, s), 2.64- 2.70 (2H, m), 2.28-2.35 (2H, m), 2.12-2.21 (1H, m), 1.99-2.08 (1H, m). 13C NMR (126 MHz, CDCI3) δ: 168.09, 162.72, 160.72,
54 157.75, 150.67, 146.59, 138.58, 138.53, 135.31 , 135.25, 132.70, 132.67, 125.73,
Figure imgf000119_0001
120.40, 120.23, 116.86, 116.66, 78.74, 58.53, 42.50, 40.34, 37.61 , 34.81 , 13.58. HRMS (M+H) calcd for C20H24N4O6FS 467.1401, found 467.1418. Anal, calcd for C20H23N4O6FS: C 51.49, H 4.97, N 12.01 , F 4.07, S 6.87; found: C 51.27, H 4.98, N 12.17, F 4.11, S 6.86.
Ex. Structure Data
Yield: 73%. 1H NMR (500 MHz, CDCI3) δ: 12.16 (1 H1 s), 8.33-8.39 (1 H, m), 7.49 (1 H1 dd, J = 8.7, 6.3 Hz), 7.17 (1H, dd, J = 9.0, 2.6 Hz), 7.07 (1 H, td, J = 8.2, 2.6 Hz), 4.97 (1 H, dd, J = 14.0, 8.9 Hz), 4.40 (1 H, dd, J = 14.3, 3.7 Hz), 3.92-3.98 (4H, m), 3.81-3.88 (1 H, m), 3.44 (1 H, dt, J = 12.6, 3.6 Hz), 3.23-3.28 (2H, m), 2.64-2.70 (2H, m), 2.32- 2.42 (2H, m), 2.20-2.29 (2H, m), 1.98-2.06 (2H, m), 1.88-1.98 (2H, m). 13C NMR (126
55 MHz, CDCI3) δ: 168.28, 163.49, 161.50, 157.79, 150.47, 146.69, 139.89, 139.82,
Figure imgf000120_0001
133.17, 132.16, 132.08, 125.81, 116.64, 116.47, 115.15, 114.97, 79.12, 58.57, 54.17, 51.07, 42.54, 38.53, 34.58, 34.52, 24.97, 24.24, 14.00. HRMS (M+H) calcd for C22H26N4O6FS 493.1557; found 493.1549. Anal, calcd for C22H25N4O6FS: C 53.65, H 5.12, N 11.38, F 3.86, S 6.51 ; found: C 53.73, H 4.91 , N 11.06, F 3.55, S 6.42.
Ex. Structure Data
Yield: 66%. 1H NMR (500 MHz, CDCI3) δ: 12.15-12.29 (1 H, br s), 8.32-8.40 (1 H1 m), 7.47-7.52 (1 H1 m), 7.42-7.47 (1H, m), 7.33- 7.39 (2H, m), 4.99 (1 H, dd, J = 14.0, 8.9 Hz), 4.47 (1 H, dd, J = 14.3, 3.7 Hz), 3.92- 3.98 (4H, m), 3.84-3.92 (1H, m), 3.41-3.47 (1H, m), 3.22-3.28 (2H, m), 2.64-2.71 (2H, m), 2.37-2.46 (1 H, m), 2.31-2.37 (1 H, m), 2.19-2.29 (2H, m), 1.98-2.06 (2H, m), 1.89-
56 1.98 (2H, m). 13C NMR (126 MHz, CDCI3) δ: 168.26, 157.82, 150.40, 146.68, 138.82,
Figure imgf000121_0001
137.01, 130.80, 129.46, 129.32, 127.72, 125.90, 79.15, 58.58, 54.15, 51.05, 42.53, 39.17, 34.58, 34.51 , 25.05, 24.34, 14.03. HRMS (M+H) calcd for C22H27N4O6S 475.1651 ; found 475.1665. Anal, calcd for C22H26N4O6S: C 55.68, H 5.52, N 11.81, S 6.76; found: C 55.53, H 5.36, N 11.77, S 6.61.
Ex. Structure Data
Yield: 55%. 1H NMR (500 MHz, CDCI3) δ: 11.93 (1 H1 s), 8.61 (1H, br), 7.98 (1 H, s), 7.70 (1 H1 dd, J = 8.5, 5.8 Hz), 7.22-7.26 (1 H, m), 7.02 (1 H, dd, J = 8.4, 2.6 Hz), 4.32 (2H, d, J = 6.7 Hz), 3.94-3.97 (4H, m), 2.72 (2H, ddd, J = 12.7, 9.2, 5.5 Hz), 2.48 (3H, s), 2.36 (2H1 ddd, J = 12.5, 10.1 , 7.3 Hz), 2.15-2.23 (1 H, m), 2.05-2.14 (1 H, m). 13C NMR (126 MHz, CDCI3) δ: 168.13, 163.04, 161.04, 157.64, 153.70, 151.42, 150.47,
Figure imgf000122_0001
146.83, 137.25, 137.17, 133.57, 133.50, 130.89, 130.86, 125.58, 117.61, 117.45, 114.43, 114.24, 78.78, 65.84, 58.62, 42.44, 38.82, 34.75, 15.29, 13.83, 12.68. HRMS (M+H) calcd for C2IH22N6O4F: 441.1687; found: 441.1692.
Ex. Structure Data
Yield: 43%. 1H NMR (500 MHz1 CDCI3) δ: 11.90 (1H, br s), 8.62 (1 H1 t, 6.7 Hz), 7.74 (1H, dd, J = 7.9, 2.8 Hz), 7.71 (1 H, dd, J = 8.6, 5.2 Hz), 7.34 (1H, dt, J = 8.0, 2.6 Hz), 4.83 (2H, d, J = 6.7 Hz), 4.36 (2H, br), 3.89 (2H, t, J = 5.7 Hz), 3.17 (3H, s), 2.69-2.79 (2H1 br), 2.37-2.46 (2H, m), 1.85-1.94 (1H, m), 1.79- .85 (2H, m), 1.63-1.73 (1H, m). 13C NMR (125.77 MHz, CDCI3) δ: 168.34, 163.12, 161.11 , 158.52, 151.12, 147.55,
Figure imgf000123_0001
140.72, 140.67, 135.12, 135.05, 132.86, 132.83, 124.42, 121.66, 121.49, 117.61 , 117.41 , 82.32, 64.43, 45.17, 40.80, 40.25, 32.02, 28.59, 12.79. HRMS (M+H) calcd for C20H23FN3O6S: 452.1292, found 452.1299.
Yield: 52%. 1H NMR (500 MHz, CDCI3) δ: 12.09 (1H, s), 7.82 (1H, br t), 7.31 (2H1 dd, J = 8.1, 5.6 Hz), 7.05 (2H, t, J = 8.5 Hz), 4.59 (2H, d, J = 6.1 Hz), 4.39 (2H, br), 3.92 (2H, t, J = 5.5 Hz), 2.63-2.71 (2H, br), 2.38- 2.46 (2H, m), 1.89 (1H, td, J = 10.0, 5.6 Hz), 1.82-1.87 (2H1 m), 1.60-1.69 (1 H1 m).
13 C, NMR (126 MHz, CDCI3) δ: 168.48, 163.46, 161.49, 158.45, 150.94, 147.73,
Figure imgf000123_0002
133.15, 133.12, 129.45, 129.39, 124.27, 115.99, 115.83, 82.11 , 64.59, 42.49, 40.81 , 31.88, 28.67, 12.85. HRMS (M+H) calcd for Ci9H2IFN3O4: 374.1516; found: 374.1515. Ex. Structure Data
Yield: 18%. 1H NMR (500 MHz, CDCI3) δ: 12.10 (1H, s), 9.02 (1 H, t, J = 6.4 Hz), 8.46 (1 H1 s), 8.13 (1 H, s), 7.71 (1 H, dd, J = 8.5, 5.8 Hz), 7.21 (1 H, td, J = 8.2, 2.7 Hz), 7.11 (1H, dd, J = 8.4, 2.6 Hz), 4.45 (2H, d, J = 7.0 Hz), 4.38 (2H, br), 3.89 (2H, t, J = 5.6 Hz), 2.82 (2H, br), 2.41-2.48 (2H, m), 1.87- 1.95 (1 H, m), 1.83 (2H, ddd, J = 10.8, 5.6, 5.5 Hz), 1.69-1.78 (1H1 m). 13C NMR (126 MHz, CDCI3) δ: 168.10, 163.20, 161.20,
Figure imgf000124_0001
158.53, 152.73, 150.74, 147.62, 143.85, 136.97, 136.89, 134.46, 134.38, 128.65, 128.61 , 124.63, 117.14, 116.98, 112.38, 112.19, 82.35, 64.46, 40.71 , 39.11 , 32.10, 28.61 , 12.71. HRMS (M+H) calcd for C2IH22FN6O4: 441.1687, found: 441.1695.
Ex. Structure Data
Yield: 33%. 1H NMR (500 MHz, CDCI3) δ: 12.02 (1 H, br s), 8.64 (1H, t, J = 6.6 Hz), 7.69 (1 H1 dd, J = 8.5, 5.5 Hz), 7.49 (1 H, dd, J = 8.2, 2.7 Hz), 7.24-7.29 (1 H, m), 4.82 (2H, 6, J = 6.7 Hz), 4.36 (2H, br), 3.88 (2H, t, J = 5.5 Hz), 2.89 (6H, s), 2.74 (2H, m), 2.37-2.44 (2H, m), 1.85-1.92 (1H, m), 1.82 (2H, dt, J = 11.0, 5.5 Hz), 1.65-1.74 (1H, m). 13C NMR (126 MHz, CDCI3) δ: 168.21 ,
61 162.69, 160.68, 158.54, 150.96, 147.55, 138.56, 138.50, 135.15, 135.09, 132.72,
Figure imgf000125_0001
132.69, 124.57, 120.38, 120.22, 116.84, 116.64, 82.37, 64.39, 40.71 , 40.22, 37.58, 32.09, 28.59, 12.77. HRMS (M+H) calcd for C2IH26FN4O6FS 481.1557, found 481.1555. Anal, calcd for C21 H25N4O6FS: C 52.49, H 5.24, N 11.66, F 3.95, S 6.67; found: C 52.22, H 5.09, N 11.43, F 3.93, S 6.60.
Yield: 82%. 1H NMR (500 MHz, CDCI3) δ: 11.90 (1H1 s), 8.03 (1 H, br t), 7.40-7.30 (5H, m), 4.67 (2H, d, J = 6.4 Hz), 3.96 (2H, t, J = 6.4 Hz), 2.63-2.57 (2H, m), 2.07-1.91 2 (8H, m). HRMS (M+H) calcd for C19H22N3O3: 340.1661 ; found: 340.1652.
Figure imgf000125_0002
Anal cald for C19H21N3O3: C, 67.24; H, 6.23; N, 12.38; found: C, 66.85; H, 6.14; N, 12.31. Ex. Structure Data
Yield: 78%. 1H NMR (500 MHz1 CDCI3) δ: 11.93 (1 H, s), 7.99 (1 H1 br t), 7.25 (2H, d, J = 6.7 Hz), 7.18 (2H, d, J = 7.6 Hz), 4.62 (2H, d, J = 6.1 Hz)1 3.96 (2H, t, J = 6.3 Hz), 2.62-2.56 (2H, m), 2.35 (3H, s), 2.07-1.90 (8H, m). HRMS (M+H) calcd for
Figure imgf000126_0001
C20H24N3O3: 354.1818; found: 354.1823.
