HK1116487A - Substituted indoles, compositions containing them, method for the production thereof and their use - Google Patents

Description

substituted indoles, compositions containing them, processes for their preparation and their use

The invention relates in particular to novel chemical compounds, in particular to novel substituted indoles, compositions containing them and their use as pharmaceuticals.

More particularly, the present invention relates to specific novel indoles and 4-azaindoles having anti-cancer activity by modulating the activity of certain kinases.

To date, most commercial compounds used in chemotherapy have caused a number of side effects and patient resistance problems. If the drug used selectively acts on these cancer cells (except normal cells), these effects may be limited. Thus, one solution to limit the adverse effects of chemotherapy consists in using drugs that act on metabolic pathways or on the constituent elements of these pathways, which are expressed predominantly in cancer cells and not or not much expressed in normal cells.

These protein kinases are a group of enzymes that catalyze the phosphorylation of hydroxyl groups of specific residues of proteins, such as tyrosine, serine or threonine residues. Such phosphorylation can greatly alter the function of proteins, and thus protein kinases play a very important role in the regulation of various cellular processes including, inter alia, metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among these diverse cellular functions involving protein kinase activity, certain functions are attractive targets for the treatment of these cancer diseases, as well as others. It is therefore an object of the present invention to provide compositions which have anti-cancer activity through action, in particular, on certain kinases. Among these kinases for which regulatory activity is sought, KDR and Tie2 are preferred.

The products which are the object of the present invention correspond to the following formula (I):

in the formula:

a) a and Ar are independently selected from: aryl, heteroaryl, substituted aryl, substituted heteroaryl;

b) r1 is H or alkyl, optionally substituted alkyl;

c) x is N or N oxide or CR 12;

d) l is selected from: a bond,

CO，NH，CO-NH，NH-CO，NH-SO，SO-NH，NH-SO₂，SO₂NH，NH-CH₂，CH₂-NH，CH₂-CO-NH，NH-CO-CH₂，NH-CH₂-CO，CO-CH₂-NH，NH-CO-NH，NH-CS-NH，NH-CO-O，O-CO-NH；

e) R5, R6, R7 and R12 are independently selected from: H. halogen, halogen,

CF₃，NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R2)C(O)R3N(R4)₂，NHC(O)R2N(R3)(R4)，N(R4)C(S)N(R2)(R3)，N(R2)C(S)R3N(R4)₂，NHC(S)R2N(R3)(R4)，N(R2)S(O₂)(R3)，OS(O)₂(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂)N(R2)(R3)；

Wherein each R2, R3, R4 is independently selected from H, alkyl, alkylene, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl, alkylheterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl; wherein R2 and R3 are simultaneously on one of R5, R6, R7 and R12, they can be linked to each other to form a ring containing 0 to 3 heteroatoms selected from O, N and S;

f) q is selected from H, CH₃And a cyclopropyl group.

Preferred products of formula (I) conform to the following definitions:

formula (I)

In the formula:

a) a and Ar are as defined above;

b) r1 is as previously defined;

c) x is N or CR 12;

d) l is as defined above;

e) r5, R6, R7 and R12 are independently from each other selected from: H. halogen, halogen,

CF₃，NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R4)C(S)N(R2)(R3)，N(R2)S(O₂)(R3)，OS(O₂)(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂)N(R2)(R3)；

Wherein each R2, R3, R4 is as previously defined;

f) q is as defined above.

More preferred products of formula (I) conform to the following definitions:

formula (I)

In the formula

a) A and Ar are independently selected from: aryl, heteroaryl, substituted aryl, substituted heteroaryl;

b) r1 is H;

c) x is CH or N;

d) l is selected from NH-SO₂And NH-CO-NH;

e) r5, R6, R7 and R12 are independently from each other selected from: H. halogen, halogen,

CF₃，NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R4)C(S)N(R2)(R3)，N(R2)S(O₂)(R3)，OS(O₂)(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂) N (R2) (R3); wherein each R2, R3, R4 is independently selected from H, alkyl, alkylene, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl, alkylheterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl; wherein R2 and R3, when both are on one of R5, R6, R7 and R12, can be linked to each other to form a ring that may optionally contain one or more heteroatoms selected from O, N and S;

f) q is H.

The product of the invention has a substituent Q, which is preferably H.

In the products of formula (I), Ar-L-A is advantageously:

wherein each of X1, X2, X3 and X4 is independently selected from N and C-R11, wherein R11 is selected from H, halogen,

NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R4)C(S)N(R2)(R3)，N(R2)S(O₂)(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂)N(R2)(R3).

Preferred substituents R11 are selected from H, F, Cl, methyl, NH₂、OCF₃And CONH₂。

Preferred substituents R5, R6, R7 and R8 are independently of one another selected from H, halogen, methyl,

OCH₃，OCF₃，OH，NH₂，NH(CH₂)₂OH，NH(CH₂)₂OCH₃，O(CH₂)COOH，O(CH₂)₂COOH，O(CH₂)₂NH(CH₂)₂OCH₃，O(CH₂)₂NH(CH₂)₂OH, pyridin-3-ylcarbonylamino-, 2- (N, N-diethylamino) ethoxy, 3- (N, N-diethylamino) propoxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (morpholin-4-yl) ethoxy and 3- (morpholin-4-yl) propylAn oxy group.

R5 and R7 are advantageously selected from H and F.

R6 is preferably H.

Preferred substituents L-A are selected from the group consisting of NH-CO-NH-A, NH-SO₂-A and NH-CO-CH₂-A. Particularly effective combinations are obtained when L-A is NHCONH-A.

The products of the invention are preferably substituents A selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl, optionally A is substituted.

More preferably, a is selected from phenyl, pyrazolyl and isoxazolyl, optionally a is substituted.

Very advantageously, the substituent A is substituted by a first substituent selected from alkyl, haloalkyl, alkylene, alkynyl, aryl, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, each of which is optionally selected from (C)₁-C₃) Alkyl, halogen, O- (C)₁-C₃) Alkyl substituents. Substituent A is preferably substituted with a second substituent selected from F, Cl, Br, I, OH, SO₃M、COOM、CN、NO₂、CON(R8)(R9)、N(R8)CO(R9)、(C₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-N (R8) (R9), (C)₁-C₃) Alkyl- (R10), (C)₁-C₃) alkyl-COOH, N (R8) (R9) and O- (C)₂-C₄) alkyl-NR 8R 9; wherein R8 and R9 are independently selected from H, (C)₁-C₃) Alkyl, (C)₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-NH₂、(C₁-C₃) alkyl-COOM, (C)₁-C₃) alkyl-SO₃M; in which, when R8 and R9 are not H at the same time, they may be linked to each other to form a compound containing 0 to 3 atomsA ring of heteroatoms selected from N, S and O; wherein M is H or an alkali metal cation selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocyclic ring containing 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S.

Particularly preferred substituents A are selected from phenyl, pyrazolyl and isoxazolyl, said substituents A preferably being substituted by halogen (in particular F), (C)₁-C₄) Alkyl, halo (C)₁-C₃) Alkyl (especially CF)₃)、O-(C₁-C₄) Alkyl, O-cycloalkyl, S- (C)₁-C₄) Alkyl, S-cycloalkyl, halo O- (C)₁-C₄) Alkyl and halogenated S- (C)₁-C₄) Alkyl substitution.

Preferred substituents A are phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from alkyl, haloalkyl, alkylene, alkynyl, aryl, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl; each substituent being optionally selected from (C)₁-C₃) Alkyl, halogen, O- (C)₁-C₃) Alkyl substituent substitution; and F, Cl, Br, I, OH, SO₃M、COOM、CN、NO₂、CON(R8)(R9)、N(R8)CO(R9)、(C₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-N (R8) (R9), (C)₁-C₃) Alkyl- (R10), (C)₁-C₃) alkyl-COOH, N (R8) (R9), O- (C)₂-C₄) alkyl-N (R8) (R9); wherein R8 and R9 are independently selected from H, (C)₁-C₃) Alkyl, (C)₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-NH₂、(C₁-C₃) alkyl-COOM, (C)₁-C₃) alkyl-SO₃M; wherein R8 and R9 are not H at the same time, they may be linked to each other to form a ring containing 0 to 3 heteroatoms selected from O, N and S; wherein M is H or an alkali metal cation selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocyclic ring containing 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S。

The products of examples 1-104 are advantageously objects of the present invention.

The product of the invention may be in the form of:

1) achiral or

2) Racemic or

3) Is enriched in stereoisomers, or

4) Enriched in enantiomers;

and optionally salified.

The products of the invention can be used for the production of a medicament for the treatment of pathological states, in particular cancer, or for the treatment of diseases associated with angiogenesis, such as psoriasis, chronic inflammation, age-related macular degeneration, rheumatoid arthritis, diabetic retinopathy, Kaposi's sarcoma or haemangioma in infants and young children.

The invention also relates to therapeutic compositions comprising the products of the invention, in combination with pharmaceutically acceptable excipients chosen according to the chosen mode of administration. The pharmaceutical composition may be in solid or liquid form or in liposome form.

Among these solid compositions, powders, capsules and tablets may be cited. In oral dosage forms, solid dosage forms which protect against attack by the acidic medium of the stomach may also be included. The carriers used in these solid dosage forms are composed in particular of inorganic carriers, such as phosphates, carbonates, or organic carriers, such as lactose, cellulose, starch or polymers. Liquid dosage forms are composed of solutions, suspensions or dispersions. They contain water or organic solvents (ethanol, NMP, etc.) or mixtures of surfactants and solvents or complexing agents and solvents as dispersing carriers.

The liquid dosage form is preferably an injection, and therefore, should be a formulation acceptable for such an application.

Acceptable routes of administration by injection include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, with the intravenous route generally being preferred.

The dosage of the compound of the present invention to be administered is adjusted by the physician according to the route of administration to the patient and the condition of said patient.

The compounds of the present invention may be administered alone or in combination with other anticancer agents. Among the possible combinations, mention may be made of:

alkylating agents, in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednisolone, carmustine, lomustine, semustine, streptozotocin, dacarbazine, temozolomide, procarbazine and altretamine;

platinum derivatives, such as in particular cisplatin, carboplatin or oxaliplatin;

antibiotics, such as in particular bleomycin, mitomycin or dactinomycin;

antimicrotubule agents, such as in particular vinblastine, vincristine, vindesine, vinorelbine or taxanes (taxol and docetaxel);

anthracyclines, such as in particular doxorubicin, daunorubicin, epirubicin, mitoxantrone or losoxantrone;

inhibitors of topoisomerase I and II, such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomotex (tomodex);

fluoropyrimidines, such as 5-fluorouracil, UFT or floxuridine;

cytidine analogs such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomullein (merptomurine), or 6-mercaptoguanine;

adenosine analogues such as pentostatin, cytarabine or fludarabine phosphate;

methotrexate and folinic acid;

a wide variety of enzymes and compounds, such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin, and estrogens and androgens;

angiogenesis inhibitors, such as derivatives of cobutadine or colchicine, and prodrugs thereof.

Combination of radiation therapy with the compounds of the invention is also possible. These treatments may be administered simultaneously, separately or sequentially. The physician adjusts these therapies according to the disease to be treated.

The products of the invention are useful as inhibitors of certain kinases. KDR, Tie2, Aurora1, Aurora2, FAK, PDGFR, FLT1, FGFR and VEGF-R3 are products of the invention that are particularly useful as inhibitors of certain kinases. Among these kinases, KDR and Tie2 are preferred. Among the products of the invention, the products of formula (I) in which X is a nitrogen atom are preferred as inhibitors of KDR, Tie2 and FAK.

The following kinases were chosen for the following reasons:

KDR

KDR (kinase insert domain receptor), also known as VEGF-R2 (vascular endothelial growth factor receptor 2), is substantially expressed in endothelial cells. This receptor immobilizes the angiogenic factor VEGF, thereby serving as a signal transduction mediator by activating its intracellular kinase domain. Direct inhibition of the kinase activity of VEGF-R2 reduces the angiogenic phenomenon in the presence of exogenous VEGF (vascular endothelial growth factor) (Strawn et al, Cancer Research, 1996, 56, 3540-3545). This process is demonstrated in particular by means of the VEGF-R2 mutant (Millauer et al, cancer research, 1996, 56 th, p 1615-1620). The VEGF-R2 receptor appears to have no effect on adults other than those involved in VEGF angiogenic activity. Therefore, selective inhibitors of the kinase activity of VEGF-R2 should only prove to be less toxic.

In addition to this major role in this dynamic angiogenic process, recent results have shown that VEGF expression contributes to tumor cell survival following chemotherapy and radiotherapy, thus underlining the potential synergistic effects of KDR inhibitors with other agents (Lee et al, cancer research, 2000, stage 60, p. 5565-5570).

Tie2

Tie-2(TEK) is a member of the tyrosine kinase receptor family and is expressed primarily in endothelial cells. Tie2 is the first receptor with tyrosine kinase activity and is known both as an agonist (angiopoietin 1 or Ang1) [ S.Davis et al (1996), [ Cell ] 87, 1161-. Angiogenin 1 and VEGF act synergistically during the final stages of neovascularization [ Asahara T., Circ. Res. (1998), 233-. Knockout experiments and transgenic manipulations of Tie2 expression or Ang1 expression resulted in animals with defects in angiogenesis [ D.J. Dumont et al (1994), Genes Dev.8, 1897-. The attachment of Ang1 to its receptor results in autophosphorylation of the Tie2 kinase region, which is essential for neovascularization and for restoration and interaction of blood vessels with pericytes and smooth muscle cells; these phenomena contribute to the maturation and stabilization of newly formed blood vessels [ p.c. maison pierre et al (1997), science 227, 55-60 ]. Lin et al (1997) j.clin.invest.100, 8: 2072 and Lin P. (1998) PNAS 95, 8829 and 8834 have demonstrated a reduction in tumor growth and angiogenesis inhibition and lung metastasis when adenovirus infection or injection of the Tie-2 extracellular domain (Tek) into xenograph models of breast tumors and melanomas.

Tie2 inhibitors may be useful in situations where neovascularization is inappropriate (i.e., in diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic angiogenesis due to macular degeneration, rheumatoid arthritis, infantile hemangiomas, and cancer).

FAK

FAK (focal adhesion kinase) is a cytoplasmic tyrosine kinase consisting ofAn important role in signal transduction by integrin transmission is the heterodimeric receptor family of cell adhesion. FAK and integrins coexist in the membrane structures known as focal adhesions. It has been shown in many cell types that activation of tyrosine residues by FAK and its phosphorylation, and in particular its autophosphorylation of tyrosine 397, is dependent on the attachment of integrins to their extracellular ligands and is therefore induced upon cell adhesion [ Kornberg L, et al, j.biol.chem.267 (33): 23439-442.(1992)]. Autophosphorylation of FAK on tyrosine suggests a site for the binding of Src, another tyrosine kinase, through its SH2 domain [ Schaller et al, mol.cell.biol.14: 1680-; xing et al, mol.cell.biol.5: 413-421, 1994]. Src is then able to phosphorylate FAK on tyrosine 925, thereby complementing Grb2 adaptor proteins and inducing the MAP kinase pathway involved in ras activation and control of cell proliferation in certain cells [ Schlaepfer et al, Nature; 372: 786-; schlaepfer et al, prog.biophy.mol. biol.71: 435-478, 1999; schlaepfer and Hunter, j.biol.chem.272: 13189-13195, 1997]. FAK activation can also cause jun NH₂The terminal kinase (JNK) signaling pathway, leading to the development of cells into the G1 phase of the cell cycle [ Otkay et al, j.cell. biol.145: 1461-1469, 1999]. phosphatidylinositol-3-OH kinase (PI 3-kinase) also binds FAK on tyrosine 397, and this interaction is essential for PI 3-kinase activation [ Chen and Guan, pro e.nat. acad.sci.usa 91: 10148-; ling et al, j.cell, biochem.73: 533-544, 1999]. FAK/Src complexes phosphorylate a variety of substrates (such as paxillin and p130CAS in fibroblasts) [ Vuori et al, mol.cell.biol.16: 2606-2613, 1996]。

Numerous research efforts support the hypothesis that FAK inhibitors may be useful for treating cancer. Studies have shown that FAK may play an important role in cell proliferation and/or survival in vitro. For example, some authors have demonstrated that overexpression of p125FAK in CHO cells results in an accelerated G1 to S transition, suggesting that p125FAK promotes cell proliferation [ Zhao j. 1997-2008, 1998]. Other authors have indicated that tumor cells treated with FAK antisense oligonucleotides lose their adhesion and begin to apoptosis (Xu et al, Cellgrowth Differ.4: 413-. FAK has also been shown to promote cell migration in vitro. Thus, deficient fibroblasts of FAK expression (FAK "knockout" mice) have a rounded morphology, and a defect in cell migration in response to chemotactic signals, and FAK re-expression abrogates these defects [ dj.sieg et al, j.cell, science.112: 2677-91, 1999]. Overexpression of the C-terminal domain (FRNK) of FAK blocks adherent cell elongation, reducing cell migration in vitro [ Richardson a. and Parsons j.t.nature.380: 538-540, 1996]. Overexpression of FAK in human astrocytoma cells promotes cell migration. FAK is involved in promoting cell proliferation and migration in many cell types in vitro, suggesting a potential role for FAK in the tumor process. Recent studies have strongly demonstrated that tumor cell proliferation increases in vivo following introduction of FAK expression in human astrocytoma cells [ Cary l.a. et al, j.cell sci.109: 1787-94, 1996; wang D et al, j.cellsci.113: 4221-4230, 2000]. Furthermore, immunohistochemical studies of human biopsies have demonstrated that FAK is overexpressed in prostate, breast, thyroid, colon, melanoma, brain and lung cancers, and that the expression levels of FAK are directly correlated with tumors with the most aggressive phenotype [ Weiner TM et al, Lancet (Lancet)342 (8878): 1024 + 1025, 1993; owens et al, Cancer Research 55: 2752 2755, 1995; maung K. et al, Oncogene (Oncogene) 18: 6824-6828, 1999; wang D et al, j.cell sci.113: 4221-4230, 2000].

Definition of

The term "halogen" refers to an element selected from the group consisting of F, Cl, Br and I.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon substituent having from 1 to 12 carbon atoms. Examples of alkyl substituents are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-dimethylbutyl, heptyl, 1-ethylpentyl, octyl, nonyl, decyl, undecyl and dodecyl substituents.

The term "alkenyl" refers to straight or branched hydrocarbon substituents of 2 to 12 carbon atoms having one or more unsaturations. Examples of such substituents are vinyl, 1-methylvinyl, prop-1-enyl, prop-2-enyl, Z-1-methylprop-1-enyl, E-1-methylprop-1-enyl, Z-1, 2-dimethylprop-1-enyl, e-1, 2-dimethylprop-1-enyl, but-1, 3-dienyl, 1-methine (methylid E nyl) -prop-2-enyl, Z-2-methyl-but-1, 3-dienyl, E-2-methylbut-1, 3-dienyl, 2-methyl-1-methine-2-enyl, undec-1-enyl and undec-10-enyl substituents.

