EP1633710A1 - Isoindolin-1-onverbindungen als kinasehemmer - Google Patents

Isoindolin-1-onverbindungen als kinasehemmer

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Publication number
EP1633710A1
EP1633710A1 EP04753845A EP04753845A EP1633710A1 EP 1633710 A1 EP1633710 A1 EP 1633710A1 EP 04753845 A EP04753845 A EP 04753845A EP 04753845 A EP04753845 A EP 04753845A EP 1633710 A1 EP1633710 A1 EP 1633710A1
Authority
EP
European Patent Office
Prior art keywords
oxo
isoindol
phenyl
dihydro
urea
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04753845A
Other languages
English (en)
French (fr)
Inventor
Michael L. Curtin
Steven K Davidsen
Robin R. Frey
Howard R. Heyman
James H. Holms
Michael Michaelides
Douglas H. Steinman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1633710A1 publication Critical patent/EP1633710A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds which are useful for inhibiting protein tyrosine kinases, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
  • PTKs Protein tyrosine kinases
  • endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas).
  • inappropriate vascularization e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas.
  • the present invention provides a compound of formula (I)
  • R is selected from the group consisting of hydrogen and alkyl
  • R is selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, carboxyalkoxy, carboxyalkyl, halo, haloalkyl, heterocyclylalkoxy, hydroxy, nitro, and -NR c R d ; and one of R and R is A-X-R and the other is hydrogen; wherein A-X-R is drawn with its left end attached to the parent molecular moiety;
  • R is selected from the group consisting of aryl, heteroaryl, and heterocyclyl
  • A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, haloalkoxy, and haloalkyl; and
  • X is selected from the group consisting of O, NR a , N(R a )C(S)N(R ), (CH 2 ) m N(R a )C(O)N(R b XCH 2 ) n , CH 2 C(O)N(R a ), and N(R a )C(O), wherein R a and R b are independently selected from the group consisting of hydrogen and alkyl, m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to A and its right end attached to R .
  • the present invention discloses a compound of formula (I) where R is hydrogen.
  • the present invention discloses a compound of formula (I) where R is A-X-R and R is hydrogen.
  • the present invention discloses a compound of formula (I) where R is A-X-R , R is hydrogen, and X is selected from the group consisting of O, NR a , N(R a )C(S)N(R b ), CH 2 C(O)N(R a ), and N(R a )C(O).
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, and X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n .
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R a and R are hydrogen, and m and n are 0.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , and R 2 is other than hydrogen.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R 2 is hydrogen, and R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are unsubstituted.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R 2 is hydrogen, and R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R 2 is hydrogen, R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted, and A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are unsubstituted.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R 2 is hydrogen, R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted, and A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH2) m N(R a )C(O)N(R b )(CH 2 )n, 2 is hydrogen, and R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are disubstituted.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R 2 is hydrogen, R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are disubstituted, and A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are unsubstituted.
  • the present invention discloses a compound of formula (I) where R 3 is A-X-R 5 , R 4 is hydrogen, X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , R 2 is hydrogen, R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are disubstituted, and A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method for inhibiting protein kinase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxyalkoxy refers to an alkoxy group attached to the parent molecular moiety through another alkoxy group.
  • alkoxyalkoxyalkyl refers to an alkoxyalkoxy group attached to the parent molecular moiety through an alkyl group.
  • alkoxyalkoxyalkylcarbonyl refers to an alkoxyalkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkoxyalkyl refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
  • alkoxyalkylcarbonyl refers to an alkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to ten carbon atoms.
  • alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylsulfanyl refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.
  • aryl refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
  • Bicyclic fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano, cyanoalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, c d.
  • the second aryl group, the aryl part of the arylalkoxy, the arylalkyl, the aryloxy, and the arylsulfanyl, the heteroaryl, the heteroaryl part of the heteroarylalkyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.
  • arylalkoxy refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkoxycarbonyl refers to an arylalkoxy group attached to the parent molecular moiety through a carbonyl group.
  • arylalkyl refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkylcarbonyl refers to an arylalkyl group attached to the parent molecular moiety through a carbonyl group.
  • arylcarbonyl refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen atom.
  • arylsulfanyl refers to an aryl group attached to the parent molecular moiety through a sulfur atom.
  • carbonyl refers to -C(O)-.
  • carboxyalkoxy refers to a carboxy group attached to the parent molecular moiety through an alkoxy group.
  • carboxyalkyl refers to a carboxy group attached to the parent molecular moiety through an alkyl group.
  • cyano refers to -CN.
  • cyanoalkyl refers to a cyano group attached to the parent molecular moiety through an alkyl group.
  • cycloalkenyl refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, wherein each five- membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine-to ten- membered ring has one to four double bonds.
  • cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.
  • cycloalkyl refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, and adamantyl.
  • halo and halogen, as used herein, refer to F, Cl, Br, or I.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
  • heteroaryl refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon.
  • the five-membered rings have two double bonds, and the six- membered rings have three double bonds.
  • the heteroaryl groups are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
  • heteroaryl also includes bicyclic systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, a heterocyclyl group, as defined herein, or an additional heteroaryl group; and tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocyclyl group, as defined herein, or an additional heteroaryl group.
  • Heteroaryls are exemplified by benzothienyl, benzoxadiazolyl, cinnolinyl, dibenzofuranyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, triazinyl, and the like.
  • heteroaryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, aryl, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano, cyanoalkyl, halo, haloalkoxy, haloalkyl, a second heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, nitro, oxo, and -NR c R d , wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, the aryloxy, and the arylsulfanyl, the second heteroaryl group, the heteroaryl part of the heteroarylalkyl, the heterocyclyl, and
  • heteroarylalkyl refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • heteroarylcarbonyl refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group.
  • heterocyclyl refers to cyclic, non-aromatic, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the five-membered rings have zero or one double bonds and the six- and seven-membered rings have zero, one, or two double bonds.
  • the heterocyclyl groups of the invention are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
  • heterocyclyl also includes bicyclic systems where a heterocyclyl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocyclyl group; and tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocyclyl group.
  • heterocyclyl groups include, but are not limited to, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, and thiomorpholinyl.
  • heterocyclyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, aryl, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano, cyanoalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, nitro, oxo, and -
  • heterocyclylalkoxy refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group.
  • heterocyclylalkyl refers to a heterocyclyl group attached to the parent molecular moiety through an alkyl group.
  • heterocyclylcarbonyl refers to a heterocyclyl group attached to the parent molecular moiety through a carbonyl group.
  • hydroxy refers to -OH.
  • nitro refers to -NO 2 .
  • R c and R d are each independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxyalkoxyalkylcarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, and -C(O)(CH 2 ) n NR e R , wherein n is 0, 1, or 2 and R e and R are independently selected from the group consisting of hydrogen and alkyl, and wherein the aryl, the aryl part of the aryl
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • therapeutically acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate,trifluoroacetate, phosphate, glutamate, bi
  • suitable nitrogen atoms in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, NN-dibenzylphenethylamine, 1-ephenamine, and N,N -dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • the present compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.
  • the compounds can be administered alone or in combination with other anticancer agents.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the anticancer effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • the rate of drug release can be controlled.
  • Transdermal patches can also provide controlled delivery of the compounds.
  • the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefore.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches.
  • the compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • Preferred compounds of the present invention are compounds of formula (I) where R is hydrogen, X is N(R a )C(O)N(R ), and R a and R are hydrogen.
  • the potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al, Nature. 373:536-539) by a test compound relative to control.
  • an exogenous substrate e.g., synthetic peptide (Z. Songyang et al, Nature. 373:536-539)
  • the coding sequence for the human KDR intra-cellular domain was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His ⁇ sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pNL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BN) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BN was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/mL, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection.