Anal cald for C2OH23N3O3: C1 67.97; H, 6.55; N1 11.89; found: C1 67.81 ; H1 6.84; N1 11.94.
Yield: 76%. 1H NMR (500 MHz1 CDCI3) δ: 11.93 (1 H, s), 7.96 (1H, t, J = 5.2 Hz), 7.29 (2H1 d, J = 8.5 Hz)1 6.90 (2H1 d, J = 8.5 Hz)1 4.59 (2H, d, J = 6.6 Hz), 3.96 (2H, t, J = 6.4 Hz), 3.81 (3H1 s) 2.62-2.56 (2H1 m), 2.07- 1.90 (8H1 m). HRMS (M+H) calcd for
Figure imgf000126_0002
C20H24N3O4: 370.1767; found: 370.1780. Anal cald for C20H23N3O4: C1 65.02; H1 6.27; N, 11.37; found: C, 64.94; H1 6.53; N1 11.46.
Yield: 74%. 1H NMR (500 MHz1 CDCI3) δ: 11.79 (1 H1 S)1 8.02 (1H1 br t), 7.34 (2H1 d, J = 8.6 Hz), 7.29 (2H1 d, J = 8.6 Hz), 4.63 (2H1 d, J = 6.4 Hz)1 3.96 (2H1 1, J = 6.4 Hz)1 2.63-2.57 (2H1 m), 2.08-1.91 (8H1 m). HRMS (M+H) calcd for Ci9H2iCIN3O3:
Figure imgf000126_0003
374.1271; found: 374.1287. Anal cald for C19H20CIN3O3: C1 61.04; H1 5.39; N, 11.24; found: C, 61.05; H, 5.41 ; N, 11.10. Ex. Structure Data
Yield: 72%. 1H NMR (500 MHz, CDCI3) δ: 11.83 (1H1 s), 8.01 (1H, br t), 7.34 (2H, dd, J = 8.6, 5.2 Hz), 7.06 (2H, t, J = 8.6 Hz), 4.62 (2H, d, J = 6.4 Hz), 3.96 (2H, t, J = 6.3
66 Hz), 2.62-2.56 (2H, m), 2.08-1.91 (8H, m).
Figure imgf000127_0001
HRMS (M+H) calcd for Ci9H2IFN3O3: 358.1567; found: 358.1551. Anal cald for C19H20FN3O3: C, 63.85; H, 5.64; N1 11.75; found: C, 63.72; H, 5.52; N, 11.63. Yield: 80%. 1H NMR (500 MHz, CDCI3) δ: 11.78 (1 H, s), 8.06 (1 H1 br t), 7.36-7.31 (1H, m), 7.14 (1 H, d, J = 7.9 Hz)1 7.06 (1 H, d, J = 9.5 Hz), 7.00 (1 H, td, J = 8.4, 2.4 Hz)1 4.66 (2H1 d, J = 6.4 Hz), 3.97 (2H, t, J
67 = 6.4 Hz), 2.64-2.58 (2H, m), 2.09-1.91 (8H1 m). HRMS (M+H) calcd for
Figure imgf000127_0002
C19H2IFN3O3: 358.1567; found: 358.1553. Anal cald for Ci9H20FN3O3: C, 63.85; H, 5.64; N1 11.75; found: C1 63.86; H1 5.64; N1 11.50.
Yield: 75%. 1H NMR (500 MHz, CDCI3) δ: 11.78 (1 H1 s), 8.14 (1 H1 br t), 7.40 (1 H1 td, J = 7.5, 1.2 Hz)1 7.32-7.28 (1 H1 m), 7.14 (1 H1 td, J = 7.5, 1.0 Hz)1 7.09 (1H1 dd, J = 10.1 , 8.2 Hz), 4.70 (2H, d, J = 6.4 Hz), 3.95 (2H, 8 t, J = 6.4 Hz), 2.65-2.59 (2H1 m), 2.09-1.90 (8H1 m). HRMS (M+H) calcd for
Figure imgf000127_0003
C19H2IFN3O3: 358.1567; found: 358.1569. Anal cald for Ci9H2oFN3O3: C1 63.85; H1 5.64; N1 11.75; found: C, 63.75; H1 5.55; N1 11.70. Ex. Structure Data
Yield: 71 %. 1H NMR (500 MHz, CDCI3) δ: 11.95 (1 H1 s), 7.99 (1 H, br t), 7.14 (1 H, d, J = 7.6 Hz),7.13 (1H, s), 7.09 (1H, d, J = 7.6 Hz), 4.59 (2H1 d, J = 6.4 Hz), 3.96 (2H1 t, J = 6.4 Hz), 2.62-2.57 (2H, m), 2.27 (3H1 s), 2.26 (3H, s), 2.07-1.90 (8H1 m). HRMS
Figure imgf000128_0001
(M+H) calcd for C2IH26N3O3: 368.1974; found: 368.1960. Anal cald for C2iH25N3O3: C1 68.64; H1 6.85; N, 11.43; found: C, 67.93; H, 5.93; N, 11.27. Yield: 91%. 1H NMR (500 MHz1 CDCI3) δ: 11.70 (1 H1 S)1 8.05 (1 H, t, J = 5.5 Hz), 7.44 (1 H, s), 7.43 (1 H1 d, J = 5.5 Hz), 7.21 (1 H1 dd, J = 8.1 , 1.7 Hz)1 4.61 (2H1 d, J = 6.4 Hz), 3.97 (2H, t, J = 6.4 Hz), 2.64-2.58 (2H, m), 2.09-1.91 (8H, m). HRMS (M+H) calcd for Ci9H20CI2N3O3: 408.0882; found:
Figure imgf000128_0003
408.0871. Anal cald for C19H19CI2N3O3: C, 55.89; H, 4.69; N, 10.29; found: C, 55.65; H, 4.51 ; N, 10.26.
Yield: 81 %. 1H NMR (500 MHz, CDCI3) δ: 11.99 (1 H1 s), 8.35 (1H1 t, J = 5.5 Hz, 7.23 (1H, d, J = 8.2 Hz), 6.49 (1 H, d, J = 2.1 Hz), 6.46 (1 H, dd, J = 8.2, 2.1 Hz)1 4.55 (2H1 d, J = 6.4 Hz), 3.94 (2H, t, J = 6.4 Hz)1 3.88
71 (3H, S)1 3.80 (3H, s), 2.65-2.59 (2H1 m),
Figure imgf000128_0002
2.10-1.89 (8H, m). HRMS (M+H) calcd for C21H26N3O5: 400.1872; found: 400.1884. Anal cald for C21H25N3O5: C, 63.14; H, 6.30; N, 10.52; found: C, 62.99; H, 6.46; N, 10.49. Ex. Structure Data
Yield: 74%. 1H NMR (500 MHz, CDCI3) δ: 11.86 (1 H, s), 7.99 (1 H1 1, J = 4.9 Hz), 7.17 (1 H1 d, J = 7.0 Hz), 7.15-7.12 (1 H, m), 6.99 (1 H, t, J = 8.9 Hz), 4.58 (2H1 d, J = 6.4 Hz), 3.96 (2H, t, J = 6.4 Hz), 2.63-2.57 (2H1 m), 2.28 (3H, d, J = 1.5 Hz), 2.08-1.91 (8H, m).
Figure imgf000129_0003
HRMS (M+H) calcd for C20H23FN3O3: 372.1723; found: 372.1737. Anal cald for C20H22FN3O3: C, 64.67; H, 5.97; N, 11.31 ; found: C, 64.73; H, 6.20; N, 11.30. Yield: 73%. 1H NMR (500 MHz, CDCI3) δ: 11.82 (1 H1 s), 8.02 (1 H, br t), 7.17 (1 H, t, J = 7.8 Hz), 7.02 (1 H, d, J = 8.6 Hz), 7.00 (1 H, d, J = 10.7 Hz), 4.61 (2H, d, J = 6.1 Hz), 3.96 (2H, t, J = 6.4 Hz), 2.63-2.57 (2H, m), 2.26 (3H, s), 2.08-1.91 (8H, m). HRMS
Figure imgf000129_0001
(M+H) calcd for C20H23FN3O3: 372.1723; found: 372.1714. Anal cald for
C20H22FN3O3: C, 64.67; H1 5.97; N, 11.31 ; found: C, 64.56; H, 6.08; N, 11.41. Yield: 73%. 1H NMR (500 MHz, CDCI3) δ: 11.78 (1 H, s), 7.91 (1 H, d, J = 7.6 Hz), 7.36-7.33 (2H, m), 7.06 (2H, td, J = 8.6, 1.2 Hz), 5.25-5.19 (H, m), 3.96 (2H, t, J = 6.4 Hz), 2.64-2.56 (2H, m), 2.11-1.91 (8H, m), 1.62 (3H, d, J = 7.0 Hz). HRMS (M+H)
Figure imgf000129_0002
calcd for C20H23FN3O3: 372.1723; found: 372.1708. Anal cald for C20H22FN3O3: C, 64.67; H, 5.97; N, 11.31 ; found: C, 63.20; H, 6.22; N, 10.74. Ex. Structure Data
Yield: 79%. 1H NMR (500 MHz1 CDCI3) δ: 11.67 (1H1 s), 8.13 (1H, br t), 7.11-7.03 (2H, m), 6.99-6.94 (1 H, m), 4.68 (2H, d, J = 6.4 Hz)1 3.96 (2H1 t, J = 6.4 Hz), 2.65-2.59 (2H, m), 2.10-1.91 (8H, m). HRMS (M+H) calcd for C19H20F2N3O3: 376.1473; found:
Figure imgf000130_0001
376.1483. Anal cald for Ci9Hi9F2N3O3: C, 60.79; H, 5.10; N1 1*1.19; found: C1 60.60; H1 5.21 ; N, 11.17.
Yield: 75%. 1H NMR (500 MHz, CDCl3) δ: 11.62 (1 H, s), 8.30 (1H, t, J = 5.8 Hz), 7.41 (1 H1 d, J = 2.5 Hz), 7.34 (1 H, d, J = 8.6 Hz), 7.25 (1H, dd, J = 8.2, 2.4 Hz), 4.69 (2H, d, J = 6.7 Hz), 3.96 (2H, t, J = 6.3 Hz), 2.66- 2.60 (2H, m), 2.11-1.91 (8H, m). HRMS (M+H) calcd for C19H20CI2N3O3: 408.0882;
Figure imgf000130_0002
found: 408.0879. Anal cald for
Ci9Hi9CI2N3O3: C, 55.89; H, 4.69; N, 10.29; found: C, 55.66; H, 4.83; N, 10.27. Yield: 51 %. 1H NMR (500 MHz, CDCI3) δ: 11.74 (1H, s), 8.97 (1 H, t, J = 6.4 Hz), 8.41 (1H, s), 8.16 (1H, s), 7.44 (1H, dd, J = 8.5, 2.8 Hz), 7.35 (1H, dd, J = 8.5, 4.9 Hz), 7.15 (1 H, td, J = 8.5, 2.8 Hz), 4.46 (2H, d, J = 6.7 Hz), 3.94 (2H, t, J = 6.4 Hz), 2.75-2.69 (2H, m), 2.16-1.90 (8H, m). HRMS (M+H) calcd for C21H22FN6O3: 425.1737; found:
Figure imgf000130_0003
425.1735. Anal cald for C2iH2i FN6O6: C, 59.42; H, 4.98; N, 19.80; found: C, 59.20; H, 4.88; N, 19.51. Ex. Structure Data
Yield: 59%. 1H NMR (500 MHz, CDCI3) δ: 11.81 (1 H1 s), 9.07 (1H, t, J = 6.4 Hz), 8.46 (1 H, s), 8.18 (1H, s), 7.73 (1 H, dd, J = 8.4, 6.0 Hz), 7.22 (1 H, td, J = 8.2, 2.4 Hz), 7.12 (1H, dd, J = 8.6, 2.4 Hz), 4.48 (2H, d, J = R 6.77 H HzyΛ), ^ 3. Q94A / (O2HH, t t, J I == R 6.-4I U HzΎ\), 29.7755.-29. R6Q9 (2H, m), 2.17-1.89 (8H, m). HRMS (M+H)
Figure imgf000131_0002
calcd for C2IH22FN6O3: 425.1737; found: 425.1727. Anal cald for C21 H2i FN6O6: C, 59.42; H, 4.98; N, 19.80; found: C, 59.35; H, 4.69; N, 19.85.
