Inhibitors of human immunodeficiency virus replication
10035760 · 2018-07-31
Assignee
Inventors
- Annapurna Pendri (South Glastonbury, CT)
- Guo Li (Wallingford, CT)
- John A. Bender (Middletown, CT)
- Zhong Yang (Southington, CT)
- Alan Xiangdong Wang (Wallingford, CT, US)
- Brett R. Beno (Cromwell, CT, US)
- Robert A. Fridell (Guilford, CT, US)
- Makonen Belema (North Haven, CT)
- Nicholas A. Meanwell (East Hampton, CT)
- Robert G. GENTLES (Killingworth, CT, US)
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
C07D307/38
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C07D333/54
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C07D271/06
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C07D261/08
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C07C311/58
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C07D205/04
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C07D317/66
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C07D209/08
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C07D407/12
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C07D405/12
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C07D231/12
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C07C2602/08
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C07D209/10
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C07D401/04
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C07D249/08
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International classification
A61K31/36
HUMAN NECESSITIES
C07C311/62
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C07C275/22
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C07C275/18
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C07C275/26
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C07C275/28
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A61K31/17
HUMAN NECESSITIES
C07D405/12
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A61K31/357
HUMAN NECESSITIES
A61K31/64
HUMAN NECESSITIES
C07D307/38
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C07D271/06
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C07D261/08
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C07D249/08
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C07D231/12
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C07D209/10
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C07D209/08
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C07D205/04
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C07D317/62
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C07D317/66
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C07D409/12
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C07D407/12
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C07D401/04
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C07D333/54
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C07C311/55
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C07C311/56
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C07C311/58
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Abstract
Compounds of Formula I with activity against HIV, including pharmaceutical compositions and methods for using these compounds in treating human immunodeficiency virus (HIV) infection, are set forth: ##STR00001##
Claims
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: ##STR00675## wherein: R.sup.1 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 aryl, arylalkyl or heteroaryl moieties are substituted with 0-4 groups independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkyl, alkylsulphonyl, alkylthioxy, aminocarbonyl, alkynyl, carboxylic acid, cyano, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, thioxy, SO.sub.2alkyl, heteroaryl, and nitro; R.sup.2 is H, C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl; or R.sup.1 and R.sup.2 together with the atoms to which they are attached form a heterocyclic ring optionally substituted with 0-2 alkyl groups; R.sup.3 is H, C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl; R.sup.4 is aryl which is substituted with 0-3 groups independently selected from the group consisting of alkenoxy, alkenyl, alkoxy, alkoxycarbonyl, alkyl, benzyloxy, carboamide, cyano, halo, haloalkyl, haloalkoxy, NHCO(alkyl), SO.sub.2NH-heterocycle, OH, nitro, and CH.sub.2OH; R.sup.5 and R.sup.6 are independently selected from H or alkyl, or R.sup.5 and R.sup.4 together with the atom to which they are attached form an aryl group, or R.sup.5 and R.sup.6 together with the atoms to which they are attached form a C.sub.3-C.sub.4 cycloalkyl; R.sup.7 is alkyl, aryl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl or dialkylaminoalkyl, wherein said aryl or heteroaryl is substituted with 0-3 groups independently selected from the group consisting of OH, NHCOalkyl, NHCON(alkyl).sub.2, NHCO.sub.2-alkyl, CONH.sub.2, CN, SO.sub.2N(alkyl).sub.2, alkoxy, alkyl, halo, haloalkoxy, and haloalkyl; and R.sup.8 is alkyl containing 1-6 carbon atoms, or C.sub.3-C.sub.4 cycloalkyl; or R.sup.7 and R.sup.8 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 consisting of alkyl, alkoxy, halo, OH, CN, and SO.sub.2N(alkyl).sub.2.
2. A compound or salt of claim 1, wherein R.sup.1 is aryl.
3. A compound or salt of claim 2, wherein R.sup.1 is phenyl, biphenyl or naphthalenyl.
4. A compound of claim 1, wherein R.sup.1 is heteroaryl.
5. A compound of claim 4, wherein R.sup.1 is selected from the group of thiophene, pyrrazolophenyl, furanylphenyl, pyridinylphenyl, pyrimidinylphenyl, thiophenylphenyl, benzothiophene, oxadiazolephenyl, indole, and azaindole.
6. A compound of claim 1, wherein R.sup.1 and R.sup.2 together with the NSO.sub.2 moiety to which they are attached form a heterocyclic ring.
7. A compound of claim 6, wherein said heterocyclic ring is isothiazolidine 1,1-dioxide.
8. A compound or salt of claim 1, wherein R.sup.4 is phenyl, naphthanenyl, or biaryl.
9. A compound of claim 1, wherein R.sup.7 is aryl.
10. A compound of claim 9, wherein R.sup.7 is phenyl or naphthalenyl.
11. A compound or salt of claim 1, wherein R.sup.7 is selected from the group of bezodioxolyl, dihalobezodioxolyl, benzothiazole, quinoline, benzothiazole, benzimidazole, quinazoline, quinoxaline, dihydrobenzofuran, chroman, benzoxazole, isoquinoline, and isoquinolinone.
12. A compound of claim 1, wherein R.sup.7 and R.sup.8 together form a heterocycle which 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.
13. A compound selected from the group consisting of: ##STR00676## ##STR00677## ##STR00678## ##STR00679## ##STR00680## ##STR00681## ##STR00682## ##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697## ##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702## ##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711## ##STR00712## ##STR00713## ##STR00714## ##STR00715## ##STR00716## ##STR00717## ##STR00718## ##STR00719## ##STR00720## ##STR00721## ##STR00722## ##STR00723## ##STR00724## ##STR00725## ##STR00726## ##STR00727## ##STR00728## ##STR00729## ##STR00730## ##STR00731## ##STR00732## ##STR00733## ##STR00734## ##STR00735## and pharmaceutically acceptable salts thereof.
14. A compound selected from the group consisting of: ##STR00736## ##STR00737## ##STR00738## ##STR00739## ##STR00740## ##STR00741## ##STR00742## ##STR00743## ##STR00744## ##STR00745## ##STR00746## ##STR00747## ##STR00748## and pharmaceutically acceptable salts thereof.
15. A composition useful for treating HIV infection comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier, excipient and/or diluent.
16. A method for treating HIV infection comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
Description
DETAILED DESCRIPTION OF THE EMBODIMENTS
(1) The singular forms a, an, and the include plural reference unless the context dictates otherwise.
(2) Unless otherwise expressly set forth elsewhere in the application, the following terms shall have the following meanings:
(3) 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.
(4) Alkenyloxy means an alkenyl group attached to the parent structure by an oxygen atom.
(5) Alkoxy means an alkyl group attached to the parent structure by an oxygen atom.
(6) Alkoxycarbonyl means an alkoxy group attached to the parent structure by a carbonyl moiety.
(7) Alkoxycarbonylamino means alkoxycabonyl group attached to the parent structure by nitrogen where the nitrogen is optionally substituted with an alkyl group.
(8) Alkyl means a straight or branched saturated hydrocarbon comprised of 1 to 10 carbons, and preferably 1 to 6 carbons.
(9) Alkylsulphonyl means an alkyl group attached to the parent structure through SO.sub.2 moiety.
(10) Alkylthioxy means an alkyl group attached to the parent structure through a sulfur atom.
(11) Alkynyl means an optionally substituted straight or branched alkyl group comprised of 2 to 10 carbons and containing at least one triple bond.
(12) 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.
(13) 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 C.sub.3 to C.sub.7 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.
(14) Arylalkyl is a C.sub.1-C.sub.5 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, (CH.sub.2).sub.nPh and CH(CH.sub.3)Ph with n=1-5.
(15) 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.
(16) C.sub.5-C.sub.10 bicycloalkyl means a bicyclic ring system comprised of 5 to 10 carbons. Examples include bicyclo[2.2.2]octane.
(17) C.sub.3-C.sub.4 cycloalkyl means a monocyclic ring system comprised of 3 to 4 carbons.
(18) Cycloalkyl means carbocycle with 1-2 rings optionally substituted with an alkyl or benzyl group.
(19) Cyano refers to CN.
(20) Dialkylaminoalkyl means a dialkylamino group attached to the parent structure through a C.sub.2 to C.sub.3 alkyl moiety.
(21) Halo or halogen refers to F, Cl, Br, or I.
(22) Haloalkyl means an alkyl group substituted by any combination of one to six halogen atoms.
(23) Haloalkoxy means a haloalkyl group attached to the parent structure through an oxygen atom.
(24) Hydroxy refers to OH.
(25) 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.
(26) Heteroarylalkyl is a heteroaryl moiety attached to the parent structure through C.sub.1-C.sub.5 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, (CH.sub.2).sub.n-pyridine, (CH.sub.2).sub.n-thiazole, (CH.sub.2).sub.n-quinoline, (CH.sub.2).sub.n-phenyl-pyrazole, (CH.sub.2).sub.n-(2-methylbenzimidazole), (CH.sub.2).sub.n(N-methylimidazole), (CH.sub.2).sub.n-(methyloxadiazole), CH(CH.sub.3)-(pyridine) with n=1-5.
(27) 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.
(28) 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.
(29) Those terms not specifically set forth herein shall have the meaning which is commonly understood and accepted in the art.
(30) 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.
(31) 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.
(32) 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 .sup.13C and .sup.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.
(33) As set forth above, the invention is directed to a compound of Formula I, including pharmaceutically acceptable salts thereof:
(34) ##STR00003##
wherein:
R.sup.1 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 R.sup.1 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, SO.sub.2alkyl, heteroaryl, and nitro;
R.sup.2 is H, C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl;
or R.sup.1 and R.sup.2 together with the atoms to which they are attached form a heterocyclic ring optionally substituted with 0-2 alkyl groups;
R.sup.3 is H, C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl;
R.sup.4 is H, alkyl, aryl, C.sub.5-C.sub.10 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), SO.sub.2N-heterocycle, OH, nitro, and CH.sub.2OH;
R.sup.5 and R.sup.6 are independently selected from H or alkyl, or R.sup.5 and R.sup.4 together with the atom to which they are attached form an aryl group; or R.sup.5 and R.sup.6 together with the atoms to which they are attached form a C.sub.3-C.sub.4 cycloalkyl;
R.sup.7 is H, alkyl, aryl, heteroaryl, heteroarylalkyl, C.sub.3-C.sub.7 cycloalkyl or dialkylaminoalkyl, wherein said aryl or heteroaryl is substituted with 0-3 groups independently selected from the group of OH, NHCOalkyl, NHCON(alkyl).sub.2, NHCO.sub.2-alkyl, CONH.sub.2, CN, SO.sub.2N(alkyl).sub.2, alkoxy, alkyl, halo, haloalkoxy, and haloalkyl; and
R.sup.8 is H, alkyl, arylalkyl, cycloalkyl, haloalkyl or heteroarylalkyl;
or R.sup.7 and R.sup.8 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 SO.sub.2N(alkyl).sub.2.
(35) In a preferred embodiment of the invention, R.sup.1 is aryl. More preferably, R.sup.1 is aryl which is selected from the group of phenyl, biphenyl, and naphthalenyl.
(36) In a further embodiment, R.sup.1 is heteroaryl. More preferably, R.sup.1 is selected from the group of thiophene, pyrrazolophenyl, furanylphenyl, pyridinylphenyl, pyrimidinylphenyl, thiophenylphenyl, benzothiophene, oxadiazolephenyl, indole, and andazaindole.
(37) In a further preferred embodiment, R.sup.1 and R.sup.2 form a heteroaryl ring. More preferably, the heteroaryl ring is isothiazolidine 1,1-dioxide.
(38) It is also preferred that R.sup.4 is aryl. More preferably, R.sup.4 is phenyl, naphthalenyl, or biaryl.
(39) In another embodiment it is preferred that R.sup.4 is heteroaryl. More preferably, R.sup.4 is triazole or thiophene.
(40) It is further preferred that R.sup.7 is aryl. More preferably, R.sup.7 is phenyl or naphthalenyl.
(41) In another embodiment it is preferred that R.sup.7 is heteroaryl. More preferably R.sup.7 is selected from the group of bezodioxolyl, dihalobezodioxolyl, benzothiazole, quinoline, benzothiazole, benzimidazole, quinazoline, quinoxaline, dihydrobenzofuran, chroman, benzoxazole, isoquinoline, and isoquinolinone.
(42) In a further embodiment of the invention, R.sup.7 and R.sup.8 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.
(43) Preferred compounds of the invention, including pharmaceutically acceptable salts thereof, are selected from the group of:
(44) ##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064##
(45) Other preferred compounds, including pharmaceutically acceptable salts thereof, are selected from the group of:
(46) ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077##
Pharmaceutical Compositions and Methods of Use
(47) 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).
(48) 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.
(49) 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.
(50) 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.
(51) 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.
(52) 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.
(53) 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.
(54) 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.
(55) 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.
(56) Treatment, therapy, regimen, HIV infection, ARC, AIDS and related terms are used as understood by practitioners in the field of AIDS and HIV infection.
