JP2006526648A - Isoindoline-1-one compounds as kinase inhibitors - Google Patents

Abstract

Compounds having formula (I) are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods for preparing the present compounds and compositions containing the present compounds.

Description

  The present invention relates to compounds useful for inhibiting protein tyrosine kinases, methods of preparing the compounds or compositions containing the compounds, and methods of treatment using the compounds.

  Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues of cellular proteins. This post-translational modification of these substrate proteins, often the enzyme itself, acts as a molecular switch that regulates cell growth, activation or differentiation. Abnormal or excessive PTK activity is a benign and malignant proliferative disease, as well as many diseases including diseases caused by inappropriate activation of the immune system (eg autoimmune diseases), allograft rejection and graft-versus-host disease Observed in state. Moreover, certain receptors on endothelial cells, such as PTKs, such as KDR and Tie-2, mediate angiogenic processes and thus other diseases including cancer and inappropriate angiogenesis (eg, diabetic retinopathy, aging Is involved in supporting the progression of choroidal neovascularization due to macular degeneration, psoriasis, arthritis, retinopathy of prematurity and hemangioma in infants).

  Thus, the identification of effective small compounds that specifically inhibit signal transduction and cell proliferation by altering the activity of tyrosine kinases to regulate and alter abnormal or inappropriate cell growth, differentiation or metabolism Is desired. In particular, it specifically identifies the function of tyrosine kinases that are essential for the formation of angiogenic processes or vascular permeability enhancement resulting in edema, ascites, exudates, exudates, and macromolecular extravasation and matrix deposition, as well as related diseases The identification of methods and compounds that inhibit the activity would be beneficial.

  In a first embodiment, the present invention provides compounds of formula (I):

の化合物又は治療上許容可能なその塩を提供する。（式中、
Ｒ^１は、水素及びアルキルからなる群より選択され；
Ｒ^２は、水素、アルコキシ、アルコキシアルコキシ、アルキル、カルボキシアルコキシ、カルボキシアルキル、ハロ、ハロアルキル、ヘテロシクリルアルコキシ、ヒドロキシ、ニトロ及び−ＮＲ^ｃＲ^ｄからなる群より選択され；
Ｒ^３及びＲ^４のうち１つは、Ａ−Ｘ−Ｒ^５であり、他方は水素であり（ここで、Ａ−Ｘ−Ｒ^５は、その左端で親分子部分と結合している。）；
Ｒ^５は、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され；
Ａは、アリール及びヘテロアリール（アリール及びヘテロアリールは、場合によっては、アルキル、ハロ、ハロアルコキシ及びハロアルキルからなる群より独立に選択される、１個又は２個の置換基で置換されている。）からなる群から選択され；
Ｘは、Ｏ、ＮＲ^ａ、Ｎ（Ｒ^ａ）Ｃ（Ｓ）Ｎ（Ｒ^ｂ）、（ＣＨ_２）_ｍＮ（Ｒ^ａ）Ｃ（Ｏ）Ｎ（Ｒ^ｂ）（ＣＨ_２）_ｎ、ＣＨ_２Ｃ（Ｏ）Ｎ（Ｒ^ａ）及びＮ（Ｒ^ａ）Ｃ（Ｏ）（式中、Ｒ^ａ及びＲ^ｂは、水素及びアルキルからなる群から独立に選択され、ｍ及びｎは、独立に０又は１であり、各基は、その左端でＡに結合しており、その右端でＲ^５に結合している。）からなる群から選択される。）。

Or a therapeutically acceptable salt thereof. (Where
R ¹ is selected from the group consisting of hydrogen and alkyl;
R ² is selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, carboxyalkoxy, carboxyalkyl, halo, haloalkyl, heterocyclylalkoxy, hydroxy, nitro and —NR ^c R ^d ;
One of R ³ and R ⁴ is AXR ⁵ and the other is hydrogen (where AXR ⁵ is attached to the parent molecular moiety at its left end). ;
R ⁵ is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
A is aryl and heteroaryl (aryl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, haloalkoxy and haloalkyl. ) Selected from the group consisting of:
X represents O, NR ^a , N (R ^a ) C (S) N (R ^b ), (CH ₂ ) _m N (R ^a ) C (O) N (R ^b ) (CH 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, and m and n are independently 0 Or each group is selected from the group consisting of A bound to A at its left end and R ⁵ at its right end. ).

In a preferred embodiment, the present invention discloses a compound of formula (I) wherein R ¹ is hydrogen.

In a preferred embodiment, the present invention discloses a compound of formula (I) wherein R ³ is A—X—R ⁵ and R ⁴ is hydrogen.

In another preferred embodiment, the invention provides that R ³ is A—X—R ⁵ , R ⁴ is hydrogen, and X is O, NR ^a , N (R ^a ) C (S) N ( Disclosed are compounds of formula (I) selected from the group consisting of R ^b ), CH ₂ C (O) N (R ^a ) and N (R ^a ) C (O).

In another preferred embodiment, the invention provides that 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) is a _{(CH 2) n,} discloses compounds of formula (I).

In another preferred embodiment, the invention provides that R ³ is A—X—R ⁵ , R ⁴ is hydrogen, and X is (CH ₂ ) _m N (R ^a ) C (O) N (R Disclosed are compounds of formula (I), wherein ^b ) (CH ₂ ) _n , R ^a and R ^b are hydrogen, and m and n are 0.

In another preferred embodiment, the invention provides that 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) a _n, ^{R 2} is other than hydrogen, discloses compounds of formula (I).

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl (aryl and heteroaryl are unsubstituted) of formula (I) Disclosed are compounds.

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are mono-substituted. The compounds are disclosed.

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl (aryl and heteroaryl are monosubstituted), and A is aryl and hetero Disclosed are compounds of formula (I), selected from the group consisting of aryl (aryl and heteroaryl are unsubstituted).

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl (aryl and heteroaryl are monosubstituted), and A is aryl and hetero Disclosed are compounds of formula (I), selected from the group consisting of aryl (aryl and heteroaryl are monosubstituted).

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl (aryl and heteroaryl are disubstituted) The compounds are disclosed.

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl (aryl and heteroaryl are disubstituted), and A is aryl and hetero Disclosed are compounds of formula (I), selected from the group consisting of aryl (aryl and heteroaryl are unsubstituted).

In another preferred embodiment, the invention provides that 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 , R ² is hydrogen, R ⁵ is selected from the group consisting of aryl and heteroaryl (aryl and heteroaryl are disubstituted), and A is aryl and hetero Disclosed are compounds of formula (I), selected from the group consisting of aryl (aryl and heteroaryl are monosubstituted).

In another embodiment, 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 invention comprises administering to the patient a therapeutically acceptable amount of a compound of formula (I) or a therapeutically acceptable salt thereof in a patient found to be in need of treatment for inhibition of protein kinases. Methods are provided for inhibiting protein kinases.

  In another embodiment, the invention administers to a patient a therapeutically acceptable amount of a compound of formula (I) or a therapeutically acceptable salt thereof in a patient found to be in need of treatment for cancer. A method for treating cancer, comprising:

DETAILED DESCRIPTION OF THE INVENTION All publications, issued patents, patent applications cited herein are hereby incorporated by reference.

  As used herein, the following terms have the meanings indicated.

  As used herein, the term “alkoxy” refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.

  As used herein, the term “alkoxyalkoxy” refers to an alkoxy group attached to the parent molecular moiety through another alkoxy group.

  As used herein, the term “alkoxyalkoxyalkyl” means an alkoxyalkoxy group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “alkoxyalkoxyalkylcarbonyl” means an alkoxyalkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “alkoxyalkyl” means an alkoxy group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “alkoxyalkylcarbonyl” means an alkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “alkoxycarbonyl” means an alkoxy group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “alkyl” means a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 10 carbon atoms.

  As used herein, the term “alkylcarbonyl” means an alkyl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “alkylsulfanyl” refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.

As used herein, the term “aryl” refers to a phenyl group or a bicyclic or tricyclic fused ring system (one or more of the fused rings being a phenyl group). .) Examples of bicyclic fused ring systems are a monocyclic cycloalkenyl group as defined herein, a monocyclic cycloalkyl group as defined herein or a phenyl group fused to another phenyl group. is there. Examples of tricyclic fused ring systems include bicyclic fused rings fused to a monocyclic cycloalkenyl group as defined herein, a monocyclic cycloalkyl group as defined herein, or another phenyl group. It is. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl group of the present invention may optionally be alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, secondary aryl group, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano, cyanoalkyl, halo, Haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, nitro, oxo and NR ^c R ^d (wherein the secondary aryl group and the aryl moiety of arylalkoxy, arylalkyl, aryloxy and arylsulfanyl) , Heteroaryl and heteroarylalkyl heteroaryl moieties, heterocyclyl and heterocyclylalkyl heterocyclyl moieties are Optionally further 1, 2, 3, 4 or 5 independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy and nitro. And may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of:

  As used herein, the term “arylalkoxy” means an aryl group that is attached to the parent molecular moiety through an alkoxy group.

  As used herein, the term “arylalkoxycarbonyl” means an arylalkoxy group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “arylalkyl” refers to an aryl group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “arylalkylcarbonyl” means an arylalkyl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “arylcarbonyl” means an aryl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “aryloxy” refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

  As used herein, the term “arylsulfanyl” means an aryl group that is attached to the parent molecular moiety through a sulfur atom.

  As used herein, the term “carbonyl” means —C (O) —.

As used herein, the term “carboxy” means —CO ₂ H.

  As used herein, the term “carboxyalkoxy” refers to a carboxy group attached to the parent molecular moiety through an alkoxy group.

  As used herein, the term “carboxyalkyl” refers to a carboxy group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “cyano” means —CN.

  As used herein, the term “cyanoalkyl” refers to a cyano group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “cycloalkenyl” refers to a non-aromatic cyclic or bicyclic ring system having 3 to 10 carbon atoms and 1 to 3 rings. Where each 5-membered ring has 1 double bond, each 6-membered ring has 1 or 2 double bonds, and each 7- and 8-membered ring has 1 to 3 And each 9 to 10 membered ring has 1 to 4 double bonds. Examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.

  As used herein, the term “cycloalkyl” means a monocyclic, bicyclic or tricyclic saturated hydrocarbon ring system having from 3 to 12 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo [3.1.1] heptyl and adamantyl.

  As used herein, the terms “halo” and “halogen” mean F, Cl, Br, or I.

  As used herein, the term “haloalkoxy” means a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

  As used herein, the term “haloalkyl” refers to an alkyl group substituted with 1, 2, 3 or 4 halogen atoms.

As used herein, the term “heteroaryl” is an aromatic 5- or 6-membered, wherein at least one atom is selected from the group consisting of N, O and S, and the remaining atoms are carbon. Means a ring. These five-membered rings have two double bonds, and the six-membered ring has three double bonds. These heteroaryl groups are attached to the parent molecular group through the ring's substitutable carbon or nitrogen atoms. The term “heteroaryl” also includes heteroaryl rings in which a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, A bicyclic ring system fused to a heterocyclyl group or a further heteroaryl group as defined above and the bicyclic ring system is a phenyl group, a monocyclic cycloalkyl group as defined herein, as defined herein Also included are tricyclic systems fused to a heterocyclyl group or a further heteroaryl group. Examples of heteroaryl include benzothienyl, benzooxadiazolyl, cinnolinyl, dibenzofuranyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, trienyl , Thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, triazinyl and the like. The heteroaryl group of the present invention may optionally be alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, aryl, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano, cyanoalkyl, halo, haloalkoxy , Haloalkyl, second heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, nitro, oxo and NR ^c R ^d (wherein the above aryl and the above arylalkoxy, arylalkyl, aryloxy and arylsulfanyl The aryl moiety, the second heteroaryl group described above and the heteroaryl moiety of the above heteroarylalkyl, and the above heterocyclyl and above The heterocyclyl moiety of the heterocyclylalkyl described is optionally 1,2,2, independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy and nitro. It may be further substituted with 3, 4 or 5 substituents.) May be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of:

  As used herein, the term “heteroarylalkyl” means a heteroaryl group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “heteroarylcarbonyl” means a heteroaryl group attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “heterocyclyl” is a cyclic, non-aromatic 5, 6 or 7 member containing at least one atom selected from the group consisting of oxygen, nitrogen and sulfur. Means a ring. These 5-membered rings have 0 or 1 double bond, and the 6- and 7-membered rings have 0, 1 or 2 double bonds. The heterocyclyl groups of the present invention are attached to the parent molecular group through the substitutable carbon or nitrogen atom of the ring. The term “heterocyclyl” also includes heterocyclyl rings on a phenyl group, a monocyclic cycloalkenyl group as defined herein, a monocyclic cycloalkyl group as defined herein, or an additional monocyclic heterocyclyl group. The fused bicyclic system and the bicyclic system is a phenyl group, a monocyclic cycloalkenyl group as defined herein, a monocyclic cycloalkyl group as defined herein or a further monocyclic heterocyclyl group. Also included are fused tricyclic systems. Examples of 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 are included. The heterocyclyl group of the present invention may optionally be alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, aryl, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano, cyanoalkyl, halo, haloalkoxy, Haloalkyl, heteroaryl, heteroarylalkyl, second heterocyclyl group, heterocyclylalkyl, hydroxy, nitro, oxo and NR ^c R ^d (wherein the above aryl and the above arylalkoxy, arylalkyl, aryloxy and arylsulfanyl An aryl moiety, a heteroaryl as described above and a heteroaryl moiety as described above, a second heterocyclyl group as described above and The heterocyclyl part of the heterocyclylalkyl is optionally selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy and nitro. It may be further substituted with 4 or 5 substituents.) May be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of:

  As used herein, the term “heterocyclylalkoxy” refers to a heterocyclyl group attached to the parent moiety through an alkoxy group.