  • MOI plaque forming units per cell
  • SF-9 cells expressing (His) 6 KDR(aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM ⁇ aCl, 10% glycerol, 1% Triton X-100, ImM PMSF, lOjg/ml aprotinin, 1 Jg/ml leupeptin) to the cell pellet from IL of cell culture.
  • the lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4°C.
  • the cell lysate was applied to a 5 ml NiCl 2 chelating sepharose column, equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCI.
  • KDR was eluted using the same buffer containing 0.25 M imidazole.
  • Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity.
  • the purified KDR was exchanged into 25mM HEPES, pH7.5, 25mM NaCI, 5 mM DTT buffer and stored at -80 °C.
  • KDR at IC50's between about 0.007 ⁇ M and about 50 ⁇ M.
  • Preferred compounds inhibited KDR at IC50's between about 0.007 ⁇ M and about 0.5 ⁇ M.
  • Most preferred compounds inhibited KDR at IC50's of between about 0.007 ⁇ M and about 0.1 ⁇ M.
  • the coding sequence for the human Tie-2 intra-cellular domain was generated through PCR using cDNAs isolated from human placenta as a template. A poly- His 6 sequence was introduced at the N-terminus and this construct was cloned into transfection vector pNL 1939 at the Xba 1 and Not 1 site. Recombinant BN was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BN was plaque purified and verified through Western analysis. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR.
  • the baculoviral expression vector pNL1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated through PCR using cD ⁇ A libraries isolated from HUNEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection.
  • EGFR was purchased from Sigma (Cat # E-3641 ; 500 units/50 Jl) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100).
  • Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may be commercially obtained (e.g., from Upstate Biotechnology Inc. (Saranac Lake, ⁇ .Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods.
  • Enzyme linked immunosorbent assays were used to detect and measure the presence of tyrosine kinase activity.
  • the ELISA were conducted according to known protocols which are described in, for example, Noller, et al, 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C.
  • the disclosed protocol was adapted for determining activity with respect to a specific PTK.
  • preferred protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as non-receptor tyrosine kinases, are well within the abilities of those in the art.
  • a universal PTK substrate e.g., random copolymer of poly(Glu Tyr), 20,000-50,000 MW
  • ATP typically 5 JM
  • Reaction Buffer lOOmM Hepes, 20mM MgCl 2 , 4mM MnCl 2 , 5mM DTT, 0.02%BSA,
  • ATP Store aliquots of lOOmM at -20°C. Dilute to 20JM in water
  • Washing Buffer PBS with 0.1% Tween 20
  • TMB Substrate mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue
  • Plate Preparation Dilute PGT stock (50mg/ml, frozen) in PBS to a 250jg/ml. Add 125 per well of Corning modified flat bottom high affinity ELISA plates (Corning #25805-96). Add 125 PBS to blank wells. Cover with sealing tape and incubate overnight 37°C. Wash lx with 250J1 washing buffer and dry for about 2hrs in 37°C dry incubator. Store coated plates in sealed bag at 4°C until used.
  • the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl 2 , 20 mM MgCl 2 , 5 mM DTT, 0.2% BSA, 200 mM NaVO 4 under the analogous assay conditions.
  • Compounds of the invention may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases.
  • Cdc2 source
  • the human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • a protocol that can be used is that provided with the purchased reagents with minor modifications.
  • the reaction is carried out in a buffer consisting of 50mM Tris pH 7.5, lOOmM NaCI, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and lOmM MgCl 2 (commercial buffer) supplemented with fresh 300 JM ATP (31 JCi/ml) and 30 Jg/ml histone type IIIss final concentrations.
  • a reaction volume of 80jL, containing units of enzyme is run for 20 minutes at 25 degrees C in the presence or absence of inhibitor.
  • the reaction is terminated by the addition of 120 JL of 10% acetic acid.
  • the substrate is separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75mM phosphoric acid. Counts are measured by a betacounter in the presence of liquid scintillant.
  • the catalytic subunit of PKC may be obtained commercially (Calbiochem).
  • a radioactive kinase assay is employed following a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166, 1220-1227 (1990)). Briefly, all reactions are performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, lOmM MgCl 2 , 2mM DTT, ImM EGTA, 100 JM ATP, 8 JM peptide, 5% DMSO and 33 P ATP (8Ci/mM). Compound and enzyme are mixed in the reaction vessel and the reaction is initiated by addition of the ATP and substrate mixture.
  • the recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods. Erk2 enzyme assay
  • reaction is carried out in a buffer consisting of 50 mM Tris pH 7.5, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl 2 (commercial buffer) supplemented with fresh 100 JM ATP (31 JCi/ml) and 30jM myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity are as described for the PKC assay (vide supra).
  • HUNEC Human Umbilical Vein Endothelial Cells
  • HUNEC cells from pooled donors can be purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer directions. Only early passages (3-8) are used for this assay. Cells are cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Madison, England) using complete EBM media (Clonetics).
  • cells are trypsinized and seeded at 0.5-1.0 x 10 5 cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA).
  • plates are typically 90-100% confluent. Medium is removed from all the wells, cells are rinsed with 5-10ml of PBS and incubated 18-24h with 5ml of EBM base media with no supplements added (i.e., serum starvation).
  • the lysate is spun at 14,000 rpm for 30min, to eliminate nuclei. Equal amounts of proteins are then precipitated by addition of cold (-20 C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. Pellets are reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min. The proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm No vex, San Deigo, CA) and transferred onto a nitrocellulose membrane using the Novex system.
  • the proteins After blocking with bovine serum albumin (3%), the proteins are probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 C. After washing and incubating for 1 hour with HRP-conjugated F(ab) 2 of goat anti-rabbit or goat-anti-mouse IgG the bands are visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Heights, BL).
  • ECL emission chemiluminescience
  • This assay measures the capacity of compounds to inhibit the acute increase in uterine weight in mice which occurs in the first few hours following estrogen stimulation.
  • This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature.
  • Cullinan-Bove and Koss (Endocrinology (1993), 133: 829-837) demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of NEGF mR ⁇ A in the uterus.
  • These results have been confirmed by the use of neutralizing monoclonal antibody to VEGF which significantly reduced the acute increase in uterine weight following estrogen stimulation (WO 97/42187).
  • this system can serve as a model for in vivo inhibition of VEGF signalling and the associated hyperpermeability and edema.
  • mice are given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG).
  • PMSG pregnant mare's serum gonadotropin
  • mice receive 15 units of human chorionic gonadotropin (hCG) i.p.
  • mice are randomized and divided into groups of 5-10. Test compounds are administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Nehicle control group receive vehicle only and two groups are left untreated. Thirty minutes later, experimental, vehicle and 1 of the untreated groups are given an i.p. injection of 17 -estradiol (500 mg/kg). After 2-3 hours, the animals are sacrificed by CO 2 inhalation. Following a midline incision, each uterus was isolated and removed by cutting just below the cervix and at the junctions of the uterus and oviducts.
  • Fat and connective tissue were removed with care not to disturb the integrity of the uterus prior to weighing (wet weight).
  • Uteri are blotted to remove fluid by pressing between two sheets of filter paper with a one liter glass bottle filled with water. Uteri are weighed following blotting (blotted weight). The difference between wet and blotted weights is taken as the fluid content of the uterus.
  • Mean fluid content of treated groups is compared to untreated or vehicle treated groups. Significance is determined by Student's test. Non-stimulated control group is used to monitor estradiol response.
  • Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization.
  • the Matrigel neovascularization model involves the formation of new blood vessels within a ⁇ clear marble of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vase. Biol. (1995), 15(11), 1857-6).
  • the model preferably runs over 3-4 days and endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors.
  • the model may alternatively employ bFGF or HGF as the stimulus.
  • the compounds of the present invention may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system.
  • diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (e.g,.