(57) 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:
(58) TABLE-US-00001 Drug Name Manufacturer Indication ANTIVIRALS Rilpivirine Tibotec HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) COMPLERA Gilead HIV infection, AIDS, ARC; combination with emtricitabine, rilpivirine, and tenofovir disoproxil fumarate 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse trans- criptase (RT) inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir Glaxo Wellcome HIV infection, (1592U89) AIDS, ARC GW 1592 (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC Neutralizes pH Concepts Labile alpha (Rockville, MD) aberrant Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis Immune globin Cytovene Syntex Sight threatening Ganciclovir CMV peripheral CMV retinitis Darunavir Tibotec-J & J HIV infection, AIDS, ARC (protease inhibitor) Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection, (DMP 266, AIDS, ARC SUSTIVA) (non-nucleoside RT ()6-Chloro-4-(S)- inhibitor) cyclopropylethynyl- 4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Etravirine Tibotec/J & J HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Famciclovir Smith Kline herpes zoster, herpes simplex GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Triton Biosciences AIDS, Kaposi's Human (Almeda, CA) sarcoma, ARC Interferon Beta Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers CMV infection Squibb Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers HIV infection, AIDS, Didehydrodeoxy- Squibb ARC Thymidine Tipranavir Boehringer HIV infection, AIDS, ARC Ingelheim (protease inhibitor) Valaciclovir Glaxo Wellcome Genital HSV & CMV Infections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies Tenofovir Gilead HIV infection, disoproxil, AIDS, fumarate salt (reverse transcriptase (VIREAD) inhibitor) EMTRIVA Gilead HIV infection, (Emtricitabine) AIDS, (FTC) (reverse transcriptase inhibitor) COMBIVIR GSK HIV infection, AIDS, (reverse transcriptase inhibitor) Abacavir succinate GSK HIV infection, (or ZIAGEN) AIDS, (reverse transcriptase inhibitor) REYATAZ Bristol-Myers HIV infection (or atazanavir) Squibb AIDs, protease inhibitor FUZEON Roche/Trimeris HIV infection (Enfuvirtide AIDs, viral Fusion or T-20) inhibitor LEXIVA GSK/Vertex HIV infection (or Fosamprenavir AIDs, viral protease calcium) inhibitor SELZENTRY Pfizer HIV infection Maraviroc; AIDs, (CCR5 antagonist, (UK 427857) in development) TRIZIVIR GSK HIV infection AIDs, (three drug combination) Sch-417690 Schering-Plough HIV infection (vicriviroc) AIDs, (CCR5 antagonist, in development) TAK-652 Takeda HIV infection AIDs, (CCR5 antagonist, in development) GSK 873140 GSK/ONO HIV infection (ONO-4128) AIDs, (CCR5 antagonist, in development) Integrase Inhibitor Merck HIV infection MK-0518 AIDs Raltegravir TRUVADA Gilead Combination of Tenofovir disoproxil fumarate salt (VIREAD) and EMTRIVA (Emtricitabine) Integrase Inhibitor Gilead/Japan HIV Infection GS917/JTK-303 Tobacco AIDs Elvitegravir in development Triple drug Gilead/Bristol- Combination of Tenofovir combination Myers Squibb disoproxil fumarate salt ATRIPLA (VIREAD), EMTRIVA (Emtricitabine), and SUSTIVA (Efavirenz) FESTINAVIR Oncolys BioPharma HIV infection AIDs in development CMX-157 Chimerix HIV infection Lipid conjugate of AIDs nucleotide tenofovir GSK1349572 GSK HIV infection Integrase inhibitor AIDs IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 Wyeth AIDS, Kaposi's Lederle Labs sarcoma FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, Macrophage Colony combination Stimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts (aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT Factor Remune Immune Response Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille Squibb Corp. Prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate for Inhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemia Erythropoietin assoc. with AZT therapy Recombinant Human Serono AIDS-related Growth Hormone wasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton Diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS
Synthetic Methods
(59) 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.
(60) 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; Et.sub.2O 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.
(61) 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, L 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, .sup.1H for proton, for delta, s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, br for broad, Hz for hertz, and , , R, S, E, and Z are stereochemical designations familiar to one skilled in the art.
(62) ##STR00078##
EXAMPLES
(63) The following examples are provided by way of illustration only, and should not be construed as limiting the scope of the invention.
(64) ##STR00079##
N-methylbenzo[d][1,3]dioxol-5-amine
(65) 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 (MgSO.sub.4), filtered and concentrated. The residue was purified using a Biotage Horizon (40 g SiO.sub.2, 10-25% EtOAc/hexanes) to afford the title compound (1.43 g) as amber oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 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).
(66) TABLE-US-00002 MS (M + H).sup.+ Calcd. 152.1 MS (M+ H).sup.+ Observ. 152.2 Retention Time 0.298 min LC Condition Solvent A 10% acetonitrile:90% Water:0.1% TFA Solvent B 90% acetonitrile:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Phenomenex LUNA C18 30 2 mm, 3
(67) ##STR00080##
(S)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(68) 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. NaHCO.sub.3 (aq) (50 mL) and EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO.sub.4) filtered and concentrated. The residue was purified using a Biotage Horizon (80 g SiO.sub.2, 10-40% EtOAc) to afford the title compound (2.15 g) as tan solidified foam. .sup.1H NMR (400 MHZ, CDCl.sub.3) 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).
(69) TABLE-US-00003 MS (M + H).sup.+ Calcd. 399.2 MS (M + H).sup.+ Observ. 399.3 Retention Time 1.68 min LC Condition Solvent A 10% acetonitrile:90% Water:0.1% TFA Solvent B 90% acetonitrile:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Phenomenex LUNA C18 30 2 mm, 3
(70) ##STR00081##
(S)-2-amino-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide
(71) 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.
(72) TABLE-US-00004 MS (M + H).sup.+ Calcd. 299.1 MS (M + H).sup.+ Observ. 299.2 Retention Time 0.99 min LC Condition Solvent A 10% acetonitrile:90% Water:0.1% TFA Solvent B 90% acetonitrile:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Phenomenex Luna 30 2.0 MM 3 u
(73) ##STR00082##
(S)-tert-butyl (1-(methyl(phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(74) 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 (MgSO.sub.4) filtered and concentrated. The residue was used without purification.
(75) TABLE-US-00005 MS (M + H).sup.+ Calcd. 355.2 MS (M + H).sup.+ Observ. 355.3 Retention Time 1.88 min LC Condition Solvent A 10% acetonitrile:90% Water:0.1% TFA Solvent B 90% acetonitrile:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Phenomenex LUNA C18 30 2 mm, 3
(76) ##STR00083##
(S)-2-amino-N-methyl-N, 3-diphenylpropanamide
(77) 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.
(78) TABLE-US-00006 MS (M + H).sup.+ Calcd. 255.1 MS (M + H).sup.+ Observ. 255.2 Retention Time 1.19 min LC Condition Solvent A 10% acetonitrile:90% Water:0.1% TFA Solvent B 90% acetonitrile:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Phenomenex LUNA C18 30 2 mm, 3
(79) ##STR00084##
(S)-2-amino-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenylpropanamide
(80) 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. 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).
(81) ##STR00085##
(S)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-4-phenylbutan-2-yl)carbamate
(82) 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. 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).
(83) ##STR00086##
(R)-tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-4-phenylbutan-2-yl)carbamate
(84) 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. 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).
(85) ##STR00087##
(S)-tert-butyl (3-(3-bromophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)carbamate
(86) 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 (240 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
(87) ##STR00088##
(S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-(3-vinylphenyl)propan-2-yl)carbamate
(88) 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 Na.sub.2CO.sub.3 (2.66 mL, 7.99 mmol) and PdCl.sub.2(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 (2150 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(89) ##STR00089##
(S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-(3-vinylphenyl)propanamide
(90) 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
(91) ##STR00090##
(S)-tert-butyl (3-(3-hydroxyphenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)carbamate
(92) 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 (240 mL) and the combined organic component was concentrated to dryness and purified (40 g SiO.sub.2, 0-30% EtOAc/DCM) to yield the title compound (0.58 g). LC-MS retention time=1.99 min; m/z=399.3 [MH].sup.. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(93) ##STR00091##
(S)-tert-butyl (3-(3-(but-3-en-1-yloxy)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)carbamate
(94) 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 Cs.sub.2CO.sub.3 (0.465 g, 1.43 mmol) in THF (8 mL), EtOH (8 mL) and H.sub.2O (8 mL) was stirred at 85 C. for 22 h. The reaction was diluted with water (80 mL), extracted with EtOAc (2100 mL) and the combined organic component was concentrated to dryness and purified (24 g SiO.sub.2, 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(95) ##STR00092##
(S)-2-amino-3-(3-(but-3-en-1-yloxy)phenyl)-N-(4-methoxyphenyl)-N-methylpropanamide
(96) 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].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
(97) ##STR00093##
tert-butyl (4-(allyloxy)phenyl)(methyl) carbamate
(98) A mixture of tert-butyl (4-hydroxyphenyl)(methyl)carbamate (1.00 g, 4.48 mmol), allyl bromide (0.58 mL, 6.7 mmol) and Cs.sub.2CO.sub.3 (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 MgSO.sub.4, filtered, and concentrated. The residue was taken up into DCM and purified by flash column chromatography. .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(99) ##STR00094##
4-(allyloxy)-N-methylaniline
(100) 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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).
(101) ##STR00095##
(S)-benzyl 3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanoate
(102) 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 MgSO.sub.4, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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).
(103) ##STR00096##
(S)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanoic acid
(104) A mixture of (S)-benzyl 3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanoate (1.00 g, 2.21 mmol) and 10% PdC (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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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).
(105) ##STR00097##
(S)-2-amino-N-(4-(2-amino-2-oxoethoxy)phenyl)-N-methyl-3-phenylpropanamide
(106) Intermediate 19 was prepared using the chemical procedures displayed in the following scheme:
(107) ##STR00098##
(108) LC-MS retention time=0.73 min; m/z=328.2 [M+H].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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).
(109) ##STR00099##
(S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(110) 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. NaHCO.sub.3 (aq) (60 mL). The organic component was washed with brine (40 mL), dried (MgSO.sub.4), filtered, concentrated and purified using a Biotage Horizon (80 g SiO.sub.2, 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].sup.+. (Column: Phenonenex-Luna C18 2.050 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220). .sup.1H NMR (400 MHz, CDCl.sub.3) 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).
(111) ##STR00100##
(S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide
(112) 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].sup.+. (Column: Phenonenex-Luna C18 2.050 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220).
(113) ##STR00101##
(S)-tert-butyl (1-(methyl(3,4,5-trimethoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(114) 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 NaHCO.sub.3 (aq) (40 mL). The organic component was washed with brine (30 mL), dried (MgSO.sub.4), filtered and concentrated. The crude residue was then purified using a Biotage Horizon (80 g SiO.sub.2, 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].sup.+. (Column: Phenonenex-Luna C18 2.050 mm 3 m. 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). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(115) ##STR00102##
N-methylbenzo[d]thiazol-5-amine
(116) 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 NaBH.sub.4 (126 mg, 3.33 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHCl.sub.3 (320 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12 g SiO.sub.2, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(117) ##STR00103##
(S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(118) 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. NaHCO.sub.3 (20 mL) and extracted with EtOAc (350 mL). The combined organic component was washed with brine (60 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (12 g SiO.sub.2, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(119) ##STR00104##
(S)-2-amino-N-(benzo[d]thiazol-5-yl)-N-methyl-3-phenylpropanamide
(120) 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 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).
(121) ##STR00105##
(S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate
(122) 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. NaHCO.sub.3 (20 mL) and extracted with EtOAc (350 mL). The combined organic component was washed with brine (60 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (24 g SiO.sub.2, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, CHLOROFORM-d) 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).
(123) ##STR00106##
(S)-2-amino-N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-N-methylpropanamide
(124) 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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).
(125) ##STR00107##
(S)-tert-butyl (1-(benzyl(4-methoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(126) 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 SiO.sub.2, 0-50% Et.sub.2O/hexanes) to yield the title compound (125 mg). LC-MS retention time=1.43 min; m/z=461.4 [M+H].sup.+. (Column: Waters Aquity BEH C18 2.150 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).
(127) ##STR00108##
(S)-2-amino-N-benzyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(128) 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].sup.+. (Column: Waters Aquity BEH C18 2.150 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).
(129) ##STR00109##
N-benzyl-4-methoxyaniline
(130) 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% Et.sub.2O/hexanes) to yield the title compound (503 mg) as yellow oil.
(131) TABLE-US-00007 MS (M + H).sup.+ Calcd. 214.1 MS (M + H).sup.+ Observ. 214.1 Retention Time 0.824 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7U
(132) ##STR00110##
4-methoxy-N-(pyridin-4-ylmethyl)aniline
(133) 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 SiO.sub.2, 0-100% Et.sub.2O/hexanes) to yield the title compound (447 mg) as yellow solid.