Yield: 53%. 1H NMR (500 MHz, CDCI3) δ: 11.96 (1H, s), 8.42 (1 H, br t), 7.49 (1 H, dd, J = 8.5, 6.4 Hz), 7.18 (1H, dd, J = 9.2, 2.4 Hz), 7.08 (1 H1 td, J = 8.2, 2.4 Hz), 4.99 (1 H, dd, J = 14.4, 8.5 Hz)1 4.42 (1 H, dd, J = 14.4, 3.7 Hz), 3.99-3.83 (3H, m), 3.45 (1H,
79 dt, J = 12.5, 4.0 Hz), 3.28-3.25 (2H, m), 2.70-2.61 (2H, m), 2.45-2.31 (2H, m), 2.03-
Figure imgf000131_0001
1.9 (1OH, m). HRMS (M+H) calcd for C23H28FN4O5S: 491.1764; found: 491.1776. Anal cald for C23H27FN4O5S: C, 56.31; H, 5.54; N, 11.41 ; found: C, 56.07; H, 5.60; N, 11.25.
Ex. Structure Data
Yield: 66%. 1H NMR (500 MHz3 CDCI3) δ: 11.87 (1 H, s), 9.11 (1 H, t, J = 6.4 Hz), 8.45 (1H, s), 8.17 (1H1 s), 7.73 (1H, dd, J = 7.3, 1.2 Hz), 7.51 (1H1 td, J = 7.3, 1.2 Hz), 7.47 (1 H, td, J = 7.6, 1.5 Hz), 7.36 (1 H, dd, J = 7.6, 1.0 Hz), 4.51 (2H, d, J = 6.7 Hz), 3.94 (2H, t, J = 6.4 Hz), 2.76-2.70 (2H, m), 2.17- 1.89 (8H, m). HRMS (M+H) calcd for
Figure imgf000132_0001
C2IH23N6O3: 407.1832; found: 407.1833. Anal cald for C21H22N6O3: C, 62.05; H, 5.45; N, 20.67; found: C, 61.86; H, 5.48; N, 20.90.
Yield: 57%. 1H NMR (500 MHz, CDCI3) δ: 11.60 (1 H, s), 8.78 (1H, t, J = 6.4 Hz), 7.76 (1 H, dd, J = 8.2, 2.4 Hz), 7.73 (1 H, dd, J = 8.6, 5.2 Hz), 7.35 (1 H, td, J = 8.2, 2.8 Hz), 4.86 (2H, d, J = 7.0 Hz), 3.93 (2H, t, J = 6.4
Hz), 3.19 (3H, s), 2.68-2.62 (2H, m), 2.15- 1.88 (8H, m). HRMS (M+H) calcd for C20H23FN3O5S: 436.1342; found: 436.1325.
Figure imgf000132_0002
Anal cald for C20H22FN3O5S: C, 55.16; H, 5.09; N, 9.65; found: C, 55.00; H, 4.93; N, 9.45.
Ex. Structure Data
Yield: 64%. 1H NMR (500 MHz, CDCI3) δ: 11.48 (1 H1 br s), 8.82 (1 H, t, J = 6.4 Hz)1 7.71 (1 H, dd, J = 8.2, 5.5 Hz), 7.51 (1 H, dd, J = 8.2, 2.1 Hz), 7.29 (1 H, dd, J = 8.2, 2.4 Hz), 4.85 (2H, d, J = 7.0 Hz), 3.94 (2H, t, J
= 6.4 Hz), 2.91 (6H, s), 2.69-2.64 (2H, m), 2.15-1.89 (8H1 m). HRMS (M+H) calcd for
Figure imgf000133_0001
C2IH26FN4O5S: 465.1608; found: 465.1593. Anal cald for C21 H25FN4O5S-0.44 CF3CO2H: C, 51.06; H, 4.98; N, 10.89; found: C1 51.41 ; H, 5.18; N1 10.50. Yield: 48%. 1H NMR (500 MHz, CDCI3) δ: 12.01 (1 H, s), 8.43-8.41 (1H1 m), 7.50-7.48 (1 H1 m), 7.46-7.45 (1 H, m), 7.35-7.35 (2H, m), 5.02 (1 H1 dd, J = 14.3, 8.6 Hz), 4.49 (1H1 dd, J = 14.3, 4.0 Hz), 3.96-3.87 (3H, m), 3.46-3.42 (1 H, m), 3.27-3.24 (2H, m), 2.71-2.61 (2H1 m), 2.45-2.31 (2H, m), 2.02- 1.84 (10H, m). HRMS (M+H) calcd for
Figure imgf000133_0002
C23H29N4O5S: 473.1859; found: 473.1866. Anal cald for C23H28N4O5S-0.12 C2H5OH»0.3 H2O: C, 57.73; H, 6.11 ; N, 11.59; found: C, 57.48; H, 5.67; N, 11.47. Yield = 47%. 1H NMR (300 MHz, CDCI3) δ: 1.65-2.02 (8 H, m), 2.07 (2 H, t, J = 7 Hz), 4.03 (2 H1 t, J = 7 Hz), 4.55 (2 H, d, J=6.2 Hz), 7.02 (2 H, t, J=8.6 Hz), 7.29 (2 H1 dd, J = 8.6, 5.3 Hz)1 7.90 (1 H, brs), 12.09 (1 H,
Figure imgf000133_0003
s). HRMS (M+H)calcd for C19H21FN3O3: 358.1567; found: 358.1578. Ex. Structure Data
Yield = 54%. 1H NMR (300 MHz, CDCI3) δ: 1.64 1.78 (4 H1 m), 1.87-2.01 (4 H, m), 2.07 (2 H, t, J = 7 Hz)1 3.15 (3H1 s), 4.01 (2 H, t, J = 7 H), 4.82 (2 H, d, J = 7.0 Hz), 7.32 (1 H, dd, J = 7.9, 2.7 Hz), 7.62-7.78 (2 H, m),
Figure imgf000134_0001
8.55 (1 H, t, J = 7.0 Hz), 11.87 (1 H, s). HRMS (M+H) calcd for C20H23FN3O5S: 436.1342; found 436.1341. Yield = 15%. 1H NMR (300 MHz, CDCI3) δ: 1.62-1.79 (4 H, m), 1.86-2.02 (4 H, m), 2.07 (2 H1 t, J = 7 Hz)1 2.86 (6 H1 s), 4.00 (2H1 t, J - 7 Hz)1 4.80 (2 H1 d, J = 6.6 Hz), 7.19-7.30 (1 H, m), 7.50 (1 H1 dd, = 8.4, 2.6 Hz), 7.66 (1 H1 dd, J = 8.6, 5.3 Hz), 8.54 (1
Figure imgf000134_0002
H1 t, J = 6.8 Hz)1 12.00 (1 H1 s). HRMS (M+H) calcd for C2IH26FN4O5S: 465.1608; found 465.1626.
Yield = 13%. 1H NMR (300 MHz, CDCI3) δ:
1.64-1.83 (4 H1 m), 1.87-2.05 (4 H, m), 1.87-2.05 (4 H1 m), 2.09 (2 H, t, J = 7 Hz), 4-01 (2 H, t, J = 7 Hz)1 4.44 (2 H1 d, J = 6.6 Hz), 7.08 (1H1 dd, J = 8.4, 2.5 Hz)1 7.19(1 H ' dt- J = 8-4> 2-5 Hz)> 7-67 C H> dd> J = 8.4, 5.9 Hz), 8.15 (1 H1 s), 8.42 (1 H, s),
Figure imgf000134_0003
8.77 (1 H1 t, J = 6.8 Hz), 12.02 (1 H, s). HRMS (M+H) calcd for C2IH22FN6O3: 425.1737; found 425.1741. Ex. Structure Data
Yield: 27%. 11HH--NNMMRR (300 MHz, CDCI3/MeOD) δ: 7.31-7.27 (2H1 m), 7.00 (2H, t, J = 8.6 Hz), 4.53 (2H, s), 3.98 (4H1
88 s), 2.98-2.84 (4H1 m), 2.14 (2H1 td, J = 10.3, 5.4 Hz), 1.84 (2H, dd, J = 12.8, 1.1
Figure imgf000135_0001
Hz). HRMS (M+H) calcd for Ci9H22N4O4F: 389.1625; found: 389.1610.
Example 89
Figure imgf000135_0002
A mixture of example 18 (52 mg, 0.124 mmol) and mCPBA (64.2 mg, 0.372 mmol) in CH2Cl2 was stirred at room temperature for 4 h. Then, concentrated and purified by preparative HPLC to afford example 89 (26.2 mg, 47%) as a purple solid. 1H NMR (500 MHz, CDCl3) δ: 11.69 (IH, s), 8.54 (IH5 1, J = 6.4 Hz), 7.75 (IH, dd, J = 8.2, 2.7 Hz), 7.70 (IH, dd, J = 8.6, 5.2 Hz), 7.34 (IH, td, J = 7.9, 2.5 Hz), 4.81 (2H, d, J = 6.7 Hz), 3.99-3.94 (4H, m), 3.16 (3H, s), 2.21-2.16 (2H, m), 2.06-2.00 (2H5 m), 1.94-1.82 (4H, m). HRMS (M+H) calcd for C20H23FN3O6S: 452.1292; found: 452.1286.
Example 90
Figure imgf000136_0001
Example 90 was prepared according to the procedure for example 89 using example 39 to afford product in 38% as a purple solid. 1H NMR (500 MHz, CDCl3) δ: 11.82 (IH, bs), 8.57 (IH, t, J = 5.8 Hz), 7.75 (IH5 dd, J = 8.0, 2. 6 Hz), 7.69 (IH, dd, J = 8.4, 5.0 Hz), 7.33 (IH, td, J = 7.9, 2.4 Hz), 4.87-4.74 (2H. m), 4.20-3.98 (8H, m), 3.18 (3H, s), 2.61-2.56 (IH, m), 2.34-2.29 (IH, m). HRMS (M+H) calcd for C19H2IFN3O7S: 454.1084; found: 454.1096.
