Patent Grant
10035760
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.
HIV (human immunodeficiency virus) infection/acquired immunodeficiency syndrome (HIV/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, with, 1.7 million people dying 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.
The invention provides technical advantages, for example, the compounds are novel and are useful in the treatment of HIV. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their 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:
R1 is alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl; wherein said aryl, arylalkyl or heteroaryl moieties are linked to the parent molecule through their respective carbon atoms, and further wherein said R1 groups are substituted with 0-4 groups independently selected from the group of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkyl, alkylsulphonyl, alkylthioxy, aminocarbonyl, alkynyl, carboxylic acid, cyano, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, thioxy, —SO2alkyl, heteroaryl, and nitro;
R2 is —H, C1-C4 alkyl or C3-C4 cycloalkyl;
or R1 and R2 together with the atoms to which they are attached form a heterocyclic ring optionally substituted with 0-2 alkyl groups;
R3 is —H, C1-C4 alkyl or C3-C4 cycloalkyl;
R4 is —H, alkyl, aryl, C5-C10 bicycloalkyl, cycloalkyl or heteroaryl which is substituted with 0-3 groups independently selected from the group of alkenoxy, alkenyl, alkoxy, alkoxycarbonyl, alkyl, benzyloxy, carboamide, cyano, halo, haloalkyl, haloalkoxy, —NHCO(alkyl), —SO2N-heterocycle, —OH, nitro, and —CH2OH;
R5 and R6 are independently selected from H or alkyl, or R5 and R4 together with the atom to which they are attached form an aryl group; or R5 and R6 together with the atoms to which they are attached form a C3-C4 cycloalkyl;
R7 is —H, alkyl, aryl, heteroaryl, heteroarylalkyl, C3-C7 cycloalkyl or dialkylaminoalkyl, wherein said aryl or heteroaryl is substituted with 0-3 groups independently selected from the group of —OH, —NHCOalkyl, —NHCON(alkyl)2, —NHCO2-alkyl, —CONH2, —CN, —SO2N(alkyl)2, alkoxy, alkyl, halo, haloalkoxy, and haloalkyl; and
R8 is —H, alkyl, arylalkyl, cycloalkyl, haloalkyl or heteroarylalkyl;
or R7 and R8 together with the nitrogen atom to which they are attached form a heterocycle which is substituted with 0-3 groups independently selected from the group of alkyl, alkoxy, halo, —OH, —CN, and —SO2N(alkyl)2.
For a compound 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.
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 expressly set forth elsewhere in the application, the following terms shall have the following meanings:
“Alkenyl” means a straight or branched alkyl group comprised of 2 to 10 carbons with at least one double bond and optionally substituted with 0-3 halo or alkoxy group.
“Alkenyloxy” means an alkenyl group attached to the parent structure by an oxygen atom.
“Alkoxy” means an alkyl group attached to the parent structure by an oxygen atom.
“Alkoxycarbonyl” means an alkoxy group attached to the parent structure by a carbonyl moiety.
“Alkoxycarbonylamino” 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 —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 one or two alkyl groups.
“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, dihydroindene, naphthalene, and tetrahydronaphthalene. The aryl group can be attached to the parent structure through any substitutable carbon atom in the group.
“Arylalkyl” is a C1-C5 alkyl group attached to 1 to 2 aryl groups and linked to the parent structure through the alkyl moiety and where the aryl component is further substituted with 0-4 groups selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy or cyano. Examples include, but are not limited to, —(CH2)nPh and —CH(CH3)Ph with n=1-5.
“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.
“C3-C4 cycloalkyl” means a monocyclic ring system comprised of 3 to 4 carbons.
“Cycloalkyl” means carbocycle with 1-2 rings optionally substituted with an alkyl or benzyl group.
“Cyano” refers to —CN.
“Dialkylaminoalkyl” means a dialkylamino group attached to the parent structure through a C2 to C3 alkyl moiety.
“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 structure 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 or sulfur.
“Heteroarylalkyl” is a heteroaryl moiety attached to the parent structure through C1-C5 alkyl group and where the aryl moiety is further substituted with halo, alkyl, alkoxy, haloalkyl, haloalkoxy or cyano. Examples include, but are not limited to, —(CH2)n-pyridine, —(CH2)n-thiazole, —(CH2)n-quinoline, —(CH2)n-phenyl-pyrazole, —(CH2)n-(2-methylbenzimidazole), —(CH2)n—(N-methylimidazole), —(CH2)n-(methyloxadiazole), —CH(CH3)-(pyridine) with n=1-5.
“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, azetidine, benzimidazole, bezodioxolyl, benzoxazole, benzothiophene, benzothiazole, chroman, dihydro-benzo[1,4]oxazine, dihalobezodioxolyl, dihydrobenzofuran, furanylphenyl, imidazo[1,2-a]pyridine, indazole, indole, indoline, isoquinoline, isoquinolinone, isothiazolidine 1,1-dioxide, morpholine, 2-oxa-5-azabicyclo[2.2.1]heptanes, oxadiazole-phenyl, pyrrazole-phenyl, pyridine-phenyl, pyridinylpyrrolidine, pyrimidine-phenyl, quinazoline, quinoxaline, quinoline, tetrahydroisoquinoline, tetrahydrothieno[3,2-c]pyridine, thiophene, thiophene-phenyl, triazole. Unless otherwise specifically set forth, the heterocyclic group can be attached to the parent structure through any suitable atom in the group that results in a stable compound.
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:
wherein:
R1 is alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl; wherein said aryl, arylalkyl or heteroaryl moieties are linked to the parent molecule through their respective carbon atoms, and further wherein said R1 groups are substituted with 0-4 groups independently selected from the group of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkyl, alkylsulphonyl, alkylthioxy, aminocarbonyl, alkynyl, carboxylic acid, cyano, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, thioxy, —SO2alkyl, heteroaryl, and nitro;
R2 is —H, C1-C4 alkyl or C3-C4 cycloalkyl;
or R1 and R2 together with the atoms to which they are attached form a heterocyclic ring optionally substituted with 0-2 alkyl groups;
R3 is —H, C1-C4 alkyl or C3-C4 cycloalkyl;
R4 is —H, alkyl, aryl, C5-C10 bicycloalkyl, cycloalkyl or heteroaryl which is substituted with 0-3 groups independently selected from the group of alkenoxy, alkenyl, alkoxy, alkoxycarbonyl, alkyl, benzyloxy, carboamide, cyano, halo, haloalkyl, haloalkoxy, —NHCO(alkyl), —SO2N-heterocycle, —OH, nitro, and —CH2OH;
R5 and R6 are independently selected from H or alkyl, or R5 and R4 together with the atom to which they are attached form an aryl group; or R5 and R6 together with the atoms to which they are attached form a C3-C4 cycloalkyl;
R7 is —H, alkyl, aryl, heteroaryl, heteroarylalkyl, C3-C7 cycloalkyl or dialkylaminoalkyl, wherein said aryl or heteroaryl is substituted with 0-3 groups independently selected from the group of —OH, —NHCOalkyl, —NHCON(alkyl)2, —NHCO2-alkyl, —CONH2, —CN, —SO2N(alkyl)2, alkoxy, alkyl, halo, haloalkoxy, and haloalkyl; and
R8 is —H, alkyl, arylalkyl, cycloalkyl, haloalkyl or heteroarylalkyl;
or R7 and R8 together with the nitrogen atom to which they are attached form a heterocycle which is substituted with 0-3 groups independently selected from the group of alkyl, alkoxy, halo, —OH, —CN, and —SO2N(alkyl)2.
In a preferred embodiment of the invention, R1 is aryl. More preferably, R1 is aryl which is selected from the group of phenyl, biphenyl, and naphthalenyl.
In a further embodiment, R1 is heteroaryl. More preferably, R1 is selected from the group of thiophene, pyrrazolophenyl, furanylphenyl, pyridinylphenyl, pyrimidinylphenyl, thiophenylphenyl, benzothiophene, oxadiazolephenyl, indole, and andazaindole.
In a further preferred embodiment, R1 and R2 form a heteroaryl ring. More preferably, the heteroaryl ring is isothiazolidine 1,1-dioxide.
It is also preferred that R4 is aryl. More preferably, R4 is phenyl, naphthalenyl, or biaryl.
In another embodiment it is preferred that R4 is heteroaryl. More preferably, R4 is triazole or thiophene.
It is further preferred that R7 is aryl. More preferably, R7 is phenyl or naphthalenyl.
In another embodiment it is preferred that R7 is heteroaryl. More preferably R7 is selected from the group of bezodioxolyl, dihalobezodioxolyl, benzothiazole, quinoline, benzothiazole, benzimidazole, quinazoline, quinoxaline, dihydrobenzofuran, chroman, benzoxazole, isoquinoline, and isoquinolinone.
In a further embodiment of the invention, R7 and R8 form a heterocycle. More preferably, the heterocycle is selected from the group of tetrahydroisoquinoline, dihydro-benzo[1,4]oxazine, dihydroindole, tetrahydrothieno[3,2-c]pyridine, 2-oxa-5-azabicyclo[2.2.1]heptanes, azetidine, and pyridinylpyrrolidine.
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 one or more carriers, 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 available 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.
“Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
“Patient” means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.
“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” and related terms are used as understood by practitioners in the field of AIDS and HIV infection.
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:
The compounds of the invention can be made by various methods available in the art including those of the following scheme and in the specific embodiments section which follows. The structure numbering and variable numbering shown in the synthetic schemes are 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. Chemical abbreviations used in the specification and 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.
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.
Benzo[d][1,3]dioxol-5-amine (1.6 g, 12 mmol) was added to a solution of 25% wt. sodium methoxide (12.6 g, 58.3 mmol) in MeOH and paraformaldehyde (3.50 g, 117 mmol) in MeOH (50 mL). The reaction mixture was stirred at r.t. for 18 h and then sodium borohydride (1.32 g, 35.0 mmol) was added in portions and the reaction was heated at 40° C. for 3 h, cooled to r.t., and then concentrated. The residue was dissolved into EtOAc (˜60 mL), washed with water (50 mL) and brine (50 mL) and then dried (MgSO4), filtered and concentrated. The residue was purified using a Biotage Horizon (40 g SiO2, 10-25% EtOAc/hexanes) to afford the title compound (1.43 g) as amber oil. 1H NMR (400 MHZ, CDCl3) δ 6.69 (d, J=8.3 Hz, 1H), 6.26 (d, J=2.5 Hz, 1H), 6.06 (dd, J=8.3, 2.5 Hz, 1H), 5.87 (s, 2H), 2.80 (s, 3H).
HATU (3.02 g, 7.94 mmol) was added to a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.93 g, 7.28 mmol) and N-methylbenzo[d][1,3]dioxol-5-amine (1.0 g, 6.6 mmol) in diisopropylethylamine (2.3 mL, 13 mmol) and DMF (35 mL) and the reaction solution was stirred at r.t. for 18 h. The reaction was concentrated to dryness and partitioned between 1/2 sat. NaHCO3 (aq) (50 mL) and EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) filtered and concentrated. The residue was purified using a Biotage Horizon (80 g SiO2, 10-40% EtOAc) to afford the title compound (2.15 g) as tan solidified foam. 1H NMR (400 MHZ, CDCl3) δ 7.34-7.20 (m, 4H), 7.02 (br. s., 2H), 6.70 (d, J=7.5 Hz, 1H), 6.36-6.19 (m, 1H), 6.01 (s, 2H), 5.19 (d, J=7.0 Hz, 1H), 4.53 (d, J=7.0 Hz, 1H), 3.15 (s, 3H), 2.92-2.77 (m, 2H), 1.40 (s, 9H).
To (S)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1070 mg, 2.69 mmol) was added 50% TFA in DCM (2 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated to give the title compound (1090 mg) as a TFA salt.
A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (26.5 mg, 0.100 mmol), N-methylaniline (11.77 mg, 0.110 mmol), HATU (38 mg, 0.100 mmol) and DIPEA (0.053 mL, 0.300 mmol) in DMF (1 mL) was stirred at room temperature for 18 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). The organic component was washed with brine (10 mL), dried (MgSO4) filtered and concentrated. The residue was used without purification.
To (S)-tert-butyl (1-(methyl(phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (20 mg, 0.056 mmol) was added 50% TFA in DCM (2 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated to give the title compound (14.5 mg) as a TFA salt.
Intermediate 6 was prepared using the analogous procedures for the preparation of Intermediates 1-3 where the benzo[d][1,3]dioxol-5-amine used in the preparation of Intermediate 1 was replaced with 2,3-dihydro-1H-inden-5-amine and then carried through the subsequent steps. LC-MS retention time=1.17 min; m/z=295.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=90% Water: 10% Acetonitrile: 0.1% TFA. Solvent B=10% Water: 90% Acetonitrile: 0.1% TFA. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220).
Intermediate 7 was prepared using the analogous procedure for the preparation of Intermediates 2 where the (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid was replaced with (S)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoic acid. LC-MS retention time=1.68 min; m/z=413.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=90% Water: 10% Acetonitrile: 0.1% TFA. Solvent B=10% Water: 90% Acetonitrile: 0.1% TFA. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220).
Intermediate 8 was prepared using the analogous procedure for the preparation of Intermediates 2 where the (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid was replaced with (R)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoic acid. LC-MS retention time=1.67 min; m/z=413.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=90% Water: 10% Acetonitrile: 0.1% TFA. Solvent B=10% Water: 90% Acetonitrile: 0.1% TFA. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220).
HATU (2.00 g, 5.26 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline (0.601 g, 4.38 mmol), (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.508 g, 4.38 mmol) and DIPEA (2.3 mL, 13 mmol) in DMF (15 mL) and the reaction mixture was stirred at RT overnight. The reaction was diluted with water (50 mL), extracted by EtOAc (2×40 mL) and the combined organic component was concentrated to dryness to yield the title compound (1.9 g) which was used without further purification. LC-MS retention time=2.40 min; m/z=363.1 [M+H-Boc]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
A solution of (S)-tert-butyl (3-(3-bromophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)carbamate (0.740 g, 1.56 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.295 g, 1.92 mmol), 3M aqueous Na2CO3 (2.66 mL, 7.99 mmol) and PdCl2(dppf) (0.117 g, 0.160 mmol) in DMF (2 mL) was degassed and heated at 110° C. for 2 h. The reaction mixture was allowed to cool, diluted with water (150 mL) and extracted with EtOAc (2×150 mL). The combined organic component was purified by silica gel chromatography (TLC (50% EtAOc/Hexanes, Rf0.66)) to yield the title compound (0.43 g). LC-MS retention time=2.38 min; m/z=411.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.23-7.15 (m, 1H), 7.01-6.55 (m, 7H), 5.68 (d, J=17.6 Hz, 1H), 5.23 (d, J=11.0 Hz, 2H), 4.52 (d, J=7.6 Hz, 1H), 3.81 (s, 3H), 3.16 (s, 3H), 2.94-2.82 (m, 1H), 2.72 (dd, J=12.6, 6.7 Hz, 1H), 1.57 (s, 9H).
A solution of (S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-(3-vinylphenyl)propan-2-yl)carbamate (0.430 g, 1.047 mmol) and TFA (3 mL, 38.9 mmol) in DCM (6 mL) was stirred at RT for 1 h. Solvent was evaporated to yield a TFA salt of the title compound (0.445 g) which was used without further purification. LC-MS retention time=1.77 min; m/z=311.2 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
HATU (0.800 g, 2.10 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline (0.240 g, 1.75 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3-(3-hydroxyphenyl)propanoic acid (0.493 g, 1.75 mmol) and DIPEA (0.92 mL, 5.3 mmol) in DMF (5 mL) and the reaction mixture was stirred at RT overnight. The reaction was diluted with water (50 mL), extracted with EtOAc (2×40 mL) and the combined organic component was concentrated to dryness and purified (40 g SiO2, 0-30% EtOAc/DCM) to yield the title compound (0.58 g). LC-MS retention time=1.99 min; m/z=399.3 [M−H]−. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.10 (t, J=7.8 Hz, 1H), 6.91-6.66 (m, 5H), 6.52 (d, J=7.6 Hz, 1H), 6.46 (s, 1H), 5.57 (br. s., 1H), 5.20 (d, J=7.6 Hz, 1H), 4.52 (d, J=7.8 Hz, 1H), 3.81 (s, 3H), 3.19 (s, 3H), 2.84 (dd, J=13.0, 7.8 Hz, 1H), 2.68 (dd, J=12.8, 6.2 Hz, 1H), 1.40 (br. s., 9H).
The reaction mixture of (S)-tert-butyl (3-(3-hydroxyphenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)carbamate (0.52 g, 1.3 mmol), 4-bromo-2-butene (0.26 mL, 2.6 mmol) and Cs2CO3 (0.465 g, 1.43 mmol) in THF (8 mL), EtOH (8 mL) and H2O (8 mL) was stirred at 85° C. for 22 h. The reaction was diluted with water (80 mL), extracted with EtOAc (2×100 mL) and the combined organic component was concentrated to dryness and purified (24 g SiO2, 0-40% EtOAc/DCM) to yield the title compound (0.28 g). LC-MS retention time=2.51 min; m/z=355.1 [M+H-Boc]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.12 (t, J=7.8 Hz, 1H), 6.93-6.67 (m, 5H), 6.55 (d, J=7.3 Hz, 1H), 6.44 (br. s., 1H), 5.91 (ddt, J=17.1, 10.4, 6.7 Hz, 1H), 5.22-5.09 (m, 3H), 4.52 (d, J=8.1 Hz, 1H), 3.90 (td, J=6.7, 3.4 Hz, 2H), 3.82 (s, 3H), 3.18 (s, 3H), 2.89-2.80 (m, 1H), 2.68 (dd, J=12.6, 6.0 Hz, 1H), 2.52 (q, J=6.6 Hz, 2H), 1.55 (s, 9H).
A solution of (S)-tert-butyl (3-(3-(but-3-en-1-yloxy)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)carbamate (0.280 g, 0.616 mmol) in TFA (1.0 mL, 13 mmol) and DCM (2 mL) was stirred at RT for 1 h. The solvent was removed to yield a TFA salt of the title compound (0.445 g) which was used without further purification. LC-MS retention time=1.87 min; m/z=355.1 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
A mixture of tert-butyl (4-hydroxyphenyl)(methyl)carbamate (1.00 g, 4.48 mmol), allyl bromide (0.58 mL, 6.7 mmol) and Cs2CO3 (2.92 g, 8.96 mmol) in acetone (40 mL) was sealed and heated to gentle reflux for 4 h. The reaction mixture was allowed to cool to rt, filtered and concentrated. The residue was taken up into EtOAc, washed with 5% citric acid and then brine, dried over MgSO4, filtered, and concentrated. The residue was taken up into DCM and purified by flash column chromatography. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.14 (d, J=8.3 Hz, 1H), 6.91-6.85 (m, 1H), 6.08 (ddt, J=17.3, 10.6, 5.3 Hz, 1H), 5.44 (dq, J=17.2, 1.6 Hz, 1H), 5.34-5.28 (m, 1H), 4.54 (dt, J=5.3, 1.5 Hz, 2H), 3.24 (s, 3H), 1.45 (s, 9H).