(134) TABLE-US-00008 MS (M + H).sup.+ Calcd. 215.1 MS (M + H).sup.+ Observ. 215.1 Retention Time 0.719 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7U
(135) ##STR00111##
4-methoxy-N-phenethylaniline
(136) 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 SiO.sub.2, 0-20% Et.sub.2O/hexanes) to yield the title compound (2.25 g) contaminated with and impurity, but used without additional purification, as red/orange oil.
(137) TABLE-US-00009 MS (M + H).sup.+ Calcd. 228.1 MS (M + H).sup.+ Observ. 228.1 Retention Time 0.867 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7 U
(138) ##STR00112##
N-isobutyl-4-methoxyaniline
(139) 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 SiO.sub.2, 0-20% Et.sub.2O/hexanes) to yield the title compound (1.02 g) as clear colorless oil.
(140) TABLE-US-00010 MS (M + H).sup.+ Calcd. 180.1 MS (M + H).sup.+ Observ. 180.1 Retention Time 0.774 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7 U
(141) ##STR00113##
N-ethyl-4-methoxy-3-methylaniline
(142) 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 (310 mL) and the combined organic component was concentrated and purified by preparative HPLC (H.sub.2O-MeOH with 0.1% TFA buffer) to yield a TFA salt of the title compound (27 mg) as dark pink oil.
(143) TABLE-US-00011 MS (M + H).sup.+ Calcd. 166.1 MS (M + H).sup.+ Observ. 166.1 Retention Time 0.787 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7 U
(144) ##STR00114##
N-ethylchroman-6-amine
(145) Prepared using the procedure outlined for Intermediate ZY-12 where 4-methoxy-3-methylaniline was replaced with chroman-6-amine.
(146) TABLE-US-00012 MS (M + H).sup.+ Calcd. 178.1 MS (M + H).sup.+ Observ. 178.1 Retention Time 0.774 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7 U
(147) ##STR00115##
N-ethylquinolin-6-amine
(148) Prepared using the procedure outlined for Intermediate ZY-12 where 4-methoxy-3-methylaniline was replaced with quinoline-6-amine.
(149) TABLE-US-00013 MS (M + H).sup.+ Calcd. 173.1 MS (M + H).sup.+ Observ. 173.1 Retention Time 0.775 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7 U
(150) ##STR00116##
N-ethyl-2-methylquinolin-6-amine
(151) 10% PdC (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 N.sub.2 (3) followed by H.sub.2 (3) and then shaken at RT under 20 psi H.sub.2 for 4 h. The reaction mixture was filtered through celite, concentrated and purified by flash silica chromatography (12 g SiO.sub.2, 0-35% EtOAc/hexanes) to yield N-ethyl-2-methylquinolin-6-amine (192 mg) as brown solid.
(152) TABLE-US-00014 MS (M + H).sup.+ Calcd. 187.1 MS (M + H).sup.+ Observ. 187.1 Retention Time 0.809 min LC Condition Solvent A 100% Water:0.05% TFA Solvent B 100% acetonitrile:0.05% TFA Start % B 2 Final % B 98 Gradient Time 1.5 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Waters Aquity BEH C18 2.1 50 mm 1.7 U
Example 1
(153) ##STR00117##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-(phenylsulfonyl)ureido)propanamide
(154) 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 (31 mL). The combined organic component was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC to afford the title compound (45.9 mg). .sup.1H NMR (600 MHZ, DMSO-d.sub.6) 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).
(155) TABLE-US-00015 MS (M + H).sup.+ Calcd. 482.1 MS (M + H).sup.+ Observ. 482.2 Retention Time 1.30 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7- particles
Example 2
(156) ##STR00118##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(157) 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. .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(158) TABLE-US-00016 MS (M + H).sup.+ Calcd. 496.2 MS (M + H).sup.+ Observ. 496.3 Retention Time 1.46 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 3
(159) ##STR00119##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3-chlorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(160) 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). .sup.1H NMR (600 MHZ, DMSO-d.sub.6) 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).
(161) TABLE-US-00017 MS (M + H).sup.+ Calcd. 516.1 MS (M + H).sup.+ Observ. 516.4 Retention Time 1.36 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 4
(162) ##STR00120##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-((1-methylcyclopropyl)sulfonyl) ureido)-3-phenylpropanamide
(163) 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(164) TABLE-US-00018 MS (M + H).sup.+ Calcd. 460.2 MS (M + H).sup.+ Observ. 460.3 Retention Time 1.43 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Examples 5-7 were synthesized using the procedure described above for Example 2.
Example 5
(165) ##STR00121##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-tosylureido)propanamide
(166) TABLE-US-00019 MS (M + H).sup.+ Calcd. 496.2 MS (M + H).sup.+ Observ. 496.2 Retention Time 1.65 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(167) .sup.1H NMR (600 MHZ, DMSO-d.sub.6) 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).
Example 6
(168) ##STR00122##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((4-chlorophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(169) TABLE-US-00020 MS (M + H).sup.+ Calcd. 516.1 MS (M + H).sup.+ Observ. 516.2 Retention Time 1.62 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(170) .sup.1H NMR (600 MHZ, DMSO-d.sub.6) 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).
Example 7
(171) ##STR00123##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-chlorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(172) TABLE-US-00021 MS (M + H).sup.+ Calcd. 516.1 MS (M + H).sup.+ Observ. 516.5 Retention Time 1.27 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(173) .sup.1H NMR (600 MHZ, DMSO-d.sub.6) 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).
(174) Examples 8-35 were synthesized using the procedure described above for Example 3.
Example 8
(175) ##STR00124##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((4-methoxyphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(176) TABLE-US-00022 MS (M + H).sup.+ Calcd. 512.1 MS (M + H).sup.+ Observ. 512.2 Retention Time 1.57 min LC Condition Solvent A 10% acetonitrile:90% Water:0.1% TFA Solvent B 90% acetonitrile:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:TFA Column Phenomenex Luna 30 2.0 MM 3 u
(177) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 9
(178) ##STR00125##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-fluorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(179) TABLE-US-00023 MS (M + H).sup.+ Calcd. 500.1 MS (M + H).sup.+ Observ. 500.2 Retention Time 1.48 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(180) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 10
(181) ##STR00126##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-(benzylsulfonyl)ureido)-N-methyl-3-phenylpropanamide
(182) TABLE-US-00024 MS (M + H).sup.+ Calcd. 496.2 MS (M + H).sup.+ Observ. 496.3 Retention Time 1.78 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(183) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 11
(184) ##STR00127##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3,5-dichlorophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(185) TABLE-US-00025 MS (M + H).sup.+ Calcd. 550.1 MS (M + H).sup.+ Observ. 550.2 Retention Time 1.82 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(186) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 12
(187) ##STR00128##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,5-dibromophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(188) TABLE-US-00026 MS (M + H).sup.+ Calcd. 638.0 MS (M + H).sup.+ Observ. 638.1 Retention Time 1.88 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(189) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 13
(190) ##STR00129##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,5-dimethylphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(191) TABLE-US-00027 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.75 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(192) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 14
(193) ##STR00130##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(trifluoromethoxy)phenyl)sulfonyl)ureido)propanamide
(194) TABLE-US-00028 MS (M + H).sup.+ Calcd. 566.1 MS (M + H).sup.+ Observ. 566.2 Retention Time 1.78 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(195) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 15
(196) ##STR00131##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,3-dichlorophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(197) TABLE-US-00029 MS (M + H).sup.+ Calcd. 550.1 MS (M + H).sup.+ Observ. 550.2 Retention Time 1.41 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(198) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 16
(199) ##STR00132##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((5-fluoro-2-methylphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(200) TABLE-US-00030 MS (M + H).sup.+ Calcd. 514.1 MS (M + H).sup.+ Observ. 514.3 Retention Time 1.57 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(201) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 17
(202) ##STR00133##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(trifluoromethyl)phenyl)sulfonyl) ureido)propanamide
(203) TABLE-US-00031 MS (M + H).sup.+ Calcd. 550.1 MS (M + H).sup.+ Observ. 550.3 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(204) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 18
(205) ##STR00134##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,4-difluorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(206) TABLE-US-00032 MS (M + H).sup.+ Calcd. 518.1 MS (M + H).sup.+ Observ. 518.2 Retention Time 1.54 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(207) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 19
(208) ##STR00135##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3-bromophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(209) TABLE-US-00033 MS (M + H).sup.+ Calcd. 560.0 MS (M + H).sup.+ Observ. 560.1 Retention Time 1.63 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(210) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 20
(211) ##STR00136##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3-methoxyphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(212) TABLE-US-00034 MS (M + H).sup.+ Calcd. 512.1 MS (M + H).sup.+ Observ. 512.2 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(213) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 21
(214) ##STR00137##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-((4-nitrophenyl)sulfonyl)ureido)-3-phenylpropanamide
(215) TABLE-US-00035 MS (M + H).sup.+ Calcd. 527.1 MS (M + H).sup.+ Observ. 527.2 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(216) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 22
(217) ##STR00138##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((4-fluorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(218) TABLE-US-00036 MS (M + H).sup.+ Calcd. 500.1 MS (M + H).sup.+ Observ. 500.3 Retention Time 1.32 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(219) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 23
(220) ##STR00139##
(S)-methyl 2-(N-((1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)sulfamoyl)benzoate
(221) TABLE-US-00037 MS (M + H).sup.+ Calcd. 540.1 MS (M + H).sup.+ Observ. 540.4 Retention Time 1.32 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(222) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 24
(223) ##STR00140##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(phenethylsulfonyl)ureido)-3-phenylpropanamide
(224) TABLE-US-00038 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.57 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(225) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 25
(226) ##STR00141##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((3-phenylpropyl)sulfonyl) ureido)propanamide
(227) TABLE-US-00039 MS (M + H).sup.+ Calcd. 524.2 MS (M + H).sup.+ Observ. 524.3 Retention Time 1.68 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(228) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 26
(229) ##STR00142##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3,4-difluorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(230) TABLE-US-00040 MS (M + H).sup.+ Calcd. 518.1 MS (M + H).sup.+ Observ. 518.2 Retention Time 1.37 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(231) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 27
(232) ##STR00143##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-((5-methylthiophen-2-yl)sulfonyl)ureido)-3-phenylpropanamide
(233) TABLE-US-00041 MS (M + H).sup.+ Calcd. 502.1 MS (M + H).sup.+ Observ. 502.3 Retention Time 1.35 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(234) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 28
(235) ##STR00144##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3-chloro-2-methylphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(236) TABLE-US-00042 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.4 Retention Time 1.53 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(237) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 29
(238) ##STR00145##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-bromophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(239) TABLE-US-00043 MS (M + H).sup.+ Calcd. 560.0 MS (M + H).sup.+ Observ. 560.3 Retention Time 1.35 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(240) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 30
(241) ##STR00146##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,5-dimethoxyphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(242) TABLE-US-00044 MS (M + H).sup.+ Calcd. 542.2 MS (M + H).sup.+ Observ. 542.5 Retention Time 1.50 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(243) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 31
(244) ##STR00147##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-(thiophen-2-ylsulfonyl) ureido)propanamide
(245) TABLE-US-00045 MS (M + H).sup.+ Calcd. 488.1 MS (M + H).sup.+ Observ. 488.2 Retention Time 1.19 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(246) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 32
(247) ##STR00148##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,5-dichlorothiophen-3-yl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(248) TABLE-US-00046 MS (M + H).sup.+ Calcd. 556.0 MS (M + H).sup.+ Observ. 556.2 Retention Time 1.42 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(249) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 33
(250) ##STR00149##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(251) TABLE-US-00047 MS (M + H).sup.+ Calcd. 534.1 MS (M + H).sup.+ Observ. 534.3 Retention Time 1.18 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(252) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 34
(253) ##STR00150##
(S)N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-(3-((2-fluorophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(254) TABLE-US-00048 MS (M + H).sup.+ Calcd. 536.1 MS (M + H).sup.+ Observ. 536.2 Retention Time 2.54 min LC Condition Solvent A 5% Methanol:95% Water:10 mM Ammonium Acetate Solvent B 95% Methanol:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair Methanol:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(255) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 35
(256) ##STR00151##
(S)N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(3,5-difluorophenyl)-2-(3-((2-fluorophenyl)sulfonyl) ureido)-N-methylpropanamide
(257) TABLE-US-00049 MS (M + H).sup.+ Calcd. 572.1 MS (M + H).sup.+ Observ. 572.4 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(258) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(259) Examples 36-41 were synthesized using the procedure described above for Example 2.