  • kidney rejection, graft versus host disease benign and neoplastic proliferative diseases
  • human cancers such as lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma, and diseases involving inappropriate vascularization (for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings).
  • diseases vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings.
  • Such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).
  • ARDS adult respiratory distress syndrome
  • the compounds of the invention may be useful in the treatment of pulmonary hypertension, particularly in patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73).
  • This invention is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • compounds of formula (2) can be treated with ammonium hydroxide to provide compounds of formula (3).
  • Compounds of formula (3) can be converted to compounds of formula (4) by treatment with an organometallic coupling partner (M-A-NH 2 , where M is a metal such as a boronic acid, boronic ester, or alkyl stannane) in the presence of a palladium catalyst and optional base.
  • organometallic coupling partner M-A-NH 2 , where M is a metal such as a boronic acid, boronic ester, or alkyl stannane
  • palladium catalysts include Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , and Pd 2 (dba) 3 with a ligand such as PPh 3 .
  • Representative bases include sodium carbonate, potassium carbonate, and cesium carbonate.
  • Scheme 2 shows the synthesis of compounds of formula (5).
  • Compounds of formula (4) can be treated with an isocyanate or thioisocyanate in the presence of a base such as N- methylmorpholine or triethylamine to provide compounds of formula (5) where X is N(R a )C(S)N(R b ) or N(R a )C(O)N(R b ).
  • compounds of formula (4) can be coupled to an appropriately substituted carboxylic acid under standard coupling conditions to provide compounds of formula (5) where X is N(R a )C(O).
  • Standard coupling conditions include a coupling agent such as EDCI or DCC, a base such as N-methylmorpholine or triethylamine, and optionally HOBT.
  • compounds of formula (3) can be converted to compounds of formula (8), where R is an alkyl group, by treatment with an alkylating agent in the presence of a base such as triethylamine or diisopropylethylamine.
  • compounds of formula (8) can be converted to compounds of formula (9) (where R is alkyl) by the methods previously described.
  • Example IA methyl 3-bromo-2-methylbenzoate
  • a suspension of 3-bromo-2-methylbenzoic acid (9.9g,46 mmol) in thionyl chloride (20 mL) was heated to 60 °C for 1 hour, cooled to room temperature, and concentrated.
  • the residue was suspended in 50 mL of methanol, cooled to 0 °C, treated slowly with triethylamine (12.7 mL, 92 mmol), warmed to room temperature, and concentrated.
  • the residue was partitioned between ethyl acetate and water and the organic phase was washed with saturated ⁇ a ⁇ CO 3 and brine, dried (MgSO 4 ), filtered, and concentrated to give 7.39g of the desired product.
  • R f 0.5 (10% ethyl acetate/hexanes).
  • Example IB methyl 3-bromo-2-(bromomethyl)benzoate
  • a suspension of Example IA (7.4g, 32.3 mmol), NBS (6.9g, 38.8 mmol), and benzoyl peroxide (0.782g, 3.2 mmol) in benzene (100 mL) was stirred at reflux for 5 hours, cooled to 0 °C, and filtered.
  • the solid was washed with diethyl ether and the filtrate was washed sequentially with 10% Na 2 S 2 O 3 (2 x 20 mL), and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the residue was purified by silica gel chromatography with 5 to 10% ethyl acetate/hexanes to give 9.32g of the desired product.
  • R f 0.2 (5% ethyl acetate/hexanes).
  • Example IC 4-bromo- 1 -isoindolinone
  • a solution of Example IB (8.3g, 26.9mmol) in THF (100 mL) was treated dropwise with concentrated NH 4 OH (9 mL, 135 mmol) stirred at room temperature for 2 days, diluted with 30 mL water, cooled to 0 °C, and filtered. The filter cake was washed with water and ethyl acetate and dried to give 3.34 g of the desired product.
  • MS (ESI(+)) m/e 212 (M+H) + .
  • Example ID 4-(4-aminophenyl)-l-isoindolinone
  • Example IE N-(3-methylphenyl)-N-F4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • An 0 °C suspension of Example ID (1.94g, 8.68 mmol) in T ⁇ F (44 mL) was sequentially treated dropwise with ⁇ -methylmorpholine (0.95 mL, 8.68 mmol) and 3- methylphenyl isocyanate (1.12 mL, 8.68 mmol). The mixture was stirred for 1 hour, diluted with T ⁇ F (20 mL), stirred at room temperature for 3 hours, and quenched with water (20 mL).
  • Example 2A 4-bromo-7 -nitro- 1 -isoindolinone
  • a 0 °C solution of Example IC (5g, 23.6 mmol) in 10 mL sulfuric acid was treated with a solution of concentrated nitric acid (1.55 mL, 24.7 mmol) in 10 mL sulfuric acid via addition funnel.
  • the resulting mixture was stirred at 0 °C for 1 hour, warmed to room temperature, stirred overnight, poured over ice, and filtered.
  • the filter cake was washed with water and diethyl ether and then dried to give 5.39g of the desired product.
  • Example 2B N-(3-methylphenyl)-N-r4-(7-nitro-l-oxo-2.3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting Example 2 A for Example IC and N- (3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID. !
  • Example 3 N-r4-(7-amino-l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyll-N'-(3-methylphenyl)urea
  • DMF diatomaceous earth
  • the filtrate was concentrated, diluted with water, cooled to 0 °C, and filtered.
  • the filter cake was washed with water and diethyl ether then dried to give 0.88g of the desired product.
  • Example 3 4-yl ⁇ acetamide A suspension of Example 3 (0.088g, 0.24 mmol) in T ⁇ F (2 mL) was treated dropwise via syringe with acetyl chloride (0.017 mL, 0.24 mmol), stirred at room temperature overnight, quenched with water, cooled to 0 °C, and filtered. The filter cake was dried to give 77mg of the desired product.
  • Example 5 N-(2-methylphenyl)-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2-methylphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 6 N-(4-methylphenyl)-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenvnurea
  • the desired product was prepared by substituting 4-methylphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 7 N-(2-methoxyphenyl)-N'- ⁇ 4-( 1 -oxo-2,3-dihydro- lH-isoindol-4-yl phenyllurea
  • the desired product was prepared by substituting 2-methoxyphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 8 N-(3-methoxyphenyl)-N- ⁇ 4-( 1 -oxo-2,3-dihydro- lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 3-methoxyphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 9 N-(4-methoxyphenyl)-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 4-methoxyphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 10 N-(2-fluorophenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2-fluorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 11 N-(3-fluorophenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 3-fluorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 12 N-(4-fluorophenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 4-fluorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 13 N-(2-chlorophenyl)-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2-chlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 14 N-(3-chlorophenyl)-N-[4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 3-chlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 15 N-(4-chlorophenyl)-N'- ⁇ 4-( 1 -oxo-2.3-dihydro- lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 4-chlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 16 N-(2-bromophenyl)-N- ⁇ 4-( 1 -oxo-2,3-dihydro- lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2-bromophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 17 N-(3-bromophenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 3-bromophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 18 N-(4-bromophenyl)-N'-[4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 4-bromophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • 1H ⁇ MR (500 MHz, DMSO-d 6 ) ⁇ 4.51 (s, 2H); 7.46 (apparent s, 4H); 7.3-7.6 (m, 5H); 7.63-7.67 (m, 2H); 8.63 (s, IH); 8.86 (s, 2H); MS (ESI(+)) m/e 422, 424 (M+H) + .
