WO2016207345A1 - Dérivés de 3-amino-pyrazin-2-yl carboxamide et 2-amino-pyridin-3-yl carboxamide en tant qu'inhibiteurs de la kinase 1 de type polo (plk -1) pour le traitement du cancer - Google Patents

Dérivés de 3-amino-pyrazin-2-yl carboxamide et 2-amino-pyridin-3-yl carboxamide en tant qu'inhibiteurs de la kinase 1 de type polo (plk -1) pour le traitement du cancer Download PDF

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WO2016207345A1
WO2016207345A1 PCT/EP2016/064659 EP2016064659W WO2016207345A1 WO 2016207345 A1 WO2016207345 A1 WO 2016207345A1 EP 2016064659 W EP2016064659 W EP 2016064659W WO 2016207345 A1 WO2016207345 A1 WO 2016207345A1
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alkyl
arom
heterocycle
compound
optionally substituted
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El Bachir Kaloun
Karim Bedjeguelal
Celine Mordant
Remi Rabot
Isabelle TAMBURLIN
Emmanuel FOURNIER
Philippe Schmitt
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Pierre Fabre Medicament SA
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Pierre Fabre Medicament SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel amino-pyridine and amino-pyrazine derivatives, their methods of preparation, pharmaceutical compositions containing the same and their use as a drug, in particular as PLK-1 inhibitors, especially for treating cancer.
  • Protein Kinases form a class of enzymes which transferring phosphate groups to substrates, other protein kinases or even themselves put them at the core of most signalling pathways. They are numerous as wild type isoforms as well as disease-causing mutated variants. Their dysregulated expression either through mutation, overexpression or amplification is often a potent driver to carcinogenesis and, as such, qualifies them as highly relevant targets to fight against neoplasia.
  • Polo-like Kinase 1 is a still undrugged serine/threonine protein kinase whose many functions qualify it as highly relevant to fight tumorigenesis.
  • Polo-Like Kinases Although four variants of Polo-Like Kinases are known in humans (PLK1-4), only PLK1 inhibition by a small molecule is documented to be sufficient to trigger a full G2/M cell cycle block, induction of apoptosis into cancerous cell line and tumor shrinkage in xenografted tumor models.
  • PLK1 has been described in several neoplastic conditions such as breast cancer, colorectal cancer, endometrial carcinoma, non small cell lung cancer, pancreatic cancer, ovarian cancer and head-and-neck squamous cell carcinomas .
  • PLK1 has also been linked to cancer-specific functions associated with PI3K and MAPK pathways as well as with activation of oncogenic chimeric transcription factors (PAX3-FOX01) .
  • the present invention relates thus to a compound of following Formula (I) :
  • A is N or C-H
  • Y is 0, S or one of the following groups : sulfoxide (S(0)), sulfone (S(0) 2 ) or N(R 3 ) with R 3 being H, or an optionally substituted alkyl, acyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl or heteroaryl;
  • Ri is H or an optionally substituted alkyl, acyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl or heteroaryl;
  • Ri and R 3 may optionally be together included into any optionally substituted 4 to 7-membered heterocycle or 8 to 10- membered heterobicycle;
  • R 2 is any of the optionally substituted following groups: alkyl, acyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heteroaryl-alkyl , heterocycle-alkyl or heteroaryl, preferably alkyl, acyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl or heteroaryl .
  • pharmaceutically acceptable means that which is used for preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable and that is acceptable for veterinary use as well as for human pharmaceutical use.
  • salts that are pharmaceutically acceptable, as defined herein, and that have the desired pharmacological activity of the parent compound.
  • Such salts include :
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and similar; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p- toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and similar; and
  • salts formed when an acid proton present in the parent compound is either replaced by a metal ion, for example an alkaline metal ion (Na + , K + or Li + for example) , an alkaline-earth metal ion (such as Ca 2+ or Mg 2+ ) or an aluminium ion; or coordinates with an organic or inorganic base.
