WO2020157199A1 - Composés dihydropyridazinone annelés utilisés en tant que composés anticancéreux - Google Patents

Composés dihydropyridazinone annelés utilisés en tant que composés anticancéreux Download PDF

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WO2020157199A1
WO2020157199A1 PCT/EP2020/052293 EP2020052293W WO2020157199A1 WO 2020157199 A1 WO2020157199 A1 WO 2020157199A1 EP 2020052293 W EP2020052293 W EP 2020052293W WO 2020157199 A1 WO2020157199 A1 WO 2020157199A1
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group
salt
trifluoromethyl
phenyl
tautomer
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PCT/EP2020/052293
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English (en)
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Manuel ELLERMANN
Stefan Nikolaus GRADL
Detlev Sülzle
Charlotte Christine KOPITZ
Martin Lange
Adrian Tersteegen
Philip Lienau
Timothy A. Lewis
Heidi GREULICH
Xiaoyun Wu
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Bayer Aktiengesellschaft
The Broad Institute, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
    • 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

Definitions

  • the present invention includes annulated dihydropyridazinone compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for their preparation, pharmaceutical compositions and combinations and their use for the treatment or prophylaxis of diseases.
  • Phenotypic screening identified some of the compounds known in the literature to be PDE3 inhibitors to be useful for the treatment of certain cancers. Co-expression of PDE3A and/or PDE3B and Schlafen 12 (SLFN12) polynucleotides or polypeptides are typically required for cells to be sensitive. PDE3A/PDE3B inhibitors which cause drug sensitivity have been found to stabilze the formation of a complex between PDE3A and/or PDE3B and SLFN12. PDE3A and/or PDE3B inhibitors which do not cause inhibition of tumor cell proliferation typically do not stabilize the PDE3A- and/or PDE3B - SLFN12 complex. Some annulated dihydropyridazinone compounds are known from J. Het. Chem. 2004, 41 (2), 259; Eur.J.Med.Chem, 2015, 95, 349; EP231744, EP167995, EP0012366, and W02008/013838.
  • the compounds of the present invention have surprisingly been found to inhibit tumor cell proliferation with IC50 values of ⁇ 100 nM in e.g. HeLa cells. Additionally, the compounds do not inhibit enzymatic PDE3A and/or PDE3B at the concentration at which they inhibit tumor cell proliferation but at concentrations where IC50 values for enzymatic PDE3A and/or PDE3B inhibition may be > 10 times higher than IC50 values for tumor cell proliferation.
  • this distinction in inhibitory properties may be associated with PDE3A- and/or PDE3B- SLFN12 complex induction and/or improved pharmacokinetic parameters in vitro or in vivo and/or improved physicochemical properties and/or improved safety
  • the compounds described herein may therefore be used for the treatment or prophylaxis of
  • hyperproliferative diseases such as cancer diseases.
  • the present invention provides compounds of general formula (I) which modulate formation of a PDE3A- and/or a PDE3B-SLFN12 complex, methods for their preparation, pharmaceutical composition and the use thereof and methods of treatment or prophylaxis of diseases, in particular of hyperproliferative diseases more particularly of cancer diseases.
  • the present invention includes compounds of general formula (I):
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a Ci-C 3 -alkyl group, or a Ci-C 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • Ci-C 3 -alkyl group which is substituted one or more times with a group independently selected from a Ci-C 3 -alkyl group, a Ci-C 3 -alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a Ci-C 3 -alkyl group;
  • a C 2 -C 6 -alkenyl group which is optionally substituted with a Ci-C 3 -alkoxy group, a C 5 -C 6 -cycloalkenyl group;
  • Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from Ci-C 3 -haloalkyl group, a hydroxy group, a Ci-C 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6- membered heteroaryl group;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C 3 -alkyl group, a Ci-C 3 -hydroxyalkyl group and a Ci-C 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group;
  • R 2 is a hydrogen atom, or a halogen atom
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a CrC 3 -alkyl group, a CrC 3 -alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a CrC 3 -alkyl group; a C 2 -C 6 -alkenyl group, which is optionally substituted with a CrC 3 -alkoxy group, a C 5 -C 6 -cycloalkenyl group;
  • a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6- membered heteroaryl group;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • a C 5 -C 6 -cycloalkyl group or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same, for use in the prophylaxis and treatment of a hyperproliferative disease, particularly a cancer disease.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, or 3, in particular 1 , or 2.