  • Example 19 jV-[4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyll-N'-r4-(trifluoromethoxy)phenyllurea
  • the desired product was prepared by substituting 4-trifluoromethoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 20 N-r4-(l-oxo-2.3-dihvdro-lH-isoindol-4-yl)phenyll-N'-(3-phenoxyphenyl)urea
  • the desired product was prepared by substituting 3-phenoxyphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 500 MHz, DMSO-d 6 ) ⁇ 4.50 (s, 2H);
  • Example 21 N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl ' )phenyll-N'-r4-(trifluoromethyl)phenynurea
  • the desired product was prepared by substituting 4-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • 1H ⁇ MR (300 MHz, DMSO-d 6 ) ⁇ 4.52 (s, 2H); 7.5-7.7 (m, 11H); 8.66 (s, IH); 8.96 (s, IH); 9.16 (s, IH); MS (ESI(+)) m/e 412 (M+H) + .
  • Example 22 N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyn-N'-(4-phenoxyphenyl)urea
  • the desired product was prepared by substituting 4-phenoxyphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 500 MHz, DMSO-d 6 ) ⁇ 4.51 (s, 2H);
  • Example 23 N-r3-(benzyloxy)phenyn-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 3-benzyloxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 25 N-(2,4-dimethylphenyl)-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenvnurea
  • the desired product was prepared by substituting 2,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 28 N-(2,3-dimethoxyphenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2,3-dimethoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 29 N-(2,4-dimethoxyphenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2,4-dimethoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 30 N-(2,5-dimethoxyphenyl " )-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2,5-dimethoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 31 N-(3,4-dimethoxyphenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 3,4-dimethoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 32 N-(3,5-dimethoxyphenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenynurea
  • the desired product was prepared by substituting 3,5-dimethoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 33 N-2.3-dihydro-lH-inden-5-yl-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 5-isocyanatoindane for 3- methylphenyl isocyanate in Example IE.
  • 1H ⁇ MR (300 MHz, DMSO-d 6 ) ⁇ 1.9-2.1 (m, 2H); 2.7-2.9 (m, 4H); 4.52 (s, 2H); 7.1-7.2 (m, 2H); 7.40 (s, IH); 7.5-7.7 (m, 7H); 8.58 (s, IH);
  • Example 35 N-(2,3-dichlorophenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting 2,3-dichlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 36 N-(2,5-dichlorophenyl)-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenynurea
  • the desired product was prepared by substituting 2,5-dichlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 37 N-(3 ,4-dichlorophenvD-N- r4-(l -oxo-2,3-dihydro- lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 3,4-dichlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 38 N-(3,5-dichlorophenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 3,5-dichlorophenyl isocyanate for 3- methylphenyl isocyanate in Example IE. ! ⁇ ⁇ MR (500 MHz, DMSO-d 6 ) ⁇ 4.51 (s, 2H);
  • Example 39 N-r4-chloro-3-(trifluoromethyl)phenyll-N-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 4-chloro-3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 40 N-(3-chloro-4-methoxyphenyl -N-r4-(l-oxo-2.3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 3-chloro-4-methoxyphenyl isocyanate for 3-methylphenyl isocyanate in Example IE. !
  • Example 41 N-(4-bromo-3-methylphenvD-N'-r4-(l-oxo-2.3-dihydro-lH-isoind l-4-yl)phenyllurea
  • the desired product was prepared by substituting 4-bromo-3-methylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 42 N-(3-chloro-4-fluorophenyD-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenyllurea
  • the desired product was prepared by substituting 3-chloro-4-fluorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 43 N-(3-chloro-4-methylphenvD-N'-r4-(l-oxo-2.3-dihvdro-lH-isoindol-4-yDphenyllurea
  • the desired product was prepared by substituting 3-chloro-4-methylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 44 N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenvn-N'-r3-(trifluoromethvDphenyllurea
  • the desired product was prepared by substituting 3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 45 N-(3-ethylphenvD-N'-F4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vDphenyl1urea
  • the desired product was prepared by substituting 3-ethylphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 46 N-(3-cvanophenyD-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenvnurea
  • the desired product was prepared by substituting 3-cyanophenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 300 MHz, DMSO-d 6 ) ⁇ 4.52 (s, 2H); 7.4-7.8 (m, 10H); 7.99 (s, IH); 8.66 (s, IH); 9.00 (s, IH); 9.08 (s, IH); MS (ESI(+)) m/e 369 (M+H) + .
  • Example 47 methyl 3-IYI F4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenvHamino ⁇ carbon v aminolbenzoate
  • the desired product was prepared by substituting methyl 3-isocyanatobenzoate for 3- methylphenyl isocyanate iii
  • Example 48 N-(3-acetylphenyl)-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenynurea
  • the desired product was prepared by substituting 3-acetylphenyl isocyanate for 3- methylphenyl isocyanate in Example IE.
  • Example 49 N-r2-fluoro-5-(trifluoromethvDphenyll-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 2-fluoro-5-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 50 N 2 N 2 -dimethyl-N 1 - ⁇ 7-r4-( ⁇ r(3-methylphenvDaminolcarbonyl ⁇ amino ' )phenyll-3-oxo-2.3- dihydro-lH-isoindol-4-yl I glycinamide
  • the desired product was prepared by substituting N,N-dimethylglycyl chloride for acetyl chloride in Example 4.
  • Example 54A 4-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yD-l-isoindolinone
  • the solution was then treated with potassium acetate (14.72g, 150 mmol), degassed with nitrogen, treated with [1.1 -bis(diphenylphosphino)- ferrocene] dichloropalladium (7g, 8.5 mmol) and heated to 90 °C overnight.
  • the reaction was cooled to room temperature and filtered through diatomaceous earth (Celite ), and concentrated.
  • the concentrate was partitioned between water and ethyl acetate and filtered through diatomaceous earth (Celite ). The organic phase was dried (Na 2 SO 4 ), filtered, and concentrated.
  • the crude product was purified by silica gel chromatography eluting with 100% ethyl acetate and triturated from hexanes to give 4.56g (35% yield) of the desired product, m.p.: 189-191 °C.
  • Example 54B N-(3-methylphenyD-N'-r6-(l-oxo-2,3-dihydro-lH-isoindol-4-yD-3-pyridinvnurea
  • a solution of Example 54A (259 mg, 1 mmol) andN-(6-bromo-3-pyridinyl)-N'-(3- methylphenyl)urea (367 mg, 1.2 mmol) (prepared from 2-amino-4-bromopyridine and m- tolylisocyanate following the procedure of Example IE) in toluene (6 mL) and ethanol (6 mL) was degassed with ⁇ 2 then treated sequentially with a solution of Na 2 CO 3 (509 mg, 4.8 mmol) in water (3 mL) and tetrakis(triphenylphosphine)palladium (0) (208 mg, 0.187 mmol) and stirred at reflux overnight.
  • Na 2 CO 3 509 mg,
  • the resulting suspension was cooled to room temperature, diluted with diethyl ether, and filtered.
  • the filter cake was washed with water, diethyl ether, dichloromethane, ethyl acetate, and methanol.
  • the combined filtrates were concentrated to give 51 mg of the desired product.
  • Example 55A 4-iodo- 1 -isoindolinone
  • the desired product was prepared by substituting 3-iodo-2-methylbenzoic acid for 3- bromo-2-methylbenzoic acid in Examples 1A,1B, and IC.
  • Example 55B 4-(4-phenoxyphenyl)-l -isoindolinone
  • a suspension of Example 55 A (301 mg, 1.16 mmol), 4-phenoxyphenylboronic acid (271 mg, 1.27 mmol) and Na 2 CO 3 (403 mg, 4.75 mmol) in DME (10 mL), water (4.8 mL), and ethanol (2.4 mL) was degassed with N 2 for 45 minutes, treated with Pd(PPh 3 ) 4 (120 mg), and heated to 80 °C overnight.
  • the suspension was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined extracts were dried (Na 2 SO 4 ), filtered, and concentrated.
  • Example 56 4- ⁇ 4- f(5 ,7-dimethyl- 1 ,3 -benzoxazol-2-yl)amino1 -3 -fluorophenyl ⁇ - 1 -isoindolinone
  • the desired product was prepared by substituting N-[2-fluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-l,3-benzoxazol-2-amine for 4- phenoxyphenylboronic acid in Example 55B.