A solution of 2 M HCl in ether (0.949 mL, 1.899 mmol) was added to tert-butyl (4-(allyloxy)phenyl)-(methyl)carbamate (50 mg, 0.190 mmol) and stirred at RT overnight. The reaction was concentrated under a stream of nitrogen to yield the title compound which was used without further purification. LC-MS retention time=0.73 min; m/z=164.2 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
2-Methylbenzenesulfonyl isocyanate (0.52 mL, 3.4 mmol) was added dropwise to an ice bath cooled mixture of (S)-benzyl 2-amino-3-phenylpropanoate, HCl (1.00 g, 3.43 mmol) and DIPEA (2.4 mL, 14 mmol) in acetonitrile (20 mL) and the resulting solution was stirred at RT for 2 h. The reaction mixture was concentrated and the residual oil was taken into EtOAc (100 mL) and washed with 5% citric acid and brine, dried over MgSO4, filtered and concentrated. The residual oil was purified by flash column chromatography (80 g silica gel cartridge, eluted with gradient 30%˜70% acetone-hexanes) to afford the title compound (1.20 g) as a white solid. LC-MS retention time=1.28 min; m/z=453.3 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
A mixture of (S)-benzyl 3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanoate (1.00 g, 2.21 mmol) and 10% Pd—C (0.118 g, 0.110 mmol) in EtOAc (15 mL) and MeOH (15 mL) was placed under a balloon of hydrogen and stirred at RT for 2 h. The reaction was filtered through celite and concentrated to dryness to yield the title compound (750 mg) as a white solid. LC-MS retention time=0.99 min; m/z=363.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
Intermediate 19 was prepared using the chemical procedures displayed in the following scheme:
LC-MS retention time=0.73 min; m/z=328.2 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
HATU (1.5 g, 4.0 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline (500 mg, 3.64 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.06 g, 4.0 mmol) in DMF (20 mL) and DIPEA (1.3 mL, 7.3 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction was concentrated and the residual crude oil was partitioned between EtOAc (˜60 mL) and 1/2 sat. NaHCO3 (aq) (˜60 mL). The organic component was washed with brine (˜40 mL), dried (MgSO4), filtered, concentrated and purified using a Biotage Horizon (80 g SiO2, 10-40% EtOAc/hexanes) to yield (S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1.34 g) as a clear amber viscous oil. LC-MS retention time=3.17 min; m/z=385.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×50 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220). 1H NMR (400 MHz, CDCl3) δ 7.25-7.20 (m, 3H), 7.03-6.64 (m, 6H), 5.20 (d, J=8.8 Hz, 1H), 4.53 (q, J=7.4 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.89 (dd, J=13.1, 7.5 Hz, 1H), 2.71 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H).
A 4M HCl (15 mL, 60.0 mmol) in dioxanes solution was added to a stirred solution of (S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (Intermediate JB-1) (1.34 g, 3.49 mmol) in THF (10 mL) and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated to dryness under vacuum to yield an HCl salt of (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (1.11 g) as a solidified foam which was used without additional purification. LC-MS retention time=2.33 min; m/z=285.2 [M+H]+. (Column: Phenonenex-Luna C18 2.0×50 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220).
HATU (776 mg, 2.04 mmol) was added to a stirred solution of 3,4,5-trimethoxy-N-methylaniline (350 mg, 1.78 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (518 mg, 1.95 mmol) in DMF (10 mL) and DIPEA (0.62 mL, 3.6 mmol) and stirred at RT ON. The reaction mixture was concentrated and the crude oil was partitioned between EtOAc (˜40 mL) and 1/2 sat NaHCO3 (aq) (˜40 mL). The organic component was washed with brine (˜30 mL), dried (MgSO4), filtered and concentrated. The crude residue was then purified using a Biotage Horizon (80 g SiO2, 10-40% EtOAc/hexanes) to yield(S)-tert-butyl (1-(methyl(3,4,5-trimethoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (474 mg) as a clear colorless solidified oil. Used without further purification. LC-MS retention time=1.60 min; m/z=385.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×50 mm 3 μm. Solvent A=90% Water: 10% Acetonitrile: 0.1% TFA. Solvent B=10% Water: 90% Acetonitrile: 0.1% TFA. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.27-7.17 (m, 3H), 7.01 (d, J=6.3 Hz, 2H), 6.11 (br. s., 2H), 5.21 (d, J=9.0 Hz, 1H), 4.76-4.64 (m, 1H), 3.86 (s, 3H), 3.77 (br. s., 6H), 3.17 (s, 3H), 3.01-2.87 (m, 1H), 2.77 (dd, J=12.8, 6.3 Hz, 1H), 1.40 (s, 9H).
Paraformaldehyde (80 mg, 2.7 mmol) was added to a stirred solution of benzo[d]thiazol-5-amine (200 mg, 1.332 mmol) in MeOH (5 mL) The resulting suspension was then treated with 25% w/w NaOMe in MeOH (1.5 mL, 6.7 mmol) and the clear reaction mixture was stirred at 60° C. for 16 h. The reaction was allowed to cool to RT and then treated with NaBH4 (126 mg, 3.33 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHCl3 (3×20 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12 g SiO2, 0-50% EtOAc/hexanes) to yield N-methylbenzo[d]thiazol-5-amine (217 mg) as yellow gum. LC-MS retention time=0.67 min; m/z=165.05 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.92 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 6.82 (dd, J=8.8, 2.3 Hz, 1H), 3.93 (br. s., 1H), 2.94 (s, 3H).
HATU (1.90 g, 5.01 mmol) was added to a solution of N-methylbenzo[d]thiazol-5-amine (Intermediate ZY-1) (685 mg, 4.17 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.33 g, 5.01 mmol) in DMF (20 mL) and DIPEA (2.18 mL, 12.5 mmol) and the reaction mixture was stirred at RT for 6 h. The crude reaction mixture was diluted with sat. aq. NaHCO3 (20 mL) and extracted with EtOAc (3×50 mL). The combined organic component was washed with brine (˜60 mL), dried (Na2SO4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (12 g SiO2, 0-40%-50% EtOAc/hexanes) to yield (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1.7 g) as a white solid. LC-MS retention time=1.19 min; m/z=412.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.07 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.27-7.19 (m, 3H), 6.94 (d, J=6.8 Hz, 3H), 5.22 (d, J=8.8 Hz, 1H), 4.58-4.48 (m, 1H), 3.26 (s, 3H), 2.93 (dd, J=12.9, 8.4 Hz, 1H), 2.78 (dd, J=12.4, 5.9 Hz, 1H), 1.40 (s, 9H).
A solution of 4M HCl (10 mL, 40.0 mmol) in dioxanes was added to a stirred solution of (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (Intermediate ZY-2) (1.7 g, 4.13 mmol) in THF (10 mL) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated, redissolved in EtOH/toluene, and then reconcentrated (3×) to yield an HCl salt of (S)-2-amino-N-(benzo[d]thiazol-5-yl)-N-methyl-3-phenylpropanamide (1.7 g, 4.42 mmol, 107% yield) as a pink sticky solid. LC-MS retention time=0.83 min; m/z=312.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, METHANOL-d4) δ 9.42 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.39-7.08 (m, 6H), 6.91 (d, J=7.0 Hz, 2H), 4.10 (dd, J=8.0, 6.5 Hz, 1H), 3.63-3.56 (m, 2H), 3.11 (dd, J=13.4, 8.2 Hz, 1H), 2.92 (dd, J=13.3, 6.5 Hz, 1H), 2.87 (s, 3H).
HATU (592 mg, 1.556 mmol) was added to a stirred solution of N-methylbenzo[d]thiazol-5-amine (Intermediate ZY-1) (213 mg, 1.30 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (469 mg, 1.56 mmol) in DMF (7 mL) and DIPEA (0.45 mL, 2.6 mmol) and the reaction mixture was stirred at RT for 16 h. The crude reaction mixture was diluted with sat. aq. NaHCO3 (20 mL) and extracted with EtOAc (3×50 mL). The combined organic component was washed with brine (˜60 mL), dried (Na2SO4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (24 g SiO2, 0-50% EtOAc/hexanes) yield (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate (581 mg) as a white solid. LC-MS retention time=1.23 min; m/z=448.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.10 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.68 (br. s., 1H), 7.05 (br. s., 1H), 6.68 (t, J=8.9 Hz, 1H), 6.44 (d, J=6.3 Hz, 2H), 5.25 (d, J=9.0 Hz, 1H), 4.54 (q, J=7.3 Hz, 1H), 2.94-2.86 (m, 1H), 2.81 (s, 3H), 2.72 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H).
TFA (1.0 mL, 13 mmol) was added to a stirred solution of (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate (Intermediate ZY-4) (0.58 g, 1.23 mmol) in DCM (2 mL) and the reaction mixture was stirred at RT for 16 h. The crude reaction mixture was concentrated and the residue was dissolved in MeOH/DCM and 4 M HCl in dioxane (2 mL) and reconcentrated. The residue was redissolved in EtOH/toluene, and then reconcentrated (3×) to yield an HCl salt of (S)-2-amino-N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-N-methylpropanamide (0.55 g) as a white solid. LC-MS retention time=0.83 min; m/z=348.1[M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
BOP-Cl (131 mg, 0.516 mmol) was added to a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (124 mg, 0.469 mmol) and N-benzyl-4-methoxyaniline (100 mg, 0.469 mmol) in DCM (3 mL), and DIPEA (0.25 mL, 1.4 mmol) and the reaction mixture was stirred at RT for 16 h. The crude reaction mixture was concentrated and the residue was purified using a Biotage Horizon (12 g SiO2, 0-50% Et2O/hexanes) to yield the title compound (125 mg). LC-MS retention time=1.43 min; m/z=461.4 [M+H]+. (Column: Waters Aquity BEH C18 2.1×50 mm 1.7 U. Solvent A=100% Water/0.05% TFA. Solvent B=100% Acetonitrile/0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
A 4M solution of HCl (1.3 mL, 5.2 mmol) in dioxane was added to a stirred solution of (S)-tert-butyl (1-(benzyl(4-methoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (Intermediate ZY-6) (120 mg, 0.261 mmol) in THF (1.3 mL) and the reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated to yield an HCl salt of the title compound (117 mg). LC-MS retention time=0.99 min; m/z=361.2 [M+H]+. (Column: Waters Aquity BEH C18 2.1×50 mm 1.7 U. Solvent A=100% Water/0.05% TFA. Solvent B=100% Acetonitrile/0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.617 g, 2.44 mmol) was added to a stirred solution of scandium trifluoromethanesulfonate (0.024 g, 0.049 mmol), benzaldehyde (0.248 mL, 2.44 mmol) and 4-methoxyaniline (0.300 g, 2.44 mmol) in DCM (10 mL) and the reaction mixture was stirred at RT for 16 h. The reaction was then concentrated and the residue was purified by silica gel chromatography (0-20% Et2O/hexanes) to yield the title compound (503 mg) as yellow oil.
Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.617 g, 2.44 mmol) was added to a stirred solution of scandium trifluoromethanesulfonate (0.024 g, 0.049 mmol), isonicotinaldehyde (0.229 mL, 2.44 mmol) and 4-methoxyaniline (0.300 g, 2.44 mmol) in DCM (10 mL) and the reaction mixture was stirred at RT for 16 h. The reaction was then concentrated and the residue was purified by silica gel chromatography (24 g SiO2, 0-100% Et2O/hexanes) to yield the title compound (447 mg) as yellow solid.
Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.03 g, 4.06 mmol) was added to a stirred solution of scandium trifluoromethanesulfonate (0.040 g, 0.081 mmol), 2-phenylacetaldehyde (0.488 g, 4.06 mmol) and 4-methoxyaniline (0.500 g, 4.06 mmol) in DCM (10 mL) and the reaction mixture was stirred at RT for 16 h and then heated at 50° C. for 2 h. Additional 2-phenylacetaldehyde (0.488 g, 4.06 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.03 g, 4.06 mmol) were added and heating at 50° C. was continued for 1 h. The reaction was then concentrated and the residue was purified by silica gel chromatography (24 g SiO2, 0-20% Et2O/hexanes) to yield the title compound (2.25 g) contaminated with and impurity, but used without additional purification, as red/orange oil.
Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.06 g, 8.12 mmol) was added to a stirred solution of scandium trifluoromethanesulfonate (0.080 g, 0.16 mmol), isobutyraldehyde (0.74 mL, 8.1 mmol) and 4-methoxyaniline (0.300 g, 2.44 mmol) in DCM (10 mL) and the reaction mixture was stirred at RT for 16 h. The reaction was then concentrated and the residue was purified by silica gel chromatography (40 g SiO2, 0-20% Et2O/hexanes) to yield the title compound (1.02 g) as clear colorless oil.
Acetic acid (0.042 mL, 0.73 mmol) was added to a stirred solution of 4-methoxy-3-methylaniline (100 mg, 0.729 mmol) and acetaldehyde (0.054 mL, 0.948 mmol) in DCM (3 mL) and the reaction mixture was stirred at RT for 5 min. Sodium triacetoxyborohydride (232 mg, 1.09 mmol) was then added to the reaction mixture and the reaction was stirred at RT for 16 h. The reaction was quenched with 1N aq. NaOH (4 mL), extracted with chloroform (3×10 mL) and the combined organic component was concentrated and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield a TFA salt of the title compound (27 mg) as dark pink oil.
Prepared using the procedure outlined for Intermediate ZY-12 where 4-methoxy-3-methylaniline was replaced with chroman-6-amine.
Prepared using the procedure outlined for Intermediate ZY-12 where 4-methoxy-3-methylaniline was replaced with quinoline-6-amine.
10% Pd—C (0.135 g, 0.126 mmol) was added to a mixture of 2-methylquinolin-6-amine (0.200 g, 1.26 mmol) in MeOH (10 mL) and MeCN (6.6 mL). The reaction mixture was vacuum flushed with N2 (3×) followed by H2 (3×) and then shaken at RT under 20 psi H2 for 4 h. The reaction mixture was filtered through celite, concentrated and purified by flash silica chromatography (12 g SiO2, 0-35% EtOAc/hexanes) to yield N-ethyl-2-methylquinolin-6-amine (192 mg) as brown solid.
2M HCl (0.5 mL, 1 mmol) in dioxane was added to (S)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (49 mg, 0.12 mmol) and the reaction was stirred 3 h at r.t and then concentrated. The residue was dissolved into acetonitrile (0.5 mL) and treated with diisopropylethylamine (0.054 mL, 0.31 mmol) and then benzenesulfonyl isocyanate (33.8 mg, 0.184 mmol) (exothermic reaction observed). The reaction was stirred 3 h, diluted with MeOH (0.5 mL) and then concentrated. The residue was partitioned between water (1.5 mL) and EtOAc (3×1 mL). The combined organic component was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to afford the title compound (45.9 mg). 1H NMR (600 MHZ, DMSO-d6) δ 7.79 (d, J=7.7 Hz, 2H), 7.71-7.62 (m, 1H), 7.61-7.52 (m, 2H), 7.20-1.14 (m, 3H), 6.90 (d, J=8.1 Hz, 1H), 6.80 (d, J=3.3 Hz, 2H), 6.69 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.7 Hz, 1H), 6.08 (s, 2H), 4.31 (d, J=6.2 Hz, 1H), 3.07 (s, 3H), 2.83-2.77 (m, 1H), 2.58-2.52 (m, 1H).
To a solution of (S)-2-amino-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide, TFA (40 mg, 0.097 mmol) in dichloromethane (2 mL) was added diisopropylethylamine (0.051 mL, 0.291 mmol) followed by a solution of 2-methylbenzenesulfonyl isocyanate (28.7 mg, 0.146 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by preparative HPLC to afford) of the title compound (34.4 mg. 1H NMR (500 MHZ, DMSO-d6) δ 7.74 (d, J=7.6 Hz, 1H), 7.48-7.01 (m, 7H), 6.87-6.81 (m, 3H), 6.73-6.17 (m, 2H), 6.06 (s, 2H), 4.26 (br. s., 1H), 3.05 (s, 3H), 2.94-2.62 (m, 2H), 2.51 (s, 3H).
To a solution of 3-chlorobenzenesulfonamide (100 mg, 0.522 mmol) in toluene (1 mL) was added 1-isocyanatobutane (5.05 mg, 0.051 mmol) followed by triphosgene (52.9 mg, 0.178 mmol). The reaction mixture was stirred at 110° C. for 24 hrs. The reaction mixture was allowed to cool and the solvent was evaporated to afford 3-chlorobenzenesulfonyl isocyanate which was used in the subsequent step without further purification. To a solution of (S)-2-amino-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide, TFA (30 mg, 0.073 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.04 mL, 0.22 mmol) followed by 3-chlorobenzenesulfonyl isocyanate (23.8 mg, 0.11 mmol) 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 preparative HPLC to afford the title compound (15.2 mg). 1H NMR (600 MHZ, DMSO-d6) δ 7.68 (br. s., 1H), 7.60 (d, J=7.3 Hz, 1H), 7.51-7.35 (m, 2H), 7.17-7.15 (m, 3H), 6.90-6.81 (m, 3H), 6.71-6.50 (m, 2H), 6.06-6.01 (m, 3H), 4.26 (br. s., 1H), 3.05 (s, 3H), 2.73-2.52 (m, 2H).
To a solution of 1-methylcyclopropane-1-sulfonamide (49.2 mg, 0.36 mmol) in toluene (1 mL) was added 1-isocyanatobutane (5.05 mg, 0.051 mmol) followed by triphosgene (34.5 mg, 0.12 mmol). The reaction mixture was stirred at 110° C. for 20 hrs. The reaction mixture (0.2 mL) was allowed to cool and then added to a solution of (S)-2-amino-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide, TFA (30 mg, 0.073 mmol) and diisopropylethylamine (0.04 mL, 0.22 mmol) in toluene (0.5 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by preparative HPLC to afford the title compound (22.4 mg). 1H NMR (500 MHZ, DMSO-d6) δ 7.35-7.13 (m, 3H), 7.05-6.86 (m, 3H), 6.82-6.60 (m, 3H), 6.11 (d, J=5.5 Hz, 2H), 4.45 (d, J=5.5 Hz, 1H), 3.11 (s, 3H), 2.96-2.55 (m, 2H), 1.34 (s, 3H), 1.27-1.11 (m, 2H), 0.91-0.69 (m, 2H).