  • the term“one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2”.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to a sulfur atom.
  • ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
  • a composite substituent be composed of more than one parts, e.g. (Ci-C4-alkoxy)-(CrC4-alkyl)-
  • the position of a given part can be at any suitable position of said composite substituent, i.e. the CrC4-alkoxy part can be attached to any carbon atom of the CrC4-alkyl part of said (Ci-C4-alkoxy)-(CrC4-alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent
  • substituent it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, or chlorine atom except where halogen is intended to be a leaving group.
  • CrC 6 -alkyl- means a linear or branched, saturated hydrocarbon group having 1 , 2, 3, 4, 5, or 6, carbon atoms, such as, for example, a methyl-, ethyl-, propyl-, iso propyl ⁇ , n-butyl-, iso- butyl-, sec-butyl-, tert- butyl-, n- pentyl-, iso- pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1 ,2-dimethylpropyl-, neo-pentyl-, 1 , 1-dimethylpropyl-, n- hexyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1 -ethyl butyl-, 3,3-dimethylbutyl
  • alkyl group be placed within a chain as a bivalent“CrC 6 -alkylene” moiety. All names as mentioned above then will bear an“ene” added to the end, thus e.g., a“pentyl” becomes a bivalent“pentylene” group.
  • a“pentyl” becomes a bivalent“pentylene” group.
  • the term“CrC 6 -heteroalkyl” refers to a CrC 6 -alkyl group in which one or more of the carbon atoms have been replaced with an atom selected from N, O, S, or P, which are substituted as mentioned herein to satisfy atom valency requirements.
  • CrC3-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“CrC 6 -alkyl” is defined supra, and in which 1 , 2 or 3 hydrogen atoms are replaced with a hydroxy group, such as, for example, a hydroxymethyl-, 1-hydroxyethyl-, 2-hydroxyethyl-, 1 ,2-dihydroxyethyl-, 3-hydroxypropyl-, 2-hydroxypropyl-, 1-hydroxypropyl-, 1-hydroxypropan-2-yl-, 2-hydroxypropan-2-yl-, 2,3- dihydroxypropyl-, or a 1 ,3-dihydroxypropan-2-yl-, group.
  • Ci-C3-haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-C3-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said Ci-C3-haloalkyl group is, for example, a fluoromethyl-, difluoromethyl-, trifluoromethyl-, 2-fluoroethyl-,
  • haloalkyl is trifluoromethyl or difluoromethyl.
  • the term“CrC 6 -alkoxy” means a linear or branched, saturated, monovalent group of formula (Ci-C 6 -alkyl)-0-, in which the term“CrC 6 -alkyl” is as defined supra, such as, for example, a methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, sec-butoxy-, isobutoxy-, tert- butoxy-, pentyloxy-, isopentyloxy or a n-hexyloxy group, or an isomer thereof.
  • C2-C6-alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then it is possible for said double bonds to be isolated from, or conjugated with, each other.
  • Said alkenyl group is for example, an ethenyl-, prop-2-enyl-, (£)-prop-1-enyl-, (Z)-prop-1-enyl-, /so-propenyl- but-3-enyl-, (£)-but-2-enyl-, (Z)-but-2-enyl-, (£)-but-1-enyl-, (Z)-but-1-enyl- 2-methylprop-2-enyl-, 1-methylprop-2-enyl-, 2-methylprop-1-enyl-
  • alkenyl group be placed within a chain as a bivalent“Ci-C 6 -alkenylene” moiety. All names as mentioned above then will bear a “ene” added to their end, thus e.g., a“pentenyl” becomes a bivalent“pentenylene” group.
  • the term“C3-C6-cycloalkyl-” means a saturated monocyclic or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6, carbon atoms (“C3-C6-cycloalkyl-”).
  • Said C3-C6-cycloalkyl- group may be, for example, a monocyclic hydrocarbon ring, such as, for example, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or a cyclohexyl- ring.
  • a cycloalkyl group may be optionally substituted as defined at the respective part wherein such term is used.
  • C4-C6-cycloalkenyl means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, or 6, carbon atoms and one double bond. Particularly, said ring contains 5 or 6 carbon atoms (“Cs-Ce-cycloalkenyl”).