The term "alkynyl" refers to a straight or branched hydrocarbon substituent of 2 to 12 carbon atoms having at least two unsaturations at one pair of adjacent carbon atoms. Examples of alkynyl substituents are ethynyl, prop-1-ynyl, prop-2-ynyl, and but-1-ynyl substituents.

The term "aryl" refers to a monocyclic or polycyclic aromatic substituent having 6 to 14 carbon atoms. Phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracen-9-yl, 1, 2, 3, 4-tetrahydronaphthalen-5-yl and 1, 2, 3, 4-tetrahydronaphthalen-6-yl substituents are examples of aryl substituents.

The term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms. Pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1, 2, 4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1, 3, 5-triazinyl, indolyl, benzo [ b ] furyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, azaindolyl, quinolinyl, isoquinolinyl, carbazolyl and acridinyl substituents are examples of heteroaryl substituents.

The term "heteroatom" herein refers to an at least divalent atom other than carbon. N, O, S and Se are examples of heteroatoms.

The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having from 3 to 12 carbon atoms. Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo [2.2.1] heptyl, cyclooctyl, bicyclo [2.2.2] octyl, adamantyl, and perhydronaphthyl substituents are examples of cycloalkyl substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms. Preferably, the saturated or partially unsaturated cyclic hydrocarbon substituent should be monocyclic, containing 4 or 5 carbon atoms and 1-3 heteroatoms.

The term "substituted" refers to substituents other than H, such as halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylene, alkynyl, OH, O-alkyl, O-alkylene, O-aryl, O-heteroaryl, NH₂NH-alkyl, NH-aryl, NH-heteroaryl, SH, S-alkyl, S-aryl, S (O)₂)H、S(O₂) Alkyl, S (O)₂) Aryl, SO₃H、SO₃Alkyl, SO₃Aryl, CHO, C (O) -alkyl, C (O) -aryl, C (O) OH, C (O) O-alkyl, C (O) O-aryl, OC (O) -alkyl, OC (O) -aryl, C (O) NH₂C (O) NH-alkyl, C (O) NH-aryl, NHCHO, NHC (O) -alkyl, NHC (O) -aryl, NH-cycloalkyl or NH-heterocyclyl.

The products of the invention can be prepared by conventional methods of organic chemistry. The following schemes 1 and 2 illustrate two methods employed in the following preparative examples. In this respect, they should not constitute a limitation of the scope of the invention relating to the process for the preparation of the claimed compounds.

The method a comprises the following steps:

scheme 1

The method b:

flow chart 2

In both cases, an alternative synthetic route consists in condensing boronic acids with urea chains with bromo (aza) indoles.

Another subject of the invention is a process for the preparation of the product of formula (I) as defined in claim 1, characterized in that the product of formula (VI):

the following steps are carried out:

halogenation in the 3-position, followed by

-carrying out a Suzuki coupling reaction in position 3 to obtain a product of formula (IV):

then the

-reduction of the nitrophenyl group in position 3 to an aminophenyl group, ester amidation in position 2, or ester amidation in position 2 and reduction of the nitrophenyl group in position 3 to an aminophenyl group to give a product of formula (II):

then the

Acylation of the aminophenyl group in position 3.

Intermediates of the formulae (II), (IV) and (VI) are also objects of the present invention.

It will be appreciated by those skilled in the art that in order to carry out the process of the invention described above, it may be necessary to add amino, carboxyl and alcohol functional protecting groups to avoid side reactions. These groups are groups that can be removed without affecting the rest of the molecule. As examples of amino-functional protecting groups, mention may be made of tert-butyl carbamate, which can be regenerated with iodotrimethylsilane, and acetyl groups, which can be regenerated in an acidic medium, such as hydrochloric acid. As the protecting group for the carboxyl function, esters (e.g., methoxymethyl ester, benzyl ester) can be cited. As protecting groups for the alcohol function, mention may be made of esters which can be regenerated in an acidic medium or by catalytic hydrogenation (for example benzoyl esters). Other useful protecting groups are described by Greene et al, protective groups in organic Synthesis, third edition, 1999, Wiley-Interscience.

These compounds of formula (I) can be isolated and purified by generally known methods, such as crystallization, chromatography or extraction.

Enantiomers and diastereomers of the compounds of formula (I) are also part of the invention.

Compounds of formula (I) containing a basic residue may optionally be converted into addition salts with such acids by the action of an organic or inorganic acid in a solvent, for example an organic solvent such as an alcohol, ketone, ether or chlorinated solvent.

The compounds of formula (I) containing an acidic residue may optionally be converted into metal salts or addition salts with nitrogen-containing bases according to methods known per se. These salts may be obtained by the action of a metal base (e.g. an alkali metal or alkaline earth metal base), ammonia, an amine or an amine salt with a compound of formula (I). The resulting salt is isolated by conventional methods.

These salts are also part of the present invention.

The products of the invention, when they have at least one free base group, can be reacted with inorganic or organic acids to prepare pharmaceutically acceptable salts. Pharmaceutically acceptable salts include chloride, nitrate, sulfate, bisulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, acetate, propionate, acrylate, 4-hydroxybutyrate, caprylate, hexanoate, caprate, oxalate, malonate, succinate, glutarate, adipate, pimelate, maleate, fumarate, citrate, tartrate, lactate, phenylacetate, mandelate, sebacate, suberate, benzoate, phthalate, methanesulfonate, propanesulfonate, xylenesulfonate, salicylate, cinnamate, glutamate, aspartate, glucuronate, galacturonate.

The products of the invention have at least one free acid function, and pharmaceutically acceptable salts can be prepared by reacting said products with inorganic or organic bases. Pharmaceutically acceptable bases include alkali metal or alkaline earth metal cation (such as Li, Na, K, Mg or Ca) hydroxides, basic amine compounds, such as ammonia, arginine, histidine, piperidine, morpholine, piperazine, triethylamine.

The invention is also described by the following examples which are intended to illustrate the invention.

LC/MS analysis was performed using a Micromass model LCT in combination with HP 1100 equipment. The product abundance was determined using an HP G1315A diode array detector and a Sedex 65 light dispersion detector in the wavelength range 200-600 nm. Mass spectra in the range 180-800 were determined. Data analysis was performed using Micromass MassLynx software. The separation was performed using a Hypersil BDS C18, 3 μm (50X 4.6mm) column, using a linear gradient elution with 5-90% acetonitrile containing 0.05% (v/v) -trifluoroacetic acid (TFA) in water containing 0.05% (v/v) TFA over 3.5 minutes at a flow rate of 1 ml/min. The total analysis time, including the column re-equilibration time, was 7 minutes.

Using electrospray technique (ES)⁺) MS spectra were measured using a Platform II instrument (Micromass). The major ions observed are described.

These melting points were determined by capillary techniques using a Mettler FP62 instrument at 2 ℃ per minute temperature rise in the range 30-300 ℃.

The retention times of examples 72-74 were determined using a XBRIDGE C18 type 3X 50mm column, 2.5 μm particle. These products were eluted using a linear gradient of 5-95% aqueous acetonitrile containing 0.1% formic acid at a flow rate of 1.1ml/min over 7 minutes.

Using Waters Xterra C₁₈Type 3X 50mm column, 3.5 μm particles, the retention time of examples 77-102 was determined. These products were eluted using a linear gradient of 5-90% aqueous acetonitrile containing 0.5% TFA at a flow rate of 600. mu.l/min over 7 minutes.

Purification by LC/MS:

these products can be purified using a Waters FractionsLynx system consisting of a Waters 600 type gradient pump, a Waters 515 type regeneration pump, a Waters Regagent Manager dilution pump, a Waters 2700 type auto-injector, two Rheodyne LabPro type valves, a Waters 996 type diode array detector, a Waters ZMD type mass spectrometer and a Gilson 204 type fraction collector using LC/MS. The system was controlled by Waters FractionLynx software. Two Waters Symmetry columns (C) were used₁₈5 μm, 19 × 50mm, catalogue reference 186000210) was alternately carried out, one column being used for the regeneration process using a water/acetonitrile mixture 95/5(v/v) containing 0.07% (v/v) trifluoroacetic acid, while the other column was used for the separation process. The columns were eluted using a linear gradient of 5-95% aqueous acetonitrile containing 0.07% (v/v) trifluoroacetic acid in 0.07% (v/v) trifluoroacetic acid at a flow rate of 10 ml/min. At the outlet of the separation column, one thousandth of the effluent was separated using an LC Packing Accurate, diluted with methanol at a flow rate of 0.5ml/min and sent to the detector, 75% of which was sent to the diode array detector and the remaining 25% to the mass spectrometer. The remaining portion (999/1000) of the effluent is sent to a fraction collectorWhen the desired product quality is not detected by the FractionLynx software in the accumulator, the stream is discarded. The molecular formula of the expected product was supplied to the FractionLynx software and the mass signal detected corresponded to the ion [ M + H ]]⁺And/or [ M + Na]⁺At that time, the software initiates collection of the product. In some cases, depending on the LC/MS analysis results, a signal corresponding to [ M +2H ] was detected]⁺⁺Corresponding to the calculated half molecular weight (MW/2) is also supplied to the FractionLynx software. Under these conditions, the ion [ M +2H ] was detected]⁺⁺And/or [ M + Na + HH]⁺⁺The collection is also initiated. These products were collected in tared glass tubes. After collection, the solvent is evaporated in a Savant AES 2000 or Genevac HT8 centrifugal evaporator and the mass of the product is determined by weighing the tube after evaporation of the solvent.

Example 1: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]-phenyl } -1H-indole-2-carboxamide (carboxamide)

The method a comprises the following steps:

3-bromo-1H-indole-2-carboxylic acid ethyl ester

To a solution of 37.8g of ethyl indole-2-carboxylate in 900ml of pyridine at 0 ℃ under argon, 67g of tribromopyridine in 300ml of pyridine are slowly added. The solution was then heated at 50 ℃ for 30 minutes and poured into 4L of ice water. The resulting solid was filtered, washed with water and dehydrated. After drying in vacuo, 48.4g of 3-bromo-1H-indole-2-carboxylic acid ethyl ester are obtained, characterized as follows:

MS (ES +) spectrum: m/z 269 MH]⁺

Melting point 148-.

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 1.38(t, J ═ 7.0Hz, 3H); 4.38(q, J ═ 7.0Hz, 2H); 7.20 (width t, J ═ 8.0Hz, 1H); 7.37 (width t, J ═ 8.0Hz, 1H); 7.50 (width d, J ═ 8.0Hz, 1H); 7.54 (width d, J ═ 8.0Hz, 1H); 12.2 (width m, 1H).

IR spectrum (KBr): 3454; 3319; 3297; 1701; 1681; 1517; 1331; 1240 and 644cm^-1。

3- (4-Nitrophenyl) -1H-indole-2-carboxylic acid ethyl ester

To a solution of 5g of ethyl 3-bromo-1H-indole-2-carboxylate and 7.8g of 4-nitrophenylboronic acid in 110ml of ethanol and 110ml of toluene, 46ml of a 1M sodium carbonate solution, 2.23g of lithium chloride and then 1.1g of tetrakis (triphenylphosphine) palladium are added successively under argon and stirring. The solution was heated under reflux for 2 hours and 30 minutes, and then concentrated under reduced pressure. The precipitate was filtered and recrystallized from ethanol to give 5.1g of ethyl 3- (4-nitrophenyl) -1H-indole-2-carboxylate, characterized as follows:

MS (ES +) spectrum: 311[ MH ] m/z]⁺

Melting point 218-.

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 1.21(t, J ═ 7.0Hz, 3H); 4.26(q, J ═ 7.0Hz, 2H); 7.14 (width t, J ═ 8.0Hz, 1H); 7.37 (width t, J ═ 8.5Hz, 1H); 7.50-7.60(m, 2H); 7.81 (width d, J ═ 8.0Hz, 2H); 8.30 (width d, J ═ 8.5Hz, 2H); 12.2 (width m, 1H).

IR spectrum (KBr): 3405; 1717; 1510; 1343; 1239, and; 859 and 757cm^-1

3- (4-nitrophenyl) -1H-indole-2-carboxamide

To a solution of 3.3g of ethyl 3- (4-nitrophenyl) -1H-indole-2-carboxylate in 50ml of 7N methanolic ammonia, a solution of 0.5g of ammonium chloride in 30ml of concentrated aqueous ammonia was added. The solution was then heated in a sealed tube at 125 ℃ for 15 hours. After cooling, the solid formed is filtered, washed with water and then dehydrated. After drying in vacuo, 1.5g of 3- (4-nitrophenyl) -1H-indole-2-carboxamide are obtained, which are characterized as follows:

MS (ES +) spectrum: m/z 282[ MH ] +

Melting point 258 ℃ and 260 ℃ (K ö fler).

Elemental analysis: c%: 63.74; h%: 3.76; n%: 14.90 (theoretical value: C%: 64.06; H%: 3.94; N%: 14.94)

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 7.13 (width t, J ═ 8.0Hz, 1H); 7.22-7.65 (very wide m, 2H with partial masking); 7.30 (width t, J ═ 8.0Hz, 1H); 7.51 (width d, J ═ 8.0Hz, 1H); 7.59 (width d, J ═ 8.0Hz, 1H); 7.79 (width d, J ═ 8.5Hz, 2H); 8.31 (width d, J ═ 8.5Hz, 2H); 11.4-11.8 (very wide m, 1H).

3- (4-aminophenyl) -1H-indole-2-carboxamide

To a suspension of 1.3g of 3- (4-nitrophenyl) -1H-indole-2-carboxamide in 50ml of 5N hydrochloric acid was added 2.7g of tin. The mixture was stirred at room temperature for 5 hours and then neutralized with 5N sodium hydroxide solution. The aqueous phase is extracted 3 times with 50ml of ethyl acetate and the organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (20/80 vol) gave 0.15g of 3- (4-aminophenyl) -1H-indole-2-carboxamide characterized as follows:

MS (ES +) spectrum: m/z is 252[ MH ] +

Melting point 180 ℃ and 182 ℃ (K ö fler).

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 5.24 (width s, 2H); 6.12 (width m, 1H); 6.70 (width d, J ═ 8.5Hz, 2H); 7.01 (width t, J ═ 8.0Hz, 1H); 7.13 (width d, J ═ 8.5Hz, 2H); 7.20 (width t, J ═ 8.0Hz, 1H); 7.33 (width d, J ═ 8.0Hz, 1H); 7.43 (width d, J ═ 8.0Hz, 1H); 7.30-7.45 (very wide m, 1H with partial masking); 11.45 (width m, 1H).

IR spectrum (KBr): 3452; 3370; 1648; 1582; 1345 and 747cm^-1

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -1H-indole-2-carboxamide

To a solution of 0.11g of 3- (4-aminophenyl) -1H-indole-2-carboxamide in 18ml of tetrahydrofuran at 10 ℃ is added dropwise a solution of 0.089ml of 2-fluoro-5-trifluoromethylisocyanate in 2ml of tetrahydrofuran. After stirring at 20 ℃ for 1 hour, 5ml of methanol and 2ml of triethylamine were added and stirring was continued for 1 hour. The reaction medium is then concentrated under reduced pressure and the residue is purified by chromatography on a silica gel column, eluting with a mixture of cyclohexane and ethyl acetate (35/65 vol) to give 0.13g of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide, characterized as follows:

MS (ES +) spectrum: m/z ═ 457[ MH ] +

Melting point 240 ℃ and 242 ℃ (K ö fler).

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.48 (width m, 1H); 7.06 (width t, J ═ 8.0Hz, 1H); 7.23 (width t, J ═ 8.0Hz, 1H); 7.36-7.57(m, 7H); 7.60 (width d, J ═ 8.5Hz, 2H); 8.65(dd, J ═ 2.5 and 7.5Hz, 1H); 8.97 (width m, 1H); 9.32 (width m, 1H); 11.6 (width m, 1H).

IR spectrum (KBr): 3463; 3338 of a polyamide resin; 1651; 1590; 1543; 1443; 1340; 1119; 1070 and 745cm^-1

Example 2: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

The method b:

3- (3-Nitropyridin-2-yl) -2-oxopropanoic acid ethyl ester

To a sodium ethoxide solution prepared by adding 4g of sodium to 400ml of ethanol stirred under argon, 121.7g of ethyl oxalate was added, and a solution of 15.8g of 2-methyl-3-nitropyridine in 100ml of ethanol was further added. The reaction mixture was stirred for 15 hours, and then the resulting solid was filtered, washed successively with 100ml of ethanol and 100ml of isopropyl ether, and then dehydrated. The solid is dissolved in 300ml of ethanol and acidified with 5N hydrochloric acid solution. The solid obtained is filtered, washed with 50ml of 5N hydrochloric acid solution and then with 100ml of ethanol and then dehydrated. After drying in vacuo, 18.7g of 3- (3-nitropyridin-2-yl) -2-oxopropanoic acid ethyl ester were obtained, characterized as follows:

MS (ES +) spectrum: m/z is 239[ MH ] +

Melting point 38 ℃ (K ö fler).

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 1.30(t, J ═ 7.0Hz, 3H); 4.29(q, J ═ 7.0Hz, 2H); 7.12(s, 1H); 7.57(dd, J ═ 5.5 and 8.5Hz, 1H); 8.66 (width d, J ═ 8.5Hz, 1H); 8.85 (width d, J ═ 5.5Hz, 1H); 14.9 (width m, 1H).

IR spectrum (KBr): 1722; 1644; 1560, preparing a composition; 1532; 1346; 1231; 1141; 1024 and 777cm^-1

1H-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester

To 500ml of ethanol were added 18.4g of ethyl 3- (3-nitropyridin-2-yl) -2-oxopropanoate and 5.5g of 10% palladium on charcoal catalyst, and the reaction mixture was hydrogenated at 20 ℃ and 2 bar for 3 hours. The reaction mixture was then filtered through a thin layer of silica gel and the filtrate was concentrated under reduced pressure to give 14.1g of ethyl 1H-pyrrolo [3, 2-b ] -pyridine-2-carboxylate, characterized as follows:

MS (ES +) spectrum: 191[ MH ] m/z]⁺

Melting point 176-.

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 1.36(t, J ═ 7.0Hz, 3H); 4.37(q, J ═ 7.0Hz, 2H); 7.20 (width s, 1H); 7.27(dd, J ═ 4.5 and 8.5Hz, 1H); 7.84 (width d, J ═ 8.5Hz, 1H); 8.45(dd, J ═ 1.5 and 4.5Hz, 1H); 12.15 (width m, 1H).