Examples 5-7 were synthesized using the procedure described above for Example 2.
1H NMR (600 MHZ, DMSO-d6) δ 7.65 (d, J=7.7 Hz, 2H), 7.33 (d, J=7.3 Hz, 2H), 7.18-7.16 (m, 3H), 6.89 (d, J=8.1 Hz, 1H), 6.81 (br. s., 2H), 6.73-6.50 (m, 3H), 6.08 (s, 2H), 4.30 (d, J=5.5 Hz, 1H), 3.07 (s, 3H), 2.84-2.52 (m, 2H), 2.37 (s, 3H).
1H NMR (600 MHZ, DMSO-d6) δ 7.79 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 2H), 7.16-7.15 (m, 3H), 6.91 (d, J=8.1 Hz, 1H), 6.85-6.53 (m, 5H), 6.08 (s, 2H), 4.31 (d, J=5.5 Hz, 1H), 3.08 (s, 3H), 2.85-2.53 (m, 2H).
1H NMR (600 MHZ, DMSO-d6) δ 7.95 (d, J=4.4 Hz, 1H), 7.66 (br. s., 2H), 7.51 (br. s., 1H), 7.23-7.09 (m, 3H), 6.88 (d, J=8.1 Hz, 1H), 6.82 (d, J=6.6 Hz, 2H), 6.76-6.54 (m, 3H), 6.06 (s, 2H), 4.29 (d, J=5.5 Hz, 1H), 3.08 (s, 3H), 2.83-2.52 (m, 2H).
Examples 8-35 were synthesized using the procedure described above for Example 3.
1H NMR (400 MHZ, MeOH-d4) δ 7.79 (d, J=9.0 Hz, 2H), 7.26-7.18 (m, 3H), 7.04 (d, J=9.0 Hz, 2H), 6.92 (d, J=3.0 Hz, 2H), 6.74 (d, J=8.3 Hz, 1H), 6.37 (br.s., 2H), 6.00 (d, J=3.3 Hz, 2H), 4.55-4.44 (m, 1H), 3.88 (s, 3H), 3.13 (s, 3H), 2.97-2.62 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.95 (s, 1H), 7.81-7.55 (m, 2H), 7.46-7.02 (m, 5H), 6.94-6.74 (m, 3H), 6.72-6.37 (m, 3H), 6.06 (s, 2H), 4.28 (d, J=4.6 Hz, 1H), 3.06 (s, 3H), 2.82-2.51 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.35-7.31 (m, 3H), 7.26-7.22 (m, 3H), 7.16 (d, J=6.7 Hz, 2H), 6.98-6.92 (m, 1H), 6.87 (d, J=6.7 Hz, 2H), 6.78-6.61 (m, 2H), 6.58-6.51 (m, 1H), 6.06 (d, J=7.6 Hz, 2H), 4.49-4.44 (m, 3H), 3.10 (s, 3H), 2.90-2.54 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.95 (s, 1H), 7.80-7.53 (m, 3H), 7.21-7.06 (m, 3H), 6.95-6.76 (m, 3H), 6.73-6.15 (m, 2H), 6.07 (s, 2H), 4.25 (d, J=5.2 Hz, 1H), 3.05 (s, 3H), 2.93-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.00 (s, 1H), 7.73-7.55 (m, 2H), 7.16 (d, J=7.3 Hz, 3H), 6.91-6.82 (m, 3H), 6.72-6.48 (m, 2H), 6.39-6.13 (m, 1H), 6.06 (s, 2H), 4.27 (br. s., 1H), 3.06 (s, 3H), 2.96-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.62 (s, 1H), 7.38-7.07 (m, 5H), 6.93-6.74 (m, 3H), 6.71-6.48 (m, 3H), 6.06 (s, 2H), 4.28 (d, J=5.2 Hz, 1H), 3.07 (s, 3H), 2.81-2.47 (m, 2H), 2.45 (s, 3H), 2.31 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.91 (d, J=7.9 Hz, 1H), 7.82 (br. s., 1H), 7.66-7.48 (m, 2H), 7.17 (br. s., 3H), 6.89 (d, J=8.2 Hz, 1H), 6.85-6.63 (m, 4H), 6.60 (d, J=7.3 Hz, 1H), 6.07 (s, 2H), 4.30 (d, J=5.8 Hz, 1H), 3.08 (s, 3H), 2.81-2.49 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.92-7.79 (m, 2H), 7.46 (br. s., 1H), 7.20-7.06 (m, 3H), 6.88 (d, J=7.9 Hz, 1H), 6.82 (d, J=6.4 Hz, 2H), 6.76-6.39 (m, 3H), 6.06 (s, 2H), 4.28 (br. s., 1H), 3.08 (s, 3H), 2.82-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.50 (d, J=7.6 Hz, 1H), 7.41-7.25 (m, 2H), 7.22-7.06 (m, 3H), 6.88 (d, J=8.2 Hz, 1H), 6.83-6.27 (m, 5H), 6.06 (s, 2H), 4.28 (br. s., 1H), 3.06 (s, 3H), 2.78-2.48 (m, 2H), 2.46 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.06 (br. s., 1H), 7.93-7.68 (m, 3H), 7.12 (br. s., 3H), 6.88 (d, J=8.2 Hz, 1H), 6.83-6.40 (m, 5H), 6.06 (s, 2H), 4.29 (d, J=5.5 Hz, 1H), 3.06 (s, 3H), 2.77-2.48 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.71 (br. s., 1H), 7.42-6.99 (m, 6H), 6.92-6.77 (m, 3H), 6.73-6.39 (m, 2H), 6.06 (s, 2H), 4.26 (br. s., 1H), 3.06 (s, 3H), 2.74-2.48 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.87 (br. s., 1H), 7.71 (d, J=8.2 Hz, 2H), 7.44 (br. s., 1H), 7.21-7.09 (m, 3H), 6.93-6.78 (m, 3H), 6.74-6.26 (m, 3H), 6.07 (s, 2H), 4.27 (d, J=6.4 Hz, 1H), 3.06 (s, 3H), 2.75-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.41 (d, J=8.1 Hz, 1H), 7.36-7.25 (m, 2H), 7.16 (m, 5H), 6.92-6.78 (m, 3H), 6.72-6.46 (m, 2H), 6.08 (s, 2H), 4.30 (d, J=5.9 Hz, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.77-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.22 (d, J=7.6 Hz, 2H), 7.90 (d, J=7.9 Hz, 2H), 7.22-7.05 (m, 3H), 6.95-6.75 (m, 3H), 6.74-6.50 (m, 2H), 6.11 (br. s., 1H), 6.05 (s, 2H), 4.24 (br. s., 1H), 3.04 (s, 3H), 2.70-2.52 (m, 2H).
1H NMR (400 MHZ, MeOH-d4) δ 7.89 (dd, J=8.6, 5.1 Hz, 2H), 7.33-7.11 (m, 6H), 6.91 (br. s., 2H), 6.73 (d, J=8.3 Hz, 1H), 6.59-6.17 (m, 2H), 5.99 (d, J=2.7 Hz, 2H), 4.57-4.40 (m, 1H), 3.11 (s, 3H), 2.93-2.64 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.85 (d, J=7.7 Hz, 1H), 7.69-7.42 (m, 3H), 7.36-7.08 (m, 3H), 6.99-6.80 (m, 3H), 6.64-6.41 (m, 3H), 6.06 (s, 2H), 4.30 (br. s., 1H), 3.78 (s, 3H), 3.06 (s, 3H), 2.81-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.40-7.08 (m, 9H), 7.00-6.84 (m, 3H), 6.81-6.31 (m, 2H), 6.09 (s, 2H), 4.39 (br. s., 1H), 3.10 (s, 3H), 2.88-2.82 (m, 4H), 2.61-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.33-7.25 (m, 3H), 7.24-7.14 (m, 6H), 6.96 (d, J=8.1 Hz, 1H), 6.90 (d, J=6.6 Hz, 2H), 6.80-6.60 (m, 2H), 6.11 (s, 2H), 4.41 (d, J=5.5 Hz, 1H), 3.23-3.15 (m, 2H), 3.11 (s, 3H), 2.87 (dd, J=13.6, 4.8 Hz, 1H), 2.68-2.54 (m, 3H), 1.91-1.79 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.78-7.42 (m, 3H), 7.22-7.11 (m, 3H), 6.90 (d, J=7.7 Hz, 1H), 6.83 (d, J=5.1 Hz, 2H), 6.76-6.17 (m, 2H), 6.08 (s, 2H), 4.27 (d, J=5.1 Hz, 1H), 3.07 (s, 3H), 2.80-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.17 (br. s., 4H), 6.97-6.80 (m, 3H), 6.76-6.53 (m, 3H), 6.22 (br. s., 1H), 6.08 (s, 2H), 4.32 (d, J=4.8 Hz, 1H), 3.07 (s, 3H), 2.82-2.53 (m, 2H), 2.43 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.30 (br. s., 1H), 7.20-7.03 (m, 4H), 6.88 (d, J=8.1 Hz, 1H), 6.79 (d, J=6.6 Hz, 2H), 6.73-6.31 (m, 2H), 6.06 (s, 2H), 4.26 (br. s., 1H), 3.06 (s, 3H), 2.80-2.55 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.94 (d, J=7.7 Hz, 1H), 7.77 (d, J=6.2 Hz, 1H), 7.48 (br. s., 2H), 7.34-7.09 (m, 3H), 6.85 (dd, J=13.0, 7.5 Hz, 3H), 6.72-6.46 (m, 3H), 6.06 (s, 2H), 4.28 (d, J=4.8 Hz, 1H), 3.07 (s, 3H), 2.81-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.30-7.10 (m, 7H), 6.92-6.77 (m, 3H), 6.75-6.47 (m, 3H), 6.07 (s, 2H), 4.29 (d, J=4.8 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.06 (s, 3H), 2.85-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.85 (br. s., 1H), 7.52 (br. s., 1H), 7.31-7.00 (m, 4H), 6.97-6.77 (m, 3H), 6.74-6.41 (m, 3H), 6.08 (s, 2H), 4.35 (d, J=6.1 Hz, 1H), 3.08 (s, 3H), 2.84-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.25-7.08 (m, 4H), 6.91 (d, J=7.9 Hz, 1H), 6.85 (d, J=6.7 Hz, 2H), 6.77-6.41 (m, 2H), 6.08 (s, 2H), 4.32 (d, J=5.2 Hz, 1H), 3.08 (s, 3H), 2.84-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.18 (br. s., 3H), 6.91 (d, J=7.9 Hz, 1H), 6.84 (d, J=5.2 Hz, 2H), 6.77-6.38 (m, 3H), 6.08 (s, 2H), 4.31 (d, J=5.8 Hz, 1H), 3.74 (s, 3H), 3.08 (s, 3H), 2.84-2.53 (m, 2H), 2.24 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.69 (br. s., 1H), 7.51 (br. s., 1H), 7.36 (d, J=8.1 Hz, 1H), 7.30-7.00 (m, 6H), 6.95-6.77 (m, 2H), 6.30 (br. s., 1H), 4.20 (br. s., 1H), 3.08 (s, 3H), 2.77-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.69 (br. s., 1H), 7.55 (br. s., 1H), 7.41 (d, J=8.4 Hz, 1H), 7.36 (br. s., 1H), 7.24 (d, J=7.7 Hz, 2H), 7.10 (br. s., 1H), 6.99 (br. s., 1H), 6.58-6.29 (m, 3H), 4.23 (d, J=5.5 Hz, 1H), 3.11 (s, 3H), 2.83-2.56 (m, 2H).
Examples 36-41 were synthesized using the procedure described above for Example 2.
1H NMR (500 MHZ, DMSO-d6) δ 7.80 (d, J=7.3 Hz, 2H), 7.67-7.50 (m, 3H), 7.41 (d, J=8.4 Hz, 1H), 7.28-7.01 (m, 4H), 6.99-6.63 (m, 4H), 4.23 (d, J=7.3 Hz, 1H), 3.09 (s, 3H), 2.84-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.81 (d, J=7.7 Hz, 1H), 7.60-7.48 (m, 1H), 7.44-7.31 (m, 3H), 7.24-7.06 (m, 4H), 6.95 (d, J=8.1 Hz, 1H), 6.81 (d, J=3.7 Hz, 2H), 6.68 (d, J=7.7 Hz, 1H), 4.23 (d, J=6.6 Hz, 1H), 3.10 (s, 3H), 2.85-2.55 (m, 2H), 2.53 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.89 (d, J=6.6 Hz, 1H), 7.50 (br. s., 2H), 7.43-7.00 (m, 8H), 6.96-6.77 (m, 2H), 6.48-6.22 (m, 1H), 4.20 (br. s., 1H), 3.08 (s, 3H), 2.79-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.88 (d, J=7.0 Hz, 1H), 7.58-7.18 (m, 5H), 7.16-6.89 (m, 2H), 6.51 (br. s., 3H), 4.25 (br. s., 1H), 3.12 (s, 3H), 2.83-2.57 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=7.0 Hz, 1H), 7.49-7.34 (m, 3H), 7.29 (d, J=5.9 Hz, 2H), 7.17-6.90 (m, 2H), 6.64-6.38 (m, 3H), 4.24 (br. s., 1H), 3.12 (s, 3H), 2.85-2.55 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.80 (d, J=7.7 Hz, 2H), 7.70-7.62 (m, 1H), 7.60-7.51 (m, 2H), 7.45 (d, J=8.4 Hz, 1H), 7.39 (br. s., 1H), 7.11 (d, J=8.4 Hz, 1H), 7.01 (t, J=8.8 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 6.51 (d, J=7.0 Hz, 2H), 4.28 (d, J=5.5 Hz, 1H), 3.13 (s, 3H), 2.87-2.58 (m, 2H).
Examples 42-46 were synthesized using the procedure described above for Example 4.
1H NMR (500 MHZ, DMSO-d6) δ 7.29-7.14 (m, 3H), 6.96 (d, J=8.2 Hz, 1H), 6.90 (d, J=7.0 Hz, 2H), 6.80-6.59 (m, 3H), 6.10 (d, J=3.4 Hz, 2H), 4.42 (d, J=5.8 Hz, 1H), 3.10 (s, 3H), 2.87-2.54 (m, 3H), 1.04-0.89 (m, 4H).
1H NMR (500 MHZ, DMSO-d6) δ 7.25-7.20 (m, 3H), 6.97 (d, J=8.2 Hz, 1H), 6.90 (d, J=7.0 Hz, 2H), 6.83-6.58 (m, 3H), 6.11 (s, 2H), 4.43 (d, J=5.5 Hz, 1H), 3.11 (s, 3H), 2.88-2.55 (m, 3H), 1.27-1.07 (m, 6H).
1H NMR (500 MHZ, DMSO-d6) δ 7.31-7.15 (m, 3H), 6.97 (d, J=8.2 Hz, 1H), 6.91 (d, J=7.0 Hz, 2H), 6.81-6.56 (m, 3H), 6.11 (d, J=2.1 Hz, 2H), 4.42 (d, J=5.8 Hz, 1H), 3.11 (s, 3H), 3.08 (s, 3H), 2.89-2.55 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (s, 1H), 7.01-6.96 (m, 3H), 6.73 (d, J=7.9 Hz, 1H), 6.66 (d, J=7.0 Hz, 2H), 6.58-6.31 (m, 3H), 5.87 (d, J=4.0 Hz, 2H), 4.19 (d, J=4.9 Hz, 1H), 2.87 (s, 3H), 2.70-2.30 (m, 4H), 1.74 (dt, J=13.0, 6.4 Hz, 1H), 0.71 (dd, J=17.5, 6.6 Hz, 6H).
1H NMR (500 MHZ, DMSO-d6) δ 7.34-7.13 (m, 3H), 6.95 (d, J=7.9 Hz, 1H), 6.91-6.81 (m, 3H), 6.77-6.60 (m, 2H), 6.10 (d, J=4.9 Hz, 2H), 4.44 (d, J=5.5 Hz, 1H), 3.09 (s, 3H), 2.94-2.54 (m, 2H), 1.21 (s, 9H).
To a solution of (S)—N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-bromophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide (30 mg, 0.054 mmol) in acetonitrile (1 mL) was added K2CO3 (74.0 mg, 0.535 mmol) followed by iodomethane (76 mg, 0.535 mmol). The reaction mixture was stirred at r.t. for 20 hrs. The solvent was filtered and evaporated and the residue was purified by preparative HPLC to afford the title compound (15.7 mg). 1H NMR (500 MHZ, DMSO-d6) δ 8.05-7.95 (m, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.66-7.56 (m, 2H), 7.53 (d, J=7.3 Hz, 1H), 7.27-7.12 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 6.83 (d, J=6.2 Hz, 2H), 6.73-6.66 (m, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.08 (s, 2H), 4.35 (d, J=3.7 Hz, 1H), 3.16 (s, 3H), 3.09 (s, 3H), 2.94-2.66 (m, 2H).
To a 0.5-2 mL microwave tube was added (S)—N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-bromophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide (17 mg, 0.030 mmol), phenylboronic acid (7.40 mg, 0.061 mmol), Pd(PPh3)4 (3.51 mg, 3.03 μmol) and DMF (1 mL), followed by 2M aq. Na2CO3 (50 μl). The reaction mixture was heated in a microwave reactor at 125° C. for 15 min. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford of the title compound (8.8 mg). 1H NMR (500 MHZ, DMSO-d6) δ 7.91 (d, J=7.0 Hz, 1H), 7.56-7.10 (m, 12H), 6.87 (d, J=6.2 Hz, 3H), 6.70-6.49 (m, 2H), 6.20-6.11 (m, 1H), 6.07 (s, 2H), 4.29 (br. s., 1H), 3.06 (s, 3H), 2.80-2.53 (m, 2H).
Examples 49-50 were synthesized using the procedure described above for Example 48.
1H NMR (500 MHZ, DMSO-d6) δ 8.00 (br. s., 1H), 7.89 (d, J=7.7 Hz, 1H), 7.62 (br. s., 1H), 7.52 (br. s., 1H), 7.38 (d, J=7.7 Hz, 2H), 7.17 (br. s., 3H), 6.92-6.78 (m, 3H), 6.69-6.29 (m, 3H), 6.06 (s, 2H), 4.27 (br. s., 1H), 3.88 (s, 3H), 3.06 (s, 3H), 2.73-2.47 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.93 (d, J=7.7 Hz, 1H), 7.81-7.61 (m, 3H), 7.52 (t, J=7.3 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.27-7.11 (m, 3H), 6.90 (d, J=8.1 Hz, 1H), 6.83 (d, J=5.5 Hz, 2H), 6.69-6.48 (m, 4H), 6.07 (s, 2H), 4.28 (d, J=5.9 Hz, 1H), 3.07 (s, 3H), 2.84-2.43 (m, 2H).