  As used herein, the term “heterocyclylalkyl” means a heterocyclyl group attached to the parent moiety through an alkyl group.

  As used herein, the term “heterocyclylcarbonyl” means a heterocyclyl group attached to the parent moiety through a carbonyl group.

As used herein, the term “hydroxy” means —OH.
As used herein, the term “nitro” means —NO ₂ .

  As used herein, the term “oxo” means ═O.

As used herein, the term “—NR ^c R ^d ” represents two groups, R ^c and R ^d , which are attached to the parent molecular moiety through a nitrogen atom. R ^c and R ^d are hydrogen, alkoxyalkyl, alkoxyalkoxyalkylcarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, heteroaryl, heteroarylalkyl, Heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl and —C (O) (CH ₂ ) _n N (R ^e R ^f ) (wherein n is 0, 1 or 2; R ^e and R ^f are Independently selected from the group consisting of hydrogen and alkyl.) Wherein each of the above-mentioned aryl and the above-mentioned arylalkoxycarbonyl, arylalkyl, aryl The aryl moiety of alkylcarbonyl and arylcarbonyl, the above heteroaryl and the above heteroarylalkyl and heteroarylcarbonyl heteroaryl moieties, the above heterocyclyl and the above heterocyclylcarbonyl heterocyclyl moieties are alkoxy, alkoxycarbonyl, alkyl, alkyl It may optionally be further substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of carbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl and nitro.

  The compounds of the present invention can exist as therapeutically acceptable salts. As used herein, the term “therapeutically acceptable salt” is soluble or dispersible in water or oil and is suitable for the treatment of diseases without inappropriate toxicity, irritation and allergic response. Represents a salt or zwitterionic form of a compound of the invention that corresponds to a reasonable benefit / risk ratio and is effective for the intended use. These salts can be prepared during final isolation and purification of the compound or can be prepared separately by reacting the appropriate nitrogen atom with the appropriate acid. Typical acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate Salt, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic acid Salt, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate Salt, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, Glutamic acid, bicarbonate, para-toluenesulfonate and undecanoate. Also suitable nitrogen atoms of the compounds of the present invention are methyl, ethyl, propyl and butyl chloride, bromide and iodide; dimethyl, diethyl, dibutyl and diamyl sulfate; decyl, lauryl, myristyl and steryl chloride, bromide and Can be quaternized with iodide; and benzyl and phenethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and oxalic acid, maleic acid, succinic acid and citric acid. Organic acids such as acids are included.

  Base addition salts are obtained by reacting the carboxy group with a suitable base, such as a metal cation hydroxide, carbonate or bicarbonate, or ammonia or an organic primary, secondary or tertiary amine. Can be prepared during final isolation and purification of the compound. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, and non-toxic 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, N, N-dibenzylphenethylamine, 1-ephamineamine And N, N′-dibenzylethylenediamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

  The compounds can also exist as therapeutically acceptable prodrugs. The term “therapeutically acceptable prodrug” is suitable for use in contact with a patient's tissue without undue toxicity, irritation and allergic response, and provides a reasonable benefit / risk ratio. Correspondingly, it represents a prodrug or zwitterion that is effective for the intended use. The term “prodrug” refers to compounds that are rapidly converted in vivo to the parent compound of formula (I), for example, by hydrolysis in blood.

  According to the therapeutic methods and pharmaceutical compositions of the present invention, the present compounds can be administered alone or in combination with other anticancer agents. When using these compounds, the specific therapeutically effective dose level for a particular patient is the disease being treated and the severity of the disease; the activity of the specific compound used; the specific composition used. The patient's age, weight, general health, sex and feeding status; administration time; route of administration; excretion rate of the compound used; duration of treatment; and the drug used in combination with the compound used It will depend on factors such as the drugs used at the same time. These compounds are administered orally, parenterally, using osmotic pressure (nasal spray), in the form of dosage unit formulations containing carriers, adjuvants, diluents, vehicles or combinations thereof. It can be administered rectally, vaginally or topically. The term “parenteral” includes infusion, as well as subcutaneous, intravenous, intramuscular and intrasternal injection.

  Aqueous or oily suspensions of the compounds administered parenterally can be formulated with dispersing, wetting, or suspending agents. The injectable agent can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents used are water, saline, Ringer's solution, buffers, fatty acids such as monoglycerides, diglycerides, oleic acid, and non-volatile oils such as monoglycerides or diglycerides.

  The anticancer effects of compounds administered parenterally can be prolonged by slowing the absorption of these compounds. One method of slowing the absorption of a particular compound is to administer it in the form of an injectable depot containing a suspension of the compound that is crystalline, amorphous or otherwise in a water-insoluble form. It is. The absorption rate of the compound depends on the dissolution rate of the compound, in other words, on the physical state of the compound. Another way of slowing the absorption of a particular compound is to administer it in the form of an injectable depot containing the compound as an oily solution or suspension. Yet another method of slowing the absorption of certain compounds is to use a microcapsule matrix of the present compound encapsulated in liposomes, microemulsions or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. In the form of an injectable depot. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.

  The compound can also be delivered in a controlled manner by a transdermal patch. The absorption rate can be reduced by using a rate controlling membrane or by trapping the compound in a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound may optionally be a diluent such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, tableting lubricant, and stearin. Tableting aids such as magnesium acid or microcrystalline cellulose may be included. Capsules, tablets and pills can also contain buffering agents, and tablets and pills can be prepared with enteric coatings or other controlled release coatings. Powders and propellants may also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or mixtures thereof. The propellant may further comprise a conventional propellant such as chlorofluorohydrocarbon or an alternative thereof.

  Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water. These compositions can also contain 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 also include animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof. Other excipients may also be included. Suppositories for rectal or vaginal administration are each a suitable non-irritating excipient, such as cocoa butter or polyethylene glycol, which is solid at normal temperatures but fluids in the rectum or vagina, respectively. It can be prepared by mixing the compounds. Ophthalmic formulations including eye drops, eye ointments, powders and solutions are also contemplated as being within the scope of the present invention.

  The total daily amount of the compound administered to the host at one time or in divided doses is from about 0.1 mg / kg body weight to about 200 mg / kg body weight, or preferably from about 0.25 mg / kg body weight to about 100 mg / kg body weight. It can be up to kg body weight. Single dose compositions may contain these amounts, or may contain sub-dimensions of these amounts that together make up the daily dose described above.

Preferred compounds of the invention are those of formula (I) wherein R ¹ is hydrogen, X is N (R ^a ) C (O) N (R ^b ), and R ^a and R ^b are hydrogen It is a compound of this.

Determination of biological activity The in vitro potency of compounds in inhibiting these protein kinases can be determined by the procedure detailed below.

  The potency of a compound can be determined by the amount of inhibition of phosphorylation of an exogenous substrate (eg, synthetic peptide (Z. Songyang et al., Nature, 373: 536-539)) by the test compound relative to the control.

Production of KDR tyrosine kinase using baculovirus system:
The coding sequence for the human KDR intracellular domain (aa789-1354) was obtained by PCR using cDNA isolated from HUVEC cells. In addition, a poly-His6 sequence was introduced at the N-terminus of this protein. This fragment was cloned into the transfection vector, pVL1393, at the Xba1 and Not1 sites. Co-transfection was performed using BaculoGold Transfection reagent (PharMingen) to produce recombinant baculovirus (BV). Recombinant BV was plaque purified and confirmed by Western analysis. To produce protein, SF-9 cells were grown at 2 × 10 6 / mL in SF-900-II medium and infected with 0.5 plaque forming units / cell (MOI). Cells were harvested 48 hours after infection.

Purification of KDR Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 10 μg / mL was added to the cell pellet obtained from 1 L of cell culture. SF-9 cells expressing (His) ₆ KDR (aa789-1354) were lysed by adding 50 mL of aprotinin, 1 μg / mL leupeptin). The lysate was centrifuged at 19000 rpm for 30 minutes at 4 ° C. in a Sorval SS-34 rotor. The cell lysate was added to a 5 mL NiCl ₂ chelate sepharose column equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. KDR was eluted using the same buffer containing 0.25 M imidazole. These column fractions were analyzed by ELISA assay (below) measuring SDS-PAGE and kinase activity. The purified KDR was transferred into 25 mM HEPES, pH 7.5, 25 mM NaCl, 5 mM DTT buffer and stored at −80 ° C.

  The compounds of the invention inhibited KDR with an IC50 between about 0.007 μM and about 50 μM. Preferred compounds inhibited KDR with an IC50 between about 0.007 μM and about 0.5 μM. Most preferred compounds inhibited KDR with an IC50 between about 0.007 μM and about 0.1 μM.

Production and purification of human Tie-2 kinase PCR was performed using cDNA isolated from human placenta as a template to obtain the coding sequence for the human Tie-2 intracellular domain (aa775-1124). A poly-His6 sequence was introduced at the N-terminus, and this construct was cloned into the transfection vector pVL 1939 at the Xba1 and Not1 sites. Co-transfection was performed using BaculoGold Transfection reagent (PharMingen) to obtain recombinant BV. Recombinant BV was plaque purified and confirmed by Western analysis. To produce the protein, SF-9 insect cells were grown at 2 × 10 6 / mL in SF-900-II medium and infected with a MOI of 0.5. Purification of the His-tagged kinase used for screening used a method similar to that described for KDR.

Production and purification of human Flt-1 tyrosine kinase The baculovirus expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. The 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 to 1338). The nucleotide sequence encoding this kinase domain was obtained by PCR using a cDNA library isolated from HUVEC cells. These histidine residues allowed affinity purification of the protein as in KDR and ZAP70. SF-9 insect cells were infected at a multiplicity of 0.5 and were harvested 48 hours after infection.

Source of EGFR tyrosine kinase EGFR was purchased from Sigma (Cat # E-3641; 500 units / 50 μl) and EGF ligand was obtained from Oncogene Research Products / Calbiochem (Cat # PF011-100).

Sources of protein kinases Lck, Fyn, Src, Blk, Csk and Lyn, and their truncated forms have been purchased (eg, Upstate Biotechnology Inc. (Saranac Lake, NY) and Santa Cruz Biotechnology Inc. ( From Santa Cruz, Ca)), or can be purified from known natural or recombinant sources using conventional methods.

Enzyme-linked immunosorbent assay (ELISA) of PTKs
An enzyme linked immunosorbent assay (ELISA) was used to detect and measure the presence of tyrosine kinase activity. ELISA is described, for example, in “Manual of Clinical Immunology”, 2nd edition, edited by Rose and Friedman, pp 359-371 (Am. Soc. Of Microbiology, Washington, D.C.), Vol. ) According to the known protocol described in “Enzyme-Linked Immunosorbent Assay”.

The disclosed protocol was modified to allow determination of activity for a specific PTK. For example, a preferred protocol for performing an ELISA experiment is shown below. Modifications of these protocols to determine the activity of compounds against other members of the receptor PTK family, as well as non-receptor tyrosine kinases, are well within the ability of one skilled in the art. To determine inhibitor selectivity, a universal PTK substrate (eg, a random copolymer of poly (Glu ₄ Tyr), 20,000-50,000 MW) was added approximately twice the apparent Km value in this assay. Used at a concentration with ATP (usually 5 μM).

  According to the following procedure, KDR, Flt-1, Flt-4, Tie-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, hck, Blk, Csk, Src, Lyn , Fgr, Fyn and ZAP70 tyrosine kinase activities were assayed for inhibitory effects of compounds of the invention.