  • a metal ion for example an alkaline metal ion (Na + , K + or Li + for example) , an alkaline-earth metal ion (such as Ca 2+ or Mg 2+ ) or an aluminium ion; or coordinates with an organic or inorganic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and similar.
  • Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • halogen means fluorine (F) , bromine (Br) , chlorine (CI) , or iodine (I) .
  • alkyl refers to a straight or branched saturated hydrocarbon chain containing preferably from 1 to 6 carbon atoms (i.e. (Ci-C 6 ) alkyl ) , including, but not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n- hexyl, and the like.
  • alkenyl refers to a straight or branched unsaturated hydrocarbon chain containing preferably from 2 to 6 carbon atoms, and comprising at least one double bond, notably one double bond, including, but not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • alkynyl refers to a straight or branched unsaturated hydrocarbon chain, containing preferably from 2 to 6 carbon atoms, and comprising at least one triple bond, notably one triple bond, including, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • cycloalkyl relates to a saturated hydrocarbon monocycle or bicycle containing preferably from 3 to 10 carbon atoms, advantageously to a saturated hydrocarbon monocycle containing from 3 to 8, notably 3, 5 or 6 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decaline, norbornane, bicyclo [ 3.2.1 ] octane and the like.
  • the two cycles can be fused, bridged or have a spiro configuration.
  • the term "cycloalkyl" refers to cyclopropyl, cyclopentyl or cyclohexyl.
  • aryl refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more fused rings, such as, for example, a phenyl or naphtyl group.
  • fused rings such as, for example, a phenyl or naphtyl group.
  • it will be a phenyl group.
  • aralkyl or "aryl-alkyl” , as used in the present invention, refers to an aryl group as defined above bound to the molecule via a alkyl group as defined above, preferably via a (Ci-C 6 ) alkyl group, in particular via a (Ci-C 2 ) alkyl group.
  • heterocycle refers to a saturated, unsaturated or aromatic hydrocarbon monocycle or bicycle, in which one or more, in particular one to three, preferably one or two, carbon atoms have been replaced with a heteroatom selected from 0, N and S, preferably selected from 0 and N.
  • each cycle is a 3- to 7-membered, preferably 5- to 6-membered, cycle.
  • the two cycles can be fused, bridged or have a spiro configuration.
  • heterocycle could be used then to refer to a heterocycle comprising 2 cycles.
  • the term "4 to 7-membered heterocycle”, as used in the present invention, refers to a heterocycle as defined above comprising one cycle having 4 to 7 members, such as a pyrrole or a pyrazole.
  • the term “8 to 10-membered heterobicycle”, as used in the present invention refers to a heterocycle as defined above comprising two cycles having 8 to 10 members, such as a benzimidazole or a benzotriazole .
  • heteroaryl refers to an aromatic heterocycle as defined above.
  • the heteroaryl is an aromatic hydrocarbon monocycle or bicycle (i.e. comprising two fused rings), each cycle having 5 or 6 members, notably 6 members, and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a nitrogen, a oxygen or a sulfur atom, preferably a nitrogen or oxygen atom, notably a nitrogen atom.
  • a heteroaryl can be notably thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazoles ( 1 , 2 , 3-triazole and 1 , 2 , 4-triazole ) , benzofuran, indole, azaindole, benzothiophene , benzimidazole, benzotriazole , benzoxazole, benzisoxazole , benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, etc.
  • it will be a pyridine, an indole, a furan, a thiophene, an azaindole notably a 7-azaindole or an indazole, a benzimidazole, or a benzothiophene.
  • heterocycle-alkyl refers to a heterocycle group as defined above bound to the molecule via an alkyl group as defined above, preferably via a ( Ci- C 6 ) alkyl group, in particular via a ( Ci-C 2 ) alkyl group.
  • heteroaryl-alkyl refers to a heteroaryl group as defined above bound to the molecule via an alkyl group as defined above, preferably via a ( Ci- C 6 ) alkyl group, in particular via a ( Ci- C 2 ) alkyl group.
  • acyl refers to a group of formula -C (0) R, wherein R is an alkyl group, preferably a ( Ci- C 6 ) alkyl group.