  • Said C4-C6-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, such as , for example, a cyclobutenyl-, cyclopentenyl-, or a cyclohexenyl-, group,
  • 4 to 6-membered heterocycloalkyl means a monocyclic, saturated or partially unsaturated heterocycle with 4, 5, or 6, ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as, for example, a azetidinyl-, oxetanyl- or thietanyl group; or a 5-membered ring, such as a tetrahydrofuranyl-, 1 ,3-dioxolanyl-, thiolanyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, 1 , 1-dioxidothiolanyl-, 1 ,2-oxazolidinyl-, 1 ,3-oxazolidinyl- or a 1 ,3-thiazolidinyl group, for example; or a 6-membered ring, such as, for example, a tetrahydropyranyl-, tetrahydrothiopyranyl-, piperidinyl-, morpholinyl-, dithi
  • aryl means a phenyl group, , which is unsubstituted or substituted with one, two, three, four or five substituents, each substituent independently selected from a halogen atom, a cyano group, a CrC3-alkyl group, aCrC3-haloalkyl group, a C1-C3- alkoxy group, a CrC3-thioalkyl group, a CrC3-haloalkoxy group, a CrC3-halothioalkyl group, a Cs-Cs-cycloalkyl group, particularly a halogen atom, a CrC3-alkyl group, a Cr C3-haloalkyl group, a CrC3-alkoxy group, and a CrC3-haloalkoxy group.
  • an “ortho substituted phenyl group R 3 ” as used in the proviso for R 3 is meant to be a phenyl group which bears a substitutent directly on the subsequent carbon atom to the bond by which the phenyl substitutent R 3 is linked to the rest of the molecule.
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, or 6, ring atoms (a“5- to 6-membered heteroaryl” group), which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, a thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl- or a tetrazolyl group; or a 6-membered heteroaryl group, such as, for example, a pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or a triazinyl group.
  • a 5-membered heteroaryl group such as, for example, a thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, for example: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C Ce as used throughout this text, e.g., in the context of the definition of“Cr C 6 -alkyl-”,“Ci-C 6 -haloalkyl-”,“Ci-C 6 -alkoxy-” or“Ci-C 6 -haloalkoxy-” is to be understood as meaning an alkyl group having a whole number of carbon atoms from 1 to 6, i.e., 1 , 2, 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term“C Ce” is to be interpreted as disclosing any sub-range comprised therein, e.g.
  • C 2 -C 6 as used throughout this text, e.g., in the context of the definitions of“C 2 -C 6 -alkenyl-” and“C 2 -C 6 -alkynyl-”, is to be understood as meaning an alkenyl- group or an alkynyl group having a whole number of carbon atoms from 2 to 6, i.e., 2, 3, 4, 5 or 6 carbon atoms.
  • C 2 -C 6 is to be interpreted as disclosing any sub-range comprised therein, e.g., C 2 -C 6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; preferably C2-C3.
  • the term“C 3 -C 7 ”, as used throughout this text, e.g., in the context of the definition of“C 3 -C 7 -cycloalkyl-”, is to be understood as meaning a cycloalkyl- group having a whole number of carbon atoms of 3 to 7, i.e., 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term“C 3 -C 7 ” is to be interpreted as disclosing any sub- range comprised therein, e.g., Cz-Ce , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C7 ; preferably C3- C 6 .
  • the term“leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular a chloro-, bromo- or iodo group, a (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-, [(trifluoromethyl)sulfonyl]oxy-, [(nonafluorobutyl)sulfonyl]oxy-, [(4- bromophenyl)sulfonyl]oxy-, [(4-nitrophenyl)sulfonyl]oxy-, [(2-nitrophenyl)sulfonyl]oxy-, [(4-isopropylphenyl)sulfonyl]oxy-,
  • the term“protective group” is a protective group attached to an oxygen or nitrogen atom in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g., by chemical modification of the respective hydroxy or amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for hydroxy and amino groups are descibed for example in T.W. Greene and P.G.M.
  • protective groups for amino groups can be selected from substituted sulfonyl groups, such as a mesyl-, tosyl- or a phenylsulfonyl group, acyl groups such as a benzoyl-, acetyl- or a tetrahydropyranoyl group, or carbamate based groups, such as a te/f-butoxycarbonyl group (Boc).
  • substituted sulfonyl groups such as a mesyl-, tosyl- or a phenylsulfonyl group
  • acyl groups such as a benzoyl-, acetyl- or a tetrahydropyranoyl group
  • carbamate based groups such as a te/f-butoxycarbonyl group (Boc).
