Patent Application
20170304239
The invention relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection.
The invention also relates to methods for making the compounds hereinafter described.
Acquired immunodeficiency syndrome (AIDS) is the result of infection by HIV. It remains a major medical problem, with an estimated 34 million people infected worldwide at the end of 2011, 3.3 million of them under the age of 15. In 2011, there were 2.5 million new infections, and 1.7 million deaths from complications due to HIV/AIDS.
Current therapy for HIV-infected individuals consists of a combination of approved anti-retroviral agents. Over two dozen drugs are currently approved for HIV infection, either as single agents or as fixed dose combinations or single tablet regimens, the latter two containing 2-4 approved agents. These agents belong to a number of different classes, targeting either a viral enzyme or the function of a viral protein during the virus life cycle. Thus, agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gp160 protein). In addition, a pharmacokinetic enhancer with no antiviral activity (cobicistat) has recently been approved for use in combinations with antiretroviral agents (ARVs) that require boosting.
Despite the armamentarium of agents and drug combinations, there remains a medical need for new anti-retroviral agents, due in part to the need for chronic dosing to combat infection. Significant problems related to long-term toxicities are documented, creating a need to address and prevent these co-morbidities (e.g. CNS, CV/metabolic, renal disease). Also, increasing failure rates on current therapies continue to be a problem, due either to the presence or emergence of resistant strains or to non-compliance attributed to drug holidays or adverse side effects. For example, despite therapy, it has been estimated that 63% of subjects receiving combination therapy remained viremic, as they had viral loads >500 copies/ml (Oette, M, Kaiser, R, Daiumer, M, et al. Primary HIV Drug Resistance and Efficacy of First-Line Antiretroviral Therapy Guided by Resistance Testing. J Acq Imm Def Synd 2006; 41(5):573-581). Among these patients, 76% had viruses that were resistant to one or more classes of antiretroviral agents. As a result, new drugs are needed that are easier to take, have high genetic barriers to the development of resistance and have improved safety over current agents. In this panoply of choices, novel MOAs that can be used as part of the preferred HAART regimen can still have a major role to play since they should be effective against viruses resistant to current agents.
Certain therapeutic compounds have now been set forth in WO 2013/006738, WO 2014/110298, and WO 2014/134566.
What is now needed in the art are additional compounds which are novel and useful in the treatment of HIV. Additionally, these compounds should provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanisms of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability. Also needed are new formulations and methods of treatment which utilize these compounds.
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions, and their use in inhibiting HIV and treating those infected with HIV or AIDS.
One aspect of the invention is a compound of Formula I, including pharmaceutically acceptable salts thereof:
wherein:
R is selected from the group of alkyl, alkenyl, alkoxy, alkylthioxy, C5-C8 bicycloalkyl, C3-C7 cycloalkyl, aryl, and 5-6 member heteroaryl; and is substituted with 0-3 substituents selected from the group of alkyl, alkenyloxy, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, aryl, benzyloxy, cyano, cycloalkoxy, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy and (heteroaryl)sulfonyl;
R1 is selected from the group of alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and 5-6 member heteroaryl; and is substituted with 0-3 substituents selected from the group of alkyl, alkoxy, alkoxycarbonyl, aryl, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, 5-6 member heteroaryl, nitro, and —NR2R3, where R2 and R3 are each independently selected from H, alkyl, and cycloalkyl, or R2 and R3 together form heterocycles comprised of 1-3 rings;
A is a five or six-member heteroaryl ring optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkyl, halo and haloalkyl; and
B is selected from the group of alkyl, aryl, arylalkyl, C3-C9 cycloalkyl, and 5-6 member heteroaryl, and is substituted with 0-3 substituents selected from the group of alkyl, alkylsulphonyl, alkoxy, alkylaryl, allyloxy, arylalkoxy, cycloalkoxy, cycloalkyl, halo, haloalkoxy, heteroarylcycloalkyl amido, hydroxymethyl, nitro, —CN, —COOR2, —NR2R3, —N(R2)COOR3, —NR2SO2R3, —CONR2R3, —NH—CO-alkyl, and morpholinyl.
The invention also relates to pharmaceutical compositions comprising a compound of Formula I, including pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.
In addition, the invention provides one or more methods of treating HIV infection comprising administering a therapeutically effective amount of a compound of Formula I to a patient.
Also provided as part of the invention are one or more methods for making the compounds of Formula I.
The present invention is directed to these, as well as other important ends, hereinafter described.
The singular forms “a”, “an”, and “the” include plural reference unless the context dictates otherwise.
Unless otherwise specifically set forth elsewhere in the application, the following terms shall have the following meanings:
“Alkenyl” means an optionally substituted straight or branched alkyl group comprised of 2 to 10 carbons with at least one double bond.
“Alkenyloxy” means an alkenyl group attached to the parent structure through oxygen atom.
“Alkoxy” means alkyl group attached to the parent structure by oxygen atom.
“Alkoxycabonyl” means an alkoxy group attached to the parent structure by a carbonyl moiety.
“Alkoxycabonylamino” means alkoxycabonyl group attached to the parent structure by nitrogen where the nitrogen is optionally substituted with an alkyl group.
“Alkyl” means a straight or branched saturated hydrocarbon comprised of 1 to 10 carbons, and preferably 1 to 6 carbons.
“Alkylsulphonyl” means an alkyl group attached to the parent structure through a —SO2— moiety.
“Alkylthioxy” means an alkyl group attached to the parent structure through a sulfur atom.
“Alkynyl” means an optionally substituted straight or branched alkyl group comprised of 2 to 10 carbons and containing at least one triple bond.
“Aminocabonyl” means an amine group attached to the parent structure through a carbonyl moiety where the amine is optionally substituted with at least one or two alkyl, aryl, heteroaryl, heterocycle or any combination thereof.
“Aryl” mean a carbocyclic group comprised of 1-3 rings that are fused and/or bonded and at least one or a combination of which is aromatic. The non-aromatic carbocyclic portion, where present, will be comprised of C3 to C7 alkyl group. Examples of an aromatic group include phenyl, biphenyl, naphthalene, and tetrahydronaphthalene. The aryl group can be attached to the parent structure through any substitutable carbon atom in the group.
“Benzyloxy” means a benzyl group attached to the parent structure through an oxygen atom. The phenyl group of the benzyl moiety could be optionally substituted by 1-3 moieties independently selected from the group of alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.
“C5-C10 bicycloalkyl” means a bicyclic ring system comprised of 5 to 10 carbons. Examples include bicyclo[2.2.2]octane and octahydropentalene.
“C3-C7 cycloalkyl” means a monocyclic ring system comprised of 3 to 7 carbons.
“Cyano” refers to —CN.
“Halo” or “halogen” refers to —F, —Cl, —Br, or —I.
“Haloalkyl” means an alkyl group substituted by any combination of one to six halogen atoms.
“Haloalkoxy” means a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
“Hydroxy” refers to —OH.
“Heteroaryl” is a subset of heterocyclic group as defined below and is comprised of 1-3 rings where at least one or a combination of which is aromatic and that the aromatic group contains at least one atom chosen from a group of oxygen, nitrogen and sulfur.
“Heterocyclic” means a cyclic group of 1-3 rings comprised of carbon and at least one other atom selected independently from the group of oxygen, nitrogen and sulfur. The rings could be fused and or bonded, through a direct or spiro attachment, with the option to have one or a combination thereof be aromatic. Examples include, but are not limited to, azaindole, azaindoline, benzimidazole, 2,3-dihydrobenzofuran, furan, imidazole, imidazo[1,2-a]pyridine, indazole, indole, indoline, morpholine, oxazole, 6-oxaspiro[2.5]octane, phenylquinoline, phenylpyrazole, piperidine, pyrazole, pyrazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline, thiazole, and thiophene. The heterocyclic group can be attached to the parent structure through any substitutable atom in the group that results in stable compound.
“—NRxRY” (as in the case of “—NR2R3”) refers to two groups, Rx and Ry, which are attached to the parent structure through nitrogen atom and with an option to form heterocycles comprised of 1-3 rings.
Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system (for example a bicyclic ring system) are intended to bond to the ring where they are drawn to append.
Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
Those terms not specifically set forth herein shall have the meaning which is commonly understood and accepted in the art.
The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers.
The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
As set forth above, the invention is directed to a compound of Formula I, including pharmaceutically acceptable salts thereof:
R is selected from the group of alkyl, alkenyl, alkoxy, alkylthioxy, C5-C8 bicycloalkyl, C3-C7 cycloalkyl, aryl, and 5-6 member heteroaryl; and is substituted with 0-3 substituents selected from the group of alkyl, alkenyloxy, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, aryl, benzyloxy, cyano, cycloalkoxy, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy and (heteroaryl)sulfonyl;
R1 is selected from the group of alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and 5-6 member heteroaryl; and is substituted with 0-3 substituents selected from the group of alkyl, alkoxy, alkoxycarbonyl, aryl, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, 5-6 member heteroaryl, nitro, and —NR2R3, where R2 and R3 are each independently selected from H, alkyl, and cycloalkyl, or R2 and R3 together form heterocycles comprised of 1-3 rings;
A is a five or six-member heteroaryl ring optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkyl, halo and haloalkyl; and
B is selected from the group of alkyl, aryl, arylalkyl, C3-C9 cycloalkyl, and 5-6 member heteroaryl, and is substituted with 0-3 substituents selected from the group of alkyl, alkylsulphonyl, alkoxy, alkylaryl, allyloxy, arylalkoxy, cycloalkoxy, cycloalkyl, halo, haloalkoxy, heteroarylcycloalkyl amido, hydroxymethyl, nitro, —CN, —COOR2, —NR2R3, —N(R2)COOR3, —NR2SO2R3, —CONR2R3, —NH—CO-alkyl, and morpholinyl.
For the compounds of Formula I, the scope of any instance of a variable substituent can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.
Preferably, aryl is a monocyclic or bicyclic structure containing C6-C10 carbon atoms.
In certain embodiments of the compound of Formula I above, it is preferred that R is phenyl, which is optionally further substituted with one or more halo groups, preferably fluoro.
In another embodiment of the invention, it is preferred that R1 is phenyl, and is optionally further substituted with one or more alkyl or halo groups.
It is also preferred that A is selected from the group of imadazole-2-yl, imidazole-3-yl, triazolyl, oxazolyl, pyridyl, pyrimidinyl, and pyrazinyl. In certain instances, the imadazole-2-yl, imidazole-3-yl, triazolyl, and pyridyl groups may be especially preferred.
Also preferred are the embodiments wherein B is phenyl. Further preferred are the embodiments wherein B is phenyl which is further substituted with at least one member selected from the group of halo, alkyl, alkoxy, haloalkoxy, and —N(R2)COOR3. Also preferred are the embodiments wherein B is a 5 to 10 membered aryl or heteroaryl group. More preferably, the aryl or heteroaryl group may be selected from the group of
In certain embodiments, it is also preferred that A is selected from the group of imadazole-2-yl, imidazole-3-yl, triazolyl, and pyridyl groups, and further wherein each of B, R and R1 are phenyl groups.
Preferred compounds of the invention, including pharmaceutically acceptable salts thereof, are selected from the group of:
Other preferred compounds, including pharmaceutically acceptable salts thereof, are selected from the group of:
The compounds of the invention herein described and set forth are generally given as pharmaceutical compositions. These compositions are comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and may contain conventional excipients and/or diluents. 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, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. Compositions are made using available formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa. (1985).
Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.
Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.
The compounds of this invention have activity against HIV. Accordingly, another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, including a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, excipient and/or diluent.
The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection. The compound can also be used in combination therapy wherein the compound and one or more of the other agents are physically together in a fixed-dose combination (FDC). Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti-infectives. In these combination methods, the compound of Formula I will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.
“Combination,” “coadministration,” “concurrent” and similar terms referring to the administration of a compound of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.
Thus, as set forth above, contemplated herein are combinations of the compounds of Formula I, together with one or more agents useful in the treatment of AIDS. For example, the compounds of the invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines, such as those in the following non-limiting table:
“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 therapeutically effective treatment include 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 the invention according to the various embodiments can be made by various methods available in the art, including those of the following schemes in the specific examples which follow. The structure numbering and variable numbering shown in the synthetic schemes may be distinct from, and should not be confused with, the structure or variable numbering 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 the invention.
Abbreviations used in the schemes generally follow conventions used in the art. Some specific chemical abbreviations used in the examples are defined as follows: “DMF” for N,N-dimethylformamide; “MeOH” for methanol; “Ar” for aryl; “TFA” for trifluoroacetic acid; “BOC” for t-butoxycarbonate, “DMSO” for dimethylsulfoxide; “h” for hours; “rt” for room temperature or retention time (context will dictate); “min” for minutes; “EtOAc” for ethyl acetate; “THF” for tetrahydrofuran; “Et2O” for diethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for 1,2-dichloroethane; “ACN” for acetonitrile; “DME” for 1,2-dimethoxyethane; “HATU” for (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) “DIEA” for diisopropylethylamine.
Certain other abbreviations as used herein, are defined as follows: “1×” for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL” for milliliter or milliliters, “μL” for microliter or microliters, “N” for normal, “M” for molar, “mmol” for millimole or millimoles, “min” for minute or minutes, “h” for hour or hours, “rt” for room temperature, “RT” for retention time, “atm” for atmosphere, “psi” for pounds per square inch, “conc.” for concentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “1H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.
The following examples are provided by way of illustration only, and should not be construed as limiting the scope of the invention.