  • Y, R x and R 3 may optionally be together included into any optionally substituted 4 to 7-membered heterocycle or 8 to 10-membered heterobicycle” means that when Y is NR 3 , R x and R 3 are together included into an optionally substituted 4 to 7-membered heterocycle or 8 to 10-membered heterobicycle.
  • the heterocycle or heterobicycle thus comprises at least one nitrogen atom which carries the group R 3 .
  • Y is S, 0 or a sulfone group (-S(0) 2 -) . More particularly, Y is S.
  • Y is N(R 3 ) and Ri and R 3 are together included into an optionally substituted 4 to 7-membered heterocycle or 8 to 10-membered heterobicycle, preferably into a 4 to 7-membered heterocycle or 8 to 10-membered heterobicycle comprising 1 to 3 nitrogen atoms, in particular a 8 to 10-membered heterobicycle comprising 1 to 3 nitrogen atoms, more particularly a heterobicycle selected from the group consisting of benzotriazole and benzimidazole .
  • R x is an optionally substituted aryl or heteroaryl .
  • Ri is an optionally substituted phenyl or pyridyl.
  • Ri is an optionally substituted phenyl or an unsubstituted pyridyl.
  • Ri is an aryl or heteroaryl, in particular a pyridyl or phenyl, notably a phenyl, optionally substituted with one or two substituent ( s ) selected from the group consisting of: halogen, nitro (N0 2 ) , R 4 , -0R 5 , -NR 7 R 8 , -C ( 0 ) R 9 , -C(O)ORi 0 , C(0) RiiRi 2 , -0C(0) Ri 3 , -NR i C (0) R15, and -NRi 6 C (0 ) Ri 7 Ri 8 ; R 4 to R 23 being, independently of one another, a hydrogen atom or one of the following groups: (Ci-C 6 ) alkyl , cycloalkyl, aryl, aralkyl, heterocycle, and heterocycle-alkyl, notably (Ci-C 6 ) alkyl , cycloalkyl, heterocycle,
  • Ri is an aryl or heteroaryl, in particular a pyridyl or phenyl, notably a phenyl, optionally substituted with one or two substituent ( s ) selected from the group consisting of: halogen, nitro (N0 2 ) , R 4 , -OR 5 , -NR 7 R 8 , - C ( 0 ) RnRi 2 , -NR 14 C ( 0 ) R i 5 , and -NRi 6 C ( 0 ) Ri 7 Ri 8 ; R 4 to R 23 being, independently of one another, a hydrogen atom or one of the following groups: ( Ci-C 6 ) alkyl , cycloalkyl, aryl, aralkyl, heterocycle, and heterocycle-alkyl, notably ( Ci-C 6 ) alkyl, cycloalkyl, heterocycle, and heterocycle- alkyl, said group being optionally substituted with one or more, preferably one to
  • the aryl of the aryl and aralkyl groups is advantageously a phenyl or naphtyl, in aprticular a phenyl.
  • the cycloalkyl comprises advantageously 3 to 6 carbon atoms, such as a cyclopropyl, a cyclopentyl or a cyclohexyl, in particular a cyclopropyl or a cyclohexyl .
  • the heterocycle of the heterocycle and heterocycle-alkyl groups is advantageously a saturated heterocycle. It will advantageously contain at least one, notable one to three, such as one or two, nitrogen atoms and optionally one or two, notably one oxygen atoms. It can be a saturated 4- to 7-, such as 5- or 6-membered heterocycle comprising one cycle and comprising one to three, such as one or two nitrogen atoms and optionally one or two, notably one oxygen atoms. It can be a pyrrolidine, piperidine, piperazine or morpholine cycle, such as a pyrrolidine, piperidine, or piperazine cycle, in particular a pyrrolidine or piperidine cycle .