  • Protective groups for hydroxy groups can be selected from acyl groups such as a benzoyl-, acetyl, pivaloyl- or a tetrahydropyranoyl group, or can include silicon, as in e.g., a tert-butyldimethylsilyl-, tert- butyldiphenylsilyl-, triethylsilyl- or a triisopropylsilyl group.
  • acyl groups such as a benzoyl-, acetyl, pivaloyl- or a tetrahydropyranoyl group
  • silicon as in e.g., a tert-butyldimethylsilyl-, tert- butyldiphenylsilyl-, triethylsilyl- or a triisopropylsilyl group.
  • substituted refers to a group “substituted” on, e.g., an alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group, replacing one or more hydrogen atoms therein.
  • the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent.
  • a substituent may itself be substituted with any one of the above substituents.
  • optionalally substituted means unsubstituted (e.g., substituted with an H) or substituted.
  • subject is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, rodent, or feline.
  • An“oxo” substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond.
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • unnatural proportion means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.
  • isotopes examples include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 1, respectively.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 125 l
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”).
  • deuterium-containing compounds of general formula (I) Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C- containing compounds of general formula (I) can be used in mass spectrometry analyses (H. J. Leis et al. , Curr. Org. Chem., 1998, 2, 131) in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D 2 0 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052).
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • Catalytic deuteration of olefinic bonds H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131 ; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889
  • acetylenic bonds N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron Letters, 2011 , 52, 3865
  • Metal catalysts i.e.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R. P.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490; A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641 ; C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L.
  • deuterium-containing compound of general formula (I) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I).
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism.
  • deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P 450 ⁇
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Preferred isomers are those which produce the more desirable biological activity should they be different for the isomers.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art including chiral high pressure liquid chromatography (HPLC), the formation and crystallization of chiral salts, or prepared by asymmetric syntheses.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention can be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • any compound of the present invention which contains an pyrazol moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, namely :
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also includes useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co- precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio.
  • polar solvents in particular water
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • “pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or“mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid, and nitric acid or with an organic acid, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, sal
  • A“pharmaceutically acceptable anion” refers to the deprotonated form of a conventional acid, such as, for example, a hydroxide, a carboxylate, a sulfate, a halide, a phosphate, or a nitrate.
  • Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, such as, by way of example and by preference, alkali metal salts (for example lithium, sodium and potassium salts), alkaline earth metal salts (for example calcium, strontium and magnesium salts) or an aluminium salt or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as by way of example and by preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, N- methylpiperidine
  • the compounds according to the invention may form salts with a quaternary ammonium ion obtainable, e.g., by quaternisation of a basic nitrogen-containing group with agents such as lower alkylhalides, such as alkylchlorides, e.g. methylchloride, ethylchloride, propylchloride and butylchloride; such as alkylbromides, e.g. methylbromide, ethylbromide, propylbromide and butylbromide; and such as alkyliodides;e.g.
  • dialkylsulfates such as dimethylsulfate, diethylsulfate, dibutylsulfate and diamylsulfates, long chain halides such as e.g.
  • decylchloride laurylchloride, myristylchloride and stearylchloride
  • decylbromide laurylbromide
  • myristylbromide and stearylbromide decyliodide
  • lauryliodide myristyliodide and stearyliodide
  • aralkylhalides such as benzylchloride, benzylbromide, benzyliodide and phenethylbromides and others.
  • quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra(n- propyl)ammonium, tetra (n-butyl)ammonium, or /V-benzyl-/V,/V,/V-trimethylammonium.
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • Solvates and hydrates of disclosed intermediates or example compounds, or salts thereof, which have been obtained, by the preparation and/or purification processes described herein, may be formed in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • a prodrug may be in the form of an in vivo hydrolysable ester of the specified compound.
  • Derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system are covered by the invention.