3-bromo-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester

To a solution of 0.5g of ethyl 1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate in 12ml of pyridine at 0 ℃ under argon, 0.9g of tribromopyridine in 5ml of pyridine is slowly added. Then, the solution was heated at 50 ℃ for 15 minutes and then poured into 100ml of ice water. The resulting solid was filtered, washed with water, and then dehydrated. After drying in vacuo, 0.56g of ethyl 3-bromo-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate are obtained, characterized as follows:

MS (ES +) spectrum: m/z is 270[ MH ] +

Melting point 180 ℃ (K ö fler).

IR spectrum (KBr): 2983; 2841; 2681; 1711; 1513; 1374, a first electrode; 1346; 1261; 1209; 1012; 767 and 651cm^-1

3- (4-Nitrophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester

To a solution of 2g of ethyl 3-bromo-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate and 1.5g of 4-nitrophenylboronic acid in 50ml of dioxane were added 3g of potassium carbonate and 0.8g of tetrakis (triphenylphosphine) palladium. The mixture was heated under reflux for 20 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (50/50 vol) to give 0.52g of ethyl 3- (4-nitrophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate, characterized as follows:

MS spectrum (ES +): 312[ MH ] m/z]⁺

Melting point 234-.

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 1.25(t, J ═ 7.0Hz, 3H); 4.32(q, J ═ 7.0Hz, 2H); 7.38(dd, J ═ 4.5 and 8.5Hz, 1H); 7.94(dd, J ═ 1.5 and 8.5Hz, 1H); 7.99 (width d, J ═ 9.0Hz, 2H); 8.30 (width d, J ═ 9.0Hz, 2H); 8.52(dd, J ═ 1.5 and 4.5Hz, 1H); 12.4 (width s, 1H).

IR spectrum (KBr): 3371; 1741; 1598; 1508; 1345; 12521158, respectively; 857 and 771cm^-1

3- (4-nitrophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide

A solution of 0.4g of ethyl 3- (4-nitrophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate in 10ml of 7N methanolic ammonia was heated at 100 ℃ for 16 hours in a closed vessel. The solvent was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate to give 0.16g of 3- (4-nitrophenyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide characterized as follows:

MS spectrum (ES +): 283[ MH ] m/z]⁺

Melting point > 260 deg.C (K ö fler).

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 7.33 (width dd, J ═ 4.5 and 8.5Hz, 1H); 7.82 (width m, 2H); 7.91 (width d, J ═ 8.5Hz, 1H); 8.16 (width d, J ═ 8.5Hz, 2H); 8.33 (width d, J ═ 8.5Hz, 2H); 8.52 (width d, J ═ 4.5Hz, 1H); 12.25 (width m, 1H).

3- (4-aminophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide

To a solution of 0.15g of 3- (4-nitrophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide in 10ml of methanol was added 0.113g Pd/C (10%). After stirring for 3.5 hours at 22 ℃ under 2 bar of hydrogen, the reaction medium is filtered over silica gel and then concentrated under reduced pressure to give 0.1g of 3- (4-aminophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide, characterized in that:

MS spectrum (ES +): 253[ MH ] m/z]⁺

Melting point 236 ℃ and 238 ℃ (K ö fler).

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 5.20 (width s, 2H); 6.46 (width m, 1H); 6.68 (width d, J ═ 8.5Hz, 2H); 7.20(dd, J ═ 4.5 and 8.5Hz, 1H); 7.28 (width d, J ═ 8.5Hz, 2H); 7.62 (width m, 1H); 7.78 (width d, J ═ 8.5Hz, 1H); 8.35 (width d, J ═ 4.5Hz, 1H); 11.65 width m, 1H).

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide

To a solution of 80mg of 3- (4-aminophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide in 18ml of tetrahydrofuran was added 73mg of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 1 hour, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with a mixture of cyclohexane and ethyl acetate (20/80 vol) to give 110mg of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide characterized as follows:

MS spectrum (ES +): m/z 458[ MH ] +

Melting point 206-.

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.91 (width m, 1H); 7.24(dd, J ═ 4.5 and 8.5Hz, 1H); 7.39 (width m, 1H); 7.51 (partially masked m, 1H); 7.56 (width d, J ═ 8.5Hz, 2H); 7.64 (width d, J ═ 8.5Hz, 2H); 7.60-7.71 (width m, 1H partially masked); 7.82(dd, J ═ 1.5 and 8.5Hz, 1H); 8.40(dd, J ═ 1.5 and 4.5Hz, 1H); 8.65 (width dd, J ═ 2.5 and 7.5Hz, 1H); 8.96 (width m, 1H); 9.31 (width s, 1H); 11.7-11.9 (very wide m, 1H).

IR spectrum (KBr): 3456; 3382; 1717; 1659; 1600; 1543; 1442; 1340; 1312; 1193, a support base; 1167; 1118; 1069 and 774cm^-1

Example 3: 3- [4- (3-phenylureido) phenyl]-1H-indole-2-carboxamides

3- [4- (3-Phenylureido) phenyl ] -1H-indole-2-carboxamide is prepared using phenyl isocyanate according to the method described above. The method is characterized in that:

MS spectrum (ES +): 371[ MH ] m/z⁺]

Melting point 232-.

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 6.43 (width m, 1H); 6.98 (width t, J ═ 8.0Hz, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.23 (width t, J ═ 8.0Hz, 1H); 7.39-7.52(m, 7H); 7.59 (width d, J ═ 8.5Hz, 2H); 8.72 (width s, 1H); 8.80 (width s, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3460; 3384; 3325; 1654; 1596; 1540; 1499; 1312; 1231 and 747cm^-1

Example 4: 3- [4- (3-m-tolylureido) phenyl]-1H-indole-2-carboxamides

3- [4- (3-m-tolylureido) phenyl ] -1H-indole-2-carboxamide was prepared using 3-methylphenyl isocyanate according to the procedure described above and characterized as follows:

MS spectrum (ES +): m/z 385[ MH ] +

Melting point 140-.

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 2.30(s, 3H); 6.42 (width m, 1H); 6.80 (width d, J ═ 8.0Hz, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.13-7.30(m, 3H); 7.32 (width s, 1H); 7.38-7.53(m, 5H); 7.59 (width d, J ═ 8.5Hz, 2H); 8.69 (width s, 1H); 8.83 (width s, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3461; 3377; 1655; 1592; 1542; 1218 and 746cm^-1。

Example 5: 3- [4- (3-trifluoromethylphenylureido) phenyl]-1H-indole-2-carboxamides

3- [4- (3-trifluoromethylphenylureido) phenyl ] -1H-indole-2-carboxamide was prepared according to the procedure described previously using 3-trifluoromethylphenyl isocyanate. The method is characterized in that:

MS spectrum (ES +): 439 MH m/z⁺]

Melting point 156 ℃ and 158 ℃.

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.45 (width m, 1H); 7.05 (width t, J ═ 7.5Hz, 1H); 7.23 (width t, J ═ 7.5Hz, 1H); 7.32 (width d, J ═ 8.5Hz, 1H); 7.43 (width d, J ═ 8.5Hz, 2H); 7.38-7.64(m, 5H); 7.61 (width d, J ═ 8.5Hz, 2H); 8.04 (width s, 1H); 8.97 (width s, 1H); 9.15 (width s, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3462; 3378; 1654; 1590; 1542; 1448; 1337; 1312; 1230; 1125; 1070; 746 and 698cm^-1

Example 6: 3- [4- (3, 5-Dimethylphenylureido) phenyl]-1H-indole-2-carboxamides

3- [4- (3, 5-Dimethylphenylureido) phenyl ] -1H-indole-2-carboxamide is prepared according to the process described above using 3, 5-dimethylphenyl isocyanate. The method is characterized in that:

MS Spectrum (ES)⁺)：m/z＝399[MH⁺]

Melting point 168-.

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 2.24(s, 6H); 6.43 (width m, 1H); 6.62 (width s, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.10 (width s, 2H); 7.23 (width t, J ═ 8.0Hz, 1H); 7.39-7.53(m, 5H); 7.58 (width d, J ═ 8.5Hz, 2H); 8.60 (width s, 1H); 8.82 (width s, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3459; 3375; 1654; 1586; 1541; 1310; 1215; 851 and 745cm^-1。

Example 7: 3- [4- (2-fluorophenylureido) phenyl]-1H-indole-2-carboxamides

3- [4- (2-fluorophenylureido) phenyl ] -1H-indole-2-carboxamide was prepared according to the method described above using 2-fluorophenyl isocyanate. The method is characterized in that:

MS Spectrum (ES)⁺)：m/z＝389[MH⁺]

Melting point 146-.

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 6.46 (width m, 1H); 6.98-7.08(m, 2H); 7.15 (width t, J ═ 8.0Hz, 1H); 7.20-7.28(m, 2H); 7.43 (width d, J ═ 8.5Hz, 2H); 7.40-7.52 (mask m, 1H); 7.46 (width d, J ═ 8.0Hz, 1H); 7.49 (width m, 1H); 7.59 (width d, J ═ 8.5Hz, 2H); 8.18 (width t, J ═ 8.0Hz, 1H); 8.64 (width s, 1H); 9.24 (width s, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3457; 3374 of a binder; 1651; 1596; 1540; 1455; 1313 and 747cm^-1。

Example 8: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]-phenyl } -1-methyl-1H-indole-2-carboxamide

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido ] -phenyl } -1-methyl-1H-indole-2-carboxamide was prepared according to the procedure described previously using 3- (4-nitrophenyl) -1H-indole-2-carboxamide (example 1):

1-methyl-3- (4-nitrophenyl) -1H-indole-2-carboxamide

To a solution of 0.3g of 3- (4-nitrophenyl) -1H-indole-2-carboxamide in 8ml of anhydrous dimethylformamide under argon was added 0.047g of sodium hydride and 73. mu.l of iodomethane. The reaction mixture was stirred at room temperature for 2 hours, and 45ml of water was added. The resulting solid was filtered, washed 3 times with 15ml of water, and then dehydrated. After drying in vacuo, 0.22g of 1-methyl-3- (4-nitrophenyl) -1H-indole-2-carboxamide is obtained, characterized as follows:

MS spectrum (ES +): 389[ MH ] m/z⁺]

Melting point 146-.

1-methyl-3- (4-aminophenyl) -1H-indole-2-carboxamide

To 8ml of methanol were added 0.2g of 1-methyl-3- (4-nitrophenyl) -1H-indole-2-carboxamide and 0.14g of a 10% palladium on charcoal catalyst, and the reaction mixture was hydrogenated at 25 ℃ and 5 bar for 4 hours and 30 minutes. The reaction mixture was then filtered through a thin layer of silica gel and the filtrate was concentrated under reduced pressure to give 0.91g of 1-methyl-3- (4-amino-phenyl) -1H-indole-2-carboxamide characterized as follows:

MS spectrum (ES +): m/z ═ MH⁺]

Melting point 96-98 ℃.

1H NMR spectrum (400MHz, DMSO-d6, delta (ppm)): 3.82(s, 3H); 5.11 (width s, 2H); 6.65 (width d, J ═ 8.0Hz, 2H); 7.08 (width t, J ═ 8.0Hz, 1H); 7.15 (width d, J ═ 8.0Hz, 2H); 7.21 (width m, 1H); 7.25 (width t, J ═ 8.0Hz, 1H); 7.50 (width d, J ═ 8.0Hz, 1H); 7.53 (width d, J ═ 8.0Hz, 1H); 7.61 (width m, 1H).

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -1-methyl-1H-indole-2-carboxamide

To a solution of 0.086g of 1-methyl-3- (4-aminophenyl) -1H-indole-2-carboxamide in 18ml of tetrahydrofuran was added 0.075g of 2-fluoro-5-trifluoromethylphenyl isocyanate and stirring was continued for 1 hour. 5ml of methanol were added, the reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with a mixture of cyclohexane and ethyl acetate (20/80 vol) to give 90mg of 3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] -phenyl } -1-methyl-1H-indole-2-carboxamide characterized as follows:

MS spectrum (ES +): 471[ MH ] m/z⁺]

Melting point: higher than 260 DEG C

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 3.83(s, 3H); 7.13 (width t, J ═ 8.0Hz, 1H); 7.29 (width t, J ═ 8.0Hz, 1H); 7.39(m, 1H); 7.45 (width d, J ═ 8.5Hz, 2H); 7.49-7.58(m, 5H); 7.62 (width d, J ═ 8.0Hz, 1H); 7.71 (width m, 1H); 8.65(dd, J ═ 2.5 and 7.5Hz, 1H); 8.95 (width m, 1H); 9.28 (width m, 1H).

IR spectrum (KBr): 3477; 3351; 3308 (b); 3281; 3181; 1712; 1650; 1600; 1537; 1442; 1310; 1116; 821 and 743cm^-1。

Example 9: 3- {4- [3- (3-chloro-4-trifluoromethylphenyl) -ureido]Phenyl } -1H-indole-2-carboxamides

3- {4- [3- (3-chloro-4-trifluoromethylphenyl) -ureido ] -phenyl } -1H-indole-2-carboxamide was prepared according to the procedure described previously using 3-chloro-4-trifluoromethylphenyl isocyanate. The method is characterized in that:

MS spectrum (ES +): 473[ MH ] m/z⁺]

Melting point is 168-170 DEG C

IH NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.49 (width m, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.40-7.54(m, 6H); 7.60 (width d, J ═ 8.5Hz, 2H); 7.75(d, J ═ 9.0Hz, 1H); 7.95(d, J ═ 1.5Hz, 1H); 9.08 (width m, 1H); 9.38 (width m, 1H); 11.6 (width m, 1H).

IR spectrum (KBr): 3463; 3343; 1650; 1590; 1536; 1312; 1100 and 745cm^-1。

Example 10: 3- {4- [3- (5-tert-butylisoxazol-3-yl) ureido]-phenyl } -1H-indole-2-carboxamides

3- {4- [3- (5-tert-butylisoxazol-3-yl) ureido ] -phenyl } -1H-indole-2-carboxamide was prepared according to the procedure described previously using 5-tert-butylisoxazol-3-isocyanate. The method is characterized in that:

MS spectrum (ES +): 418[ MH ] m/z⁺]

The melting point is 176-178 DEG C

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 1.31(s, 9H); 6.47 (width m, 1H); 6.52(s, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.23 (width t, J ═ 8.0Hz, 1H); 7.39-7.52(m, 5H); 7.58 (width d, J ═ 8.5Hz, 2H); 8.94 (width s, 1H); 9.52 (width s, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3461; 3275; 2968; 1695 parts of (1); 1653; 1607; 1539; 1280 and 745cm^-1。

Example 11: 3- {4- [3- (4-Trifluoromethylphenyl) ureido]-phenyl } -1H-indole-2-carboxamides

3- {4- [3- (4-trifluoromethoxyphenyl) ureido ] phenyl } -1H-indole-2-carboxamide was prepared according to the procedure described previously using 4-trifluoromethoxyphenyl isocyanate. The method is characterized in that:

MS spectrum (ES +): 455[ MH ] m/z⁺]

Melting point: 162 ℃ C. & lt 164 ℃ C. & gt

Elemental analysis: c%: 60.92; h%: 3.66; n%: 11.85 (theoretical value: C%: 60.79; H%: 3.77; N%: 12.33)

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.44 (width m, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.23 (width t, J ═ 8.0Hz, 1H); 7.30 (width d, J ═ 8.5Hz, 2H); 7.38-7.52(m, 5H); 7.58(m, 4H); 8.86 (width s, 1H); 8.94 (width s, 1H); 11.6 (width s, 1H).

Example 12: 3- {4- [3- (2-methoxy-5-trifluoromethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides

3- {4- [3- (2-methoxy-5-trifluoromethylphenyl) -ureido ] -phenyl } -1H-indole-2-carboxamide was prepared according to the procedure described previously using 2-methoxy-5-trifluoromethylphenyl isocyanate. The method is characterized in that:

MS spectrum (ES +): m/z 469[ MH + ]

Melting point: 178-

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 3.99(s, 3H); 6.46 (width m, 1H); 7.05 (width t, J ═ 8.0Hz, 1H); 7.19-7.27(m, 2H); 7.33(dd, J ═ 2.0 and 8.5Hz, 1H); 7.40-7.54(m, 5H); 7.60 (width d, J ═ 8.5Hz, 2H); 8.56 (width s, 1H); 8.59(d, J ═ 2.0Hz, 1H); 9.55 (width s, 1H); 11.6 (width m, 1H).

IR spectrum (KBr): 3463; 3342; 1655; 1593; 1540; 1447; 1269; 1134 and 746cm^-1。

Example 13: 3- [4- (2-fluoro-5-trifluoromethylbenzenesulfonylamino) phenyl]-1H-indole-2-carboxamides

To a solution of 100mg of 3- (4-aminophenyl) -1H-indole-2-carboxamide (example 1) in 12ml of pyridine, 162mg of 2-fluoro-5-trifluoromethylphenylsulfonyl chloride in 6ml of pyridine are added dropwise at 0 ℃. The mixture was stirred at room temperature for 6 hours, then poured into 50ml of ice water, and the resulting precipitate was filtered. Purification by flash chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (20/80 vol) gave 50mg of 3- [4- (2-fluoro-5-trifluoromethylbenzenesulfonyl-amino) -phenyl ] -1H-indole-2-carboxamide characterized as follows:

MS(ES+)：m/z＝478[MH⁺]

melting point: 176-

Elemental analysis: c%: 55.11; h%: 3.47; n%: 8.34 (theoretical values: C%: 55.35; H%: 3.17; N%: 8.80).

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.50 (width m, 1H); 7.02 (width t, J ═ 8.0Hz, 1H); 7.18-7.25(m, 3H); 7.31 (width d, J ═ 8.0Hz, 1H); 7.35-7.50(m, 4H); 7.72 (width t, J ═ 8.0Hz, 1H); 8.07-8.18(m, 2H); 10.9 (width s, 1H); 11.6 (width s, 1H).

Example 14: 3- [4- (2, 3-Dichlorobenzenesulfonylamino) -phenyl]-1H-indole-2-carboxamides

3- [4- (2, 3-Dichlorobenzenesulfonylamino) phenyl ] -1H-indole-2-carboxamide was prepared according to example 13 using 3, 4-dichlorophenylsulfonyl chloride. The method is characterized in that:

MS spectrum (ES +): 460[ MH ] m/z⁺]

Melting point: higher than 260 DEG C

1H NMR spectrum (300MHz, DMSO-d6, delta (ppm)): 6.54 (width m, 1H); 7.02 (width t, J ═ 8.0Hz, 1H); 7.17-7.25(m, 3H); 7.31-7.50(m, 5H); 7.58(t, J ═ 8.0Hz, 1H); 7.95(dd, J ═ 2.5 and 8.0Hz, 1H); 8.10(dd, J ═ 2.5 and 8.0Hz, 1H); 10.9 (width m, 1H); 11.6 (width s, 1H).