Buffers and solutions:
PGT poly (Glu, Tyr) 4: 1
Store the powder at -20 ° C. Dissolve the powder in phosphate buffered saline (PBS) to a 50 mg / mL solution. Store 1 mL of aliquot at −20 ° C. When preparing plates, dilute to 250 μg / mL with Gibco PBS.
Reaction _{Buffer: 100mM Hepes, 20mM MgCl 2,} 4mM MnCl 2, 5mM DTT, 0.02% BSA, 200μM NaVO 4, pH7.10.
ATP: 100 mM dispensing solution is stored at -20 ° C. Dilute to 20 μM with water.
Wash buffer: PBS containing 0.1% Tween 20
Antibody dilution buffer: 0.1% bovine serum albumin (BSA) in PBS
TMB substrate: Mix TMB substrate and peroxide solution in a 9: 1 ratio immediately before use, or use Neogen K-Blue substrate.
Stop solution: 1M phosphoric acid.

Procedure 1. Plate preparation:
PGT stock (50 mg / mL, frozen) is diluted with PBS to 250 μg / mL. Add 125 μl to each well of Corning's modified flat bottom high affinity ELISA plates (Corning # 25805-96). Add 125 μl of PBS to the blank well. Cover with sealing tape and incubate overnight at 37 ° C. Wash once with 250 μl wash buffer and dry in a 37 ° C. dry incubator for about 2 hours. The coated plate is placed in a sealed bag and stored at 4 ° C. until use.

2. Tyrosine kinase reaction:
Prepare inhibitor solution to 4x concentration with 20% DMSO in water.
-Prepare the reaction buffer.
- as desired units are present in the 50 [mu] l, for example, in the case of KDR, and 1 ng / mu ^l, in the reaction system, so 50ng exists in total per well, to prepare an enzyme solution. Store on ice.
-Dilute with water from a 100 mM stock to 20 μM to prepare a 4xATP solution. Store on ice.
Add 50 μl of enzyme solution to each well (usually 5-50 ng enzyme / well depending on the specific activity of the kinase).
Add -25 μL of 4x inhibitor.
Add 25 μl of 4 × ATP for inhibitor assay.
Incubate for 10 minutes at room temperature.
Stop the reaction by adding 50 μl 0.05N HCl to each well.
-Wash the plate.
^** Final concentration in reaction: 5 μM ATP, 5% DMSO

3. Antibody binding—PY20-HRP (Pierce) antibody (phosphotyrosine antibody) 1 mg / mL aliquot is diluted to 50 ng / mL in PBS containing 0.1% BSA by two-step dilution (100 × then 200 ×). Dilute.
Add 100 μL of Ab to each well. Incubate for 1 hour at room temperature. Incubate for 1 hour at 4 ° C.
-Wash the plate 4 times.

4). Color reaction-Prepare TMB substrate and add 100 μL to each well.
-Monitor OD at 650 nm until OD reaches 0.6.
The reaction is stopped with -1M phosphoric acid. Shake on a plate reader.
Read OD immediately at -450 nm.
The optimal incubation time and enzyme reaction conditions vary slightly depending on the enzyme preparation and are determined experimentally for each lot.

For lck, reaction buffer used was in the same assay _{conditions, 100mM MOPSO, pH6.5,4mM MnCl 2,} 20mM MgCl 2, 5mM DTT, 0.2% BSA, was 200 mM NaVO _4.

  The compounds of the present invention may be therapeutically useful in the treatment of diseases involving both identified and unidentified protein tyrosine kinases, including those not mentioned herein.

Sources of Cdc2 Human recombinant enzymes and assay buffers can be purchased (New England Biolabs, Beverly, MA. USA) or known natural or recombinant so- lution using conventional methods. It can be purified from

Cdc2 assay The protocol that can be used is a slightly modified version of the protocol attached to the purchased reagents. Briefly, this reaction is performed in a buffer (commercial buffer) consisting of 50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM / EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl _2. At a final concentration in buffer supplemented with fresh 300 μM ATP (31 μCi / mL) and 30 μg / mL histone Type IIIss. The reaction is allowed to proceed for 20 minutes at 25 ° C. in the presence or absence of inhibitors in an 80 μL reaction volume containing various units of enzyme. The reaction is stopped by adding 120 μL of 10% acetic acid. The mixture is spotted on phosphocellulose paper, followed by 3 washes with 75 mM phosphoric acid for 5 minutes to separate the substrate from unincorporated label. Counts are measured with a beta counter in the presence of liquid scintillant.

Source of PKC kinase The catalytic subunit of PKC can be purchased (Calbiochem).

PKC kinase assay Published procedures (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y., Biochemical and Biophysical Research 3: 1) 1227 (1990)). The radioactive kinase assay is performed. Briefly, in a kinase buffer consisting of 50 mM Tris-HCl, pH 7.5, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and ³³ P ATP (8 Ci / mM), Perform all reactions. The reaction is initiated by mixing the compound and enzyme in a reaction vessel and adding a mixture of ATP and substrate. After stopping the reaction by adding 10 μL of stop buffer (5 mM ATP in 75 mM phosphate), a portion of this mixture is spotted onto a phosphocellulose filter. The spotted sample is washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. Incorporation of radiolabel is quantified by liquid scintillation counting.

Erk2 Enzyme Sources Recombinant mouse enzyme and assay buffer can be purchased (from New England Biolabs, Beverly, MA. USA) or from known natural or recombinant sources using conventional methods. It can be purified.

Erk2 enzyme assay Briefly, a buffer consisting of 50 mM Tris, pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl ₂ under the conditions recommended by the manufacturer (commercially available) The reaction is performed in buffer supplemented with 100 μM fresh ATP (31 μCi / mL) and 30 μM myelin basic protein. The assay method for reaction volume and incorporated radioactivity is as described in the PKC assay (see above).

Cellular Receptor PTK Assay The following cellular assay was used to determine the activity levels and effects of various compounds of the invention on KDR / VEGFR2. Similar receptor PTK assays with specific ligand stimulation can be designed in the same manner as for other tyrosine kinases using techniques known in the art.

VEGF-induced KDR phosphorylation in human umbilical vein endothelial cells (HUVEC) as measured by Western blot:
1. HUVEC cells (from pooled donors) can be purchased from Clonetics (San Diego, Calif.) And cultured according to the manufacturer's instructions. In this assay, only those from the first passage (3 to 8) are used. Cells are cultured in 100 mm dishes (for Falcon tissue culture; Becton Dickinson; Plymouth, England) using complete EBM medium (Clonetics).

2. To assess the inhibitory activity of the compounds, the cells are trypsinized and seeded in each well of a 6-well cluster plate (Costar; Cambridge, MA) at 0.5 to 1.0 × 10 ⁵ cells / well. To do.

  3. Three to four days after sowing, the plates are typically 90% to 100% confluent. Media is removed from all wells and cells are rinsed with 5 mL to 10 mL PBS and incubated with 5 mL EBM basal media without supplements (ie serum starvation) for 18-24 hours.

4). Serial dilutions of inhibitor are added to 1 mL of EBM medium (25 μM, 5 μM or 1 μM final concentration for cells) and incubated at 37 ° C. for 1 hour. Next, human recombinant VEGF ₁₆₅ (R & D Systems) is added to all wells to a final concentration of 50 ng / mL in 2 mL of EBM medium and incubated at 37 ° C. for 10 minutes. Control cells untreated or treated with VEGF alone are used to assess background phosphorylation and induction of phosphorylation by VEGF.

  Next, all wells were rinsed with 5 mL to 10 mL of cold PBS containing 1 mM sodium orthovanadate (Sigma) to lyse the cells and protease inhibitors (PMSF 1 mM, aprotinin 1 μg / mL, pepstatin 1 μg / mL, leupeptin 1 μg / mL 200 mL (50 mM Tris-HCl) RIPA buffer containing mL, 1 mM Navanadate, 1 mM Na fluoride) and 1 μg / mL Dnase (all chemicals are obtained from Sigma Chemical Company, St Louis, Mo.) 150 mM NaCl, 0.1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA). The lysate is centrifuged at 14,000 rpm for 30 minutes to eliminate nuclei.

Next, an equal amount of protein is precipitated by adding cold (−20 ° C.) ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. The pellet is redissolved in Laemli sample buffer (BioRad; Hercules, CA) containing 5% -mercaptoethanol and boiled for 5 minutes. These proteins are separated by polyacrylamide gel electrophoresis (6%, 1.5 mm Novex, San Diego, Calif.) And transferred onto a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), anti-KDR polyclonal antibody (C20, Santa Cru Biotechnology; Santa Cruz, CA) or anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology) at 4 ° C. These proteins are probed overnight using Lake Placid, NY). After washing and incubation with goat-anti-rabbit or goat-anti-mouse IgG HRP-conjugated F (ab) ₂ for 1 hour, using a luminescent chemiluminescence (ECL) system (Amersham Life Sciences, Arlington Heights, IL) Visualize these bands.

In Vivo Uterine Edema Model This assay measures the ability of a compound to inhibit the rapid increase in mouse uterine weight that occurs in the first few hours after estrogen stimulation. It is known that this early onset of uterine weight increase is due to edema caused by increased permeability of the uterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993), 133: 829-837) have shown that there is a close temporal relationship between estrogen-stimulated uterine edema and increased VEGF mRNA expression in the uterus. These results were confirmed by using a neutralizing monoclonal antibody against VEGF, which significantly reduced the sudden increase in uterine weight after estrogen stimulation (WO 97/42187). issue). Thus, this system can serve as a model for VEGF signaling and the associated hyperpermeability, as well as in vivo inhibition of edema.

  Materials: All hormones can be purchased from Sigma (St. Louis, Mo.) or Cal Biochem (La Jolla, Calif.) As lyophilized powders and prepared according to the supplier's instructions. Vehicle components (DMSO, Cremaphor EL) can be purchased from Sigma (St. Louis, MO). Mice (Balb / c, 8-12 weeks old) can be purchased from Taconic (Germantown, NY) and kept in a sterile animal facility according to the institutional Animal Care and Use Committees Guidelines. .

Method:
Day 1: Balb / c mice are injected intraluminally (ip) with 12.5 units of pregnant mare serum gonadotropin (PMSG).
Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) i. p. Administer.
Day 4: Mice are randomly divided into groups of 5 to 10 animals. In a dose range of 1 mg / kg to 100 mg / kg, depending on solubility and vehicle i. p. I. v. Or p. o. The test compound is administered by the route. The vehicle control group receives vehicle only and the two groups are untreated.

After 30 minutes, the experimental group, vehicle group, and one of the untreated groups were treated with 17-estradiol (500 mg / kg) i. p. Make an injection. After 2-3 hours, these experimental animals are sacrificed by CO ₂ inhalation. After the midline incision, each uterus is separated, and the cervix and the junction between the uterus and the fallopian tube are cut and removed. Weigh out (wet weight) after removing fat and connective tissue, taking care not to damage the uterus. The uterus is sandwiched between two filter papers and squeezed with a 1 liter glass bottle filled with water to suck and remove liquid from the uterus. Weigh the uterus after sucking (weight after sucking). The difference between the wet weight and the weight after sucking is the uterine liquid content. The average liquid content of the treated group is compared to the untreated group or the vehicle treated group. Test significant difference by student test. The estradiol response is monitored using an unstimulated control group.

  Certain compounds of the present invention that are inhibitors of angiogenic receptor tyrosine kinases can also be shown to be active in Matrigel transplantation models of neovascularization. This Matrigel neovascularization model involves the formation of new blood vessels within a transparent marble of an extracellular matrix implanted subcutaneously induced by the presence of pre-angiogenic factor-producing tumor cells (eg, Passani, 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; Vasc. Biol. (1995), 15 (11), 1857-6). Experiments using this model are preferably carried out for 3 to 4 days, and the measures included are macroscopic neovascularization compared to controls from animals that were not treated with inhibitors after removal of the implant. Includes visual / image assessment, microvascular density measurement with a microscope, and hemoglobin quantification (Drabkin method). In this model, alternatively, bFGF or HGF can be used as a stimulant.

  The compounds of the present invention can be used in the treatment of conditions mediated by protein kinases such as benign and neoplastic proliferative diseases and disorders of the immune system. Such 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, organs Transplant rejection (eg, kidney rejection, graft-versus-host disease), benign and neoplastic proliferative diseases, lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer and rectal cancer, And diseases involving human cancer such as hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma and inappropriate angiogenesis (eg diabetic retinopathy, retinopathy of prematurity, Choroidal neovascularization due to age-related macular degeneration, and infantile hemangioma). Such inhibitors can be useful in the treatment of disorders including, for example, macular edema, brain edema, acute lung injury and VEGF-mediated edema including adult respiratory distress syndrome (ARDS), ascites, exudates and exudates. Furthermore, the compounds of the present invention may be useful in the treatment of pulmonary hypertension, particularly pulmonary hypertension in patients with thromboembolic diseases (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73). .