Example 36
(260) ##STR00152##
(S)N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-(phenylsulfonyl)ureido)propanamide
(261) TABLE-US-00050 MS (M + H).sup.+ Calcd. 518.1 MS (M + H).sup.+ Observ. 518.3 Retention Time 1.65 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(262) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 37
(263) ##STR00153##
(S)N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(264) TABLE-US-00051 MS (M + H).sup.+ Calcd. 532.1 MS (M + H).sup.+ Observ. 532.4 Retention Time 1.68 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(265) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 38
(266) ##STR00154##
(S)-2-(3-((2-chlorophenyl)sulfonyl)ureido)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide
(267) TABLE-US-00052 MS (M + H).sup.+ Calcd. 552.1 MS (M + H).sup.+ Observ. 552.4 Retention Time 1.59 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(268) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 39
(269) ##STR00155##
(S)-2-(3-((2-chlorophenyl)sulfonyl)ureido)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(3,5-difluorophenyl)-N-methylpropanamide
(270) TABLE-US-00053 MS (M + H).sup.+ Calcd. 588.1 MS (M + H).sup.+ Observ. 588.4 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(271) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 40
(272) ##STR00156##
(S)N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(273) TABLE-US-00054 MS (M + H).sup.+ Calcd. 568.1 MS (M + H).sup.+ Observ. 568.4 Retention Time 1.71 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(274) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 41
(275) ##STR00157##
(S)N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(phenylsulfonyl) ureido)propanamide
(276) TABLE-US-00055 MS (M + H).sup.+ Calcd. 554.1 MS (M + H).sup.+ Observ. 554.3 Retention Time 1.62 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(277) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(278) Examples 42-46 were synthesized using the procedure described above for Example 4.
Example 42
(279) ##STR00158##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-(cyclopropylsulfonyl)ureido)-N-methyl-3-phenylpropanamide
(280) TABLE-US-00056 MS (M + H).sup.+ Calcd. 446.1 MS (M + H).sup.+ Observ. 446.2 Retention Time 1.71 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(281) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 43
(282) ##STR00159##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-(isopropylsulfonyl) ureido)-N-methyl-3-phenylpropanamide
(283) TABLE-US-00057 MS (M + H).sup.+ Calcd. 448.2 MS (M + H).sup.+ Observ. 448.2 Retention Time 1.72 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(284) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 44
(285) ##STR00160##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(methylsulfonyl) ureido)-3-phenylpropanamide
(286) TABLE-US-00058 MS (M + H).sup.+ Calcd. 420.1 MS (M + H).sup.+ Observ. 420.2 Retention Time 1.42 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(287) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 45
(288) ##STR00161##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-(isobutylsulfonyl) ureido)-N-methyl-3-phenylpropanamide
(289) TABLE-US-00059 MS (M + H).sup.+ Calcd. 462.2 MS (M + H).sup.+ Observ. 462.3 Retention Time 1.45 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(290) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 46
(291) ##STR00162##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-(tert-butylsulfonyl)ureido)-N-methyl-3-phenylpropanamide
(292) TABLE-US-00060 MS (M + H).sup.+ Calcd. 462.2 MS (M + H).sup.+ Observ. 462.3 Retention Time 1.52 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(293) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 47
(294) ##STR00163##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-bromophenyl)sulfonyl)-3-methylureido)-N-methyl-3-phenylpropanamid
(295) 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 K.sub.2CO.sub.3 (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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(296) TABLE-US-00061 MS (M + H).sup.+ Calcd. 574.1 MS (M + H).sup.+ Observ. 574.5 Retention Time 1.98 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 48
(297) ##STR00164##
(S)-2-(3-([1,1-biphenyl]-2-ylsulfonyl)ureido)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide
(298) 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(PPh.sub.3).sub.4 (3.51 mg, 3.03 mol) and DMF (1 mL), followed by 2M aq. Na.sub.2CO.sub.3 (50 l). 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(299) TABLE-US-00062 MS (M + H).sup.+ Calcd. 558.2 MS (M + H).sup.+ Observ. 558.3 Retention Time 1.74 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Examples 49-50 were synthesized using the procedure described above for Example 48.
Example 49
(300) ##STR00165##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-((2-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)ureido)-3-phenylpropanamide
(301) TABLE-US-00063 MS (M + H).sup.+ Calcd. 562.2 MS (M + H).sup.+ Observ. 562.3 Retention Time 1.43 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(302) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 50
(303) ##STR00166##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-(furan-3-yl)phenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(304) TABLE-US-00064 MS (M + H).sup.+ Calcd. 548.1 MS (M + H).sup.+ Observ. 548.3 Retention Time 1.58 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(305) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(306) Examples 51-85 were synthesized using the procedure described above for Example 2.
Example 51
(307) ##STR00167##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(308) TABLE-US-00065 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.3 Retention Time 1.60 min LC Condition Solvent A 5% acetonitrile:95% Water:10mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(309) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 52
(310) ##STR00168##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-ethoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(311) TABLE-US-00066 MS (M + H).sup.+ Calcd. 540.2 MS (M + H).sup.+ Observ. 540.3 Retention Time 1.55 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(312) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 53
(313) ##STR00169##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-(o-tolyl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(314) TABLE-US-00067 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.65 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(315) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 54
(316) ##STR00170##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(2-chlorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(317) TABLE-US-00068 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.3 Retention Time 1.59 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(318) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 55
(319) ##STR00171##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3-chlorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(320) TABLE-US-00069 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.2 Retention Time 1.64 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(321) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 56
(322) ##STR00172##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(323) TABLE-US-00070 MS (M + H).sup.+ Calcd. 526.2 MS (M + H).sup.+ Observ. 526.3 Retention Time 1.51 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(324) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 57
(325) ##STR00173##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(326) TABLE-US-00071 MS (M + H).sup.+ Calcd. 574.1 MS (M + H).sup.+ Observ. 574.3 Retention Time 1.64 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(327) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 58
(328) ##STR00174##
(S)-3-(4-(allyloxy)phenyl)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(329) TABLE-US-00072 MS (M + H).sup.+ Calcd. 552.2 MS (M + H).sup.+ Observ. 552.4 Retention Time 1.64 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(330) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 59
(331) ##STR00175##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3,4-dichlorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(332) TABLE-US-00073 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.2 Retention Time 1.69 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(333) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 60
(334) ##STR00176##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3,4-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(335) TABLE-US-00074 MS (M + H).sup.+ Calcd. 532.1 MS (M + H).sup.+ Observ. 532.2 Retention Time 1.71 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(336) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 61
(337) ##STR00177##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)-3-(4-(trifluoromethyl)phenyl)propanamide
(338) TABLE-US-00075 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.2 Retention Time 1.69 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(339) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 62
(340) ##STR00178##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3-cyanophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(341) TABLE-US-00076 MS (M + H).sup.+ Calcd. 521.1 MS (M + H).sup.+ Observ. 521.3 Retention Time 1.35 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(342) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 63
(343) ##STR00179##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-cyanophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(344) TABLE-US-00077 MS (M + H).sup.+ Calcd. 521.1 MS (M + H).sup.+ Observ. 521.3 Retention Time 1.60 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(345) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 64
(346) ##STR00180##
(S)-methyl 3-(3-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-3-oxo-2-(3-(o-tolylsulfonyl)ureido)propyl)benzoate
(347) TABLE-US-00078 MS (M + H).sup.+ Calcd. 554.2 MS (M + H).sup.+ Observ. 554.3 Retention Time 1.48 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(348) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 65
(349) ##STR00181##
(2S,3S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)butanamide
(350) TABLE-US-00079 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.48 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(351) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 66
(352) ##STR00182##
(S)-2-(3-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-3-oxo-2-(3-(o-tolylsulfonyl) ureido)propyl)benzamide
(353) TABLE-US-00080 MS (M + H).sup.+ Calcd. 539.2 MS (M + H).sup.+ Observ. 539.3 Retention Time 1.41 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(354) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 67
(355) ##STR00183##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(356) TABLE-US-00081 MS (M + H).sup.+ Calcd. 532.1 MS (M + H).sup.+ Observ. 532.2 Retention Time 1.52 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(357) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 68
(358) ##STR00184##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-(benzyloxy)phenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(359) TABLE-US-00082 MS (M + H).sup.+ Calcd. 602.2 MS (M + H).sup.+ Observ. 602.3 Retention Time 1.81 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(360) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 69
(361) ##STR00185##
(S)-3-([1,1-biphenyl]-4-yl)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(362) TABLE-US-00083 MS (M + H).sup.+ Calcd. 572.2 MS (M + H).sup.+ Observ. 572.4 Retention Time 1.81 min LC Condition Solvent A 5% acetonitrile: 95% Water: 10 mM Ammonium Acetate Solvent B 95% acetonitrile: 5% Water: 10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile: Water: Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(363) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 70
(364) ##STR00186##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(2-fluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(365) TABLE-US-00084 MS (M + H).sup.+ Calcd. 514.1 MS (M + H).sup.+ Observ. 514.3 Retention Time 1.49 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(366) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 71
(367) ##STR00187##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)-3-(3-(trifluoromethyl)phenyl)propanamide
(368) TABLE-US-00085 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.3 Retention Time 1.64 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(369) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 72
(370) ##STR00188##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-(p-tolyl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(371) TABLE-US-00086 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.58 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(372) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 73
(373) ##STR00189##
(S)-3-(4-acetamidophenyl)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(374) TABLE-US-00087 MS (M + H).sup.+ Calcd. 553.2 MS (M + H).sup.+ Observ. 553.3 Retention Time 1.33 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(375) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 74
(376) ##STR00190##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(2,4-dichlorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(377) TABLE-US-00088 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.3 Retention Time 1.71 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(378) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 75
(379) ##STR00191##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)-3-(2,4,5-trifluorophenyl)propanamide
(380) TABLE-US-00089 MS (M + H).sup.+ Calcd. 550.1 MS (M + H).sup.+ Observ. 550.3 Retention Time 1.56 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(381) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 76
(382) ##STR00192##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(2-bromophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(383) TABLE-US-00090 MS (M + H).sup.+ Calcd. 574.1 MS (M + H).sup.+ Observ. 574.2 Retention Time 1.72 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(384) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 77
(385) ##STR00193##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(2-cyanophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(386) TABLE-US-00091 MS (M + H).sup.+ Calcd. 521.1 MS (M + H).sup.+ Observ. 521.3 Retention Time 1.42 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(387) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 78
(388) ##STR00194##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3-methoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(389) TABLE-US-00092 MS (M + H).sup.+ Calcd. 526.2 MS (M + H).sup.+ Observ. 526.3 Retention Time 1.50 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(390) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 79
(391) ##STR00195##
(1S,2S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-phenyl-1-(3-(o-tolylsulfonyl)ureido)cyclopropanecarboxamide
(392) TABLE-US-00093 MS (M + H).sup.+ Calcd. 508.2 MS (M + H).sup.+ Observ. 508.3 Retention Time 1.42 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(393) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 80
(394) ##STR00196##
(S)-3-(3-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-3-oxo-2-(3-(o-tolylsulfonyl) ureido)propyl)benzamide
(395) TABLE-US-00094 MS (M + H).sup.+ Calcd. 539.2 MS (M + H).sup.+ Observ. 539.3 Retention Time 1.30 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(396) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 81
(397) ##STR00197##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-(3-(morpholinosulfonyl)phenyl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(398) TABLE-US-00095 MS (M + H).sup.+ Calcd. 645.2 MS (M + H).sup.+ Observ. 645.3 Retention Time 1.37 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(399) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 82
(400) ##STR00198##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(4-hydroxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(401) TABLE-US-00096 MS (M + H).sup.+ Calcd. 512.1 MS (M + H).sup.+ Observ. 512.3 Retention Time 1.45 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(402) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 83
(403) ##STR00199##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-(naphthalen-1-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(404) TABLE-US-00097 MS (M + H).sup.+ Calcd. 546.2 MS (M + H).sup.+ Observ. 546.3 Retention Time 1.68 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(405) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 84
(406) ##STR00200##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-((S)-2,3-dihydro-1H-inden-1-yl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)acetamide
(407) TABLE-US-00098 MS (M + H).sup.+ Calcd. 522.2 MS (M + H).sup.+ Observ. 522.3 Retention Time 1.87 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 85
(408) ##STR00201##
(S)N-(benzo[d][1,3]dioxol-5-yl)-3-(3-fluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(409) TABLE-US-00099 MS (M + H).sup.+ Calcd. 514.1 MS (M + H).sup.+ Observ. 514.2 Retention Time 1.51 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(410) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
(411) 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.
Example 86
(412) ##STR00202##
(R)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl2-(3phenylsulfonyl)ureido)propanamide
(413) TABLE-US-00100 MS (M + H).sup.+ Calcd. 482.1 MS (M + H).sup.+ Observ. 482.2 Retention Time 1.67 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(414) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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)
Example 87
(415) ##STR00203##
(S)N-methyl-N, 3-diphenyl-2-(3-(phenylsulfonyl)ureido)propanamide
(416) 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).
(417) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(418) TABLE-US-00101 MS (M + H).sup.+ Calcd. 438.1 MS (M + H).sup.+ Observ. 438.3 Retention Time 1.36 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m
Examples 88-97 were synthesized using the procedure described above for Example 87.