IR spectrum (KBr): 3476; 3422; 3389; 3358; 1670; 1651; 1583; 1540; 1404; 1343; 1166; 935; 748 and 596cm^-1。

Example 15: 3- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) ureido]Phenyl } -1H-indole-2-carboxamides

To a solution of 100mg of 3- (4-aminophenyl) -1H-indole-2-carboxamide (example 1) in 18ml of tetrahydrofuran at 0 ℃ were added 43mg of triphosgene and 110. mu.l of triethylamine. The mixture was stirred at room temperature for 1 hour, then 110mg of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine were added. The mixture was stirred for 1 hour and then concentrated under reduced pressure, and the residue was triturated with 2ml ethyl acetate to give a white solid. After filtration and drying, 150mg of 3- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) ureido ] phenyl } -1H-indole-2-carboxamide are obtained, which are characterized as follows:

MS spectrum (ES +): m/z 507[ MH + ]

Melting point: higher than 260 DEG C

1H NMR spectrum: (300MHz, DMSO-d6, delta (ppm)): 1.29(s, 9H); 2.39(s, 3H); 6.38(s, 1H); 6.41 (width m, 1H); 7.05 (width t, J ═ 7.5Hz, 1H); 7.22 (width t, J ═ 7.5Hz, 1H); 7.35 (width d, J ═ 8.5Hz, 2H); 7.37-7.48(m, 7H); 7.54 (width d, J ═ 8.5Hz, 2H); 8.37 (width s, 1H); 9.13 (width s, 1H); 11.65 (width s, 1H).

IR spectrum (KBr): 3457; 3374 of a binder; 1651; 1596; 1540; 1455; 1313; 1246; 1181 of a water-soluble polymer; 854 and 747cm^-1。

Example 16: 3- {4- [3- (2-fluoro-5-methylphenyl) ureido]-phenyl } -1H-indole-2-carboxamides

To 0.2g (0.796mmol) of 3- (4-aminophenyl) -1H-indole-2-carboxamide at 10cm under an argon atmosphere at a temperature of about 20 deg.C³Adding 0.115cm of tetrahydrofuran solution³(0.876mmol) of 2-fluoro-5-methylphenyl isocyanate. After stirring at a temperature of about 20 ℃ for 18 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7kPa) to give 400mg of a residue, which was purified by flash chromatography [ eluent: ethyl acetate/cyclohexane (7/3 vol)]. After concentration of the fractions containing the desired product under reduced pressure, 250mg of a yellow residue are obtained, which is present at 10cm³Stirring in dichloromethane, then filtration and drying under reduced pressure (2.7kPa) gave 180mg of 3- {4- [3- (2-fluoro-5-methylphenyl) ureido]Phenyl } -1H-indole-2-carboxamide, in the form of a light brown solid, which melts at 220 ℃;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 2.28 (s: 3H); 6.46 (width s: 1H); 6.81 (m: 1H); 7.06 (width t, J ═ 8 Hz: 1H); 7.11 (width t, J ═ 10 Hz: 1H); 7.23 (width t, J ═ 8 Hz: 1H); 7.36-7.53 (m: 5H); 7.59(d, J ═ 9 Hz: 2H); 8.02 (width d, J ═ 8 Hz: 1H); 8.55 (width s: 1H); 9.21 (s: 1H); 11.61 (s: 1H); MS-ES⁺：m/z＝403(+)＝(M+H)(+)；

MS-ES：m/z＝401(-)＝(M-H)(-)。

Example 17: 3- {4- [3- (5-dimethylamino-2-fluorophenyl) -ureido ] -urea]Phenyl } -1H-indole-2-carboxamides

To 0.2g (0.796mmol) of 3- (4-amino-phenyl) -1H-indole-2-carboxamide is added 18cm at a temperature of about 20 ℃ under an argon atmosphere³(2.52mmol) of 5-dimethylamino-2-fluorophenyl isocyanate in 0.14N tetrahydrofuran, followed by addition of 0.1cm³(0.796mmol) triethylamine. After stirring at a temperature of about 20 ℃ for 18 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7kPa) to give 0.7g of a brown oil, which was purified by flash chromatography [ eluent: ethyl acetate/cyclohexane (7/3 vol)]. After concentration of the fractions containing the desired product under reduced pressure, 220mg of a yellow residue are obtained, which is present at 10cm³Stirring in diethyl ether, followed by filtration and drying under reduced pressure (2.7kPa) gave 200mg of 3- {4- [3- (5-dimethylamino-2-fluorophenyl) ureido]-phenyl } -1H-indole-2-carboxamide, as a light brown solid, melting at 180 ℃ and 220 ℃;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 2.86 (s: 6H); 6.32(dt, J ═ 3 and 9 Hz: 1H); 6.43 (very Wide s: 1H); 7.00-7.08 (m: 2H); 7.23(t, J ═ 7 Hz: 1H); 7.38-7.54 (m: 5H); 7.59(d, J ═ 9 Hz: 2H); 7.68(dd, J ═ 3 and 7 Hz: 1H); 8.45 (width s: 1H); 9.19 (s: 1H); 11.6 (s: 1H).

MS-ES⁺：m/z＝432(+)＝(M+H)(+)。

A solution of 5-dimethylamino-2-fluorophenyl isocyanate in 0.14N tetrahydrofuran may be prepared as follows:

at a temperature of about 5 ℃ under an argon atmosphere, 2.82g (9.5mmol) of triphosgene are introduced at 150cm³To the solution in methylene chloride, 1.09g (7.1mmol) of 4-fluoro-N1, N1-dimethylbenzene-1, 3-diamine was added, followed by 4.6cm³Pyridine. After stirring at a temperature of about 20 ℃ for 18 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7kPa) to give a residue of 40cm³Grinding in tetrahydrofuran. After filtration, a solution of 5-dimethylamino-2-fluorophenyl isocyanate in about 0.14N tetrahydrofuran is obtained and used directly in the subsequent step.

4-fluoro-N1, N1-dimethylbenzene-1, 3-diamine can be prepared in the following manner:

to 0.6g (5.63mmol) of a 10% palladium on charcoal catalyst at 100cm at a temperature of about 20 deg.C³To the suspension in methanol was added 3.23g (17.54mmol) of (4-fluoro-3-nitrophenyl) -dimethylamine. After hydrogenation in an autoclave at a temperature of about 25 ℃ under 5 bar of hydrogen for 30 minutes, the reaction mixture is filtered and the catalyst is rinsed 3 times with 10cm each of methanol³Then the filtrate was concentrated to dryness under reduced pressure (2.7kPa) to give 2.7g of 4-fluoro-N1, N1-dimethylbenzene-1, 3-diamine as a brown oil;

MS-EI：m/z＝1 54(+)＝(M)(+)。

(4-fluoro-3-nitrophenyl) dimethylamine may be prepared in the following manner:

5g (32mmol) of 4-fluoro-3-nitroaniline are added at 50cm under an argon atmosphere at a temperature of about 20 DEG³To a solution in dimethylformamide was added 13.27g (96mmol) of potassium carbonate, followed by 4.6cm at a temperature of about 5 deg.C³(73.6mmol) methyl iodide. After stirring at a temperature of about 20 ℃ for 63 hours, the reaction mixture was poured into 100cm³Extracting with dichloromethane in water for 3 times (each time 100 cm)³. The organic phases were combined and washed 3 times with 100cm of water each time³Dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7kPa) to give 5.5g of residue which was purified by flash chromatography [ eluent: ethyl acetate/cyclohexane (2/8 vol)]. After concentrating the fraction containing the desired product under reduced pressure, 2.78g of (4-fluoro-3-nitrophenyl) dimethylamine were obtained as an orange-red solid;

MS-ES⁺：m/z＝185(+)＝(M+H)(+)。

example 18: 3- {4- [3- (3-dimethylaminophenyl) ureido]Phenyl } -1H-indole-2-carboxamides

To 0.1g (0.4mmol) of 3- (4-aminophenyl) -1H-indole-2-carboxamide is added 8.5cm at a temperature of about 20 ℃ under an argon atmosphere³(0.8mmol) of 3-dimethylamino-phenyl isocyanate in 0.14N tetrahydrofuran, followed by addition of 0.055cm³(0.4mmol) triethylamine. After stirring at about 20 ℃ for 18 hours, 0.1cm was added³Water, the reaction mixture was then concentrated to dryness under reduced pressure (2.7kPa) to give 0.7g of residue which was purified by flash chromatography [ eluent: methylene chloride/methanol (95/5 (vol))]. After concentration of the fraction containing the desired product under reduced pressure, 81mg of 3- {4- [3- (3-dimethylaminophenyl) ureido are obtained]Phenyl } -1H-indole-2-carboxamide, as a white solid, which melts at 160-220 ℃;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 2.89 (s: 6H); 6.38(d, J ═ 9 Hz: 1H); 6.42 (width s: 1H); 6.74(d, J ═ 9 Hz: 1H); 6.94 (width s: 1H); 7.00-7.12 (m: 2H); 7.23(t, J ═ 7 Hz: 1H); 7.40(d, J ═ 8 Hz: 2H); 7.43 (partially masked d, J ═ 8 Hz: 1H); 7.46(d, J ═ 8 Hz: 1H); 7.49 (width s: 1H); 7.58(d, J ═ 8 Hz: 2H); 8.56 (s: 1H); 8.72 (s: 1H); 11.60 (s: 1H); MS-ES⁺：m/z＝414(+)＝(M+H)(+)。

A solution of 3-dimethylaminophenyl isocyanate in 0.14N tetrahydrofuran may be prepared as follows:

at a temperature of about 5 ℃ under an argon atmosphere, 2.82g (9.5mmol) of triphosgene are introduced at 150cm³To the solution in methylene chloride, 1.46g (7mmol) of N1, N1-dimethylbenzene-1, 3-diamine dihydrochloride was added, followed by 9.9cm³(71.64mmol) Triethylamine. After stirring at a temperature of about 20 ℃ for 20 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7kPa) to give a residue of 50cm³Grinding in tetrahydrofuran. After filtration, a solution of 3-dimethylaminophenyl isocyanate in about 0.14N tetrahydrofuran was obtained and used directly in the subsequent step.

Example 19: 3- {4- [3- (2-pyrrolidin-1-ylmethyl-5-trifluoromethylphenyl) ureido]Phenyl radical} -1H-indole-2-carboxamides

To 0.05g (0.2mmol) of 4- (4-aminophenyl) -1H-pyrrole-3-carboxamide at 10cm under an argon atmosphere at a temperature of about 20 deg.C³To the solution in tetrahydrofuran, 19.7mg (0.066mmol) of triphosgene was added, followed by 0.056cm³(0.4mmol) triethylamine. After stirring for one hour at a temperature of about 20 ℃ 48.61mg (0.2mmol) of 2-pyrrolidin-1-ylmethyl-5-trifluoromethylaniline were added at 2cm³Solution in tetrahydrofuran. After stirring at a temperature of about 20 ℃ for 3 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7kPa) and 0.15g of the residue obtained is purified by flash chromatography [ eluent: methylene chloride/methanol (95/5 (vol))]. After concentration of the fractions containing the desired product under reduced pressure, 45mg of 3- {4- [3- (2-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) ureido are obtained]Phenyl } -1H-indole-2-carboxamide, in the form of a light brown solid, which melts at 190 ℃ and 250 ℃;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 1.74 (m: 4H); 2.50 (partially hidden m: 4H); 3.73 (s: 2H); 6.52 (width s: 1H); 7.05(t, J ═ 7 Hz: 1H); 7.23(t, J ═ 7 Hz: 1H); 7.31(d, J ═ 8 Hz: 1H); 7.40-7.52 (m: 6H); 7.63(d, J ═ 8 Hz: 2H); 8.37 (s: 1H); 9.63 (s: 1H); 9.86 (s: 1H); 11.68 (width s: 1H).

MS-ES⁺：m/z＝521(+)＝(M+H)(+)。

2-pyrrolidin-1-ylmethyl-5-trifluoromethylaniline may be prepared in the following manner:

to 0.05g (0.47mmol) of 10% palladium on charcoal catalyst at 25cm at a temperature of about 25 deg.C³To the suspension in methanol was added 0.44g (1.604mmol) of 1- (2-nitro-4-trifluoromethyl-benzyl) pyrrolidine. After hydrogenation in an autoclave at a temperature of about 25 ℃ under 5 bar of hydrogen for 3 hours, the reaction mixture is filtered and the catalyst is rinsed 3 times with 5cm of methanol each time³The filtrate was then concentrated to dryness under reduced pressure (2.7kPa) to give 0.4g of 2-pyrrolidin-1-ylmethyl-5-trifluoromethylaniline as an orange oil;

MS-ES⁺：m/z＝245(+)＝(M+H)(+)。

1- (2-nitro-4-trifluoromethylbenzyl) pyrrolidine can be prepared in the following manner:

to 0.5g (2.087mmol) of 1-chloromethyl-2-nitro-4-trifluoromethylbenzene at 20cm under an argon atmosphere at a temperature of about 20 deg.C³Adding 0.35cm of water into the solution in dichloromethane³(4.174mmol) pyrrolidine. After stirring at a temperature of about 20 ℃ for 16 hours, the reaction mixture was used for 250cm³Diluting with dichloromethane, rinsing with water for 3 times (200 cm each time)³Dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7kPa) to give 458mg of 1- (2-nitro-4-trifluoromethylbenzyl) -pyrrolidine as an oil;

MS-EI：m/z＝274(+)＝(M)(+)；257(+)＝(M-OH)(+)；226(+)＝(M-H₂NO₂)(+)；70(+)＝(C₄H₈N)(+)。

example 20: 3- {4- [3- (2-methoxymethyl-5-trifluoromethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides

To a solution of 134.7mg (0.536mmol) of 4- (4-amino-phenyl) -1H-pyrrole-3-carboxamide at 20cm under argon at a temperature of about 20 deg.C³To a solution in tetrahydrofuran, 52.5mg (0.177mmol) of triphosgene was added, followed by 0.15cm³(1.072mmol) triethylamine. After stirring at a temperature of about 20 ℃ for 1 hour, 110mg (0.536mmol) of 2-methoxymethyl-5-trifluoromethylaniline were added thereto at 2cm³Solution in tetrahydrofuran. After stirring at about 20 ℃ for 3 hours, 0.1cm was added³Water, the reaction mixture is then concentrated to dryness under reduced pressure (2.7kPa) to give 0.4g of a yellow solid which is purified by flash chromatographyPurification was performed [ eluent: ethyl acetate/cyclohexane (7/3 vol)]. After concentrating the fractions containing the desired product under reduced pressure, 20mg of 3- {4- [3- (2-methoxymethyl-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamide, in the form of a light brown solid, which melts at 220 ℃ at 170-;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 3.38 (partially masked s: 3H); 4.58 (s: 2H); 6.46 (width s: 1H); 7.05(t, J ═ 7 Hz: 1H); 7.23(t, J ═ 7 Hz: 1H); 7.32-7.51 (m: 6H); 7.56(d, J ═ 7 Hz: 1H); 7.64(d, J ═ 9 Hz: 2H); 8.32 (width s: 1H); 8.77 (very Wide s: 1H); 9.96 (very wide s: 1H); 11.63 (very Wide s: 1H).

MS-ES⁺：m/z＝482(+)＝(M+H)(+)。

2-methoxymethyl-5-trifluoromethylaniline can be prepared in the following manner:

to 0.02g (0.188mmol) of a 10% palladium on charcoal catalyst at 20cm at a temperature of about 25 deg.C³To the suspension in methanol was added 0.15g (0.638mmol) of 1-methoxymethyl-2-nitro-4-trifluorotoluene. After hydrogenation in an autoclave at a temperature of about 25 ℃ under 1 bar of hydrogen for 3 hours, the reaction mixture is filtered and the catalyst is rinsed 3 times with 5cm each of methanol³Then the filtrate was concentrated to dryness under reduced pressure (2.7kPa) to give 0.12g of 2-methoxymethyl-5-trifluoromethylaniline as a yellow oil;

MS-ES⁺：m/z＝206(+)＝(M+H)(+)；174(+)＝(M-CH₃O)(+)。

1-methoxymethyl-2-nitro-4-trifluoromethylbenzene can be prepared in the following manner:

to 0.222g (1mmol) of (2-nitro-4-trifluoromethylphenyl) methanol in 10cm under an argon atmosphere at a temperature of about 20 deg.C³Adding 0.65cm of water into the solution in dichloromethane³(10mmol) of methyl iodide followed by 1.163g (5mmol) of silver oxide and 0.07cm³And (3) water. After stirring in the dark at a temperature of about 20 ℃ for 18 hours, the reaction mixture is stirred with Celite^®Filtration is carried out. Celite^®By 10cm³Rinsing with dichloromethane. The filtrate was then concentrated to dryness under reduced pressure (2.7 kPa). The residue was dissolved in 10cm³Adding 0.65cm of dichloromethane at about 20 deg.C under argon atmosphere³(10mmol) of methyl iodide followed by 1.163g (5mmol) of silver oxide and 0.07cm³And (3) water. After stirring in the dark at a temperature of about 20 ℃ for 60 hours, the reaction mixture is stirred with Celite^®Filtration is carried out. Celite^®By 10cm³Rinsing with dichloromethane. The filtrate was then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography [ eluent: methylene dichloride]. After concentration of the fraction containing the desired product under reduced pressure, 157mg of 1-methoxymethyl-2-nitro-4-trifluoro-methylbenzene were obtained as an oil;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 3.40 (s: 3H); 4.83 (s: 2H); 7.96(d, J ═ 8 Hz: 1H); 8.16(dd, J ═ 8 and 1.5 Hz: 1H); 8.49(d, J ═ 1.5 Hz: 1H).