Example 91
Figure imgf000136_0002
A solution of intermediate 45 (0.096 g, 0.190 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 2 hours, and then solvent was removed in- vacuo to give a yellow oil. The oil was triturated with a minimal volume of 95% ethanol, and solids were collected by filtration to give 91 (0.056 g, 71%) as a white solid after vacuum pump drying: 1H NMR (500 MHz, DMSO-D6) δ: 12.19 (IH, s), 9.37 (IH, t, J- 6.4 Hz), 8.56 - 8.61 (IH, m), 7.44 (IH, dd, J- 8.5, 5.8 Hz), 7.36 (IH, dd, J= 9.3, 2.6 Hz), 7.31 (IH, td, J= 8.5, 2.6 Hz), 4.58 (2H, d, J= 6.7 Hz), 3.92 (2H, t, J= 5.3 Hz), 3.80 (2H, t, J= 5.2 Hz), 2.79 (3H, d, J= 4.6 Hz), 2.65-2.72 (2H, m), 2.19-2.25 (2H, m), 2.12 - 2.18 (IH, m), 1.88-1.96 (IH, m). 13C NMR (126 MHz5 DMSO-D6) δ: 167.68, 161.68, 159.73, 156.73, 150.37, 145.81, 137.24, 137.19, 132.61, 131.33, 131.27, 125.22, 116.87, 116.70, 114.88, 114.70, 77.99, 57.88, 41.96, 40.33, 33.95, 26.06, 13.08. HRMS (M+H) calc'd for C20H22N4O5F: 417.1574; found: 417.1589.
Example 92
Figure imgf000137_0001
Spiro[cyclopentane-l,9'(6'H)-[4H]pyrazino[l,2-a]pyrimidine]-2'- carboxamide, N-[(4-fluorophenyl)methyl]- 7 ', 8 '-dihydro-3 '-hydroxy-8 '-methyl-4 '-oxo- . 1H NMR (500 MHz, CHLOROFORM-D) 6 ppm 1.82 - 1.91 (m, 2 H) 1.96 - 2.05 (m, 2 H) 2.37 (d, J=7.32 Hz, 4 H) 2.88 (s, 3 H) 3.81 (t, J=6.41 Hz, 2 H) 4.27 - 4.35 (m, 2 H) 4.58 (d, J=6.10 Hz, 2 H) 7.03 - 7.09 (m, 2 H) 7.29 (dd, J=8.55, 5.19 Hz, 2 H). 13C NMR (125 MHz, CHLOROFORM-D) 6 25.48, 25.67, 37.53, 37.70, 39.57, 42.78, 46.18, 73.38, 115.99, 116.16, 125.28, 129.41, 132.64, 146.79, 147.64, 157.41, 161.61, 167.67.
Example 93
Figure imgf000137_0002
Spiro[cyclopentane-1, 9 '(6'H)-[4H]pyrazino[l, 2-a]pyrimidine] -2 '- carboxamide, N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3'- hydroxy-8'-methyl-4'-oxo-. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.04 (d, J=5.19 Hz, 4 H) 2.38 - 2.46 (m, 4 H) 2.82 (s, 3 H) 3.78 (t, J=6.26 Hz, 2 H) 4.28 (t, J=6.56 Hz, 2 H) 4.44 (d, J=6.71 Hz, 12H) 7.14 (m, 1 H), 7.24 (m, 1 H), 7.74 (m, 1 H), 8.17 (s, 1 H), 8.51 (s, 1 H), 8.59 (m 1 H). 13 C NMR ( 125 MHz, CHLOROFORM-D) δ 25.78, 37.50, 37.71, 39.19, 46.13, 73.32, 112.09, 112.29, 117.19, 117.36, 125.50, 128.24, 134.76, 134.83, 144.05, 146.68, 147.81, 152.56, 157.41, 161.33, 163.33, 167.59.
Example 94
Figure imgf000138_0001
Spiro[cyclopentane-1, 9 '(6'H)-[4H]pyrazino[l, 2-a]pyrimidine]-2 '- carboxamide, N-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'- dihydro-3'-hydroxy-8'-methyl-4'-oxo-. 1H NMR (500 MHz, MeOD) δ ppm 1.94 - 2.03 (m, 2 H) 2.10 (m, 2 H) 2.47 (s, 3 H) 2.65 (m, 2 H) 3.07 (s, 3 H) 3.92,( m, 2 H)4.29 (t, J=6.41 Hz, 2 H) 4.35 - 4.42 (m, 2 H) 7.36 - 7.42 (m, 2 H), 7.71 (m, 1), 8.10 (s, 1).
Example 95
Figure imgf000138_0002
Spiro[cyclohexane-1, 9 '(6'H)-[4HJpyrazino[l , 2-a]pyrimidine]-2 '- carboxamide, N-[(4-fluorophenyl)methyl]-7', 8 '-dihydro-3 '-hydroxy-8 '-methyl-4 '-oxo- 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41-1.69 (br m, 4 H), 2.08 (m, 2), 2.50 (s, 3 H), 3.60 (m, 2), 3.91 (br m, 4 H), 4.05 (m, 2 H) 4.51 (d, J=6.10 Hz, 2 H) 7.12 - 7.20 (m, 2 H) 7.33 - 7.39 (m, 2 H), 9.34 (m, 1 H), 12.37 (br s, 1 H). Example 96
Figure imgf000139_0001
Spiro[cycJohexane-l, 9 '(6'H)-[4H]pyrazino[l, 2-a]pyrimidine]-2 '- carboxamide, N-[[4-fluoro-2-(lH-l, 2, 4-triazol-l-yl)phenyl] methyl]- 7', 8 '-dihydro-3 '- hydroxy-8'-mβthyl-4'-oxo-. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41-1.68 (br m, 4 H), 2.04 (br m 2), 2.50 (s, 3 H) 3.46-3.56 (br m, 4 H)3 3.90 (t, J= 6.40, 2 H), 4.46 (d, J=6.10 Hz, 2 H) 7.43 - 7.54 (m, 1 H), 7.56-7.61 (m, 2 H), 8.27 (s, 1 H), 9.01 (s, 1 H).
Example 97
Figure imgf000139_0002
Spiro[cyclohexane-1, 9 '(6'H)-[4H]pyrazino[l, 2-a]pyrimidine] -2 '- carboxamide, N-[[4-fluoro-2-(5-methyl-lH-l, 2, 4-triazol-l -yljphenyl] methyl]- 7 ',8'- dihydro-3'-hydroxy-8'-methyl-4'-oxo-. 1H NMR (500 MHz, DMSOd6) δ ppm 1.60- 1.69 (br m, 4 H) 2.22 (br m, 2 H), 2.35 (s, 3 H), 2.50 (s, 3 H), 3.60-4.04 (br m, 6 H), 4.26 (d, J=6.10 Hz, 2 H), 7.47 (m, 1 H) 7.57 (td, J=5.95, 3.05 Hz, 2 H), 8.09 (s, 1 H), 9,08 (m, 1 H), 12.06 (br s, 1 H). Example 98
Figure imgf000140_0001
Spiro[cyclobutane-l,9'(6'H)-[4H]pyrazino[l,2-a]pyrimidine]-2'- carboxamide, N-[(4-fluorophenyl)methyl]- 7', 8 '-dihydro-3 '-hydroxy-8 '-methyl-4 '-oxo-. 1H NMR (500 MHz, DMSO-d6) 6 ppm 1.80-1.87 (m, 1 H), 2.05 - 2.14 (m, 1 H) 2.46 - 2.54 (m, 2 H), 2.50 (s, 3 H) 2.71 (s, 2 H) 3.53 (t, J=5.95 Hz, 2 H) 3.95 - 4.04 (m, 2 H) 4.53 (t, J=5.80 Hz, 2 H) 7.16 - 7.22 (m, 2 H) 7.37 - 7.43 (m, 2 H), 9.36 (m, 1 H), 12.59 (br s, 1 H).
Example 99
Figure imgf000140_0002
Spiro[cyclobutane-1, 9 '(6'H)-[4H]pyrazino[l, 2-a]pyrimidine]-2 '- carboxamide, N-[[4-fluoro-2-(lH-l, 2, 4-triazol-l-yl)phenyl] methyl] -7', 8 '-dihydro-3 '- hydroxy-8'-methyl-4'-oxo-. 1H NMR (500 MHz5 DMSO-d6) δ ppm 1.87-1.89 (m, 1 H), 2.11-2.15 (m, 1 H), 2.50 (s, 3 H), 2.52 - 2.61 (m, 2 H) 2.74 (s, 2 H) 3.61 (t, J=5.80 Hz, 2 H), 4.00 (d, J=5.49 Hz, 2 H) 4.48 (m, 2 H), 7.43 (m, 1 H) 7.59 (m, 2 H), 8.29 (s, 1 H), 9.07 (s, 1 H), (9.27 (m, 1 H), 12.27 (br s, 1 H). Example 100
Figure imgf000141_0001
Spiro[cyclobutane-1 , 9 '(6Η)-[4HJpyrazino[l , 2-aJpyrimidinej '-2 '- carboxamide, N-[[4-fluoro-2-(5-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'- dihydro-3'-hydroxy-8'-methyl-4'-oxo- 1H NMR (500 MHz, DMSOd6) δ ppm 1.88- 1.92 (m, 1 H), 2.10-2.16 (m, 1 H), 2.36 (s, 3 H) 2.50 (s, 3 H) 2.58 - 2.62 (m, 4 H) 2.78 (br s, 2) 3.65 (t, J=6.10 Hz, 2 H) 4.03 (br s, 2 H) 4.27 (d, J=6.41 Hz, 2 H)5 7.46- 7.49 (m, 1 H), 7.56 - 7.63 (m, 2 H), 8.08 (s, 1 H), 9.16 (m, 1 H), 12.31 (br s, 1 H).
Example 101
Figure imgf000141_0002
Spiro [cyclobutane-1 , 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide, N-[[4-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl]methyl]-6',7'-dihydro-3'-hydroxy-4'- oxo- 1H NMR (400 MHz, CDCl3) δ ppm: 11.95 (1 H, s), 8.80 (1 H, s), 7.92 (2 H, s), 7.76 (1 H, dd, J=8.6, 5.8 Hz), 7.20 - 7.27 (1 H, m), 7.11 (1 H, dd, J=8.5, 2.7 Hz), 4.46 (2 H, d, J=6.8 Hz), 3.95 (4 H, s), 2.69 - 2.78 (2 H, m), 2.27 - 2.38 (3 H, m), 2.03 - 2.14 (1 H, m), MS (ESI+) m/e 427 [M+H +], HRMS (ESI+) calculated for C20H20FN6O4 [M+H+] 427.1530; found: 427.1547. Example 102
Figure imgf000142_0001
Spiro[cyclobutane-1, 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide,
N-[.[2-(4, 5-dimethyl-lH-l,2, 3-triazol-l-yl)-4-fluorophenyl]methyl]-6', 7'-dihydro-3 '- hydroxy-4'-oxo- 1H NMR 400 MHz (CDCl3) δ (ppm): 11.97 (1 H, s), 8.54 (1 H, m), 7.74 (1 H, dd, /=8.6, 5.8 Hz), 7.25 - 7.32 (1 H, m), 7.01 (1 H, dd, J=8.3, 2.5 Hz), 4.30 (2 H, d, J=6.6 Hz), 3.95 - 4.02 (4 H, m), 2.73 - 2.82 (2 H, m), 2.29 - 2.40 (6 H, m), 2.23 (3 H, s), 2.13 (I H, m),.