Synthetic Methods Abbreviations used in the following scheme and example descriptions are as follows: PPh ₃ is triphenylphosphine, dba is dibenzylideneacetone, EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, DCC is 1,3-dicyclohexylcarbodiimide, HOBT is 1-hydroxybenzotriazole, NBS is N-bromosuccinimide, THF is tetrahydrofuran, DME is 1,2-dimethoxyethane, DMSO Is dimethyl sulfoxide, DMF is N, N-dimethylformamide, TFA is trifluoroacetic acid, and DEAD is diethyl azodicarboxylate.

The compounds and processes of the present invention will be better understood by associating with the following synthetic schemes that illustrate how the compounds of the present invention can be prepared. Starting materials can be purchased commercially or can be prepared by well-established literature methods known to those skilled in the art. The groups A, X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above unless otherwise noted below.

  The present invention is intended to encompass compounds having the formula (I) when prepared by synthetic or metabolic processes. Preparation of compounds of the present invention by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

As shown in Scheme 1, a compound of formula (2) (wherein X ′ is Br or I) can be treated with ammonium hydroxide to give a compound of formula (3). Treatment with an organometallic coupling partner (MA-NH ₂ , M is a metal such as a boronic acid, boronic ester or alkylstannane) in the presence of a palladium catalyst and optionally a base. By doing so, the compound of the formula (3) can be converted into the compound of the formula (4). Examples of palladium catalysts include Pd ₂ (dba) ₃ with ligands such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ and PPh ₃ . Exemplary bases include sodium carbonate, potassium carbonate, and cesium carbonate.

Treatment with nitric acid in the presence of sulfuric acid can convert a compound of formula (3) in which R ² is hydrogen to a compound of formula (3) in which R ² is nitro. By the methods described above, the compound of formula (3) R ² is nitro, R ² can be converted to a compound of formula (4) is nitro.

Scheme 2 shows the synthesis of the compound of formula (5). A compound of formula (4) is treated with an isocyanate or thioisocyanate in the presence of a base such as N-methylmorpholine or triethylamine, and X is N (R ^a ) C (S) N (R ^b ) or N (R ^a A compound of formula (5) can be obtained which is C) (O) (R ^b ).

Alternatively, a compound of formula (5), wherein X is N (R ^a ) C (O) by coupling a compound of formula (4) with an appropriately substituted carboxylic acid under standard coupling conditions Can be obtained. Standard coupling conditions include a coupling agent such as EDCI or DCC, a base such as N-methylmorpholine or triethylamine, and optionally HOBT.

Reduction under conditions known to those skilled in the art (eg treatment with 10% Pd / C) yields a compound of formula (5) in which R ² is nitro and a compound of formula (5) in which R ² is NH ₂ Can be converted to compounds. The compound of formula (5) in which R ² is NH ₂ can be further functionalized via reaction with an alkylating agent or acylating agent in the presence of a base.

As shown in Scheme 3, under the conditions described in Scheme 1, a compound of formula (3) wherein X ′ is Br or I is converted to an appropriately substituted organometallic coupling partner (M-A-X— R ⁵ , where M is a metal such as boronic acid, boronic acid ester or alkylstannane) to give a compound of formula (5).

The synthesis of the compound of formula (5) is shown in Scheme 4. Compound of formula (6) by treatment with an appropriately substituted halide (X′-A—X—R ⁵ , X ′ is Br or I) under the conditions described in Scheme 1. (R ^a is an alkyl group) can be converted to a compound of formula (5).

An alternative synthesis method for compounds of formula (5) is shown in Scheme 5. Using the conditions described in Scheme 1, coupling the compound of formula (6) to an appropriately substituted halide (X′-A-NH ₂ , X ′ is Br or I) A compound of formula (7) can be obtained and can be converted to a compound of formula (5) using the conditions described in Scheme 2.

As shown in Scheme 6, the compound of formula (3) is treated with an alkylating agent in the presence of a base such as triethylamine or diisopropylethylamine to give a compound of formula (8) wherein R ¹ is an alkyl group Yes.) By the above-described method, the compound of the formula (8) can be converted into a compound of the formula (9) (wherein R ¹ is an alkyl group).

By replacing the appropriate starting materials, the above-described method can also be used to prepare compounds of formula (I) wherein R ³ is hydrogen and R ⁴ is AX—R ⁵ .

  The invention will now be described in connection with certain preferred embodiments, which are not intended to limit the scope of the invention. Rather, the present invention covers all alternatives, modifications and equivalents that can be included within the scope of the claims. Accordingly, the following examples, including preferred embodiments, illustrate preferred implementations of the present invention, but these examples are intended to illustrate certain preferred embodiments and are intended to illustrate the procedures and concepts of the present invention. It should be understood that these are provided to provide the most useful and easily understood belief about these aspects.

  The compounds of the present invention were named by ACD / ChemSketch version 5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada).

  N- (3-methylphenyl) -N '-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea

Example 1A
Methyl 3-bromo-2-methylbenzoate A suspension of 3-bromo-2-methylbenzoic acid (9.9 g, 46 mmol) in thionyl chloride (20 mL) was heated to 60 ° C. for 1 hour and 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. Partition the residue between ethyl acetate and water and wash the organic phase with saturated NaCO ₃ solution and brine, dry (MgSO ₄ ), filter and concentrate to give 7.39 g of the desired product. It was. _Rf = 0.5 (10% ethyl acetate / hexane).

(Example 1B)
Methyl 3-bromo-2- (bromomethyl) benzoate Example 1A (7.4 g, 32.3 mmol), NBS (6.9 g, 38.8 mmol) and benzoyl peroxide (0.782 g, 3 mL) in benzene (100 mL) .2 mmol) was stirred at reflux temperature for 5 hours, cooled to 0 ° C. and filtered. The solid was washed with diethyl ether and the filtrate was washed successively with 10% Na ₂ S ₂ O ₃ ( ₂ × 20 mL) and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography using 5% to 10% ethyl acetate / hexanes to give 9.32 g of the desired product. _Rf = 0.2 (5% ethyl acetate / hexane).

(Example 1C)
4-Bromo-1-isoindolinone A solution of Example 1B (8.3 g, 26.9 mmol) in THF (100 mL) was treated dropwise with concentrated NH ₄ OH (9 mL, 135 mmol) at room temperature for 2 days. Stir, dilute with 30 mL water, cool to 0 ° C. and filter. 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 1D)
4- (4-aminophenyl) -1-isoindolinone Example 1C (2 g, 9.43 mmol), 4- (4,4,5,5-tetramethyl- in DME (68 mL) and water (17 mL) A suspension of 1,3,2-dioxaborolan-2-yl) aniline (2.5 g, 11.3 mmol) and Na ₂ CO ₃ (2.2 g, 20.8 mmol) was purged with nitrogen and Pd (PPh ₃ ) ₄ (1 g, 0.9 mmol) and stirred at 90 ° C. for 19 hours. The reaction mixture was cooled to room temperature, concentrated to one third of the original volume, diluted with ethyl acetate (30 mL) and water (20 mL) and filtered. The filter cake was washed with water and ethyl acetate and dried to give 1.25 g of the desired product. MS (ESI (+)) m / e 225 (M + H) ^<+> .

(Example 1E)
N- (3-Methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Example 1D in THF (44 mL) (1. 94 g, 8.68 mmol) at 0 ° C. was treated dropwise with N-methylmorpholine (0.95 mL, 8.68 mmol) and 3-methylphenyl isocyanate (1.12 mL, 8.68 mmol) successively. . The mixture was stirred for 1 hour, diluted with THF (20 mL), stirred at room temperature for 3 hours, and quenched with water (20 mL). The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated. The residue was suspended in 5% methanol / dichloromethane and filtered. The filter cake was washed with dichloromethane and dried to give 2.94 g of the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 358.1 (M + H) ^<+> .

  N- (3-methylphenyl) -N '-[4- (7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea

(Example 2A)
4-Bromo-7-nitro-1-isoindolinone 10 mL of a solution of Example 1C (5 g, 23.6 mmol) in sulfuric acid was added via an additional funnel to concentrated nitric acid (1.55 mL) in 10 mL sulfuric acid. , 24.7 mmol). The resulting mixture was stirred at 0 ° C. for 1 hour, warmed to room temperature, stirred overnight, poured onto ice and filtered. The filter cake was washed with water and diethyl ether and then dried to give 5.39 g of the desired product.

(Example 2B)
N- (3-Methylphenyl) -N ′-[4- (7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1D, Example 1C In Example 2A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline of Example 1D was converted to N- (3-methylphenyl) -N The desired product was prepared by replacing with '-[4- (4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０３（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 403 (M + H) ^<+> .

N- [4- (7-Amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea DMF under hydrogen atmosphere (10 mL) Of Example 2 (1.29 g, 3.21 mmol) and 10% Pd on carbon (100 mg) was stirred overnight at room temperature. The mixture was filtered through diatomaceous earth ^{(Celite (R)),} the pad was washed with methanol. The filtrate was concentrated, diluted with water, cooled to 0 ° C. and filtered. The filter cake was washed with water and diethyl ether and then dried to give 0.88 g of the desired product.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３７１（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 371 (M−H) ⁻ .

N- {7- [4-({[(3-Methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} acetamide THF (2 mL) The suspension of Example 3 (0.088 g, 0.24 mmol) in was treated by dropwise addition of acetyl chloride (0.017 mL, 0.24 mmol) via syringe, stirred overnight at room temperature, The reaction was quenched with, cooled to 0 ° C. and filtered. The filter cake was dried to give 77 mg of the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１５（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 415 (M + H) ^<+> .

N- (2-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by replacing with methylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 358 (M + H) ^<+> .

N- (4-Methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 4 -The desired product was prepared by replacing with methylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 358 (M + H) ^<+> .

N- (2-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by replacing with -methoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 374 (M + H) ^<+> .

N- (3-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 3 The desired product was prepared by replacing with -methoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 374 (M + H) ^<+> .

N- (4-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 4 The desired product was prepared by replacing with -methoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 374 (M + H) ^<+> .

N- (2-fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by replacing with -fluorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３６２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 362 (M + H) ^<+> .

N- (3-Fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is 3 The desired product was prepared by replacing with -fluorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３６２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 362 (M + H) ^<+> .

N- (4-Fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 4 The desired product was prepared by replacing with -fluorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３６２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 362 (M + H) ^<+> .

N- (2-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is The desired product was prepared by replacing with chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 378 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is The desired product was prepared by replacing with chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 378 (M + H) ^<+> .

N- (4-Chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 4- The desired product was prepared by replacing with chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 378 (M + H) ^<+> .

N- (2-Bromophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by replacing with bromophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２２，４２４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 422, 424 (M + H) ^<+> .

N- (3-Bromophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 3 The desired product was prepared by replacing with bromophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２２，４２４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 422, 424 (M + H) ^<+> .

N- (4-Bromophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 4 The desired product was prepared by replacing with bromophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２２，４２４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 422, 424 (M + H) ^<+> .

N- [4- (1-Oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4- (trifluoromethoxy) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 4-trifluoromethoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 428 (M + H) ^<+> .

N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-phenoxyphenyl) urea In Example 1E, 3-methylphenyl isocyanate is converted to 3 The desired product was prepared by replacing with -phenoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３６（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 436 (M + H) ^<+> .

N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4- (trifluoromethyl) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 4-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412 (M + H) ^<+> .

N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(4-phenoxyphenyl) urea In Example 1E, 3-methylphenyl isocyanate is converted to 4 The desired product was prepared by replacing with -phenoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３６（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 436 (M + H) ^<+> .

N- [3- (Benzyloxy) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl The desired product was prepared by replacing the isocyanate with 3-benzyloxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４５０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 450 (M + H) ^<+> .

N- (2,3-Dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 2,3-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

N- (2,4-Dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 2,4-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

N- (2,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 2,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

N- (3,4-Dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 3,4-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

N- (2,3-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 2,3-dimethoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 404 (M + H) ⁺ .

N- (2,4-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 2,4-dimethoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 404 (M + H) ⁺ .

N- (2,5-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 2,5-dimethoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 404 (M + H) ⁺ .

N- (3,4-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 3,4-dimethoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 404 (M + H) ⁺ .

N- (3,5-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 3,5-dimethoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 404 (M + H) ⁺ .