(2-nitro-4-trifluoromethylphenyl) methanol can be prepared in the following manner:

at a temperature of about 20 ℃ to 0.5g (1.9mmol) of 2-nitro-4-trifluoromethyl-benzyl-acetate at 50cm³Adding 1.9cm of methanol solution³(1.9mmol) of a 1M aqueous solution of sodium hydroxide. After stirring at about 20 ℃ for 2 hours, 20cm of water was added³Saturated aqueous solution of sodium phosphate, and extracting the mixture with dichloromethane for 3 times (50 cm each time)³. The organic phases were combined and used for 50cm³Washing with saturated aqueous solution of sodium chloride, drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure (2.7kPa) to dryness to give 0.424g of (2-nitro-4-trifluoromethylphenyl) methanol as an oil;

MS-ES^-：m/z＝220(-)＝(M-H)(-)。

2-nitro-4-trifluoromethylbenzyl acetate may be prepared in the following manner:

at a temperature of about 20 ℃ under an argon atmosphere, 20g (244mmol) of sodium acetate are added to a reaction vessel of 100cm³To the solution in acetic acid was added 2g (8.348mmol) of 1-chloromethyl-2-nitro-4-trifluoro-methylbenzene. After stirring at a temperature of about 100 ℃ for 60 hours, the reaction mixture was used for 200cm³Diluting with water, and extracting with dichloromethane for 2 times (300 cm each time)³. The organic phases were combined over 100cm³Washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7kPa) to give 2.15g of 2-nitro-4-trifluoromethylbenzyl acetate as an orange oil;

MS-CI：m/z＝281(+)＝(M+NH₄)(+)。

example 21: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -4-oxo-1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

To 0.1g (0.218mmol) of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido at a temperature of about 0 ℃ under an argon atmosphere]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamide at 4cm³To a solution of 109.5mg (0.444mmol) of 3-chloroperoxybenzoic acid in 6cm in chloroform was added³Solution in dichloromethane. After stirring at a temperature of about 0 ℃ for 1 hour and at a temperature of about 20 ℃ for 24 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7kPa) to give 87mg of a residue which was purified by flash chromatography [ eluent: dichloromethane/methanol/acetonitrile (90/5/5 (vol))]. After concentration of the fractions containing the desired product under reduced pressure, 65mg of a yellow solid were obtained, which was present at 4cm³Grinding in cyclohexane. After filtration at a temperature of about 30 ℃ and drying under reduced pressure (2.7kPa), 57mg of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido are obtained]Phenyl } -4-oxo-1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamide, in the form of a white solid, which melts at 283 ℃;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 6.12 (width s: 1H); 7.17(dd, J ═ 9 and 6 Hz: 1H); 7.35-7.55 (m: 3H); 7.37(d, J ═ 9 Hz: 1H); 7.43(d, J ═ 9 Hz: 1H); 7.49(d, J ═ 9 Hz: 2H); 7.69 (width s: 1H); 7.96(d, J ═ 6 Hz: 1H); 8.64 (width d, J ═ 6 Hz: 1H); 9.03 (s: 1H); 9.38 (s: 1H); 12.37 (width s: 1H);

MS-ES⁺：m/z＝474(+)＝(M+H)(+)

example 22: 3- {4- [3- (2-methoxy-5-trifluoromethylphenyl) -ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

To 0.2g (0.793mmol) of 3- (4-aminophenyl) -1H-pyrrolo [3, 2-b ] at a temperature of about 20 ℃ under an argon atmosphere]Pyridine-2-carboxamide at 18cm³To a solution in tetrahydrofuran, 82.4mg (0.278mmol) of triphosgene was added, followed by 0.223cm³Triethylamine. After stirring at a temperature of about 20 ℃ for 1 hour, 182mg (0.952mmol) of 2-methoxy-5-trifluoromethylaniline are added at 17cm³Solution in tetrahydrofuran. After stirring at a temperature of about 20 ℃ for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7kPa), and the resulting residue was purified by flash chromatography [ eluent: dichloromethane/methanol/acetonitrile](90/5/5 (vol))]. After concentration of the fraction containing the desired product under reduced pressure, 109mg of 3- {4- [3- (2-methoxy-5-trifluoromethylphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamide, in the form of a yellow solid, which melts at 194 ℃;

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 3.99 (s: 3H); 6.97 (width s: 1H); 7.18-7.27 (m: 2H); 7.33(dd, J ═ 9 and 1 Hz: 1H); 7.56(d, J ═ 9 Hz: 2H); 7.63(d, J ═ 9 Hz: 2H); 7.66 (very Wide s: 1H); 7.81(dd, J ═ 8 and 1.5 Hz: 1H); 8.40(dd, J ═ 4.5 and 1.5 Hz: 1H); 8.58 (m: 2H); 9.56 (s: 1H); 11.88 (very wide s: 1H).

MS-ES⁺：m/z＝470(+)＝(M+H)(+)。

3- (4-aminophenyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide was prepared according to the procedure described in example 2.

Example 23: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -6- (2-methoxyethoxy) -1H-indole-2-carboxamide

To a solution of 79mg (0.24mmol)3- (4-amino-phenyl) -6- (2-methoxyethoxy) -1H-indole-2-carboxamide in 6ml tetrahydrofuran at room temperature under argon was added 40. mu.l (0.28mmol) 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring at room temperature under argon for 22h, the reaction mixture was concentrated to dryness under reduced pressure. The residue obtained is dissolved in ethyl acetate, washed with water and the organic phase is then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.

The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (96/4 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 78mg of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -6- (2-methoxyethoxy) -1H-indole-2-carboxamide are obtained as a white solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 3.32 (partially masked s, 3H); 3.69(m, 2H); 4.09(m, 2H); 6.31 (width m, 1H); 6.72(dd, J ═ 2.5 and 9.0Hz, 1H); 6.91(d, J ═ 2.5Hz, 1H); 7.28(d, J ═ 9.0Hz, 1H); 7.32-7.45 (width m, 1H); 7.39(m, 1H); 7.42 (width d, J ═ 8.5Hz, 2H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.59 (width d, J ═ 8.5Hz, 2H); 8.64(dd, J ═ 2.0 and 7.5Hz, 1H); 8.98 (width s, 1H); 9.34 (width s, 1H); 11.4(s, 1H).

ES：m/z＝531(MH⁺)，m/z＝514(MH⁺-NH₃) The basal peak.

3- (4-aminophenyl) -6- (2-methoxyethoxy) -1H-indole-2-carboxamide may be prepared in the following manner:

to 80mg (0.24mmol) of methyl 3- (4-aminophenyl) -6- (2-methoxyethoxy) -1H-indole-2-carboxylate are added 8ml of a 7N methanolic ammonia solution and 4ml of 28% aqueous ammonia, and the reaction medium is then heated 16 ℃ in a sealed, closed glass tube. 2ml of 28% aqueous ammonia are added and the reaction is heated at 100 ℃ for 24 h. The reaction medium is evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (98/2, then 95/5 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 40mg of 3- (4-aminophenyl) -6- (2-methoxyethoxy) -1H-indole-2-carboxamide are obtained as a brown oil.

EI：m/z＝325(M⁺) Basic peak, M/z 308 (M-NH)₃)⁺，m/z＝249(m/z＝308-C₃H₇O)⁺，m/z＝221(m/z＝249-CO)⁺，m/z＝59(C₃H₇O⁺)。

Methyl 3- (4-aminophenyl) -6- (2-methoxyethoxy) -1H-indole-2-carboxylate can be prepared in the following manner:

to 396mg (2.29mmol) of (4-aminophenyl) boronic acid hydrochloride in a methanol/toluene (30ml/25ml) mixture are added 0.321ml (2.29mmol) triethylamine at room temperature. The mixture is stirred at room temperature for 15 minutes, then 300mg (0.91mmol) of 3-bromo-6- (2-methoxy-ethoxy) -1H-indole-2-carboxylic acid methyl ester are added at room temperature, followed by a solution of 242mg (2.28mmol) of sodium carbonate in 5ml of water. 108mg (2.55mmol) of lithium chloride are added at room temperature under argon, followed by 74mg (0.06mmol) of tetrakis (triphenylphosphine) palladium. The reaction was heated to reflux under argon for 4h30min, then at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue obtained is dissolved in ethyl acetate and washed with water, and the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (99/1 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 219mg of methyl 3- (4-aminophenyl) -6- (2-methoxyethoxy) -1H-indole-2-carboxylate were obtained as a yellow solid.

EI：m/z＝340(M⁺) Fundamental peak，m/z＝308(M-CH₃OH)⁺，m/z＝281(M-C₂H₃O₂)⁺，m/z＝221(m/z＝281-C₃H₈O)⁺，m/z＝59(C₃H₇O⁺)。

Methyl 3-bromo-6- (2-methoxyethoxy) -1H-indole-2-carboxylate can be prepared as follows:

a solution of 104mg (0.42mmol) of methyl 6- (2-methoxyethoxy) -1H-indole-2-carboxylate in 3ml of dimethylformamide is cooled to-40 ℃ in an acetone/solid carbon dioxide bath, and a solution of 74mg (0.41mmol) of N-bromosuccinimide in 1ml of dimethylformamide is then added at-40 ℃. The solution was stirred at-45- -30 ℃ for 30 minutes, then a solution of 30mg (0.17mmol) of N-bromosuccinimide in 1ml of dimethylformamide was added at-40 ℃. The solution was stirred at-45- -30 ℃ for 1 h.

The solution was diluted with ethyl acetate, the temperature was returned to room temperature, and then the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: ethyl acetate/cyclohexane (1/2 (vol)) ]. After concentration of the desired product-containing fraction under reduced pressure, 92mg of methyl 3-bromo-6- (2-methoxyethoxy) -1H-indole-2-carboxylate were obtained as a white solid.

EI：m/z＝327(M⁺)，m/z＝269(M-C₂H₂O₂)⁺，m/z＝237(m/z＝269-CH₃OH)⁺，m/z＝59(C₃H₇O⁺)，m/z＝45(C₂H₅O⁺) The basal peak.

Methyl 6- (2-methoxyethoxy) -1H-indole-2-carboxylate can be prepared in the following manner:

to a suspension of 2g (10.46mmol) of methyl 6-hydroxy-1H-indole-2-carboxylate, 8.68g (52.30mmol) of potassium iodide and 7.23g (52.30mmol) of potassium carbonate in 150ml of acetone at room temperature are added 4.915ml (52.30mmol) of 2-bromoethyl methyl ether. The reaction medium is heated to reflux for 22 h. The reaction medium is brought to room temperature and ethyl acetate is then added. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: acetone/cyclohexane (1/6 (vol)) ]. After concentration of the desired product-containing fraction under reduced pressure, 630mg of methyl 6- (2-methoxyethoxy) -1H-indole-2-carboxylate were obtained as a yellow solid.

EI：m/z＝249(M⁺) Basic peak, M/z 191 (M-C)₂H₂O₂)⁺，m/z＝159(m/z＝191-CH₃OH)⁺。

Methyl 6-hydroxy-1H-indole-2-carboxylate can be prepared in the following manner:

to a solution of 5.98g (33.75mmol) of 6-hydroxy-1H-indole-2-carboxylic acid in 350ml of methanol was added 0.144ml (2.70mmol) of concentrated sulfuric acid at room temperature. The mixture was heated to reflux for 9 days, then the reaction mixture was concentrated to dryness under reduced pressure. The residue obtained is dissolved in water, basified to pH9 with 38% potassium hydroxide solution and the product is then extracted 6 times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give 5.81g of methyl 6-hydroxy-1H-indole-2-carboxylate as a brown solid.

EI：m/z＝191(M⁺) Basic peak, M/z 159 (M-CH)₃OH)⁺，m/z＝131(m/z＝159-CO)⁺。

6-hydroxy-1H-indole-2-carboxylic acid can be prepared in the following manner:

to a solution of 10g (48.73mmol) of methyl 6-methoxy-2-indolecarboxylate in 500ml of dichloromethane at 0 ℃ was slowly added 146ml (146mmol) of a solution of 1M boron tribromide in dichloromethane. The reaction medium is stirred at 0 ℃ for 1h and then at room temperature for 2 h. The reaction medium is cooled to 0 ℃ and 100ml (100mmol) of a 1M solution of boron tribromide in dichloromethane are added slowly at 0 ℃. The reaction was stirred at 0 ℃ for 1h and then at room temperature for 16 h. The reaction medium is then cooled to about 0 ℃ and a 1N hydrochloric acid solution (247ml) is slowly added with stirring. The resulting mixture was filtered through a sintered glass filter. The organic phase of the filtrate (dichloromethane) was separated, then the aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate. The organic phase (ethyl acetate) was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 6.39g of 6-hydroxy-1H-indole-2-carboxylic acid as a brown solid.

ES：m/z＝176(M-H)^-Fundamental peak

Example 24: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide

To a solution of 45mg (0.12mmol) of 3- (4-amino-phenyl) -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide in 6ml of tetrahydrofuran at room temperature under argon was added 17. mu.l (0.12mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring under argon at room temperature for 22h, the reaction mixture was dissolved in ethyl acetate and washed with water, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (70/30 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 32mg of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide are obtained as a brown solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 1.69(m, 4H); 2.54(m, 4H); 2.81(t, J ═ 6.0Hz, 2H); 4.08(t, J ═ 6.0Hz, 2H); 6.30 (width m, 1H); 6.72(dd, J ═ 2.5 and 9.0Hz, 1H); 6.91(d, J ═ 2.5Hz, 1H); 7.27(d, J ═ 9.0Hz, 1H); 7.32-7.48 (width m, 1H); 7.39(m, 1H); 7.42 (width d, J ═ 8.5Hz, 2H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.60 (width d, J ═ 8.5Hz, 2H); 8.65(dd, J ═ 2.5 and 7.5Hz, 1H); 8.99(d, J ═ 2.5Hz, 1H); 9.36(s, 1H); 11.4(s, 1H).

ES：m/z＝570(MH⁺) Fundamental peak

3- (4-aminophenyl) -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide may be prepared in the following manner:

to 133mg (0.35mmol) of methyl 3- (4-aminophenyl) -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate are added 8ml of a 7N methanolic ammonia solution and 4ml of 28% aqueous ammonia and the reaction medium is heated at 100 ℃ for 16H in a sealed glass tube. Then 2ml of 28% aqueous ammonia are added and the reaction medium is heated at 100 ℃ for 24 h. The reaction medium is evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: ethyl acetate/methanol (70/30 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 25mg of 3- (4-amino-phenyl) -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide are obtained as a pale yellow solid.

ES：m/z＝365(MH⁺) Fundamental peak

Methyl 3- (4-aminophenyl) -6- (2-pyrrolidin-1-yl-ethoxy) -1H-indole-2-carboxylate may be prepared in the following manner:

to a solution of 275mg (1.59mmol) of (4-aminophenyl) boronic acid hydrochloride in a methanol/toluene mixture (30ml/25ml) was added 0.223ml (1.59mmol) of triethylamine at room temperature. The mixture is stirred at room temperature for 15 minutes, then 222mg (0.60mmol) of methyl 3-bromo-6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate are added at room temperature, followed by a solution of 168mg (1.58mmol) of sodium carbonate in 5ml of water. 75mg (1.77mmol) of lithium chloride are added at room temperature under argon, followed by 51mg (0.04mmol) of tetrakis (triphenylphosphine) palladium. The reaction medium is heated to reflux under argon for 5h and then at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue obtained is dissolved in ethyl acetate, washed with water and the organic phase is then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (98/2 (vol)) ]. After concentration of the desired product-containing fraction under reduced pressure, 252mg of methyl 3- (4-aminophenyl) -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate were obtained as an orange solid.

EI：m/z＝379(M⁺)，m/z＝84(C₅H₁₀N⁺) Fundamental peak

Methyl 3-bromo-6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate may be prepared in the following manner:

a solution of 495mg (1.72mmol) of methyl 6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate in 11ml of dimethylformamide is cooled to-40 ℃ in an acetone/solid carbon dioxide bath, and a solution of 306mg (1.72mmol) of N-bromosuccinimide in 6ml of dimethylformamide is then added dropwise at-40 ℃. The solution was stirred at 40 ℃ and then slowly returned to room temperature over 5 h. The obtained residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (90/10 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 263mg of 3-bromo-6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate are obtained as a gray solid.

ES：m/z＝367(MH⁺) Fundamental peak

Methyl 6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate may be prepared in the following manner:

to 800mg (4.18mmol) of methyl 6-hydroxy-1H-indole-2-carboxylate in 60ml of tetrahydrofuran are added 2.20g (8.37mmol) of triphenylphosphine under a stream of argon at room temperature. Then 0.979ml (8.37mmol) of 1- (2-hydroxyethyl) pyrrolidine are added to the reaction medium at room temperature. The reaction was then cooled to about 5 ℃ in a water/ice bath and a solution of 1.46g (8.37mmol) of diethyl azedicarboxylate in 5ml of tetrahydrofuran was then added dropwise to the reaction medium, the temperature being kept between 5 and 10 ℃ during the addition. The reaction was then stirred at 5 ℃ for 15 minutes and at room temperature for 40 h. To the reaction medium was added ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (90/10 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 880mg of methyl 6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxylate are obtained as a brown solid.

EI：m/z＝288(M⁺)，m/z＝84(C₅H₁₀N⁺) The basal peak.

Methyl 6-hydroxy-1H-indole-2-carboxylate was prepared according to the procedure described for example 23.

Example 25: 3- {6- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]-pyridin-3-yl } -6-methoxy-1H-indole-2-carboxamide

A suspension of 100mg (0.37mmol) of 3-bromo-6-methoxy-1H-indole-2-carboxamide and 43mg (0.04mmol) of tetrakis (triphenylphosphine) palladium (0) in 5ml of dioxane is stirred at room temperature for 10 minutes. Then, 190mg (0.45mmol) of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea and 6ml of dioxane were added at room temperature, followed by a solution of 86mg (1.48mmol) of potassium fluoride in 1ml of water. The mixture was heated to reflux for 16h45 min. The reaction medium is evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (99/1, then 98/2, then 97/3, finally 94/4 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 60mg of 3- {6- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] pyridin-3-yl } -6-methoxy-1H-indole-2-carboxamide are obtained as a yellow solid.

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 3.81(s, 3H); 6.75(dd, J ═ 2.0 and 8.5Hz, 1H); 6.93(d, J ═ 2.0Hz, 1H); 7.00 (width m, 1H); 7.35(d, J ═ 8.5Hz, 1H); 7.39-7.59(m, 4H); 7.89(dd, J ═ 2.0 and 8.5Hz, 1H); 8.35(d, J ═ 2.0Hz, 1H); 8.70 (width d, J ═ 7.5Hz, 1H); 10.05 (width s, 1H); 11.3 (very wide m, 1H); 11.5 (width s, 1H).

ES：m/z＝488(MH⁺) The basal peak.

3-bromo-6-methoxy-1H-indole-2-carboxamide may be prepared in the following manner:

a solution of 540mg (2.84mmol) 6-methoxy-1H-indole-2-carboxamide in 8ml pyridine is cooled to 0 ℃ and then a solution of 908mg (2.84mmol) tribromopyridine in 6ml pyridine is added dropwise thereto. The reaction medium is stirred at 0 ℃ for 30 minutes and at room temperature for 19 hours. To the reaction medium was added 20ml of ice-water. It was then stirred at room temperature for 1H and filtered through sintered glass to give 538mg of 3-bromo-6-methoxy-1H-indole-2-carboxamide as a white solid.

ES：m/z＝269(MH⁺) The basal peak.

6-methoxy-1H-indole-2-carboxamide may be prepared in the following manner:

a suspension of 4g (19.49mmol) methyl 6-methoxy-2-indolecarboxylate in 60ml 28% ammonia water was heated in an autoclave at 50 ℃ for 14 h. After the mixture was filtered through a sintered glass filter, the resulting white solid was washed with water, dried and then added to a hot mixture of ethyl acetate/cyclohexane (100ml/10 ml). The medium is cooled in a water/ice bath and filtered through a sintered glass filter to give 1.05g of 6-methoxy-1H-indole-2-carboxamide as a white solid.