Examples 51-85 were synthesized using the procedure described above for Example 2.
1H NMR (500 MHZ, DMSO-d6) δ 7.74 (d, J=7.7 Hz, 1H), 7.54-7.08 (m, 5H), 6.98-6.59 (m, 5H), 6.52-6.31 (m, 1H), 6.07 (s, 2H), 4.27 (br. s., 1H), 3.07 (s, 3H), 2.73-2.54 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=8.1 Hz, 1H), 7.42 (br. s., 1H), 7.29 (br. s., 2H), 6.87 (d, J=8.1 Hz, 1H), 6.76-6.26 (m, 6H), 6.07 (s, 2H), 4.22 (br. s., 1H), 3.96 (q, J=6.7 Hz, 2H), 3.06 (s, 3H), 2.72-2.35 (m, 5H), 1.31 (t, J=6.6 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.74 (d, J=7.7 Hz, 1H), 7.43 (br. s., 1H), 7.29 (d, J=7.0 Hz, 2H), 7.10-7.04 (m, 1H), 7.03-6.96 (m, 2H), 6.80 (t, J=8.4 Hz, 2H), 6.40 (br. s., 2H), 6.04 (d, J=5.5 Hz, 2H), 4.38 (d, J=6.6 Hz, 1H), 3.02 (s, 3H), 2.77-2.48 (m, 5H), 1.82 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (d, J=7.7 Hz, 1H), 7.40 (br. s., 1H), 7.32-7.08 (m, 6H), 7.01 (br. s., 1H), 6.84 (d, J=7.3 Hz, 1H), 6.73-6.27 (m, 2H), 6.04 (d, J=7.0 Hz, 2H), 4.51 (br. s., 1H), 3.06 (s, 3H), 2.89-2.60 (m, 2H), 2.50 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.74 (d, J=7.0 Hz, 1H), 7.44-7.32 (m, 1H), 7.31-7.12 (m, 4H), 6.89 (d, J=8.4 Hz, 1H), 6.85-6.25 (m, 4H), 6.07 (d, J=5.9 Hz, 2H), 4.32-4.17 (m, 1H), 3.07 (s, 3H), 2.75-2.48 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77-7.69 (m, 1H), 7.45-7.17 (m, 3H), 6.90-6.83 (m, 1H), 6.71 (s, 4H), 6.66-6.31 (m, 2H), 6.04 (s, 2H), 4.29-4.12 (m, 1H), 3.69 (s, 3H), 3.04 (s, 3H), 2.71-2.35 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (d, J=7.7 Hz, 1H), 7.49-7.07 (m, 5H), 6.87 (d, J=7.7 Hz, 1H), 6.80-6.34 (m, 4H), 6.06 (s, 2H), 4.26 (br. s., 1H), 3.06 (s, 3H), 2.79-2.34 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=7.3 Hz, 1H), 7.54-7.25 (m, 3H), 6.89 (d, J=8.4 Hz, 1H), 6.78-6.66 (m, 5H), 6.63-6.45 (m, 2H), 6.13-5.96 (m, 3H), 5.45-5.17 (m, 2H), 4.51 (d, J=5.1 Hz, 2H), 4.24 (d, J=5.1 Hz, 1H), 3.07 (s, 3H), 2.78-2.38 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.73 (d, J=7.7 Hz, 1H), 7.51-7.06 (m, 5H), 7.00 (br. s., 1H), 6.90 (d, J=8.1 Hz, 1H), 6.85-6.66 (m, 3H), 6.42 (br. s., 1H), 6.08 (d, J=7.7 Hz, 2H), 4.29 (br. s., 1H), 3.08 (s, 3H), 2.79-2.46 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=8.1 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.40-7.29 (m, 2H), 7.24-7.13 (m, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.86 (s, 1H), 6.82-6.47 (m, 4H), 6.08 (d, J=7.3 Hz, 2H), 4.31 (d, J=4.0 Hz, 1H), 3.09 (s, 3H), 2.84-2.45 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.3 Hz, 1H), 7.55-7.42 (m, 3H), 7.38-7.26 (m, 2H), 7.00 (d, J=7.7 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 6.83-6.55 (m, 3H), 6.08 (d, J=2.6 Hz, 2H), 4.34 (d, J=4.8 Hz, 1H), 3.09 (s, 3H), 2.92-2.57 (m, 2H), 2.50 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.71 (d, J=7.7 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.45-7.04 (m, 6H), 6.89 (d, J=8.1 Hz, 1H), 6.79-6.28 (m, 2H), 6.06 (d, J=8.1 Hz, 2H), 4.28 (br. s., 1H), 3.06 (br. s., 3H), 2.83-2.55 (m, 2H), 2.48 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.75-7.51 (m, 3H), 7.41-7.07 (m, 3H), 6.98 (d, J=5.1 Hz, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.78-6.17 (m, 2H), 6.06 (br. s., 2H), 4.29 (br. s., 1H), 3.06 (s, 3H), 2.84-2.56 (m, 2H), 2.48 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (dd, J=19.6, 7.5 Hz, 2H), 7.42-7.04 (m, 6H), 6.91-6.24 (m, 3H), 6.05 (d, J=10.6 Hz, 2H), 4.27 (br. s., 1H), 3.83 (s, 3H), 3.05 (s, 3H), 2.85-2.54 (m, 2H), 2.47 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.71 (d, J=8.1 Hz, 1H), 7.41 (br. s., 1H), 7.33-7.10 (m, 6H), 6.94 (d, J=6.6 Hz, 2H), 6.90-6.57 (m, 3H), 6.08 (s, 2H), 4.45 (br. s., 1H), 3.08 (s, 3H), 2.85 (t, J=7.0 Hz, 1H), 2.51 (s, 3H), 0.94 (d, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.71 (br. s., 2H), 7.54-7.03 (m, 7H), 6.99-6.78 (m, 1H), 6.64 (br. s., 2H), 6.07 (s, 2H), 4.33 (br. s., 1H), 3.08 (s, 3H), 2.90-2.62 (m, 2H), 2.48 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.73 (d, J=7.7 Hz, 1H), 7.37 (br. s., 1H), 7.23 (br. s., 2H), 7.04-6.80 (m, 3H), 6.78-6.65 (m, 1H), 6.48 (d, J=7.0 Hz, 2H), 6.36 (br. s., 1H), 6.07 (d, J=6.6 Hz, 2H), 4.29 (br. s., 1H), 3.08 (s, 3H), 2.82-2.54 (m, 2H), 2.49 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=7.3 Hz, 1H), 7.53-7.22 (m, 8H), 6.90-6.77 (m, 3H), 6.71 (d, J=8.4 Hz, 3H), 6.62-6.39 (m, 2H), 6.07 (s, 2H), 5.05 (s, 2H), 4.24 (br. s., 1H), 3.06 (s, 3H), 2.75-2.35 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=6.6 Hz, 1H), 7.62 (d, J=7.3 Hz, 2H), 7.46 (d, J=7.3 Hz, 4H), 7.41-7.18 (m, 4H), 6.90 (d, J=7.0 Hz, 3H), 6.79-6.38 (m, 3H), 6.08 (s, 2H), 4.32 (br. s., 1H), 3.09 (s, 3H), 2.86-2.42 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.73 (d, J=7.7 Hz, 1H), 7.41 (br. s., 1H), 7.33-7.16 (m, 3H), 7.05-6.95 (m, 2H), 6.94-6.81 (m, 2H), 6.77-6.25 (m, 3H), 6.07 (s, 2H), 4.37 (br. s., 1H), 3.06 (s, 3H), 2.80-2.54 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (d, J=7.7 Hz, 1H), 7.50 (br. s., 1H), 7.39 (t, J=7.7 Hz, 1H), 7.34 (br. s., 1H), 7.27-7.02 (m, 5H), 6.86 (d, J=8.1 Hz, 1H), 6.78-6.24 (m, 2H), 6.13-5.94 (m, 2H), 4.34-4.18 (m, 1H), 3.06 (s, 3H), 2.85-2.59 (m, 2H), 2.49 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.7 Hz, 1H), 7.46 (d, J=7.0 Hz, 1H), 7.37-7.24 (m, 2H), 6.96 (d, J=7.7 Hz, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.74-6.39 (m, 5H), 6.07 (s, 2H), 4.25 (d, J=5.9 Hz, 1H), 3.06 (s, 3H), 2.77-2.39 (m, 5H), 2.23 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 9.86 (br. s., 1H), 7.71 (d, J=7.7 Hz, 1H), 7.38-7.34 (m, 3H), 7.21 (br. s., 2H), 6.84 (d, J=8.1 Hz, 1H), 6.77-6.15 (m, 4H), 6.03 (s, 2H), 4.21 (br. s., 1H), 3.03 (s, 3H), 2.65-2.41 (m, 5H), 2.01 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.2 Hz, 1H), 7.39-7.26 (m, 3H), 7.18 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.83-6.52 (m, 3H), 6.06 (d, J=8.8 Hz, 2H), 4.53 (d, J=4.4 Hz, 1H), 3.10 (s, 3H), 2.92-2.56 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.73 (d, J=7.7 Hz, 1H), 7.54-7.43 (m, 1H), 7.38-7.17 (m, 3H), 7.03-6.46 (m, 5H), 6.08 (d, J=7.0 Hz, 2H), 4.41 (d, J=4.0 Hz, 1H), 3.11 (s, 3H), 2.87-2.52 (m, 2H), 2.49 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.70 (d, J=7.3 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.38-7.29 (m, 1H), 7.20 (br. s., 3H), 7.12 (d, J=7.3 Hz, 1H), 6.77 (br. s., 4H), 6.01 (d, J=8.8 Hz, 2H), 4.54-4.38 (m, 1H), 3.02 (s, 3H), 2.81-2.66 (m, 2H), 2.49 (br. s., 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.74-7.59 (m, 2H), 7.53-7.30 (m, 3H), 7.28-7.13 (m, 2H), 7.00-6.78 (m, 2H), 6.71 (br. s., 2H), 6.21-6.09 (m, 1H), 6.04 (d, J=8.4 Hz, 2H), 4.54-4.39 (m, 1H), 3.05 (s, 3H), 2.93-2.74 (m, 2H), 2.49 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (d, J=7.7 Hz, 1H), 7.48-7.01 (m, 4H), 6.86 (d, J=8.1 Hz, 1H), 6.77-6.53 (m, 2H), 6.42 (d, J=7.3 Hz, 1H), 6.32 (br. s., 2H), 6.03 (s, 2H), 4.24 (br. s., 1H), 3.63 (s, 3H), 3.05 (s, 3H), 2.78-2.34 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.65 (d, J=7.7 Hz, 1H), 7.48-7.33 (m, 1H), 7.30-7.15 (m, 5H), 7.07 (br. s., 2H), 6.79-6.48 (m, 3H), 5.98 (d, J=17.2 Hz, 2H), 3.01 (s, 3H), 2.81-2.62 (m, 1H), 2.37 (s, 3H), 1.99-1.92 (m, 1H), 1.19-1.07 (m, 1H).
1H NMR (500 MHZ, DMSO-d6) δ 7.93-7.55 (m, 3H), 7.47-7.04 (m, 6H), 6.93 (d, J=7.3 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.67-6.18 (m, 2H), 6.04 (d, J=9.9 Hz, 2H), 4.28 (br. s., 1H), 3.04 (s, 3H), 2.83-2.37 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.75-7.66 (m, 1H), 7.47 (s, 8H), 6.91-6.82 (m, 1H), 6.81-6.30 (m, 2H), 6.05 (d, J=6.6 Hz, 2H), 3.62 (br. s., 4H), 3.07 (br. s., 3H), 2.87-2.61 (m, 6H), 2.50-2.35 (m, 4H).
1H NMR (500 MHZ, DMSO-d6) δ 7.72 (d, J=7.7 Hz, 1H), 7.47-7.09 (m, 3H), 6.84 (d, J=8.1 Hz, 1H), 6.71-6.48 (m, 5H), 6.32-6.16 (m, 1H), 6.04 (s, 2H), 4.28-4.10 (m, 1H), 3.04 (s, 3H), 2.68-2.30 (m, 5H).
1H NMR (500 MHZ, DMSO-d6) δ 7.84 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.67 (br. s., 1H), 7.48-7.08 (m, 8H), 6.75-6.20 (m, 3H), 6.07-5.89 (m, 2H), 4.57 (br. s., 1H), 3.00 (br. s., 4H), 2.48 (s, 3H), 2.37 (br. s., 1H).
1H NMR (400 MHZ, MeOH-d4) δ 7.95 (d, J=7.6 Hz, 1H), 7.54-7.41 (m, 1H), 7.39-7.27 (m, 2H), 7.25-7.12 (m, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.73 (dd, J=13.1, 7.9 Hz, 2H), 6.63 (d, J=9.8 Hz, 1H), 6.50-6.23 (m, 2H), 6.00 (s, 2H), 4.57-4.43 (m, 1H), 3.13 (s, 3H), 2.95-2.57 (m, 5H).
Example 86 was synthesized using the procedure described above for Example 2 starting from (R)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate.
1H NMR (500 MHZ, DMSO-d6) δ 7.66 (dd, J=7.8, 1.5 Hz, 2H), 7.36-7.31 (m, 3H), 7.23-7.10 (m, 4H), 6.93-6.76 (m, 4H), 6.64-6.56 (m, 2H), 6.06-5.98 (m, 2H), 4.27 (br. s., 1H), 3.05 (br. s., 3H), 2.76-2.51 (m, 2H)
To a solution of (S)-tert-butyl (1 methyl(phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, TFA (12.7 mg, 0.050 mmol) in dichloromethane (2 mL) was added diisopropylethylamine (0.026 mL, 0.15 mmol) followed by a solution of 2-methylbenzenesulfonyl isocyanate (13.7 mg, 0.075 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was purified by preparative HPLC to afford the title compound (16.9 mg).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=6.6 Hz, 2H), 7.64-7.33 (m, 6H), 7.14 (br. s., 5H), 6.72 (br. s., 2H), 6.58 (br. s., 1H), 4.29 (br. s., 1H), 3.13 (s, 3H), 2.73 (d, J=6.2 Hz, 2H).
Examples 88-97 were synthesized using the procedure described above for Example 87.
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=6.2 Hz, 2H), 7.60 (d, J=6.2 Hz, 1H), 7.54 (d, J=7.0 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.23-7.05 (m, 5H), 6.79 (br. s., 2H), 6.63 (br. s., 1H), 4.24 (br. s., 1H), 3.09 (s, 3H), 2.81-2.64 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=7.0 Hz, 2H), 7.62-7.43 (m, 3H), 7.28 (t, J=7.9 Hz, 1H), 7.15 (br. s., 3H), 6.92 (d, J=7.3 Hz, 1H), 6.77 (br. s., 3H), 6.66-6.46 (m, 2H), 4.34 (br. s., 1H), 3.70 (s, 3H), 3.11 (s, 3H), 2.81-2.68 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.79 (d, J=7.7 Hz, 2H), 7.70-7.47 (m, 3H), 7.32-7.23 (m, 1H), 7.17 (br. s., 4H), 6.91-6.72 (m, 4H), 6.66 (d, J=7.0 Hz, 1H), 4.27 (br. s., 4H), 3.09 (s, 3H), 2.81-2.68 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.7 Hz, 2H), 7.68-7.48 (m, 3H), 7.30-7.04 (m, 7H), 6.77 (br. s., 2H), 6.64 (d, J=6.6 Hz, 1H), 4.22 (d, J=5.5 Hz, 1H), 3.10 (s, 3H), 2.82-2.67 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.7 Hz, 2H), 7.67-7.50 (m, 3H), 7.15 (d, J=2.9 Hz, 3H), 7.07-6.89 (m, 4H), 6.76 (br. s., 2H), 6.63 (d, J=7.7 Hz, 1H), 4.27 (br. s., 1H), 3.78 (s, 3H), 3.09 (s, 3H), 2.81-2.66 (m, 2H).
1H NMR (400 MHZ, MeOH-d4) δ 7.88 (d, J=7.6 Hz, 2H), 7.65-7.46 (m, 3H), 7.39-7.29 (m, 1H), 7.26-7.17 (m, 3H), 7.09 (br. s., 1H), 6.90 (d, J=5.1 Hz, 2H), 6.81-6.74 (m, 1H), 6.59-6.46 (m, 1H), 4.47 (br. s., 1H), 3.16 (s, 3H), 2.96-2.63 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.09-7.76 (m, 3H), 7.68 (br. s., 3H), 7.58 (br. s., 2H), 7.50-7.35 (m, 3H), 7.32-7.18 (m, 2H), 7.14-7.03 (m, 2H), 6.61 (d, J=7.0 Hz, 1H), 6.51 (d, J=7.0 Hz, 1H), 4.19 (d, J=4.8 Hz, 1H), 3.23-3.08 (m, 3H), 2.86 (br. s., 2H).
1H NMR (400 MHZ, MeOH-d4) δ 8.07-7.88 (m, 4H), 7.63-7.43 (m, 3H), 7.31-6.92 (m, 7H), 4.60-4.31 (m, 3H), 3.22-2.90 (m, 2H), 2.80 (s, 3H), 2.67 (s, 3H).
Examples 98-120 were synthesized using the procedure described above for Example 3.