(S)-tert-butyl (1-(1H-imidazol-2-yl)-2-phenylethyl)carbamate: To a mixture of (S)-tert-butyl (1-oxo-3-phenylpropan-2-yl)carbamate (4.4 g, 17.65 mmol) in MeOH (75 mL) at −10° C. was added 40% Glyoxal in water (2.024 mL, 17.65 mmol). At −10° C., ammonia gas was bubbled through the reaction mixture for 60 minutes. The reaction was warmed up to r.t. and stirred for 100 hrs. Most of the methanol was evaporated. Water was added to the reaction mixture and solid precipitated out. The solid was filtered and purified by silica gel chromatography to afford (1.7 g, 33.5%) of the title compound.
1H NMR (400 MHz, DMSO-d6) δ 11.74-11.59 (m, 1H), 7.24 (br. s., 2H), 7.20-7.13 (m, 3H), 7.10-7.02 (m, 1H), 7.01-6.94 (m, 1H), 6.80 (s, 1H), 4.89-4.74 (m, 1H), 3.23-3.14 (m, 1H), 3.03-2.90 (m, 1H), 1.31 (s, 9H).
(S)-tert-butyl (1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate: To a mixture of (S)-tert-butyl (1-(1H-imidazol-2-yl)-2-phenylethyl)carbamate (80 mg, 0.278 mmol), (4-methoxyphenyl)boronic acid (85 mg, 0.557 mmol), copper (II) acetate (50.6 mg, 0.278 mmol) was added dichloromethane (5 mL) followed by diisopropylethylamine (0.146 mL, 0.835 mmol) and molecular sieves. The reaction mixture was stirred at r.t. under an atmosphere of air for 4 days. The reaction mixture was filtered through a pad of silica gel and washed by 10% MeOH/DCM. The solvent was evaporated and the residue was purified by prep HPLC to afford (45 mg, 41%) of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ 7.24-7.06 (m, 4H), 7.05-6.76 (m, 7H), 4.82-4.71 (m, 1H), 3.83 (s, 3H), 3.13-2.95 (m, 2H), 1.38 (s, 9H).
(S)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethanamine, TFA salt: To (S)-tert-butyl (1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate (20 mg, 0.051 mmol) was added 50% TFA in dichloromethane (1 ml). The reaction mixture was stirred at r.t. for 2 hrs. The solvent was evaporated to give (20 mg, 97%) of the title compound. It was used without further purification.
(S)—N-((1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)-2-methylbenzene-sulfonamide: To a solution of (S)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethanamine, TFA (20 mg, 0.049 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.026 mL, 0.147 mmol) followed by 2-methylbenzenesulfonyl isocyanate (14.5 mg, 0.074 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by prepHPLC to afford (16.5 mg, 68.5%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=7.7 Hz, 1H), 7.61-7.52 (m, 1H), 7.45-7.32 (m, 2H), 7.18-7.08 (m, 4H), 7.03 (s, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.91-6.79 (m, 4H), 6.70 (d, J=6.2 Hz, 2H), 4.69 (q, J=7.5 Hz, 1H), 3.77 (s, 3H), 3.02-2.71 (m, 2H), 2.53 (s, 3H).
(S)-tert-butyl (1-(1-(4-nitrophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate: To (S)-tert-butyl (1-(1H-imidazol-2-yl)-2-phenylethyl)carbamate (200 mg, 0.696 mmol) in DMF (1 mL) was added cesium carbonate (454 mg, 1.392 mmol) followed by 1-fluoro-4-nitrobenzene (196 mg, 1.392 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. The reaction mixture was cooled down and filtered. Purification by prepHPLC afforded (135 mg, 47.5%) of the title compound.
1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.29 (s, 1H), 7.15-7.05 (m, 4H), 6.94-6.86 (m, 2H), 4.81 (d, J=7.8 Hz, 1H), 3.15-2.90 (m, 2H), 1.22 (s, 9H).
(S)-tert-butyl (1-(1-(4-aminophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate A mixture of 10% palladium on carbon (6 mg, 5.64 μmol) in methanol (1 mL) was stirred under H2 balloon for 5 mins. (S)-tert-butyl (1-(1-(4-nitrophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate (25 mg, 0.061 mmol) in methanol (1 mL) was added. The reaction mixture was stirred under H2 balloon for 4 hrs. The palladium catalyst was filtered off and the solvent was evaporated to afford (20 mg, 86%) of the title compound.
1H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J=8.5 Hz, 1H), 7.18-7.11 (m, 3H), 7.00 (s, 1H), 6.93 (s, 1H), 6.90-6.83 (m, 2H), 6.69 (d, J=8.3 Hz, 2H), 6.53 (d, J=8.3 Hz, 2H), 5.35 (s, 2H), 4.63 (d, J=7.8 Hz, 1H), 3.04-2.80 (m, 2H), 1.29 (s, 9H).
(S)-methyl (4-(2-(1-tert-butoxycarbonylamido-2-phenylethyl)-1H-imidazol-1-yl)phenyl)carbamate: To a solution of (S)-tert-butyl (1-(1-(4-aminophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate (24 mg, 0.063 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.033 mL, 0.190 mmol) followed by methylchloroformate (7.2 mg, 0.076 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by prepHPLC to afford (20 mg, 72.3%) of the title compound.
(S)-methyl (4-(2-(2-phenyl-1-(3-(o-tolylsulfonyl)ureido)ethyl)-1H-imidazol-1-yl)phenyl)carbamate: To (S)-methyl (4-(2-(1-tert-butoxycarbonylamido-2-phenylethyl)-1H-imidazol-1-yl)phenyl)carbamate (20 mg, 0.046 mmol) was added 50% TFA in dichloromethane (1 ml). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated to afford (S)-methyl (4-(2-(1-amino-2-phenylethyl)-1H-imidazol-1-yl)phenyl)carbamate, TFA salt. It was used for next step without further purification. To a solution of (S)-methyl (4-(2-(1-amino-2-phenylethyl)-1H-imidazol-1-yl)phenyl)carbamate, TFA salt in dichloromethane (1 mL) was added diisopropylethylamine (0.024 mL, 0.137 mmol) followed by 2-methylbenzenesulfonyl isocyanate (13.6 mg, 0.069 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by prepHPLC to afford (11.6 mg, 47.4%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.51 (d, J=7.0 Hz, 1H), 7.46-7.29 (m, 4H), 7.18-7.06 (m, 4H), 7.03 (s, 1H), 6.82 (d, J=8.1 Hz, 2H), 6.70 (d, J=6.6 Hz, 2H), 4.70 (d, J=6.2 Hz, 1H), 3.00-2.74 (m, 2H), 2.53 (s, 3H).
(S)-methyl (4-(2-(1-(3-(naphthalen-1-ylsulfonyl)ureido)-2-phenylethyl)-1H-imidazol-1-yl)phenyl)carbamate: To a solution of naphthalene-1-sulfonamide (13.80 mg, 0.067 mmol) in toluene (1 mL) was added 1-isocyanatobutane (1.32 mg, 0.013 μmol) followed by triphosgene (6.59 mg, 0.022 mmol). The reaction mixture was stirred at 110° C. for 24 hrs. The reaction mixture was cooled down and the solvent was evaporated to afford naphthalene-1-sulfonyl isocyanate. It was used for next step without further purification. To a solution of (S)-methyl (4-(2-(1-amino-2-phenylethyl)-1H-imidazol-1-yl)phenyl)carbamate, TFA (20 mg, 0.044 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.023 mL, 0.133 mmol) followed by naphthalene-1-sulfonyl isocyanate in dichloromethane (0.5 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by prepHPLC to afford (13.1 mg, 51.8%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 9.83 (br. s., 1H), 8.55 (d, J=8.1 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.20-8.07 (m, 2H), 7.80-7.58 (m, 3H), 7.36 (d, J=8.1 Hz, 2H), 7.21-6.83 (m, 7H), 6.74 (d, J=8.4 Hz, 2H), 6.56 (d, J=7.3 Hz, 2H), 4.63 (d, J=6.6 Hz, 1H), 3.69 (s, 3H), 2.89-2.60 (m, 2H).
(S)-tert-butyl (1-(1-(3-(1H-pyrrol-1-yl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate: To a 0.5-2 ml microwave tube was added (S)-tert-butyl (1-oxo-3-phenylpropan-2-yl)carbamate (150 mg, 0.602 mmol), 3-(1H-pyrrol-1-yl)aniline (95 mg, 0.602 mmol), ammonium acetate (46.4 mg, 0.602 mmol), 40% Glyoxal in water (87 mg, 0.602 mmol), acetic acid (0.172 mL, 3.01 mmol) and ethanol (3 mL). The reaction mixture was heated in a microwave reactor at 160° C. for 20 min. The reaction mixture was filtered and the filtrate was purified by PrepHPLC to afford (25 mg, 10%) of the title compound.
1H NMR (500 MHz, METHANOL-d4) δ 7.53 (br. s., 1H), 7.42 (s, 1H), 7.23 (t, J=2.0 Hz, 2H), 7.18-7.01 (m, 6H), 6.85-6.72 (m, 3H), 6.32 (t, J=2.0 Hz, 2H), 4.95-4.88 (m, 1H), 3.15-3.00 (m, 2H), 1.42 (s, 9H).
(S)—N-((1-(1-(3-(1H-pyrrol-1-yl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)-2-methyl-benzenesulfonamide: To (S)-tert-butyl (1-(1-(3-(1H-pyrrol-1-yl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate (25 mg, 0.058 mmol) was added 50% TFA in dichloromethane (1 ml). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated to afford (S)-1-(1-(3-(1H-pyrrol-1-yl)phenyl)-1H-imidazol-2-yl)-2-phenylethanamine, TFA salt. It was used for next step without further purification. To a solution of (S)-1-(1-(3-(1H-pyrrol-1-yl)phenyl)-1H-imidazol-2-yl)-2-phenylethanamine, TFA salt in dichloromethane (1 mL) was added diisopropylethylamine (0.031 mL, 0.175 mmol) followed by 2-methylbenzenesulfonyl isocyanate (17.3 mg, 0.088 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by prepHPLC to afford (16 mg, 52%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.3 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.44-7.28 (m, 5H), 7.22 (br. s., 2H), 7.16 (s, 1H), 7.09-6.92 (m, 4H), 6.63 (br. s., 3H), 6.26 (s, 2H), 4.96-4.68 (m, 1H), 2.97-2.77 (m, 2H), 2.54 (s, 3H).
Examples 5-32 were synthesized using the procedure described above for Example 1.
1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=7.7 Hz, 1H), 7.60-7.49 (m, 1H), 7.46-7.31 (m, 2H), 7.23-7.16 (m, 3H), 7.15-7.03 (m, 4H), 6.96 (br. s., 3H), 6.70 (d, J=6.6 Hz, 2H), 4.70 (d, J=7.0 Hz, 1H), 3.05-2.68 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.99-7.87 (m, 1H), 7.66-7.39 (m, 3H), 7.11 (d, J=5.9 Hz, 4H), 7.02 (s, 1H), 6.92-6.78 (m, 4H), 6.76-6.68 (m, 2H), 4.67 (d, J=6.2 Hz, 1H), 3.76 (s, 3H), 3.01-2.75 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J=8.1 Hz, 1H), 7.40 (br. s., 1H), 7.33-7.21 (m, 2H), 7.15-7.04 (m, 4H), 7.00 (s, 1H), 6.88-6.75 (m, 4H), 6.70 (d, J=6.2 Hz, 2H), 4.67 (br. s., 1H), 4.03 (q, J=6.4 Hz, 2H), 2.97-2.70 (m, 2H), 2.53 (s, 3H), 1.33 (t, J=6.8 Hz, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.73 (d, J=7.7 Hz, 1H), 7.46-7.20 (m, 3H), 7.19-6.98 (m, 5H), 6.92 (br. s., 1H), 6.85-6.66 (m, 3H), 6.55 (d, J=7.3 Hz, 1H), 4.37-4.24 (m, 1H), 3.74 (s, 3H), 3.03-2.79 (m, 2H), 2.55 (s, 3H), 2.50 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J=7.3 Hz, 1H), 7.44 (br. s., 1H), 7.34-7.26 (m, 2H), 7.22 (t, J=8.1 Hz, 1H), 7.15 (br. s., 1H), 7.12-7.00 (m, 4H), 6.92 (d, J=8.4 Hz, 1H), 6.67 (d, J=7.0 Hz, 2H), 6.59 (br. s., 1H), 6.47 (d, J=7.0 Hz, 1H), 4.80 (br. s., 1H), 3.66 (s, 3H), 2.99-2.75 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J=7.7 Hz, 1H), 7.39 (br. s., 1H), 7.30-7.20 (m, 2H), 7.13-7.04 (m, 4H), 7.01 (br. s., 1H), 6.83 (d, J=8.4 Hz, 1H), 6.73-6.55 (m, 3H), 6.35 (d, J=7.7 Hz, 1H), 4.81-4.68 (m, 1H), 3.75 (s, 6H), 3.02-2.76 (m, 2H), 2.52 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=7.7 Hz, 1H), 7.57-7.47 (m, 1H), 7.42-7.30 (m, 4H), 7.23 (s, 1H), 7.16-6.86 (m, 7H), 6.67 (d, J=7.3 Hz, 2H), 4.74 (d, J=6.6 Hz, 1H), 2.95-2.77 (m, 3H), 2.54 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.0 Hz, 1H), 7.51-7.26 (m, 5H), 7.19 (br. s., 1H), 7.16-7.02 (m, 4H), 6.98 (d, J=6.6 Hz, 1H), 6.78 (s, 1H), 6.67 (d, J=6.6 Hz, 2H), 4.70 (br. s., 1H), 2.96-2.80 (m, 2H), 2.54 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J=7.3 Hz, 1H), 7.49 (br. s., 1H), 7.40-7.27 (m, 2H), 7.19-7.07 (m, 6H), 7.03 (s, 1H), 6.79 (d, J=7.3 Hz, 3H), 6.70 (d, J=6.6 Hz, 2H), 4.70 (d, J=5.9 Hz, 1H), 3.00-2.74 (m, 2H), 2.52 (s, 3H), 2.31 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J=7.3 Hz, 1H), 7.50-7.24 (m, 5H), 7.20-7.01 (m, 5H), 6.94 (d, J=8.4 Hz, 2H), 6.71 (d, J=7.0 Hz, 2H), 4.70 (d, J=6.2 Hz, 1H), 2.99-2.78 (m, 2H), 2.52 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J=7.3 Hz, 1H), 7.48 (d, J=7.0 Hz, 2H), 7.35 (br. s., 1H), 7.24 (br. s., 2H), 7.14-6.98 (m, 5H), 6.88 (br. s., 2H), 6.71 (d, J=6.2 Hz, 2H), 4.70 (br. s., 1H), 2.99-2.77 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J=6.2 Hz, 1H), 7.57-7.48 (m, 1H), 7.45-7.32 (m, 3H), 7.18-6.97 (m, 6H), 6.91-6.57 (m, 4H), 4.50 (br. s., 1H), 2.89-2.63 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J=8.1 Hz, 1H), 7.56-7.45 (m, 1H), 7.41-7.29 (m, 2H), 7.28-7.20 (m, 1H), 7.17 (s, 1H), 7.13-7.02 (m, 4H), 6.96 (d, J=8.4 Hz, 1H), 6.67 (d, J=7.0 Hz, 2H), 6.62-6.57 (m, 1H), 6.47 (d, J=7.3 Hz, 1H), 6.09-5.91 (m, 1H), 5.43-5.20 (m, 2H), 4.81 (d, J=6.6 Hz, 1H), 4.50 (br. s., 2H), 3.00-2.76 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.7 Hz, 1H), 7.49 (br. s., 1H), 7.40-7.25 (m, 2H), 7.20-7.08 (m, 3H), 7.06 (s, 1H), 7.01 (s, 1H), 6.71 (d, J=6.6 Hz, 2H), 6.68-6.59 (m, 2H), 6.47 (br. s., 1H), 4.70-4.51 (m, 3H), 3.14-2.77 (m, 4H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.41-7.27 (m, 3H), 7.21 (s, 1H), 7.15-7.02 (m, 4H), 6.99 (d, J=7.0 Hz, 1H), 6.87 (br. s., 1H), 6.67 (d, J=7.0 Hz, 2H), 4.72 (d, J=7.3 Hz, 1H), 3.00-2.79 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=8.1 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.46 (d, J=7.0 Hz, 1H), 7.38-7.24 (m, 3H), 7.21-6.94 (m, 6H), 6.91-6.77 (m, 1H), 6.67 (d, J=7.3 Hz, 2H), 4.69 (br. s., 1H), 2.98-2.80 (m, 2H), 2.54 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J=8.1 Hz, 1H), 7.47 (br. s., 1H), 7.39-7.26 (m, 2H), 7.17-7.05 (m, 4H), 7.01 (s, 1H), 6.88-6.75 (m, 4H), 6.69 (d, J=7.0 Hz, 2H), 4.76-4.54 (m, 2H), 2.98-2.71 (m, 2H), 2.53 (s, 3H), 1.27 (d, J=6.2 Hz, 6H).
