Novel bis-azaindole derivatives, preparation and pharmaceutical use thereof as kinase inhibitors

Abstract

Disclosed are compounds of formula (I): wherein R1, R2, R3, R4, and R5 have the meanings given in the description, and to salts thereof, pharmaceutical compositions comprising said compounds and the use thereof as protein kinase inhibitors.

1 ) A compound of formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         R1 represents a hydrogen atom, alkyl or alkenyl, optionally substituted; 
         R2 represents alkoxy optionally substituted and R3 represents alkyl or alkoxy, optionally substituted; 
         R4 represents a hydrogen atom; a halogen atom; a dioxolane radical; a —CH═O; —CH═N—OH; —CH═N-phenyl radicals with optionally substituted phenyl; or a cyano, alkyl or alkoxy radical, optionally substituted; 
         R5 represents a hydrogen atom or a halogen atom; 
         the alkyl, alkenyl and alkoxy radicals represented by R1, R2, R3 or R4 being optionally substituted by one or more identical or different radicals selected from halogen atoms and the following radicals: cyano; hydroxyl; oxo; nitro; —NR6R7; —C(═O)—NR6R7; —C(═O)—R9; —C(═O)—OR10; —N(R11)-C(═O)—R9; —N(R11)-C(═O)—OR10; —N(R11)-C(═O)—NR6R7; —S(O)n-R9; —N(R11)-S(O)n-R9; —S(O)n-NR6R7; —N(R11)-S(O)n-NR6R7; alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, aryl, aryloxy and heteroaryl, optionally substituted; 
         R6 and R7, which may be identical or different, are selected from hydrogen, alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl and heteroaralkyl, all these radicals being optionally substituted, 
         or alternatively R6 and R7 form, with the nitrogen atom to which they are bound, a heterocyclic radical, unsaturated or alternatively partially or fully saturated, made up of 3 to 10 units and containing one or more heteroatoms selected from O, S, N and NR8, this heterocyclic radical being optionally substituted; 
         n represents an integer from 0 to 2; 
         R8 represents a hydrogen atom or an acyl, alkyl or aryl radical, optionally substituted; 
         R9 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, or heteroaralkyl, all these radicals being optionally substituted; 
         R10 represents the values of R9 or hydrogen; 
         R11 represents hydrogen or alkyl, optionally substituted; 
         all these alkoxy, alkylthio, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl radicals which can be represented by R6, R7, R8, R9, R10 or R11 or which can constitute substituents of R1, R2, R3 and R4 as well as the heterocyclic radical that can be formed by R6 and R7 with the nitrogen atom to which they are attached, being optionally substituted by one or more identical or different radicals selected from halogen atoms and the following radicals: hydroxyl; oxo; nitro; cyano; cycloalkyl; acyl; carboxy free or esterified; alkoxy optionally substituted; amino optionally substituted by one or two identical or different radicals selected from the radicals acyl, carboxy free or esterified, alkyl, phenyl and phenylalkyl, optionally substituted; pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, alkyl, phenyl and phenylalkyl, optionally substituted; 
         the above alkoxy, alkyl, pyrrolidinyl, piperidyl, piperazinyl, phenyl and phenylalkyl radicals, being optionally substituted by one or more radicals selected from halogen atoms and the radicals hydroxyl, oxo, nitro, cyano, alkyl, hydroxyalkyl, CF3, alkoxy, hydroxyalkoxy, OCF3, carboxy free or esterified, amino, mono or dialkylamino, phenyl, phenylalkyl, pyrrolidinyl, piperidyl and pyridyl; 
         all the above aryl, heteroaryl and heterocycloalkyl radicals being moreover optionally substituted by an alkylenedioxy radical; 
         all the above alkyl, alkenyl, alkoxy and alkylthio radicals being linear or branched and containing at most 6 carbon atoms; 
         all the above cycloalkyl radicals containing at most 7 carbon atoms; 
         all the above aryl, heteroaryl and heterocycloalkyl radicals containing at most 10 carbon atoms; 
         or a prodrug of said compound; 
         or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base; 
         or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt. 
       