  • Said biological system may be, for example, a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
  • the present invention includes compounds of general formula (I), supra,
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a CrC 3 -alkyl group, a CrC 3 -alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a CrC 3 -alkyl group;
  • a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6- membered heteroaryl group; a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of general formula (I), supra,
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a Ci-C 3 -alkyl group, or a Ci-C 3 -haloalkyl group;
  • R 2 is a hydrogen atom, or a halogen atom;
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • Ci-C 3 -alkyl group which is substituted one or more times with a group independently selected from a CrC 3 -alkyl group, a CrC 3 -alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a CrC 3 -alkyl group;
  • a C 2 -C 6 -alkenyl group which is optionally substituted with a Ci-C 3 -alkoxy group, a C 5 -C 6 -cycloalkenyl group;
  • Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from Ci-C 3 -haloalkyl group, a hydroxy group, a Ci-C 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6- membered heteroaryl group;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C 3 -alkyl group, a Ci-C 3 -hydroxyalkyl group and a Ci-C 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a Ci-C 3 -alkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of general formula (I), supra,
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group
  • a 5- to 1 0-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group
  • a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a NR 5 R 6 group, and
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of general formula (I), supra,
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C 3 -alkyl group, a Ci-C 3 -hydroxyalkyl group and a Ci-C 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from Ci-C 3 -haloalkyl group, a hydroxy group, a Ci-C 3 -alkyoxy group, a NR 5 R 6 group, and
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • Ci-C 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a Ci-C 3 -alkoxy group, a hydroxy group, a Ci-C 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of general formula (I), supra,
  • A is -CH 2 -
  • R 1 is a hydrogen atom, a halogen atom, a Ci-C 3 -alkyl group, or a Ci-C 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 1 0-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a NR 5 R 6 group, and
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of general formula (I), supra,
  • A is -CH 2 -
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 1 0-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a NR 5 R 6 group, and
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group, and
  • the present invention includes compounds of general formula (I), supra,
  • A is -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC 3 -alkyl group;
  • a 5- to 1 0-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a NR 5 R 6 group, and
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of general formula (I), supra,
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, and a CrC3-alkoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra,
  • R 1 is a hydrogen atom, a halogen atom, a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, a CrC3-hydroxyalkyl group and a CrC3-haloalkyl group;
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, and a CrC3-alkoxy group,
  • the present invention includes compounds of general formula (I), supra,
  • R 1 is a hydrogen atom, a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from a halogen atom, a CrC3-alkyl group, a CrC3-hydroxyalkyl group, and a CrC3-haloalkyl group;
  • a 5-membered heteroaryl group which is substituted with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted with a group independently selected from a 5- membered heteroaryl group, and a CrC3-alkyoxy group,
  • the present invention includes compounds of general formula (I), supra,
  • R 1 is a hydrogen atom, a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from a halogen atom, a CrC3-alkyl group, a CrC3-hydroxyalkyl group, and a CrC3-haloalkyl group;
  • a 5-membered heteroaryl group which is substituted with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted with a group selected from a 5-membered heteroaryl group, and a CrC3-alkyoxy group,
  • the present invention includes compounds of general formula (I), supra,
  • R 1 is a hydrogen atom, a chlorine atom, or a trifluoromethyl group
  • R 2 is a hydrogen atom, or a chlorine atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from a fluorine atom, a methyl group, a hydroxymethyl group, and a trifluoromethyl group;
  • a 5-membered heteroaryl group which is substituted with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC2-alkyl group which is substituted with a group independently selected from a 5- membered heteroaryl group, and a methoxy group
  • the present invention includes compounds of general formula (I), supra,
  • R 1 is a hydrogen atom, a chlorine atom, or a trifluoromethyl group
  • R 2 is a hydrogen atom, or a chlorine atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • a phenyl group which is substituted one or more times with a group independently selected from a fluorine atom, a methyl group, a hydroxymethyl group, and a trifluoromethyl group;
  • a 5-membered heteroaryl group which is substituted with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 2 -alkyl group which is substituted with a group selected from a 5-membered heteroaryl group, and a methoxy group
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CHr
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a CrC 3 -haloalkyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • R 3 is
  • a 5- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 5-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a Ci-C3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which: A IS -CH2-;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -(CH 2 ) 2 -;
  • R 1 is a chlorine atom, ,
  • R 2 is a hydrogen atom, or a chlorine atom