1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J=8.1 Hz, 1H), 7.51 (br. s., 1H), 7.35 (d, J=8.1 Hz, 2H), 7.11 (d, J=7.0 Hz, 4H), 7.00 (s, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.69 (d, J=7.0 Hz, 2H), 6.47-6.33 (m, 2H), 4.73 (d, J=8.1 Hz, 1H), 4.26 (br. s., 4H), 2.99-2.75 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J=8.1 Hz, 1H), 7.39 (br. s., 1H), 7.31-7.15 (m, 5H), 7.15-7.06 (m, 5H), 7.03 (br. s., 1H), 6.69 (d, J=7.0 Hz, 2H), 6.49 (br. s., 1H), 4.70 (br. s., 1H), 2.99-2.77 (m, 2H), 2.53 (s, 3H), 2.20 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J=8.1 Hz, 1H), 7.38-7.29 (m, 1H), 7.27-7.15 (m, 3H), 7.13-6.97 (m, 5H), 6.89 (d, J=8.1 Hz, 1H), 6.74-6.36 (m, 4H), 4.89-4.69 (m, 1H), 3.93 (q, 2H), 2.92-2.79 (m, 2H), 2.51 (s, 3H), 1.29 (t, J=6.8 Hz, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.0 Hz, 1H), 7.46 (br. s., 1H), 7.32 (br. s., 2H), 7.19-6.97 (m, 6H), 6.89 (br. s., 1H), 6.70 (br. s., 3H), 4.64 (d, J=6.2 Hz, 1H), 4.03 (t, J=5.9 Hz, 2H), 2.99-2.77 (m, 2H), 2.54 (s, 3H), 1.81-1.69 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.0 Hz, 1H), 7.48 (br. s., 1H), 7.34 (d, J=7.0 Hz, 2H), 7.19-6.97 (m, 6H), 6.88 (d, J=7.3 Hz, 1H), 6.75-6.62 (m, 3H), 4.64 (d, J=7.7 Hz, 1H), 4.12 (q, J=6.8 Hz, 2H), 3.01-2.79 (m, 2H), 2.54 (s, 3H), 1.36 (t, J=7.0 Hz, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.7 Hz, 1H), 7.49 (br. s., 1H), 7.41-7.28 (m, 2H), 7.12 (d, J=7.0 Hz, 4H), 7.01 (br. s., 1H), 6.83 (d, J=8.1 Hz, 1H), 6.71 (d, J=6.2 Hz, 2H), 6.47-6.30 (m, 2H), 6.08 (d, J=2.2 Hz, 2H), 4.73 (br. s., 1H), 3.00-2.76 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.73 (d, J=7.0 Hz, 1H), 7.39 (br. s., 1H), 7.34-7.19 (m, 4H), 7.18-6.87 (m, 6H), 6.82-6.67 (m, 2H), 6.61-6.40 (m, 1H), 4.57-4.22 (m, 1H), 3.01-2.76 (m, 2H), 2.54 (s, 3H), 2.51 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J=7.0 Hz, 1H), 7.51-7.31 (m, 6H), 7.28-7.14 (m, 3H), 7.13-6.94 (m, 6H), 6.74 (br. s., 1H), 6.65 (d, J=7.3 Hz, 3H), 6.46 (d, J=5.5 Hz, 1H), 5.15-4.93 (m, 2H), 4.82 (br. s., 1H), 2.99-2.76 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=7.9 Hz, 1H), 7.64 (br. s., 1H), 7.59-7.53 (m, 2H), 7.51-7.32 (m, 8H), 7.24-7.12 (m, 3H), 7.05 (d, J=8.9 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 6.81 (d, J=7.3 Hz, 2H), 5.16 (s, 2H), 4.81-4.70 (m, 1H), 3.05 (d, J=7.3 Hz, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.77 (br. s., 1H), 7.47-7.20 (m, 6H), 7.19-6.99 (m, 5H), 6.94 (br. s., 2H), 6.68 (d, J=7.0 Hz, 2H), 6.60 (br. s., 1H), 4.75 (br. s., 1H), 2.99-2.75 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J=5.9 Hz, 1H), 7.42 (br. s., 1H), 7.29 (d, J=7.0 Hz, 3H), 7.19-6.98 (m, 5H), 6.84 (d, J=5.5 Hz, 1H), 6.78-6.61 (m, 3H), 4.68 (br. s., 1H), 3.00-2.78 (m, 2H), 2.53 (s, 3H), 2.32 (s, 3H).
Examples 33-41 were synthesized using the procedure described above for Example 2.
1H NMR (500 MHz, DMSO-d6) δ 8.18 (d, J=8.4 Hz, 2H), 7.80 (d, J=7.3 Hz, 1H), 7.54-7.46 (m, 1H), 7.40-7.22 (m, 5H), 7.17-7.01 (m, 4H), 6.92 (br. s., 1H), 6.74 (d, J=7.3 Hz, 2H), 4.84 (d, J=7.3 Hz, 1H), 3.04-2.82 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J=7.3 Hz, 1H), 7.47 (br. s., 1H), 7.41 (d, J=8.8 Hz, 2H), 7.37-7.27 (m, 2H), 7.17-7.05 (m, 4H), 7.01 (s, 1H), 6.80 (d, J=8.1 Hz, 2H), 6.70 (d, J=6.6 Hz, 2H), 4.69 (d, J=7.0 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 2.99-2.74 (m, 2H), 2.51 (s, 3H), 1.25 (t, J=7.0 Hz, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J=6.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.45 (br. s., 1H), 7.31 (d, J=8.8 Hz, 2H), 7.17-7.05 (m, 4H), 7.02 (s, 1H), 6.81 (d, J=7.3 Hz, 2H), 6.69 (d, J=7.0 Hz, 3H), 4.70 (d, J=5.9 Hz, 1H), 2.99-2.74 (m, 2H), 2.51 (s, 3H), 2.06 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 9.84 (br. s., 1H), 8.06-7.81 (m, 1H), 7.66-7.36 (m, 5H), 7.16-7.06 (m, 4H), 7.02 (s, 1H), 6.82 (d, J=7.7 Hz, 2H), 6.72 (d, J=6.6 Hz, 2H), 4.70 (br. s., 1H), 3.69 (s, 3H), 3.03-2.76 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.82 (d, J=7.3 Hz, 2H), 7.69-7.51 (m, 3H), 7.42 (d, J=8.4 Hz, 2H), 7.19-7.06 (m, 4H), 7.03 (s, 1H), 6.93 (br. s., 1H), 6.79 (d, J=8.1 Hz, 2H), 6.71 (d, J=7.0 Hz, 2H), 4.72 (d, J=7.3 Hz, 1H), 3.70 (s, 3H), 3.02-2.76 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.86 (br. s., 1H), 7.68 (d, J=7.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.3 Hz, 2H), 7.18-7.06 (m, 4H), 7.02 (s, 1H), 6.79 (d, J=8.1 Hz, 3H), 6.71 (d, J=7.0 Hz, 2H), 4.71 (d, J=6.6 Hz, 1H), 3.69 (s, 3H), 3.03-2.76 (m, 2H), 2.37 (s, 3H).
Chiral separation of Example 2 gave the title compound (6%) as byproduct.
(R)-metyl (4(2-(2-phenyl-1-(3-(o-tolysulfonyl)ureido)ethyl)-1H-imidazol-1-
1H NMR (400 MHz, METHANOL-d4) δ 8.01-7.87 (m, 1H), 7.49-7.22 (m, 5H), 7.10 (s, 4H), 7.00-6.88 (m, 1H), 6.85-6.74 (m, 2H), 6.66-6.47 (m, 2H), 4.90-4.82 (m, 1H), 3.77 (s, 3H), 3.06-2.93 (m, 2H), 2.64 (s, 3H).
1H NMR (600 MHz, DMSO-d6) δ 7.83 (d, J=8.1 Hz, 1H), 7.58-7.50 (m, 1H), 7.44-7.33 (m, 2H), 7.18-7.09 (m, 3H), 7.02 (s, 1H), 6.95-6.84 (m, 6H), 6.80 (d, J=8.4 Hz, 2H), 4.94 (q, J=7.3 Hz, 1H), 4.89-4.76 (m, 2H), 3.72 (s, 3H), 2.96-2.90 (m, 2H), 2.49 (s, 3H).
1H NMR (600 MHz, DMSO-d6) δ 8.01-7.89 (m, 1H), 7.72-7.31 (m, 4H), 7.14 (br. s., 3H), 7.05-6.98 (m, 1H), 6.91 (br. s., 5H), 6.83-6.73 (m, 2H), 4.95 (d, J=7.7 Hz, 1H), 4.89-4.80 (m, 2H), 3.72 (s, 3H), 3.03-2.91 (m, 2H).
(S)—N-((1-(1-(4-aminophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)-2-methylbenzenesulfonamide: A mixture of 10% palladium on carbon (2 mg, 1.88 μmol) in methanol (1 mL) was stirred under H2 balloon for 5 mins. (S)-2-methyl-N-((1-(1-(4-nitrophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)benzenesulfonamide (14 mg, 0.028 mmol) in methanol (1 mL) was added. The reaction mixture was stirred under H2 balloon for 4 hrs. The palladium catalyst was filtered off and the solvent was evaporated. The residue was purified by prepHPLC to afford (11.3 mg, 86%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=7.7 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.34 (m, 2H), 7.19-7.08 (m, 3H), 7.06 (s, 1H), 6.98 (s, 1H), 6.89 (d, J=7.3 Hz, 1H), 6.69 (d, J=5.5 Hz, 2H), 6.59-6.51 (m, 2H), 6.50-6.39 (m, 2H), 4.68 (q, J=7.5 Hz, 1H), 2.98-2.65 (m, 2H), 2.53 (s, 3H).
Examples 43-58 were synthesized using the procedure described above for Example 3.