EI：m/z＝190(M⁺) Basic peak, M/z 173 (M-NH)₃)⁺，m/z＝145(M-CH₃NO)⁺

1- (2-fluoro-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea can be prepared in the following manner:

a suspension of 505mg (1.80mmol) of tricyclohexylphosphine and 276mg (0.48mmol) of palladium bis (dibenzylideneacetone) in 20ml of dioxane is stirred at room temperature under argon for 10 minutes. To this reaction medium was added 4.54g (12.01mmol) of 1- (5-bromopyridin-2-yl) -3- (2-fluoro-5-trifluoromethylphenyl) urea followed by 80ml of dioxane, 4.12g (16.20mmol) of bis (pinacol) diborane and 1.77g (18.04mmol) of potassium acetate. The reaction medium is heated to reflux under argon for 16h, and then 300ml of water are added at room temperature. The mixture was stirred at room temperature for 10 minutes, filtered through a sintered glass filter and the solid was washed with a small amount of water. The resulting solid was dissolved in 350ml of boiling ethyl acetate, filtered under heating, and the filtrate was evaporated to dryness under reduced pressure. This gave 3.05g of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea as a pale yellow solid.

ES：m/z＝426(MH⁺) The basal peak.

1- (5-bromopyridin-2-yl) -3- (2-fluoro-5-trifluoromethyl-phenyl) urea can be prepared in the following manner:

to a solution of 4.06g (23.47mmol) of 2-amino-5-bromopyridine in 200ml of anhydrous tetrahydrofuran at 0 ℃ was added 3.27ml (23.44mmol) of triethylamine. Then 3.39ml (23.44mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate were added dropwise at 0 ℃. The reaction medium is stirred at room temperature for 64 h. To the reaction medium was added 400ml of ethyl acetate. The organic phase is then washed with water, then with a saturated aqueous solution of sodium chloride and finally filtered through a sintered glass filter. 4.55g of 1- (5-bromopyridin-2-yl) -3- (2-fluoro-5-trifluoromethylphenyl) urea are obtained as a white solid.

EI：m/z＝377(M⁺)，m/z＝179(C₇H₅NF₄ ⁺)，m/z＝172(C₅H₅N₂Br⁺) The basal peak.

Example 26: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -6-methoxy-1H-indole-2-carboxamide

A suspension of 2.54g (9.44mmol) 3-bromo-6-methoxy-1H-indole-2-carboxamide and 1.09g (0.94mmol) tetrakis (triphenylphosphine) palladium (0) in 125ml dioxane was stirred at room temperature for 10 min. 4.81g (11.33mmol) of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] urea and 150ml of dioxane are then added at room temperature, followed by a solution of 2.19g (37.77mmol) of potassium fluoride in 25ml of water. The mixture was heated to reflux for 18 h. The reaction medium is evaporated to dryness under reduced pressure. The residue obtained is dissolved in ethyl acetate and washed with water, and the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (98/2 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 1.73g of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -6-methoxy-1H-indole-2-carboxamide are obtained as a brown solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 3.78(s, 3H); 6.30 (width m, 1H); 6.71(dd, J ═ 2.5 and 9.0Hz, 1H); 6.91(d, J ═ 2.5Hz, 1H); 7.28(d, J ═ 9.0Hz, 1H); 7.32-7.45 (width m, 1H); 7.39(m, 1H); 7.42 (width d, J ═ 8.5Hz, 2H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.60 (width d, J ═ 8.5Hz, 2H); 8.64(dd, J ═ 2.0 and 7.5Hz, 1H); 8.99 (width s, 1H); 9.37 (width s, 1H); 11.4 (width s, 1H).

ES：m/z＝487(MH⁺)，m/z＝470(MH⁺-NH₃) The basal peak.

1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] urea may be prepared according to the procedure described in US 2005043347A 1.

3-bromo-6-methoxy-1H-indole-2-carboxamide was prepared according to the procedure described for example 25.

Example 27: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -6-hydroxy-1H-indole-2-carboxamide

A suspension of 1.11g (2.28mmol)3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] phenyl } -6-methoxy-1H-indole-2-carboxamide in 100ml dichloromethane was cooled to-5 ℃ in an acetone/solid carbon dioxide bath and 12.34ml (12.34mmol) of a 1M solution of boron tribromide in dichloromethane were added dropwise at-5 ℃. The reaction medium is stirred at about 0 ℃ for 2h and then at room temperature for 26 h. The reaction medium is cooled to about 0 ℃ in a water/ice bath, 30ml of 1N hydrochloric acid are added dropwise, followed by 50ml of dichloromethane and 30ml of water. The mixture was stirred at about 0 ℃ for 15 minutes and then at room temperature for 30 minutes. The reaction medium is filtered again through a sintered glass filter to give a brown solid. The latter was purified by flash chromatography [ eluent: dichloromethane/methanol (95/5 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 840mg of 3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] phenyl } -6-hydroxy-1H-indole-2-carboxamide are obtained as a brown solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 6.21 (width m, 1H); 6.58(dd, J ═ 2.0 and 8.5Hz, 1H); 6.80(d, J ═ 2.0Hz, 1H); 7.18(d, J ═ 8.5Hz, 1H); 7.30 (width m, 1H); 7.40(m, 3H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.58 (width d, J ═ 8.5Hz, 2H); 8.65(dd, J ═ 2.0 and 7.5Hz, 1H); 8.92(d, J ═ 3.0Hz, 1H); 9.23(s, 1H); 9.29(s, 1H); 11.2(s, 1H).

ES：m/z＝471(M-H)^-The basal peak.

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -6-methoxy-1H-indole-2-carboxamide may be prepared according to the method described in example 26.

Example 28: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -6- (2-hydroxyethoxy) -1H-indole-2-carboxamide

To a solution of 280mg (0.59mmol) of 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -6-hydroxy-1H-indole-2-carboxamide in 10ml of dimethylformamide at room temperature was added 1.23g (8.90mmol) of potassium carbonate. Then 0.69ml (8.89mmol) of iodoethanol was added at room temperature. The reaction medium is heated at 110 ℃ for 2h30 min. The medium is dissolved in ethyl acetate and washed with water, and the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.

The crude product was purified by preparative LC/MS. After evaporation of the solvent to dryness under reduced pressure, the residue obtained is triturated with ethyl acetate and diisopropyl ether and, after filtration, 48mg of 3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) ureido ] phenyl } -6- (2-hydroxyethoxy) -1H-indole-2-carboxamide are obtained as a gray solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 3.75(q, J ═ 5.5Hz, 2H); 4.00(t, J ═ 5.5Hz, 2H); 4.86(t, J ═ 5.5Hz, 1H); 6.30 (width m, 1H); 6.73(dd, J ═ 2.0 and 9.0Hz, 1H); 6.91(d, J ═ 2.0Hz, 1H); 7.28(d, J ═ 9.0Hz, 1H); 7.32-7.47 (width m, 1H); 7.39(m, 1H); 7.42 (width d, J ═ 8.5Hz, 2H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.59 (width d, J ═ 8.5Hz, 2H); 8.65(dd, J ═ 2.5 and 7.5Hz, 1H); 8.97 (width s, 1H); 9.33 (width s, 1H); 11.4(s, 1H).

ES：m/z＝517(MH⁺) Basic peak, m/z 500 (MH)⁺-NH₃)。

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -6-hydroxy-1H-indole-2-carboxamide may be prepared according to the method described in example 27.

Example 29: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -7-nitro-1H-indole-2-carboxamides

A suspension of 2.70g (9.5mmol) of 3-bromo-7-nitro-1H-indole-2-carboxamide and 1.10g (0.95mmol) of tetrakis (triphenylphosphine) palladium (0) in 135ml of dioxane was stirred at room temperature for 10 minutes. 4.84g (11.41mmol) of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -urea and 165ml of dioxane were then added at room temperature, followed by 2.215g (38.13mmol) of a solution of potassium fluoride in 27ml of water. The mixture was heated to reflux for 18 h. A blade of carbon black was then added to the reaction medium at about 50 ℃ and then stirred for 10 minutes at 50 ℃. The reaction medium is filtered through celite and then washed with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure. The residue obtained is dissolved in ethyl acetate, washed with water and the organic phase is then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (99/1, then 98/2 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 3.44g of 3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] -phenyl } -7-nitro-1H-indole-2-carboxamide are obtained as a yellow solid.

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 7.33(t, J ═ 7.5Hz, 1H); 7.40(m, 1H); 7.45 (width d, J ═ 8.5Hz, 2H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.59 (width d, J ═ 8.5Hz, 2H); 7.69 (width m, 2H); 7.96(d, J ═ 7.5Hz, 1H); 8.27(d, J ═ 7.5Hz, 1H); 8.65(dd, J ═ 2.5 and 7.5Hz, 1H); 8.95 (width d, J ═ 2.5Hz, 1H); 9.32(s, 1H); 11.55(s, 1H).

ES：m/z＝500(M-H)^-The basal peak.

3-bromo-7-nitro-1H-indole-2-carboxamide may be prepared in the following manner:

a suspension of 2.57g (12.53mmol) of 7-nitro-1H-indole-2-carboxamide in 35ml of pyridine is cooled to 0 ℃ in a water/ice bath. A solution of 4.01g (12.53mmol) of tribromopyridine in 20ml of pyridine is then added dropwise at 0 ℃ and the reaction medium is stirred for a further 30 minutes at 0 ℃ and then for 16h at room temperature. 70ml of ice-water are then added to the reaction medium. After stirring at room temperature for another 15 minutes, the mixture was filtered through a sintered glass filter to obtain 2.81g of 3-bromo-7-nitro-1H-indole-2-carboxamide as a brown solid.

EI：m/z＝283(M⁺) Basic peak, M/z 266 (M-NH)₃)⁺，m/z＝220(m/z＝266-NO₂)⁺，m/z＝141(m/z＝220-Br)⁺。

7-nitro-1H-indole-2-carboxamide may be prepared in the following manner:

a suspension of 133mg (0.57mmol) of ethyl 7-nitroindole-2-carboxylate in 3.84ml of 28% ammonia water was heated at 50 ℃ for 18h in a stoppered glass tube. The reaction medium was filtered through a sintered glass filter. The resulting yellow solid was washed with water and then cyclohexane and then dried under vacuum. This gave 70mg of 7-nitro-1H-indole-2-carboxamide as a yellow solid.

ES：m/z＝206(MH⁺) The basal peak.

Example 30: 7-amino-3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides

To a suspension of 3.42g (6.82mmol)3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) ureido ] phenyl } -7-nitro-1H-indole-2-carboxamide in 480ml methanol was added 3.28g of palladium on charcoal catalyst. The reaction mixture was hydrogenated in an autoclave at 30 ℃ and 3 bar for 2h and then filtered over celite. The filtrate was evaporated to dryness under reduced pressure. The residue obtained is triturated with ethyl acetate and a little dichloromethane and then filtered. This gave 1.30g of 7-amino-3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] phenyl } -1H-indole-2-carboxamide as a gray solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 5.40 (width s, 2H); 6.17 (width m, 1H); 6.41(d, J ═ 7.5Hz, 1H); 6.62(d, J ═ 7.5Hz, 1H); 6.78(t, J ═ 7.5Hz, 1H); 7.39(m, 1H); 7.41 (width d, J ═ 8.5Hz, 2H); 7.47 (width m, 1H); 7.51(dd, J ═ 9.0 and 11.0Hz, 1H); 7.61 (width d, J ═ 8.5Hz, 2H); 8.65(dd, J ═ 2.0 and 7.5Hz, 1H); 8.99 (width m, 1H); 9.33 (width m, 1H); 11.25 (width s, 1H).

ES：m/z＝472(MH⁺) Basic peak, m/z 455 (MH)⁺-NH₃)。

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -phenyl } -7-nitro-1H-indole-2-carboxamide may be prepared according to the method described in example 29.

Example 31: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Phenyl } -7- (2-hydroxyethylamino) -1H-indole-2-carboxamide

A suspension of 160mg (0.34mmol) of 7-amino-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide and 20mg (0.34mmol) of 2-hydroxyacetaldehyde in 16ml of methanol and 19.43. mu.l (0.34mmol) of acetic acid is heated at 50 ℃ for 3H, then 64mg (1.02mmol) of sodium cyanoborohydride are added at room temperature and the reaction is stirred at this temperature for 16H. The reaction medium is evaporated to dryness under reduced pressure. The resulting residue was dissolved with ethyl acetate and water, then basified with 30% sodium hydroxide to pH 10. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (94/6 (vol)) ]. The resulting brown solid was triturated with ethyl acetate and a small amount of ether and filtered to give 14mg of 3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] phenyl } -7- (2-hydroxyethylamino) -1H-indole-2-carboxamide as a brown solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 3.25 (partially masked m, 2H); 3.67(q, J ═ 6.0Hz, 2H); 4.72(t, J ═ 6.0Hz, 1H); 5.95(t, J ═ 6.0Hz, 1H); 6.17 (width m, 1H); 6.32(d, J ═ 7.5Hz, 1H); 6.64(d, J ═ 7.5Hz, 1H); 6.86(t, J ═ 7.5Hz, 1H); 7.35-7.48(m, 4H); 7.51(m, 1H); 7.60 (width d, J ═ 8.5Hz, 2H); 8.65 (width d, J ═ 7.5Hz, 1H); 8.97 (width s, 1H); 9.33(s, 1H); 11.4(s, 1H).

ES：m/z＝516(MH⁺) Basic peak, m/z 499 (MH)⁺-NH₃)。

7-amino-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido ] phenyl } -1H-indole-2-carboxamide is obtained according to the procedure described in example 30.

Example 32: 7- (2-Dimethylaminoacetylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

To a suspension of 50mg (0.11mmol) of 7-amino-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide, 11mg (0.11mmol) of N, N-dimethylglycine, 20mg (0.10mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 16mg (0.10mmol) of 1-hydroxybenzotriazole hydrate in 6ml of dichloromethane are added 14.78. mu.l (0.11mmol) of triethylamine at room temperature. The mixture was dissolved by adding 2ml of dimethylformamide. The reaction medium is stirred at room temperature for 24 h. The reaction medium is diluted with dichloromethane and then washed successively with saturated aqueous sodium bicarbonate solution and water. The aqueous phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (95/5 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 50mg of 7- (2-dimethylaminoacetylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide are obtained as a cream-colored solid.

1H NMR (300MHz, (CD3)2SO d6, - δ (ppm)): 2.34(s, 6H); 3.21(s, 2H); 6.35 (width m, 1H); 7.02(t, J ═ 7.5Hz, 1H); 7.16(d, J ═ 7.5Hz, 1H); 7.39(m, 1H); 7.43 (width d, J ═ 8.5Hz, 2H); 7.51(m, 1H); 7.58 (width m, 1H); 7.63 (width d, J ═ 8.5Hz, 2H); 7.85(d, J ═ 7.5Hz, 1H); 8.64(dd, J ═ 2.5 and 7.5Hz, 1H); 9.00 (width s, 1H); 9.38(s, 1H); 9.86(s, 1H); 11.55(s, 1H).

ES：m/z＝557(MH⁺) Basic peak, m/z 540 (MH)⁺-NH₃)。

7-amino-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido ] phenyl } -1H-indole-2-carboxamide is obtained according to the procedure described in example 30.

Example 33: 3- {6- [3- (2-methoxy-5-trifluoromethylphenyl) -ureido]Pyridin-3-yl-

1H-indole-2-carboxamides

A suspension of 400mg (1.67mmol) of 3-bromo-1H-indole-2-carboxamide and 193mg (0.17mmol) of tetrakis (triphenylphosphine) palladium (0) in 9.25ml of dioxane is stirred at room temperature for 10 minutes. 805mg (1.84mmol) of 1- (2-methoxy-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea and 10ml of dioxane were then added at room temperature, followed by 389mg (6.69mmol) of potassium fluoride in 1.75ml of water. The mixture was refluxed for 18 h. The reaction medium is dissolved in ethyl acetate and washed with water, and the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (97/3 (vol)) ]. After concentrating the fractions to dryness under reduced pressure, the resulting pale brown solid was triturated with methanol and filtered through a sintered glass filter to give 26mg of 3- {6- [3- (2-methoxy-5-trifluoromethyl-phenyl) ureido ] pyridin-3-yl } -1H-indole-2-carboxamide as a white solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 4.00(s, 3H); 7.03 (width m, 1H); 7.10 (width t, J ═ 7.5Hz, 1H); 7.22(d, J ═ 9.0Hz, 1H); 7.27 (width t, J ═ 7.5Hz, 1H); 7.36(dd, J ═ 2.5 and 9.0Hz, 1H); 7.42 (width m, 1H); 7.49(m, 3H); 7.88(dd, J ═ 2.5 and 8.5Hz, 1H); 8.41(d, J ═ 2.5Hz, 1H); 8.65(d, J ═ 2.5Hz, 1H); 10.05(s, 1H); 11.5 (very wide m, 1H); 11.75 (width s, 1H).

ES：m/z＝470(MH⁺) The basal peak.

3-bromo-1H-indole-2-carboxamide may be prepared in the following manner:

a mixture of 5g (18.65mmol) of methyl 3-bromo-1H-indole-2-carboxylate and 70ml of 7N methanolic ammonia solution is heated at 100 ℃ for 23H in an autoclave. The reaction medium is then evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: ethyl acetate/heptane (50/50 (vol)) ]. After these fractions were evaporated to dryness under reduced pressure, the resulting pink solid was dissolved in about 100ml of ethyl acetate, to which a knife of vegetable charcoal was added. After stirring for a few minutes, it was filtered and the filtrate was evaporated under reduced pressure to give 3.11g of 3-bromo-1H-indole-2-carboxamide as a pale yellow solid.

ES：m/z＝239(MH⁺) The basal peak.

Methyl 3-bromo-1H-indole-2-carboxylate may be prepared according to the method described in example 1.

1- (2-methoxy-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea can be prepared in the following manner:

a suspension of 539mg (1.92mmol) tricyclohexylphosphine and 295mg (0.52mmol) bis (dibenzylideneacetone) palladium in 25ml dioxane is stirred at room temperature under argon for 10 minutes. To this reaction medium was added 5g (12.82mmol) of 1- (5-bromopyridin-2-yl) -3- (2-methoxy-5-trifluoromethylphenyl) urea followed by 125ml of dioxane, 4.40g (17.3mmol) of bis (pinacol) diborane and 1.89g (19.2mmol) of potassium acetate. The reaction medium is heated to reflux under argon for 5h30min, then 300ml of water are added at room temperature. The mixture was stirred at room temperature for 15 minutes, and then filtered through a sintered glass filter, and the resulting solid was washed with a small amount of water. 5.42g of 1- (2-methoxy-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea are obtained as a pale green solid.