  • Example 57A 4-(4-amino-3-fluorophenyP-l-isoindolinone The desired product was prepared by substituting Example 54A and 4-bromo-2- fluoroaniline for 4-phenoxyphenylboronic acid and Example 55A, respectively, in Example 55B. MS (ESI(+)) m/e 241 (M+ ⁇ ) + .
  • Example 57B N-r2-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenyn-N'-(3-methylphenyDurea The desired product was prepared by substituting Example 57A for Example ID in Example IE.
  • Example 58 N-(3-chlorophenvD-N-r2-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-yl)phenyllurea
  • the desired product was prepared by substituting Example 57A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 60 N-(4-chlorophenvD-N-r2-fluoro-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-yDphenvnurea
  • the desired product was prepared by substituting Example 57A for Example ID and 4-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 61 N-(3-bromophenvD-N'-r2-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 57A for Example ID and 3-bromophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 62 N-(3.4-dimethylphenvD-N'-r2-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenyllurea
  • the desired product was prepared by substituting Example 57A for Example ID and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 63A 4-r4-amino-3-(trifluoromethoxy)phenyll-l-isoindolinone
  • the desired product was prepared by substituting Example 54A and 2- trifluoromethoxy-4-bromoaniline for 4-phenoxyphenylboronic acid and Example 55A, respectively in Example 55B.
  • MS (ESI(+)) m/e 309 (M+ ⁇ ) + .
  • Example 63B N-(3-methylphenvD-N'-r4-(l-oxo-2.3-dihvdro-lH-isoindol-4-vD-2- (trifluoromethoxy)phenvnurea
  • the desired product was prepared by substituting Example 63A for Example ID in Example IE.
  • Example 64 N-(3-chlorophenvD-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vD-2- (trifluoromethoxy)phenyll urea
  • the desired product was prepared by substituting Example 63 A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 65 N-(3,5-dimethylphenyD-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vDphenynurea
  • the desired product was prepared by substituting 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 67 N-r4-fluoro-3-(trifluoromethyDphenyll-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4- yDphenyllurea
  • the desired product was prepared by substituting 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 68A 4-(4-Amino-3-methyl-phenyl-2, 3-dihydro-isoindol-l-one
  • the desired product was prepared by substituting Example 54A and 2-methyl-4- bromoaniline for 4-phenoxyphenylboronic acid and Example 55A, respectively, in Example 55B MS (ESI(+)) m/e 239 (M+ ⁇ ) + .
  • Example 68B N-r2-methyl-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vDphenyn-N'-(3-methylphenyDurea The desired product was prepared by substituting Example 68A for Example ID in Example IE.
  • Example 69 N-(3-chlorophenyD-N'-r2-methyl-4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenyllurea
  • the desired product was prepared by substituting Example 68A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 70 N-(3,4-dimethylphenvD-N'-r2-methyl-4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenyllurea
  • the desired product was prepared by substituting Example 68 A for Example ID and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 71 N-r4-fluoro-3-(trifluoromethvDphenyll-N'-r2-methyl-4-(l-oxo-2,3-dihvdro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 68A for Example ID and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 72 N-(5-methyl-3-pyridinyD-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4- vDphenyllurea hydrochloride
  • a -5 °C solution of 5-methylnicotinohydrazide (353 mg, 2.33 mmol) in water (2.3 mL) and concentrated ⁇ C1 (2.75 mL) was treated dropwise with a solution of ⁇ a ⁇ 2 (161 mg, 2.3 mmol) in water (2.3 mL), stirred at -5 °C for 30 minutes, adjusted to p ⁇ >7 with 10% aqueous K 2 CO- 3 , and filtered.
  • Example 73A 4-(4-amino-2-methylphenvD-l-isoindolinone The desired product was prepared by substituting Example 54A and 3-methyl-4- bromoaniline for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 73B N-(3,4-dimethylphenvD-N'-r3-methyl-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-yDphenyllurea
  • the desired product was prepared by substituting Example 73 A for Example ID and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 74 N-(3,5-dimethylphenyD-N'-r3-methyl-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-yDphenyllurea
  • the desired product was prepared by substituting Example 73 A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 75 N-r3-methyl-4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenyll-N-(3-methylphenvDurea The desired product was prepared by substituting Example 73 A for Example ID in Example IE.
  • Example 76 N-(3-chlorophenyD-N'-r3-methyl-4-(l-oxo-2.3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 73A for Example ID and 3-chlorophenylisocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 77 N-r3-methyl-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vDphenyll-N'-r3- (trifluoromethyDphenyllurea
  • the desired product was prepared by substituting Example 73 A for Example ID and 3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 78 N-[4-fluoro-3-(trifluoromethyPphenyll-N'-r3-methyl-4-(l-oxo-2,3-dihydro-lH-isoindol-4- vPphenyllurea
  • the desired product was prepared by substituting Example 73 A for Example ID and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 79A 4-(4-amino-3-chlorophenyP-l-isoindolinone
  • the desired product was prepared by substituting Example 54A and 2-chloro-4- bromoaniline for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 79B N-r2-chloro-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vPphenyn-N'-(3-methylphenvPurea
  • the desired product was prepared by substituting Example 79A for Example ID in Example IE.
  • Example 79A for Example ID and j 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 300
  • Example 81 N-r2-chloro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-yPphenyll-N-(3,5-dimethylphenyPurea
  • the desired product was prepared by substituting Example 79A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 82 N-F2-chloro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenv ⁇ -N-phenylurea
  • the desired product was prepared by substituting Example 79A for Example ID and phenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 83A 4-(4-amino-2-chlorophenvP- 1 -isoindolinone
  • the desired product was prepared by substituting Example 54A and 3-chloro-4- bromoaniline for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 83B N-r3-chloro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-yPphenyll-N'-(3-methylphenvPurea
  • the desired product was prepared by substituting Example 83 A for Example ID in Example IE. !
  • Example 84 N-[3-chloro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-vPphenyll-N'-(3-chlorophenvPurea
  • the desired product was prepared by substituting Example 83A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 85 N-r3-chloiO-4-(l-oxo-2.3-dihvdro-lH-isoindol-4-vPphenyll-N'-[3- (trifluoromethyPphenyllurea
  • the desired product was prepared by substituting Example 83A for Example ID and 3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 86 N- r3-chloro-4-( 1 -oxo-2.3-dihvdro- lH-isoindol-4-vDphenyll -N- r4-fluoro-3 - (trifluoromethypphenyllurea
  • the desired product was prepared by substituting Example 83A for Example ID and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 87 N- f3-chloro-4-( 1 -oxo-2,3-dihydro- lH-isoindol-4-yDphenyll-N '-(3 ,5-dimethylphenvDurea
  • the desired product was prepared by substituting Example 83A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 88 A 4-(4-amino-2-fluorophenyP- 1 -isoindolinone The desired product was prepared by substituting Example 54A and 3-fluoro-4- bromoaniline for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID. MS (ESI(+) m/e 243 (M+ ⁇ ) + .
  • Example 88 N-(3-chlorophenyP-N'-r3-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 88 A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 89 N-r3-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenyll-N-(3-methylphenyDurea The desired product was prepared by substituting Example 88 A for Example ID in Example IE. !
  • Example 90 N-(3,5-dimethylphenyD-N'-[3-fluoro-4-(l-oxo-2,3-dihydro-lH-isoindol-4-yDphenvnurea
  • the desired product was prepared by substituting Example 88 A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 91 A 4-F4-amino-3-(trifluoromethyDphenyH-l-isoindolinone
  • the desired product was prepared by substituting Example 54A and 2- trifluoromethyl-4-bromoaniline for 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 9 IB N-(3-methylphenvD-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vD-2- (trifluoromethvDphenyll urea
  • the desired product was prepared by substituting Example 91 A for Example ID in Example IE.