1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 7.67 (br. s., 1H), 7.52-7.31 (m, 3H), 7.27-7.02 (m, 6H), 6.99 (s, 1H), 6.81 (br. s., 2H), 6.72 (d, J=6.6 Hz, 2H), 4.71 (br. s., 1H), 3.69 (s, 3H), 3.00-2.77 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.73 (d, J=7.3 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.15-6.95 (m, 7H), 6.83-6.65 (m, 4H), 4.75-4.57 (m, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 3.03-2.75 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 7.83 (d, J=7.3 Hz, 1H), 7.56 (br. s., 1H), 7.39 (d, J=7.7 Hz, 4H), 7.19-7.03 (m, 4H), 7.00 (s, 1H), 6.78 (d, J=7.7 Hz, 2H), 6.71 (d, J=7.0 Hz, 2H), 4.69 (d, J=8.1 Hz, 1H), 3.68 (s, 3H), 3.01-2.77 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.87 (br. s., 1H), 7.45 (d, J=8.4 Hz, 1H), 7.37 (br. s., 1H), 7.22-7.07 (m, 4H), 7.03 (s, 1H), 6.88-6.63 (m, 5H), 4.76 (d, J=7.3 Hz, 1H), 3.70 (s, 3H), 3.04-2.78 (m, 2H), 2.48 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 9.90 (br. s., 1H), 7.51 (d, J=8.1 Hz, 1H), 7.33 (br. s., 3H), 7.23-7.12 (m, 6H), 7.07 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.84 (br. s., 2H), 4.88 (d, J=7.7 Hz, 1H), 4.49 (br. s., 2H), 3.69 (s, 3H), 3.09-2.90 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.90 (br. s., 1H), 7.50 (d, J=8.4 Hz, 2H), 7.46-7.41 (m, 1H), 7.41-7.31 (m, 2H), 7.23-7.11 (m, 5H), 7.07 (s, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.83 (d, J=3.7 Hz, 3H), 4.92-4.80 (m, 1H), 4.62 (s, 2H), 3.69 (s, 3H), 3.09-2.91 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.21-6.94 (m, 6H), 6.84 (d, J=8.4 Hz, 2H), 6.72 (d, J=7.3 Hz, 2H), 4.72 (q, J=7.3 Hz, 1H), 3.70 (s, 3H), 3.05-2.75 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.73 (br. s., 1H), 7.43 (d, J=8.4 Hz, 2H), 7.28 (t, J=9.0 Hz, 2H), 7.21-7.01 (m, 5H), 6.95 (br. s., 1H), 6.84 (d, J=7.7 Hz, 2H), 6.73 (d, J=7.0 Hz, 2H), 4.73 (d, J=7.0 Hz, 1H), 3.69 (s, 3H), 3.06-2.76 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.94-7.77 (m, 2H), 7.56-7.34 (m, 3H), 7.21-7.07 (m, 4H), 7.04 (br. s., 1H), 6.86 (d, J=8.1 Hz, 2H), 6.72 (d, J=7.0 Hz, 2H), 4.70 (d, J=5.9 Hz, 1H), 3.69 (s, 3H), 3.02-2.76 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.88 (br. s., 1H), 7.48 (d, J=8.4 Hz, 2H), 7.16 (d, J=2.9 Hz, 4H), 7.04 (s, 1H), 6.96-6.68 (m, 5H), 4.92-4.73 (m, 1H), 3.70 (s, 3H), 3.50-3.39 (m, 1H), 3.09-2.83 (m, 2H), 1.26-1.08 (m, 6H).
1H NMR (500 MHz, DMSO-d6) δ 9.87 (br. s., 1H), 7.46 (d, J=7.7 Hz, 2H), 7.25-7.07 (m, 4H), 7.03 (s, 1H), 6.93-6.65 (m, 4H), 4.91-4.73 (m, 1H), 3.69 (s, 3H), 3.01 (d, J=8.4 Hz, 1H), 2.95-2.62 (m, 2H), 0.91 (d, J=16.9 Hz, 4H).
1H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.82 (br. s., 1H), 7.79-7.68 (m, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.18-7.06 (m, 4H), 7.04 (s, 1H), 6.84 (d, J=8.1 Hz, 2H), 6.72 (d, J=7.0 Hz, 2H), 4.73 (d, J=6.6 Hz, 1H), 3.70 (s, 3H), 3.02-2.76 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.83 (br. s., 1H), 7.42 (d, J=8.4 Hz, 2H), 7.16-6.96 (m, 6H), 6.92-6.68 (m, 4H), 4.74 (br. s., 1H), 3.69 (s, 3H), 2.98-2.77 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 7.95-7.78 (m, 2H), 7.47 (br. s., 1H), 7.11 (br. s., 5H), 6.86 (br. s., 4H), 6.73 (br. s., 2H), 4.67 (br. s., 1H), 3.77 (s, 3H), 3.05-2.75 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 7.95-7.79 (m, 2H), 7.47 (br. s., 1H), 7.20-6.97 (m, 5H), 6.85 (br. s., 4H), 6.73 (br. s., 2H), 4.67 (br. s., 1H), 4.03 (d, J=7.0 Hz, 2H), 3.05-2.75 (m, 2H), 1.33 (t, J=7.0 Hz, 3H).
1H NMR (400 MHz, METHANOL-d4) δ 7.90 (t, J=7.3 Hz, 1H), 7.65 (br. s., 1H), 7.41-7.05 (m, 6H), 6.98 (br. s., 1H), 6.87-6.73 (m, 4H), 6.64 (d, J=7.0 Hz, 2H), 4.82 (br. s., 1H), 3.80 (s, 3H), 3.13-2.90 (m, 2H).
(S)—N-((1-(1-(4-(furan-3-yl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)-2-methylbenzenesulfonamide: To a 0.5-2 ml microwave tube was added (S)—N-((1-(1-(4-bromophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)-2-methylbenzenesulfonamide (20 mg, 0.037 mmol), 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.79 mg, 0.056 mmol), Tetrakis(triphenylphosphine)palladium(0) (4.28 mg, 3.71 μmol), followed by DMF (1 mL), 2M K2CO3 solution (50 μL, 0.100 mmol). The reaction mixture was heated in a microwave reactor at 125° C. for 15 mins. The reaction mixture was filtered and the filtrate was purified by PrepHPLC to afford (8.9 mg, 45.6%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.85-7.74 (m, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.45 (br. s., 1H), 7.37-7.26 (m, 2H), 7.22-7.04 (m, 5H), 7.00 (s, 1H), 6.94 (d, J=8.1 Hz, 2H), 6.71 (d, J=7.0 Hz, 2H), 4.78 (d, J=5.9 Hz, 1H), 3.02-2.77 (m, 2H), 2.53 (m, 3H).
Examples 60-65 were synthesized using the procedure described above for Example 59.
1H NMR (400 MHz, METHANOL-d4) δ 7.96 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (dd, J=2.9, 1.5 Hz, 1H), 7.59-7.43 (m, 6H), 7.40-7.27 (m, 2H), 7.17-7.07 (m, 4H), 7.03 (d, J=1.2 Hz, 1H), 6.85-6.70 (m, 4H), 4.91 (d, 2H), 3.13-2.93 (m, 2H), 2.64 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.89 (s, 1H), 7.81-7.72 (m, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.44-7.21 (m, 3H), 7.17-6.99 (m, 5H), 6.88 (d, J=7.0 Hz, 2H), 6.71 (d, J=6.6 Hz, 2H), 4.81-4.71 (m, 1H), 3.91 (s, 3H), 2.96-2.79 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=7.7 Hz, 1H), 7.60 (s, 1H), 7.52 (br. s., 1H), 7.45-7.31 (m, 4H), 7.22 (s, 1H), 7.16-7.04 (m, 4H), 7.02-6.88 (m, 3H), 6.75 (s, 1H), 6.71 (d, J=7.0 Hz, 2H), 4.79 (d, J=7.0 Hz, 1H), 3.00-2.76 (m, 2H), 2.54 (s, 3H), 2.45 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.81 (d, J=7.3 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.49 (br. s., 1H), 7.40-7.30 (m, 2H), 7.22 (br. s., 2H), 7.15-6.98 (m, 6H), 6.94 (d, J=8.8 Hz, 1H), 6.73 (d, J=7.0 Hz, 2H), 4.80 (d, J=5.5 Hz, 1H), 3.91 (s, 3H), 3.03-2.76 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.82-7.72 (m, 2H), 7.67 (br. s., 1H), 7.57 (d, J=8.1 Hz, 2H), 7.46-7.29 (m, 2H), 7.21-7.03 (m, 5H), 7.01-6.81 (m, 4H), 6.73 (d, J=6.6 Hz, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.03-2.77 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.50-7.26 (m, 5H), 7.19 (s, 1H), 7.10-6.98 (m, 4H), 6.92 (s, 1H), 6.74-6.61 (m, 3H), 4.84 (d, J=6.6 Hz, 1H), 3.00-2.78 (m, 2H), 2.54 (s, 3H).
Examples 66-82 were synthesized using the procedure described above for Example 4.
1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.40 (br. s., 1H), 7.33-7.21 (m, 2H), 7.20-6.99 (m, 6H), 6.77 (d, J=8.1 Hz, 1H), 6.68 (d, J=7.7 Hz, 2H), 4.74 (br. s., 1H), 3.86 (s, 3H), 2.99-2.74 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.76 (br. s., 2H), 7.46 (d, J=8.4 Hz, 1H), 7.38-6.89 (m, 10H), 6.68 (br. s., 2H), 4.86-4.65 (m, 1H), 3.05-2.78 (m, 2H), 2.68 (s, 3H), 2.53 (s, 3H).
1H NMR (400 MHz, METHANOL-d4) δ 8.18-7.78 (m, 1H), 7.57-7.23 (m, 3H), 7.16-6.93 (m, 6H), 6.84-6.71 (m, 2H), 6.61-6.46 (m, 1H), 6.16-5.73 (m, 2H), 5.17-4.98 (m, 1H), 3.25-2.90 (m, 6H), 2.63 (s, 3H), 2.12-1.89 (m, 4H).
1H NMR (500 MHz, DMSO-d6) δ 8.04-7.87 (m, 2H), 7.83 (d, J=8.1 Hz, 1H), 7.72 (br. s., 1H), 7.66-7.48 (m, 3H), 7.46-7.24 (m, 4H), 7.20-6.94 (m, 6H), 6.71 (d, J=7.3 Hz, 2H), 4.79 (d, J=5.5 Hz, 1H), 3.10-2.75 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.80-7.68 (m, 1H), 7.56 (br. s., 1H), 7.39-7.28 (m, 1H), 7.18 (s, 3H), 7.12-6.94 (m, 5H), 6.68 (d, J=7.3 Hz, 3H), 4.85-4.71 (m, 1H), 2.97-2.83 (m, 2H), 2.52 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.68 (br. s., 1H), 7.57 (br. s., 1H), 7.43 (br. s., 1H), 7.25-6.95 (m, 8H), 6.68 (d, J=7.3 Hz, 2H), 6.44 (d, J=6.6 Hz, 1H), 4.80 (br. s., 1H), 3.00-2.80 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=7.0 Hz, 1H), 7.33-7.24 (m, 2H), 7.21 (s, 1H), 7.15-7.00 (m, 4H), 6.91 (d, J=7.6 Hz, 1H), 6.80 (br. s., 1H), 6.69 (d, J=7.3 Hz, 2H), 4.81 (d, J=6.1 Hz, 1H), 3.01-2.78 (m, 5H), 2.54 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J=8.4 Hz, 1H), 7.71 (br. s., 1H), 7.49 (br. s., 2H), 7.31-7.16 (m, 3H), 7.13-7.00 (m, 4H), 6.92 (d, J=8.1 Hz, 1H), 6.69 (d, J=7.3 Hz, 2H), 4.81 (d, J=5.9 Hz, 1H), 3.01-2.76 (m, 5H).
1H NMR (500 MHz, DMSO-d6) δ 8.00-7.92 (m, 1H), 7.87 (d, J=5.2 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.43 (d, J=6.1 Hz, 1H), 7.36-7.24 (m, 3H), 7.22-7.00 (m, 6H), 6.92 (d, J=7.6 Hz, 1H), 6.81 (br. s., 1H), 6.71 (d, J=7.0 Hz, 2H), 4.73 (d, J=4.9 Hz, 1H), 3.05-2.77 (m, 2H), 2.54 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.82 (t, J=7.3 Hz, 1H), 7.73 (d, J=5.5 Hz, 1H), 7.45 (t, J=9.3 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.19-7.11 (m, 3H), 7.10 (s, 1H), 7.04 (s, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.77-6.61 (m, 4H), 4.72-4.63 (m, 1H), 4.62-4.49 (m, 2H), 3.14-3.03 (m, 2H), 3.01-2.78 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 9.93-9.67 (m, 1H), 7.82-7.65 (m, 1H), 7.50-7.32 (m, 2H), 7.29-6.93 (m, 9H), 6.70 (br. s., 3H), 4.86-4.70 (m, 1H), 3.67 (s, 3H), 2.90-2.74 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.42 (br. s., 1H), 7.35-7.23 (m, 2H), 7.19-6.97 (m, 6H), 6.94-6.62 (m, 5H), 4.70 (d, J=5.2 Hz, 1H), 3.01-2.77 (m, 2H), 2.54 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.78 (t, J=7.3 Hz, 1H), 7.69 (d, J=5.2 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.49-7.27 (m, 2H), 7.23-6.99 (m, 6H), 6.96-6.80 (m, 3H), 6.71 (d, J=7.3 Hz, 2H), 4.71 (d, J=7.0 Hz, 1H), 3.03-2.77 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.61-7.29 (m, 8H), 7.15-7.09 (m, 3H), 6.82-6.72 (m, 3H), 4.83 (d, J=7.3 Hz, 1H), 3.05-2.85 (m, 2H), 2.51 (s, 3H), 2.31 (t, J=7.3 Hz, 2H), 1.68-1.56 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).
1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.60-7.49 (m, 4H), 7.46-7.27 (m, 5H), 7.26-7.01 (m, 5H), 6.84 (d, J=6.6 Hz, 2H), 4.89 (q, J=7.2 Hz, 1H), 3.12-2.93 (m, 2H), 2.52 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J=7.3 Hz, 1H), 7.66 (br. s., 1H), 7.48 (br. s., 1H), 7.40-7.28 (m, 5H), 7.27-7.17 (m, 3H), 7.16-6.96 (m, 5H), 6.81 (br. s., 1H), 6.71 (d, J=7.3 Hz, 2H), 5.27 (s, 2H), 4.76 (d, J=6.2 Hz, 1H), 3.01-2.77 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J=7.7 Hz, 1H), 7.56-7.48 (m, 1H), 7.40-7.30 (m, 2H), 7.12 (s, 1H), 7.02 (s, 1H), 6.96 (t, J=9.2 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.80-6.66 (m, 3H), 6.43 (d, J=7.3 Hz, 2H), 4.73 (d, J=7.3 Hz, 1H), 4.56 (t, J=8.6 Hz, 2H), 3.11 (t, J=8.6 Hz, 2H), 3.01-2.85 (m, 2H), 2.50 (s, 3H).