EI：m/z＝437(M⁺) Basic peak, m/z 220 (C)₁₁H₁₇N₂O₂B⁺)，m/z＝191(C₈H₈NOF₃ ⁺)。

1- (5-bromopyridin-2-yl) -3- (2-methoxy-5-trifluoromethylphenyl) urea can be prepared in the following manner:

to a solution of 6g (20.23mmol) of triphosgene in 500ml of anhydrous tetrahydrofuran at 0 ℃ over the course of 3 minutes is added a solution of 11.05g (57.80mmol) of 2-methoxy-5-trifluoromethylaniline in 100ml of anhydrous tetrahydrofuran. 16.50ml (116.80mmol) triethylamine were added at 0 ℃. The reaction medium is stirred at 0 ℃ for 10 minutes and at room temperature for 1h45 min. A solution of 10g (57.80mmol) of 2-amino-5-bromopyridine in 100ml of anhydrous tetrahydrofuran is then added at room temperature. The reaction medium is stirred at room temperature for 20 h. The mixture was filtered through a sintered glass filter and the resulting white solid was washed with tetrahydrofuran and a small amount of ethyl acetate. The filtrate was evaporated to dryness under reduced pressure to give a pale yellow solid. It was further triturated with ethyl acetate and water and filtered through a sintered glass filter to give 12.04g of 1- (5-bromopyridin-2-yl) -3- (2-methoxy-5-trifluoromethylphenyl) urea as a white solid.

EI：m/z＝389(M⁺)，m/z＝191(C₈H₈NOF₃ ⁺)，m/z＝172(C₅H₅N₂Br⁺) The basal peak.

Example 34: 3- {6- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]Pyridin-3-yl } -1H-indole-2-carboxamides

A suspension of 186mg (0.78mmol) of 3-bromo-1H-indole-2-carboxamide and 90mg (0.08mmol) of tetrakis (triphenylphosphine) palladium (0) in 9.25ml of dioxane is stirred at room temperature for 10 minutes. 398mg (0.94mmol) of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] urea and 10ml of dioxane were then added at room temperature, followed by a solution of 181mg (3.12mmol) of potassium fluoride in 1.75ml of water. The mixture was heated to reflux for 18 h. The reaction medium is evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography [ eluent: dichloromethane/methanol (98/2 (vol)) ]. After concentration of the fractions containing the desired product under reduced pressure, 28mg of 3- {6- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] pyridin-3-yl } -1H-indole-2-carboxamide are obtained as a white solid.

1H NMR (400MHz, (CD3)2SO d6, - δ (ppm)): 7.10 (width t, J ═ 7.5Hz, 1H); 7.12 (width m, 1H); 7.28 (width t, J ═ 7.5Hz, 1H); 7.40-7.58(m, 6H); 7.91(dd, J ═ 2.0 and 8.5Hz, 1H); 8.37 (width d, J ═ 2.0Hz, 1H); 8.71(dd, J ═ 2.0 and 7.5Hz, 1H); 10.05 (width s, 1H); 11.3 (very wide m, 1H); 11.75 (width s, 1H).

ES：m/z＝458(MH⁺) The basal peak.

Examples 35 to 54:

the following procedure was applied to each target reaction using reactants 1-20 and 3- (4-aminophenyl) -1H-indole-2-carboxamide.

Table a: reactants used

#	Name of isocyanate precursor	Chemical formula (II)	MW(g/mol)	Quantity (mg)
					1	4-chlorophenyl isocyanate	C7H4CINO	153.57	59.800
2	P-tolyl isocyanate	C8H7NO	133.15	51.928
					3	4-fluorophenyl isocyanate	C7H4FNO	137.11	53.472
4	4-dimethylaminophenyl isocyanate	C9H10N2O	162.19	63.254
					5	4-tert-butylphenyl-isocyanates	C11H13NO	175.23	68.339
6	3-fluoro-4-methylphenyl isocyanate	C8H6FNO	151.14	59.944
					7	4- (trifluoromethylthio) phenyl isocyanate	C8H4F3NOS	219.19	85.484
8	4- (difluoromethoxy) phenyl isocyanate	C8H5F2NO2	185.13	72.200
					9	2- (difluoromethoxy) phenyl isocyanate	C8H5F2NO2	185.13	73.680
10	3-methoxyphenyl isocyanate	C8H7NO2	149.15	59.360
					11	4-methoxyphenyl isocyanate	C8H7NO2	149.15	59.360
12	3-chloro-4-fluorophenyl isocyanate	C7H3CIFNO	171.56	68.280
					13	2-thienyl isocyanates	C5H3NOS	125.15	49.810
14	3-bromophenyl isocyanate	C7H4BrNO	198.02	78.810
					15	3-fluorophenyl isocyanic acidAcid esters	C7H4FNO	137.11	54.570
16	3-chlorophenyl isocyanate	C7H4CINO	153.57	61.120
					17	4- (trifluoromethyl) phenyl isocyanate	C8H4F3NO	187.12	74.470
18	3-ethylphenyl isocyanate	C9H9NO	147.18	58.580
					19	4-isopropylphenyl isocyanate	C10H11NO	161.2	64.160
20	5-methyl-2- (trifluoromethyl) -3-furyl isocyanate	C7H4F3NO2	191.11	76.000

A solution of 3- (4-aminophenyl) -1H-indole-2-carboxamide in a solvent was prepared so that 100mg of the compound was dispensed in 9ml of THF (reactions 1-13) or 5ml of toluene (reactions 14-20) per reactor used.

In a reactor suitable for parallel synthesis (Carrousel Radley or Buchi Syncore) 100mg of 3- (4-aminophenyl) -1H-indole-2-carboxamide solution at 20 ℃ are added, followed by the corresponding isocyanate (Nos. 1-20, Table A). The reaction mixture was stirred at 20 ℃ for 39 hours. The entire mixture was concentrated to dryness under reduced pressure and then dissolved in 5ml of dichloromethane.

These compounds are treated in different ways depending on their solubility profile in dichloromethane:

1. the compounds formed from the dichloromethane-soluble precursors 2, 5, 14 were purified by silica gel chromatography; after combining, the fractions containing the desired compound were evaporated. The characteristics of the isolated compounds are described below.

TABLE B1

2. The compounds formed from precursors 1, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13 and 15-20 which are insoluble under these conditions are triturated in dichloromethane, filtered, washed and then dried. The following compounds from precursors 3, 7, 9-13 and 15-20 were isolated and characterized. The characteristics of the isolated compounds are described below.

TABLE B2

Precursor body	Isolated Compound, quantity (mg)
		3	3- {4- [3- (4-fluorophenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 106.8mg
7	3- {4- [3- (4-trifluoromethylsulfanyl) phenyl ] -ureido]Phenyl } -1H-indole-2-carboxamide, 180.7mg
		9	3- {4- [3- (2-Difluoromethoxyphenyl) ureido]-phenyl } -1H-indole-2-carboxamide, 86.8mg
10	3- {4- [3- (3-methoxyphenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 102.1mg
		11	3- {4- [3- (4-methoxyphenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 117.4mg
12	3- {4- [3- (3-chloro-4-fluorophenyl) ureido]-phenyl } -1H-indole-2-carboxamide, 29mg
		13	3- [4- (3-thiophen-2-yl) -ureido ] phenyl]-1H-indole-2-carboxamide, 17.7mg
15	3- {4- [3- (3-fluorophenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 109mg
		16	3- {4- [3- (3-chlorophenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 120mg
17	3- {4- [3- (4-trifluoromethylphenyl) ureido]-phenyl } -1H-indole-2-carboxamide, 147mg
		18	3- {4- [3- (3-ethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 133mg
19	3- {4- [3- (4-isopropylphenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 140mg
		20	3- {4- [3- (5-methyl-2-trifluoromethylfuran-3-yl) ureido]Phenyl } -1H-indole-2-carboxamide, 120mg

3. The compounds from precursors 6 and 8 were dissolved in acetonitrile, triturated, filtered, washed and dried. These compounds were isolated, identified and characterized. The characteristics of the isolated compounds are described below.

TABLE B3

Precursor body	Isolated compounds and amounts
		6	3- {4- [3- (3-fluoro-4-methylphenyl) ureido]-phenyl } -1H-indole-2-carboxamide, 147mg
8	3- {4- [3- (4-Difluoromethoxyphenyl) ureido]-phenyl } -1H-indole-2-carboxamide, 135mg

4. Compounds from precursors 1 and 4 were purified using preparative LCMS.

TABLE B4

Precursor body	Isolated compounds and amounts
		1	3- {4- [3- (4-chlorophenyl) ureido]Phenyl } -1H-indole-2-carboxamide, 73.8mg
4	3- {4- [3- (4-dimethylaminophenyl) ureido]-phenyl } -1H-indole-2-carboxamide, 83.6mg

Table C: isolation and characterization of the product and its characteristics

Examples	Precursor body	Name of isolated Compound	MH+	Retention time (min)	Analytical method
						35	5	3- {4- [3- (4-tert-butyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	427	9.83	Method B
36	7	3- {4- [3- (4-trifluoromethylsulfanyl-phenyl) ureido]-phenyl } -1H-indole-2-carboxamides	471	9.92	Method B
						37	8	3- {4- [3- (4-difluoromethoxy-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	437	3.99	Method A
38	6	3- {4- [3- (3-fluoro-4-methylphenyl) ureido]-phenyl } -1H-indole-2-carboxamides	403	7.17	Method A
						39	1	3- {4- [3- (4-chloro-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	405	4.08	Method A
40	4	3- {4- [3- (4-dimethylaminophenyl) -ureido]Phenyl } -1H-indole-2-carboxamides	414	2.73	Method A
						41	2	3- [4- (3-p-tolyl-ureido) phenyl]-1H-indole-2-carboxamides	385	8.83	Method B
42	3	3- {4- [3- (4-fluorophenyl) ureido]Phenyl } -1H-indole-2-carboxamides	389	8.59	Method B
						43	12	3- {4- [3- (3-chloro-4-fluorophenyl) ureido]-phenyl } -1H-indole-2-carboxamides	423	4.17	Method A
44	13	3- [4- (3-thiophen-2-yl-ureido) phenyl]-1H-indole-2-carboxamides	377	3.64	Method A
						45	9	3- {4- [3- (2-difluoro-methoxyphenyl) ureido]-phenyl } -1H-indole-2-carboxamides	437	4.08	Method A
46	10	3- {4- [3- (3-methoxy-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	401	3.85	Method A
						47	11	3- {4- [3- (4-methoxy-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	401	3.7	Method A

48	14	3- {4- [3- (3-bromo-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	450	4.19	Method A
						49	15	3- {4- [3- (3-fluorophenyl) ureido]Phenyl } -1H-indole-2-carboxamides	389	3.94	Method A
50	16	3- {4- [3- (3-chloro-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	405	4.13	Method A
						51	17	3- {4- [3- (4-trifluoro-methylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides	439	4.28	Method A
52	18	3- {4- [3- (3-ethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	399	4.16	Method A
						53	19	3- {4- [3- (4-isopropyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides	413	4.34	Method A
54	20	3- {4- [3- (5-methyl-2-trifluoromethylfuran-3-yl) ureido]Phenyl } -1H-indole-2-carboxamides	443	4.24	Method A

LCMS analysis method

Method A	T min	％A
			LCMS micromass type platform ii chromatography conditions: eluent: a: water + 0.1% HCOOH/B: acetonitrile column: thermo Hypersil Gold, 50X 3mm, 3 μ M (Ref 25003-: at the side of	0	95
5	5
		5.5		5
6.5	95
		7		95

MethodB	T min	％A
			LC/MS micromass type platform II. The chromatographic conditions are as follows: composition water a + 0.1% HCOOH/MeOH b. column: waters, Xbridge, 3 × 100mm, 3.5 μm (Ref 186003027), gradient: at the side of	0	95
10	5
		11		95
13	95

LCMS preparation method:

these products were purified by LC/MS using a Waters FractionsLynx system consisting of a Waters model 600 gradient pump, a Waters model 515 regeneration pump, a Waters reagent manager dilution pump, a Waters model 2700 auto-injector, two Rheodyne model LeLabPro valves, a Waters model 996 diode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector. The system is controlled by Waters FractionLynx software. Two Waters Symmetry columns (C) were used alternately₁₈5 μm, 19 × 50mm, catalogue reference 186000210), one column was used for the regeneration process using a water/acetonitrile mixture 95/5(v/v) containing 0.07% (v/v) trifluoroacetic acid, while the other column was used for the separation process. The columns were eluted at a flow rate of 10ml/min using a linear gradient of 5-95% acetonitrile in water containing 0.07% (v/v) trifluoroacetic acid, with 0.07% (v/v) trifluoroacetic acid in water. At the outlet of the separation column, one thousandth of the effluent was separated using an LC Packing Accurate, diluted with methanol at a flow rate of 0.5ml/min, sent to the detector again, sent to the diode array detector at 75% and the remaining 25% sent to the mass spectrometer. The remaining effluent (999/1000) is sent to a fraction collector where it is discarded when the desired product quality is not detected by the FractionLynx software. The molecular formula of the expected product was supplied to the FractionLynx software when the mass signal was detected for the corresponding ion [ M + H ]]⁺And/or [ M + Na]⁺At that time, the software initiates collection of the product. In some cases, depending on the LC/MS analysis results, a signal corresponding to [ M +2H ] was detected]⁺⁺Corresponding to half the calculated molecular weight (MW/2), is also supplied to the FractionLynx software. Under these conditions, the ion [ M +2H ] was detected]⁺⁺And/or [ M + Na + HH]⁺⁺The product also starts to be collected. The product was collected using tared glass tubes. After collection, the solvent is evaporated in a centrifugal evaporator and the amount of product can be determined by weighing the tube after evaporation of the solvent.

Example 55: 5-fluoro-3- {4- [3- (2-fluoro-5-trifluoro-methyl-phenyl) ureido]-phenyl } -1H-indole-2-carboxamides

Example 56: 6-fluoro-3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) ureido]-phenyl } -1H-indole-2-carboxamides

Example 57: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -methyl-carbonylamino]Phenyl } -1H-indole-2-carboxamides

Example 58: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]-3-fluorophenyl } -1H-indole-2-carboxamide

Example 59: 3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido]-3-methylphenyl } -1H-indole-2-carboxamide

Example 60: 4-methoxy-3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) -ureido]Phenyl } -1H-indole-2-carboxamides

Example 61: 5-methoxy-3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 62: 5-Nitro-3- {4- [3- (2-fluoro-)-5-trifluoro-methylphenyl) -ureido]Phenyl } -1H-indole-2-carboxamides

Example 63: 5-trifluoromethoxy-3- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 64: 7- (2-morpholin-1-ylethoxy) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 65: 7- (2-pyrrolidin-1-ylethoxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 66: 7- (3-pyridin-3-ylcarbonylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 67: 7- (3-methoxyethylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 68: 7-hydroxy-3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) -ureido]Phenyl } -1H-indole-2-carboxamides

Example 69: 7-methoxy-3- {4- [3- (2-fluoro-5-trifluoro-methylphenyl) -ureido]Phenyl } -1H-indole-2-carboxamides

Example 70: 6- (2-morpholin-1-ylethoxy) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 71: 3- {4- [3- (2-fluoro-4-hydroxy-5-trifluoro-methylphenyl) -ureido]Phenyl } -1H-indole-2-carboxamides

Example 72: 3- {4- [3- (4-chloro-5-trifluoromethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides

MS：m/z＝473(MH⁺)。

Retention time (min) ═ 4.2

Example 73: 7- (2-morpholin-1-ylethoxy) -3- {4- [3- (4-fluoro-5-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

MS：m/z＝457(MH⁺)。

Retention time (min) ═ 4.0

Example 74: 7- (2-morpholin-1-ylethoxy) -3- {4- [3- (4-methyl-3-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

MS：m/z＝453(MH⁺).

Retention time (min) 4.12

Example 75: 3- {4- [3- (4- (pyrrolidin-1-ylmethoxy) -3-trifluoromethyl-phenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 76: 3- {4- [3- (4- (4-methylpiperazin-1-ylmethyl) -3-trifluoromethylphenyl) ureido]Phenyl } -1H-indole-2-carboxamides

Example 77: 3- {4- [3- (2-fluorophenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝390(MH⁺)。

Retention time (min) ═ 2.8

Example 78: 3- {4- [3- (2-methoxyphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝402(MH⁺).

Retention time (min) ═ 2.9

Example 79: 3- {4- [3- (2-trifluoromethylphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝440(MH⁺)。

Retention time (min) ═ 3.1

Example 80: 3- [4- (3-o-tolylureido) phenyl]-1H-pyrrolo [3, 2-b]Pyridine-2-carboxamides

MS：m/z＝386(MH⁺)。

Retention time (min) ═ 2.9

Example 81: 3- {4- [3- (3-fluorophenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝390(MH⁺)。

Retention time (min) ═ 3

Example 82: 3- {4- [3- (3-methoxyphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝402(MH⁺)。

Retention time (min) ═ 2.8

Example 83: 3- {4- [3- (3-trifluoromethylphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝440(MH⁺)。

Retention time (min) 3.3

Example 84: 3- [4- (3-m-tolylureido) phenyl]-1H-pyrrolo [3, 2-b]Pyridine-2-carboxamides

MS：m/z＝386(MH⁺)。

Retention time (min) ═ 3

Example 85: 3- {4- [3- (4-fluorophenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝390(MH⁺)。

Retention time (min) ═ 2.9

Example 86: 3- {4- [3- (4-methoxyphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝402(MH⁺)。

Retention time (min) ═ 2.7

Example 87: 3- {4- [3- (4-trifluoromethylphenyl) -ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝440(MH⁺)。

Retention time (min) ═ 3.4

Example 88: 3- [4- (3-p-tolylureido) phenyl]-1H-pyrrolo [3, 2-b]Pyridine-2-carboxamides

MS：m/z＝386(MH⁺)。

Retention time (min) ═ 3

Example 89: 3- {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝474(MH⁺)。

Retention time (min) 3.6

Example 90: 3- {4- [3- (2-amino-5-trifluoromethylphenyl) -ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝474(MH⁺)。

Retention time (min) ═ 3.4

Example 91: 3- {4- [3- (2-fluoro-3-trifluoromethylphenyl) -ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝458(MH⁺)。

Retention time (min) ═ 3.4

Example 92: 3- {4- [3- (4-fluoro-3-trifluoromethylphenyl) -ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝458(MH⁺)。

Retention time (min) ═ 3.4

Example 93: 3- {4- [3- (3-fluoro-5-trifluoromethylphenyl) -ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝458(MH⁺)。

Retention time (min) 3.5

Example 94: 3- {4- [3- (4-methyl-3-trifluoromethylphenyl) -ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝454(MH⁺)。

Retention time (min) 3.5

Example 95: 3- {4- [3- (4-trifluoromethoxyphenyl) -ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝456(MH⁺)。

Retention time (min) 3.5

Example 96: 3- {4- [3- (4-Difluoromethoxyphenyl) -ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝438(MH⁺)。

Retention time (min) 3.2

Example 97: 3- {4- [3- (3, 4-dimethylphenyl) ureido]Phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝400(MH⁺)。

Retention time (min) 3.2

Example 98: 3- {4- [3- (3, 4-Dimethoxyphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝432(MH⁺)。

Retention time (min) ═ 2.6

Example 99: 3- {4- [3- (3, 5-Dimethoxyphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝432(MH⁺)。

Retention time (min) ═ 2.9

Example 100: 3- {4- [3- (2, 5-dimethylphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝400(MH⁺)。

Retention time (min) ═ 3.1

Example 101: 3- {4- [3- (2-methoxy-5-methylphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝416(MH⁺)。

Retention time (min) ═ 3.1

Example 102: 3- {4- [3- (2, 5-Dimethoxyphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝432(MH⁺)。

Retention time (min) ═ 3

Example 103: 3- {4- [3- (3-chloro-4-difluoromethoxyphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝471(MH⁺)。

Example 104: 3- {4- [3- (3, 5-dimethylphenyl) ureido]-phenyl } -1H-pyrrolo [3, 2-b)]Pyridine-2-carboxamides

MS：m/z＝400(MH⁺)。

Determination of Compound Activity-protocol

1、KDR

Inhibition of compounds was determined in vitro using KDR enzyme in matrix phosphorylation assays using scintillation technology (96-well plate, NEN).