N-2,3-dihydro-1H-inden-5-yl-N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E The desired product was prepared by replacing 3-methylphenyl isocyanate with 5-isocyanate indane.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 384 (M + H) ^<+> .

N-1,3-benzodioxol-5-yl-N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3 The desired product was prepared by replacing methylphenyl isocyanate with 5-isocyanate-1,3-benzodioxole.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 388 (M + H) ^<+> .

N- (2,3-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is The desired product was prepared by replacing with 2,3-dichlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412 (M + H) ^<+> .

N- (2,5-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is The desired product was prepared by replacing with 2,5-dichlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412 (M + H) ^<+> .

N- (3,4-Dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is The desired product was prepared by replacing with 3,4-dichlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412 (M + H) ^<+> .

N- (3,5-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is The desired product was prepared by replacing with 3,5-dichlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412 (M + H) ^<+> .

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E The desired product was prepared by replacing 3-methylphenyl isocyanate with 4-chloro-3-trifluoromethylphenyl isocyanate.

（ＥＳＩ（−））ｍ／ｅ ４４４（Ｍ−Ｈ）⁻．

(ESI (−)) m / e 444 (M−H) ⁻ .

N- (3-Chloro-4-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 3-chloro-4-methoxyphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 408 (M + H) ^<+> .

N- (4-Bromo-3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 4-bromo-3-methylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３６（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 436 (M + H) ^<+> .

N- (3-Chloro-4-fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 3-chloro-4-fluorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９６（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 396 (M + H) ^<+> .

N- (3-Chloro-4-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 3-chloro-4-methylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 392 (M + H) ^<+> .

N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[3- (trifluoromethyl) phenyl] urea In Example 1E, 3-methyl The desired product was prepared by replacing phenyl isocyanate with 3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412 (M + H) ^<+> .

N- (3-Ethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate is converted to 3 The desired product was prepared by replacing with ethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

N- (3-cyanophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by replacing with -cyanophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３６９（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 369 (M + H) ^<+> .

Methyl 3-[({[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] amino} carbonyl) amino] benzoate In Example 1E, 3-methylphenyl isocyanate was converted to methyl The desired product was prepared by replacing with 3-isocyanate benzoate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１９（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 419 (M + H) ^<+> .

N- (3-acetylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by replacing with acetylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８６（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 386 (M + H) ^<+> .

N- [2-Fluoro-5- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E The desired product was prepared by replacing 3-methylphenyl isocyanate with 2-fluoro-5-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 430 (M + H) ^<+> .

N ^{2, N 2} - dimethyl ^{-N 1 - {7- [4 -} ({[(3- methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro -1H- isoindole - 4-yl} glycinamide In Example 4, the desired product was prepared by replacing acetyl chloride with N, N-dimethylglycyl chloride.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４５８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 458 (M + H) ^<+> .

N- {7- [4-({[(3-Methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} nicotinamide Example 4 The desired product was prepared by replacing acetyl chloride with nicotinoyl chloride.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４７８（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 478 (M + H) ^<+> .

N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} -2-phenylacetamide In Example 4, the desired product was prepared by replacing acetyl chloride with phenylacetyl chloride.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ４８９（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 489 (M−H) ⁻ .

2- (2-methoxyethoxy) -N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindole- 4-yl} acetamide In Example 4, the desired product was prepared by replacing acetyl chloride with (2-methoxyethoxy) acetyl chloride.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４８９（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 489 (M + H) ^<+> .

  N- (3-methylphenyl) -N '-[6- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3-pyridinyl] urea

(Example 54A)
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-isoindolinone Examples 1C (10.6 g, 50 mmol) and 4 in DMF (390 mL) , 4,5,5,4 ′, 4 ′, 5 ′, 5′-octamethyl- [2,2 ′] bi [1,3,2] dioxaborolanyl] (15.23 g, 60 mmol) The suspension was stirred until a clear yellow solution was obtained. The solution was then treated with potassium acetate (14.72 g, 150 mmol), degassed with nitrogen, and [1.1′-bis (diphenylphosphino) -ferrocene] dichloropalladium [II] .CH ₂ Cl ₂ ( 7 g, 8.5 mmol) and heated to 90 ° C. overnight. The reaction was cooled to room temperature, filtered through diatomaceous earth ^{(Celite (R)),} 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 4.56 g (35% recovery) of the desired product. m. p. : 181-191 ° C.

(Example 54B)
N- (3-methylphenyl) -N ′-[6- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3-pyridinyl] urea Toluene (6 mL) and ethanol (6 mL) In Example 54A (259 mg, 1 mmol) and N- (6-bromo-3-pyridinyl) -N ′-(3-methylphenyl) urea (367 mg, 1.2 mmol) (according to the method of Example 1E, 2- A solution of amino-4-bromopyridine and m-tolyl isocyanate.) Was degassed with N ₂ and then 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 overnight at reflux temperature. 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 filtrate was concentrated to give 51 mg of the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５９（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 359 (M + H) ^<+> .

  4- (4-phenoxyphenyl) -1-isoindolinone

(Example 55A)
4-Iodo-1-isoindolinone The desired product was prepared by replacing 3-bromo-3-methylbenzoic acid in Examples 1A, 1B and 1C with 3-iodo-2-methylbenzoic acid. MS (DCI (+)) m / e 277 (M + NH 4) +.

(Example 55B)
4- (4-phenoxyphenyl) -1-isoindolinone Example 55A (301 mg, 1.16 mmol), 4-phenoxyphenylboron in DME (10 mL), water (4.8 mL) and ethanol (2.4 mL) A suspension of acid (271 mg, 1.27 mmol) and Na ₂ CO ₃ (403 mg, 4.75 mmol) was degassed with N ₂ for 45 min, treated with Pd (PPh ₃ ) ₄ (120 mg) and overnight. And heated to 80 ° C. 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. The concentrate was triturated with hot ethanol to give 183 mg of the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３０２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 302.1 (M + H) ^<+> .

4- {4-[(5,7-dimethyl-1,3-benzoxazol-2-yl) amino] -3-fluorophenyl} -1-isoindolinone In Example 55B, 4-phenoxyphenylboronic acid N- [2-Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -5,7-dimethyl-1,3-benzoxazole The desired product was prepared by replacing with 2-amine.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 388.1 (M + H) ^<+> .

  N- [2-Fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N '-(3-methylphenyl) urea

(Example 57A)
4- (4-Amino-3-fluorophenyl) -1-isoindolinone In Example 55B, replace 4-phenoxyphenylboronic acid and Example 55A with Example 54A and 4-bromo-2-fluoroaniline, respectively. To prepare the desired product. MS (ESI (+)) m / e 241 (M + H) ^<+> .

(Example 57B)
N- [2-Fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 57A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 376.1 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared in Example 57A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９６．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 396.0 (M + H) ⁺ .

N- [2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4-fluoro-3- (trifluoromethyl) phenyl] urea In Example 1E, the desired product was prepared by replacing Example 1D with Example 57A and replacing 3-methylphenyl isocyanate with 3-trifluoromethyl-4-fluorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 448.1 (M + H) ^<+> .

N- (4-Chlorophenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared in Example 57A and by replacing 3-methylphenyl isocyanate with 4-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９６．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 396.0 (M + H) ⁺ .

N- (3-Bromophenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D Was prepared in Example 57A and by replacing 3-methylphenyl isocyanate with 3-bromophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３９．９，４４１．９（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 439.9, 441.9 (M + H) ^<+> .

N- (3,4-Dimethylphenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 57A and replacing 3-methylphenyl isocyanate with 3,4-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９０．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 390.1 (M + H) ^<+> .

  N- (3-methylphenyl) -N '-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethoxy) phenyl] urea

(Example 63A)
4- [4-Amino-3- (trifluoromethoxy) phenyl] -1-isoindolinone In Example 55B, 4-phenoxyphenylboronic acid and Example 55A were combined with Example 54A and 2-trifluoromethoxy-4. The desired product was prepared by replacing each with -bromoaniline. MS (ESI (+)) m / e 309 (M + H) ^<+> .

(Example 63B)
N- (3-Methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethoxy) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 63A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４２．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 442.0 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethoxy) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 63A and replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４６２．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 462.0 (M + H) ^<+> .

N- (3,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, 3-methylphenyl isocyanate The desired product was prepared by substituting for 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372.1 (M + H) ^<+> .

N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N′-phenylurea In Example 1E, by replacing 3-methylphenyl isocyanate with phenyl isocyanate The desired product was prepared.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３４２．１（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 342.1 (M−H) ⁻ .

N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E The desired product was prepared by replacing 3-methylphenyl isocyanate with 4-fluoro-3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３０．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 430.1 (M + H) ^<+> .

  N- [2-Methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N '-(3-methylphenyl) urea

(Example 68A)
4- (4-Amino-3-methyl-phenyl-2,3-dihydro-isoindol-1-one In Example 55B, 4-phenoxyphenylboronic acid and Example 55A were combined with Example 54A and 2-methyl- The desired product was prepared by replacing each with 4-bromoaniline: MS (ESI (+)) m / e 239 (M + H) ⁺ .

(Example 68B)
N- [2-Methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 68A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372.1 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared in Example 68A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９２．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 392.0 (M + H) ^<+> .

N- (3,4-Dimethylphenyl) -N ′-[2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 68A and replacing 3-methylphenyl isocyanate with 3,4-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 386.1 (M + H) ^<+> .

N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, the desired product was prepared by replacing Example 1D with Example 68A and replacing 3-methylphenyl isocyanate with 4-fluoro-3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４４．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 444.1 (M + H) ^<+> .

N- (5-methyl-3-pyridinyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea hydrochloride water (2.3 mL) and A −5 ° C. solution of 5-methylnicotinohydrazide (353 mg, 2.33 mmol) in concentrated HCl (2.75 mL) was added dropwise with a solution of NaNO ₂ (161 mg, 2.3 mmol) in water (2.3 mL). Treated, stirred at −5 ° C. for 30 minutes, adjusted to pH> 7 with 10% aqueous K ₂ CO ₃ and filtered. The filter cake was dried at room temperature under vacuum to give acyl azide. A portion of this intermediate (63 mg) in toluene (6 mL) was heated to reflux for 1 hour, cooled, and a suspension of Example 1D (75 mg, 0.33 mmol) in dichloromethane (4 mL). Processed. The reaction was stirred at room temperature overnight and filtered. The filter cake was purified by silica gel chromatography using 6% methanol / dichloromethane. The purified product was stirred with a saturated solution of NH ₄ Cl and filtered to give 53 mg of the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５９．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 359.1 (M + H) ^<+> .

  N- (3,4-dimethylphenyl) -N '-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea

(Example 73A)
4- (4-Amino-2-methylphenyl) -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl) aniline and The desired product was prepared by replacing Example 1C with Example 54A and 3-methyl-4-bromoaniline, respectively. MS (ESI (+) m / e 239 (M + H) ^<+> .

(Example 73B)
N- (3,4-Dimethylphenyl) -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 73A and replacing 3-methylphenyl isocyanate with 3,4-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 386.1 (M + H) ^<+> .

N- (3,5-dimethylphenyl) -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 73A and replacing 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 386.1 (M + H) ^<+> .

N- [3-Methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 73A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372.1 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared in Example 73A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 392.1 (M + H) ^<+> .

N- [3-Methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[3- (trifluoromethyl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 73A and replacing 3-methylphenyl isocyanate with 3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 426.1 (M + H) ^<+> .

N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, the desired product was prepared by replacing Example 1D with Example 73A and replacing 3-methylphenyl isocyanate with 4-fluoro-3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４４．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 444.1 (M + H) ^<+> .

  N- [2-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N '-(3-methylphenyl) urea

(Example 79A)
4- (4-Amino-3-chlorophenyl) -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline and The desired product was prepared by replacing Example 1C with Example 54A and 2-chloro-4-bromoaniline, respectively. MS (ESI (+) m / e 259, 261 (M + H) ⁺ .

(Example 79B)
N- [2-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 79A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９２．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 392.0 (M + H) ^<+> .

N- [2-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-chlorophenyl) urea In Example 1E, Example 1D The desired product was prepared in Example 79A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１２．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 412.0 (M + H) ^<+> .

N- [2-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3,5-dimethylphenyl) urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 79A and replacing 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 406.1 (M + H) ^<+> .

N- [2-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N′-phenylurea In Example 1E, Example 1D is replaced with Example 79A. And the desired product was prepared by replacing 3-methylphenyl isocyanate with phenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７８．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 378.0 (M + H) ^<+> .