(S)—N-((1-(5-bromo-1-(4-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)-4-methylbenzenesulfonamide: A solution of (S)-tert-butyl (1-(5-bromo-1-(4-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamate (24.3 mg, 50 μmol) in 1:1 TFA/DCM (1 mL) was stirred for 2 h. The solvent was evaporated to afford 1-(5-bromo-1-(4-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine, TFA salt. It was used for next step without further purification. To a solution of 1-(5-bromo-1-(4-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine, TFA salt in dichloromethane (1 mL) was added diisopropylethylamine (0.044 mL, 0.25 mmol) followed by 4-methylbenzenesulfonyl isocyanate (11 mg, 0.060 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by prepHPLC to afford (18.6 mg, 65%) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 7.69 (d, J=7.9 Hz, 2H), 7.36 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.6 Hz, 4H), 7.03-6.92 (m, 5H), 6.81 (d, J=8.5 Hz, 2H), 4.98 (d, J=7.6 Hz, 1H), 3.73 (s, 3H), 2.93 (d, J=7.3 Hz, 2H), 2.51 (br. s., 3H).
2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethanamine: A solution of 1M lithium bis(trimethylsilyl)amide (0.47 mL, 0.47 mmol) in THF was added to a stirred solution of 1-(4-methoxyphenyl)-1H-imidazole-2-carbaldehyde (0.079 g, 0.391 mmol) in THF (1.5 mL) at −78° C. and then the reaction mixture was stirred for 15 min and at −78° C. and treated with (3,5-difluorobenzyl)magnesium chloride (1.875 mL, 0.469 mmol) in THF and stirred for 3 h at −78° C. The reaction was quenched with NH4Cl (aq) (˜10 mL) and then extracted with EtOAc (15 mL). The organic component was washed with water (˜10 mL) and brine (˜10 mL), dried (MgSO4), filtered and conc to a yellow oil. Used as is in the next step.
(rac)-N-((2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)carbamoyl)-2-fluorobenzenesulfonamide: 2-Fluorobenzenesulfonyl isocyanate (30 mg, 0.149 mmol) was added to a stirred solution of 1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethanamine (49 mg, 0.149 mmol) in methylene chloride (2 mL) and DIPEA (0.25 mL, 1.46 mmol) and the resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated, dissolved into EtOAc (˜2 mL), washed with 1M HCl (˜1.5 mL), water (˜1.5 mL), and brine (˜1.5 mL). The solvent was evaporated and the residue was purified by prepHPLC to afford (5 mg) of the title compound.
1H NMR (500 MHz, DMSO-d6) δ 7.69 (br. s., 1H), 7.58 (br. s., 1H), 7.35-7.14 (m, 4H), 7.08-6.89 (m, 4H), 6.42 (d, J=6.2 Hz, 3H), 4.28 (br. s., 1H), 3.78 (s, 3H), 2.78-2.54 (m, 2H).
5-(2,3-dihydrobenzofuran-5-yl)-1-methyl-1H-imidazole-4-carbonitrile: Nitrogen was bubbled through a stirred clear colorless solution of 5-bromo-1-methyl-1H-imidazole-4-carbonitrile (500 mg, 2.69 mmol), triphenylphosphine (11 mg, 0.040 mmol) and sodium carbonate (513 mg, 4.84 mmol) in iPrOH (7 mL) and H2O (4 mL) for 10 min. Palladium (II) acetate (6.03 mg, 0.027 mmol) was added to the reaction mixture, the reaction was flushed with nitrogen and then the reaction vessel was sealed and heated at 100° C. for 3 h. The reaction was cooled to rt, diluted with water (˜30 mL) and DCM (˜40 mL) and the layers were separated. The organic component was washed with sat. NH4Cl (aq) (25 mL), and brine (25 mL), dried (MgSO4) and concentrated. The crude residue was purified with a Biotage Horizon (40 g SiO2, 75-100% EtOAc/hexanes, loading with DCM) to yield the title compound (536 mg) as an off-white solid.
1H NMR (400 MHz, CHLOROFORM-d) δ 7.53 (s, 1H), 7.31 (s, 1H), 7.19 (dd, J=8.3, 1.8 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 4.68 (t, J=8.8 Hz, 2H), 3.66 (s, 3H), 3.31 (t, J=8.8 Hz, 2H). LCMS:
(rac)-N-((1-(5-(2,3-dihydrobenzofuran-5-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylethyl)carbamoyl)benzenesulfonamide: In a 5 mL microwave vessel, 5-(2,3-dihydrobenzofuran-5-yl)-1-methyl-1H-imidazole-4-carbonitrile (100 mg, 0.44 mmol) was slurried into THF (2 mL) and then treated with 2 M benzylmagnesium chloride (0.44 mL, 0.89 mmol) in THF. The reaction mixture was flushed with nitrogen (5 min) and then sealed and heated at 100° C. for 10 min with microwave irradiation. The crude reaction mixture was then treated with 3-methylbenzenesulfonyl isocyanate (210 mg, 1.07 mmol) in THF (1 mL) and stirred ON. NaBH4 (50 mg, 1.3 mmol) was added to the reaction mixture and stirred at rt for 3 h, then additional NaBH4 (40 mg) was added and the reaction mixture was and at rt for 1.5 h. The reaction was quenched with water (˜20 mL), diluted with EtOAc (˜20 mL) and stirred ON. The layers were separated and the organic component was washed with brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved into DMF, filtered and purified via preparative HPLC to yield racemic N-((1-(5-(2,3-dihydrobenzofuran-5-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylethyl)carbamoyl)benzene-sulfonamide (18.8 mg).
Column: XBridge C18, 19×200 mm, 5-μm particles;
Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid;
Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid;
Gradient: 20-80% B over 30 minutes, then a 5-minute hold at 100% B;
Flow: 20 mL/min.
5-(4-methoxyphenyl)-1-methyl-1H-imidazole-4-carbonitrile Nitrogen was bubbled through a stirred solution of 5-bromo-1-methyl-1H-imidazole-4-carbonitrile (500 mg, 2.69 mmol), (4-methoxyphenyl)boronic acid (613 mg, 4.03 mmol), triphenylphosphine (10.6 mg, 0.040 mmol) and sodium carbonate (513 mg, 4.84 mmol) in iPrOH (7 mL) and H2O (4 mL) for 10 min. Then palladium(II) acetate (6.03 mg, 0.027 mmol) was added, the reaction was flushed with nitrogen and the reaction vessel was sealed and heated at 100° C. for 3 h. The reaction was cooled to rt, diluted with water (˜30 mL) and DCM (˜40 mL) and the layers were separated. The organic component was washed with sat. NH4Cl (aq) (25 mL), and brine (25 mL), dried (MgSO4) and concentrated to a brown oil. The crude residue was purified with a Biotage Horizon (40 g SiO2, 80-100% EtOAc/hexanes) to yield the title compound (536 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54 (s, 1H), 7.44-7.38 (m, 2H), 7.09-7.03 (m, 2H), 3.89 (s, 3H), 3.67 (s, 3H). LCMS:
(rac)-N-((1-(5-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)-2-phenylethyl)carbamoyl)benzene-sulfonamide: A solution of 2M benzylmagnesium chloride (0.50 mL, 1.0 mmol) in THF was added to a solution of 5-(4-methoxyphenyl)-1-methyl-1H-imidazole-4-carbonitrile (110 mg, 0.516 mmol) in THF (2 mL) and the reaction solution was flushed with nitrogen, sealed and heated with microwave irradiation at 100° C. for 10 min. Then the reaction mixture was cooled to rt, treated with a solution of 3-methylbenzenesulfonyl isocyanate (203 mg, 1.03 mmol) in THF (1 mL) and stirred at rt for 3 h. Then NaBH4 (60 mg, 1.5 mmol) was added and the reaction mixture was stirred at rt for an additional 3 h. The reaction was added to water (˜20 mL) and EtOAc (˜20 mL) and stirred. The layers were separated and the organic component was washed with brine (˜20 mL) and concentrated. The crude material was dissolved into DMF, filtered and 50% was purified via preparative HPLC to yield racemic title compound (11.8 mg).
Column: XBridge C18, 19×200 mm, 5-μm particles;
Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid;
Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid;
Gradient: 20-80% B over 30 minutes, then a 5-minute hold at 100% B;
Flow: 20 mL/min.
5-(4-methoxyphenyl)-1-((trimethylsilyl)methyl)-4-(((trimethylsilyl)oxy)methyl)-1H-1,2,3-triazole: A 2.5M solution of n-BuLi (0.70 mL, 1.8 mmol) in hexanes was added dropwise to a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (505 mg, 1.69 mmol) in THF (5.6 mL) at −78° C. and the reaction mixture was then stirred at −78° C. for 1 h. ZnCl2 (276 mg, 2.02 mmol) was quickly added to the reaction under a blanket of nitrogen and the reaction mixture was stirred at −78° C. for 1 h, warm to rt and stirred 30 min. The reaction solution was then treated with 1-bromo-4-methoxybenzene (315 mg, 1.69 mmol), Pd2(dba)3 (31 mg, 0.034 mmol) and 2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl (63 mg, 0.14 mmol), flushed with nitrogen, sealed and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with EtOAc (˜30 mL), washed with water (˜15 mL) and brine (˜10 mL), dried (MgSO4), filtered and concentrated. The crude residue was purified with a Biotage Horizon (40 g SiO2, 10-30% EtOAc/hexanes) to yield a 2:1 mixture of the title compound and the starting material 1-((trimethylsilyl)methyl)-4-(((trimethylsilyl)oxy)methyl)-1H-1,2,3-triazole (335 mg) as a yellow oil. The mixture of material was used in the subsequent step without further purification. LCMS:
(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)methanol: A solution of 1M TBAF (2.66 mL, 2.66 mmol) in THF was added to a stirred solution of a 2:1 mixture of 5-(4-methoxyphenyl)-1-((trimethylsilyl)methyl)-4-(((trimethylsilyl)oxy)methyl)-1H-1,2,3-triazole (240 mg, 0.592 mmol) and 1-((trimethylsilyl)methyl)-4-(((trimethylsilyl)oxy)methyl)-1H-1,2,3-triazole (89 mg, 0.296 mmol) in THF (7 mL) and H2O (0.032 mL, 1.8 mmol) at 0° C. The reaction mixture was allowed to warm to rt over ˜3 h and then quenched with 12 sat. NH4Cl (aq) (˜40 mL) and diluted with EtOAc (˜20 mL). The layers were separated and the organic component was washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The crude residue was purified with a Biotage Horizon (12 g SiO2, 60-100% EtOAc/hexanes) to yield the title compound (114 mg) as a white solid.
1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 4.70 (s, 2H), 4.01 (s, 3H), 3.89 (s, 3H), 2.27 (br. s., 1H). LCMS:
5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-4-carbaldehyde: Dess-Martin periodinane (225 mg, 0.532 mmol) was added to a stirred solution of (5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)methanol (111 mg, 0.506 mmol) in DCM (5 mL) and the reaction was stirred under nitrogen at rt for 4 h. The reaction mixture was diluted with Et2O (˜20 mL), treated with 1N Na2S2O3 (aq.) (˜20 mL) and stirred until both layers were clear. The layers were separated and the organic component was washed with sat. aq. NaHCO3 (˜15 mL) and brine (˜10 mL), filtered and concentrated to dryness. The crude material was purified with a Biotage Horizon (12 g SiO2, 40-100% EtOAc/hexanes) to yield the title compound (88 mg) as a white solid.
1H NMR (400 MHz, CHLOROFORM-d) δ 10.16 (s, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 4.05 (s, 3H), 3.90 (s, 3H). LCMS:
1-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-phenylethanamine: A solution of 1M lithium bis(trimethylsilyl)amide (0.47 mL, 0.47 mmol) in THF was added to a stirred solution of 5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (85 mg, 0.39 mmol) in THF (1.5 mL) at 0° C. and then the reaction mixture was allowed to warm to rt and stirred for 1.5 h. The reaction mixture was cooled to 0° C. and treated with 2M benzylmagnesium chloride (0.24 mL, 0.47 mmol) in THF and allowed to slowly warm to rt and stirred ON. The reaction was quenched with NH4Cl (aq) (˜10 mL) and then extracted with EtOAc (15 mL). The organic component was washed with water (˜10 mL) and brine (˜10 mL), dried (MgSO4), filtered and conc. to a yellow oil. The crude oil was dissolved into DCM and then treated with 2M HCl in ether until pH<2. The crude solution was concentrated, treated with EtOAc (˜3 mL) and stirred ON. The free flowing yellow solid was collected by filtration to yield a hydrochloride salt of the title compound (66 mg) as a yellow solid.
1H NMR (400 MHz, METHANOL-d4) δ 7.28-7.20 (m, 3H), 6.98-6.91 (m, 4H), 6.70-6.64 (m, 2H), 4.32 (dd, J=9.0, 6.5 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.38-3.32 (m, 2H) (partially hidden under MeOH peak). LCMS:
(rac)-N-((1-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-phenylethyl)carbamoyl)-2-methylbenzenesulfonamide: 2-Methylbenzenesulfonyl isocyanate (24 mg, 0.12 mmol) was added to a stirred solution of 1-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-phenylethanamine hydrochloride (21 mg, 0.061 mmol) in acetonitrile (1 mL) and DIPEA (0.04 mL, 0.2 mmol) and the resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated, dissolved into EtOAc (˜2 mL), washed with 1M HCl (˜1.5 mL), water (˜1.5 mL), and brine (˜1.5 mL) and then concentrated. The crude amber oil was dissolved into MeOH, filtered and purified via preparative HPLC to yield the title compound (13 mg).