1H NMR (500 MHZ, DMSO-d6) δ 7.41 (br. s., 1H), 7.31-7.09 (m, 4H), 7.07-6.78 (m, 5H), 6.73-6.42 (m, 2H), 6.05 (s, 2H), 4.27 (br. s., 1H), 3.18 (s, 3H), 2.73-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.49-7.09 (m, 7H), 6.92-6.78 (m, 3H), 6.73-6.52 (m, 2H), 6.06 (s, 2H), 4.26 (br. s., 1H), 3.06 (s, 3H), 2.79-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.68-7.41 (m, 3H), 7.17 (d, J=7.3 Hz, 4H), 6.96-6.79 (m, 3H), 6.75-6.47 (m, 2H), 6.07 (s, 2H), 4.30 (br. s., 1H), 3.08 (s, 3H), 2.79-2.53 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.46 (d, J=8.4 Hz, 1H), 7.38-7.14 (m, 7H), 7.02-6.88 (m, 3H), 6.82-6.57 (m, 2H), 6.11 (s, 2H), 4.72-4.46 (m, 3H), 3.11 (s, 3H), 2.89-2.56 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.60-7.42 (m, 2H), 7.32-7.11 (m, 4H), 7.03-6.85 (m, 3H), 6.83-6.58 (m, 2H), 6.10 (s, 2H), 4.51-4.26 (m, 3H), 3.11 (s, 3H), 2.85-2.55 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.49-7.07 (m, 7H), 7.02-6.84 (m, 3H), 6.68-6.26 (m, 3H), 6.11 (s, 2H), 4.48 (br. s., 3H), 3.11 (s, 3H), 2.88-2.56 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.35-7.04 (m, 8H), 7.01-6.86 (m, 3H), 6.83-6.60 (m, 2H), 6.11 (s, 2H), 4.58-4.38 (m, 3H), 3.12 (s, 3H), 2.89-2.56 (m, 2H), 2.31 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.64 (d, J=6.6 Hz, 2H), 7.41 (d, J=7.7 Hz, 2H), 7.27-7.21 (m, 3H), 7.03-6.64 (m, 5H), 6.11 (br. s., 2H), 4.64-4.36 (m, 3H), 3.13 (s, 3H), 2.87-2.54 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.31-7.16 (m, 3H), 7.00-6.83 (m, 3H), 6.80-6.52 (m, 3H), 6.10 (s, 2H), 4.43 (br. s., 1H), 3.09 (s, 3H), 2.89-2.56 (m, 2H), 1.28-1.00 (m, 3H), 0.96-0.74 (m, 8H).
1H NMR (500 MHZ, DMSO-d6) δ 7.34-7.16 (m, 6H), 7.13 (d, J=7.0 Hz, 2H), 7.00-6.85 (m, 3H), 6.81-6.55 (m, 3H), 6.11 (d, J=4.8 Hz, 2H), 4.45 (d, J=5.9 Hz, 1H), 3.22-3.06 (m, 5H), 2.89-2.55 (m, 2H), 1.34-1.11 (m, 2H), 0.57 (br. s., 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.69 (d, J=8.8 Hz, 1H), 7.62-7.52 (m, 1H), 7.18 (d, J=7.0 Hz, 4H), 7.04 (t, J=7.3 Hz, 1H), 6.91-6.77 (m, 3H), 6.70-6.45 (m, 3H), 6.06 (s, 2H), 4.28 (d, J=5.9 Hz, 1H), 3.81 (s, 3H), 3.06 (s, 3H), 2.85-2.45 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.40 (d, J=8.4 Hz, 2H), 7.33-7.15 (m, 5H), 7.00 (d, J=8.1 Hz, 1H), 6.92 (d, J=7.0 Hz, 2H), 6.85-6.49 (m, 3H), 6.13 (d, J=5.1 Hz, 2H), 4.64-4.44 (m, 3H), 3.14 (s, 3H), 2.95-2.56 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.23 (d, J=5.9 Hz, 6H), 7.10 (br. s., 2H), 7.01-6.87 (m, 3H), 6.85-6.61 (m, 2H), 6.11 (s, 2H), 4.52-4.26 (m, 3H), 3.12 (s, 3H), 2.87-2.55 (m, 2H).
1H NMR (400 MHZ, MeOH-d4) δ 7.31-7.20 (m, 3H), 6.97 (dd, J=7.3, 2.0 Hz, 2H), 6.84 (d, J=8.3 Hz, 1H), 6.59 (d, J=9.8 Hz, 2H), 6.04 (s, 2H), 4.61 (br. s., 1H), 3.33 (dt, J=3.2, 1.7 Hz, 1H), 3.19 (s, 3H), 2.73 (dd, J=13.4, 8.3 Hz, 2H), 2.09-1.17 (m, 10H).
1H NMR (500 MHZ, DMSO-d6) δ 7.90 (br. s., 1H), 7.85-7.68 (m, 2H), 7.48 (t, J=8.3 Hz, 1H), 7.15 (d, J=2.2 Hz, 3H), 6.93 (br. s., 4H), 6.80 (br. s., 2H), 6.48 (br. s., 1H), 4.17 (d, J=6.6 Hz, 1H), 3.79 (s, 3H), 3.67-3.41 (m, 2H), 2.80-2.45 (m, 2H), 0.95 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.06-7.95 (m, 2H), 7.91 (t, J=7.2 Hz, 1H), 7.85-7.78 (m, 1H), 7.18-7.07 (m, 3H), 7.04-6.90 (m, 4H), 6.89-6.73 (m, 3H), 4.26-4.15 (m, 1H), 3.79 (s, 3H), 3.68-3.43 (m, 2H), 2.83-2.44 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.93 (d, J=7.7 Hz, 1H), 7.80-7.73 (m, 1H), 7.69 (d, J=5.1 Hz, 2H), 7.17-7.09 (m, 3H), 7.03-6.85 (m, 5H), 6.80 (d, J=3.3 Hz, 2H), 4.24-4.13 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.67-3.44 (m, 2H), 2.82-2.43 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.3 Hz, 1H), 7.69 (br. s., 1H), 7.14 (br. s., 5H), 7.00-6.73 (m, 6H), 4.12 (d, J=5.9 Hz, 1H), 3.77 (s, 3H), 3.66-3.41 (m, 2H), 2.72-2.44 (m, 5H), 0.94 (br. s., 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.59 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.11 (d, J=7.0 Hz, 2H), 7.78-7.54 (m, 3H), 7.12-7.04 (m, 1H), 7.03-6.95 (m, 2H), 6.81 (br. s., 4H), 6.66 (d, J=7.3 Hz, 2H), 4.13-4.01 (m, 1H), 3.73 (s, 3H), 3.62-3.37 (m, 2H), 2.69-2.33 (m, 2H), 0.91 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.63 (t, J=7.7 Hz, 1H), 7.42 (br. s., 1H), 7.22-7.08 (m, 6H), 6.93-6.78 (m, 6H), 4.15 (br. s., 1H), 3.77 (s, 3H), 3.66-3.25 (m, 2H), 2.72-2.52 (m, 2H), 0.94 (t, J=6.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.45 (br. s., 1H), 7.22-7.11 (m, 4H), 7.04 (br. s., 2H), 6.94-6.79 (m, 6H), 4.17 (br. s., 1H), 3.76 (s, 3H), 3.60-3.44 (m, 2H), 2.73-2.46 (m, 2H), 0.93 (t, J=5.9 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.84 (d, J=7.7 Hz, 1H), 7.74 (br. s., 1H), 7.38 (br. s., 1H), 7.19-7.11 (m, 3H), 6.98-6.76 (m, 6H), 4.19-4.09 (m, 1H), 3.76 (s, 3H), 3.69-3.40 (m, 2H), 2.76-2.45 (m, 2H), 0.95 (t, J=6.6 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.87 (s, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.15-7.14 (m, 3H), 6.93 (br. s., 4H), 6.77 (d, J=3.3 Hz, 2H), 6.50 (br. s., 1H), 4.16 (d, J=7.0 Hz, 1H), 3.78 (s, 3H), 3.67-3.43 (m, 2H), 2.79-2.38 (m, 5H), 0.95 (t, J=7.2 Hz, 3H).
Examples 121-133 were synthesized using the procedure described above for Example 48.
1H NMR (500 MHZ, DMSO-d6) δ 8.31 (s, 1H), 7.98 (br. s., 1H), 7.86 (d, J=6.6 Hz, 1H), 7.81 (s, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.13 (br. s., 3H), 7.00 (s, 1H), 6.97-6.55 (m, 7H), 4.22-4.11 (m, 1H), 3.75 (s, 3H), 3.66-3.42 (m, 2H), 2.80-2.46 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.88 (s, 1H), 7.83-7.76 (m, 2H), 7.54 (d, J=7.3 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.13 (d, J=2.6 Hz, 3H), 7.02-6.86 (m, 4H), 6.82-6.43 (m, 4H), 4.21-4.09 (m, 1H), 3.77 (s, 3H), 3.68-3.41 (m, 2H), 2.81-2.45 (m, 5H), 0.93 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.26 (s, 1H), 7.98 (s, 1H), 7.83-7.74 (m, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.21-7.09 (m, 3H), 7.00-6.83 (m, 5H), 6.76 (br. s., 2H), 6.70 (d, J=8.4 Hz, 1H), 4.22-4.07 (m, 1H), 3.73 (s, 3H), 3.67-3.41 (m, 2H), 2.80-2.42 (m, 5H), 0.93 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.92 (d, J=8.1 Hz, 1H), 7.70-7.59 (m, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.36-7.08 (m, 9H), 6.91 (d, J=7.7 Hz, 1H), 6.86 (d, J=7.0 Hz, 2H), 6.71-6.48 (m, 3H), 6.08 (s, 2H), 4.58 (br. s., 2H), 4.31 (br. s., 1H), 3.08 (s, 3H), 2.98-2.77 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.90 (d, J=7.3 Hz, 1H), 7.69-7.61 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.33-7.03 (m, 8H), 6.94-6.75 (m, 3H), 6.67 (br. s., 2H), 6.60-6.45 (m, 2H), 6.07 (s, 2H), 4.30 (d, J=6.6 Hz, 1H), 3.06 (s, 3H), 2.99-2.76 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.00-7.92 (m, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.53-7.46 (m, 1H), 7.33 (d, J=7.3 Hz, 2H), 7.23-7.18 (m, 6H), 6.91 (d, J=8.4 Hz, 1H), 6.87-6.79 (m, 2H), 6.70-6.49 (m, 2H), 6.08 (s, 2H), 4.35-4.24 (m, 1H), 3.93 (s, 3H), 3.07 (s, 3H), 2.98-2.75 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 9.25 (s, 1H), 8.65 (br. s., 2H), 8.00 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H), 7.23-7.20 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 6.85 (d, J=7.0 Hz, 2H), 6.72-6.53 (m, 3H), 6.08 (s, 2H), 4.29 (d, J=6.6 Hz, 1H), 3.07 (s, 3H), 2.98-2.76 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.64 (d, J=3.7 Hz, 1H), 8.43 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.77-7.69 (m, 1H), 7.67-7.56 (m, 2H), 7.44 (dd, J=7.7, 5.1 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.24-7.19 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 6.85 (d, J=6.6 Hz, 2H), 6.71-6.54 (m, 3H), 6.08 (s, 2H), 4.30 (d, J=5.5 Hz, 1H), 3.08 (s, 3H), 2.86-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.41 (s, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.22-7.19 (m, 3H), 6.91 (d, J=8.1 Hz, 1H), 6.85 (d, J=6.6 Hz, 2H), 6.58 (d, J=7.3 Hz, 3H), 6.08 (s, 2H), 4.35-4.21 (m, 1H), 4.01 (s, 3H), 3.07 (s, 3H), 2.94-2.77 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.08 (br. s., 1H), 7.95-7.88 (m, 2H), 7.74-7.67 (m, 1H), 7.62-7.56 (m, 1H), 7.45 (br. s., 1H), 7.32-7.18 (m, 6H), 6.92 (d, J=8.1 Hz, 1H), 6.86 (d, J=6.6 Hz, 2H), 6.69-6.55 (m, 3H), 6.08 (s, 2H), 4.32 (d, J=5.9 Hz, 1H), 3.08 (s, 3H), 2.86-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.92 (d, J=7.7 Hz, 1H), 7.68-7.63 (m, 1H), 7.60-7.51 (m, 2H), 7.38-7.03 (m, 6H), 6.91 (d, J=8.1 Hz, 1H), 6.84 (d, J=5.9 Hz, 2H), 6.75-6.55 (m, J=8.1 Hz, 3H), 6.08 (s, 2H), 4.30 (d, J=8.4 Hz, 1H), 3.07 (s, 3H), 2.85-2.51 (m, 2H).
To a 0.5-2 mL microwave tube was added (S)—N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-bromophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide (30 mg, 0.054 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.1 mL, 0.080 mmol), Pd(PPh3)4 (6.19 mg, 5.35 μmol), DMF (1 mL), followed by 2M K2CO3 (60 μl, 0.120 mmol). The reaction mixture was heated in a microwave reactor at 125° C. for 15 min. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford the title compound (13.4 mg).
1H NMR (500 MHZ, DMSO-d6) δ 7.81 (d, J=7.7 Hz, 1H), 7.50 (br. s., 1H), 7.36 (br. s., 1H), 7.16 (br. s., 4H), 6.88 (d, J=7.7 Hz, 1H), 6.82 (d, J=4.4 Hz, 2H), 6.69-6.39 (m, 3H), 6.06 (s, 2H), 5.12 (br. s., 1H), 4.67 (br. s., 1H), 4.27 (d, J=5.1 Hz, 1H), 3.06 (s, 3H), 2.82-2.43 (m, 2H), 1.99 (s, 3H).
A mixture of 10% palladium on carbon (1.0 mg, 0.94 mol) in methanol (1 mL) was stirred under H2 balloon for 5 min. (S)—N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(prop-1-en-2-yl)phenyl)sulfonyl)ureido)propanamide (15 mg, 0.029 mmol) in methanol (1 mL) was added. The reaction mixture was stirred under H2 balloon for 16 hrs. The palladium catalyst was filtered off and the solvent was evaporated. The residue was purified by preparative HPLC to afford the title compound (8.2 mg). 1H NMR (500 MHZ, DMSO-d6) δ 7.74 (d, J=7.3 Hz, 1H), 7.44 (br. s., 2H), 7.29-7.03 (m, 5H), 6.90-6.77 (m, 3H), 6.64-6.45 (m, 2H), 6.05 (br. s., 2H), 4.23 (d, J=5.9 Hz, 1H), 4.01-3.91 (m, 1H), 3.14-2.68 (m, 5H), 1.20-0.95 (m, 6H).
Examples 136-140 were synthesized using the procedure described above for Example 134.
1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=7.7 Hz, 1H), 7.68 (br. s., 1H), 7.62-7.41 (m, 2H), 7.39-7.05 (m, 5H), 6.92-6.76 (m, 3H), 6.72-6.42 (m, 2H), 6.05 (s, 2H), 5.75 (d, J=15.4 Hz, 1H), 5.32 (d, J=11.4 Hz, 1H), 4.24 (br. s., 1H), 3.05 (s, 3H), 2.73-2.42 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.84 (d, J=7.3 Hz, 1H), 7.55 (br. s., 1H), 7.39 (br. s., 1H), 7.32 (d, J=7.0 Hz, 1H), 7.17 (br. s., 3H), 6.91-6.76 (m, 4H), 6.64-6.37 (m, 3H), 6.06 (s, 2H), 5.83 (dd, J=11.6, 7.9 Hz, 1H), 4.25 (br. s., 1H), 3.05 (s, 3H), 2.80-2.38 (m, 2H), 1.60 (d, J=6.6 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.85 (s, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.58-7.40 (m, 1H), 7.15 (d, J=2.9 Hz, 3H), 7.00-6.73 (m, 7H), 6.59 (br. s., 1H), 5.93 (d, J=17.6 Hz, 1H), 5.40 (d, J=11.0 Hz, 1H), 4.24-4.10 (m, J=5.9 Hz, 1H), 3.78 (s, 3H), 3.67-3.39 (m, 2H), 2.83-2.43 (m, 2H), 0.94 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.91 (s, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.62-7.50 (m, 1H), 7.20-7.08 (m, 3H), 6.92 (br. s., 4H), 6.83-6.66 (m, 3H), 5.52 (s, 1H), 5.26 (s, 1H), 4.24-4.12 (m, 1H), 3.78 (s, 3H), 3.66-3.41 (m, 2H), 2.86-2.44 (m, 2H), 2.14 (s, 3H), 0.94 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (s, 1H), 7.67 (d, J=7.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.15 (br. s., 3H), 6.93 (br. s., 4H), 6.82-6.64 (m, 3H), 6.51 (d, J=11.4 Hz, 1H), 5.93 (dd, J=11.6, 7.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 1H), 3.78 (s, 3H), 3.68-3.42 (m, 2H), 2.82-2.45 (m, 2H), 1.86 (d, J=7.0 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H).
Examples 141-146 were synthesized using the procedure described above for Example 135.
1H NMR (500 MHZ, DMSO-d6) δ 7.66 (s, 1H), 7.61 (d, J=7.3 Hz, 1H), 7.56-7.45 (m, 2H), 7.21-7.11 (m, 3H), 6.93 (br. s., 4H), 6.82-6.66 (m, 3H), 4.23-4.14 (m, 1H), 3.78 (s, 3H), 3.67-3.42 (m, 2H), 2.81-2.46 (m, 4H), 1.19 (t, J=7.7 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.66-7.57 (m, 2H), 7.54-7.45 (m, 2H), 7.16 (d, J=3.7 Hz, 3H), 6.93 (br. s., 4H), 6.77 (d, J=3.7 Hz, 2H), 6.72 (d, J=8.1 Hz, 1H), 4.22-4.14 (m, 1H), 3.78 (s, 3H), 3.65-3.46 (m, 2H), 2.81-2.42 (m, 4H), 1.65-1.52 (m, 2H), 0.94 (t, J=7.0 Hz, 3H), 0.88 (t, J=7.3 Hz, 3H).
1H NMR (400 MHZ, MeOH-d4) δ 7.81 (s, 1H), 7.71-7.65 (m, 1H), 7.53 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.24-7.15 (m, 3H), 6.93-6.83 (m, 6H), 4.41 (s, 1H), 3.82 (s, 3H), 3.75-3.45 (m, 2H), 3.02 (dt, J=13.9, 6.9 Hz, 1H), 2.94-2.60 (m, 2H), 1.30 (dd, J=6.8, 1.5 Hz, 6H), 1.04 (t, J=7.2 Hz, 3H).
1H NMR (400 MHZ, MeOH-d4) δ 7.83 (d, J=1.5 Hz, 1H), 7.40-7.24 (m, 2H), 7.21-7.12 (m, 3H), 6.89-6.79 (m, 6H), 4.40 (t, J=6.7 Hz, 1H), 3.80 (s, 3H), 3.73-3.47 (m, 2H), 2.70 (d, J=7.8 Hz, 4H), 1.97 (s, 3H), 1.26 (t, J=7.6 Hz, 3H), 1.02 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=8.1 Hz, 1H), 7.55-7.08 (m, 7H), 6.91-6.78 (m, 3H), 6.70-6.40 (m, 2H), 6.06 (br. s., 2H), 4.27 (d, J=6.2 Hz, 1H), 3.06 (s, 3H), 2.94-2.69 (m, 2H), 2.58-2.41 (m, 2H), 1.62-1.42 (m, 2H), 0.94 (t, J=6.8 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.7 Hz, 1H), 7.56-7.07 (m, 7H), 6.88 (d, J=8.4 Hz, 1H), 6.80 (d, J=2.9 Hz, 2H), 6.71-6.35 (m, 2H), 6.06 (s, 2H), 4.27 (d, J=5.5 Hz, 1H), 3.06 (s, 3H), 2.94 (q, J=7.2 Hz, 2H), 2.82-2.45 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).