  N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N '-(3-methylphenyl) urea

(Example 83A)
4- (4-Amino-2-chlorophenyl) -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline and The desired product was prepared by replacing Example 1C with Example 54A and 3-chloro-4-bromoaniline, respectively. MS (ESI (+) m / e 259, 261 (M + H) ⁺ .

(Example 83B)
N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 83A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９２．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 392.0 (M + H) ^<+> .

N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-chlorophenyl) urea In Example 1E, Example 1D The desired product was prepared in Example 83A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１１．９（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 411.9 (M + H) ^<+> .

N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[3- (trifluoromethyl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 83A and replacing 3-methylphenyl isocyanate with 3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４６．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 446.0 (M + H) ^<+> .

N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4-fluoro-3- (trifluoromethyl) phenyl] urea In Example 1E, the desired product was prepared by replacing Example 1D with Example 83A and replacing 3-methylphenyl isocyanate with 4-fluoro-3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４６４．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 464.0 (M + H) ^<+> .

N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3,5-dimethylphenyl) urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 83A and replacing 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４０６．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 406.0 (M + H) ^<+> .

  N- (3-chlorophenyl) -N '-[3-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea

(Example 88A)
4- (4-Amino-2-fluorophenyl) -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline The desired product was prepared by replacing Example 1C with Example 54A and 3-fluoro-4-bromoaniline, respectively. MS (ESI (+) m / e 243 (M + H) ^<+> .

(Example 88)
N- (3-Chlorophenyl) -N ′-[3-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared in Example 88A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３９４．０（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 394.0 (M−H) ⁻ .

N- [3-Fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 88A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７６．１（Ｍ＋Ｈ）＋.

MS (ESI (+)) m / e 376.1 (M + H) +.

N- (3,5-dimethylphenyl) -N ′-[3-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 88A and replacing 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３９０．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 390.1 (M + H) ^<+> .

  N- (3-methylphenyl) -N '-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea

(Example 91A)
4- [4-Amino-3- (trifluoromethyl) phenyl] -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The desired product was prepared by replacing -yl) aniline and Example 1C with Example 54A and 2-trifluoromethyl-4-bromoaniline, respectively. MS (ESI (+) m / e 293 (M + H) ^<+> .

(Example 91B)
N- (3-Methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 91A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 426.1 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 91A and replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４６．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 446.0 (M + H) ^<+> .

  N- [4-Fluoro- (3-trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl ) Phenyl] urea

(Example 93A)
4- (4-Amino-3-trifluoromethyl-phenyl-2,3-dihydro-isoindol-1-one In Example 1D, 4- (4,4,5,5-tetramethyl-1,3, The desired product was prepared by replacing 2-dioxaborolan-2-yl) aniline and Example 1C with Example 54A and 3-trifluoromethyl-4-bromoaniline, respectively (MS (ESI (+)) m. / E 293 (M + H) ⁺ .

(Example 93B)
N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl ) Phenyl] urea The desired product was prepared in Example 1E by replacing Example 1D with Example 93A and 3-methylphenyl isocyanate with 4-fluoro-3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４９８．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 498.0 (M + H) ^<+> .

N- (3,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea Examples In 1E, the desired product was prepared by replacing Example 1D with Example 91A and 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４０．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 440.1 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 93A and replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 446.1 (M + H) ^<+> .

N- (3-Methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea In Example 1E The desired product was prepared by replacing Example 1D with Example 93A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４２６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 426.1 (M + H) ^<+> .

N- (3,4-Dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea Examples In 1E, the desired product was prepared by replacing Example 1D with Example 93A and 3-methylphenyl isocyanate with 3,4-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４０．２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 440.2 (M + H) ^<+> .

N- (3,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea Examples In 1E, the desired product was prepared by replacing Example 1D with Example 93A and 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４４０．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 440.1 (M + H) ^<+> .

  N- [2-Ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N '-(3-methylphenyl) urea

(Example 99A)
4- (4-Amino-3-ethylphenyl) -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline And Example 1C was replaced by Example 54A and 2-ethyl-4-bromoaniline, respectively, to prepare the desired product. MS (ESI (+) m / e 253 (M + H) ^<+> .

(Example 99B)
N- [2-Ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1E, Example 1D The desired product was prepared by replacing with Example 99A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８６．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 386.1 (M + H) ^<+> .

N- (3-Chlorophenyl) -N ′-[2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared in Example 99A and by replacing 3-methylphenyl isocyanate with 3-chlorophenyl isocyanate.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ４０４．１（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 404.1 (M−H) ⁻ .

N- [2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4-fluoro-3- (trifluoromethyl) phenyl] urea In Example 1E, the desired product was prepared by replacing Example 1D with Example 99A and replacing 3-methylphenyl isocyanate with 4-fluoro-3-trifluoromethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４５８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 458.1 (M + H) ^<+> .

N- (3,5-Dimethylphenyl) -N ′-[2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Performed in Example 1E The desired product was prepared by replacing Example 1D with Example 99A and replacing 3-methylphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４００．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 400.1 (M + H) ^<+> .

  4- (2-anilino-1H-benzimidazol-5-yl) -1-isoindolinone

(Example 103A)
5-Bromo-N-phenyl-1H-benzimidazol-2-amine To a 0 ° C. solution of thiocarbonyldiimidazole (1.02 g, 5.7 mmol) in pyridine (20 mL) was added aniline (0.49 mL, 5. 4 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C. for 1.5 hours, treated with 2-amino-4-bromoaniline (1 g, 5.3 mmol), stirred at room temperature overnight, and then EDCI (1. 23 g, 6.4 mmol) and heated to 50 ° C. for 24 hours. The reaction was concentrated and the residue purified by silica gel chromatography, eluting with 20-75% ethyl acetate / hexanes, to give 375 mg (25%) of the desired product. MS (ESI (+)) m / e 288 (M + H) ^<+> .

(Example 103B)
4- (2-anilino-1H-benzimidazol-5-yl) -1-isoindolinone In Example 1D, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -The desired product was prepared by replacing yl) aniline and Example 1C with Example 54A and Example 103A, respectively.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３４１．１（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 341.1 (M−H) ⁻ .

  N- {4- [6- (2-methoxyethoxy) -1-oxo-2,3-dihydro-1H-isoindol-4-yl] phenyl} -N '-(3-methylphenyl) urea

(Example 104A)
4-Bromo-6-methoxy-1-isoindolinone In Example 1B-C, methyl 3-bromo-2-methylbenzoate was converted to methyl 3-bromo-5-methoxy-2-methylbenzoate (J. Am. Chem. Soc., 1967, 1695-1704, prepared according to the method described in Soc. MS (ESI (+)) m / e 242,244 (M + H) ^<+> .

(Example 104B)
4-Bromo-6-hydroxy-1-isoindolinone A suspension of Example 104A (100 mg, 0.41 mmol) in dichloromethane (13 mL) at −78 ° C. was washed with 1M BBr _{3 in} dichloromethane (1.2 mL, 1.2 mmol), and stirred at −78 ° C. for 1 hour and at room temperature for 2 hours. The mixture was treated with additional 1M BBr _{3 in} dichloromethane (0.8 mL) and 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-isobutyl Example 104B in indolinone _{DMF (2.2mL) (100mg, 0.44mmol} ), Cs 2 CO 3 (163mg, 0.5mmol) and 2 A mixture of bromoethyl methyl ether (0.045 mL, 0.46 mmol) was warmed to 60 ° C. for 4 h, 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. MS (ESI (+)) m / e 286, 288 (M + H) ⁺ .

(Example 104D)
N- {4- [6- (2-methoxyethoxy) -1-oxo-2,3-dihydro-1H-isoindol-4-yl] phenyl} -N ′-(3-methylphenyl) urea Example 1D In Example 104C and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline in N- (3-methylphenyl)- The desired product was prepared by replacing with N ′-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 432.1 (M + H) ^<+> .

  ({7- [4-({[(3-Methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-yl} oxy) acetic acid

(Example 105A)
tert-butyl [(7-bromo-3-oxo-2,3-dihydro-1H-isoindol-5-yl) oxy] acetate Example 104B (103 mg, 0.45 mmol) in DMF (2.2 mL), _{cs 2 CO 3 (164mg, 0.5mmol} ) and t- butyl bromoacetate (0.075 mL, 0.5 mmol) the mixture of stirred at room temperature overnight, diluted with water and filtered. The filter cake was dried to give 154 mg (45%) of the desired product. MS (ESI (+)) m / e 342, 344 (M + H) ^<+> .

(Example 105B)
tert-Butyl ({7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-yl} oxy) acetate In Example 1D, Example 1C is Example 105A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline is N- (3-methyl The desired product was prepared by replacing with phenyl) -N ′-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea. MS (ESI (+)) m / e 486 (M + H) ^<+> .

(Example 105C)
({7- [4-({[(3-Methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-yl} oxy) acetic acid TFA (4 mL ) Was stirred for 4 hours at room temperature and then concentrated to give the desired product.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ４３０．１（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 430.1 (M−H) ⁻ .

  N- [4- (7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea

(Example 106A)
Methyl 6-amino-3-bromo-2-methylbenzoate A −20 ° C. solution of methyl 3-bromo-2-methylbenzoate (10 g, 43.7 mmol) in concentrated H ₂ SO ₄ (100 mL) was added at a temperature of − A solution of concentrated HNO ₃ (2.75 mL) in concentrated H ₂ SO ₄ (50 mL) was treated dropwise at a rate maintained below 15 ° C. The reaction was then stirred at 0 ° C. for 30 minutes, poured onto ice and extracted with diethyl ether. The extract was washed with aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 9.32 g of the nitrated product. The crude product was added to a solution of SnCl ₂ (32.2 g, 170 mmol) in concentrated HCl (34 mL) and methanol (52 mL) and the resulting suspension was stirred at room temperature for 4 hours. The resulting solution was concentrated, adjusted to pH 7 with aqueous NaOH, and filtered through diatomaceous earth (Celite® ⁾ . The pad was washed with diethyl ether and dichloromethane and the combined filtrate was concentrated. The concentrate was purified by silica gel chromatography using 10-20% ethyl acetate / hexanes to give 3.59 g of the desired product. MS (ESI (−)) m / e 243 (M−H) ⁻ .

(Example 106B)
Methyl 3-bromo-6-hydroxy-2-methylbenzoate A suspension of Example 106A (1 g, 4.1 mmol) in water (6 mL) at 0 ° C. was added NaNa ₂ (285 mg) in water (1.25 mL). ) And stirred at 0 ° C. for 15 minutes, then slowly added 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. The combined extracts were washed with aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated to give 0.87 g of the desired product. MS (ESI (−)) m / e 226 (M−H) ⁻ .

(Example 106C)
Methyl 6- (acetyloxy) -3-bromo-2-methylbenzoate A solution of Example 106B (1.05 g, 4.3 mmol) in pyridine (3 mL) was treated with acetic anhydride (0.82 mL, 8.6 mmol). And stirred at room temperature for 2 hours and partitioned between ethyl acetate and 2N HCl. The organic phase was washed successively with aqueous NaHCO ₃ , water and brine, dried (MgSO ₄ ), filtered and concentrated to give 1.19 g (97% yield) of the desired product. MS (ESI (+)) m / e 304, 306 (M + H) ⁺ .

(Example 106D)
4-Bromo-7-hydroxy-1-isoindolinone In Examples 1B and 1C, the desired product was prepared by replacing Example 1A with Example 106C. MS (ESI (+)) m / e 226, 228 (M + H) ⁺ .

(Example 106E)
N- [4- (7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1D, Example 1C In Example 106D and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline as N- (3-methylphenyl) -N ′-[4 The desired product was prepared by replacing with-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７４．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 374.1 (M + H) ^<+> .

  N- [4- (7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N '-(3-methylphenyl) urea

(Example 107A)
4-Bromo-7-methoxy-1-isoindolinone A solution of Example 106D (103 mg, 0.45 mmol) in DMF (4 mL) was added to Cs ₂ CO ₃ (162 mg, 0.5 mmol) and methyl iodide (0 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 + H) ^<+> .

(Example 107B)
N- [4- (7-Methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1D, Example 1C Example 107A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline as N- (3-methylphenyl) -N ′-[4 The desired product was prepared by replacing with-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＤＣＩ）ｍ／ｅ ３８８．２（Ｍ＋Ｈ）^＋．

MS (DCI) m / e 388.2 (M + H) ^<+> .

  Sodium ({7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} oxy) acetate

(Example 108A)
tert-Butyl [(7-bromo-3-oxo-2,3-dihydro-1H-isoindol-4-yl) oxy] acetate desired in Example 105A by replacing Example 104B with Example 106D The product was prepared. MS (DCI) m / e 342, 344 (M + H) ⁺ .