Column: XBridge C18, 19×200 mm, 5-μm particles;
Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate;
Gradient: 20-65% B over 30 minutes, then a 5-minute hold at 100% B;
Flow: 20 mL/min
To the solution of 3-bromopicolinaldehyde (3.2 g, 17.20 mmol) and (R)-2-methylpropane-2-sulfinamide (2.279 g, 18.80 mmol) in dichloromethane (40 mL) stirred at RT was added cupric sulfate (5.49 g, 34.4 mmol). The resulted was stirred at RT for 5 h. The reaction mixture was filtered and then conc. and purified by Biotage (15-50% EtOAc/hexanes, 80 g SiO2, Rf 0.26 with 30% EtOAc/Hexanes) to afford (3.40 g, 68.3% yield) of the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ 9.05 (s, 1H), 8.74 (dd, J=4.5, 1.0 Hz, 1H), 8.01 (dd, J=8.0, 1.3 Hz, 1H), 7.29 (dd, J=8.0, 4.5 Hz, 1H), 1.32 (s, 9H).
Benzylmagnesium bromide (8.02 ml, 7.22 mmol) was added dropwise over 30 min to a solution of (R,Z)—N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.74 g, 6.02 mmol) in dichloromethane (128 ml) in a 500-mL round bottom flask at −78° C. The reaction mixture was stirred at −78° C. for 3 hours. Another 2 mL of 0.9 M benzylmagnesium bromide was added and the reaction mixture was stirred at −78° C. for another hour. NH4Cl (aqueous solution, 20 mL) was added to the reaction and the mixture was allowed to warm to RT. Layers were separated and the aqueous was extracted with EtOAc (2×40 mL). The combined organic solution was dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without purification.
To the solution of (R)—N-(1-(3-bromopyridin-2-yl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.270 g, 0.708 mmol) in MeOH (3 mL) was added 1.5 mL of HCl (6.00 mmol, 4.0 M in dioxane). The resulted was stirred at RT for 1 h. Solvent was evaporated in vacuo and the product was purified by preparative HPLC (0.1% TFA, MeOH/H2O) to afford 0.181 g (82% yield) of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ 8.66 (dd, J=4.6, 1.2 Hz, 1H), 8.03 (dd, J=8.2, 1.3 Hz, 1H), 7.35 (dd, J=8.1, 4.6 Hz, 1H), 7.31-7.25 (m, 3H), 7.12 (dd, J=7.1, 2.4 Hz, 2H), 5.09 (t, J=7.1 Hz, 1H), 3.36-3.26 (m, 1H), 3.21-3.13 (m, 1H).
N-((1-(3-bromopyridin-2-yl)-2-phenylethyl)carbamoyl)-2-methylbenzenesulfonamide: The suspension of 1-(3-bromopyridin-2-yl)-2-phenylethanamine, TFA (126 mg, 0.322 mmol) in 5 mL of dichloromethane was added DIEA (0.225 mL, 1.288 mmol). A solution of 2-methylbenzenesulfonyl isocyanate (76 mg, 0.387 mmol) in 1 mL of dichloromethane was added dropwise. The resulted solution was stirred at RT for 1 h. Solvent was evaporated in vacuo. The product was purified by preparative HPLC (0.1% TFA, MeOH/H2O) to afford 110 mg (55% yield) of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ 8.55-8.47 (m, 1H), 8.00-7.91 (m, 2H), 7.58-7.49 (m, 1H), 7.43-7.29 (m, 2H), 7.22 (dd, J=8.1, 4.6 Hz, 1H), 7.17-7.05 (m, 3H), 6.95-6.82 (m, 2H), 5.51 (t, J=6.5 Hz, 1H), 3.10 (dd, J=13.6, 5.7 Hz, 1H), 2.91 (dd, J=13.4, 7.6 Hz, 1H), 2.62 (s, 3H).
To a mixture of N-((1-(3-bromopyridin-2-yl)-2-phenylethyl)carbamoyl)-2-methylbenzenesulfonamide (76 mg, 0.160 mmol), (4-ethoxyphenyl)boronic acid (31.9 mg, 0.192 mmol), sodium carbonate (0.3 mL, 0.900 mmol) and PdCl2(dppf) (11.72 mg, 0.016 mmol) was added DMF (1 mL). The mixture was degassed and heated at 115° C. for 3 h. Water (20 mL) was added. The product was extracted with EtOAc (2×20 mL). Solvent was evaporated in vacuo. The product was purified by preparative HPLC (0.1% TFA, MeOH/H2O) and the two enantiomers were separated by chiral preparative HPLC to afford 3.7 mg of the title compound and 4.8 mg of the R-enantiomer (Example 105).
1H NMR (500 MHz, DMSO-d6) δ 8.59 (d, J=4.4 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.55-7.46 (m, 2H), 7.40-7.28 (m, 3H), 7.12-6.93 (m, 6H), 6.89 (d, J=8.4 Hz, 2H), 6.62 (d, J=6.6 Hz, 2H), 5.09-5.00 (m, 1H), 4.04 (q, J=7.0 Hz, 2H), 3.35 (br. s., 1H), 2.85 (dd, J=13.2, 6.2 Hz, 1H), 2.66 (dd, J=13.0, 7.5 Hz, 1H), 1.34 (t, J=7.0 Hz, 3H).
3,5-difluorobenzylmagnesium bromide (18.76 mL, 4.69 mmol) was added dropwise over 30 min to a solution of (R,Z)—N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.13 g, 3.91 mmol) in dichloromethane (90 mL) at −78° C. The reaction mixture was stirred at −78° C. for 3 hours. NH4Cl (aqueous solution, 20 mL) was added to the reaction and the mixture was allowed to warm to RT. Layers were separated and the aqueous was extracted with EtOAc (2×40 mL). The combined organic solution was dried over Na2SO4 overnight, filtered and concentrated. The crude product was purified by Biotage (Silica 80 gram flash column, EtOAc/hexanes gradient 20-55% EtOAc, Rf 0.36 with 50% EtOAc) to give 0.74 g (45.4% yield) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.50 (dd, J=4.6, 1.4 Hz, 1H), 7.80 (dd, J=8.0, 1.6 Hz, 1H), 7.09 (dd, J=8.0, 4.6 Hz, 1H), 6.66-6.51 (m, 3H), 5.20 (dt, J=9.7, 6.8 Hz, 1H), 4.46 (d, J=9.8 Hz, 1H), 3.31 (d, J=6.9 Hz, 2H), 1.15 (s, 9H).
To a mixture of (R)—N—((S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.240 g, 0.575 mmol), methyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.207 g, 0.748 mmol), 3.0 M sodium carbonate (1.150 mL, 3.45 mmol) and PdCl2(dppf) (0.042 g, 0.058 mmol) was added DMF (5 mL). The mixture was degassed and heated at 110° C. for 2.5 h. Water (50 mL) was added to the reaction mixture. The product was extracted with EtOAc (2×40 mL). The combined extract was filtered through celite. The product was purified by preparative HPLC (0.1% TFA, MeOH/H2O) to afford 60 mg (21% yield) of the title compound.
To the solution of methyl (4-(2-((S)-2-(3,5-difluorophenyl)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)pyridin-3-yl)phenyl)carbamate (60 mg, 0.123 mmol) in MeOH (2 mL) was added 4.0 M HCl in dioxane (1.11 mL, 4.43 mmol). The resulted was stirred at RT for 1 h. Solvent was evaporated in vacuo to afford the title compound, which was used in the next step without purification.
To the solution of (S)-methyl (4-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)phenyl)carbamate (23.39 mg, 0.061 mmol) in 1 mL of dichloromethane in an 8-mL glass vial was added DIEA (0.043 mL, 0.244 mmol). The solution was stirred at RT while a solution of 2-methylbenzenesulfonyl isocyanate (14.4 mg, 0.073 mmol) in 1 mL of dichloromethane was added dropwise. The resulted was stirred at RT for 2 h. Solvent was evaporated in vacuo. The residue was dissolved in methanol and the product was purified by preparative HPLC (0.1% TFA, MeOH/H2O) to afford 11 mg (25% yield) of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ 8.65 (dd, J=4.8, 1.5 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.65 (dd, J=7.7, 1.6 Hz, 1H), 7.54-7.43 (m, 4H), 7.37 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 6.93 (d, J=8.5 Hz, 2H), 6.64 (tt, J=9.2, 2.2 Hz, 1H), 6.25-6.11 (m, 2H), 5.27 (t, J=7.2 Hz, 1H), 3.76 (s, 3H), 2.93-2.86 (m, 1H), 2.84-2.77 (m, 1H), 2.61 (s, 3H).
The title compound was prepared with the procedures described in Example 89.
1H NMR (400 MHz, DMSO-d6) d 10.67 (s, 1H), 9.59 (s, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.68 (d, J=6.0 Hz, 1H), 8.32 (d, J=6.0 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.89 (dd, J=8.5, 1.5 Hz, 1H), 7.82-7.73 (m, 2H), 7.58-7.46 (m, 2H), 7.39-7.27 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.33 (d, J=6.3 Hz, 2H), 4.99 (q, J=7.7 Hz, 1H), 2.98 (dd, J=13.3, 6.5 Hz, 1H), 2.91-2.79 (m, 1H), 2.48 (br. s., 3H).
The title compound was prepared with the procedures described in Example 89.
1H NMR (400 MHz, METHANOL-d4) δ 8.64 (dd, J=4.9, 1.6 Hz, 1H), 8.08 (dd, J=7.9, 1.1 Hz, 1H), 7.69-7.56 (m, 3H), 7.52-7.40 (m, 4H), 6.95 (d, J=8.5 Hz, 2H), 6.64 (tt, J=9.2, 2.2 Hz, 1H), 6.20 (d, J=6.3 Hz, 2H), 5.28 (t, J=7.2 Hz, 1H), 3.76 (s, 3H), 2.95-2.87 (m, 1H), 2.86-2.78 (m, 1H)
The title compound was prepared with the procedures described in Example 89.
1H NMR (400 MHz, DMSO-d6) δ 10.82 (br. s., 1H), 9.61 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.69 (d, J=6.3 Hz, 1H), 8.34 (d, J=6.0 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J=7.8 Hz, 2H), 7.78 (dd, J=7.7, 1.6 Hz, 1H), 7.68-7.57 (m, 2H), 7.56-7.45 (m, 2H), 7.26 (d, J=8.8 Hz, 1H), 6.97-6.87 (m, 1H), 6.35 (d, J=6.5 Hz, 2H), 4.99 (q, J=7.8 Hz, 1H), 2.99 (dd, J=13.3, 6.3 Hz, 1H), 2.93-2.78 (m, 1H)
The title compound was prepared with the procedures described in Example 88.
1H NMR (500 MHz, DMSO-d6) δ 10.68 (br. s., 1H), 8.59 (d, J=3.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.56-7.48 (m, 2H), 7.40-7.28 (m, 5H), 7.21 (s, 2H), 7.15-7.10 (m, 2H), 7.08-7.02 (m, 3H), 7.00-6.94 (m, 2H), 6.89 (d, J=8.8 Hz, 2H), 6.62 (d, J=6.6 Hz, 2H), 5.04 (q, J=7.3 Hz, 1H), 2.85 (dd, J=13.4, 6.1 Hz, 1H), 2.66 (dd, J=13.2, 7.7 Hz, 1H), 1.34 (t, J=7.0 Hz, 3H).
To the solution of (R)—N—((S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.692 g, 1.658 mmol) in MeOH (8 mL) stirred at RT was added 4.0 M HCl in dioxane (4 mL, 16.00 mmol). The resulted was stirred at RT for 1 h. Solvent was evaporated in vacuo to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ 8.70 (dd, J=4.5, 1.3 Hz, 1H), 8.56 (br. s., 3H), 8.14 (dd, J=8.2, 1.3 Hz, 1H), 7.43 (dd, J=8.1, 4.6 Hz, 1H), 7.14 (tt, J=9.5, 2.2 Hz, 1H), 6.84-6.74 (m, 2H), 4.99 (t, J=6.8 Hz, 1H), 3.28-3.09 (m, 2H).
(S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine, HCl (0.580 g, 1.658 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of DIEA (1.448 mL, 8.29 mmol) and a solution of 2-methylbenzenesulfonyl isocyanate (0.343 g, 1.741 mmol) in 3 mL of dichloromethane dropwise. The resulted was stirred at RT for 1 h. Solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (150 mL) and washed with aqueous NaHCO3 (2×70 mL). 42 mg of the crude product was purified by preparative HPLC (0.1% TFA, MeOH/H2O). The remaining was used in the next step without purification.
1H NMR (400 MHz, METHANOL-d4) δ 8.54 (d, J=4.8 Hz, 1H), 7.97 (t, J=7.2 Hz, 2H), 7.57-7.48 (m, 1H), 7.39-7.29 (m, 2H), 7.25 (dd, J=8.0, 4.5 Hz, 1H), 6.76-6.65 (m, 1H), 6.49 (d, J=6.3 Hz, 2H), 5.50 (dd, J=7.5, 5.8 Hz, 1H), 3.09 (dd, J=13.6, 5.8 Hz, 1H), 2.89 (dd, J=13.6, 7.8 Hz, 1H), 2.61 (s, 3H).
To a mixture of (S)—N-((1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamoyl)-2-methylbenzenesulfonamide (50 mg, 0.098 mmol), (4-ethoxyphenyl)boronic acid (19.51 mg, 0.118 mmol), sodium carbonate 3.0 M aq. solution (0.25 mL, 0.750 mmol) and PdCl2(dppf) (7.2 mg, 9.80 μmol) was added DMF (1 mL). The mixture was degassed and stirred at 115° C. for 16 h. The reaction mixture was filtered and acidified by addition of acetic acid. The product was purified by preparative HPLC (0.1% TFA, ACN/H2O) to afford 8.2 mg (13% yield).