Example 103
Figure imgf000142_0002
Spiro[cyclobutane-l,9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide, N-[[2-[4-(lJ-dimethylethyl)-lH-lJ,3-tria∑ol-l-yl]-4-fluorophenyl]methyl]-6', 7'- dihydro-3'-hydroxy-4'-oxo- 1H NMR (400 MHz, CDCl3) 6 ppm: 12.00 (1 H, s), 8.95 - 9.04 (1 H, m), 7.72 (1 H, dd, J=8.6, 6.1 Hz), 7.61 (1 H, s), 7.19 (1 H, td, J=8.2, 2.8 Hz), 7.11 (1 H, dd,.J=8.7, 2.7 Hz), 4.50 (2 H, d, J=6.8 Hz), 3.95 (4 H, s), 2.71 - 2.81 (2 H, m), 2.26 - 2.37 (3 H, m), 2.02 - 2.12 (1 H, m), 1.42 (9 H, s), MS (ESf ) m/e 483 [M+H +], HRMS (ESf) calculated for C24H28FN6O4 [M+H+] 483.2156; found: 483.2179. Example 104
Figure imgf000143_0001
Spirofcyclobutane-l , 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide,
N-[[4-fluoro-2-(5-methyl-lH-l,2, 3-triazol-l-yl)phenyl]methyl]-6', 7'-dihydro-3 '- hydroxy-4'-oxo- 1H NMR (400 MHz, CDCl3) δ ppm: 11.90 (1 H, s), 8.49 (1 H, t, J=6.3 Hz), 7.73 (1 H, dd, J=8.6, 5.8 Hz), 7.65 (1 H, s), 7.22 - 7.30 (1 H, m), 7.01 (1 H5 dd, J=8.3, 2.8 Hz), 4.26 (2 H, d, J=6.6 Hz), 3.95 (4 H, s), 2.70 - 2.80 (2 H, m), 2.27 - 2.38 (6 H, m), 2.05 - 2.17 (1 H, m), LCMS (^ESI, M+H+) m/z 441.
Example 105
Figure imgf000143_0002
Spiro[cyclobutane-1, 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide, N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-6', 7'-dihydro-3'-hydroxy-4'- OXO-. 1H NMR 400 MHz (MeOD) δ (ppm): 7.56 (1 H, m), 7.22 (1 H, m), 7.12 (1 H, m), 4.59 (2 H, m), 4.10 (2 H5 m), 3.99 (2 H, m), 3.90 (2 H, m), 2.80 (2H, m), 2.24 (2H, m), 2.13 (2 H, m), 2.02 (2 H, m). HRMS (ESI1+) calculated for C21H22FN4O6 [M+H+] 445.1523; found: 445.1506. Example 106
Figure imgf000144_0001
Spiro [cyclohutane-1 , 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide,
N-[[4-fluoro-2-(2-oxo-l-azetidinyl)phenyl]methyl]-6',7'-dihydro-3'-hydroxy-4'-oxo-. 1H NMR 400 MHz (MeOD) 6 (ppm): 7.61 (1 H, m), 7.04 (2 H, m), 4.65 (2 H, m), 4.01 (2 H, m), 3.96 (2 H, m), 3.85 (2 H, m), 3.18 (2 H, m), 2.78 (2 H, m), 2.31 (2 H, m), 2.21- 2.02 (2 H, m). HRMS (ESI1+) calculated for C21H22FN4O6 [M+H+] 429.1574; found: 429.1561.
Example 107
Figure imgf000144_0002
Spiro [cyclobutane-1, 10 '(4 Η)-[6H]pyrimido[2, l-c][l, 4] oxazepine] -2 '- carboxamide, N-[[2-(4, 5 -dimethyl- IH-1, 2, 3-triazol-l -yl)-4-fluorophenyl] methyl] - 7',8'-dihydro-3'-hydroxy-4'-oxo- 1H NMR (400 MHz, CDCl3) 6 ppm: 12.02 (1 H, s), 8.34 (1 H, t, J=6.3 Hz), 7.67 (1 H, dd, J=8.6, 5.8 Hz), 7.20 - 7.28 (1 H, m), 6.97 (1 H, dd, J=8.3, 2.5 Hz), 4.36 (2 H, brs), 4.26 (2 H, d, J=6.6 Hz), 3.89 (2 H, t, J=5.7 Hz), 2.79 (2 H, t, J=8.3 Hz), 2.39 - 2.48 (2 H, m), 2.35 (3 H, s), 2.18 (3 H5 s), 1.73 - 1.95 (4 H, m), LCMS (4ESL M+H+) m/z 469. Example 108
Figure imgf000145_0001
Spiro[oxetane-3 ,9'(4'H)-pyrimido [2, 1-c] [1 ,4] oxazine] -2'-carboxamide, N-
[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6', 7'-dihydro-3'- hydroxy-4'-oxo-. A suspension of N-(4-fluoro-2-(3 -methyl- IH-1, 2,4-triazol-l- yl)benzyl)-9-(chloromethyl)-3-hydroxy-9-(hydroxymethyl)-4-oxo-4,6,7,9- tetrahydropyrimido[2,l-c][l,4]oxazine-2-carboxamide (0.220 g, 0.459 mmol) and tetrabutyl ammonium bromide (0.075 g, 0.23 mmol) in 1.0 N NaOH solution (2.5 mL) and water (2.5 mL) was heated (800C, oil bath) for 4 hrs. The reaction was quenched with 1.0 N HCl solution (4 mL), and extracted into ethyl acetate (2 x 10 mL) and CH2Cl2 (10 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated in-vacuo. The crude material was dissolved in dimethylformamide (3 mL) and purified by C-18 reverse phase column chromatography, eluting with 10% - 30% acetonitrile in water. Product fractions were concentrated to dryness by rotary evaporator, or optionally reduced in volume and extracted with CH2Cl2. The product was then triturated with 95% ethanol or, optionally, AcCN. The resulting solid was collected by filtration to give the title compound as crystalline white solid: 1H NMR (500 MHz, CDCl3) δ ppm 12.38 (IH, s), 8.84 (IH, t, J=6.41 Hz), 8.31 (IH, s), 7.70 (IH, dd, J=8.70, 5.95 Hz), 7.17 (IH, td, J=8.24, 2.75 Hz), 7.08 (IH, dd, J=8.55, 2.44 Hz), 5.09 (2H, d, J=6.41 Hz), 4.74 (2H, d, J=6.41 Hz), 4.51 (2H, d, J=6.71 Hz), 4.01 (4H, s), 2.56 (3H, s); 13C NMR (126 MHz, CDCl3) δ ppm 168.00, 163.19, 161.23, 157.40, 147.55, 145.78, 144.02, 137.11, 137.03, 134.27, 134.20, 128.33, 125.69, 116.59, 116.42, 111.99, 111.79, 81.76, 59.90, 42.20, 39.37, 13.90; HRMS (ESI) calcd for C20H20N6O5F (M+H) 443.1479, found 443.1477, Elem. Anal, calcd for C20H19N6O5F • 0.1 H2O: C54.08, H 4.36, N 18.92, found: C 54.04, H 4.07, N 18.99. Example 109
Figure imgf000146_0001
Spiro[oxetane-3, 9 '(4 'H)-pyrimido[2,l-c][l, 4]oxazine]-2 '-carboxamide, N-
[(4-fluorophenyl)methyl]-6', 7'-dihydro-3'-hydroxy-4'-oxo-. 1H NMR (500 MHz, CDCl3) 6 ppm 12.30 (IH, s), 8.10 (IH, br), 7.29 - 7.36 (2H, m), 7.02 - 7.08 (2H, m, J=8.55, 8.55 Hz), 5.02 (2H, d, J=6.41 Hz), 4.78 (2H, d, J=6.41 Hz), 4.61 (2H, d, J=6.41 Hz), 4.01 (4H, s); HRMS (ESI) calcd for C17H17N3O5F (M+H) 362.1152, found 362.1148. HPLC purity: 98% AP (rt = 1.92 min). White solid
Example 1 10
Figure imgf000146_0002
Spiro[oxetane-3, 9 '(4 'H)-pyrimido[2, 1 -cjfl, 4] oxazine] -2 '-carboxamide, N- [[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-6', 7'-dihydro-3'-hydroxy-4'-oxo-. 1H NMR (500 MHz, CDCl3) δ ppm 12.10 (IH, s), 9.29 (IH, t, J=6.56 Hz), 8.45 (IH, s), 8.36 (IH, s), 7.70 (IH, dd, J=8.70, 5.95 Hz), 7.21 (IH, td, J=8.16, 2.59 Hz), 7.10 (IH, dd, J=8.39, 2.59 Hz), 5.14 (2H, d, J=6.41 Hz), 4.79 (2H, d, J=6.71 Hz), 4.47 (2H, d, J=6.71 Hz), 4.00 (4H, s); 13C NMR (126 MHz, CDCl3) δ ppm 167.62, 161.24, 157.40, 153.43, 147.18, 145.97, 143.94, 134.27, 134.20, 128.63, 128.60, 125.85, 117.05, 116.89, 112.79, 112.59, 82.18, 59.99, 42.17, 39.40; HRMS (ESI) calcd for Ci9H18N6O5F (M+H) 429.1323, found 429.1330. HPLC rt = 1.60 min. White crystalline solid Example 111
Figure imgf000147_0001
Spiro[oxetane-3,9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide, N-
[[4-fluoro-2-(methylsulfonyl)phenyl] methyl] -6', 7'-dihydro-3 '-hydroxy-4'-oxo-. 1H NMR (500 MHz, CDCl3) δ ppm 11.98 (IH5 s), 8.78 (IH, t, J=6.56 Hz), 7.76 (IH, dd, J=7.93, 2.75 Hz)3 7.69 (IH, dd, J=8.55, 5.19 Hz), 7.34 (IH, td, J=7.93, 2.75 Hz), 5.06 (2H, d, J=6.71 Hz), 4.88 (2H, d, J=6.71 Hz), 4.77 (2H, d, J=6.71 Hz), 4.00 (4H, s), 3.22 (3H, s); 13C NMR (126 MHz, CDCl3) δppm 168.10, 163.08, 157.31, 147.33, 146.21, 140.79, 134.57, 134.51, 132.73, 132.70 125.54, 121.50, 121.34, 117.64, 117.44, 81.88, 59.93, 45.01, 42.15, 40.34; HRMS (ESI) calcd for C18H19N3O7FS (M+H) 440.0928, found 440.0937. Elem. Anal, calcd for Ci8Hi8N3O7FS • 0.1 CH2Cl2: C 48.53, H 4.10, N 9.38, found: C 48.29, H 3.79, N 9.33. HPLC rt = 1.77 min. White solid
Example 112
Figure imgf000147_0002
Spiro[4H-pyran-4,9'(4'H)-pyrimido[2,l-c] [1 ,4] oxazine] -2'-carboxamide, N- [[4-fluoro-2-(lH-l, 2, 3-ti'iazol-l-yl)phenyl] methyl] -2, 3, 5, 6, 6\ T-hexahydro-3 '- hydroxy-4'-oxo-. 1E NMR 400 MHz (CDCl3) 5 (ppm): 11.94 (1 H, s), 8.55 (1 H, m), 7.98 (1 H, s), 7.95 (1 H, s) 7.71 (1 H, dd, J=8.6, 5.8 Hz), 7.24 - 7.30 (1 H, m), 7.16 (1 H, dd, J=8.3, 2.5 Hz), 4.51 (2 H, d, J=6.8 Hz), 4.05 (4 H, s), 3.87 - 3.97 (2 H, m), 3.77 - 3.87 (2 H, m), 2.45 (2 H, td, J=13.2, 5.2 Hz), 1.81 (2 H, d, J=13.6 Hz).
Example 113
Figure imgf000148_0001
Spiro[cyclopentane-1, 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide, N-[[4-fluoro-2-(lH-l, 2, 3-triazol-l-yl)phenyl]metlτyl]-6', 7'-dihydro-3 '-hydroxy-4 '- OXO-. 1H NMR 400 MHz (CDCl3) δ (ppm): 11.87 (1 H, s), 8.68 (1 H, m), 7.95 (IH, d, J=I.2 Hz), 7.94 (1 H, d, J= 1.2 Hz), 7.76 (1 H, dd, J=8.6, 5.8 Hz), 7.26 (1 H, dd, J=8.6, 2.5 Hz), 7.13 (1 H, dd, J=8.5, 2.7 Hz), 4.47 (2 H, d, J=6.8 Hz), 3.95 - 4.05 (4 H, m), 2.25 - 2.35 (2 H, m), 2.00 - 2.11 (4 H, m), 1.89 (2 H, m).