  • R 2 is a group selected from (d-C 6 ) alkyl, aryl- (d-C 6 ) alkyl, aryl, heteroaryl, heterocycle- (Ci-C 6 ) alkyl or heteroaryl- (d-C 6 ) alkyl , in particular aryl- (d ⁇ d) alkyl, aryl, heteroaryl, heterocycle- (d ⁇ d) alkyl or heteroaryl- (d ⁇ d) alkyl, such as aryl- (d _ d) alkyl, aryl, heteroaryl, heterocycle- (d _ d) alkyl or heteroaryl- (d _ d) alkyl, more particularly aryl- (d ⁇ d) alkyl or heteroaryl- (d ⁇ d) alkyl , such as aryl- (d _ d) alkyl or heteroaryl- (d _ d) alkyl , wherein the aryl (in the
  • R 2 is a group selected from aryl- (d-C 6 ) alkyl , aryl, heteroaryl, heterocycle- (Ci-C 6 ) alkyl or heteroaryl- (d-C 6 ) alkyl , such as aryl- (Ci-C 2 ) alkyl , aryl, heteroaryl, heterocycle- (Ci-C 2 ) alkyl or heteroaryl- (d- d) alkyl, more particularly aryl- (d _ d) alkyl or heteroaryl- (d _ d) alkyl, such as aryl- (d _ d) alkyl or heteroaryl- (d _ d) alkyl , wherein the aryl (in the aryl and aryl-alkyl groups) is a phenyl or a naphtyl; and the heterocycle and heteroaryl (in the heterocycle, heterocycle-alkyl, heteroaryl, heteroaryl, heteroaryl
  • R 27 to R 46 being, independently of one another, an hydrogen atom or one of the following groups: (Ci-C 6 ) alkyl , aralkyl, and heterocycle-alkyl , said groups being optionally substituted with one or more, preferably one to five, notably one to two, halogen, (d-C 6 ) alkyl , NR 47 R 48 or OR 49 , R 47 to R 49 being an hydrogen atom or
  • R 2 is a group selected from aryl- (d-C 6 ) alkyl , aryl, heteroaryl, heterocycle- (Ci-C 6 ) alkyl or heteroaryl- (d-C 6 ) alkyl , such as aryl- (Ci-C 2 ) alkyl , aryl, heteroaryl, heterocycle- (Ci-C 2 ) alkyl or heteroaryl- (d _ d) alkyl, more particularly aryl- (d _ d) alkyl or heteroaryl- (d _ d) alkyl, such as aryl- (d _ d) alkyl or heteroaryl- (d _ d) alkyl , wherein the aryl (in the aryl and aryl-alkyl groups) is a phenyl or a naphtyl; and the heterocycle and heteroaryl (in the heterocycle, heterocycle-alkyl, heteroaryl, heteroaryl, heteroary
  • the present invention relates to a compound of formula (I) wherein:
  • ⁇ A is N or C-H, preferably N;
  • Y is S, 0 or a sulfone group (-S(0) 2 -), preferably S;
  • Ri is a phenyl, optionally substituted with one or two, substituent ( s ) , preferably selected from the group consisting of: halogen, nitro (N0 2 ) , R , -0R 5 , -NR 7 R 8 , -C (0) RnRi 2 , -NR i4 C (0) R i5 , and -NRi 6 C (0) Ri 7 Ri 8 ; R to Ri 8 being, independently of one another, an hydrogen atom or one of the following groups: a (Ci-C 6 ) alkyl , cycloalkyl, heterocycle, and heterocycle-alkyl, said group being optionally substituted with one to three, halogen, (d-C 6 ) alkyl , NR 2 R 2 5 or OR 26 , 24 to R 26 being an hydrogen atom or a (Ci-C 6 ) alkyl .
  • substituent ( s ) preferably selected from the group consisting of: halogen,
  • the present invention relates to a compound of formula (I) wherein:
  • A is N or C-H, preferably N
  • Y is S, 0 or a sulfone group (-S(0) 2 -), preferably S;
  • ⁇ Ri is a phenyl, optionally substituted with a -C(0)NRnRi 2 group, R 11 and R i2 being an hydrogen atom or a (Ci-C 6 ) alkyl , preferably an hydrogen atom.