1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=4.0 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.0 Hz, 1H), 7.53-7.48 (m, 1H), 7.39 (dd, J=7.7, 4.8 Hz, 1H), 7.36-7.30 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.99-6.84 (m, 3H), 6.29 (d, J=6.6 Hz, 2H), 5.14-5.03 (m, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.90 (s, 1H), 3.41 (br. s., 1H), 3.17 (s, 1H), 2.92-2.81 (m, 1H), 2.79-2.67 (m, 1H), 1.34 (t, J=6.8 Hz, 3H).
The title compound was prepared with the procedures described in Example 89.
1H NMR (400 MHz, METHANOL-d4) δ 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.50-7.41 (m, 2H), 7.34 (d, J=6.0 Hz, 1H), 7.24-7.16 (m, 2H), 6.64 (t, J=9.3 Hz, 1H), 6.25 (d, J=6.3 Hz, 2H), 5.13 (t, J=7.4 Hz, 1H), 3.05-2.80 (m, 2H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=4.4 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.55-7.51 (m, 1H), 7.41 (dd, J=7.7, 4.8 Hz, 1H), 7.38-7.32 (m, 2H), 7.25-7.01 (m, 4H), 6.98-6.89 (m, 3H), 6.29 (d, J=6.2 Hz, 2H), 5.17-4.99 (m, 1H), 3.79 (s, 3H), 2.91-2.82 (m, 1H), 2.78-2.69 (m, 1H), 2.51 (s, 3H).
The title compound was prepared with the procedures described in Example 89.
1H NMR (500 MHz, METHANOL-d4) δ 8.71 (dd, J=4.9, 1.7 Hz, 1H), 7.91 (dd, J=7.9, 1.3 Hz, 1H), 7.64 (dd, J=7.8, 1.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.36 (d, J=7.6 Hz, 1H), 7.32 (dd, J=6.9, 2.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.23-7.14 (m, 2H), 6.64 (tt, J=9.2, 2.3 Hz, 1H), 6.28-6.17 (m, 2H), 5.13 (t, J=7.3 Hz, 1H), 3.01-2.84 (m, 2H), 2.60 (s, 3H).
The title compound was prepared with the procedures described in Example 88.
1H NMR (400 MHz, METHANOL-d4) δ 8.72 (dd, J=4.9, 1.5 Hz, 1H), 7.89 (dd, J=7.9, 1.1 Hz, 1H), 7.66 (dd, J=7.8, 1.7 Hz, 1H), 7.53-7.46 (m, 2H), 7.36 (d, J=7.3 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.21-6.99 (m, 6H), 6.65-6.58 (m, 2H), 5.08 (dd, J=8.1, 6.8 Hz, 1H), 3.00-2.89 (m, 2H), 2.59 (s, 3H)
To the solution of 3-bromopicolinaldehyde (3.2 g, 17.20 mmol) and (S)-2-methylpropane-2-sulfinamide (2.279 g, 18.80 mmol) in dichloromethane (40 mL) stirred at RT was added cupric sulfate (5.49 g, 34.4 mmol). The resulted was stirred at RT overnight. The reaction mixture was filtered and then conc. and purified by Biotage (15-50% EtOAc/hexanes, 120 g SiO2) to afford (3.40 g, 68.3% yield) of the title compound.
1H NMR (500 MHz, CHLOROFORM-d) δ 9.05 (s, 1H), 8.76 (dd, J=4.5, 1.3 Hz, 1H), 8.04 (dd, J=8.2, 1.4 Hz, 1H), 7.31 (dd, J=8.2, 4.6 Hz, 1H), 1.33 (s, 9H).
3,5-difluorobenzylmagnesium bromide (10 mL, 2.500 mmol) was added dropwise to a solution of (S,Z)—N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.500 g, 1.729 mmol) in dichloromethane (40 mL) at −78° C. The reaction was stirred at −78° C. for 5 hours. NH4Cl (aq., 10 mL) was added to the reaction and the mixture was allowed to warm to RT. Layers were separated and the aqueous was extracted with EtOAc (2×40 mL). The combined organic solution was dried over Na2SO4 overnight, filtered and concentrated. The crude product was purified by Biotage (Silica 24 gram flash column, EtOAc/hexanes gradient 20-55% EtOAc, Rf 0.36 with 50% EtOAc) to afford (0.242 g, 33.5% yield) of the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (dd, J=4.6, 1.1 Hz, 1H), 7.80 (dd, J=8.2, 1.4 Hz, 1H), 7.09 (dd, J=8.2, 4.6 Hz, 1H), 6.65-6.51 (m, 3H), 5.20 (dt, J=9.5, 6.8 Hz, 1H), 4.51-4.43 (m, 1H), 3.31 (d, J=6.8 Hz, 2H), 1.15 (s, 9H).
To the solution of (S)—N—((R)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.300 g, 0.719 mmol) in MeOH (3 mL) stirred at RT was added 4.0 M HCl in dioxane (1.5 mL, 6.00 mmol). The resulted was stirred at RT for 1 h. Solvent was evaporated in vacuo to give 0.251 g (100% yield) of the title compound.
1H NMR (400 MHz, DMSO-d6) δ 8.70 (dd, J=4.6, 1.2 Hz, 1H), 8.58 (br. s., 3H), 8.14 (dd, J=8.1, 1.5 Hz, 1H), 7.43 (dd, J=8.3, 4.6 Hz, 1H), 7.13 (tt, J=9.4, 2.3 Hz, 1H), 6.83-6.73 (m, 2H), 4.99 (br. s., 1H), 3.18 (qd, J=13.5, 7.1 Hz, 2H).
(R)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine, HCl (0.251 g, 0.719 mmol) was dissolved in 7 mL of dichloromethane, followed by the addition of DIEA (0.63 mL, 3.60 mmol) and a solution of 2-chlorobenzenesulfonyl isocyanate (0.219 g, 1.01 mmol) in 2.5 mL of dichloromethane dropwise. The resulted was stirred at RT for 1 h. Solvent was evaporated in vacuo. The product was purified by Biotage (24 g, EtOAc/DCM, 10-75%) to afford (0.253 g, 66.3% yield) of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ 8.58-8.49 (m, 1H), 8.17-8.07 (m, 1H), 7.97 (dd, J=8.0, 1.3 Hz, 1H), 7.65-7.55 (m, 2H), 7.52-7.40 (m, 1H), 7.24 (dd, J=8.2, 4.6 Hz, 1H), 6.69 (tt, J=9.3, 2.2 Hz, 1H), 6.59-6.47 (m, 2H), 5.50 (dd, J=7.4, 5.9 Hz, 1H), 3.09 (dd, J=13.6, 5.5 Hz, 1H), 2.91 (dd, J=13.6, 7.8 Hz, 1H).
To a mixture of (R)—N-((1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamoyl)-2-chlorobenzenesulfonamide (25 mg, 0.047 mmol), isoquinolin-7-ylboronic acid (10.6 mg, 0.061 mmol), tripotassium phosphate (0.071 mL, 0.141 mmol) and 2nd generation Xphos precatalyst (1.9 mg, 2.36 μmol) was added dioxane (1 mL) and water (0.200 mL). The mixture was degassed and stirred at 90° C. overnight. The product was purified by preparative HPLC (0.1% TFA, MeOH/H2O) to afford (2.0 mg, 4.84% yield) of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ 9.68 (s, 1H), 8.80 (dd, J=4.8, 1.5 Hz, 1H), 8.62 (d, J=6.5 Hz, 1H), 8.50 (d, J=6.5 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.09 (d, J=9.3 Hz, 2H), 7.84 (d, J=7.0 Hz, 1H), 7.73 (dd, J=7.8, 1.5 Hz, 1H), 7.65-7.55 (m, 2H), 7.53-7.44 (m, 2H), 6.73-6.57 (m, 1H), 6.18 (d, J=6.3 Hz, 2H), 5.17 (t, J=7.4 Hz, 1H), 3.04-2.82 (m, 2H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (400 MHz, METHANOL-d4) δ 8.77 (dd, J=4.8, 1.3 Hz, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.04-7.89 (m, 2H), 7.61 (dd, J=7.7, 1.4 Hz, 1H), 7.53-7.43 (m, 2H), 7.36 (d, J=7.5 Hz, 1H), 7.32-7.23 (m, 2H), 6.69 (t, J=9.2 Hz, 1H), 6.22 (d, J=6.3 Hz, 2H), 5.06 (t, J=7.4 Hz, 1H), 2.94 (d, J=7.3 Hz, 2H), 2.61 (s, 3H)
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=5.3 Hz, 1H), 8.61 (d, J=7.8 Hz, 1H), 8.26-8.11 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.63 (dd, J=7.8, 5.3 Hz, 1H), 7.57-7.48 (m, 2H), 7.42-7.33 (m, 2H), 7.32-7.20 (m, 1H), 7.16 (t, J=7.7 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.39 (t, J=8.9 Hz, 1H), 6.11 (d, J=6.0 Hz, 2H), 5.63-5.50 (m, 1H), 3.08-2.99 (m, 1H), 2.97-2.87 (m, 1H), 1.68 (s, 9H)
The title compound was prepared by removing the Boc protecting group of the compound in Example 101 with TFA.
1H NMR (400 MHz, METHANOL-d4) δ 8.65 (dd, J=5.0, 1.3 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.01-7.95 (m, 1H), 7.65-7.56 (m, 3H), 7.50-7.40 (m, 2H), 7.20 (s, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.00-6.90 (m, 1H), 6.57-6.42 (m, 1H), 6.08 (d, J=6.3 Hz, 2H), 5.51 (t, J=7.0 Hz, 1H), 3.09 (dd, J=13.7, 5.6 Hz, 1H), 2.94-2.77 (m, 2H)
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.78 (dd, J=4.6, 1.4 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.03-7.91 (m, 2H), 7.62 (dd, J=7.8, 1.5 Hz, 1H), 7.55-7.43 (m, 2H), 7.37 (d, J=7.5 Hz, 1H), 7.33-7.23 (m, 2H), 6.77-6.64 (m, 1H), 6.23 (d, J=6.3 Hz, 2H), 5.07 (t, J=7.4 Hz, 1H), 2.94 (d, J=7.3 Hz, 2H), 2.63 (s, 3H)
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.72-8.60 (m, 1H), 8.14-8.04 (m, 1H), 7.65-7.54 (m, 3H), 7.49-7.40 (m, 2H), 6.67 (t, J=9.3 Hz, 1H), 6.26 (d, J=6.3 Hz, 2H), 6.10 (br. s., 1H), 5.07 (br. s., 1H), 2.95-2.77 (m, 2H), 2.35 (s, 3H), 1.89 (s, 3H)
The title compound was prepared with the procedures described in Example 88.
1H NMR (500 MHz, DMSO-d6) δ 8.59 (d, J=3.7 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.55-7.46 (m, 2H), 7.39-7.29 (m, 3H), 7.12-6.93 (m, 6H), 6.89 (d, J=8.4 Hz, 2H), 6.62 (d, J=7.0 Hz, 2H), 5.04 (q, J=7.7 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H), 3.90 (s, 1H), 3.35 (br. s., 1H), 2.89 (s, 1H), 2.85 (dd, J=13.4, 6.1 Hz, 1H), 2.73 (s, 1H), 2.66 (dd, J=13.4, 7.5 Hz, 1H), 1.34 (t, J=7.0 Hz, 3H).
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.70 (dd, J=4.8, 1.3 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.68-7.54 (m, 3H), 7.50-7.40 (m, 4H), 7.16 (d, J=7.5 Hz, 1H), 6.62 (t, J=9.2 Hz, 1H), 6.17 (d, J=6.0 Hz, 2H), 5.21 (t, J=7.3 Hz, 1H), 3.01-2.75 (m, 3H), 0.90-0.75 (m, 2H), 0.71-0.63 (m, 2H).
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.54 (dd, J=4.5, 1.3 Hz, 1H), 8.02-7.93 (m, 2H), 7.56-7.47 (m, 1H), 7.41-7.29 (m, 2H), 7.25 (dd, J=8.2, 4.6 Hz, 1H), 6.70 (tt, J=9.2, 2.3 Hz, 1H), 6.49 (d, J=6.3 Hz, 2H), 5.50 (dd, J=7.5, 5.8 Hz, 1H), 3.09 (dd, J=13.6, 5.8 Hz, 1H), 2.89 (dd, J=13.4, 7.7 Hz, 1H), 2.61 (s, 3H)
The title compound was prepared with the procedures described in Example 88.
1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.48 (s, 1H), 8.76 (dd, J=4.6, 1.6 Hz, 1H), 8.66 (d, J=6.0 Hz, 1H), 8.25 (d, J=6.0 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.83 (s, 1H), 7.74-7.63 (m, 4H), 7.55-7.46 (m, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.11-6.97 (m, 3H), 6.62 (d, J=7.3 Hz, 2H), 5.00-4.84 (m, 1H), 2.96 (dd, J=13.2, 6.9 Hz, 1H), 2.77 (dd, J=13.2, 6.9 Hz, 1H).
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.12-8.05 (m, 1H), 7.65-7.54 (m, 3H), 7.50-7.39 (m, 2H), 7.36-7.30 (m, 1H), 7.23-7.15 (m, 2H), 6.63 (t, J=9.3 Hz, 1H), 6.24 (d, J=6.3 Hz, 2H), 5.13 (t, J=7.4 Hz, 1H), 2.92 (qd, J=13.3, 7.4 Hz, 2H)
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.99 (s, 1H), 7.66-7.54 (m, 3H), 7.50-7.41 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 6.74-6.63 (m, 1H), 6.24 (d, J=6.3 Hz, 2H), 5.07 (t, J=7.4 Hz, 1H), 2.95 (d, J=7.3 Hz, 2H)
The title compound was prepared with the procedures described in Example 88.