Example 114
Figure imgf000148_0002
Spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide, N- [(4-fluorophenyl)methyl] -2,3,5,6, 7',8'-hexahydro-3'-hydroxy-4'-oxo-. 1HNMR 400 MHz (CDCl3) δ (ppm) : 1.85 (2H, m, CH2), 2.05 (2H, m, CH2), 2.3 (2H, m, CH2), 3.75 (2H, m, CH2), 3.8 -3.9 (4H, m, 2 x CH2), 4.5 - 4.7 (4H, m, 2 x CH2), 7.1 (2H, m , aromatics), 7.35 (2H, m , aromatics), 7.75 (IH, broad t, NH), 12.1 (IH, s, OH). MS (ESI+) m/e 404 [M+H +]. Example 115
Figure imgf000149_0001
Spiro[4H-pyran-4, 10 '(4 'H)-[6H]pyrimido[2, l-cjfl, 4JoxazepineJ-2 '- carboxamide, N-[[4-fluoro-2-[(methylamino)carbonyl] phenyl] methyl] -2, 3, 5, 6, 7 ',8 '- hexahydro-3'-hydroxy-4'-oxo-. White crystals; mp 211 0C (dec.) (ethyl acetate).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.87 (2H, m, CH2), 1.99 (2H, m, CH2), 2.43 (2H, m, CH2), 3.05 (3H, d, J = 4.8 Hz, NCH3), 3.72 (2H, m, CH2), 3.8 -3.9 (4H, m, 2 x CH2), 4.55 (2H, m, CH2), 4.61 (2H, d, J = 6.5 Hz, NCH2), 6.24 (IH, m , NH), 7.15 (IH, m , aromatic), 7.21 (IH, dd , J =2.7 Hz and J =8.6 Hz, aromatic), 7.52 (IH, dd , J =5.4 Hz and J =8.6 Hz, aromatic), 9.00 (IH, broad t, NH), 12.18 (IH, s, OH). MS (ESI+) m/e 461 [M+H +].
Example 116
Figure imgf000149_0002
Spiro[4H-pyran-4, 10 '(4 'H)-[6H]pyrimido[2, l-c][l,4]oxazepine]-2 '- carboxamide, N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6, 7',8'- hexahydro-3'-hydroxy-4'-oxo-. White crystals; mp 257 0C (dec.) (ethanol).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.85 (2H, m, CH2), 1.99 (2H5 m, CH2), 2.33 (2H, m, CH2), 3.22 (3H, s, SCH3), 3.71 (2H, m, CH2), 3.75 -3.9 (4H, m, 2 x CH2), 4.56 (2H, m, CH2), 4.85 (2H, d, J = 6.8 Hz, NCH2), 7.37 (IH, m , aromatic), 7.72 (IH, dd , J =5.0 Hz and J =8.6 Hz, aromatic), 7.78 (IH, dd , J =2.6 Hz and J =8.3 Hz, aromatic), 8.55 (IH, broad t, NH), 11.87 (IH, s, OH). Anal. Calcd for C21H24FN3O7S: C 52.38, H 5.02, N 8.72; Found: C 52.17, H 5.21, N 8.44.
Example 117
Figure imgf000150_0001
Phosphonic acid, [5-fluoro-2-[[[(2,3,5,6, 7',8'-hexahydro-3'-hydroxy-4'- oxospiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepin]-2'- yl)carbonyl] amino] methyl] phenyl]-, dimethyl ester. White crystals; mp 234 0C (dec.) (ethyl acetate).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.85 (2H, m, CH2), 1.99 (2H, m, CH2), 2.41 (2H, m, CH2), 3.71 (2H, m, CH2), 3.8 -3.9 (4H, m, 2 x CH2), 3.86 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.56 (2H, m, CH2), 4.78 (2H, d, J = 6.6 Hz, NCH2), 7.26 (IH, m , aromatic), 7.49 (IH, m , aromatic), 7.63 (IH, m , aromatic), 9.02 (IH, broad t, NH), 12.18 (IH, s, OH). MS (ESI"1) m/e 512 [M+H+].
Example 118
Figure imgf000150_0002
Spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide, N-[[4-fluoro-2-(lH-l, 2, 4-triazol-l-yl)phenyl] methyl] -2, 3, 5, 6, 7' ,8 '- hexahydro-3'-hydroxy-4'-oxo-. White crystals; mp 247 0C (dec.) (ethyl acetate).1HNMR 400 MHz (CDCl3) 6 (ppm) : 1.89 (2H, m, CH2), 2.01 (2H, m, CH2), 2.43 (2H, m, CH2), 3.74 (2H, m, CH2), 3.8 -3.9 (4H, m, 2 x CH2), 4.47 (2H, d, J = 6.9 Hz, NCH2), 4.56 (2H, m, CH2), 7.14 (IH, dd , J =2.5 Hz and J =8.6 Hz, aromatic), 7.24 (IH, m , aromatic), 7.72 (IH, dd , J =6.0 Hz and J =8.6 Hz, aromatic), 8.31 (IH, s , CH), 8.49 (IH, s , CH), 9.01 (IH, broad t, NH), 11.99 (IH, s, OH). MS (ESf) m/e 471 [M+H +]. Anal. Calcd for C22H23FN6O5 . 0.5 H2O: C 55.11, H 5.05, N 17.53; Found: C 55.17, H 4.91, N l 7.02.
Example 119
Figure imgf000151_0001
Spiro[4H-pyran-4, 10 '(4 'H)-[6H]pyrimido[2, l-c][l, 4]oxazepine]-2 '- carboxamide, N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol~l-yl)phenyl]methyl]- 2,3,5,6,7',8'-hexahydro-3'-hydroxy-4'-oxo-. White crystals; mp 240 0C (dec.) (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm) : 1.86 (2H, m, CH2), 2.01 (2H, m, CH2), 2.37 (2H, m, CH2), 2.61 (3H, s, CH3), 3.72 (2H, m, CH2), 3.8 -3.9 (4H, m, 2 x CH2), 4.51 (2H, d, J = 6.9 Hz, NCH2), 4.56 (2H, m, CH2), 7.12 (IH, dd , J =2.5 Hz and J =8.6 Hz, aromatic), 7.20 (IH, m , aromatic), 7.72 (IH, dd , J =5.9 Hz and J =8.6 Hz, aromatic), 8.34 (IH, s , CH), 8.72 (IH, broad t, NH), 12.27 (IH, s, OH). MS (ESI+) m/e 485 [M+H +]. Anal. Calcd for C23H25FN6O5: C 57.02, H 5.20, N 17.35; Found: C 56.92, H 5.09, N 16.74. Example 120
Figure imgf000152_0001
Spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide, N-[[4-fluoro-2-(5-methyl-lH-l,2,4-tj'iazol-l-yl)phenyl]methyl]- 2,3,5,6, 7',8'-hexahydro-3'-hydroxy-4'-oxo-. White crystals; mp 204 0C (ethyl acetate).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.87 (2H, m, CH2), 2.01 (2H, m, CH2), 2.5 (2H, m, CH2), 2.52 (3H, s, CH3), 3.74 (2H, m, CH2), 3.8 -3.9 (4H, m, 2 x CH2), 4.32 (2H, d, J = 6.6 Hz, NCH2), 4.56 (2H, m, CH2), 7.05 (IH, dd , J =2.5 Hz and J =8.3 Hz, aromatic), 7.26 (IH, m , aromatic), 7.70 (IH, dd , J =6.1 Hz and J =8.6 Hz, aromatic), 8.14 (IH, s, CH), 8.76 (IH, broad t, NH), 11.96 (IH, s, OH). Anal. Calcd for C23H25FN6O5: C 57.02, H 5.20, N 17.34; Found: C 52.08, H 5.35, N 17.21.
Example 121
Figure imgf000152_0002
Spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide, 2,3,5,6, 7',8'-hexahydro-3'-hydroxy-N-[[2-(3-methyl-lH-l,2,4-triazol-l- yl)phenyl] methyl] -4'-OXO-. White crystals; mp 247 0C (dec.) (ethanol).1HNMR 400 MHz (CDCl3) δ (ppm) : 1.86 (2H, m, CH2), 2.0 (2H5 m, CH2), 2.38 (2H, m, CH2), 2.61 (3H, s, CH3), 3.73 (2H, m, CH2), 3.85 -3.9 (4H, m, 2 x CH2), 4.53 (2H, d, J = 6.9 Hz, NCH2), 4.56 (2H, m, CH2), 7.35 - 7.4 (IH, m, aromatic), 7.45 - 7.52 (2H, m, aromatics), 7.69 - 7.74 (IH, m, aromatic), 8.33 (IH, s, CH), 8.74 (IH, broad t, NH), 12.33 (IH5 s, OH). Anal. Calcd for C23H26N6O5: C 59.21, H 5.61, N 18.01; Found: C 59.46, H 5.50, N 17.80.
Example 122
Figure imgf000153_0001
Spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide, N-[[4-fluoro-2-(lH-l, 2, 3-triazol-l-yl)phenyl] methyl] -2,3,5, 6, 7',8'- hexahydro-3'-hydroxy-4'-oxo-. White crystals; mp 239 0C (dec.) (ethyl acetate).1HNMR 400 MHz (CDCl3) 6 (ppm) : 1.90 (2H, m, CH2), 1.99 (2H, m, CH2), 2.45 (2H, broad m, CH2), 3.74 (2H, m, CH2), 3.84 -3.95 (4H, m, 2 x CH2), 4.48 (2H, d, J = 6.8 Hz, NCH2), 4.58 (2H, m, CH2), 7.14 (IH, dd, J = 2.5 Hz and J = 8.6 Hz, aromatic), 7.26 (IH, m, aromatic), 7.73 (IH, dd, J = 6.0 Hz and J = 8.6 Hz, aromatic), 7.95 (IH, s, CH), 7.97 (IH, s, CH), 8.75 (IH, broad t, NH), 11.97 (IH, s, OH). MS (ESI+) m/e 471 [M+H +].