A mixture of 10% palladium on carbon (4.0 mg, 3.8 μmol) in methanol (4 mL) was stirred under H2 balloon for 5 min. (S)—N-ethyl-N-(4-methoxyphenyl)-2-(3-((2-nitrophenyl)sulfonyl)ureido)-3-phenylpropanamide (20 mg, 0.038 mmol) in methanol (1 mL) was added. The reaction mixture was stirred under a H2 balloon for 3 hrs. The palladium catalyst was filtered off and the solvent was evaporated. The residue was purified by preparative HPLC to afford the title compound (14 mg).
1H NMR (500 MHZ, DMSO-d6) δ 7.47 (d, J=8.1 Hz, 1H), 7.28-7.12 (m, 4H), 6.90 (br. s., 4H), 6.83-6.72 (m, 3H), 6.63-6.48 (m, 2H), 4.21-4.11 (m, J=6.6 Hz, 1H), 3.77 (s, 3H), 3.67-3.43 (m, 2H), 2.79-2.46 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).
Example 148 was synthesized using the procedure described above for Example 48.
1H NMR (500 MHZ, DMSO-d6) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.85 (br. s., 1H), 7.68-7.51 (m, 2H), 7.34-7.08 (m, 6H), 6.95-6.80 (m, 3H), 6.71-6.48 (m, 2H), 6.07 (s, 2H), 4.29 (d, J=5.1 Hz, 1H), 3.06 (s, 3H), 2.83-2.52 (m, 2H).
To a 0.5-2 mL microwave tube was added (S)-2-(3-((3-bromophenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide (18.5 mg, 0.033 mmol), 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.6 mg, 0.060 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)chloride dichloromethane complex (1.23 mg, 1.05 μmol), 1,4-dioxane (1 mL), followed by 2M K3PO4 (100 μL). The reaction mixture was heated in a microwave reactor at 100° C. for 15 min. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford the title compound (8.8 mg).
Examples 150-154 were synthesized using the procedure described above for Example 149.
1H NMR (500 MHZ, DMSO-d6) δ 8.02 (br. s., 1H), 7.89-7.78 (m, 2H), 7.72-7.57 (m, 3H), 7.28 (d, J=5.9 Hz, 2H), 7.12 (br. s., 3H), 6.90 (br. s., 4H), 6.78 (br. s., 2H), 4.18 (d, J=6.6 Hz, 1H), 3.77 (s, 3H), 3.66-3.45 (m, 2H), 2.80-2.51 (m, 2H), 2.51 (s, 3H), 0.93 (t, J=7.0 Hz, 4H).
1H NMR (500 MHZ, DMSO-d6) δ 8.08 (br. s., 1H), 8.01-7.88 (m, 1H), 7.77-7.66 (m, 2H), 7.58 (d, J=5.5 Hz, 2H), 7.20-7.08 (m, 3H), 6.88 (br. s., 4H), 6.79 (br. s., 2H), 6.58 (br. s., 1H), 4.17 (d, J=6.2 Hz, 1H), 3.75 (s, 3H), 3.64-3.42 (m, 2H), 2.79-2.44 (m, 2H), 2.51 (s, 3H), 0.92 (t, J=6.8 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.90 (br. s., 1H), 7.83-7.74 (m, 2H), 7.71-7.61 (m, 1H), 7.52 (s, 1H), 7.21-7.09 (m, 3H), 6.91 (br. s., 4H), 6.78 (br. s., 2H), 6.58-6.41 (m, 2H), 4.17 (d, J=5.9 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H), 3.64-3.44 (m, 2H), 2.79-2.38 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.12 (s, 1H), 8.05 (s, 1H), 7.93-7.82 (m, 3H), 7.78-7.66 (m, 1H), 7.53-7.34 (m, 2H), 7.06 (d, J=3.3 Hz, 3H), 6.95-6.83 (m, 4H), 6.76 (d, J=3.7 Hz, 2H), 6.67 (br. s., 1H), 4.26-4.13 (m, 1H), 3.73 (s, 3H), 3.61-3.36 (m, 2H), 2.81-2.45 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 11.75 (br. s., 1H), 8.25 (br. s., 1H), 8.03 (br. s., 1H), 7.70-7.45 (m, 3H), 7.11 (br. s., 2H), 7.06-7.03 (m, 2H), 6.98 (br. s., 1H), 6.86-6.78 (m, 4H), 6.52 (d, J=5.5 Hz, 1H), 4.18 (br. s., 1H), 3.89 (s, 3H), 3.69 (br. s., 3H), 3.62-3.37 (m, 2H), 2.82-2.45 (m, 2H), 0.90 (br. s., 3H).
To a 0.5-2 mL microwave tube was added (S)-2-(3-((3-bromo-2-methylphenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide (17.3 mg, 0.030 mmol), 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.6 mg, 0.060 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)chloride dichloromethane complex (1.2 mg, 1.5 μmol), 1,4-dioxane (1 mL), followed by 2M K3PO4 (100 μL). The reaction mixture was heated in a microwave reactor at 100° C. for 15 min. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford the title compound (5.5 mg).
1H NMR (500 MHZ, DMSO-d6) δ 7.89-7.74 (m, 2H), 7.63 (br. s., 1H), 7.30 (br. s., 1H), 7.12 (d, J=4.0 Hz, 3H), 6.93-6.78 (m, 6H), 6.74-6.56 (m, 2H), 4.14 (br. s., 1H), 3.75 (br. s., 3H), 3.63-3.41 (m, 2H), 2.76-2.52 (m, 2H), 2.59 (s, 3H), 0.92 (br. s., 3H).
Examples 156-162 were synthesized using the procedure described above for Example 149.
1H NMR (500 MHZ, DMSO-d6) δ 7.82 (d, J=8.1 Hz, 1H), 7.68 (br. s., 1H), 7.58-7.48 (m, 2H), 7.36 (br. s., 1H), 7.27-7.11 (m, 4H), 7.05-6.90 (m, 4H), 6.79 (br. s., 2H), 4.17 (br. s., 1H), 3.77 (s, 3H), 3.67-3.43 (m, 2H), 2.79-2.48 (m, 2H), 2.57 (s, 3H), 0.93 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.88 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.33 (br. s., 2H), 7.14 (br. s., 3H), 6.97-6.88 (m, 4H), 6.80 (br. s., 2H), 6.23 (br. s., 1H), 4.15 (br. s., 1H), 3.78 (s, 3H), 3.51 (s, 3H), 3.51-3.45 (m, 2H), 2.76-2.47 (m, 2H), 2.51 (s, 3H) 0.93 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.10 (d, J=8.1 Hz, 1H), 7.76 (br. s., 1H), 7.59-7.53 (m, 1H), 7.49 (d, J=7.3 Hz, 1H), 7.46-7.40 (m, 1H), 7.26 (d, J=15.0 Hz, 2H), 7.14 (br. s., 3H), 6.95 (br. s., 4H), 6.81 (br. s., 2H), 6.60 (br. s., 1H), 4.22 (br. s., 1H), 3.78 (s, 3H), 3.69-3.46 (m, 2H), 2.82-2.53 (m, 2H), 2.31 (s, 3H), 0.94 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 11.39 (br. s., 1H), 7.96 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.52-7.38 (m, 1H), 7.14 (br. s., 3H), 7.09-6.87 (m, 5H), 6.80 (d, J=3.7 Hz, 2H), 6.58-6.39 (m, 2H), 4.18 (br. s., 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.68-3.43 (m, 2H), 2.82-2.56 (m, 2H), 2.61 (s, 3H), 0.94 (t, J=7.2 Hz, 3H).
Examples 163-205 were synthesized using the procedure described above for Example 87.
1H NMR (500 MHZ, DMSO-d6) δ 7.79 (d, J=7.7 Hz, 2H), 7.63 (d, J=7.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.32-7.23 (m, 1H), 7.17 (br. s., 5H), 6.88 (d, J=6.2 Hz, 1H), 6.76 (br. s., 1H), 6.66 (d, J=7.0 Hz, 1H), 4.27 (br. s., 1H), 3.09 (s, 3H), 2.51 (s, 3H), 2.81-2.42 (m, 2H), 2.24 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=5.9 Hz, 1H), 7.41 (d, J=7.7 Hz, 4H), 7.29 (br. s., 3H), 7.20-7.06 (m, 3H), 6.79 (br. s., 2H), 6.42 (br. s., 1H), 4.22 (br. s., 1H), 3.09 (br. s., 3H), 2.77-2.56 (m, 2H), 2.51 (s, 3H),
1H NMR (500 MHZ, DMSO-d6) δ 7.79 (dd, J=17.8, 7.9 Hz, 2H), 7.59-7.08 (m, 5H), 7.04-6.98 (m, 2H), 6.87 (t, J=7.5 Hz, 1H), 6.78-6.59 (m, 3H), 6.52 (br. s., 1H), 4.28 (br. s., 1H), 3.85 (s, 3H), 3.06 (s, 3H), 2.77-2.56 (m, 2H), 2.55 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.75 (d, J=7.3 Hz, 2H), 7.37 (br. s., 1H), 7.24 (d, J=7.7 Hz, 3H), 7.14 (br. s., 3H), 6.90 (br. s., 1H), 6.76 (br. s., 2H), 6.59 (br. s., 1H), 6.30 (br. s., 1H), 4.30 (br. s., 1H), 3.67 (br. s., 3H), 3.10 (br. s., 3H), 2.79-2.34 (m, 2H), 2.51 (br. s., 3H),
1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=8.1 Hz, 1H), 7.50 (br. s., 1H), 7.40-7.28 (m, 2H), 7.15 (br. s., 3H), 7.05 (d, J=8.1 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.75 (br. s., 2H), 6.55 (d, J=7.3 Hz, 1H), 4.26 (br. s., 1H), 3.77 (s, 3H), 3.09 (s, 3H), 2.79-2.34 (m, 2H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.79 (d, J=7.0 Hz, 1H), 7.52-7.38 (m, 3H), 7.36-7.29 (m, 2H), 7.26-7.10 (m, 4H), 7.03-6.92 (m, 2H), 6.77 (br. s., 2H), 6.54 (br. s., 1H), 4.27 (br. s., 1H), 3.12 (br. s., 3H), 2.51 (s, 3H), 2.76-2.41 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=7.7 Hz, 1H), 7.45 (br. s., 1H), 7.31 (br. s., 2H), 7.23-7.05 (m, 7H), 6.77 (br. s., 2H), 6.46 (br. s., 1H), 4.21 (br. s., 1H), 3.10 (s, 3H), 2.51 (s, 3H), 2.76-2.41 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.7 Hz, 1H), 7.32 (br. s., 2H), 7.21 (br. s., 2H), 7.09 (d, J=8.8 Hz, 5H), 6.77 (br. s., 1H), 6.31 (br. s., 1H), 4.93 (br. s., 1H), 3.91-3.81 (m, 2H), 3.39-3.27 (m, 2H), 2.61-2.35 (m, 2H), 2.54 (br. s., 3H), 1.72-1.48 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.84 (d, J=6.6 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.45-7.34 (m, 2H), 7.27-6.98 (m, 4H), 6.81-6.51 (m, 4H), 4.92 (br. s., 1H), 3.95-3.83 (m, 2H), 3.73 (s, 3H), 3.41-3.29 (m, 2H), 2.70-2.35 (m, 2H), 2.55 (s, 3H), 1.80-1.44 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.85 (br. s., 1H), 7.64 (br. s., 1H), 7.51 (d, J=6.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.26-7.01 (m, 4H), 6.84 (br. s., 1H), 6.74 (br. s., 1H), 6.50-6.32 (m, 2H), 4.85 (br. s., 1H), 4.03 (br. s., 2H), 3.70 (br. s., 3H), 3.51-3.38 (m, 4H), 2.55 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.82 (br. s., 1H), 7.47 (br. s., 1H), 7.33 (br. s., 3H), 7.25-7.08 (m, 2H), 6.94 (br. s., 1H), 6.75 (br. s., 1H), 6.60-6.29 (m, 3H), 4.92 (br. s., 1H), 3.91-3.36 (m, 2H), 2.54 (s, 3H), 2.70-2.35 (m, 2H), 2.45-2.29 (m, 2H), 1.74-1.48 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 8.05 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.53-7.29 (m, 2H), 7.25-7.09 (m, 7H), 7.02 (d, J=6.6 Hz, 1H), 6.68 (br. s., 1H), 4.58 (br. s., 1H), 4.21-3.76 (m, 2H), 3.42-2.68 (m, 4H), 2.58 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.81 (d, J=8.1 Hz, 1H), 7.62-7.48 (m, 1H), 7.46-7.35 (m, 2H), 7.17 (d, J=3.3 Hz, 3H), 7.11 (d, J=8.1 Hz, 1H), 6.81-6.57 (m, 4H), 4.22-4.08 (m, 1H), 3.66-3.45 (m, 2H), 3.14-2.81 (m, 2H), 2.53 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H), 0.94 (t, J=7.2 Hz, 3H).
1H NMR (400 MHZ, MeOH-d4) δ 8.00 (d, J=1.0 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.6, Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.43-7.36 (m, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.26-7.19 (m, 3H), 7.15 (t, J=7.5 Hz, 2H), 7.01 (d, J=7.3 Hz, 2H), 4.48 (s, 1H), 3.13 (s, 3H), 3.09-2.93 (m, 2H), 2.27 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.66 (d, J=4.4 Hz, 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), 7.37 (t, J=4.2 Hz, 2H), 7.34 (d, J=9.5 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.08-7.02 (m, 3H), 6.93 (t, J=9.2 Hz, 1H), 6.33 (d, J=6.6 Hz, 2H), 4.7 (s, 1H), 3.81-3.6 (m, 2H), 3.01-2.70 (m, 2H), 2.51 (br s, 3H), 1.17 (t, J=7.3 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.80 (d, J=7.7 Hz, 1H), 7.59-7.50 (m, 1H), 7.45-7.33 (m, 4H), 7.22 (d, J=8.1 Hz, 2H), 7.14 (d, J=7.0 Hz, 3H), 6.77-6.56 (m, 3H), 4.12 (d, J=4.8 Hz, 1H), 3.78-3.43 (m, 2H), 2.99-2.68 (m, 2H), 2.52 (br s., 3H), 0.96 (t, J=7.0 Hz, 3H).
1H NMR (400 MHZ, MeOH-d4) δ 8.01 (dd, J=8.1, 2.0 Hz, 1H), 7.62-7.53 (m, 1H), 7.46-7.38 (m, 2H), 7.30-7.17 (m, 3H), 7.15-7.05 (m, 2H), 4.82 (t, J=7.1 Hz, 1H), 4.28-4.17 (m, 1H), 2.97-2.80 (m, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 1.84-0.80 (m, 10H).
1H NMR (500 MHZ, DMSO-d6) δ 8.48 (d, J=4.8 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.75-7.60 (m, 2H), 7.36 (br. s., 1H), 7.29-7.18 (m, 3H), 7.17-7.10 (m, 2H), 7.07 (br. s., 1H), 6.98 (br. s., 1H), 6.90 (d, J=8.1 Hz, 1H), 6.37 (br. s., 1H), 4.93-4.64 (m, 1H), 4.60-4.29 (m, 2H), 3.18 (s, 3H), 2.87 (br. s., 3H), 2.85-2.63 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.80 (d, J=8.1 Hz, 1H), 7.62-7.53 (m, 1H), 7.48-7.29 (m, 5H), 7.18 (br. s., 3H), 7.03 (d, J=7.3 Hz, 2H), 6.79 (br. s., 2H), 6.66 (d, J=7.0 Hz, 1H), 4.12 (d, J=7.0 Hz, 1H), 3.70-3.48 (m, 2H), 2.83-2.56 (m, 2H), 2.52 (s, 3H), 0.94 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.84 (d, J=7.3 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.33 (m, 3H), 7.20 (br. s., 4H), 6.84 (br. s., 2H), 6.75 (d, J=7.7 Hz, 1H), 4.03 (d, J=7.7 Hz, 1H), 3.69-3.45 (m, 2H), 2.83-2.56 (m, 2H), 2.53 (s, 3H), 0.91 (t, J=6.8 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.84 (d, J=7.3 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.33 (m, 3H), 7.20 (br. s., 4H), 6.84 (br. s., 2H), 6.75 (d, J=7.7 Hz, 1H), 4.03 (d, J=7.7 Hz, 1H), 3.69-3.45 (m, 2H), 2.83-2.56 (m, 2H), 2.53 (s, 3H), 1.29 (m. 2H), 0.91 (t, J=6.8 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.79 (d, J=7.7 Hz, 1H), 7.60-7.50 (m, 1H), 7.43-7.31 (m, 2H), 7.16-7.14 (m, 3H), 7.03-6.90 (m, 4H), 6.77-6.75 (m, 2H), 6.62 (d, J=8.8 Hz, 1H), 4.24 (br. s., 1H), 3.77 (s, 3H), 3.69-3.40 (m, 2H), 2.80-2.50 (m, 2H), 2.55 (s, 3H), 0.95 (t, J=7.0 Hz, 3H).