1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.77 (s, 1H), 8.61 (dd, J=4.5, 1.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.66 (d, J=4.0 Hz, 2H), 7.58-7.49 (m, 2H), 7.47-7.36 (m, 3H), 7.14 (d, J=8.8 Hz, 1H), 7.10-7.01 (m, 3H), 6.94 (d, J=8.3 Hz, 2H), 6.68-6.58 (m, 2H), 5.01 (q, J=7.3 Hz, 1H), 3.68 (s, 3H), 2.89 (dd, J=13.4, 6.4 Hz, 1H), 2.75-2.62 (m, 1H).
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.59-7.47 (m, 1H), 7.41-7.32 (m, 2H), 7.29 (dd, J=8.1, 4.6 Hz, 1H), 7.18-7.05 (m, 4H), 6.93-6.84 (m, 2H), 5.37-5.22 (m, 1H), 2.97 (dd, J=13.6, 5.5 Hz, 1H), 2.81 (dd, J=13.4, 7.8 Hz, 1H), 2.52 (s, 3H)
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.58-8.49 (m, 1H), 8.10 (dd, J=8.2, 1.1 Hz, 1H), 7.97 (dd, J=8.0, 1.3 Hz, 1H), 7.67-7.55 (m, 2H), 7.51-7.42 (m, 1H), 7.24 (dd, J=8.0, 4.8 Hz, 1H), 6.69 (tt, J=9.3, 2.2 Hz, 1H), 6.53 (d, J=6.0 Hz, 2H), 5.50 (dd, J=7.5, 5.8 Hz, 1H), 3.09 (dd, J=13.6, 5.5 Hz, 1H), 2.91 (dd, J=13.6, 7.8 Hz, 1H).
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.62 (dd, J=4.9, 1.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.69-7.56 (m, 3H), 7.52-7.38 (m, 2H), 7.02-6.86 (m, 4H), 6.64 (t, J=9.3 Hz, 1H), 6.19 (d, J=6.0 Hz, 2H), 5.28 (t, J=7.2 Hz, 1H), 3.82 (s, 3H), 2.94-2.85 (m, 1H), 2.84-2.75 (m, 1H)
The title compound was prepared with the procedures described in Example 94.
1H NMR (400 MHz, METHANOL-d4) δ 8.54 (d, J=4.8 Hz, 1H), 7.97 (t, J=7.2 Hz, 2H), 7.57-7.48 (m, 1H), 7.39-7.29 (m, 2H), 7.25 (dd, J=8.0, 4.5 Hz, 1H), 6.76-6.65 (m, 1H), 6.49 (d, J=6.3 Hz, 2H), 5.50 (dd, J=7.5, 5.8 Hz, 1H), 3.09 (dd, J=13.6, 5.8 Hz, 1H), 2.89 (dd, J=13.6, 7.8 Hz, 1H), 2.61 (s, 3H)
The title compound was prepared with the procedures described in Example 88.
1H NMR (400 MHz, METHANOL-d4) δ 8.55-8.47 (m, 1H), 8.00-7.91 (m, 2H), 7.58-7.49 (m, 1H), 7.43-7.29 (m, 2H), 7.22 (dd, J=8.1, 4.6 Hz, 1H), 7.17-7.05 (m, 3H), 6.95-6.82 (m, 2H), 5.51 (t, J=6.5 Hz, 1H), 3.10 (dd, J=13.6, 5.7 Hz, 1H), 2.91 (dd, J=13.4, 7.6 Hz, 1H), 2.62 (s, 3H)
The title compound was prepared with the procedures described in Example 99.
1H NMR (400 MHz, METHANOL-d4) δ 8.71 (dd, J=4.8, 1.5 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.63 (dd, J=7.7, 1.4 Hz, 1H), 7.53-7.42 (m, 2H), 7.39-7.12 (m, 5H), 6.69-6.59 (m, 1H), 6.23 (d, J=6.3 Hz, 2H), 5.13 (t, J=7.4 Hz, 1H), 3.02-2.82 (m, 2H), 2.60 (s, 3H).
The title compound was prepared with the procedures described in Example 88.
1H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.61 (d, J=3.7 Hz, 1H), 7.99-7.88 (m, 4H), 7.73-7.62 (m, 3H), 7.56-7.49 (m, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.05 (d, J=7.3 Hz, 3H), 6.94 (d, J=8.4 Hz, 2H), 6.64 (d, J=6.2 Hz, 2H), 5.07-4.93 (m, 1H), 3.68 (s, 3H), 2.68 (dd, J=13.4, 7.5 Hz, 1H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.68-8.65 (m, 1H), 8.40 (s, 1H), 7.79-7.68 (m, 3H), 7.54-7.49 (m, 1H), 7.46 (dd, J=7.3, 4.8 Hz, 1H), 7.40 (s, 1H), 7.37-7.29 (m, 2H), 7.22 (s, 1H), 7.16-7.10 (m, 1H), 6.91 (t, J=9.5 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.27 (d, J=6.6 Hz, 2H), 5.21-5.07 (m, 1H), 4.20 (s, 3H), 2.98-2.87 (m, 1H), 2.74 (dd, J=13.0, 8.6 Hz, 1H), 2.51 (br. s., 3H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.63 (br. s., 1H), 7.74 (d, J=7.3 Hz, 2H), 7.56 (d, J=7.3 Hz, 2H), 7.39 (br. s., 3H), 7.31 (d, J=7.7 Hz, 3H), 7.28-7.19 (m, 3H), 7.11 (d, J=6.6 Hz, 2H), 6.90 (t, J=9.4 Hz, 1H), 6.79 (br. s., 1H), 6.23 (d, J=7.3 Hz, 2H), 5.09 (d, J=7.0 Hz, 1H), 2.20 (s, 3H), 1.92 (s, 6H)
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 10.66 (br. s., 1H), 8.66 (d, J=4.4 Hz, 1H), 7.96 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.44 (dd, J=7.7, 4.8 Hz, 1H), 7.40-7.29 (m, 4H), 7.13 (d, J=8.8 Hz, 1H), 7.09-7.02 (m, 2H), 6.93 (t, J=9.2 Hz, 1H), 6.33 (d, J=6.6 Hz, 2H), 5.11-4.94 (m, 1H), 4.50 (d, J=3.7 Hz, 2H), 2.98-2.91 (m, 2H), 2.80-2.75 (m, 1H), 1.17 (t, J=7.3 Hz, 2H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=3.7 Hz, 1H), 7.76 (dd, J=15.6, 7.2 Hz, 2H), 7.56-7.49 (m, 1H), 7.45 (dd, J=7.7, 4.8 Hz, 1H), 7.38-7.27 (m, 3H), 7.26-7.18 (m, 1H), 7.15-7.08 (m, 1H), 7.04 (s, 1H), 6.95 (t, J=9.5 Hz, 1H), 6.44 (d, J=6.6 Hz, 2H), 5.42-5.24 (m, 1H), 4.55 (br. s., 2H), 4.05-3.42 (m, 6H), 3.30-2.98 (m, 2H), 2.94 (dd, J=13.6, 5.9 Hz, 1H), 2.88-2.78 (m, 1H), 2.48 (s, 3H)
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 10.67 (br. s., 1H), 8.64 (d, J=4.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.55-7.50 (m, 1H), 7.40 (dd, J=7.7, 4.8 Hz, 1H), 7.37-7.31 (m, 2H), 7.19-7.09 (m, 2H), 6.99-6.85 (m, 3H), 6.31 (d, J=7.0 Hz, 2H), 5.06 (q, J=7.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.96-2.84 (m, 1H), 2.77 (dd, J=13.2, 7.7 Hz, 1H), 2.73 (s, 3H), 1.36 (t, J=7.0 Hz, 3H).
The title compound was prepared with the procedures described in Example 94.
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.69-8.62 (m, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.69-7.62 (m, 3H), 7.60-7.56 (m, 2H), 7.55-7.50 (m, 1H), 7.44 (dd, J=7.7, 4.8 Hz, 1H), 7.37-7.31 (m, 2H), 7.20-7.12 (m, 4H), 6.92 (t, J=9.4 Hz, 1H), 6.29 (d, J=6.2 Hz, 2H), 5.10 (q, J=7.6 Hz, 1H), 2.92-2.84 (m, 1H), 2.81-2.73 (m, 1H), 2.50 (s, 3H).
The title compound was prepared with the procedures described in Example 94.
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.71 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.78 (t, J=7.9 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.56-7.46 (m, 2H), 7.41-7.28 (m, 3H), 7.23-7.13 (m, 3H), 6.83 (t, J=9.5 Hz, 1H), 6.28 (d, J=6.2 Hz, 2H), 5.12 (q, J=7.5 Hz, 1H), 2.95-2.87 (m, 1H), 2.85-2.76 (m, 1H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=4.8 Hz, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.56-7.50 (m, 1H), 7.46 (dd, J=7.7, 4.8 Hz, 1H), 7.39-7.31 (m, 4H), 7.16 (d, J=8.4 Hz, 1H), 6.94 (t, J=9.5 Hz, 1H), 6.31 (d, J=6.6 Hz, 2H), 4.96 (q, J=7.5 Hz, 1H), 2.88-2.83 (m, 1H), 2.83-2.77 (m, 1H), 2.73 (s, 1H).
The title compound was prepared with the procedures described in Example 94.
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.72 (d, J=4.0 Hz, 1H), 7.98-7.89 (m, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.65 (d, J=6.6 Hz, 1H), 7.58 (s, 1H), 7.56-7.49 (m, 2H), 7.48-7.40 (m, 2H), 7.37-7.30 (m, 2H), 7.18-7.11 (m, 1H), 6.88 (t, J=9.5 Hz, 1H), 6.33 (d, J=6.2 Hz, 2H), 4.99 (q, J=7.9 Hz, 1H), 2.96-2.91 (m, 1H), 2.87-2.81 (m, 1H), 2.51 (br. s., 3H), 1.54 (s, 9H)
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=4.4 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.55-7.41 (m, 4H), 7.38-7.30 (m, 3H), 7.14 (d, J=8.8 Hz, 1H), 6.87 (t, J=9.5 Hz, 1H), 6.36 (d, J=7.0 Hz, 2H), 4.96 (q, J=7.5 Hz, 1H), 3.37 (br. s., 1H), 2.96-2.90 (m, 1H), 2.87-2.80 (m, 1H), 2.51 (br. s., 3H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=4.8 Hz, 1H), 8.16-8.05 (m, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.71-7.59 (m, 2H), 7.58-7.42 (m, 4H), 7.40-7.06 (m, 4H), 7.03-6.91 (m, 2H), 6.90-6.83 (m, 1H), 6.74 (t, J=9.2 Hz, 1H), 6.17 (d, J=7.3 Hz, 1H), 5.98 (d, J=6.2 Hz, 1H), 4.68 (d, J=7.3 Hz, 1H), 4.44-4.27 (m, 1H).
The title compound was prepared with the procedures described in Example 94.
1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=4.8 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.39 (dd, J=7.3, 4.8 Hz, 1H), 7.36-7.30 (m, 2H), 7.20 (s, 1H), 7.16-7.08 (m, 1H), 7.01-6.92 (m, 1H), 6.26 (d, J=6.6 Hz, 3H), 4.87 (br. s., 1H), 2.85-2.77 (m, 1H), 2.75-2.66 (m, 1H), 2.33 (s, 3H), 1.85 (s, 3H).
HIV cell culture assay—MT-2 cells, 293T cells and the proviral DNA clone of NL4-3 virus were obtained from the NIH AIDS Research and Reference Reagent Program. MT-2 cells were propagated in RPMI 1640 media supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 ug/ml penicillin G and up to 100 units/ml streptomycin. The 293T cells were propagated in DMEM media supplemented with 10% heat inactivated FBS, 100 ug/ml penicillin G and 100 ug/ml streptomycin. A recombinant NL4-3 proviral clone, in which a section of the nef gene was replaced with the Renilla luciferase gene, was used to make the reference virus used in these studies. The recombinant virus was prepared through transfection of the recombinant NL4-3 proviral clone into 293T cells using Transit-293 Transfection Reagent from Mirus Bio LLC (Madison, Wis.). Supernatent was harvested after 2-3 days and the amount of virus present was titered in MT-2 cells using luciferase enzyme activity as a marker by measuring luciferase enzyme activity. Luciferase was quantitated using the EnduRen Live Cell Substrate from Promega (Madison, Wis.). Antiviral activities of compounds toward the recombinant virus were quantified by measuring luciferase activity in MT-2 cells infected for 4-5 days with the recombinant virus in the presence of serial dilutions of the compound.
The 50% effective concentration (EC50) was calculated by using the exponential form of the median effect equation where (Fa)=1/[1+(ED50/drug conc.)m] (Johnson V A, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed. Aldovini A, Walker B D. 71-76. New York: Stockton Press. 1990).
Compound cytotoxicity and the corresponding CC50 values were determined using the same protocol as described in the antiviral assay except that uninfected cells were used. Cytotoxicity was assessed on day 4 in uninfected MT2 cells by using a XTT (2,3-bis[2-Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt)-based colorimetric assay (Sigma-Aldrich, St Louis, Mo.).
Compounds demonstrate antiviral activity as depicted in Table 1 below. Activity equal to A refers to a compound having an EC50≦100 nM, while B and C denote compounds having an EC50 between 100 nM and 1 uM (B) or >1 uM (C).
The disclosure is not limited to the foregoing illustrative examples and the examples should be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced.
This non-provisional application claims the benefit of U.S. Provisional Application Ser. No. 62/048,017 filed Sep. 9, 2014 which is herein incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2015/048271 | 9/3/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62048017 | Sep 2014 | US |