Example 123
Figure imgf000153_0002
Spiro[cyclobutane-1, 10 '(4 'H)-[6H]pyrimido[2, l-c][l, 4] oxazepine] -2 '- carboxamide, N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8'- dϊhydro-3'-hydroxy-4'-oxo-. 1H NMR (500 MHz, CDCl3) δ ppm 12.24 (IH, s), 8.73 (IH, br), 8.35 (IH, br), 7.70 (IH, dd, J=8.55, 5.80 Hz), 7.15 - 7.22 (IH, m), 7.08 (IH, d, J=8.24 Hz), 4.49 (2H, d, J=6.71 Hz), 4.38 (2H, br), 3.89 (2H, t, J=5.34 Hz), 2.80 (2H, br), 2.49 (3H, s), 2.39 - 2.47 (2H, m), 1.86 - 1.93 (IH, m), 1.79 - 1.86 (2H, m), 1.68 - 1.75 (IH, m); 13C NMR (126 MHz, CDCl3) δ ppm 168.33, 163.20, 162.01, 158.53, 150.67, 147.81, 143.86, 136.80, 136.73, 134.33, 134.26, 128.55, 124.54, 116.92, 116.76, 112.00, 111.80, 82.11, 64.54, 40.77, 39.06, 32.00, 28.65, 13.88, 12.72; HRMS calcd for C22H24N6O4F (M+H) 455.1843, found 455.1849. HPLC rt = 2.12 min. White crystalline solid
Example 124
Figure imgf000154_0001
Spiro[cyclobutane-l,9'(4'H)-pyrimido[2,l-c] [1, 4] oxazine] -2' -carboxamide, N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6', 7'-dihydro-3'- hydroxy-4'-oxo-. 1H NMR (500 MHz, CDCl3) δ ppm 12.18 (IH, s), 8.66 (IH, br m), 8.32 (IH, s), 7.69 - 7.75 (IH, m), 7.18 (IH, td, J=8.16, 2.59 Hz), 7.04 - 7.11 (IH, m), 4.51 (2H, d, J=6.71 Hz), 3.96 (4H, s), 2.64 - 2.72 (2H, m), 2.50 (3H, s), 2.30 - 2.38 (2H, m), 2.07 - 2.16 (IH, m), 2.00 - 2.07 (IH, m); 13C NMR (126 MHz, CDCl3) δ ppm 168.33, 163.20, 162.01, 158.53, 150.67, 147.81, 143.86, 136.80, 134.33, 134.26, 128.55, 124.54, 116.92, 116.76, 112.00, 111.80, 82.11, 64.54, 40.77, 39.06, 32.00, 28.65, 13.88, 12.72; HRMS calcd for C21H22N6O4F (M+H) 441.1687, found 441.1679. HPLC rt = 2.07 min. White crystalline solid Example 125
Figure imgf000155_0001
Spiro[cyclobutane-1, 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide,
6', 7'-dihydro-3 '-hydi:oxy-4'-oxo-N-[[2-(2-oxo-l-azetidinyl)phenyl]methyl]-. 1H NMR (500 MHz, CDCl3) 5 ppm 12.28 (IH, br), 9.15 (IH, t, J=6.10 Hz), 7.62 (IH, d, J=7.63 Hz), 7.32 (IH, t, J=7.63 Hz), 7.22 (IH, t, J=7.48 Hz), 7.06 (IH, d, J=7.93 Hz), 4.64 (2H, d, J=6.71 Hz), 3.92 - 3.98 (4H, m), 3.76 (2H, t, J=4.43 Hz), 3.15 (2H, t, J=AXl Hz), 2.67 - 2.74 (2H, m), 2.25 - 2.32 (2H, m), 2.12 - 2.21 (IH, m), 1.96 - 2.05 (IH, m); 13CNMR (126 MHz, CDCl3) δ ppm 168.38, 165.98, 157.89, 150.28, 146.64, 136.09, 132.30, 131.12, 128.84, 126.73, 126.17, 120.50, 78.90, 58.58, 42.47, 39.88, 35.44, 34.68, 13.65; ; HRMS calcd for C2iH23N4O5 (M+H) 411.1668, found 411.1682; Elem. Anal, calcd for C21H22N4O5: C 61.45, H 5.40, N 13.65, found: C 61.43, H 5.56, N 13.62. HPLC rt = 2.24 min. White crystalline solid
Example 126
Figure imgf000155_0002
Spiro[cyclobutane-1, 9 '(4 Η)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide, 6', 7'-dihydro-3 '-hydroxy-4 '-oxo-N-[[2- (2-oxo-3-oxazolidinyl)phenyl] methyl]-. 1H NMR (500 MHz, CDCl3) δ ppm 12.14 (IH, s), 8.63 (IH, t, J=5.95 Hz), 7.56 (IH, d, J=7.32 Hz), 7.32 - 7.40 (2H, m), 7.24 - 7.27 (IH, m), 4.61 (2 H, d, J=6.41 Hz), 4.57 (2H, t, J=T '.93 Hz), 4.07 (2H, t, J=7.93 Hz)5 3.92 - 3.99 (4H, m), 2.69 (2 H, ddd, J=12.13, 9.23, 6.10 Hz), 2.23 - 2.30 (2H, m), 2.08 - 2.17 (IH, m), 1.96 - 2.05 (IH5 m); 13C NMR (126 MHz, CDCl3) δ ppm 168.35, 157.84, 157.49, 150.51, 146.66, 136.05, 135.17, 131.29, 129.20, 128.71, 125.91, 125.20, 79.00, 62.62, 58.56, 48.12, 42.53, 38.96, 34.65, 13.79; HRMS calcd for C2JH23N4O6 (M+H) 427.1618, found 427.1616; Elem. Anal, calcd for C21H22N4O6: C 59.15, H 5.20, N 13.13, found: C 59.10, H 4.99, N 13.26.. HPLC rt = 1.97 min. Crystalline solid
Example 127
Figure imgf000156_0001
Spiro[cyclobutane-1, 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide, N-[[2-(3, 5 -dimethyl- IH-1, 2, 4-triazol-l-yl)-4-βuorophenyl] methyl] -6', 7'-dihydro-3 '- hydroxy-4'-oxo-. 1H NMR (500 MHz5 CDCl3) δ ppm 12.09 (IH, s), 8.36 (IH5 1,
J=6.26 Hz)5 7.68 (IH5 dd, J=8.55, 6.10 Hz)5 7.21 (IH5 td, J=8.24, 2.44 Hz), 7.00 (IH, dd, J=8.24, 2.44 Hz)5 4.35 (2H5 d, J=6.71 Hz)5 3.96 (4H5 br), 2.65 - 2.72 (2H, m), 2.43 (3H, s), 2.42 (3H, s), 2.29 - 2.38 (2H, m), 2.03 - 2.13 (2H, m); LC/MS m/z 455.04 (M+H). HPLC rt = 1.87 min. White crystalline solid
Example 128
Figure imgf000156_0002
Spiro[cyclobutane-1, 10 '(4 'H)-[6H]pyrimido[2, l-c][l, 4] oxazepine] -2 '- carboxamide, N-[[2-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-4-fluorophenyl]methyl]- 7',8'-dihydro-3'-hydroxy-4'-oxo-. 1H NMR (500 MHz, CDCl3) δ ppm 12.17 (IH, s), 8.44 (IH5 1, J=6.26 Hz), 7.67 (IH, dd, J=8.55, 5.80 Hz), 7.21 (IH, td, J=8.24, 2.75 Hz), 6.99 (IH, dd, J=8.55, 2.44 Hz), 4.36 - 4.43 (2H, m), 4.33 (2H, d, J=6.41 Hz), 3.90 (2H, t, J=5.49 Hz)5 2.75 - 2.84 (2H, m), 2.46 - 2.40 (2H5 m), 2.44 (3H, s), 2.41 (3H, s), 1.85 - 1.94 (1 H, m), 1.83 (2 H, dt, J=I 0.76, 5.46 Hz), 1.65 - 1.74 (1 H, m); 13C NMR (126 MHz, CDCl3) δ ppm 168.31, 160.95, 160.48, 158.49, 153.70, 150.76, 147.81, 136.90, 133.38, 133.31, 130.81, 124.43, 117.50, 117.33, 114.25, 114.06, 82.13, 64.54, 40.77, 38.62, 31.96, 28.66, 13.77, 12.77, 12.68; HRMS (ESI) calcd for C23H26N6O4F (M+H) 469.2000, found 469.1999; Elem. Anal, calcd for C23H25N6O4F: C 58.96, H 5.37, N 17.93, found: C 59.03, H 5.25, N 17.82. HPLC rt = 1.91 min. White crystalline solid
Example 129
Figure imgf000157_0001
Spiro[cyclopentane-l,9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide, N-[[4-βuoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6', 7'-dihydro-3'- hydroxy-4'-oxo-. 1HNMR (500 MHz, CDCl3) δ: 12.10 (IH5 s), 8.55 (IH, t, J = 6.1 Hz), 8.29 (IH, s), 7.69 (IH, dd, J = 8.5, 5.8 Hz), 7.17 (IH, td, J = 8.2, 2.5 Hz), 7.08 (IH, dd, J = 8.5 , 2.5 Hz), 4.47 (2H, d, J = 6.7 HzO, 4.02-3.94 (4H, m), 2.52 (3H, s), 2.23-2.16 (2H, m), 2.09-2.04 (2H, m), 1.88-1.83 (4H, m). HRMS (M + H) cald. for C22H24FN6O4: 455.1843, found: 455.1833. Elem. anal, calcd for C22H23FN6O4: C, 58.14, H, 5.10; N, 18.49; found: C, 57.98; H, 4.92; 18.40. Example 130
Figure imgf000158_0001
Spiro [cyclopentane-1 , 9 '(4 'H)-pyrimido[2, l-c][l, 4]oxazine]-2 '-carboxamide,
N-[[2-(3, 5 -dimethyl- IH-1, 2, 4-triazol-l-yl)-4-fluorophenyl] methyl] -6', 7'-dihydro-3 '- hydroxy-4'-oxo-. LC/MS m/z 469 (M+H). 1H NMR (CDCl3, 500 MHz) δ ppm 1.80- 1.93 (4H, m, 11, CH2), 2.00-2.13 (2H, m, CH2), 2.14-2.25 (2H, m, CH2), 2.41 (3H, s, CH3), 2.42 (3H, s, CH3), 3.93-3.98 (2H, m, OCH2), 4.00 (2H, q, J=SA Hz, 7-NCH2), 4.31 (2H, d, J=6.7 Hz, CH2), 6.99 (IH, dd, J=8.4, 2.6 Hz, CH), 7.20 (IH, dt, J=8.5, 2.5 Hz, CH), 7.64 (IH, dd, J=8.5, 5.9 Hz, CH), 8.25 (IH, t, J=6.4 Hz, NH), 12.00 (IH, s, OH). 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.7 (CH3), 13.8 (CH3), 24.5 (CH2), 38.6 (NCH2), 40.4 (CH2), 42.9 (NCH2), 58.7 (OCH2), 86.2 (C), 114.2 (d, J=24 Hz, CH), 117.3 (d, J= 21 Hz, CH), 125.6 (C), 130.8 (d, J=3.8 Hz, C), 133.2 (d, J=8.7 Hz, CH), 137.0 (d, J=9.6 Hz, C), 146.4 (C), 151.5 (C), 153.8 (C), 157.8 (C), 160.5 (C), 161.9 (d, J=250 Hz, CF), 168.2 (C=O). HRMS (ESI) calcd for C23H26FN6O4 (M+H) 469.2000, found 469.1990. UV (MeOH) λ max 317 nm (ε 7.8OxIO3). Anal, calcd for C23H25FN6O4: C58.96, H5.37, N17.93; found C58.69, H5.12, N17.95.
Example 131
Figure imgf000158_0002
Spiro[cyclobutane-1, 9 '(6'H)-[4H]pyrazino[l, 2-a]pyrimidine]-2 '- carboxamide, N-[[4-fluoro-2-(lH-l, 2, 4-triazol-l-yl)phenyl] methyl]- 7', 8 '-dihydro-3 '- hydroxy-4'-oxo-. 1E NMR (500 MHz, DMSO-d6) δ ppm 2.08 (m, 1 H) 2.15 (m, 1 H) 2.45 - 2.52 (m, 2 H) 2.82 - 2.90 (m, 2 H) 3.53 (t, J=5.95 Hz, 2 H) 4.00 (t, J=5.80 Hz, 2 H) 4.48 (d, J=6.41 Hz, 2 H) 7.43 (td, J=8.39, 2.44 Hz, 1 H) 7.55 - 7.62 (m, 2 H) 8.31 (s, 1 H) 9.07 (s, 1 H) 9.28 (t, J=6.41 Hz, 1 H), 12.25 (brs, 1 H).