  • Example 93A 4-(4-Amino-3-trifluoromemyl-phenyl-2, 3-dihydro-isoindol-l-one
  • the desired product was prepared by substituting Example 54A and 3- trifluoromethyl-4-bromoaniline for 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 94 N-f3.5-dimethylphenvP-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vP-2- (trifluoromethvPphenyllurea
  • the desired product was prepared by substituting Example 91 A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 95 N-(3-chlorophenvP-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vP-3- (trifluoromethvPphenyll urea
  • the desired product was prepared by substituting Example 93 A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 300 MHz, DMSO-d 6 ) ⁇ 3.95 (br. s, IH); 4.22 (br.
  • Example 96 N-(3-methylphenvP-N'-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vP-3- (trifluoromethyPphenyllurea
  • the desired product was prepared by substituting Example 93 A for Example ID in Example IE.
  • ⁇ ⁇ MR 300 MHz, DMSO-d 6 ) ⁇ 2.29 (s, 3H); 3.95 (br. s, IH); 4.21 (br.
  • Example 97 N-(3.4-dimethylphenvP-N'-[4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vD-3- (trifluoromethyDphenyll urea
  • the desired product was prepared by substituting Example 93 A for Example ID and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 300 MHz, DMSO-d 6 ) ⁇ 2.17 (s, 3H); 2.20 (br. s, 3H); 3.94 (br.
  • Example 98 N-(3.5-dimethylphenvD-N'-r4-(l-oxo-2.3-dihvdro-lH-isoindol-4-vD-3- (trifluorometh vDphenyllurea
  • the desired product was prepared by substituting Example 93 A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • ⁇ ⁇ MR 300 MHz, DMSO-d 6 ) ⁇ 2.25 (s, 6H); 3.95 (br. s, IH); 4.22 (br.
  • Example 99A 4-(4-amino-3-ethylphenvD- 1 -isoindolinone
  • the desired product was prepared by substituting Example 54A and 2-ethyl-4- bromoaniline for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 99B N-r2-ethyl-4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vPphenyll-N-(3-methylphenvPurea
  • the desired product was prepared by substituting Example 99A for Example ID in Example IE. !
  • Example 100 N-(3-chlorophenyD-N'-F2-ethyl-4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 99A for Example ID and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 102 N-(3,5-dimethylphenyD-N'-r2-ethyl-4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 99A for Example ID and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate in Example IE.
  • Example 103A 5-bromo-N-phenyl-lH-benzimidazol-2-amine Aniline (0.49 mL, 5.4 mmol) was added dropwise to a 0 °C solution of thiocarbonyldiimidazole(1.02g, 5.7mmol) in pyridine (20 mL). The resulting mixture was . stirred at 0 °C for 1.5 hours, treated with 2-amino-4-bromoaniline (lg, 5.3mmol), stirred overnight at room temperature, then treated with EDCI (1.23g, 6.4 mmol) and heated to 50 °C for 24 hours.
  • Example 103B 4-(2-anilino-lH-benzimidazol-5-yD-l-isoindolinone
  • the desired product was prepared by substituting Example 54A and Example 103A for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example IC, respectively, in Example ID.
  • Example 104A 4-bromo-6-methoxy-l-isoindolinone
  • the desired product was prepared by substituting methyl 3-bromo-5-methoxy-2- methylbenzoate (prepared according to the procedure described in 7.Am .Chem. Soc. 1967, 1695-1704) for methyl 3-bromo-2-methylbenzoate in Examples IB-C.
  • MS (ESI(+)) m/e 242, 244 (M+H) + .
  • Example 104B 4-bromo-6-hydroxy- 1 -isoindolinone A -78 °C suspension of Example 104 A (100 mg, 0.41 mmol) in dichloromethane (13 mL) was treated dropwise with 1M BBr 3 in dichloromethane (1.2 mL, 1.2 mmol), stirred at -78 °C for 1 hour, and stirred at room temperature for 2 hours. The mixture was treated with additional 1M BBr 3 in dichloromethnae (0.8 mL), heated to reflux overnight, then cooled to room temperature, and partitioned between water and ethyl acetate. The organic phase was dried (Na 2 SO 4 ), filtered, and concentrated to give 91 mg (97%) of the desired product. MS (ESI(-)) m/226, 228 (M-H) ⁇
  • Example 104C 4-bromo-6-(2-methoxyethoxy)- 1 -isoindolinone
  • a mixture of Example 104B (100 mg, 0.44 mmol), Cs 2 CO 3 (163 mg, 0.5 mmol) and 2-bromoethyl methyl ether (0.045 mL, 0.46 mmol) in DMF (2.2 mL) was warmed to 60 °C for 4 hours, stirred at room temperature overnight, and partitioned between water and ethyl acetate. The organic phase was dried (Na 2 SO 4 ), filtered, and concentrated to give 128 mg of the desired product.
  • Examplel04D N- 14- r6-(2-methoxyethoxy)- 1 -oxo-2,3-dihydro- lH-isoindol-4-yllphenyl ⁇ -N-(3- methylphenypurea
  • the desired product was prepared by substituting Example 104C for Example IC and N-(3-methylphenyl)-N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • Example 105 A tert-butyl r(7-bromo-3-oxo-2,3-dihydro-lH-isoindol-5-vPoxylacetate
  • MS (ESI(+)) m/e 342,344 (M+ ⁇ ) + .
  • Example 105B tert-butyl (
  • the desired product was prepared by substituting Example 105A for Example IC and N-(3-methylphenyl)-N- [4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • MS (ESI(+)) m/e 486 (M+ ⁇ ) + .
  • Example 106A methyl 6-amino-3 -bromo-2-methylbenzoate
  • a -20 °C solution of methyl 3-bromo-2-methylbenzoate (lOg, 43.7 mmol) in concentrated ⁇ 2 SO 4 (100 mL) was treated dropwise with a solution of concentrated H ⁇ O 3 (2.75 mL) in concentrated H 2 SO 4 (50 mL) at a rate that maintained the temperature below - 15 °C.
  • the reaction was then stirred at 0 °C for 30 minutes, poured into ice, and extracted with diethyl ether.
  • Example 106B methyl 3 -bromo-6-h ydroxy-2-methylbenzoate A 0 °C suspension of Example 106A (lg, 4.1 mmol) in water (6 mL) was treated dropwise with a solution of NaNO 2 (285 mg) in water (1.25 mL), stirred at 0 °C for 15 minutes, then added slowly to a 90 °C solution of concentrated H 2 SO 4 (4 mL) in water (4 mL). The reaction was stirred at 90 °C for 45 minutes, cooled to room temperature, and extracted three times with diethyl ether.
  • Examplel06C methyl 6-(acetyloxy)-3-bromo-2-methylbenzoate
  • pyridine 3 mL
  • acetic anhydride 0.82 mL, 8.6 mmol
  • the organic phase was washed sequentially with aqueous NaHCO 3 , water, and brine, dried (MgSU 4 ), filtered, and concentrated to give 1.19g (97% yield) of the desired product.
  • MS (ESI(+)) m/e 304, 306 (M+H) + .
  • Example 106D 4-bromo-7 -hydroxy- 1 -isoindolinone The desired product was prepared by substituting Example 106C for Example IA in Examples IB and IC. MS (ESI(+)) m/e 226,228 (M+H) + .
  • Example 106E N-r4-(7-hvdroxy-l-oxo-2,3-dihydro-lH-isoindol-4-vPphenyl1-N-(3-methylphenvPurea
  • the desired product was prepared by substituting Example 106D for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • Example 107 A 4-bromo-7-methoxy- 1 -isoindolinone
  • a solution of Example 106D (103mg, 0.45 mmol) in DMF (4 mL) was treated with CS 2 CO- 3 (162mg, 0.5 mmol) and methyl iodide (0.03 mL, 0.48 mmol), stirred at room temperature for 3 hours, then poured into water. The resulting precipitate was filtered to give 76 mg (70%) of the desired product.