  • the present invention relates to a compound of formula (I) wherein:
  • A is N or CH, preferably N;
  • Ri and R 3 are together included into an optionally substituted 4 to 7-membered heterocycle or 8 to 10-membered heterobicycle, preferably into a 4 to 7-membered heterocycle or 8 to 10-membered heterobicycle comprising 1 to 3 nitrogen atoms, in particular a a 8 to 10-membered heterobicycle comprising 1 to 3 nitrogen atoms, more particularly a heterobicycle selected from the group consisting of benzotriazole and benzimidazole.
  • the present invention relates to a compound of formula (I) wherein:
  • Ri is phenyl optionally substituted by one of the following groups: hydroxy, hydroxy-alkyl more particularly hydroxymethyl , In the above definitions of Ri :
  • the alkyl group is preferably a (Ci-C 6 )alkyl group, in particular a (C 1 -C3) alkyl group;
  • the aryl group in the aryl and aralkyl groups is preferably a phenyl group
  • heteroaryl in the heteroaryl and heteroaryl-alkyl groups is preferably a pyridyl group
  • the cycloalkyl group is preferably a (C 3 -C 6 ) cycloalkyl group, in particular a cyclopropyl, cyclopentyl or a cyclohexyl, such as a cyclopropyl or a cyclohexyl; and
  • the heterocycle group in the heterocycle and heterocycle-alkyl groups is preferably a saturated heterocycle containing at least one, notable one to three, such as one or two, nitrogen atoms and optionally one or two, notably one oxygen atoms. It can be a saturated 4- to 7-, such as 5- or 6-membered heterocycle comprising one cycle and comprising one to three, such as one or two nitrogen atoms and optionally one or two, notably one oxygen atoms. It can be a pyrrolidine, piperidine, piperazine or morpholine cycle, such as a pyrrolidine, piperidine, or piperazine cycle, in particular a pyrrolidine or piperidine cycle.
  • R 2 In the above definitions of R 2 :
  • the alkyl group is preferably a (Ci-C 6 )alkyl group, in particular a (Ci-C 4 ) alkyl group, more particularly a (Ci ⁇ C 2 ) alkyl group;
  • the aryl group in the aryl and aralkyl groups is preferably a phenyl or a naphtyl
  • the heteroaryl group in the heteroaryl and heteroaryl-alkyl groups is preferably a heteroaryl comprising one or two fused cycles comprising one to three, notably one or two, heteroatoms selected from 0, S and N, such as a thiophene, a furane, a pyrrole, a pyrazole, an imidazole, an oxazole, an isoxazole, a thiazole, an isothiazole, a triazole, a pyridine, an indole, an azaindole (such as an indazole or a 7-azainole) , an indoline, a benzofurane or a benzothiophene, in particular a thiophene, a furane, a pyridine, an indole, an indazole, a 7-azainole, an indoline or a benzothiophene, for example an indole
  • the heterocycle group in the heterocycle and heterocycle-alkyl groups is preferably a saturated 4- to 7-, notably 5- or 6- membered heterocycle comprising one to three, notably one or two heteroatoms chosen from 0, N and S, notably chosen from N and 0, such as a pyrrolidine, piperidine, piperazine or morpholine cycle, in particular a piperazine or morpholine cycle .
  • the compound according to the present invention can be in particular selected from the compounds 1001 to 1119 of the examples below and the pharmaceutically acceptable salts thereof.
  • the present invention also relates to a compound of formula (I) as defined above for use as a drug, in particular as PLK-1 inhibitors, notably for treating cancer.
  • the invention also relates to the use of a compound of the invention for manufacturing a drug, notably useful as PLK-1 inhibitors, in particular intended for treating cancer.
  • the invention further relates to a method for treating cancer, comprising the administration of an effective quantity of at least one compound of formula (I) as defined above to a patient in need thereof.