Example 132
Figure imgf000159_0001
Spiro[cyclobutane-1, 9 '(6'H)-[4HJpyrazino[l , 2-a]pyrimidine]-2 '- carboxamide, N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-4'-oxo-. 1H NMR (500 MHz, DMSOd6) δ ppm 2.05 - 2.14 (m, 2 H) 2.42 - 2.49 (m, 2 H) 2.92 (ddd, J=13.20, 9.23, 6.26 Hz, 2 H) 3.53 (t, J=5.95 Hz, 2 H) 4.02 (t, J=6.10 Hz, 2 H) 4.53 (d, J=6.41 Hz, 2 H) 7.18 (t, J=9.00 Hz, 2 H) 7.39 (dd, J=8.55, 5.49 Hz, 2 H) 9.45 (t, J=6.41 Hz, 1 H), 12.54 (brs, 1 H).

Claims

CLAIMSI claim:
1. A compound of Formula I selected from the group consisting of
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-8'-metriyl-4'-oxo- spiro[cyclopentane-l,9χ6Η)-[4H]pyrazino[l52-a]pyrimidine]-2'-carboxamide;
N-[[4-fluoro-2-(l H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl]-7'58'-dihydro-3'-hydroxy-8'- methyl-4'-oxo-spiro[cyclopentane-l,9'(6Η)-[4H]pyrazmo[l,2-a]pyrimidine]-2'- carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,254-triazol-l-yl)phenyl]methyl]-7t,8I-diliydro-3'- hydroxy-8'-methyl-4'-oxo-spiro[cyclopentane- 159'(6Η)-[4H]pyrazino[ 1 ,2- a]pyrimidine]-2'-carboxamide;
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3t-hydroxy-8t-methyl-4'-oxo- spirofcyclohexane-l^Xό^-^HJpyrazinofl^-aJpyrimidineJ^'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7t,8t-dihydro-3l-liydroxy-8'- metliyl-4'-oxo-spiro[cyclohexane-l,9'(6Η)-[4H]pyrazino[l,2-a]pyrimidine]-2'- carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l52,4-triazol-l-yl)phenyl]methyl]-7',8'-dihydro-3l- liydroxy-8'-methyl-4'-oxo-spiro[cyclohexane-l,9'(6Η)-[4H]pyrazino[l,2- a]pyrimidine]-2'-carboxamide;
N-[(4-fluorophenyl)methyl]-7',8t-dihydro-3I-hydroxy-8'-methyl-4'-oxo- spiro[cyclobutane- 1 ,9'(6Η)-[4H]pyrazino[ 1 ,2-a]pyrimidine]-2'-carboxamide; N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8t-dihydro-3'-hydroxy-8t- methyl-4'-oxo-spiro[cyclobutane-l,9'(6'H)-[4H]pyrazino[l,2-a]pyrimidine]-2'- carboxamide;
N-[[4-fluoro-2-(5-methyl- IH- 1 ,2,4-triazol- 1 -yOphenylJmethyη-V^'-dihydro-S1- hydroxy-8'-methyl-4'-oxo-spiro[cyclobutane- 1 ,9'(6Η)-[4H]pyrazino[ 1 ,2- ajpyrimidine] -2'-carboxamide;
N-[[4-fluoro-2-(l H- 1 ,2,3-triazol- 1 -yl)phenyl]methyl]-6',7'-dihydro-3 '-hydroxy-4'- oxo-spiro[cyclobutane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4] oxazine]-2'-carboxamide;
N-[[2-(4,5-dimethyl-lH-l,2,3-triazol-l-yl)-4-fluorophenyl]methyl]-6t,7'-dihydro-3'- hydroxy-4'-oxo- spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine]-2'- carboxamide;
N-tP-^-C^l-dimethylethyO-lH-l^^-triazol-l-ylJ^-fluoroplienyljmethylJ-o',?'- dihydro-3 '-liydroxy-4'-oxo-spiro[cyclobutane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]- 2'-carboxamide;
N-[[4-fluoro-2-(5-methyl-lH-l,2,3-triazol-l-yl)phenyl]methyl]-6',7'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclobutane-l ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'- carboxamide;
N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-6'57'-dihydro-3'-hydroxy-4'- oxo-spiro[cyclobutane-l,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(2-oxo-l-azetidinyl)phenyl]methyl]-6',7l-dihydro-3'-hydroxy-4l-oxo- spiro[cyclobutane-l,9'(4'H)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-[[2-(4,5-dimethyl- 1 H- 1 ,2,3-triazol- 1 -yl)-4-fluorophenyl]methyl]-7',8'-dihydro-3I- hydroxy-4'-oxo-spiro[cyclobutane- 1 , 10'(4'H)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepine]-2'- carboxamide; N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7t-dihydro-3l- hydroxy-4l-oxo-spiro[oxetane-3,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'- carboxamide;
N-[(4-fluorophenyl)methyl]-6',7'-dihydro-3'-hydroxy-4'-oxo-spiro[oxetane-3,9'(4'H)- pyriniido[2, 1 -c] [ 1 ,4] oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-6',7t-dihydro-3'-hydroxy-4I- oxo-spiro[oxetane-3,9'(4Η)-pyrimido[2,l-c][l54]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(rQethylsulfonyl)phenyl]methyl]-6l,7'-dihydro-3l-hydroxy-4'-oxo- spiro[oxetane-3,9'(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'-carboxamide;
N-[[4-fluoro-2-(lH-l,2,3-triazol-l-yl)plienyl]inetliyl]-2,3,5,6,6?,7'-hexahydro-3'- hydroxy-4'-oxo-spiro[4H-pyran-4,9'(4Η)-pyriinido[251 -c] [ 1 ,4] oxazinej-2'- carboxamide;
N-[[4-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl]metliyl]-6t,7'-dihydro-3l-hydroxy-4t- oxo-spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
N-[(4-fluorophenyl)methyl]-2,3,5,6,7',8'-hexahydro-3'-hydroxy-4'-oxo-spiro[4H- pyran-4, 10'(4'H)-[6H]pyrimido[2, 1 -c] [ 1 ,4] oxazepine] -2'-carboxamide;
N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-2,3,5,6,7',8l-hexahydro-3'- hydroxy-4'-oxo-spiro[4H-pyran-4,10'(4'H)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide;
N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,7l,8'-hexahydro-3l-hydroxy- 4'-oxo-spiro[4H-pyran-4, 10'(4Η)-[6H]pyrimido[2, 1 -c] [ 1 ,4] oxazepine] -2'- carboxamide; [5-fluoro-2-[[[(2,3,5,6,7',8'-hexahydro-3'-hydroxy-4'-oxospiro[4H-pyran-4,10'(4'H)- [6H]pyrimido[2,l-c][l,4]oxazepin]-2'-yl)carbonyl]amino]methyl]phenyl]-phosphonic acid, dimethyl ester;
N-tμ-fluoro^-ClH-l^^-triazol-l-yOphenyηmethylj^^^^J'^'-hexahydro-3'- hydroxy-4'-oxo-spiro[4H-pyran-4,10l(4Η)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2l- carboxamide;
N-[[4-fluoro-2-(3-methyl-lH-1,2,4-triazol-l-yl)phenyl]methyl]-2,3,5,6,7',8'- hexahydro-3'-hydroxy-4'-oxo-spiro[4H-pyran-4, 10'(4'H)-[6H]pyrimido[2, 1 - c] [ 1 ,4]oxazepine]-2'-carboxamide;
N-t^-fluoro^-(5-methyl-lH-l^^-triazol-l-y1)phenylJmethyl]-2,3,5,6,7, 8'- hexahydro-3 '-hydroxy-4'-oxo-spiro[4H-pyran-4, 10'(4'H)-[6H]pyrimido[2, 1 - c] [ 1 ,4] oxazepine] -2'-carboxamide;
2,3,5,6,7',8'-hexahydro-3 '-hydroxy-N-[[2-(3-methyl- IH- 1 ,2,4-triazol- 1 - yl)phenyl]methyl]-4'-oxo-spiro[4H-pyran-4,101(4'H)-[6H]pyrimido[2,l- c] [ 1 ,4] oxazepine] -2 '-carboxamide;
N-[[4-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl]methyl]-2,3,5,6,7',8t-hexahydro-3l- hydroxy-4'-oxo-spiro[4H-pyran-4,10'(4Η)-[6H]pyrimido[2,l-c][l,4]oxazepine]-2'- carboxamide;
N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]metliyl]-7',8t-dihydro-3I- hydroxy-4'-oxo-spiro[cyclobutane- 1 , 10'(4Η)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepine]-2'- carboxamide; N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl]methyl]-6I 57'-diliydro-3t- hydroxy-4'-oxo-spiro[cyclobutane-l,9!(4Η)-pyrimido[2,l-c][l,4]oxazine]-2'- carboxamide;
6',7'-dihydro-3'-hydroxy-4'-oxo-N-[[2-(2-oxo-l-azetidinyl)phenyl]metliyl]- spiro[cyclobutane- 1 ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4]oxazine]-2'-carboxamide;
6',7'-dihydro-3 '-hydroxy-4'-oxo-N- [ [2-(2-oxo-3 -oxazolidinyl)phenyl]methyl] - spiro[cyclobutane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'-carboxamide;
N-[[2-(3,5-dimethyl- 1 H- 1 ,2,4-triazol- 1 -yl)-4-fluorophenyl]metliyl]-6',7'-dihydro-3l- hydroxy-4'-oxo-spiro[cyclobutane-l ,9'(4Η)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'- carboxamide;
N-[[2-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-4-fluorophenyl]methyl]-7',8'-dihydro-3l- hydroxy-4'-oxo-spiro[cyclobutane-l , 10'(4Η)-[6H]pyrimido[2, 1 -c] [ 1 ,4]oxazepine]-2'- carboxamide;
N-[[4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)ρhenyl]methyl]-6',7'-dihydro-31- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [1 ,4] oxazine] -T- carboxamide;
N-[[2-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-4-fluorophenyl]methyl]-6',7'-dihydro-3'- hydroxy-4'-oxo-spiro[cyclopentane- 1 ,9'(4'H)-pyrimido[2, 1 -c] [ 1 ,4] oxazine] -2'- carboxamide;
N-[[4-fluoro-2-(lH-l,2,4-triazol-l-yl)phenyl]methyl]-7',8t-dihydro-3'-hydroxy-4I- oxo-spiro[cyclobutane- 1 ,9'(6Η)-[4H]pyrazino[ 1 ,2-a]pyrimidine]-2'-carboxamide; and
N-[(4-fluorophenyl)methyl]-7',8'-dihydro-3'-hydroxy-4'-oxo-spiro[cyclobutane- l,9'(6'H)-[4H]pyrazino[l,2-a]pyrimidine]-2'-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
2. A composition comprising a therapeutic amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
3. A method of inhibiting HIV integrase comprising contacting a compound of Claim 1 with HIV integrase.
4. A method of inhibiting HIV viral DNA integration into human DNA comprising administering an effective amount of a compound of Claim 1 to a patient infected with HIV.
5. A method for treating HIV infection comprising administering a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a patient infected with HFV.
6. The method of claim 5, further comprising a therapeutically effective amount of one or more other HIV treatment agents selected from the group consisting of HFV protease inhibitors, HFV nucleoside reverse transcriptase inhibitors, HIV non- nucleoside reverse transcriptase inhibitors, HlV-entry inhibitors, HIV integrase inhibitors, immunomodulators, or a combination thereof.
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