(Example 108B)
Sodium ({7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} oxy) acetate Examples In 1D, Example 1C is Example 108A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline is N- (3-methylphenyl). Replacing with -N '-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea and replacing methanol with toluene yields the desired product. Prepared.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 432.1 (M + H) ^<+> .

N- {4- [7- (2-methoxyethoxy) -1-oxo-2,3-dihydro-1H-isoindol-4-yl] phenyl} -N ′-(3-methylphenyl) urea Example 104C And in Example 104D, the desired product was prepared by replacing Example 104B with Example 106D.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４３２．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 432.1 (M + H) ^<+> .

  N- [4- (2-Methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea

(Example 110A)
4-Bromo-2-methyl-1-isoindolinone Example 1B (1 g, 3.25 mmol), methylamine hydrochloride (1.1 g, 16.2 mL) and triethylamine (2.2 mL, in methanol (16 mL) (16.2 mmol) was refluxed for 10 hours, cooled to room temperature, concentrated to a quarter volume and partitioned between NH ₄ Cl saturated solution 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- [4- (2-Methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1D, Example 1C Example 110A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline as N- (3-methylphenyl) -N ′-[4 The desired product was prepared by replacing with-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea and replacing methanol with toluene.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 358.1 (M + H) ^<+> .

  Benzyl 7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate

(Example 111A)
Methyl 5-{[(benzyloxy) carbonyl] amino} -2-methyl-3-nitrobenzoate Methyl 5-amino-2-methyl-3-nitrobenzoate (1 g, 4.76 mmol, J.I.) in THF (24 mL). Chem. Chem. 1984, 27, 386.) and a 0 ° C. solution of diisopropylethylamine (0.91 mL, 5.24 mmol) with benzyl chloroformate (0.65 mL, 5.34 mmol). The mixture was 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 1.7 g of the desired product. MS (ESI (−)) m / e 343 (M−H) ⁻ .

(Example 111B)
Methyl 5-{[(benzyloxy) carbonyl] amino} -3-iodo-2-methylbenzoate Suspension of iron powder (0.83 g, 14.8 mmol) and ammonium chloride (1.33 g, 24.7 mmol) in water the liquid, example 111A in ethanol (1.7 g, 4.94 mmol) was treated dropwise with a suspension of was stirred for 6 hours at 80 ° C., cooled to room temperature, diatomaceous earth ^{(Celite (R))} Through. 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 1.49 g of the intermediate amine. The crude product was dissolved in DMF (10 mL), cooled to 0 ° C., 6M HCl (2.4 mL), then a solution of NaNO ₂ (0.327 g, 4.75 mmol) in water (5 mL). It was processed by dripping. The solution was stirred at 0 ° C. for 30 minutes, treated with KI (788 mg, 4.75 mmol), partitioned with DMF (10 mL), stirred at 0 ° C. for 2 hours, warmed to room temperature for 30 minutes, Extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate solution, water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography using dichloromethane to give 0.86 g of the desired product. MS (ESI (+)) m / e 443 (M + NH 4) +.

(Example 111C)
Benzyl 7-iodo-3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate In Example 1B and 1C, the desired product was prepared by replacing Example 1A with Example 111B. . MS (ESI (+)) m / e 426 (M + NH 4) +.

(Example 111D)
Benzyl 7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate In Example 1D, the Example 1C in Example 111C and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline in N- (3-methylphenyl) -N ′-[ The desired product was prepared by replacing with 4- (4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ５０５．０（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 505.0 (M−H) ⁻ .

N- (3-methylphenyl) -N ′-[3- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Examples 1D and 1E, 4- (4 The desired product was prepared by replacing 4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl) aniline with 3-aminophenylboronic acid.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 358.1 (M + H) ^<+> .

N- [4- (6-Methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 1D, Example 1C In Example 104A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline as N- (3-methylphenyl) -N ′-[4 The desired product was prepared by replacing with-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３８８．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 388.1 (M + H) ^<+> .

  N- (3-methylphenyl) -N ′-(4- {7- [3- (4-morpholinyl) propoxy] -1-oxo-2,3-dihydro-1H-isoindol-4-yl} phenyl) urea

(Example 114A)
4-Bromo-7- (3-chloropropoxy) -1-isoindolinone Example 106D (250 mg, 1.1 mmol), 3-chloropropanol (0.095 mL, 1. 0) in dichloromethane (5 mL) at 0 ° C. A suspension of 1 mmol) and triphenylphosphine (350 mg, 1.3 mmol) was treated with DEAD (0.21 mL, 1.3 mmol) dropwise over 10 minutes. The resulting mixture was stirred at 0 ° C. for 1 hour, warmed to room temperature overnight and concentrated. The residue was purified by silica gel chromatography using 50-60% ethyl acetate / hexanes to give 227 mg of the desired product contaminated with triphenylphosphine oxide. MS (ESI (+)) m / e 304, 306 (M + H) ⁺ .

(Example 114B)
4-Bromo-7- [3- (4-morpholinyl) propoxy] -1-isoindolinone Example 114A (227 mg, 0.75 mmol), morpholine (0.33 mL, 3.8 mmol) and DMF (3 mL) and A solution of potassium iodide (70 mg, 0.42 mmol) was heated in a sealed reaction vessel to 100 ° C. overnight, 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 using 5-7% methanol / dichloromethane containing 1% trimethylamine to give 130 mg of the desired product. MS (ESI (+)) m / e 355, 357 (M + H) ^<+> .

(Example 114C)
N- (3-methylphenyl) -N ′-(4- {7- [3- (4-morpholinyl) propoxy] -1-oxo-2,3-dihydro-1H-isoindol-4-yl} phenyl) Urea In Example 1D, Example 1C is Example 114B and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline is converted to N- (3- The desired product was prepared by replacing with methylphenyl) -N ′-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ５０１．２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 501.2 (M + H) ^<+> .

  N- (3-methylphenyl) -2- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] acetamide

(Example 115A)
2- (4-Bromophenyl) -N- (3-methylphenyl) acetamide 4-Bromophenylacetic acid (502 mg, 2.33 mmol), m-toluidine (0.25 mL, 2.33 mmol) in DMF (10 mL), A solution of HOBT (350 mg, 2.59 mmol) and N-methylmorpholine (0.51 mL, 4.64 mmol) was treated with EDCI (496 mg, 2.59 mmol), stirred at room temperature overnight 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 + H) ⁺ .

(Example 115B)
N- (3-Methylphenyl) -2- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] acetamide In Example 54B, N- (6-bromo-3 The desired product was prepared by replacing -pyridinyl) -N '-(3-methylphenyl) urea with Example 115A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３５７．１（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 357.1 (M + H) ^<+> .

N-methyl-N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea Example in dioxane (3 mL) A suspension of 1D (0.25 g, 1.1 mmol) was treated sequentially with triethylamine (0.17 mL, 1.2 mmol) and triphosgene (0.11 g, 0.37 mmol) and heated to 70 ° C. for 2 hours. And concentrated. The concentrate was resuspended in THF (3 mL), treated with N-methyltoluidine, stirred at room temperature for 18 hours, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography using 2% methanol / dichloromethane to give 76 mg (20% recovery) of the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

N- (3-Chlorophenyl) -N-methyl-N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 116, N-methyltoluidine The desired product was prepared by substituting for 3-chloro-N-methylaniline.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３９０（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 390 (M−H) ⁻ .

N- {7- [4-({[(3-Methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} benzamide In Example 4 The desired product was prepared by replacing acetyl chloride with benzoyl chloride.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ４７５（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 475 (M−H) ⁻ .

3- (Dimethylamino) -N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindole-4- Il} benzamide In Example 4, the desired product was prepared by replacing acetyl chloride with 3-dimethylaminobenzoyl chloride.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ５１８（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 518 (M−H) ⁻ .

N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide In Example 115A, 4-bromophenylacetic acid and m- The desired product was prepared by replacing toluidine with 1,3-thiazole-2-carboxylic acid and Example 1D, respectively.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３３４（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 334 (M−H) ⁻ .

N- (3-Methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] thiourea Example 1D (0 mL) in DMF (3 mL) .1 g, 0.44 mmol) is treated with m-tolyl isothiocyanate (0.06 mL, 0.45 mmol) and stirred at room temperature overnight, then cooled to 0 ° C. and treated with water, Extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography using 3% methanol / dichloromethane to give 72 mg of the desired product.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３７２（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 372 (M−H) ⁻ .

  N-methyl-N '-(3-methylphenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea

(Example 122A)
4- [4- (Methylamino) phenyl] -1-isoindolinone In Example 54B, N- (6-bromo-3-pyridinyl) -N ′-(3-methylphenyl) urea was converted to 4-bromo-N The desired product was prepared by replacing with methylaniline (Tetrahedron. Lett. 1993, 34, 2115). MS (ESI (+)) m / e 239 (M + H) ^<+> .

(Example 122B)
N-methyl-N ′-(3-methylphenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea In Example 1E, Example 1D The desired product was prepared by substituting for Example 122A.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７２（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 372 (M + H) ^<+> .

4- (2,5-Dimethoxyphenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide Examples Prepare the desired product by replacing 4-bromophenylacetic acid and m-toluidine in 115A with 4- (2,5-dimethoxyphenyl) -1,3-thiazole-2-carboxylic acid and Example 1D, respectively. did.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ４７０（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 470 (M−H) ⁻ .

4- (3-Bromophenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide in Example 115A The desired product was prepared by replacing 4-bromophenylacetic acid and m-toluidine with 4- (3-bromophenyl) -1,3-thiazole-2-carboxylic acid and Example 1D, respectively.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ４８８（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 488 (M−H) ⁻ .

  4- (4-{[4- (4-Methoxyphenyl) -1,3-thiazol-2-yl] amino} phenyl) -1-isoindolinone

(Example 125A)
[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -thiourea A solution of ammonium thioisocyanate (78 mg, 1.07 mmol) in acetone (5 mL) was added to benzoyl chloride. (0.118 mL, 1.07 mmol), heated to reflux temperature for 20 minutes, removed from heat, treated with Example 1D (200 mg, 0.89 mmol) and stirred at reflux temperature for 1 hour. The resulting mixture was poured into ice water and the precipitate was filtered, washed with water and dried to give 295 mg of an off-white solid that was added to 5% aqueous NaOH (5 mL). The suspension was heated to 80 ° C. for 30 minutes, cooled to room temperature and poured into 1 N cold HCl. The pH of the solution was adjusted to pH 8 with saturated aqueous Na ₂ CO ₃ and the cloudy mixture was filtered. The filter cake was washed with water and dried to give 194 mg (77% recovery) of the desired product. MS (ESI (−)) m / e 282 (M−H) ⁻ .

(Example 125B)
4- (4-{[4- (4-Methoxyphenyl) -1,3-thiazol-2-yl] amino} phenyl) -1-isoindolinone Example 125A in ethanol (3 mL) (90 mg,. 32 mmol) and 2-bromo-1- (4-methoxy-phenyl) ethanone (73 mg, 0.32 mmol) were stirred at reflux temperature 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.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ４１４（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 414 (M + H) ^<+> .

4- [4- (1H-benzimidazol-2-ylamino) phenyl] -1-isoindolinone trifluoroacetate A solution of thiocarbonyldiimidazole (442 mg, 2.32 mmol) in pyridine (8 mL) at 0 ° C. Treated dropwise with a solution of Example 1D (500 mg, 2.23 mmol) in (8 mL), stirred at 0 ° C. for 1.5 hours, warmed to room temperature, and 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 / THF and water. The organic extract was dried (MgSO ₄ ), filtered and concentrated. Purify the concentrate by silica gel chromatography using 5% methanol / dichloromethane, then 10% to 100% acetonitrile: 0.1% TFA water over a flow rate of 40 mL / min for 8 minutes (10 minutes uptime). Was further purified by preparative HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, 7 μm particle size) to give 17 mg of the desired product.

ＭＳ（ＥＳＩ（−））ｍ／ｅ ３３９（Ｍ−Ｈ）⁻．

MS (ESI (−)) m / e 339 (M−H) ⁻ .

  N- (3-methylphenyl) -N '-[5- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2-thienyl] urea

(Example 127A)
Methyl 5- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2-thiophenecarboxylate In Example 54B, N- (6-bromo-3-pyridinyl) -N ′-( The desired product was prepared by replacing 3-methylphenyl) urea with methyl 5-bromo-2-thiophenecarboxylate. _{R f = 0.45 (10% CH} 3 OH / CH 2 Cl 2).