  • MS (ESI(+)) m/e 242,244 (M+ ⁇ ) + .
  • Example 107B N-r4-(7-methoxy-l-oxo-2,3-dihydro-lH-isoindol-4-yPphenvn-N'-(3-methylphenyPurea
  • the desired product was prepared by substituting Example 107 A for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • Example 108 sodium ( ⁇ 7-r4-( ⁇ r(3-methylphenyDamino1carbonyllamino)phenyll-3-oxo-2,3-dihydro-lH- isoindol-4-yl ) oxy)acetate
  • Example 108A tert-butyl r(7-bromo-3-oxo-2,3-dihydro-lH-isoindol-4-vDoxylacetate
  • MS (DCI) m/e 342, 344 (M+ ⁇ ) + .
  • Example 108B sodium ( ⁇ 7-r4-(
  • the desired product was prepared by substituting Example 108 A for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and substituting toluene for methanol in Example ID. !
  • Example 109 N- ⁇ 4-r7-(2-methoxyethoxy)-l-oxo-2,3-dihvdro-lH-isoindol-4-yllphenyll-N'-(3- methylphenypurea
  • the desired product was prepared by substituting Example 106D for Example 104B in Examples 104C and 104D.
  • Example 110A 4-bromo-2-methyl- 1 -isoindolinone
  • a solution of Example IB (lg, 3.25 mmol), methylamine hydrochloride (l.lg, 16.2 mL) and triethylamine (2.2 mL, 16.2 mmol) in methanol (16 mL) was refluxed for 10 hours, cooled to room temperature, concentrated to l ⁇ volume, and partitioned between saturated ⁇ 4 CI and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (MgSO 4 ), filtered, and concentrated to give 707 mg of the desired product.
  • MS (ESI(+)) m/e 226 (M+H) + .
  • Example 110B N-r4-(2-methyl-l-oxo-2,3-dihvdro-lH-isoindol-4-yPphenyll-N-(3-methylphenyPurea
  • the desired product was prepared by substituting Example 110A for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and substituting toluene for methanol in Example ID.
  • Example 111 A methyl 5- ⁇ r(benzyloxy)carbonyllamino ⁇ -2-methyl-3-nitrobenzoate
  • a 0 °C solution of methyl 5-amino-2-methyl-3-nitrobenzoate (lg, 4.76 mmol, prepared according to the procedure described in J.Med.Chem. 1984, 27, 386) and diisopropylethylamine (0.91 mL, 5.24 mmol) in THF (24 mL) was treated with benzyl chloroformate (0.65 mL, 5.34 mmol), stirred at 0 °C for 30 minutes, warmed to room temperature for 2 hours, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated to give 1.7g of the desired product.
  • Example 11 IB methyl 5-f r(benzyloxy)carbonyllamino ⁇ -3-iodo-2-methylbenzoate
  • a suspension of iron powder (0.83g, 14.8 mmol) and ammonium chloride (1.33g, 24.7 mmol) in water was treated dropwise with a suspension of Example 111A (1.7g, 4.94 mmol) in ethanol, stirred at 80 °C for 6 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite ). The pad was washed with warm methanol and the filtrate was concentrated. The concentrate was partitioned between ethyl acetate and water.
  • the extract was washed with brine, dried (MgSO 4 ), filtered, and concentrated to give 1.49g of the intermediate amine.
  • the crude product was dissolved in DMF (10 mL), cooled to 0 °C, and treated dropwise with 6M HC1 (2.4 mL) followed by a solution of NaNO 2 (0.327g, 4.75 mmol) in water (5 mL). The solution was stirred at 0 °C for 30 minutes, treated portionwise with KI (788 mg, 4.75 mmol), diluted with DMF (10 mL), stirred at 0 °C for 2 hours, warmed to room temperature for 30 minutes, and extracted with diethyl ether.
  • Example 111C benzyl 7-iodo-3-oxo-2,3-dihydro- lH-isoindol-5-ylcarbamate
  • the desired product was prepared by substituting Example 11 IB for Example 1 A in Examples IB and IC.
  • Example 11 benzyl 7-r4-( ⁇ r(3-methylphenyPaminolcarbonyl)amino phenyl1-3-oxo-2.3-dihydro-lH- isoindol-5-ylcarbamate
  • the desired product was prepared by substituting Example 111C for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • Example 112 N-(3-methylphenyD-N'-r3-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 3-aminophenylboronic acid for 4- (4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)aniline in Examples ID and IE.
  • Examplell3 N- r4-(6-methoxy- 1 -oxo-2,3-dihydro- lH-isoindol-4-yPpheny ⁇ -N -(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 104 A for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • Example 114A 4-bromo-7-(3-chloropropoxy)- 1 -isoindolinone
  • Example 114B 4-bromo-7- ⁇ 3 -(4-morpholinyPpropoxyl - 1 -isoindolinone
  • a solution of Example 114A (227mg, 0.75 mmol), morpholine (0.33 mL, 3.8 mmol), and potassium iodide (70mg, 0.42 mmol) in DMF (3 mL) was heated to 100 °C overnight in a sealed reaction vessel, poured into water, and filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by silica gel chromatography with 5 to 7% methanol/dichloromethane containing 1% triethylamine to give 130mg of the desired product.
  • MS (ESI(+)) m/e 355,357 (M+H) + .
  • Example 114C N-(3-methylphenvP-N'-(4- ⁇ 7-r3-(4-morpholinyPpropoxyl-l-oxo-2,3-dihydro-lH-isoindol-4- yllphenyPurea
  • the desired product was prepared by substituting Example 114B for Example IC and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example ID.
  • Example 115 A 2-(4-bromophenvP-N-(3-methylphenvPacetamide
  • a solution of 4-bromophenylacetic acid (502 mg, 2.33 mmol), m-toluidine (0.25 mL, 2.33 mmol), ⁇ OBT (350 mg, 2.59 mmol), and ⁇ -methylmorpholine (0.51 mL, 4.64 mmol) in DMF (10 mL) was treated with EDCI (496 mg, 2.59 mmol), stirred overnight at room temperature, and poured into ice water. The resulting white precipitate was collected by filtration to give 672 mg of the desired product.
  • MS (ESI(+)) m/e 304, 306 (M+ ⁇ ) + .
  • Example 115B N-(3-methylphenvP-2-r4-(l-oxo-2,3-dihvdro-lH-isoindol-4-vPphenvnacetamide
  • the desired product was prepared by substituting Example 115A for N-(6-bromo-3- pyridinyl)-N'-(3-methylphenyl)urea in Example 54B. !
  • Example 116 N-methyl-N-(3-methylphenyp-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • a suspension of Example ID (0.25g, 1.1 mmol) in dioxane (3 mL) was sequentially treated with triethylamine (0.17 mL, 1.2 mmol) and triphosgene (O.llg, 0.37 mmol), heated to 70 °C for 2 hours, and concentrated.
  • the concentrate was resuspended in T ⁇ F (3 mL), treated with N-methyltoluidine, stirred at room temperature for 18 hours, and partitioned between water and ethyl acetate.
  • Example 117 N-(3-chlorophenvD-N-methyl-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting 3-chloro-N-methylaniline for N- methyltoluidine in Example 116.
  • Example 119 3-(dimethylamino)-N- ⁇ 7-r4-(ir(3-methylphenvDaminolcarbonyl ⁇ amino phenyll-3-oxo-2,3- dihydro-lH-isoindol-4-yl ⁇ benzamide
  • the desired product was prepared by substituting 3-dimethylaminobenzoyl chloride for acetyl chloride in Example 4.