1H NMR (400 MHZ, MeOH-d4) δ 8.52 (br. s., 1H), 8.29 (d, J=8.1 Hz, 2H), 7.95 (d, J=6.8 Hz, 2H), 7.64-7.53 (m, 2H), 7.47-7.37 (m, 3H), 7.29-7.26 (m, 3H), 4.75 (br. s., 1H), 4.20 (br. s., 1H), 3.63 (br. s., 1H), 3.16-2.87 (m, 4H), 2.70 (s, 3H), 2.67 (s, 3H), 2.64 (S, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.83 (d, J=7.7 Hz, 1H), 7.48 (br. s., 1H), 7.35 (br. s., 1H), 7.24-7.26 (m, 4H), 7.08 (d, J=7.3 Hz, 2H), 6.47 (br. s., 1H), 4.17 (d, J=6.6 Hz, 1H), 3.85-3.68 (m, 2H), 3.66-3.54 (m, 2H), 2.82-2.63 (m, 2H), 2.51 (m, 3H), 2.16-1.90 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.75 (d, J=7.3 Hz, 1H), 7.36-7.06 (m, 8H), 6.16 (br. s., 1H), 4.15 (br. s., 1H), 4.07-3.74 (m, 4H), 3.61-3.23 (m, 2H), 3.12 (s, 3H), 2.51 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.77 (d, J=7.3 Hz, 1H), 7.36-7.03 (m, 8H), 6.12 (br. s., 1H), 4.12 (br. s., 1H), 3.67-3.00 (m, 6H), 2.51 (s, 3H), 1.07 (s, 3H), 0.91 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.34 (d, J=4.0 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.58 (t, J=7.3 Hz, 1H), 7.54-7.47 (m, 1H), 7.39-7.31 (m, 2H), 7.21-7.14 (m, 1H), 7.07 (d, J=8.1 Hz, 2H), 6.97-6.82 (m, 3H), 6.61 (br. s., 1H), 4.44 (br. s., 1H), 3.76 (s, 3H), 3.07 (s, 3H), 2.93-2.63 (m, 2H), 2.5 (s J=13.4, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.24 (s, 1H), 7.87-7.74 (m, 2H), 7.53 (d, J=6.6 Hz, 1H), 7.44-7.33 (m, 2H), 7.15-7.11 (m, 3H), 6.92 (d, J=8.4 Hz, 2H), 6.83 (br. s., 1H), 4.46 (br. s., 1H), 4.31-4.02 (m, 2H), 3.76 (s, 3H), 3.09 (s, 3H), 2.54 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.34 (br. s., 1H), 7.72 (d, J=7.7 Hz, 1H), 7.36 (br. s., 1H), 7.24 (br. s., 2H), 7.15-7.11 (m, 4H), 6.91-6.94 (m, 3H), 6.29 (br. s., 1H), 4.25 (br. s., 1H), 3.77 (br. s., 3H), 3.09 (s, 3H), 2.76-2.49 (m, 2H), 2.5 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.86 (d, J=7.7 Hz, 1H), 7.59-7.48 (m, 1H), 7.43-7.32 (m, 2H), 7.19 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.51 (br. s., 1H), 4.21 (t, J=7.7 Hz, 1H), 3.75 (s, 3H), 3.09 (s, 3H), 2.56 (s, 3H), 1.54-1.37 (m, 2H), 1.35-1.17 (m, 4H), 1.06-0.85 (m, 7H).
1H NMR (500 MHZ, DMSO-d6) δ 7.76 (d, J=7.7 Hz, 1H), 7.59-7.52 (m, 1H), 7.42-7.34 (m, 2H), 7.21-7.12 (m, 4H), 6.98-6.81 (m, 4H), 6.38 (br. s., 1H), 4.40-4.43 (m, 1H), 3.78 (s, 3H), 3.11 (s, 3H), 2.84-2.87 (m, 1H), 2.46 (s, 3H), 0.90 (d, J=7.3 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.81 (d, J=7.7 Hz, 1H), 7.51 (br. s., 1H), 7.42-7.32 (m, 2H), 7.25 (d, J=4.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 2H), 6.93 (s, 1H), 6.87-6.81 (m, 1H), 6.66-6.49 (m, 2H), 4.24 (br. s., 1H), 3.76 (s, 3H), 3.09 (s, 3H), 2.99-2.67 (m, 2H), 2.55 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.31 (d, J=5.5 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.43-7.22 (m, 3H), 7.13 (d, J=7.3 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.75 (d, J=5.1 Hz, 2H), 6.36 (br. s., 1H), 4.29 (br. s., 1H), 3.78 (br. s., 3H), 3.10 (s, 3H), 2.74-2.54 (m, 2H), 2.5 (s, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.89 (d, J=7.7 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.46-7.31 (m, 2H), 7.15 (br. s., 3H), 6.94-6.72 (m, 5H), 6.33 (br. s., 1H), 4.15 (br. s., 1H), 3.70 (s, 3H), 3.69-3.41 (m, 2H), 2.77-2.4 (m, 2H), 0.94 (t, J=7.0 Hz, 3H).
1H NMR (500 MHZ, DMSO-d6) δ 8.00 (br. s., 1H), 7.53 (br. s., 4H), 7.11 (br. s., 4H), 6.91-6.74 (m, 6H), 6.59 (br. s., 1H), 6.41 (br. s., 1H), 4.32-4.10 (m, 1H), 3.74 (br. s., 3H), 3.35 (br. s., 2H), 2.95-2.65 (m, 4H), 1.34 (br. s., 3H), 0.92 (br. s., 3H).
1H NMR (500 MHZ, DMSO-d6) δ 7.74-7.50 (m, 2H), 7.32-7.15 (m, 4H), 6.96-6.97 (m, 3H), 6.41-6.43 (m, 3H), 4.28 (br. s., 1H), 3.78 (s, 3H), 3.10 (s, 3H), 2.77-2.52 (m, 2H).
1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=8.1 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.36 (d, J=7.7 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 6.97-7.00 (m, 3H), 6.68 (d, J=8.1 Hz, 1H), 6.38 (d, J=6.6 Hz, 2H), 4.33-4.20 (m, 1H), 3.78 (s, 3H), 3.12 (s, 3H), 2.81-2.53 (m, 2H), 2.50 (s, 3H).
HATU (1.5 g, 4.0 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline (500 mg, 3.64 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.06 g, 4.0 mmol) in DMF (20 mL) and DIPEA (1.3 mL, 7.3 mmol) and the reaction mixture was stirred at rt for 4 h. The reaction was concentrated and the residual crude oil was partitioned between EtOAc (˜60 mL) and 1/2 sat. NaHCO3 (aq) (˜60 mL). The organic component was washed with brine (˜40 mL), dried (MgSO4), filtered, concentrated and purified using a Biotage Horizon (80 g SiO2, 10-40% EtOAc/hexanes) to yield (S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1.34 g) as a clear amber viscous oil. LC-MS retention time=3.17 min; m/z=385.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×50 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220). 1H NMR (400 MHZ, CDCl3) δ 7.25-7.20 (m, 3H), 7.03-6.64 (m, 6H), 5.20 (d, J=8.8 Hz, 1H), 4.53 (q, J=7.4 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.89 (dd, J=13.1, 7.5 Hz, 1H), 2.71 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H).
A 4M HCl (15 mL, 60.0 mmol) in dioxanes solution was added to a stirred solution of (S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (Intermediate JB-1) (1.34 g, 3.49 mmol) in THF (10 mL) and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated to dryness under vacuum to yield an HCl salt of (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (1.11 g) as a solidified foam which was used without additional purification. LC-MS retention time=2.33 min; m/z=285.2 [M+H]+. (Column: Phenonenex-Luna C18 2.0×50 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220).
HATU (776 mg, 2.04 mmol) was added to a stirred solution of 3,4,5-trimethoxy-N-methylaniline (350 mg, 1.78 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (518 mg, 1.95 mmol) in DMF (10 mL) and DIPEA (0.62 mL, 3.6 mmol) and stirred at rt ON. The reaction mixture was concentrated and the crude oil was partitioned between EtOAc (˜40 mL) and 1/2 sat NaHCO3 (aq) (˜40 mL). The organic component was washed with brine (˜30 mL), dried (MgSO4), filtered and concentrated. The crude residue was then purified using a Biotage Horizon (80 g SiO2, 10-40% EtOAc/hexanes) to yield(S)-tert-butyl (1-(methyl(3,4,5-trimethoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (474 mg) as a clear colorless solidified oil. Used without further purification. LC-MS retention time=1.60 min; m/z=385.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×50 mm 3 μm. Solvent A=90% Water: 10% Acetonitrile: 0.1% TFA. Solvent B=10% Water: 90% Acetonitrile: 0.1% TFA. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220). 1H NMR (400 MHZ, CDCl3) δ 7.27-7.17 (m, 3H), 7.01 (d, J=6.3 Hz, 2H), 6.11 (br. s., 2H), 5.21 (d, J=9.0 Hz, 1H), 4.76-4.64 (m, 1H), 3.86 (s, 3H), 3.77 (br. s., 6H), 3.17 (s, 3H), 3.01-2.87 (m, 1H), 2.77 (dd, J=12.8, 6.3 Hz, 1H), 1.40 (s, 9H).
Paraformaldehyde (80 mg, 2.7 mmol) was added to a stirred solution of benzo[d]thiazol-5-amine (200 mg, 1.332 mmol) in MeOH (5 mL) The resulting suspension was then treated with 25% w/w NaOMe in MeOH (1.5 mL, 6.7 mmol) and the clear reaction mixture was stirred at 60° C. for 16 h. The reaction was allowed to cool to rt and then treated with NaBH4 (126 mg, 3.33 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHCl3 (3×20 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12 g SiO2, 0-50% EtOAc/hexanes) to yield N-methylbenzo[d]thiazol-5-amine (217 mg) as yellow gum. LC-MS retention time=0.67 min; m/z=165.05 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 6.82 (dd, J=8.8, 2.3 Hz, 1H), 3.93 (br. s., 1H), 2.94 (s, 3H).
HATU (1.90 g, 5.01 mmol) was added to a solution of N-methylbenzo[d]thiazol-5-amine (Intermediate ZY-1) (685 mg, 4.17 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.33 g, 5.01 mmol) in DMF (20 mL) and DIPEA (2.18 mL, 12.5 mmol) and the reaction mixture was stirred at rt for 6 h. The crude reaction mixture was diluted with sat. aq. NaHCO3 (20 mL) and extracted with EtOAc (3×50 mL). The combined organic component was washed with brine (˜60 mL), dried (Na2SO4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (12 g SiO2, 0-40%-50% EtOAc/hexanes) to yield (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1.7 g) as a white solid. LC-MS retention time=1.19 min; m/z=412.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.27-7.19 (m, 3H), 6.94 (d, J=6.8 Hz, 3H), 5.22 (d, J=8.8 Hz, 1H), 4.58-4.48 (m, 1H), 3.26 (s, 3H), 2.93 (dd, J=12.9, 8.4 Hz, 1H), 2.78 (dd, J=12.4, 5.9 Hz, 1H), 1.40 (s, 9H).
A solution of 4M HCl (10 mL, 40.0 mmol) in dioxanes was added to a stirred solution of (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (Intermediate ZY-2) (1.7 g, 4.13 mmol) in THF (10 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, redissolved in EtOH/toluene, and then reconcentrated (3×) to yield an HCl salt of (S)-2-amino-N-(benzo[d]thiazol-5-yl)-N-methyl-3-phenylpropanamide (1.7 g, 4.42 mmol, 107% yield) as a pink sticky solid. LC-MS retention time=0.83 min; m/z=312.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHZ, MeOH-d4) δ 9.42 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.39-7.08 (m, 6H), 6.91 (d, J=7.0 Hz, 2H), 4.10 (dd, J=8.0, 6.5 Hz, 1H), 3.63-3.56 (m, 2H), 3.11 (dd, J=13.4, 8.2 Hz, 1H), 2.92 (dd, J=13.3, 6.5 Hz, 1H), 2.87 (s, 3H).
HATU (592 mg, 1.556 mmol) was added to a stirred solution of N-methylbenzo[d]thiazol-5-amine (Intermediate ZY-1) (213 mg, 1.30 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (469 mg, 1.56 mmol) in DMF (7 mL) and DIPEA (0.45 mL, 2.6 mmol) and the reaction mixture was stirred at rt for 16 h. The crude reaction mixture was diluted with sat. aq. NaHCO3 (20 mL) and extracted with EtOAc (3×50 mL). The combined organic component was washed with brine (˜60 mL), dried (Na2SO4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (24 g SiO2, 0-50% EtOAc/hexanes) yield (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate (581 mg) as a white solid. LC-MS retention time=1.23 min; m/z=448.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220). 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.68 (br. s., 1H), 7.05 (br. s., 1H), 6.68 (t, J=8.9 Hz, 1H), 6.44 (d, J=6.3 Hz, 2H), 5.25 (d, J=9.0 Hz, 1H), 4.54 (q, J=7.3 Hz, 1H), 2.94-2.86 (m, 1H), 2.81 (s, 3H), 2.72 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H).
TFA (1.0 mL, 13 mmol) was added to a stirred solution of (S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate (Intermediate ZY-4) (0.58 g, 1.23 mmol) in DCM (2 mL) and the reaction mixture was stirred at rt for 16 h. The crude reaction mixture was concentrated and the residue was dissolved in MeOH/DCM and 4 M HCl in dioxane (2 mL) and reconcentrated. The residue was redissolved in EtOH/toluene, and then reconcentrated (3×) to yield an HCl salt of (S)-2-amino-N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-N-methylpropanamide (0.55 g) as a white solid. LC-MS retention time=0.83 min; m/z=348.1[M+H]+. (Column: Waters Aquity BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=100% Water: 0.05% TFA. Solvent B=100% Acetonitrile: 0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
BOP-Cl (131 mg, 0.516 mmol) was added to a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (124 mg, 0.469 mmol) and N-benzyl-4-methoxyaniline (100 mg, 0.469 mmol) in DCM (3 mL), and DIPEA (0.25 mL, 1.4 mmol) and the reaction mixture was stirred at rt for 16 h. The crude reaction mixture was concentrated and the residue was purified using a Biotage Horizon (12 g SiO2, 0-50% Et2O/hexanes) to yield the title compound (125 mg). LC-MS retention time=1.43 min; m/z=461.4 [M+H]+. (Column: Waters Aquity BEH C18 2.1×50 mm 1.7 U. Solvent A=100% Water/0.05% TFA. Solvent B=100% Acetonitrile/0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
A 4M solution of HCl (1.3 mL, 5.2 mmol) in dioxane was added to a stirred solution of (S)-tert-butyl (1-(benzyl(4-methoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (Intermediate ZY-6) (120 mg, 0.261 mmol) in THF (1.3 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture concentrated to yield an HCl salt of the title compound (117 mg). LC-MS retention time=0.99 min; m/z=361.2 [M+H]+. (Column: Waters Aquity BEH C18 2.1×50 mm 1.7 U. Solvent A=100% Water/0.05% TFA. Solvent B=100% Acetonitrile/0.05% TFA. Flow Rate=0.8 mL/min. Start % B=2. Final % B=98. Gradient Time=1.5 min. Wavelength=220).
A solution of 4M HCl (1 mL, 4.0 mmol) in dioxane was added to a stirred solution of Intermediate JB-7 (77 mg, 0.17 mmol) was dissolved into THF (1 mL) and the reaction was stirred at rt for 3 h. The reaction mixture was concentrated to dryness dissolved into CH3CN (1 mL) and Hunig's Base (0.11 mL, 0.61 mmol) and then treated with 2-methylbenzenesulfonyl isocyanate (51 mg, 0.26 mmol) and stirred at rt for 3 h. The reaction mixture was quenched with MeOH (5 mL), stirred 5 min. and then concentrated to dryness. The residue was partitioned between EtOAc (10 mL) and water (5 mL) and the organic component was further washed with brine (5 mL) and concentrated. The residue was dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (50.3 mg). LC-MS retention time=1.98 min; m/z=542.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
Examples JB-83 and JB-84 were prepared using the procedure detailed for Example JB-82 where the 3,4,5-trimethoxy-N-methylaniline used in the preparation of Intermediate JB-7 was replaced with the appropriate amine.
LC-MS retention time=1.97 min; m/z=496.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.03 min; m/z=510.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220.
A solution of sulfurisocyanatidic chloride (0.048 mL, 0.56 mmol) in DCM (1.5 mL) was added dropwise at 0° C. to a stirred solution of Intermediate JB-2 (140 mg, 0.37 mmol) in DCM (˜1 mL) and the reaction mixture was stirred at 0° C. for 1 h. Then TEA (0.17 mL, 1.2 mmol) in DCM (0.6 mL) was added and reaction mixture was stirred at 0° C. for 3 min. A portion of this crude reaction mixture (˜0.8 mL, 25%) was added to a stirred solution of 1,2-dimethyl-1H-indole (43.1 mg, 0.297 mmol) in DCM (1 mL) and stirred at rt for 2 h. The reaction was concentrated diluted with EtOAc (˜2 mL) and washed with sat. aq. NaHCO3 (aq) (1 mL) and brine (1 mL). The organic component was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (10.8 mg). LC-MS retention time=1.74 min; m/z=535.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (500 MHZ, DMSO-d6) δ 7.78 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.20 (m, 1H), 7.11-7.07 (m, 1H), 7.04-6.99 (m, 2H), 6.98-6.94 (m, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.64 (d, J=7.3 Hz, 2H), 6.57 (d, J=8.1 Hz, 1H), 4.26-4.19 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.06 (s, 3H), 2.69 (dd, J=13.8, 5.3 Hz, 1H), 2.61 (s, 3H), 2.41 (dd, J=13.4, 7.5 Hz, 1H).
To a stirred solution of Intermediate ZY-7 (32 mg, 0.081 mmol) in CH3CN (1 mL) and DIPEA (0.042 mL, 0.242 mmol) was added 2-methylbenzenesulfonyl isocyanate (24 mg, 0.12 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (44.6 mg). LC-MS retention time=1.91 min; m/z=558.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (500 MHZ, DMSO-d6) δ 7.80 (d, J=7.7 Hz, 1H), 7.49 (d, J=7.0 Hz, 1H), 7.38-7.31 (m, 2H), 7.27-7.12 (m, 7H), 7.06 (br. s., 2H), 6.79 (br. s., 6H), 4.87 (d, J=15.0 Hz, 1H), 4.63 (d, J=14.3 Hz, 1H), 4.23 (d, J=6.2 Hz, 1H), 3.71 (s, 3H), 2.81 (dd, J=13.6, 5.1 Hz, 1H), 2.59-2.53 (m, 4H).
Examples ZY-4 through ZY-6 were prepared using the procedure detailed for Example ZY-3 where the N-benzyl-4-methoxyaniline used in the preparation of Intermediate ZY-6 was replaced with the appropriate amine.
LC-MS retention time=1.48 min; m/z=559.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.87 min; m/z=572.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAC. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.84 min; m/z=524.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (600 MHZ, DMSO-d6) δ 7.76 (d, J=7.7 Hz, 1H), 7.47 (d, J=6.6 Hz, 1H), 7.36-7.27 (m, 2H), 7.17-6.86 (m, 7H), 6.80-6.53 (m, 3H), 4.18 (d, J=5.9 Hz, 1H), 3.76 (s, 3H), 3.58-3.16 (m, 2H), 2.78-2.72 (m, 2H), 1.58-1.49 (m, 1H), 0.76 (dd, J=17.8, 6.4 Hz, 6H).
2-Methylbenzenesulfonyl isocyanate (28.4 mg, 0.144 mmol) was added to a stirred solution of an HCl salt of Intermediate ZY-5 (55 mg, 0.131 mmol) in CH3CN (1 mL) and DIPEA (0.11 mL, 0.65 mmol) and the reaction mixture was stirred at rt ON. Additional 2-methylbenzenesulfonyl isocyanate (20 mg) was added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (49.8 mg).