The cytoplasmic domain of the human KDR enzyme was cloned as a GST fusion in a pFastBac baculovirus expression vector. The protein was expressed in these SF21 cells and purified to about 60% homogeneity.

At 10mM MgCl₂、100μM Na₃VO₄In the presence of 1mM NaF in 20mM OPS, 10mM MgCl₂、10mM MnCl₂KDR kinase activity was determined in 1mM DTT, 2.5mM EGTA, 10 mMb-glycerophosphate, pH 7.2. Mu.l of compound was added to 70. mu.l of kinase buffer containing 100ng KDR enzyme at 4 ℃. By adding 2. mu.g of matrix (SH 2-SH3 fragment of PLC. gamma. expressed as a GST fusion protein), 2. mu. Ci. gamma³³p[ATP]And 2. mu.M of cold ATP in 20. mu.l to prime the reaction. After incubation at 37 ℃ for 1 hour, the reaction was stopped by adding 1 volume (100. mu.l) of 200mM EDTA. The culture buffer was removed and the wells were washed three times with 300. mu.l each in PBS. The radioactivity in each well was determined using a Top Count NXT radioactivity counter (Packard).

Background noise was measured by measuring radioactivity in four different wells containing radioactive ATP and matrix only.

In the presence of all these reactants (. gamma.)³³P-[ATP]KDR and PLC γ matrix) but no compound in four different wells.

The inhibition of KDR activity by a compound of the invention is expressed as the percent inhibition of control activity determined in the absence of compound.

Compound SU5614(Calbiochem) (1 μ M) was included in each plate as an inhibition control.

2、Tie2

Using cDNA isolated from the human placenta as a model, the human Tie2 coding sequence corresponding to the intracellular domain amino acids 776-1124 was generated using PCR. This sequence was added to a baculovirus pFastBacGT expression vector in the form of a GST fusion protein.

Inhibition of the molecule was determined in phosphorylation assays of PLC using Tie2 in the presence of GST-Tie2 purified to about 80% homogeneity. The matrix consists of SH2-SH3 fragments of PLC expressed as GST fusion proteins.

The kinase activity of Tie2 was determined in 20mM MOPS buffer, pH7.2, containing 10mM mgCl₂、10mM MnCl₂1mM DTT and 10mM glycerol phosphate. In a 96-well FlashPlate plate on ice, a reaction mixture consisting of 70. mu.l of kinase buffer containing 100ng GST-Tie2 enzyme per well was placed. Then 10. mu.l of the molecule to be tested diluted in DMSO are added, the maximum concentration being 10%. For a given concentration, each measurement was performed in four samples. Add the solution containing 2. mu.g GST-PLC, 2. mu.M cold ATP and 1. mu. Ci³³P[ATP]The reaction was started with 20. mu.l of solution. After incubation at 37 ℃ for 1 hour, the reaction was stopped by adding 1 volume (100. mu.l) of 200mM EDTA. The culture buffer was removed and the wells were washed three times with 300. mu.l each in PBS. Radioactivity was measured using a Wallac MicroBeta 1450.

Inhibition of Tie2 activity was calculated and expressed as percent inhibition as the control activity determined in the absence of compound.

In general, the IC50 of KDR or Tie2 or both of the products of the invention is below 1 μm, preferably below 500nM, even more preferably below 100 nM. Of these products, some of the products FAK generally have an IC50 of less than 1 μm, preferably less than 500nM, and even more preferably less than 100 nM. For example, the IC50 value for the product FAK of example 10 was 303 nM.

As a result: table 1:

Claims (31)

1. A product corresponding to the following formula (I):

in the formula:

a) a and Ar are independently selected from: aryl, heteroaryl, substituted aryl, substituted heteroaryl;

b) r1 is H or alkyl, optionally substituted alkyl;

c) x is N or N-oxide or CR 12;

d) l is selected from: a bond,

CO，NH，CO-NH，NH-CO，NH-SO，SO-NH，NH-SO₂，SO₂NH，NH-CH₂，CH₂-NH，CH₂-CO-NH，NH-CO-CH₂，NH-CH₂-CO，CO-CH₂-NH，NH-CO-NH，NH-CS-NH，NH-CO-O，O-CO-NH；

e) R5, R6, R7 and R12 are independently from each other selected from: H. halogen, halogen,

CF₃，NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R2)C(O)R3N(R4)₂，NHC(O)R2N(R3)(R4)，N(R4)C(S)N(R2)(R3)，N(R2)C(S)R3N(R4)₂，NHC(S)R2N(R3)(R4)，N(R2)S(O₂)(R3)，OS(O)₂(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂)N(R2)(R3)；

Wherein each R2, R3, R4 is independently selected from H, alkyl, alkylene, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl, alkylheterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl; wherein R2 and R3 are simultaneously on one of R5, R6, R7 and R12, they can be linked to each other to form a ring containing 0 to 3 heteroatoms selected from O, N and S;

f) q is selected from H, CH₃And a cyclopropyl group.

2. The product according to claim 1, corresponding to the following formula (I):

in the formula

a) A and Ar are as defined in claim 1;

b) r1 is as defined in claim 1;

c) x is N or CR 12;

d) l is as defined in claim 1;

e) r5, R6, R7 and R12 are independently from each other selected from: H. halogen, halogen,

CF₃，NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R4)C(S)N(R2)(R3)，N(R2)S(O₂)(R3)，OS(O₂)(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂)N(R2)(R3)；

Wherein each R2, R3, R4 is as defined in claim 1;

f) q is as defined in claim 1.

3. A product according to claim 1 or 2, characterized in that Q is H.

4. The product of claim 3, wherein:

a) a and Ar are independently selected from aryl, heteroaryl, substituted aryl, substituted heteroaryl;

b) r1 is H;

c) x is CH or N; and

d) l is selected from NH-SO₂And NH-CO-NH.

5. The product according to any one of claims 1 to 4, characterized in that Ar-L-A is:

wherein each of X1, X2, X3 and X4 is independently selected from N and C-R11, wherein R11 is selected from H, halogen,

NO₂，R2，CN，O(R2)，OC(O)(R2)，OC(O)N(R2)(R3)，OS(O₂)(R2)，N(R2)(R3)，N＝C(R2)(R3)，N(R2)C(O)(R3)，N(R2)C(O)O(R3)，N(R4)C(O)N(R2)(R3)，N(R4)C(S)N(R2)(R3)，N(R2)S(O₂)(R3)，C(O)(R2)，C(O)O(R2)，C(O)N(R2)(R3)，C(＝N(R3))(R2)，C(＝N(OR3))(R2)，S(R2)，S(O)(R2)，S(O₂)(R2)，S(O₂)O(R2)，S(O₂)N(R2)(R3)。

6. The product according to claim 5, characterized in that R11 is selected from H, F, Cl, methyl, NH₂、OCF₃And CONH₂。

7. Product according to any one of claims 1 to 6, characterized in that R5, R6, R7 and R8 are independently of one another selected from H, halogen, methyl,

OCH₃，OCF₃，OH，NH₂，NH(CH₂)₂OH，NH(CH₂)₂OCH₃，O(CH₂)COOH，O(CH₂)₂COOH，O(CH₂)₂NH(CH₂)₂OCH₃，O(CH₂)₂NH(CH₂)₂OH, pyridin-3-ylcarbonylamino-, 2- (N, N-diethylamino) ethoxy, 3- (N, N-diethylamino) propoxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (morpholin-4-yl) ethoxy and 3- (morpholin-4-yl) propoxy.

8. Product according to any one of claims 1 to 7, characterized in that R5 and R7 are independently selected from H and F.

9. Product according to any one of claims 1 to 8, characterized in that R6 is H.

10. The product according to claim 1, characterized in that L-A is selected from the group consisting of NH-CO-NH-A, NH-SO₂-A and NH-CO-CH₂-A。

11. The product according to any one of claims 1 to 10, characterized in that a is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl; optionally a is substituted.

12. Product according to claim 11, characterized in that a is chosen from phenyl, pyrazolyl and isoxazolyl; optionally substituted.

13. The product according to any one of claims 10 to 12, characterized in that a is substituted with a first substituent selected from the group consisting of alkyl, haloalkyl, alkylene, alkynyl, aryl, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, S-alkyl, S-cycloalkyl, S-aryl and S-heteroaryl, each substituent being optionally selected from the group consisting of (C)₁-C₃) Alkyl, halogen and O- (C)₁-C₃) Alkyl substituents.

14. Product according to any one of claims 10 to 13, characterized in that a is substituted by a second substituent selected from the group consisting of F, Cl, Br, I, OH, SO₃M、COOM、CN、NO₂、CON(R8)(R9)、N(R8)CO(R9)、(C₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-N (R8) (R9), (C)₁-C₃) Alkyl- (R10), (C)₁-C₃) alkyl-COOH, N (R8) (R9), O- (C)₂-C₄) alkyl-N (R8) (R9); wherein R8 and R9 are independently selected from H, (C)₁-C₃) Alkyl, (C)₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-NH₂、(C₁-C₃) alkyl-COOM and (C)₁-C₃) alkyl-SO₃M; wherein when R8 and R9 are simultaneously other than H, they may be linked to each other to form a ring containing 0 to 3 heteroatoms selected from N, S and O; wherein M is H or an alkali metal cation selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocyclic ring containing 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S.

15. Product according to any one of claims 10 to 14, characterized in that a is phenyl, pyrazolyl or isoxazolyl, (C) substituted by halogen, in particular F₁-C₄) Alkyl, halo (C)₁-C₃) Alkyl, especially CF₃、O-(C₁-C₄) Alkyl, O-cycloalkyl, S- (C)₁-C₄) Alkyl, S-cycloalkyl, halo O- (C)₁-C₄) Alkyl or halogenated S- (C)₁-C₄) An alkyl group.

16. The product according to any one of claims 1 to 14, characterized in that a is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from alkyl, haloalkyl, alkylene, alkynyl, aryl, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl; each substituent is optionally substituted with a substituent selected from: (C)₁-C₃) Alkyl, halogen、O-(C₁-C₃) An alkyl group; and F, Cl, Br, I, OH, SO₃M、COOM、CN、NO₂、CON(R8)(R9)、N(R8)CO(R9)、(C₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-N (R8) (R9), (C)₁-C₃) Alkyl- (R10), (C)₁-C₃) alkyl-COOH, N (R8) (R9), O- (C)₂-C₄) alkyl-N (R8) (R9); wherein R8 and R9 are independently selected from H, (C)₁-C₃) Alkyl, (C)₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-NH₂、(C₁-C₃) alkyl-COOM, (C)₁-C₃) alkyl-SO₃M; wherein R8 and R9 are simultaneously other than H, they may be linked to each other to form a ring containing 0 to 3 heteroatoms selected from O, N and S; wherein M is H or an alkali metal cation selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocyclic ring containing 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S.

17. The product according to claim 1, characterized in that it is selected from:

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- [4- (3-phenylureido) phenyl ] -1H-indole-2-carboxamide,

3- [4- (3-m-tolylureido) phenyl ] -1H-indole-2-carboxamide,

3- [4- (3-trifluoromethylphenylureido) phenyl ] -1H-indole-2-carboxamide,

3- [4- (3, 5-dimethylphenylureido) phenyl ] -1H-indole-2-carboxamide,

3- [4- (2-fluorophenylureido) phenyl ] -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1-methyl-1H-indole-2-carboxamide,

3- {4- [3- (3-chloro-4-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (5-tert-butylisoxazol-3-yl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-trifluoromethoxyphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-methoxy-5-trifluoromethylphenyl) -ureido ] phenyl } -1H-indole-2-carboxamide,

3- [4- (2-fluoro-5-trifluoromethylbenzenesulfonylamino) phenyl ] -1H-indole-2-carboxamide,

3- [4- (2, 3-dichlorobenzenesulfonylamino) phenyl ] -1H-indole-2-carboxamide,

3- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-methylphenyl) ureido ] phenyl } 1H-indole-2-carboxamide,

3- {4- [3- (5-dimethylamino-2-fluorophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-dimethylaminophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-pyrrolidin-1-ylmethyl-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-methoxymethyl-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -4-oxo-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-methoxy-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -6- (2-methoxyethoxy) -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -6- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide,

3- {6- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] pyridin-3-yl } -6-methoxy-1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -6-methoxy-1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -6-hydroxy-1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -6- (2-hydroxyethoxy) -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -7-nitro-1H-indole-2-carboxamide,

7-amino-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -7- (2-hydroxyethylamino) -1H-indole-2-carboxamide,

7- (2-dimethylaminoacetylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {6- [3- (2-methoxy-5-trifluoromethylphenyl) ureido ] pyridin-3-yl } -1H-indole-2-carboxamide,

3- {6- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] pyridin-3-yl } -1H-indole-2-carboxamide,

3- {4- [3- (4-tert-butylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-trifluoromethylsulfanylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-difluoromethoxyphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-fluoro-4-methylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-chlorophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-dimethylaminophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- [4- (3-p-tolylureido) phenyl ] -1H-indole-2-carboxamide,

3- {4- [3- (4-fluorophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-chloro-4-fluorophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- [4- (3-thiophen-2-ylureido) phenyl ] -1H-indole-2-carboxamide,

3- {4- [3- (2-difluoromethoxyphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-methoxyphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-methoxyphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-bromophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-fluorophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-chlorophenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (3-ethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-isopropylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (5-methyl-2-trifluoromethylfuran-3-yl) ureido ] phenyl } -1H-indole-2-carboxamide,

5-fluoro-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

6-fluoro-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) methylcarbonylamino ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -3-fluorophenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] -3-methylphenyl } -1H-indole-2-carboxamide,

4-methoxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

5-methoxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

5-nitro-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

5-trifluoromethoxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7- (2-morpholin-1-ylethoxy) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7- (2-pyrrolidin-1-ylethoxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7- (3-pyridin-3-ylcarbonylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7- (3-methoxyethylamino) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7-hydroxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7-methoxy-3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

6- (2-morpholin-1-ylethoxy) -3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluoro-4-hydroxy-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4-chloro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7- (2-morpholin-1-ylethoxy) -3- {4- [3- (4-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

7- (2-morpholin-1-ylethoxy) -3- {4- [3- (4-methyl-3-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4- (pyrrolidin-1-ylmethoxy) -3-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (4- (4-methylpiperazin-1-ylmethyl) -3-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide,

3- {4- [3- (2-fluorophenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-methoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- [4- (3-o-tolylureido) phenyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3-fluorophenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3-methoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- [4- (3-m-tolylureido) phenyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-fluorophenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-methoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- [4- (3-p-tolylureido) phenyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-chloro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-fluoro-3-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-fluoro-3-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-methyl-3-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-trifluoromethoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (4-difluoromethoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3, 4-dimethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3, 4-dimethoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3, 5-dimethoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2, 5-dimethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2-methoxy-5-methylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (2, 5-dimethoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3-chloro-4-difluoromethoxyphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide,

3- {4- [3- (3, 5-dimethylphenyl) ureido ] phenyl } -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide.

18. The product according to claim 1, characterized in that it relates to:

3- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-indole-2-carboxamide.

19. Product according to any one of claims 1 to 18, characterized in that it is in one of the following forms:

1) achiral or

2) Racemic or

3) Is enriched in stereoisomers, or

4) Enriched in enantiomers;

it is also characterized in that it can optionally be salified.

20. Process for the preparation of the product of formula (I) according to claim 1, characterized by the product of formula (VI):

the following steps are carried out:

halogenation in the 3-position, followed by

-carrying out a Suzuki coupling reaction in position 3 to obtain a product of formula (IV):

then the

-reduction of the nitrophenyl group to aminophenyl at the 3-position, amidation of the ester at the 2-position, or amidation of the ester at the 2-position and reduction of the nitrophenyl group at the 3-position to aminophenyl, to obtain a product of formula (II):

then the

Acylation of the aminophenyl group in the-3 position.

21. Pharmaceutical product, characterized in that it comprises a product of formula (I) according to any one of claims 1 to 19, or an addition salt of such a compound with a pharmaceutically acceptable acid, or a hydrate or solvate of a product of formula (I).

22. A pharmaceutical composition comprising a product according to any one of the preceding claims, together with a pharmaceutically acceptable excipient.

23. Use of a product according to any of claims 1-19 as an inhibitor of a kinase catalysed reaction.

24. Use of the product according to any one of claims 1 to 19, according to claim 23, wherein the kinase is selected from KDR, Tie2, Aurora1, Aurora2, FAK, PDGFR, FLT1, FGFR, VEGF-R1 and VEGF-R3.

25. Use of a product according to any one of claims 1 to 19 according to claim 24, characterised in that the kinase is selected from KDR and Tie 2.

26. Use of a product according to any one of claims 1 to 19 as claimed in claim 24 as an inhibitor of kinase catalysed reactions selected from KDR, Tie2, Aurora1, Aurora2, FAK, PDGFR, FLT1, FGFR, VEGF-R1 and VEGF-R3.

27. Use of the product according to any one of claims 1-19, according to claim 26, characterized in that the kinases are KDR and Tie2, or KDR, Tie2 and FAK.

28. Use of a product according to any one of claims 1 to 19 in the manufacture of a medicament for the treatment of a pathological condition.

29. Use according to claim 28, characterized in that the pathological state is cancer.

30. Use according to claim 28, characterized in that the pathological condition is a disease associated with deregulation of angiogenesis, such as psoriasis, chronic inflammation, age-related macular degeneration, rheumatoid arthritis, diabetic retinopathy, Kaposi's sarcoma or haemangioma in infants.

31. As intermediate products, products of formulae (VI), (IV) and (II) as defined in claim 19, wherein R1, R5, R6, R7 and X are as defined in claim 1.