     
     
         2 ) A compound of formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         R1 represents alkyl or alkenyl, optionally substituted; 
         R2 represents alkoxy optionally substituted and R3 represents alkyl or alkoxy, optionally substituted; 
         R4 represents a hydrogen atom, a halogen atom or a cyano, alkyl or alkoxy radical, optionally substituted; 
         R5 represents a hydrogen or a halogen atom; 
         the alkyl, alkenyl and alkoxy radicals represented by R1, R2, R3 or R4 being optionally substituted by one or more identical or different radicals selected from halogen atoms and the following radicals: cyano; hydroxyl; oxo; nitro; —NR6R7; —C(═O)—NR6R7; —C(═O)—R9; —C(═O)—OR10; —N(R11)-C(═O)—R9; —N(R11)-C(═O)—OR10; —N(R11)-C(═O)—NR6R7; —S(O)n-R9; —N(R11)-S(O)n-R9; —S(O)n-NR6R7; —N(R11)-S(O)n-NR6R7; alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted; 
         R6 and R7, which may be identical or different, are selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl, all these radicals being optionally substituted, 
         or alternatively R6 and R7 form, with the nitrogen atom to which they are bound, a heterocyclic radical, unsaturated or alternatively partially or fully saturated, made up of 3 to 10 units and containing one or more heteroatoms selected from O, S, N and NR8, this heterocyclic radical being optionally substituted; 
         n represents an integer from 0 to 2; 
         R8 represents a hydrogen atom or an acyl, alkyl or aryl radical, optionally substituted; 
         R9 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl, all these radicals being optionally substituted; 
         R10 represents the values of R9 or hydrogen; 
         R11 represents hydrogen or alkyl, optionally substituted; 
         all these alkoxy, alkylthio, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl radicals which can be represented by R6, R7, R8, R9, R10 or R11 or which can constitute substituents of R1, R2, R3 and R4 as well as the heterocyclic radical that can be formed by R6 and R7 with the nitrogen atom to which they are attached, being optionally substituted by one or more identical or different radicals selected from halogen atoms and the following radicals: hydroxyl; oxo; nitro; cyano; cycloalkyl; acyl; carboxy free or esterified; alkoxy optionally substituted; amino optionally substituted by one or two identical or different radicals selected from acyl, alkyl, phenyl and phenylalkyl radicals, optionally substituted; pyrrolidinyl, piperidyl, piperazinyl, alkyl, phenyl and phenylalkyl, optionally substituted; 
         the above alkoxy, alkyl, pyrrolidinyl, piperidyl, piperazinyl, phenyl and phenylalkyl radicals being optionally substituted by one or more radicals selected from halogen atoms and the radicals hydroxyl, oxo, nitro, cyano, alkyl, hydroxyalkyl, CF3, alkoxy, hydroxyalkoxy, OCF3, carboxy free or esterified, amino, mono or dialkylamino, phenyl, phenylalkyl, pyrrolidinyl, piperidyl and pyridyl; 
         all the above aryl, heteroaryl and heterocycloalkyl radicals being moreover optionally substituted by an alkylenedioxy radical; 
         all the above alkyl, alkenyl, alkoxy and alkylthio radicals being linear or branched and containing at most 6 carbon atoms; 
         all the above cycloalkyl radicals containing at most 7 carbon atoms; 
         all the above aryl, heteroaryl and heterocycloalkyl radicals containing at most 10 carbon atoms; 
         or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base; 
         or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt. 
       
     
     