Example 88
(419) ##STR00204##
(S)N-(4-chlorophenyl)-N-methyl-3-phenyl-2(3-phenylsulfonyl)ureido)propanamide
(420) TABLE-US-00102 MS (M + H).sup.+ Calcd. 472.1 MS (M + H).sup.+ Observ. 472.2 Retention Time 1.56 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(421) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 89
(422) ##STR00205##
(S)N-(3-methoxyphenyl)-N-methyl-3-phenyl-2-(3-phenylsulfonyl)ureido)-propanamide
(423) TABLE-US-00103 MS (M + H).sup.+ Calcd. 468.2 MS (M + H).sup.+ Observ. 468.3 Retention Time 1.44 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(424) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 90
(425) ##STR00206##
(S)N-methyl-3-phenyl-2-(3-phenylsulfonyl)ureido)-N-(m-tolyl)propanamide
(426) TABLE-US-00104 MS (M + H).sup.+ Calcd. 452.2 MS (M + H).sup.+ Observ. 452.3 Retention Time 1.50 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(427) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 91
(428) ##STR00207##
(S)N-(4-fluorophenyl)-N-methyl-3-phenyl-2(3-phenylsulfonyl)ureido)propanamide
(429) TABLE-US-00105 MS (M + H).sup.+ Calcd. 456.1 MS (M + H).sup.+ Observ. 456.3 Retention Time 1.40 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(430) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 92
(431) ##STR00208##
(S)N-(4-methoxyphenyl)-N-methyl-3-phenyl-2(3-phenylsulfonyl)ureido)propanamide
(432) TABLE-US-00106 MS (M + H).sup.+ Calcd. 468.2 MS (M + H).sup.+ Observ. 468.3 Retention Time 1.39 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(433) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 93
(434) ##STR00209##
(S)N-(3-fluorophenyl)-N-methyl-3-phenyl-2(3-phenylsulfonyl) ureido)propanamide
(435) TABLE-US-00107 MS (M + H).sup.+ Calcd. 456.1 MS (M + H).sup.+ Observ. 456.1 Retention Time 1.41 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(436) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 94
(437) ##STR00210##
(S)N-methyl-N-(naphthalen-1-yl)-3-phenyl-2-(3-(phenylsulfonyl)ureido)-propanamide
(438) TABLE-US-00108 MS (M + H).sup.+ Calcd. 488.2 MS (M + H).sup.+ Observ. 488.2 Retention Time 1.47 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(439) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 95
(440) ##STR00211##
(S)N-(2-methoxyphenyl)-N-methyl-3-phenyl-2-(3 (phenylsulfonyl)ureido)-propanamide
(441) TABLE-US-00109 MS (M + H).sup.+ Calcd. 468.2 MS (M + H).sup.+ Observ. 468.2 Retention Time 1.48 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 96
(442) ##STR00212##
(S)N-(2-(diethylamino)ethyl)-N-methyl-3-phenyl-2-(3-(phenylsulfonyl)ureido)propanamide
(443) TABLE-US-00110 MS (M + H).sup.+ Calcd. 461.2 MS (M + H).sup.+ Observ. 461.4 Retention Time 1.84 min LC Condition Solvent A 5% Methanol:95% Water:10 mM Ammonium Acetate Solvent B 95% Methanol:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 97
(444) ##STR00213##
(S)N-methyl-N-(4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)-3-phenyl-2-(3-(phenylsulfonyl)ureido)propanamide
(445) TABLE-US-00111 MS (M + H).sup.+ Calcd. 534.2 MS (M + H).sup.+ Observ. 534.3 Retention Time 2.37 min LC Condition Solvent A 5% Methanol:95% Water:10 mM Ammonium Acetate Solvent B 95% Methanol:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(446) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
(447) Examples 98-120 were synthesized using the procedure described above for Example 3.
Example 98
(448) ##STR00214##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,6-difluorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(449) TABLE-US-00112 MS (M + H).sup.+ Calcd. 518.1 MS (M + H).sup.+ Observ. 518.4 Retention Time 1.65 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(450) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 99
(451) ##STR00215##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,5-difluorophenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(452) TABLE-US-00113 MS (M + H).sup.+ Calcd. 518.1 MS (M + H).sup.+ Observ. 518.3 Retention Time 1.48 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(453) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 100
(454) ##STR00216##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2,6-dichlorophenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(455) TABLE-US-00114 MS (M + H).sup.+ Calcd. 550.1 MS (M + H).sup.+ Observ. 550.4 Retention Time 1.55 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(456) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 101
(457) ##STR00217##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-chlorobenzyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(458) TABLE-US-00115 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.4 Retention Time 1.39 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(459) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 102
(460) ##STR00218##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3,4-dichlorobenzyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(461) TABLE-US-00116 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.4 Retention Time 1.53 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(462) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 103
(463) ##STR00219##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3-chlorobenzyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(464) TABLE-US-00117 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.2 Retention Time 1.55 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(465) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 104
(466) ##STR00220##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-((2-methylbenzyl)sulfonyl)ureido)-3-phenylpropanamide
(467) TABLE-US-00118 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(468) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 105
(469) ##STR00221##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl) ureido)propanamide
(470) TABLE-US-00119 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.2 Retention Time 1.63 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(471) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 106
(472) ##STR00222##
(2S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-isopropylcyclopropyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(473) TABLE-US-00120 MS (M + H).sup.+ Calcd. 488.2 MS (M + H).sup.+ Observ. 488.5 Retention Time 1.60 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(474) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 107
(475) ##STR00223##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((1-benzylcyclopropyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(476) TABLE-US-00121 MS (M + H).sup.+ Calcd. 536.2 MS (M + H).sup.+ Observ. 536.3 Retention Time 1.82 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(477) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 108
(478) ##STR00224##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-methoxyphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(479) TABLE-US-00122 MS (M + H).sup.+ Calcd. 512.1 MS (M + H).sup.+ Observ. 512.2 Retention Time 1.51 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(480) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 109
(481) ##STR00225##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((4-chlorobenzyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(482) TABLE-US-00123 MS (M + H).sup.+ Calcd. 530.1 MS (M + H).sup.+ Observ. 530.2 Retention Time 1.56 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(483) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 110
(484) ##STR00226##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((4-fluorobenzyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(485) TABLE-US-00124 MS (M + H).sup.+ Calcd. 514.1 MS (M + H).sup.+ Observ. 514.2 Retention Time 1.49 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(486) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 111
(487) ##STR00227##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-(cyclohexylsulfonyl) ureido)-N-methyl-3-phenylpropanamide
(488) TABLE-US-00125 MS (M + H).sup.+ Calcd. 488.2 MS (M + H).sup.+ Observ. 488.5 Retention Time 1.54 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(489) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 112
(490) ##STR00228##
(S)-2-(3-((3-bromophenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(491) TABLE-US-00126 MS (M + H).sup.+ Calcd. 560.1 MS (M + H).sup.+ Observ. 560.2 Retention Time 1.62 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(492) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 113
(493) ##STR00229##
(S)N-ethyl-N-(4-methoxyphenyl)-2-(3-((2-nitrophenyl)sulfonyl)ureido)-3-phenylpropanamide
(494) TABLE-US-00127 MS (M + H).sup.+ Calcd. 527.2 MS (M + H).sup.+ Observ. 527.2 Retention Time 1.49 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(495) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 114
(496) ##STR00230##
(S)-methyl 2-(N-((1-(ethyl(4-methoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)sulfamoyl)benzoate
(497) TABLE-US-00128 MS (M + H).sup.+ Calcd. 540.2 MS (M + H).sup.+ Observ. 540.2 Retention Time 1.50 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(498) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 115
(499) ##STR00231##
(S)-2-(3-((3-bromo-2-methylphenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(500) TABLE-US-00129 MS (M + H).sup.+ Calcd. 574.1 MS (M + H).sup.+ Observ. 574.2 Retention Time 1.70 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(501) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 116
(502) ##STR00232##
(S)N-ethyl-N-(4-methoxyphenyl)-2-(3-(naphthalen-1-ylsulfonyl)ureido)-3-phenylpropanamide
(503) TABLE-US-00130 MS (M + H).sup.+ Calcd. 532.2 MS (M + H).sup.+ Observ. 532.2 Retention Time 1.65 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(504) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 117
(505) ##STR00233##
(S)N-ethyl-2-(3-((2-fluorophenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(506) TABLE-US-00131 MS (M + H).sup.+ Calcd. 500.2 MS (M + H).sup.+ Observ. 500.1 Retention Time 1.40 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(507) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 118
(508) ##STR00234##
(S)-2-(3-((2,6-difluorophenyl)sulfonyl) ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(509) TABLE-US-00132 MS (M + H).sup.+ Calcd. 518.2 MS (M + H).sup.+ Observ. 518.1 Retention Time 1.47 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(510) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 119
(511) ##STR00235##
(S)-2-(3-((2,3-dichlorophenyl)sulfonyl) ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(512) TABLE-US-00133 MS (M + H).sup.+ Calcd. 550.1 MS (M + H).sup.+ Observ. 550.2 Retention Time 1.62 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(513) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 120
(514) ##STR00236##
(S)-2-(3-((5-bromo-2-methylphenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(515) TABLE-US-00134 MS (M + H).sup.+ Calcd. 574.1 MS (M + H).sup.+ Observ. 574.2 Retention Time 1.76 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(516) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(517) Examples 121-133 were synthesized using the procedure described above for Example 48.
Example 121
(518) ##STR00237##
(S)N-ethyl-2-(3-((3-(furan-3-yl)phenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(519) TABLE-US-00135 MS (M + H).sup.+ Calcd. 548.2 MS (M + H).sup.+ Observ. 548.2 Retention Time 1.67 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(520) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 122
(521) ##STR00238##
(S)N-ethyl-2-(3-((3-(furan-3-yl)-2-methylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(522) TABLE-US-00136 MS (M + H).sup.+ Calcd. 562.2 MS (M + H).sup.+ Observ. 562.3 Retention Time 1.74 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(523) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 123
(524) ##STR00239##
(S)N-ethyl-2-(3-((5-(furan-3-yl)-2-methylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(525) TABLE-US-00137 MS (M + H).sup.+ Calcd. 562.2 MS (M + H).sup.+ Observ. 562.3 Retention Time 1.87 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(526) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 124
(527) ##STR00240##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((4-(hydroxymethyl)-[1,1-biphenyl]-2-yl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(528) TABLE-US-00138 MS (M + H).sup.+ Calcd. 588.2 MS (M + H).sup.+ Observ. 588.2 Retention Time 1.57 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(529) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 125
(530) ##STR00241##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((3-hydroxy-[1,1-biphenyl]-2-yl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(531) TABLE-US-00139 MS (M + H).sup.+ Calcd. 574.2 MS (M + H).sup.+ Observ. 574.2 Retention Time 1.56 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(532) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 126
(533) ##STR00242##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-(6-methoxypyridin-3-yl)phenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(534) TABLE-US-00140 MS (M + H).sup.+ Calcd. 589.2 MS (M + H).sup.+ Observ. 589.2 Retention Time 1.55 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(535) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 127
(536) ##STR00243##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(pyrimidin-5-yl)phenyl)sulfonyl)ureido)propanamide
(537) TABLE-US-00141 MS (M + H).sup.+ Calcd. 560.2 MS (M + H).sup.+ Observ. 560.2 Retention Time 1.35 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(538) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 128
(539) ##STR00244##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(pyridin-3-yl)phenyl)sulfonyl)ureido)propanamide
(540) TABLE-US-00142 MS (M + H).sup.+ Calcd. 559.2 MS (M + H).sup.+ Observ. 559.2 Retention Time 1.39 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(541) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 129
(542) ##STR00245##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-(2-methoxypyridin-3-yl)phenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(543) TABLE-US-00143 MS (M + H).sup.+ Calcd. 589.2 MS (M + H).sup.+ Observ. 589.2 Retention Time 1.63 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 130
(544) ##STR00246##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-(2-methoxypyrimidin-5-yl)phenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(545) TABLE-US-00144 MS (M + H).sup.+ Calcd. 590.2 MS (M + H).sup.+ Observ. 590.2 Retention Time 1.34 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(546) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 131
(547) ##STR00247##
(S)-2-(N-((1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)sulfamoyl)-[1,1-biphenyl]-4-carboxamide
(548) TABLE-US-00145 MS (M + H).sup.+ Calcd. 601.2 MS (M + H).sup.+ Observ. 601.3 Retention Time 1.36 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(549) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 132
(550) ##STR00248##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(thiophen-3-yl)phenyl)sulfonyl)ureido)propanamide
(551) TABLE-US-00146 MS (M + H).sup.+ Calcd. 564.1 MS (M + H).sup.+ Observ. 564.2 Retention Time 1.63 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(552) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 133
(553) ##STR00249##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-(3-((2-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)ureido)-3-phenylpropanamide
(554) TABLE-US-00147 MS (M + H).sup.+ Calcd. 562.2 MS (M + H).sup.+ Observ. 562.1 Retention Time 1.38 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 134
(555) ##STR00250##
(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
(556) 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(PPh.sub.3).sub.4 (6.19 mg, 5.35 mol), DMF (1 mL), followed by 2M K.sub.2CO.sub.3 (60 l, 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).
(557) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(558) TABLE-US-00148 MS (M + H).sup.+ Calcd. 522.2 MS (M + H).sup.+ Observ. 522.2 Retention Time 1.79 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 135
(559) ##STR00251##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-isopropylphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(560) A mixture of 10% palladium on carbon (1.0 mg, 0.94 mol) in methanol (1 mL) was stirred under H.sub.2 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 H.sub.2 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(561) TABLE-US-00149 MS (M + H).sup.+ Calcd. 524.2 MS (M + H).sup.+ Observ. 524.3 Retention Time 1.72 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Examples 136-140 were synthesized using the procedure described above for Example 134.