  • the cancer can be more particularly in this case a colon cancer, breast cancer, kidney cancer, liver cancer, pancreas cancer, prostate cancer, lung cancer, ovarian cancer, head and neck cancer, glioblastoma, neuroblastoma, lymphoma, leukaemia, inflammatory myofibroblastic tumour, myelodysplastic syndrome, or myelofibrosis .
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention and at least one pharmaceutically acceptable carrier.
  • the compound of the invention can be administered by oral, sublingual, parenteral, subcutaneous, intramuscular, intravenous, transdermal, local or rectal route, preferably by oral, intravenous or subcutaneous route.
  • the active ingredient can be administered in unit dosage forms, in mixture with traditional pharmaceutical carriers, to animals or humans .
  • Suitable unit dosage forms comprise forms for oral route such as tablets, gelatine capsules, powders, granules and oral solutions or suspensions; sublingual and oral administration forms; parenteral, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms; and forms for rectal administration.
  • the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
  • the tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.
  • a preparation in gelatin capsules can be obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or an elixir may contain the active ingredient together with a sweetener, an antiseptic, a taste enhancer or a suitable coloring agent.
  • the water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents, wetting agents, or suspending agents, and with flavor correctors or sweeteners.
  • aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents can be used.
  • the active principle may also be formulated in the form of microcapsules, optionally with one or more carrier additives.
  • the compounds of the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day.
  • the daily administered dose is advantageously comprises between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art.
  • compositions according to the present invention can further comprise at least another active principle, such as an anticancer agent.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the present invention also relates to a pharmaceutical composition as defined previously for use as a drug, in particular as PLK-1 inhibitors, notably for treating cancer.
  • the present invention also relates to a method for treating cancer comprising the administration to a person in need thereof of an effective amount of a pharmaceutical composition according to the invention.
  • the present invention relates also to the processes to prepare the compound according to the present invention.
  • the present invention concerns thus a first process to prepare a compound according to the present invention comprising the following steps:
  • step (bl) optionally salifying the compound of formula (I) obtained in step (al) to give a pharmaceutically acceptable salt of a compound of formula (I) .
  • activated form of COOH is meant a COOH group in which the OH moiety has been replaced with an activated leaving group (LG) enabling coupling of the activated COOH group with an amino group by formation of an amide bond and release of the compound LG-H.
  • Activated forms may be activated esters, activated amides, anhydrides or acyl halides such as acyl chlorides.
  • Activated esters include derivatives formed by reaction of the COOH group with N-hydroxybenzotriazole or N-hydroxysuccinimide . It can be in particular COC1.
  • step (al) can be performed by a peptide coupling .
  • the peptide coupling will be advantageously carried out in the presence of a coupling agent, such as diisopropylcarbodiimide (DIC) , dicyclohexylcarbodiimide (DCC) , 1- (3-dimethylaminopropyl ) - 3-ethylcarbodiimide hydrochloride (EDC) , carbonyldiimidazole (CDI), hexafluorophosphate 2- ( lH-benzotriazole-l-yl ) -1 , 1 , 3 , 3- tetramethyluronium (HBTU) , tetrafluoroborate 2- ( lH-benzotriazole- 1-yl) -1, 1, 3, 3-tetramethyluronium (TBTU) , hexafluorophosphate 0- (7-azobenzotriazol-l-yl) -1,1,3, 3-tetramethyluronium (HATU) , (benzotriazol-l
  • This reaction can be carried out for example in dimethylformamide (DMF) as solvent.
  • DMF dimethylformamide
  • reaction can be performed in the presence of a base in conditions well-known to the one skilled in the art.
  • X 3 CO- (Ci-C 6 ) alkyl, such as COMe or COEt, notably COMe, and A, Y and Ri are as defined previously.
  • the hydrolysis can be performed in acidic conditions or basic conditions (saponification) . It can be performed notably according to Heterocycles , 2005, vol. 65(10), 2321-2327 or US5252538.
  • the compound of formula (IV) can be prepared by coupling of a compound of formula RiYH with Y and Ri as defined above and a compound of following formula
  • the salification step can be carried out by methods well known to the one skilled in the art, in particular by reaction of the compound of formula (I) obtained in step (a) with a pharmaceutically acceptable acid (organic or inorganic acid) , base (organic or inorganic base) or solvent, as defined previously .