         3 ) The compound of formula (I) according to  claim 1  in which:
 R1 represents alkyl or alkenyl, optionally substituted;   R2 represents alkoxy optionally substituted and R3 represents alkyl or alkoxy, optionally substituted;   R4 represents a hydrogen atom, a halogen atom or a cyano, alkoxy or alkyl radical, optionally substituted;   R5 represents a hydrogen atom or a halogen atom;   the alkyl, alkenyl and alkoxy radicals represented by R1, R2, R3 or R4 being optionally substituted by one or more identical or different radicals selected from halogen atoms and the following radicals: hydroxyl; oxo; nitro; —NR6R7; —C(═O)—NR6R7; —C(═O)—R9; —C(═O)—OR10; —N(R11)-C(═O)—R9; —N(R11)-C(═O)—OR10; —N(R11)-C(═O)—NR6R7; alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl, optionally substituted;   R6 and R7, which may be identical or different, are selected from hydrogen and alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals, all these radicals being optionally substituted;   or alternatively R6 and R7 form, with the nitrogen atom to which they are bound, a heterocyclic radical, unsaturated or alternatively partially or fully saturated, made up of 3 to 10 units and containing one or more heteroatoms selected from O, S, N and NR8, this heterocyclic radical being optionally substituted;   R8 represents hydrogen, acyl, alkyl or phenyl, optionally substituted;   R9 represents alkyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, all these radicals being optionally substituted;   R10 represents the values of R9 or hydrogen;   R11 represents hydrogen or alkyl, optionally substituted;   the alkoxy, alkylthio, alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl radicals, which can be represented by R6, R7, R8, R9, R10 or R11 or which can constitute substituents of R1, R2, R3 and R4 as well as the heterocyclic radical that can be formed by R6 and R7 with the nitrogen atom to which they are attached, being optionally substituted by one or more identical or different radicals selected from halogen atoms and the radicals hydroxyl; oxo; nitro; cyano; cycloalkyl; carboxy free or esterified; alkoxy; OCF3; hydroxyalkoxy; amino being optionally substituted by one or two identical or different radicals selected from the radicals acyl, alkyl, phenyl and phenylalkyl themselves optionally substituted; pyrrolidinyl, piperidyl and piperazinyl themselves optionally substituted by one or more radicals selected from the radicals hydroxyl, alkyl, alkoxy, carboxy free or esterified, phenyl and phenylalkyl; alkyl, phenyl and phenylalkyl optionally substituted;   the above alkyl, phenyl and phenylalkyl radicals being optionally substituted by one or more radicals selected from halogen atoms and the radicals hydroxyl, nitro, cyano, alkyl, CF3, alkoxy, hydroxyalkoxy, OCF3, carboxy free or esterified, amino, mono- and di-alkylamino, phenyl, pyrrolidinyl and pyridyl;   the phenyl and phenylalkyl radicals being moreover optionally substituted by a dioxol radical;   all the above alkyl, alkenyl, alkoxy and alkylthio radicals being linear or branched and containing at most 4 carbon atoms;   all the above cycloalkyl radicals containing at most 6 carbon atoms;   all the above heteroaryl and heterocycloalkyl radicals containing at most 10 carbon atoms;   or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base;   or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt.   
     
     
         4 ) The compound of formula (I) according to  claim 1  in which:
 R1 represents alkyl or alkenyl, optionally substituted;   R2 represents alkoxy optionally substituted;   R3 represents alkyl or alkoxy, optionally substituted;   R4 represents a hydrogen atom, a halogen atom or a cyano or alkyl radical, optionally substituted;   R5 represents hydrogen or halogen;   the alkyl, alkenyl and alkoxy radicals represented by R1, R2, R3 or R4 being optionally substituted by one or more identical or different radicals selected from halogen atoms; and the radicals hydroxyl; —NR6R7; —CO—NR6R7; carboxy free or esterified; alkoxy; heterocycloalkyl, heteroaryl and phenyl optionally substituted by one or more identical or different radicals selected from halogen atoms and the radicals hydroxyl, nitro, cyano, alkyl, CF3, carboxy free or esterified, alkoxy and phenyl;   R6 and R7, which may be identical or different, are selected from hydrogen or an alkyl, cycloalkyl, phenyl or heterocyclic radical selected from pyrrolidinyl, piperidyl, pyrimidinyl, thienyl, thiazolyl, pyran, furyl, tetrahydrofuryl, tetrahydro-furan-2-yl, imidazolinyl, piperazinyl, indolyl, pyrrole, benzopyran, quinolyl, pyridyl, purinyl and morpholinyl, all these radicals being optionally substituted;   or alternatively R6 and R7 form, with the nitrogen atom to which they are bound, a heterocyclic radical selected from the radicals pyrrolidinyl; imidazolyl; thiazolyl; diazepine; piperidyl; morpholinyl; piperazinyl; perhydro-1,4-diazepine; spiro[4.5]decane; pyrrolyl; dihydropyrrolyl; tetrahydropyrrolyl; tetrahydropyrrolo[3,4-c]pyrrolyl; 1-tetrahydro-pyrrolo[3,4-c]pyrrol-2-one; piperidinyl; indolinyl; pyrindolinyl; tetrahydroquinolinyl; thiazolidinyl; naphthyridyl; azetidine; and quinazolinyl; all these radicals being optionally substituted;   the alkyl, phenyl and heterocyclic radicals that can be represented by R6 and R7 as well as the heterocycle that can be formed by R6 and R7 with the nitrogen atom to which they are bound, being optionally substituted by one or more radicals selected from halogen atoms and the radicals hydroxyl; oxo; nitro; cyano; carboxy free or esterified; alkoxy; OCF3; amino optionally substituted by one or two identical or different radicals selected from acyl, alkyl, hydroxyalkyl, alkoxyalkyl, phenyl and phenylalkyl optionally substituted; pyrrolidinyl; piperidyl; piperazinyl; alkyl, phenyl and phenylalkyl optionally substituted;   the above alkyl, phenyl and phenylalkyl radicals being optionally substituted by one or more identical or different radicals selected from halogen atoms and the radicals hydroxyl, nitro, cyano, alkyl, CF3, alkoxy, hydroxyalkoxy, carboxy free or esterified, phenyl and pyridyl;   all the alkyl and alkoxy radicals being linear or branched and containing at most 4 carbon atoms;   or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base;   or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt.   
     