(Example 127B)
5- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2-thiophenecarboxylic acid Example 127A (0.34 g, 1.24 mmol) in THF (30 mL) and methanol (30 mL). ) Was treated with 1N LiOH (10 mL) and stirred at room temperature for 5 hours, then acidified with 1N HCl 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−H) ⁻ .

(Example 127C)
N- (3-Methylphenyl) -N ′-[5- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2-thienyl] urea Example 127B in DMF (8 mL) (70 mg, 0.27 mmol) and triethylamine (0.046 mL, 0.32 mmol) were treated with diphenylphosphoryl azide (0.072 mL, 0.32 mmol), heated to 80 ° C. for 2 hours, cooled to room temperature, Treated with 3-methylaniline (0.03 mL, 0.27 mmol). 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 using 3% methanol / dichloromethane to give the desired product (13% recovery).

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３６４．０（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 364.0 (M + H) ^<+> .

  N- (3-methylphenyl) -N '-[4- (6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea

(Example 128A)
Methyl 4′-amino-2-methyl-5-nitro-1,1′-biphenyl-3-carboxylate Example 1A (20 g, 87.3 mmol) was cooled to −5 ° C. and the internal temperature decreased to 10 ° C. Treated dropwise with H ₂ SO ₄ (100 mL) at a sustained rate. The reaction mixture was cooled to −30 ° C. and treated dropwise with nitric acid (5.7 mL, 91.7 mmol) at a rate that kept the internal temperature below −12 ° C. After the addition was complete, the reaction flask was placed in an ice bath for 30 minutes and poured over crushed ice. The resulting suspension was extracted twice with diethyl ether and the combined extracts were washed with aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered, concentrated, and methyl 3-bromo-2- 23 g of a mixture of methyl-5-nitrobenzoate and methyl 3-bromo-2-methyl-6-nitrobenzoate was obtained. In Example 1D, Example 1C was replaced with this mixture and then purified by silica gel chromatography using 10-40% ethyl acetate / hexanes to give the desired product.

(Example 128B)
Methyl 4 ′-[(tert-butoxycarbonyl) amino] -2-methyl-5-nitro-1,1′-biphenyl-3-carboxylate Example 128A in THF (10 mL) (1.606 g, 5.6 mmol) ) Was treated with triethylamine (0.78 mL, 5.6 mmol) and di-tert-butyl dicarbonate (1.34 g, 6.17 mmol) and stirred at room temperature for 18 hours. The formed precipitate was removed by filtration, and the filtrate was concentrated. The concentrate was purified by silica gel chromatography using 20-30% ethyl acetate / hexanes to give 1.36 g of the desired product. m. p. 131-132 ° C.

(Example 128C)
4- (4-Aminophenyl) -6-nitro-1-isoindolinone tert-butyl 4- (6-nitro-1-oxo-2,3- in TFA (3 mL) and CH ₂ Cl ₂ (3 mL) A solution of dihydro-1H-isoindol-4-yl) phenylcarbamate (0.276 g, prepared by replacing Example 1A with Example 128B in Examples 1B and 1C) was stirred at room temperature for 1 hour, Concentration then afforded 0.085 g of the desired product.

(Example 128D)
N- (3-Methylphenyl) -N ′-[4- (6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl) -phenyl] urea In Example 1E, the Example The desired product was prepared by replacing 1D with Example 128C. MS (ESI (−)) m / e 401 (M−H) ⁻ ;

N- [4- (6-Amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea In Example 3, Example 2 Was replaced by Example 128D to prepare the desired product.

ＭＳ（ＥＳＩ（＋））ｍ／ｅ ３７３（Ｍ＋Ｈ）^＋．

MS (ESI (+)) m / e 373 (M + H) ^<+> .

N- {7- [4-({[(3-Methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-yl} acetamide In Example 4 The desired product was prepared by replacing Example 3 with Example 129. MS (ESI (−)) m / e 413 (M−H) ⁻ .

  It will be apparent to those skilled in the art that the present invention is not limited to the above-described exemplary embodiments, and that the present invention may be embodied in other specific forms without departing from its essential attributes. Therefore, the examples are to be considered in all respects as illustrative and not restrictive, and the reference should be made to the appended claims rather than the above examples, and therefore All changes that come within the meaning and range of equivalency of the claims are intended to be embraced by the claims.

Claims (23)

Compound of formula (I)

Or a therapeutically acceptable salt thereof.
(Where
R ¹ is selected from the group consisting of hydrogen and alkyl;
R ² is selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, carboxyalkoxy, carboxyalkyl, halo, haloalkyl, heterocyclylalkoxy, hydroxy, nitro and —NR ^c R ^d ;
One of R ³ and R ⁴ is AXR ⁵ and the other is hydrogen (where AXR ⁵ is attached to the parent molecular moiety at its left end). ;
R ⁵ is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
A is aryl and heteroaryl (aryl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, haloalkoxy and haloalkyl. ) Selected from the group consisting of:
X represents O, NR ^a , N (R ^a ) C (S) N (R ^b ), (CH ₂ ) _m N (R ^a ) C (O) N (R ^b ) (CH 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, and m and n are independently 0 Or each group is selected from the group consisting of A bound to A at its left end and R ⁵ at its right end. ) The compound of claim 1, wherein R ³ is AXR ⁵ and R ⁴ is hydrogen. 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 compound according to claim 2. 4- (4-phenoxyphenyl) -1-isoindolinone;
4- {4-[(5,7-dimethyl-1,3-benzoxazol-2-yl) amino] -3-fluorophenyl} -1-isoindolinone;
4- (2-anilino-1H-benzimidazol-5-yl) -1-isoindolinone;
N- (3-methylphenyl) -2- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] acetamide;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide;
N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] thiourea;
4- (2,5-dimethoxyphenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide;
4- (3-bromophenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide;
4- (4-methoxyphenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -1,3-thiazole-2-carboxamide; 4. The compound of claim 3, selected from the group consisting of [4- (1H-benzimidazol-2-ylamino) phenyl] -1-isoindolinone. X _{is, (CH 2) m N (} R a) C (O) N (R b) (CH 2) a _n, A compound according to claim 2. R ² is other than hydrogen, compound of Claim 5. N- (3-methylphenyl) -N ′-[4- (7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4- (7-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} acetamide;
N ^{2, N 2} - dimethyl ^{-N 1 - {7- [4 -} ({[(3- methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro -1H- isoindole - 4-yl} glycinamide;
N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} nicotinamide;
N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} -2-phenylacetamide ;
2- (2-methoxyethoxy) -N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindole- 4-yl} acetamide;
N- {4- [6- (2-methoxyethoxy) -1-oxo-2,3-dihydro-1H-isoindol-4-yl] phenyl} -N ′-(3-methylphenyl) urea;
({7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-yl} oxy) acetic acid;
N- [4- (7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- [4- (7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
({7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} oxy) acetic acid;
N- {4- [7- (2-methoxyethoxy) -1-oxo-2,3-dihydro-1H-isoindol-4-yl] phenyl} -N ′-(3-methylphenyl) urea;
Benzyl 7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate;
N- [4- (6-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- (3-methylphenyl) -N ′-(4- {7- [3- (4-morpholinyl) propoxy] -1-oxo-2,3-dihydro-1H-isoindol-4-yl} phenyl) urea;
N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} benzamide;
3- (Dimethylamino) -N- {7- [4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindole-4- Il} benzamide;
N- (3-methylphenyl) -N ′-[4- (6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4- (6-Amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea; and N- {7- [ 6. The compound selected from the group consisting of 4-({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-5-yl} acetamide. 6. The compound according to 6. R ² is hydrogen, A compound according to claim 5. R ⁵ is aryl and heteroaryl (aryl and heteroaryl is unsubstituted.) Is selected from the group consisting of A compound according to claim 8. N-2,3-dihydro-1H-inden-5-yl-N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N-1,3-benzodioxol-5-yl-N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N′-phenylurea; and N- [2-chloro-4- (1-oxo-2) , 3-Dihydro-1H-isoindol-4-yl) phenyl] -N′-phenylurea selected from the group consisting of: R ⁵ is aryl and heteroaryl (aryl and heteroaryl is mono-substituted.) Are selected from the group consisting of A compound according to claim 8.   12. A compound according to claim 11 wherein A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are unsubstituted. N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (4-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (4-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2-fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (4-fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (4-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2-bromophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-bromophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (4-bromophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4- (trifluoromethoxy) phenyl] urea;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-phenoxyphenyl) urea;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4- (trifluoromethyl) phenyl] urea;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(4-phenoxyphenyl) urea;
N- [3- (benzyloxy) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[3- (trifluoromethyl) phenyl] urea;
N- (3-ethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-cyanophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
Methyl 3-[({[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] amino} carbonyl) amino] benzoate;
N- (3-acetylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-methylphenyl) -N ′-[6- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3-pyridinyl] urea;
N- (5-methyl-3-pyridinyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4- (2-Methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- (3-methylphenyl) -N ′-[3- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N-methyl-N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-chlorophenyl) -N-methyl-N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N-methyl-N ′-(3-methylphenyl) -N- [4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea; and N- (3-methyl 13. A compound according to claim 12 selected from the group consisting of (phenyl) -N '-[5- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2-thienyl] urea. .   12. A compound according to claim 11 wherein A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are monosubstituted. N- [2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- (3-chlorophenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4-fluoro-3- (trifluoromethyl) phenyl] urea ;
N- (4-chlorophenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-bromophenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethoxy) phenyl] urea;
N- (3-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethoxy) phenyl] urea;
N- [2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- (3-chlorophenyl) -N ′-[2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- (3-chlorophenyl) -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[3- (trifluoromethyl) phenyl] urea;
N- [2-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- [2-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-chlorophenyl) urea;
N- [3-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- [3-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-chlorophenyl) urea;
N- [3-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[3- (trifluoromethyl) phenyl] urea;
N- (3-chlorophenyl) -N ′-[3-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [3-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea;
N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea;
N- (3-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea;
N- (3-chlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea;
N- (3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea;
N- [2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3-methylphenyl) urea; and N- (3-chlorophenyl 15. The compound according to claim 14, selected from the group consisting of:) -N '-[2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea. . R ³ is aryl and heteroaryl (aryl and heteroaryl are disubstituted.) Is selected from the group consisting of A compound according to claim 8.   17. A compound according to claim 16, wherein A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are unsubstituted. N- (2,3-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,4-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,4-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,3-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,4-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,5-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,4-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,5-dimethoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,3-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (2,5-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,4-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,5-dichlorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-chloro-4-methoxyphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (4-bromo-3-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-chloro-4-fluorophenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3-chloro-4-methylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [2-fluoro-5- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea; and N- [4-fluoro-3 18. The method according to claim 17, selected from the group consisting of-(trifluoromethyl) phenyl] -N '-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea. The described compound.   17. A compound according to claim 16, wherein A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are monosubstituted. N- (3,4-dimethylphenyl) -N ′-[2-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,4-dimethylphenyl) -N ′-[2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[2-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea ;
N- (3,4-dimethylphenyl) -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- (3,5-dimethylphenyl) -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[3-methyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea ;
N- [2-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3,5-dimethylphenyl) urea;
N- [3-Chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4-fluoro-3- (trifluoromethyl) phenyl] urea ;
N- [3-chloro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-(3,5-dimethylphenyl) urea;
N- (3,5-dimethylphenyl) -N ′-[3-fluoro-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea;
N- [4-Fluoro-3- (trifluoromethyl) phenyl] -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl ) Phenyl] urea;
N- (3,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -2- (trifluoromethyl) phenyl] urea;
N- (3,4-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea;
N- (3,5-dimethylphenyl) -N ′-[4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) -3- (trifluoromethyl) phenyl] urea;
N- [2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] -N ′-[4-fluoro-3- (trifluoromethyl) phenyl] urea And N- (3,5-dimethylphenyl) -N ′-[2-ethyl-4- (1-oxo-2,3-dihydro-1H-isoindol-4-yl) phenyl] urea 20. A compound according to claim 19, which is selected.   A pharmaceutical composition comprising a compound according to claim 1 or a therapeutically acceptable salt thereof in combination with a therapeutically acceptable carrier.   A protein kinase comprising administering to the patient a therapeutically acceptable amount of the compound of claim 1 or a therapeutically acceptable salt thereof in a patient found to require treatment for inhibition of the protein kinase. Method to inhibit.   A method for treating cancer comprising administering to a patient a therapeutically acceptable amount of a compound according to claim 1 or a therapeutically acceptable salt thereof in a patient found to be in need of treatment for cancer. the method of.