  • Example 120 N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenyn-l,3-thiazole-2-carboxamide
  • the desired product was prepared by substituting l,3-thiazole-2-carboxylic acid and Example ID for 4-bromophenylacetic acid and -toluidine respectively, in Example 115 A.
  • Example 121 N-(3-methylphenyD-N'-r4-(l-oxo-2,3-dihydro-lH-isoindol-4-vDphenvnthiourea
  • DMF dimethyl methyl
  • m- tolylisothiocyanate 0.06 mL, 0.45 mmol
  • Example 122 A 4- r4-(methylamino)phenyl, - 1 -isoindolinone The desired product was prepared by substituting 4-bromo-N-methylaniline (Tetrahedron. Lett. 1993, 34, 2115) for N-(6-bromo-3-pyridinyl)-N '-(3-methylphenyl)urea in Example 54B. MS (ESI(+)) m/e 239 (M+H) + .
  • Example 122B N-methyl-N'-(3-methylphenyD-N-r4-(l-oxo-2,3-dihydro-lH-isoindol-4- vDphenyllurea
  • the desired product was prepared by substituting Example 122A for Example ID in Example IE.
  • Example 123 4-(2,5-dimethoxyphenyD-N-r4-(l-oxo-2.3-dihydro-lH-isoindol-4-yDphenyll- 3-thiazole-2- carboxamide
  • the desired product was prepared by substituting 4-(2,5-dimethoxyphenyl)-l,3- thiazole-2-carboxylic acid and Example ID for 4-bromophenylacetic acid and m-toluidine, respectively, in Example 115A.
  • Example 124 4-(3-bromophenyD-N-r4-(l-oxo-2,3-dihvdro-lH-isomdol-4-vDphenyll-l,3-thiazole-2- carboxamide
  • the desired product was prepared by substituting 4-(3-bromophenyl)-l,3-thiazole-2- carboxylic acid and Example ID for 4-bromophenylacetic acid and m-toluidine, respectively, in Example 115A.
  • Example 125 A r4-(l-oxo-2, 3-dihydro-lH-isoindol-4-vD-phenyll-thiourea
  • a solution of ammonium thioisocyanate (78 mg, 1.07 mmol) in acetone (5 mL) was treated with benzoyl chloride (0.118 mL, 1.07 mmol), heated to reflux for 20 minutes, removed from heat, treated with Example ID (200 mg, 0.89 mmol) and stirred at reflux for 1 hour.
  • the resulting mixture was poured into ice water and the precipitate filtered, washed with water, and dried to give 295 mg of an off white solid which was added to 5% aqueous NaOH solution (5 mL).
  • Example 125B 4-(4- ⁇ [4-(4-methoxyphenyD-1.3-thiazol-2-yllamino ⁇ phenvD-l-isoindolinone
  • a suspension of Example 125A (90 mg, 0.32 mmol) and 2-bromo-l-(4-methoxy- phenyl)ethanone (73 mg, 0.32 mmol) in ethanol (3 mL) was stirred at reflux for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dichloromethane and dried to give 118 mg (90% yield) of the desired product as the hydrobromide salt.
  • Example 126 4-r4-(lH-benzimidazol-2-ylamino phenyll-l-isoindolinone trifluoroacetate
  • thiocarbonyldiimidazole 442 mg, 2.23 mmol
  • pyridine 8 mL
  • Example ID 500 mg, 2.23 mmol
  • 1,2- diaminobenzene 241 mg, 2.68 mmol
  • stirred at room temperature overnight treated with EDCI (513 mg, 2.68 mmol), heated to 50 °C overnight, and concentrated.
  • the residue was partitioned between ethyl acetate/T ⁇ F and water.
  • the organic extract was dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by silica gel chromatography with 5% methanol/dichloromethane, then further purified by preparative ⁇ PLC on a Waters Symmetry C8 column (25mm X 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40mL/min to give to give 17 mg of the desired product.
  • Example 127 N-(3-methylphenvD-N-r5-(l-oxo-2,3-dihvdro-lH-isoindol-4-yD-2-thienyllurea
  • Examplel27A methyl 5-(l-oxo-2,3-dihydro-lH-isoindol-4-vD-2-thiophenecarboxylate
  • the desired product was prepared by substituting methyl 5-bromo-2- thiophenecarboxylate for N-(6-bromo-3-pyridinyl)-N'-(3-methylphenyl)urea in Example 54B.
  • R f 0.45 (10% C ⁇ 3 O ⁇ /C ⁇ 2 Cl 2 ).
  • Examplel27B 5-(l-oxo-2,3-dihvdro-lH-isoindol-4-vD-2-thiophenecarboxylic acid
  • a suspension of Example 127 A (0.34g, 1.24 mmol) in T ⁇ F (30 mL) and methanol (30 mL) was treated with IN LiO ⁇ (10 mL), stirred at room temperature for 5 hours, then acidified with IN ⁇ C1 and diluted with diethyl ether. The resulting suspension was filtered and the filter cake was washed with water and dried to give 288 mg of the desired product.
  • MS (ESI(-)) m/e 258 (M- ⁇ ) " MS (ESI(-)) m/e 258 (M- ⁇ ) " .
  • Example 127C N-(3-methylphenvD-N'-r5-(l-oxo-2,3-dihydro-lH-isoindol-4-yD-2-thienynurea
  • a solution of Example 127B (70 mg, 0.27 mmol) and triethylamine (0.046 mL, 0.32 mmol) in DMF (8 mL) was treated with diphenylphosphorylazide (0.072 mL, 0.32 mmol), heated to 80 °C for 2 hours, cooled to room temperature, and treated with 3-methylaniline (0.03 mL, 0.27 mL).
  • the resulting mixture was heated to 80 °C for 2 hours, cooled to room temperature, diluted with water, and extracted with dichloromethane and ethyl acetate. The combined extracts were dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by silica gel chromatography, with 3% methanol/dichloromethane to give the desired product (13% yield).
  • Example 128A methyl 4'-amino-2-methyl-5-nitro- 1 , 1 -biphenyl-3 -carboxylate
  • Example IA (20g, 87.3 mmol) was cooled to -5 °C and treated dropwise with ⁇ 2 SO 4 (100 mL) at such a rate as to maintain the internal temperature below 10 °C.
  • the reaction mixture was cooled to -30 °C and treated dropwise with nitric acid (5.7 mL, 91.7 mmol) at such a rate as to maintain the internal temperature below -12 °C.
  • nitric acid 5.7 mL, 91.7 mmol
  • Example 128B methyl 4 -r(tert-butoxycarbonvDaminol-2-methyl-5-nitro-l, -biphenyl-3-carboxylate
  • THF 10 mL
  • triethylamine 0.8 mL, 5.6 mmol
  • di-tert-butyldicarbonate 1.34g, 6.17 mmol
  • the concentrate was purified by silica gel cliromatography with 20 to 30% ethyl acetate/hexanes to give 1.36g of the desired product, m.p.131-132 °C.
  • Example 128C 4-(4-aminophenyD-6-nitro- 1 -isoindolinone
  • a solution of tert-butyl 4-(6-nitro-l-oxo-2,3-dihydro-lH-isoindol-4- yl)phenylcarbamate (0.276g, prepared by substituting Example 128B for Example IA in Examples IB and IC) in TFA (3 mL) and C ⁇ 2 CI 2 (3 mL) was stirred at room temperature for 1 hour, then concentrated to give 0.085g of the desired product.
  • Example 128D N-(3-methylphenyD-N'-r4-(6-nitro-l-oxo-2,3-dihydro-lH-isoindol-4-vDphenyllurea
  • the desired product was prepared by substituting Example 128C for Example ID in Example IE.
  • Example 129 N-[4-(6-amino-l-oxo-2,3-dihvdro-lH-isoindol-4-vDphenyll-N'-(3-methylphenyDurea The desired product was prepared by substituting Example 128D for Example 2 in Example 3.

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