Example 136
(562) ##STR00252##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-vinylphenyl)sulfonyl)ureido)propanamide
(563) TABLE-US-00150 MS (M + H).sup.+ Calcd. 508.2 MS (M + H).sup.+ Observ. 508.1 Retention Time 1.56 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(564) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 137
(565) ##STR00253##
(S,Z)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-(prop-1-en-1-yl)phenyl)sulfonyl)ureido)propanamide
(566) TABLE-US-00151 MS (M + H).sup.+ Calcd. 522.2 MS (M + H).sup.+ Observ. 522.2 Retention Time 1.76 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(567) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 138
(568) ##STR00254##
(S)N-ethyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-((3-vinylphenyl)sulfonyl)ureido)propanamide
(569) TABLE-US-00152 MS (M + H).sup.+ Calcd. 508.2 MS (M + H).sup.+ Observ. 508.2 Retention Time 1.62 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(570) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 139
(571) ##STR00255##
(S)N-ethyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-((3-(prop-en-2-yl)phenyl)sulfonyl)ureido)propanamide
(572) TABLE-US-00153 MS (M + H).sup.+ Calcd. 522.2 MS (M + H).sup.+ Observ. 522.2 Retention Time 1.68 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(573) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 140
(574) ##STR00256##
(S,Z)N-ethyl-N-(4-methoxyphenyl-2-(3-((3-(prop-1-en-1-yl)phenyl)sulfonyl) ureido)propanamide
(575) TABLE-US-00154 MS (M + H).sup.+ Calcd. 522.2 MS (M + H).sup.+ Observ. 522.2 Retention Time 1.70 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(576) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(577) Examples 141-146 were synthesized using the procedure described above for Example 135.
Example 141
(578) ##STR00257##
(S)N-ethyl-2-(3-((3-ethylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(579) TABLE-US-00155 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.2 Retention Time 1.81 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(580) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 142
(581) ##STR00258##
(S)N-ethyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-((3-propylphenyl)sulfonyl) ureido)propanamide
(582) TABLE-US-00156 MS (M + H).sup.+ Calcd. 524.2 MS (M + H).sup.+ Observ. 524.3 Retention Time 1.91 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(583) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 143
(584) ##STR00259##
(S)N-ethyl-2-(3-((3-isopropylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(585) TABLE-US-00157 MS (M + H).sup.+ Calcd. 524.2 MS (M + H).sup.+ Observ. 524.2 Retention Time 1.85 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(586) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 144
(587) ##STR00260##
(S)N-ethyl-2-(3-((5-ethyl-2-methylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(588) TABLE-US-00158 MS (M + H).sup.+ Calcd. 524.2 MS (M + H).sup.+ Observ. 524.3 Retention Time 1.89 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(589) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 145
(590) ##STR00261##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenyl-2-(3-((2-propylphenyl)sulfonyl) ureido)propanamide
(591) TABLE-US-00159 MS (M + H).sup.+ Calcd. 524.2 MS (M + H).sup.+ Observ. 524.3 Retention Time 1.88 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(592) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 146
(593) ##STR00262##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-ethylphenyl)sulfonyl)ureido)-N-methyl-3-phenylpropanamide
(594) TABLE-US-00160 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.3 Retention Time 1.73 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(595) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 147
(596) ##STR00263##
(S)-2-(3-((2-aminophenyl)sulfonyl) ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(597) A mixture of 10% palladium on carbon (4.0 mg, 3.8 mol) in methanol (4 mL) was stirred under H.sub.2 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 H.sub.2 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).
(598) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(599) TABLE-US-00161 MS (M + H).sup.+ Calcd. 497.2 MS (M + H).sup.+ Observ. 497.2 Retention Time 1.49 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 148 was synthesized using the procedure described above for Example 48.
Example 148
(600) ##STR00264##
(S)N-(benzo[d][1,3]dioxol-5-yl)-2-(3-((2-(6-fluoropyridin-3-yl)phenyl)sulfonyl) ureido)-N-methyl-3-phenylpropanamide
(601) TABLE-US-00162 MS (M + H).sup.+ Calcd. 577.2 MS (M + H).sup.+ Observ. 577.2 Retention Time 1.54 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(602) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 149
(603) ##STR00265##
(S)N-ethyl-2-(3-(((3furan-2-phenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(604) 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 mol), 1,4-dioxane (1 mL), followed by 2M K.sub.3PO.sub.4 (100 L). 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).
(605) TABLE-US-00163 MS (M + H).sup.+ Calcd. 548.1 MS (M + H).sup.+ Observ. 548.1 Retention Time 1.73 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Examples 150-154 were synthesized using the procedure described above for Example 149.
Example 150
(606) ##STR00266##
(S)-2-(3-((3-(2-chlorothiophen-3-yl)phenyl)sulfonyl)ureido)-N-ethyl-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(607) TABLE-US-00164 MS (M + H).sup.+ Calcd. 598.1 MS (M + H).sup.+ Observ. 598.1 Retention Time 1.82 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair acetonitrile:Water:Ammonium Acetate Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(608) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 151
(609) ##STR00267##
(S)N-ethyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-((3-(thiophen-3-yl)phenyl)sulfonyl)ureido)propanamide
(610) TABLE-US-00165 MS (M + H).sup.+ Calcd. 564.2 MS (M + H).sup.+ Observ. 564.2 Retention Time 1.75 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(611) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 152
(612) ##STR00268##
(S)N-ethyl-N-(4-methoxyphenyl)-2-(3-((3-(1-methyl-1H-pyrazol-5-yl)phenyl)sulfonyl)ureido)-3-phenylpropanamide
(613) TABLE-US-00166 MS (M + H).sup.+ Calcd. 562.4 MS (M + H).sup.+ Observ. 562.4 Retention Time 1.59 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(614) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 153
(615) ##STR00269##
(S)-2-(3-((3-(benzo[b]thiophen-3-yl)phenyl)sulfonyl) ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(616) TABLE-US-00167 MS (M + H).sup.+ Calcd. 614.2 MS (M + H).sup.+ Observ. 614.2 Retention Time 1.94 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(617) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 154
(618) ##STR00270##
(S)N-ethyl-2-(3-((3-(4-methoxy-1H-indol-2-yl)phenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(619) TABLE-US-00168 MS (M + H).sup.+ Calcd. 627.2 MS (M + H).sup.+ Observ. 627.2 Retention Time 2.79 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(620) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 155
(621) ##STR00271##
(S)N-ethyl-2-(3-(((3furan-2-phenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(622) 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 mol), 1,4-dioxane (1 mL), followed by 2M K.sub.3PO.sub.4 (100 L). 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).
(623) TABLE-US-00169 MS (M + H).sup.+ Calcd. 562.2 MS (M + H).sup.+ Observ. 562.2 Retention Time 1.78 min LC condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(624) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(625) Examples 156-162 were synthesized using the procedure described above for Example 149.
Example 156
(626) ##STR00272##
(S)-2-(3-((3-(2-chlorothiophen-3-yl)-2-methylphenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(627) TABLE-US-00170 MS (M + H).sup.+ Calcd. 612.1 MS (M + H).sup.+ Observ. 612.3 Retention Time 1.93 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 157
(628) ##STR00273##
(S)N-ethyl-N-(4-methoxyphenyl)-2-(3-((2-methyl-3-(thiophen-3-yl)phenyl)sulfonyl)ureido)-3-phenylpropanamide
(629) TABLE-US-00171 MS (M + H).sup.+ Calcd. 578.2 MS (M + H).sup.+ Observ. 578.3 Retention Time 1.93 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(630) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 158
(631) ##STR00274##
(S)N-ethyl-N-(4-methoxyphenyl)-2-(3-((2-methyl-3-(1-methyl-1H-pyrazol-5-yl)phenyl)sulfonyl)ureido)-3-phenylpropanamide
(632) TABLE-US-00172 MS (M + H).sup.+ Calcd. 576.2 MS (M + H).sup.+ Observ. 576.3 Retention Time 1.58 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(633) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 159
(634) ##STR00275##
(S)N-ethyl-2-(3-((3-(isoxazol-4-yl)-2-methylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(635) TABLE-US-00173 MS (M + H).sup.+ Calcd. 563.2 MS (M + H).sup.+ Observ. 563.3 Retention Time 1.63 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 160
(636) ##STR00276##
(S)-4-(3-(N-((1-(ethyl(4-methoxyphenylpropan-2-yl)carbamoyl)sulfamoyl)-2-methylphenyl)thiophene-2-carboxylic acid
(637) TABLE-US-00174 MS (M + H).sup.+ Calcd. 622.2 MS (M + H).sup.+ Observ. 622.3 Retention Time 1.45 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 161
(638) ##STR00277##
(S)-2-(3-((3-(benzo[b]thiophen-3-yl)-2-methylphenyl)sulfonyl) ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(639) TABLE-US-00175 MS (M + H).sup.+ Calcd. 628.3 MS (M + H).sup.+ Observ. 628.3 Retention Time 2.05 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(640) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 162
(641) ##STR00278##
(S)N-ethyl-2-(3-((3-(4-methoxy-1H-indol-2-yl)-2-methylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(642) TABLE-US-00176 MS (M + H).sup.+ Calcd. 641.2 MS (M + H).sup.+ Observ. 641.3 Retention Time 1.88 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(643) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(644) Examples 163-205 were synthesized using the procedure described above for Example 87.