     
         5 ) The compound of formula (I) according to  claim 1 , in which R1, R2, R3, R4 and R5 are as defined in  claim 1 , and wherein:
 R6 and R7, which may be identical or different, are selected from the radicals hydrogen, alkyl, hydroxyalkyl, pyrrolidinylalkyl, piperidylalkyl, piperazinylalkyl, phenyl and phenylalkyl in which the alkyl, phenyl and piperazinyl radicals are optionally substituted;   or alternatively R6 and R7 can form, with the nitrogen atom to which they are bound, a heterocyclic radical selected from the following radicals: thiazolyl; diazepine; perhydro-1,4-diazepine; 1-tetrahydro-pyrrolo[3,4-c]pyrrol-2-one; piperidyl; morpholinyl; piperazinyl; all these radicals being optionally substituted;   the above alkyl, phenyl and piperazinyl radicals as well as the heterocycle that can be formed by R6 and R7 with the nitrogen atom to which they are bound, being optionally substituted by one or more identical or different radicals selected from the hydroxyl; oxo; piperidyl; alkyl and phenyl radicals themselves optionally substituted by one or more identical or different radicals selected from the halogen atoms and the hydroxyl, alkoxy and hydroxyalkoxy radicals;   the phenyl radicals being moreover optionally substituted by one or more alkyl radicals;   the alkyl and alkoxy radicals containing at most 4 carbon atoms;   or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base;   or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt.   
     
     
         6 ) The compound according to  claim 1  of formula (Ia) 
       
         
           
           
               
               
           
         
         in which: 
         R1a represents hydrogen, alkyl optionally substituted by one or more identical or different substituents selected from halogen atoms; an alkoxy radical, itself optionally substituted by hydroxyl or alkoxy; a radical NR6R7 or a radical —C(═O)—NR6R7; 
         R2a and R3a, which may be identical or different, represent alkoxy; 
         R4a represents a hydrogen atom; a halogen atom; a dioxolane radical; a —CH═O; —CH═N—OH; —CH═N-phenyl radical with phenyl optionally substituted by —OH or alkoxy; or a cyano or alkyl radical, optionally substituted by one or more identical or different radicals selected from halogen atoms, hydroxyl, alkoxy, phenoxy or thiophenylsulfanyl radicals and the radical NR6R7; 
         R5a represents a hydrogen atom or chlorine or fluorine; 
         R6 and R7 are as defined in  claim 1 ; 
         or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base; 
         or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt. 
       