  • a pharmaceutically acceptable acid organic or inorganic acid
  • base organic or inorganic base
  • solvent solvent
  • a and R 2 are as defined previously, and X 2 represents a halogen atom, such as CI, Br or I,
  • step (b2) optionally salifying the compound of formula (I) obtained in step (a2) to give a pharmaceutically acceptable salt of a compound of formula (I) .
  • Step (a2) The coupling reaction of step (a2) can be performed notably in the presence of Cul .
  • the compound of formula (III) can be prepared by coupling of a compound of formula R 2 NH 2 and a compound of following formula (VI) :
  • Such a coupling reaction can be carried out in the conditions detailed in step (al) above.
  • Step (b2) cf. step (bl)
  • Protection / deprotection steps or functionalization steps can be carried out in the processes described above, such steps and their reaction conditions being well known to the one skilled in the art.
  • the compound obtained can be separated from the reaction medium by methods well known to the person skilled in the art, such as by extraction, evaporation of the solvent or by precipitation or crystallisation (followed by filtration) .
  • the compound can also be purified if necessary by methods well known to the person skilled in the art, such as by recrystallisation, by distillation, by chromatography on a column of silica gel or by high performance liquid chromatography (HPLC) .
  • methods well known to the person skilled in the art such as by recrystallisation, by distillation, by chromatography on a column of silica gel or by high performance liquid chromatography (HPLC) .
  • the main final product may either be an ester (-3a-z-) or an acid (-4a-z-) derivative.
  • esterification of acids to the corresponding methyl or ethyl esters were conducted using standard well-known procedures (ex.: Heterocycles, 2005, vol. 65(10), 2321-2327; US5252538) .
  • reaction mixture is agitated for a two hours period while the temperature is progressively allowed to rise to ambient and then to 50°C.
  • Reaction crude is then poured into 25 mL of dichloromethane and successively washed with NaHC0 3 saturated water, water and brine. The combined organic layers are dried over Na 2 S0 4 , evaporated to dryness and the crude purified by preparative reverse-phase HPLC (yield: 74%) .
  • Molecules are designated by an incremented four digits serial number followed, if available, by a 1 digit & 1-2 letters code referencing the synthetic methodology used for its synthesis .
  • Substrate coated 96- ell microplates [Packard #6005182] are generated by addition of 100 ⁇ per well of a lmg/ml phosphate buffer saline (PBS) solution of dephosphorylated casein [Sigma # C-4032] for two hours under mild agitation. Casein solution is then replaced with blocking solution comprising 5% bovine serum albumin (BSA) [Sigma #B-7906] in PBS buffer and placed two hours under mild agitation.
  • PBS lmg/ml phosphate buffer saline
  • BSA bovine serum albumin
  • Compound is added to the desired final concentration (typical range between 30 ⁇ and 10 nM) and the enzymatic reaction is carried out for 30 minutes at 30°C under the following condition: Tris 20mM pH 7.5; MgCl 2 lOmM; dithiothreitol (DTT) ImM ; ⁇ -glycerophosphate 40mM; sodium orthovanadate ImM; glycerol 2%; adenosine 5 ' -triphosphate (ATP) [Sigma #A-2383] 20 ⁇ and 0.5 ⁇ 1 of purified PLK1 in a final volume of ⁇ per well.
  • DTT dithiothreitol
  • ⁇ -glycerophosphate 40mM sodium orthovanadate ImM
  • glycerol 2% adenosine 5 ' -triphosphate (ATP) [Sigma #A-2383] 20 ⁇ and 0.5 ⁇ 1 of purified PLK1 in a final volume of ⁇ per well.