Example 163
(645) ##STR00279##
(S)N-methyl-3-phenyl-N-(m-tolyl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(646) TABLE-US-00177 MS (M + H).sup.+ Calcd. 466.2 MS (M + H).sup.+ Observ. 466.2 Retention Time 1.47 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(647) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 164
(648) ##STR00280##
(S)N-(4-chlorophenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(649) TABLE-US-00178 MS (M + H).sup.+ Calcd. 486.1 MS (M + H).sup.+ Observ. 486.3 Retention Time 1.60 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(650) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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),
Example 165
(651) ##STR00281##
(S)N-(2-methoxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(652) TABLE-US-00179 MS (M + H).sup.+ Calcd. 482.5 MS (M + H).sup.+ Observ. 482.5 Retention Time 1.49 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(653) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 166
(654) ##STR00282##
(S)N-(3-methoxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(655) TABLE-US-00180 MS (M + H).sup.+ Calcd. 482.2 MS (M + H).sup.+ Observ. 482.2 Retention Time 1.59 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(656) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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),
Example 167
(657) ##STR00283##
(S)N-(4-methoxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(658) TABLE-US-00181 MS (M + H).sup.+ Calcd. 482.2 MS (M + H).sup.+ Observ. 482.5 Retention Time 1.34 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(659) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 168
(660) ##STR00284##
(S)N-(3-fluorophenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(661) TABLE-US-00182 MS (M + H).sup.+ Calcd. 470.2 MS (M + H).sup.+ Observ. 470.2 Retention Time 1.58 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(662) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 169
(663) ##STR00285##
(S)N-(4-fluorophenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(664) TABLE-US-00183 MS (M + H).sup.+ Calcd. 470.2 MS (M + H).sup.+ Observ. 470.3 Retention Time 1.50 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(665) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 170
(666) ##STR00286##
(S)N-((1-(3,4-dihydroquinolin-1(2H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(667) TABLE-US-00184 MS (M + H).sup.+ Calcd. 478.2 MS (M + H).sup.+ Observ. 478.4 Retention Time 1.51 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(668) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 171
(669) ##STR00287##
(S)N-((1-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(670) TABLE-US-00185 MS (M + H).sup.+ Calcd. 508.5 MS (M + H).sup.+ Observ. 508.5 Retention Time 1.48 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(671) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 172
(672) ##STR00288##
(S)N-((1-(7-methoxy-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(673) TABLE-US-00186 MS (M + H).sup.+ Calcd. 510.2 MS (M + H).sup.+ Observ. 510.2 Retention Time 1.52 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(674) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 173
(675) ##STR00289##
(S)N-((1-(6-hydroxy-3,4-dihydroquinolin-1 (2H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(676) TABLE-US-00187 MS (M + H).sup.+ Calcd. 494.2 MS (M + H).sup.+ Observ. 494.5 Retention Time 1.20 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(677) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 174
(678) ##STR00290##
(S)N-((1-(indolin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(679) TABLE-US-00188 MS (M + H).sup.+ Calcd. 464.2 MS (M + H).sup.+ Observ. 464.4 Retention Time 1.43 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(680) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 175
(681) ##STR00291##
(S)N-(3,4-dimethylphenyl)-N-ethyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(682) TABLE-US-00189 MS (M + H).sup.+ Calcd. 494.2 MS (M + H).sup.+ Observ. 494.3 Retention Time 1.94 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(683) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 176
(684) ##STR00292##
(S)N-(benzo[d]thiazol-2-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(685) TABLE-US-00190 MS (M + H).sup.+ Calcd. 509.1 MS (M + H).sup.+ Observ. 509.3 Retention Time 1.71 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(686) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 177
(687) ##STR00293##
(S)N-ethyl-N-(naphthalen-2-yl)-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(688) TABLE-US-00191 MS (M + H).sup.+ Calcd. 516.2 MS (M + H).sup.+ Observ. 516.3 Retention Time 1.82 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(689) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 178
(690) ##STR00294##
(S)N-ethyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)-N-(4-(trifluoromethoxy)phenyl)propanamide
(691) TABLE-US-00192 MS (M + H).sup.+ Calcd. 550.2 MS (M + H).sup.+ Observ. 550.5 Retention Time 1.81 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(692) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 179
(693) ##STR00295##
(S)N-cyclohexyl-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(694) TABLE-US-00193 MS (M + H).sup.+ Calcd. 458.2 MS (M + H).sup.+ Observ. 458.5 Retention Time 1.54 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(695) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 180
(696) ##STR00296##
(S)N-methyl-3-phenyl-N-(pyridin-2-ylmethyl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(697) TABLE-US-00194 MS (M + H).sup.+ Calcd. 467.2 MS (M + H).sup.+ Observ. 467.3 Retention Time 1.27 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(698) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 181
(699) ##STR00297##
(S)N-(4-chlorophenyl)-N-ethyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(700) TABLE-US-00195 MS (M + H).sup.+ Calcd. 500.1 MS (M + H).sup.+ Observ. 500.2 Retention Time 1.72 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(701) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 182
(702) ##STR00298##
(S)N-(4-chloro-3-(trifluoromethyl)phenyl)-N-ethyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(703) TABLE-US-00196 MS (M + H).sup.+ Calcd. 568.1 MS (M + H).sup.+ Observ. 568.5 Retention Time 1.87 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(704) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 183
(705) ##STR00299##
(S)N-(3,4-dichlorophenyl)-3-phenyl-N-propyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(706) TABLE-US-00197 MS (M + H).sup.+ Calcd. 548.11 MS (M + H).sup.+ Observ. 548.5 Retention Time 1.91 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(707) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 184
(708) ##STR00300##
(S)N-ethyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(709) TABLE-US-00198 MS (M + H).sup.+ Calcd. 496.2 MS (M + H).sup.+ Observ. 496.3 Retention Time 1.58 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(710) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 185
(711) ##STR00301##
(S)N,N-dimethyl-1-(3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanoyl)indoline-5-sulfonamide
(712) TABLE-US-00199 MS (M + H).sup.+ Calcd. 571.2 MS (M + H).sup.+ Observ. 571.5 Retention Time 2.27 min LC Condition Solvent A 5% Methanol:95% Water:10 mM Ammonium Acetate Solvent B 95% Methanol:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(713) .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Example 186
(714) ##STR00302##
(S)N-((1-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(715) TABLE-US-00200 MS (M + H).sup.+ Calcd. 484.1 MS (M + H).sup.+ Observ. 484.2 Retention Time 1.73 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 187
(716) ##STR00303##
N(((S)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-oxo-3-phenylpropan-2-yl) carbamoyl)-2-methylbenzenesulfonamide
(717) TABLE-US-00201 MS (M + H).sup.+ Calcd. 444.2 MS (M + H).sup.+ Observ. 444.2 Retention Time 1.11 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 188
(718) ##STR00304##
(S)N-((1-(azetidin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(719) TABLE-US-00202 MS (M + H).sup.+ Calcd. 402.1 MS (M + H).sup.+ Observ. 402.2 Retention Time 1.14 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(720) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 189
(721) ##STR00305##
2-methyl-N-(((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)benzenesulfonamide
(722) TABLE-US-00203 MS (M + H).sup.+ Calcd. 493.2 MS (M + H).sup.+ Observ. 493.2 Retention Time 1.28 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 190
(723) ##STR00306##
(S)N-((1-(3-methoxyazetidin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(724) TABLE-US-00204 MS (M + H).sup.+ Calcd. 432.2 MS (M + H).sup.+ Observ. 432.4 Retention Time 1.98 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(725) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 191
(726) ##STR00307##
(S)N-((1-(3,3-dimethylazetidin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)-2-methylbenzenesulfonamide
(727) TABLE-US-00205 MS (M + H).sup.+ Calcd. 430.2 MS (M + H).sup.+ Observ. 430.3 Retention Time 1.36 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(728) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 192
(729) ##STR00308##
(S)N-(4-methoxyphenyl)-N-methyl-3-(pyridin-2-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(730) TABLE-US-00206 MS (M + H).sup.+ Calcd. 483.2 MS (M + H).sup.+ Observ. 483.2 Retention Time 1.22 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(731) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 193
(732) ##STR00309##
(S)N-(4-methoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)-3-(1H-1,2,4-triazol-1-yl)propanamide
(733) TABLE-US-00207 MS (M + H).sup.+ Calcd. 473.2 MS (M + H).sup.+ Observ. 473.1 Retention Time 1.85 min LC Condition Solvent A 5% Methanol:95% Water:10 mM Ammonium Acetate Solvent B 95% Methanol:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(734) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 194
(735) ##STR00310##
(S)N-(4-methoxyphenyl)-N-methyl-3-(pyridin-3-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(736) TABLE-US-00208 MS (M + H).sup.+ Calcd. 483.2 MS (M + H).sup.+ Observ. 483.2 Retention Time 1.15 LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(737) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 195
(738) ##STR00311##
(S)-3-cyclohexyl-N-(4-methoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(739) TABLE-US-00209 MS (M + H).sup.+ Calcd. 488.2 MS (M + H).sup.+ Observ. 488.2 Retention Time 1.72 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(740) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 196
(741) ##STR00312##
(S)-3-cyclopentyl-N-(4-methoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(742) TABLE-US-00210 MS (M + H).sup.+ Calcd. 474.2 MS (M + H).sup.+ Observ. 474.2 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 197
(743) ##STR00313##
(2S,3S)N-(4-methoxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)butanamide
(744) TABLE-US-00211 MS (M + H).sup.+ Calcd. 496.2 MS (M + H).sup.+ Observ. 496.2 Retention Time 1.73 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(745) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 198
(746) ##STR00314##
(S)N-(4-methoxyphenyl)-N-methyl-3-(thiophen-2-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(747) TABLE-US-00212 MS (M + H).sup.+ Calcd. 488.1 MS (M + H).sup.+ Observ. 488.1 Retention Time 1.4 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(748) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 199
(749) ##STR00315##
(S)N-(4-methoxyphenyl)-N-methyl-3-(pyridin-4-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(750) TABLE-US-00213 MS (M + H).sup.+ Calcd. 483.3 MS (M + H).sup.+ Observ. 483.1 Retention Time 1.09 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(751) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 200
(752) ##STR00316##
(S)N-(4-methoxyphenyl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)-N-(2,2,2-trifluoroethyl)propanamide
(753) TABLE-US-00214 MS (M + H).sup.+ Calcd. 550.2 MS (M + H).sup.+ Observ. 550.3 Retention Time 2.0 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
Example 201
(754) ##STR00317##
(S)-2-(3-((2-bromophenyl)sulfonyl)ureido)-N-ethyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(755) TABLE-US-00215 MS (M + H).sup.+ Calcd. 560.1 MS (M + H).sup.+ Observ. 560.1 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(756) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 203
(757) ##STR00318##
(S)N-ethyl-2-(3-((1-ethyl-1H-indol-5-yl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(758) TABLE-US-00216 MS (M + H).sup.+ Calcd. 549.2 MS (M + H).sup.+ Observ. 549.4 Retention Time 2.62 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(759) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 204
(760) ##STR00319##
(S)-3-(3,5-difluorophenyl)-2-(3-((2-fluorophenyl)sulfonyl) ureido)-N-(4-methoxyphenyl)-N-methylpropanamide
(761) TABLE-US-00217 MS (M + H).sup.+ Calcd. 522.1 MS (M + H).sup.+ Observ. 522.2 Retention Time 1.61 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(762) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example 205
(763) ##STR00320##
(S)-3-(3,5-difluorophenyl)-N-(4-methoxyphenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(764) TABLE-US-00218 MS (M + H).sup.+ Calcd. 518.2 MS (M + H).sup.+ Observ. 518.2 Retention Time 1.73 min LC Condition Solvent A 5% acetonitrile:95% Water:10 mM Ammonium Acetate Solvent B 95% acetonitrile:5% Water:10 mM Ammonium Acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Column Waters BEH C18, 2.0 50 mm, 1.7-m particles
(765) .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Intermediate JB-1
(766) ##STR00321##
(S)-tert-butyl (1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(767) 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. NaHCO.sub.3 (aq) (60 mL). The organic component was washed with brine (40 mL), dried (MgSO.sub.4), filtered, concentrated and purified using a Biotage Horizon (80 g SiO.sub.2, 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].sup.+. (Column: Phenonenex-Luna C18 2.050 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220). .sup.1H NMR (400 MHZ, CDCl.sub.3) 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).
Intermediate JB-2
(768) ##STR00322##
(S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide
(769) 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].sup.+. (Column: Phenonenex-Luna C18 2.050 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. Flow Rate=0.8 mL/min. Start % B=0. Final % B=100. Gradient Time=4 min. Wavelength=220).
Intermediate JB-7
(770) ##STR00323##
(S)-tert-butyl (1-(methyl(3,4,5-trimethoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(771) 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 NaHCO.sub.3 (aq) (40 mL). The organic component was washed with brine (30 mL), dried (MgSO.sub.4), filtered and concentrated. The crude residue was then purified using a Biotage Horizon (80 g SiO.sub.2, 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].sup.+. (Column: Phenonenex-Luna C18 2.050 mm 3 m. 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). .sup.1H NMR (400 MHZ, CDCl.sub.3) 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).
Intermediate ZY-1
(772) ##STR00324##
N-methylbenzo[d]thiazol-5-amine
(773) 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 NaBH.sub.4 (126 mg, 3.33 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHCl.sub.3 (320 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12 g SiO.sub.2, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, CDCl.sub.3) 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).
Intermediate ZY-2
(774) ##STR00325##
(S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(775) 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. NaHCO.sub.3 (20 mL) and extracted with EtOAc (350 mL). The combined organic component was washed with brine (60 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (12 g SiO.sub.2, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, CDCl.sub.3) 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).
Intermediate ZY-3
(776) ##STR00326##
(S)-2-amino-N-(benzo[d]thiazol-5-yl)-N-methyl-3-phenylpropanamide
(777) 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHZ, MeOH-d.sub.4) 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).
Intermediate ZY-4
(778) ##STR00327##
(S)-tert-butyl (1-(benzo[d]thiazol-5-yl(methyl)amino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate
(779) 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. NaHCO.sub.3 (20 mL) and extracted with EtOAc (350 mL). The combined organic component was washed with brine (60 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude material was then purified using a Biotage Horizon (24 g SiO.sub.2, 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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). .sup.1H NMR (400 MHz, CDCl.sub.3) 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).
Intermediate ZY-5
(780) ##STR00328##
(S)-2-amino-N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-N-methylpropanamide
(781) 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].sup.+. (Column: Waters Aquity BEH C18, 2.050 mm, 1.7-m 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 ZY-6
(782) ##STR00329##
(S)-tert-butyl (1-(benzyl(4-methoxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(783) 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 SiO.sub.2, 0-50% Et.sub.2O/hexanes) to yield the title compound (125 mg). LC-MS retention time=1.43 min; m/z=461.4 [M+H].sup.+. (Column: Waters Aquity BEH C18 2.150 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).
Intermediate ZY-7
(784) ##STR00330##
(S)-2-amino-N-benzyl-N-(4-methoxyphenyl)-3-phenylpropanamide
(785) 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].sup.+. (Column: Waters Aquity BEH C18 2.150 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).
Example JB-82
(786) ##STR00331##
(S)N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)-N-(3,4,5-trimethoxyphenyl)propanamide
(787) 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 CH.sub.3CN (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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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.
Example JB-83
(788) ##STR00332##
(S)N-(4-methoxy-2-methylphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(789) LC-MS retention time=1.97 min; m/z=496.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example JB-84
(790) ##STR00333##
(S)N-(4-methoxy-2,5-dimethylphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(791) LC-MS retention time=2.03 min; m/z=510.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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.
Example JB-85
(792) ##STR00334##
(S)-2-(3-((1,2-dimethyl-1H-indol-3-yl)sulfonyl)ureido)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide
(793) 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. NaHCO.sub.3 (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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example ZY-3
(794) ##STR00335##
(S)N-benzyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(795) To a stirred solution of Intermediate ZY-7 (32 mg, 0.081 mmol) in CH.sub.3CN (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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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.
Example ZY-4
(796) ##STR00336##
(S)N-(4-methoxyphenyl)-3-phenyl-N-(pyridin-4-ylmethyl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(797) LC-MS retention time=1.48 min; m/z=559.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example ZY-5
(798) ##STR00337##
(S)N-(4-methoxyphenyl)-N-phenethyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(799) LC-MS retention time=1.87 min; m/z=572.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAC. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example ZY-6
(800) ##STR00338##
(S)N-isobutyl-N-(4-methoxyphenyl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(801) LC-MS retention time=1.84 min; m/z=524.4 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (600 MHZ, DMSO-d.sub.6) 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).