     
     
         7 ) The compound according to  claim 1  of formula (Ia): 
       
         
           
           
               
               
           
         
         in which R1a represents alkyl optionally substituted by a NR6R7 radical; 
         R2a and R3a, which may be identical or different, represent alkoxy; 
         R4a represents a hydrogen atom, a halogen atom or a cyano or alkyl radicals optionally substituted by one or more radicals selected from halogen atoms, alkoxy radicals and an NR6R7 radical; 
         R5a represents a hydrogen atom or chlorine or fluorine; 
         R6 and are R7 are as defined in  claim 1 ; 
         or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base; 
         or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt. 
       
     
     
         8 ) The compound of formula (I) according to  claim 1 , in which R1, R2, R3 and R5 are as defined in  claims 1 , and R4 is selected from a hydrogen atom or chlorine or fluorine,
 or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base;   or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt.   
     
     
         9 ) The compound of formula (I) according to  claim 1 , in which R1, R2, R3 and R4 are as defined in  claims 1  and R5 represents hydrogen or fluorine;
 or an addition salt of said compound with a mineral or organic acid or with a mineral or organic base;   or a racemic mixture, enantiomer, diastereoisomer or mixture thereof of said compound or said salt.   
     
     
         10 ) A pharmaceutical composition containing, as active principle, at least one compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         11 ) A pharmaceutical composition containing, as active principle, at least one compound according to  claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         12 ) A pharmaceutical composition according to  claim 8 , additionally containing active principles of other medicinal products for chemotherapy against cancer. 
     
     
         13 ) A method for inhibiting the activity of a protein kinase, comprising adding a compound according to  claim 1  to a composition comprising a protein kinase. 
     
     
         14 ) The method according to  claim 13 , wherein the protein kinase is in a cell culture. 
     
     
         15 ) The method according to  claim 13 , wherein the protein kinase is in a mammal. 
     
     
         16 ) A method for treating or preventing a disease or disorder by inhibiting a protein kinase comprising administering to a person in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         17 ) The method according to  claim 16  wherein the protein kinase is a protein-tyrosine kinase. 
     
     
         18 ) The method according to  claim 16  wherein the protein kinase is selected from IGF1, Raf, EGF, PDGF, VEGF, Tie2, KDR, Flt1-3, FAK, Src, Abl, cKit, cdk1-9, Aurora1-2, cdc7, Akt, Pdk, S6K, Jnk, IR, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, PLK, Pyk2, CDK7, CDK2 and EGFR. 
     
     
         19 ) The method according to  claim 16  wherein the protein kinase is selected from IGF1, cdc7, Aurora1-2, Src, Jnk, FAK, KDR, IR, Tie2, CDK7, CDK2 and EGFR. 
     
     
         20 ) The method according to  claim 16  wherein the protein kinase is IGF1R. 
     
     
         21 ) A method for treating or preventing a disease characterized by dysfunction of the activity of a protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         22 ) The method according to  claim 21  wherein the disease is selected from the group consisting of disorders of proliferation of blood vessels, fibrotic disorders, disorders of proliferation of mesangial cells, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, thromboses, diseases of the nervous system, retinopathies, psoriasis, rheumatoid arthritis, diabetes, muscular degeneration, geriatrics, muscular degeneration due to age, diseases in oncology, and cancers. 
     
     
         23 ) The method according to  claim 21  wherein the disease to be treated is cancer. 
     
     
         24 ) The method according to  claim 21  wherein the disease to be treated is a cancer with solid tumors. 
     
     
         25 ) The method according to  claim 21  wherein the disease to be treated is a cancer that is resistant to cytotoxic agents. 
     
     
         26 ) A method of treating breast cancer, stomach cancer, colon cancer, lungs, ovarian cancer, uterine cancer, brain cancer, kidney cancer, cancer of the larynx, cancer of the lymphatic system, cancer of the thyroid, cancer of the urogenital tract, bone cancer, cancer of the pancreas, or a melanoma, in a patient in need thereof, comprising administering to such patient a pharmaceutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         27 ) A method of treating cancer, in a patient in need thereof, comprising administering to such patient a pharmaceutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with chemotherapy or radiotherapy or in combination with at least one other therapeutic agent. 
     
     
         28 ) A method according to  claim 27 , wherein the therapeutic agent is a commonly used antitumour agent.