LC-MS retention time=2.33 min; m/z=545.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (500 MHZ, DMSO-d6) δ 9.49 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.54-7.48 (m, 1H), 7.41-7.30 (m, 3H), 6.95 (t, J=9.2 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.35 (d, J=6.6 Hz, 2H), 4.31 (d, J=4.4 Hz, 1H), 3.23 (s, 3H), 2.90-2.80 (m, 1H), 2.60 (dd, J=13.6, 8.8 Hz, 1H), 2.50 (br. s., 3H).
For Examples CA-67 through CA-101, the following procedure was used:
A solution of POCl3 (0.15 mmol) in pyridine (0.5 mL) was added to a solution of the appropriate aniline (0.11 mol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (0.10 mmol) in pyridine (0.5 mL) at 0° C. The reaction mixture was allowed to warm to rt while being shaken ON.
The reaction was cooled using ice bath, quenched with MeOH (0.5 mL) and concentrated to dryness. The crude residue was treated with DCM (0.5 mL) and TFA (0.5 mL) and the reaction mixture was shaken at rt for 4 h. The reaction mixture was concentrated to dryness and the crude residue was dissolved into DIPEA (0.3 mmol) in DCM (0.5 mL) and treated with a solution of 2-methylbenzenesulfonyl isocyanate (0.15 mmol) in DCM (0.5 mL). The reaction mixture was shaken at rt for 2 h, diluted with MeOH (0.5 mL) and concentrated to dryness. The crude residue was dissolved into DMF (1 mL), filtered and purified by preparative HPLC to yield the title compound.
LC-MS retention time=2.42 min; m/z=452.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.54 min; m/z=466.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.52 min; m/z=466.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=3.06 min; m/z=480.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.22 min; m/z=503.1 [M+H]. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.50 min; m/z=517.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.07 min; m/z=506.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.23 min; m/z=534.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.15 min; m/z=504.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.38 min; m/z=494.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.56 min; m/z=496.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.67 min; m/z=510.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.65 min; m/z=508.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.48 min; m/z=517.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.66 min; m/z=522.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.76 min; m/z=466.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.66 min; m/z=531.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.54 min; m/z=496.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.43 min; m/z=525.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.49 min; m/z=507.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.69 min; m/z=523.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.22 min; m/z=509.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.31 min; m/z=525.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.96 min; m/z=511.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.28 min; m/z=477.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.08 min; m/z=538.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (500 MHZ, DMSO-d6) δ 8.41 (br. s., 1H), 7.76 (d, J=8.8 Hz, 1H), 7.47 (d, J=7.7 Hz, 3H), 7.30 (br. s., 2H), 7.15 (br. s., 3H), 6.92 (d, J=7.0 Hz, 2H), 6.78 (br. s., 2H), 6.45 (br. s., 1H), 4.29 (br. s., 1H), 3.08 (s, 3H), 2.93 (s, 6H), 2.73-2.69 (m, 1H), 2.55-2.46 (m, 4H).
LC-MS retention time=2.73 min; m/z=525.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (500 MHZ, DMSO-d6) δ 9.81 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.57-7.51 (m, 1H), 7.48-7.34 (m, 4H), 7.15 (d, J=4.0 Hz, 3H), 7.02 (d, J=8.4 Hz, 2H), 6.74 (d, J=4.0 Hz, 2H), 6.65 (d, J=8.1 Hz, 1H), 4.32-4.24 (m, 1H), 3.68 (s, 3H), 3.09 (s, 3H), 2.78-2.71 (m, 1H), 2.50 (s, 3H), 2.50-2.45 (m, 1H).
LC-MS retention time=2.05 min; m/z=495.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.19 min; m/z=509.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220). 1H NMR (500 MHZ, DMSO-d6) δ 9.46 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.72 (br. s., 1H), 7.51 (d, J=6.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.26 (d, J=7.7 Hz, 1H), 7.14 (d, J=7.0 Hz, 3H), 6.73 (d, J=6.6 Hz, 2H), 6.65 (br. s., 1H), 4.21 (d, J=5.5 Hz, 1H), 3.18 (s, 3H), 2.80 (d, J=7.3 Hz, 1H), 2.57-2.47 (m, 4H).
LC-MS retention time=2.00 min; m/z=504.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.61 min; m/z=476.9 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.22 min; m/z=503.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.48 min; m/z=519.0 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.23 min; m/z=513.0 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.26 min; m/z=492.0 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
For Examples CA-102 through CA-112, the following procedure was utilized:
A solution of POCl3 (0.15 mmol) in pyridine (0.5 mL) was added to a solution of the appropriate aniline (0.11 mol) and (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (0.10 mmol) in pyridine (0.5 mL) at 0° C. The reaction mixture was allowed to warm to rt while being shaken ON. The reaction was cooled using ice bath, quenched with MeOH (0.5 mL) and concentrated to dryness. The crude residue was treated with DCM (0.5 mL) and TFA (0.5 mL) and the reaction mixture was shaken at rt for 4 h. The reaction mixture was concentrated to dryness and the crude residue was dissolved into DIPEA (0.3 mmol) in DCM (0.5 mL) and treated with a solution of 2-methylbenzenesulfonyl isocyanate (0.15 mmol) in DCM (0.5 mL). The reaction mixture was shaken at rt for 2 h, diluted with MeOH (0.5 mL) and concentrated to dryness. The crude residue was dissolved into DMF (1 mL), filtered and purified by preparative HPLC to yield the title compound.
A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (30.1 mg, 100 μmol) and HATU (41.8 mg, 110 μmol) in DMF (0.5 mL) was added to a solution of 2-fluoro-5-(methylamino)benzamide (16.8 mg, 100 μmol) in DIPEA (0.044 mL, 250 μmol) and DMF (0.5 mL) and the reaction mixture was shaken at rt ON. The reaction mixture was concentrated to dryness, dissolved into DCM (0.5 mL) and TFA (0.5 mL) and the reaction mixture was shaken at rt for 4 h. The reaction mixture was concentrated to dryness. The crude residue was dissolved into DCM (1.0 mL) and treated with DIPEA (0.052 mL, 300 μmol) and 2-methylbenzenesulfonyl isocyanate (0.023 mL, 150 μmol), and then the reaction mixture was shaken at rt for 2 h and concentrated to dryness. The crude residue was dissolved into DMF (1 mL), filtered and purified by preparative HPLC to yield the title compound (19.4 mg). LC-MS retention time=1.14 min; m/z=549.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.11 min; m/z=555.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.32 min; m/z=539.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.46 min; m/z=539.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.32 min; m/z=581.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.47 min; m/z=506.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.83 min; m/z=572.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.36 min; m/z=539.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.34 min; m/z=539.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=2.66 min; m/z=522.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
LC-MS retention time=1.56 min; m/z=524.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH4OAc, Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
Prepared using the procedure described for Example ZY-7 where 2-methylbenzenesulfonyl isocyanate was replaced by 2-chlorobenzenesulfonyl isocyanate. LC-MS retention time=2.23 min; m/z=565.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
Triphosgene (0.051 g, 0.17 mmol) was added to a stirred suspension of 2,5-difluorobenzenesulfonamide (0.10 g, 0.52 mmol) and 1-isocyanatobutane (5.8 μl, 0.052 mmol) in toluene (2 mL) and the reaction mixture was heated at 110° C. for 16 h. The reaction mixture was allowed to cool to rt, and ½ (1 mL) of the crude solution was added to a solution of an HCL salt of Intermediate ZY-5 (30 mg, 0.071 mmol) in CH3CN (1 mL) and DIPEA (0.050 mL, 0.29 mmol) and stirred at rt for 2 h. The reaction mixture was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (23.1 mg). LC-MS retention time=2.61 min; m/z=566.9 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
Prepared using the procedure described for Example ZY-14 where 2,5-difluorobenzenesulfonamide was replaced by 2-fluorobenzenesulfonamide. LC-MS retention time=1.28 min; m/z=549.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
Prepared using the procedure described for Example ZY-14 where 2,5-difluorobenzenesulfonamide was replaced by 2,4-difluorobenzenesulfonamide. LC-MS retention time=2.23 min; m/z=567.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
A solution of 2-chlorobenzenesulfonyl isocyanate (21 mg, 0.098 mmol) in DCM (0.5 mL) was added dropwise to a stirred solution of a TFA salt of (S)-2-amino-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenylpropanamide (Intermediate 6) (40 mg, 0.098 mmol) and triethylamine (40 mg, 0.39 mmol) in DCM (1 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, dissolved into DMF, filtered and purified by preparative HPLC to yield the title compound (23.6 mg). LC-MS retention time=1.57 min; m/z=512.5 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
A solution of 2-methylbenzenesulfonyl isocyanate (19 mg, 0.098 mmol) in DCM (0.5 mL) was added dropwise to a stirred solution of a TFA salt of (S)-2-amino-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenylpropanamide (Intermediate 6) (40 mg, 0.098 mmol) and triethylamine (40 mg, 0.39 mmol) in DCM (1 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, dissolved into DMF, filtered and purified by preparative HPLC to yield the title compound (36.5 mg). LC-MS retention time=1.90 min; m/z=492.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
A solution of benzenesulfonyl isocyanate (18 mg, 0.098 mmol) in DCM (0.5 mL) was added dropwise to a stirred solution of a TFA salt of (S)-2-amino-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenylpropanamide (Intermediate 6) (40 mg, 0.098 mmol) and triethylamine (40 mg, 0.39 mmol) in DCM (1 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, dissolved into DMF, filtered and purified by preparative HPLC to yield the title compound (34.4 mg). LC-MS retention time=1.81 min; m/z=478.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
A solution of 4M HCl (0.67 mL, 2.7 mmol) in dioxane was added to a stirred solution of (S)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-4-phenylbutan-2-yl)carbamate (Intermediate 7) (110 mg, 0.267 mmol) in dioxane (0.67 mL) and the reaction mixture was stirred at RT for 2 h. The crude reaction mixture was concentrated to dryness and the residue was dissolved into acetonitrile (1.1 mL) and DIPEA (0.116 mL, 0.667 mmol) and then treated with 2-methylbenzenesulfonyl isocyanate (79 mg, 0.40 mmol) and stirred at RT for 2.5 h. The reaction was quenched with MeOH (˜5 mL), concentrated and the residue was partitioned between EtOAc (˜8 mL) and water (˜5 mL). The organic component was washed with brine (5 mL), concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (63.1 mg). LC-MS retention time=1.88 min; m/z=510.3 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
A solution of 4M HCl (0.54 mL, 2.2 mmol) in dioxane was added to a stirred solution of (R)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-4-phenylbutan-2-yl)carbamate (Intermediate 8) (89 mg, 0.22 mmol) in dioxane (0.54 mL) and the reaction mixture was stirred at RT for 2 h. The crude reaction mixture was concentrated to dryness and the residue was dissolved into acetonitrile (1 mL) and DIPEA (0.0.94 mL, 0.54 mmol) and then treated with 2-methylbenzenesulfonyl isocyanate (64 mg, 0.32 mmol) and stirred at RT for 2.5 h. The reaction was quenched with MeOH (˜5 mL), concentrated and the residue was partitioned between EtOAc (˜8 mL) and water (˜5 mL). The organic component was washed with brine (5 mL), concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (58.7 mg). LC-MS retention time=2.44 min; m/z=510.2 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% MeOH: 10 mM NH4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
A suspension of 2-vinylbenzenesulfonamide (77.4 mg, 0.422 mmol) in toluene (1 mL) in an 8-mL glass vial was treated with butyl isocyanante (4.2 mg, 0.042 mmol) and triphosgene (44 mg, 0.15 mmol). The vial was sealed and the reaction mixture was stirred at 115° C. overnight. The crude reaction mixture was concentrated to dryness, dissolved into DCM (1 mL) and added dropwise to a suspension of (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-(3-vinylphenyl)propanamide, TFA (Intermediate 11) (179 mg, 0.422 mmol) in DIPEA (0.368 mL, 2.11 mmol) and DCM (5 mL) and the resulting reaction solution was stirred at RT for 1 h. The reaction was concentrated and purified by preparative HPLC (0.1% TFA, MeOH/H2O) to yield the title compound (76 mg). LC-MS retention time=1.97 min; m/z=520.2 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.82 (dd, J=7.8, 1.0 Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.49-7.43 (m, 1H), 7.35 (dd, J=17.4, 11.0 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 6.75 (s, 1H), 6.71-6.54 (m, 3H), 5.83 (d, J=17.1 Hz, 1H), 5.67 (d, J=17.4 Hz, 1H), 5.45 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.2 Hz, 1H), 4.23 (td, J=8.0, 5.3 Hz, 1H), 3.75 (s, 3H), 3.08 (s, 3H), 2.74 (dd, J=13.4, 5.1 Hz, 1H), 2.46 (d, J=8.1 Hz, 1H).
A suspension of 2-vinylbenzenesulfonamide (121 mg, 0.66 mmol) in toluene (1.4 mL) in an 8-mL glass vial was treated with butyl isocyanante (6.6 mg, 0.066 mmol) and triphosgene (69 mg, 0.23 mmol). The vial was sealed and the reaction mixture was stirred at 115° C. overnight. The crude reaction mixture was concentrated under a stream of nitrogen, dissolved into DCM (1 mL) and added dropwise to a suspension of (S)-2-amino-3-(3-(but-3-en-1-yloxy)phenyl)-N-(4-methoxyphenyl)-N-methylpropanamide, TFA (136 mg, 0.290 mmol) (Intermediate 14) in DIPEA (0.253 mL, 1.45 mmol) and DCM (5 mL) and the resulting reaction solution was stirred at RT for 1 h. The reaction was concentrated and purified by preparative HPLC (0.1% TFA, MeOH/H2O) to yield the title compound (96 mg). LC-MS retention time=2.11 min; m/z=564.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0×30 mm 3 μm. Solvent A=95% Water: 5% Acetonitrile: 10 μM ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 μM ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60-7.53 (m, 1H), 7.08-7.01 (m, 3H), 6.94 (d, J=8.8 Hz, 2H), 6.90-6.68 (m, 3H), 6.37 (d, J=7.6 Hz, 1H), 6.24 (s, 1H), 6.00-5.80 (m, 2H), 5.43 (d, J=11.0 Hz, 1H), 5.22-5.05 (m, 2H), 4.28 (td, J=8.2, 5.1 Hz, 1H), 3.86 (t, J=6.5 Hz, 2H), 3.78 (s, 3H), 3.09 (s, 3H), 2.75 (dd, J=13.6, 5.0 Hz, 1H), 2.48-2.41 (m, 3H).
Example 214 was synthesized using the procedure described above for Example 149. LC-MS retention time=1.64 min; m/z=618.1 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
10% Palladium on carbon (7.4 mg, 6.9 μmol) was added to a solution of (S)—N-(4-methoxyphenyl)-N-methyl-3-(3-vinylphenyl)-2-(3-((2-vinylphenyl)sulfonyl)ureido)propanamide (18 mg, 0.035 mmol) in MeOH (4 mL) and DCM (3 mL) and the reaction mixture was stirred under a balloon of hydrogen at RT for 1 h. The catalyst was removed by filtration and the reaction mixture was concentrated to dryness. The reaction mixture was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (8.2 mg). LC-MS retention time=2.13 min; m/z=524.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
HATU (63.5 mg, 0.167 mmol) was added to a solution of 4-(allyloxy)-N-methylaniline, HCl (36.4 mg, 0.182 mmol), (S)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanoic acid (55 mg, 0.15 mmol) and DIPEA (0.11 mL, 0.61 mmol) in DMF (1.4 mL) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was transferred into a microwave vial and heated in a microwave system at 65° C. for 2 h. The reaction mixture was filtered and purified by preparative HPLC to yield the title compound (8.3 mg). LC-MS retention time=1.48 min; m/z=508.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
2-Methylbenzenesulfonyl isocyanate (0.015 mL, 0.10 mmol) was added dropwise to an ice bath cooled stirred solution of (S)-2-amino-N-(4-(2-amino-2-oxoethoxy)phenyl)-N-methyl-3-phenylpropanamide (33 mg, 0.10 mmol) and DIPEA (0.070 mL, 0.40 mmol) in acetonitrile (1 mL) and the resulting reaction solution was stirred at RT overnight. The reaction mixture was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (17.6 mg). LC-MS retention time=1.04 min; m/z=525.4 [M+H]+. (Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH4OAc. Flow Rate=0.5 mL/min. Start % B=0. Final % B=100. Gradient Time=3 minutes, then a 0.5-minute hold at 100% B. Wavelength=220).
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 after transfection, and the amount of virus present was titered in MT-2 cells using luciferase enzyme activity as a marker. Luciferase activity 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-based (2,3-bis[2-Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt)-based colorimetric assay (Sigma-Aldrich, St Louis, Mo.).
Compounds demonstrated antiviral activity as depicted in the table below. Activity equal to A refers to a compound having an EC50 value which is <0.1 μM, B is 0.1 to <1.0 μM, C is 1.0 to <10 μM, and D is 10 to <100 μM.
It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
This application claims the priority of U.S. Provisional Application Ser. No. 61/895,102 filed Oct. 24, 2013 which is herein incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2014/061870 | 10/23/2014 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2015/061518 | 4/30/2015 | WO | A |
| Number | Date | Country |
|---|---|---|
| WO 9509614 | Apr 1995 | WO |
| Entry |
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| STN Registry database entry: CAS RN 1322021-53-3 (Entered STN: Aug. 23, 2011). (Year: 2011). |
| STN Registry database entry: CAS RN 1321895-85-5 (Entered STN: Aug. 23, 2011). (Year: 2011). |
| STN Registry database entry: CAS RN 1321806-34-1 (Entered STN: Aug. 23, 2011). (Year: 2011). |
| Clare, B. and C. Supuran, “Predictive Flip Regression: A Technique for QSAR of Derivatives of Symmetric Molecules”, J. Chem. Inf. Model. (2005), 45, pp. 1385-1391. (Year: 2005). |
| Scozzafava, et al., “Carbonic anhydrase activators,” European Journal of Pharmaceutical Sciences, vol. 10, No. 1, Mar. 1, 2000, pp. 29-41. |
| Scozzafava, et al., “Carbonic anhydrase activators: synthesis of high affinity isozymes I, II and IV activators, derivatives of 4-(4-tosylureido-amino acyl)ethyl-1H-imidazole (histamine derivatives),” J. Enzyme Inhibition, vol. 15, 2000, pp. 139-161. |
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| Number | Date | Country | |
|---|---|---|---|
| 20160257645 A1 | Sep 2016 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61895102 | Oct 2013 | US |