Example ZY-7
(802) ##STR00339##
(S)N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(803) 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 CH.sub.3CN (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).
(804) LC-MS retention time=2.33 min; m/z=545.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
(805) For Examples CA-67 through CA-101, the following procedure was used:
(806) A solution of POCl.sub.3 (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.
Example CA-67
(807) ##STR00340##
(S)N-methyl-N, 3-diphenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(808) LC-MS retention time=2.42 min; m/z=452.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-68
(809) ##STR00341##
(S)N-ethyl-N, 3-diphenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(810) LC-MS retention time=1.54 min; m/z=466.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-69
(811) ##STR00342##
(S)N-methyl-3-phenyl-N-(o-tolyl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(812) LC-MS retention time=1.52 min; m/z=466.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-70
(813) ##STR00343##
(S)N-isopropyl-N, 3-diphenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(814) LC-MS retention time=3.06 min; m/z=480.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-71
(815) ##STR00344##
(S)N-methyl-3-phenyl-N-(quinolin-6-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(816) LC-MS retention time=2.22 min; m/z=503.1 [M+H]. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-72
(817) ##STR00345##
(S)N-methyl-N-(2-methylquinolin-6-yl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(818) LC-MS retention time=1.50 min; m/z=517.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-73
(819) ##STR00346##
(S)N-methyl-N-(1-methyl-H-benzo[d]imidazol-6-yl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(820) LC-MS retention time=2.07 min; m/z=506.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-74
(821) ##STR00347##
(S)N-(1-ethyl-2-methyl-1H-benzo[d]imidazol-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(822) LC-MS retention time=2.23 min; m/z=534.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-75
(823) ##STR00348##
(S)N-methyl-3-phenyl-N-(quinoxalin-6-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(824) LC-MS retention time=2.15 min; m/z=504.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-76
(825) ##STR00349##
(S)N-(2,3-dihydrobenzofuran-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(826) LC-MS retention time=2.38 min; m/z=494.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-77
(827) ##STR00350##
(S)N-(4-methoxy-3-methylphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(828) LC-MS retention time=2.56 min; m/z=496.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-78
(829) ##STR00351##
(S)N-ethyl-N-(4-methoxy-3-methylphenyl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(830) LC-MS retention time=2.67 min; m/z=510.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-79
(831) ##STR00352##
(S)N-(chroman-6-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(832) LC-MS retention time=1.65 min; m/z=508.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-80
(833) ##STR00353##
(S)N-ethyl-3-phenyl-N-(quinolin-6-yl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(834) LC-MS retention time=1.48 min; m/z=517.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-81
(835) ##STR00354##
(S)N-(chroman-6-yl)-N-ethyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(836) LC-MS retention time=2.66 min; m/z=522.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-82
(837) ##STR00355##
(S)N-methyl-3-phenyl-N-(p-tolyl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(838) LC-MS retention time=1.76 min; m/z=466.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-83
(839) ##STR00356##
(S)N-ethyl-N-(2-methylquinolin-6-yl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(840) LC-MS retention time=1.66 min; m/z=531.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-84
(841) ##STR00357##
(S)N-(4-ethoxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamide
(842) LC-MS retention time=2.54 min; m/z=496.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-85
(843) ##STR00358##
(S)N-(4-acetamido-3-hydroxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(844) LC-MS retention time=2.43 min; m/z=525.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-86
(845) ##STR00359##
(S)N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(846) LC-MS retention time=1.49 min; m/z=507.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-87
(847) ##STR00360##
(S)N-methyl-N-(2-methylbenzo[d]thiazol-5-yl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(848) LC-MS retention time=1.69 min; m/z=523.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-88
(849) ##STR00361##
(S)N-(benzo[d]thiazol-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(850) LC-MS retention time=2.22 min; m/z=509.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-89
(851) ##STR00362##
(S)N-ethyl-N-(3-formamido-4-hydroxyphenyl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(852) LC-MS retention time=1.31 min; m/z=525.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-90
(853) ##STR00363##
(S)N-(3-formamido-4-hydroxyphenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(854) LC-MS retention time=1.96 min; m/z=511.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-91
(855) ##STR00364##
(S)N-(3-cyanophenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(856) LC-MS retention time=2.28 min; m/z=477.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-92
(857) ##STR00365##
(S)N-(4-(3,3-dimethylureido)phenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(858) LC-MS retention time=2.08 min; m/z=538.4 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example CA-93
(859) ##STR00366##
(S)-methyl (4-(N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamido)phenyl)carbamate
(860) LC-MS retention time=2.73 min; m/z=525.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example CA-94
(861) ##STR00367##
(S)-3-(N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl) ureido)propanamido)benzamide
(862) LC-MS retention time=2.05 min; m/z=495.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-95
(863) ##STR00368##
(S)N-(benzo[d]thiazol-6-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(864) LC-MS retention time=2.19 min; m/z=509.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 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).
Example CA-96
(865) ##STR00369##
(S)N-methyl-3-phenyl-N-(quinazolin-6-yl)-2-(3-(o-tolylsulfonyl) ureido)propanamide
(866) LC-MS retention time=2.00 min; m/z=504.4 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-97
(867) ##STR00370##
(S)N-(4-cyanophenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(868) LC-MS retention time=2.61 min; m/z=476.9 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-98
(869) ##STR00371##
(S)N-methyl-3-phenyl-N-(quinolin-7-yl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(870) LC-MS retention time=2.22 min; m/z=503.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-99
(871) ##STR00372##
(S)N-methyl-N-(1-oxo-1,2-dihydroisoquinolin-7-yl)-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(872) LC-MS retention time=2.48 min; m/z=519.0 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-100
(873) ##STR00373##
(S)-2-fluoro-5-(N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamido)benzamide
(874) LC-MS retention time=1.23 min; m/z=513.0 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-101
(875) ##STR00374##
(S)N-(1H-benzo[d]imidazol-4-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(876) LC-MS retention time=1.26 min; m/z=492.0 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
(877) For Examples CA-102 through CA-112, the following procedure was utilized:
(878) A solution of POCl.sub.3 (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.
Example CA-102
(879) ##STR00375##
(S)-5-(3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamido)-2-fluorobenzamide
(880) A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (30.1 mg, 100 mol) and HATU (41.8 mg, 110 mol) in DMF (0.5 mL) was added to a solution of 2-fluoro-5-(methylamino)benzamide (16.8 mg, 100 mol) in DIPEA (0.044 mL, 250 mol) 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 mol) and 2-methylbenzenesulfonyl isocyanate (0.023 mL, 150 mol), 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-103
(881) ##STR00376##
(S)-3-(3,5-difluorophenyl)-N-methyl-N-(1-oxo-1,2-dihydroisoquinolin-7-yl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(882) LC-MS retention time=2.11 min; m/z=555.4 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-104
(883) ##STR00377##
(S)-3-(3,5-difluorophenyl)-N-methyl-N-(quinolin-7-yl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(884) LC-MS retention time=1.32 min; m/z=539.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-105
(885) ##STR00378##
(S)-3-(3,5-difluorophenyl)-N-(isoquinolin-3-yl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(886) LC-MS retention time=1.46 min; m/z=539.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-106
(887) ##STR00379##
(S)-3-(3,5-difluorophenyl)-N-methyl-N-(3-(N-methylsulfamoyl)phenyl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(888) LC-MS retention time=1.32 min; m/z=581.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-107
(889) ##STR00380##
(S)-3-(3,5-difluorophenyl)-N-(2-fluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(890) LC-MS retention time=1.47 min; m/z=506.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example CA-108
(891) ##STR00381##
(S)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl) ureido)-N-(4-(trifluoromethoxy)phenyl)propanamide
(892) LC-MS retention time=1.83 min; m/z=572.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example CA-109
(893) ##STR00382##
(S)-3-(3,5-difluorophenyl)-N-methyl-N-(quinolin-5-yl)-2-(3-(o-tolylsulfonyl)ureido)propanamide
(894) LC-MS retention time=2.36 min; m/z=539.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-110
(895) ##STR00383##
(S)-3-(3,5-difluorophenyl)-N-(isoquinolin-5-yl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(896) LC-MS retention time=2.34 min; m/z=539.2 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc, 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).
Example CA-111
(897) ##STR00384##
(S)N-(3-chlorophenyl)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(898) LC-MS retention time=2.66 min; m/z=522.3 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example CA-112
(899) ##STR00385##
(S)N-(2,4-difluorophenyl)-3-(3,5-difluorophenyl)-N-methyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(900) LC-MS retention time=1.56 min; m/z=524.1 [M+H].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent % B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc, 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).
Example ZY-13
(901) ##STR00386##
(S)N-(benzo[d]thiazol-5-yl)-2-(3-((2-chlorophenyl)sulfonyl)ureido)-3-(3,5-difluorophenyl)-N-methylpropanamide
(902) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example ZY-14
(903) ##STR00387##
(S)N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-2-(3-((2,5-difluorophenyl)sulfonyl) ureido)-N-methylpropanamide
(904) 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 l, 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 (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 CH.sub.3CN (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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example ZY-16
(905) ##STR00388##
(S)N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-2-(3-((2-fluorophenyl)sulfonyl)ureido)-N-methylpropanamide
(906) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example ZY-17
(907) ##STR00389##
(S)N-(benzo[d]thiazol-5-yl)-3-(3,5-difluorophenyl)-2-(3-((2,4-difluorophenyl)sulfonyl) ureido)-N-methylpropanamide
(908) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 206
(909) ##STR00390##
(S)-2-(3-((2-chlorophenyl)sulfonyl)ureido)-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenylpropanamide
(910) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 207
(911) ##STR00391##
(S)N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(912) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 208
(913) ##STR00392##
(S)N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3-phenyl-2-(3-(phenylsulfonyl)ureido)propanamide
(914) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 209
(915) ##STR00393##
(S)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-4-phenyl-2-(3-(o-tolylsulfonyl) ureido)butanamide
(916) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 210
(917) ##STR00394##
(R)N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-4-phenyl-2-(3-(o-tolylsulfonyl) ureido)butanamide
(918) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% MeOH: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% MeOH: 10 mM NH.sub.4OAc. 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).
Example 212
(919) ##STR00395##
(S)N-(4-methoxyphenyl)-N-methyl-3-(3-vinylphenyl)-2-(3-((2-vinylphenyl)sulfonyl)ureido)propanamide
(920) 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/H.sub.2O) to yield the title compound (76 mg). LC-MS retention time=1.97 min; m/z=520.2 [M+H].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).
Example 213
(921) ##STR00396##
(S)-3-(3-(but-3-en-1-yloxy)phenyl)-N-(4-methoxyphenyl)-N-methyl-2-(3-((2-vinylphenyl)sulfonyl)ureido)propanamide
(922) 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/H.sub.2O) to yield the title compound (96 mg). LC-MS retention time=2.11 min; m/z=564.3 [M+H].sup.+. (Column: Phenonenex-Luna C18 2.030 mm 3 m. Solvent A=95% Water: 5% Acetonitrile: 10 M ammonium acetate. Solvent B=5% Water: 95% Acetonitrile: 10 M ammonium acetate. Flow Rate=1.0 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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
(923) ##STR00397##
(S)N-ethyl-2-(3-((3-(1-isobutyl-1H-pyrazol-5-yl)-2-methylphenyl)sulfonyl)ureido)-N-(4-methoxyphenyl)-3-phenylpropanamide
(924) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 215
(925) ##STR00398##
(S)-3-(3-ethylphenyl)-2-(3-((2-ethylphenyl)sulfonyl) ureido)-N-(4-methoxyphenyl)-N-methylpropanamide
(926) 10% Palladium on carbon (7.4 mg, 6.9 mol) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 216
(927) ##STR00399##
(S)N-(4-(allyloxy)phenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(928) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Example 217
(929) ##STR00400##
(S)N-(4-(2-amino-2-oxoethoxy)phenyl)-N-methyl-3-phenyl-2-(3-(o-tolylsulfonyl)ureido)propanamide
(930) 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].sup.+. (Column: Waters BEH C18, 2.050 mm, 1.7-m particles. Solvent A=95% Water: 5% Acetonitrile: 10 mM NH.sub.4OAc. Solvent B=5% Water: 95% Acetonitrile: 10 mM NH.sub.4OAc. 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).
Biological Methods
(931) HIV cell culture assayMT-2 cells, 293T cells and the proviral DNA clone of NL.sub.4-3 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 NL.sub.4-3 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 NL.sub.4-3 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.
(932) The 50% effective concentration (EC.sub.50) was calculated by using the exponential form of the median effect equation where (Fa)=1/[1+(ED.sub.50/drug conc.).sup.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).
(933) Compound cytotoxicity and the corresponding CC.sub.50 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.).
(934) Compounds demonstrated antiviral activity as depicted in the table below. Activity equal to A refers to a compound having an EC.sub.50 value which is <0.1 M, B is 0.1 to <1.0 M, C is 1.0 to <10 M, and D is 10 to <100 M.
(935) TABLE-US-00219 TABLE 1 EC.sub.50 Example Structure Activity (M) 1
(936) 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.