  • the level of PLKl-dependent casein phosphorylation is detected by sequential addition of ⁇ of anti-Phospho-Threonine antibody [Cell Signaling #9381] and Horseradish Peroxidase (HRP) conjugated anti-rabbit antibody [Amersham #NA934V] intertwined with washing steps in PBS tween-20 0.1%. Both antibodies are diluted to 1/1000 in 5% BSA PBS solution and left for incubation at room temperature for 1 hour. The reaction is finally quantified by addition of chemiluminescent HRP substrate SuperSignal ELISA Pico according to manufacturer's instruction [Pierce #37070] and detected with Envision plate reader [Perkin Elmer] .
  • A549 human lung adenocarcinoma epithelial cell line
  • HCT116 human colon cancer cell lines
  • Namalwa human Burkitt lymphoma cell lines
  • Adherent cells (either from A549 or HCT116) and nonadherent cells (Namalwa cell lines) are transferred into 96-well plates (10 000 cells/ml for A549, 15 000 cells/ml for HCT116 and 300,000 cells/ml for Namalwa) at day 0 for A549 and HCT116, and day 1 for Namalwa, at a concentration compatible with logarithmic growth for the 72 hours required for the evaluation of the compounds. All of the cells are treated with the assayed molecules at day 1 and then placed in an incubator at 37 °C under an atmosphere of 5% C0 2 . Cell viability is evaluated at day 4 by assaying released ATP, which is characteristic of viable cells.
  • ATPLite induces a luminescent signal read by TopCount microplate reader.
  • IC50s are determined by nonlinear regression on the basis of a sigmoidal dose/response relationship model, wherein the Hill coefficient is left variable, carried out on the GraphPad (Prism) software package according to the algorithm provided . d) Results
  • Potencies are designated by IC 50 binned into four activity classes as follows:
  • D IC 50 > 10 ⁇
  • C 10 ⁇ > IC 50 > ⁇
  • B ⁇ > IC 50 > ⁇
  • A IC 50 ⁇ ⁇ ; not conducted.

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Abstract

La présente invention concerne des dérivés de 2-amino-pyridin-3-yl carboxamide et de 3-amino-pyrazin-2-yl decarboxamide correspondant à la formule (I) : (I) ou un sel pharmaceutiquement acceptable de ces derniers, où: • A est N ou C-H, • Y est 0, S ou l'un des groupes suivants : sulfoxyde (-S (O) -), sulfone (- S(0)2-) ou N (R3) avec R3 étant H ou un alkyle, acyle, alcényle, alcynyle, cycloalkyle, aralkyle, aryle ou hétéroaryle éventuellement substitué, • R1 est H ou un alkyle, acyle, alcényle, alcynyle, cycloalkyle, aralkyle, aryle ou hétéroaryle éventuellement substitué, ou lorsque Y est NR 3, R1 et R3 sont inclus ensemble dans un hétérocycle de 4 à 7 éléments éventuellement substitué ou un hétérobicycle de 8 à 10 éléments, et • R 2 est l'un quelconque des groupes suivants, éventuellement substitué: alkyle, acyle, alcényle, alcynyle, cycloalkyle, aralkyle, aryle, hétéroaryle-alkyle ou hétéroaryle. Ces dérivés peuvent être utilisés en tant qu'inhibiteurs de la kinase 2 de type polo pour le traitement du cancer; l'invention concerne aussi des compositions pharmaceutiques contenant un tel composé et des procédés pour préparer un tel composé.
PCT/EP2016/064659 2015-06-24 2016-06-24 Dérivés de 3-amino-pyrazin-2-yl carboxamide et 2-amino-pyridin-3-yl carboxamide en tant qu'inhibiteurs de la kinase 1 de type polo (plk -1) pour le traitement du cancer Ceased WO2016207345A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12600721B2 (en) 2021-02-19 2026-04-14 Sudo Biosciences Limited TYK2 inhibitors and uses thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12103937B2 (en) 2021-02-19 2024-10-01 Sudo Biosciences Limited Substituted pyridines and pyridazines as TYK2 inhibitors
US12122785B2 (en) 2021-02-19 2024-10-22 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US12600721B2 (en) 2021-02-19 2026-04-14 Sudo Biosciences Limited TYK2 inhibitors and uses thereof

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