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • R 3 is a 5- to 6-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 5-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 6-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 5- to 6-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a 5-membered heteroaryl group which is substituted with a group independently selected from a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • a CrC 3 -alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra, in which:
  • A is -CH 2 -;
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom, ,
  • a CrC 3 -alkoxy group which is optionally substituted with a hydroxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of general formula (I), supra, in which:
  • R 1 is a hydrogen atom, a chlorine atom, or a trifluoromethyl group
  • R 2 is a hydrogen atom, or a chlorine atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time;
  • R 3 is selected from 4-fluoro-2-methyl-phenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro-2- hydroxymethylphenyl,
  • the present invention includes compounds of general formula (I), supra, selected from (1S,6R)-5-(4'-fluoro-2'-methyl[1 ,1 '-biphenyl]-4-yl)-3,4-diazabicyclo[4.1.0]hept-4-en-2-one
  • the present invention includes compounds of formula (I), supra, selected from:
  • the present invention includes compounds of formula (I), supra, selected from:
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a Ci-C 3 -alkyl group, a Ci-C 3 -alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a Ci-C 3 -alkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a Ci-C 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • a C 2 -C 6 -alkenyl group which is optionally substituted with a Ci-C 3 -alkoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a Ci-C 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from Ci-C 3 -haloalkyl group, a hydroxy group, a Ci-C 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6- membered heteroaryl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group;
  • R 2 is a hydrogen atom, or a halogen atom
  • a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, a CrC3-hydroxyalkyl group and a CrC3-haloalkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of formula (I), supra, in which: A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a group, a group
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a halogen atom, or a CrC3-haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a 5- to 6-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a halogen atom, or a CrC 3 -haloalkyl group
  • R 2 is a hydrogen atom, or a halogen atom
  • R 3 is a NR 5 R 6 group
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • a C 5 -C 6 -cycloalkyl group or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, a CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group, and a CrC 3 -haloalkyl group,
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, a CrC3-alkyl group, a CrC3-haloalkyl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 -;
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, a CrC3-alkyl group, a CrC3-hydroxyalkyl group and a CrC3-haloalkyl group,
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC3-haloalkyl group, a hydroxy group, a CrC3-alkyoxy group, a C 4 -C 6 - cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, a CrC3-hydroxyalkyl group and a C1-C3- haloalkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a C1-C3- alkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of formula (I), supra, in which: A is -CH 2 -
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is a NR 5 R 6 group
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group,
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 -
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is 4-fluoro-2-methyl-phenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro-2- hydroxymethylphenyl,
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is piperazin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl,
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 -
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is 1-(difluoromethyl)-1 H-pyrazol-4-yl, 3-(trifluoromethyl)-1 H-pyrazol-1-y, difluoromethyl-1 H-pyrazol-4-yl,
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 -
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is -0-(CH 2 ) 2 -CH 3 , -0-(CH 2 ) 2 -0H,
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 -
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 is -NH-(CH 2 ) 2 -0-CH 3 , and -NH-CH 2 -1 H-pyrazol-3-yl,
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or -(CH 2 ) 2 -;
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -CH 2 - or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • A is -(CH 2 ) 2 -;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group; with the proviso that both, R 1 and R 2 , may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group; with the proviso that both, R 1 and R 2 , may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 2 is a hydrogen atom, or a halogen atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom
  • both, R 1 and R 2 may not be a hydrogen atom at the same time with the exception that if R 3 is a substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a trifluormethyl group
  • R 2 is; a hydrogen atom
  • the present invention includes compounds of formula (I), supra, in which:
  • R 1 is a hydrogen atom
  • R 2 is; a hydrogen atom if R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, a CrC3-hydroxyalkyl group and a C1-C3- haloalkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a CrC3-alkyl group which is substituted one or more times with a group independently selected from a CrC3-alkyl group, a CrC3-alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a Cr C3-alkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a C 2 -C 6 -alkenyl group, which is optionally substituted with a CrC 3 -alkoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a C 5 -C 6 -cycloalkenyl group
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC3-haloalkyl group, a hydroxy group, a CrC3-alkyoxy group, a C4-C6- cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a CrC6-alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a CrC6-alkoxy group which is optionally substituted a hydroxy group
  • the present invention includes compounds of formula (I), supra, in which:
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a C 1 -C 3 - haloalkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a phenyl group which is substituted one or more times with a group independently selected from fluorine atom, a methyl group, a hydroxymethyl group and a trifluoromethyl group;
  • the present invention includes compounds of formula (I), supra, in which: R 3 is a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a C1-C3- alkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a CrC3-alkyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a CrC3-alkyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is selected from a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, and a morpholin-4-yl group,
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a difluoromethyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 5- to 6-membered heteroaryl group which is substituted one or more times with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 5-membered heteroaryl group which is substituted one or more times with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a 5-membered heteroaryl group which is substituted one or more times with a group independently selected from, a trifluoromethyl group, and a difluoromethyl group;
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is selected from a 1-(difluoromethyl)-1 H-pyrazol-4-yl group, a 3-(trifluoromethyl)-1 H- pyrazol-1-yl group, a difluoromethyl-1 H-pyrazol-4-yl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a NR 5 R 6 group
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, a CrC3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a CrC3-hydroxyalkyl group,
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is a NR 5 R 6 group
  • R 5 is a hydrogen atom
  • R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, and a CrC3-alkoxy group,
  • the present invention includes compounds of formula (I), supra, in which:
  • R 3 is selected from -NH-(CH 2 ) 2 -0-CH 3 , and -NH-CH 2 -1 H-pyrazol-3-yl,
  • the present invention includes compounds of formula (I), R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a CrC 3 -hydroxyalkyl group,
  • the present invention includes compounds of formula (I), supra, in which
  • R 6 is selected from
  • a CrC 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, and a CrC 3 -alkoxy group,
  • the present invention includes compounds of formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
  • the present invention includes compounds of formula (I), or a tautomer, an N-oxide, or a salt thereof or a salt of a tautomer or a salt of an N-oxide or a mixture of same
  • the present invention includes compounds of formula (I), or a tautomer, or a salt thereof, or a salt of a tautomer, or a mixture of same
  • the present invention includes compounds of formula (I), or a salt thereof or a mixture of same
  • the present invention includes compounds of formula (I), which are salts.
  • the present invention includes compounds of formula (I), which are amine salts or salts with organic acids. In further embodiments, the present invention includes compounds of formula (I), which are salts with organic acids particularly formed with pharmaceutically acceptable organic acids.
  • the present invention includes compounds of formula (I), which are amine salts, particularly formed with pharmaceutically acceptable amines.
  • the present invention includes compounds of formula (I), which are a tautomer, or a salt thereof or a salt of a tautomer or a mixture of same
  • the present invention includes compounds of formula (I), which are a an N-oxide, or a salt thereof or a salt of an N-oxide or a mixture of same
  • the present invention includes combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.
  • the present invention includes any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention includes any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (IV) and (V).
  • the present invention includes the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
  • the compounds according to the invention of general formula (I) can be prepared according to the following schemes 1 , 2, and 3.
  • the schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in schemes 1 , 2, and 3 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, R 1 , R 2 , R 3 , or R 4 can be achieved before and/or after the exemplified transformations.
  • Scheme 1 Route for the preparation of compounds of general formula (I) from compounds of formulae (II) and (III), in which R 1 , R 2 , R 3 (potentially containing functional groups which are suitably protected), and A have the meaning as defined supra and M is a metal-containing group, such as Li, or MgBr, or MgCI.
  • R 1 , R 2 , R 3 potentially containing functional groups which are suitably protected
  • A have the meaning as defined supra
  • M is a metal-containing group, such as Li, or MgBr, or MgCI.
  • Compounds of formulae (II) and (III) are known to the person skilled in the art and can be readily prepared from commercially available precursors by known methods.
  • Scheme 2 Route for the preparation of intermediate compounds of formula (Vila), in which R 1 , R 2 and A have the meaning as defined supra ; the meaning of X is as defined below in context of Scheme 3 and the paragraphs (i), (j), (k) for compounds of formula (Vila).
  • R 3 a substituted alkyl group, an optionally substituted alkenyl group, a cycloalkenyl group, a substituted phenyl group, or a substituted heteroaryl group,
  • R 3 NR 5 R 6 , opt. subst. N-linked heterocycloalkyl, or subst. N-linked heteroaryl,
  • Scheme 3 Route for the preparation of compounds of general formula (la) via formula (Vila) in which R 1 , R 2 and A have the meaning as defined supra, in which R 3 in general formula (la) is selected from a substituted methyl group, an optionally substituted alkenyl group, a cycloalkenyl group, a substituted phenyl group, and a substituted heteroaryl group as defined in more detail below in paragraph (i) for R x ; or R 3 is NR 5 R 6 , or an optionally substituted N-linked heterocycloalkyl group, or a substituted N-linked heteroaryl group, as defined in more detail below in paragraph (j) and (k), respectively; and in which the terms“N-linked heterocycloalkyl”, and“N-linked heteroaryl” refer to a 4- to 6-membered heterocycloalkyl, or a heteroaryl group, as defined for R 3 supra, which is bonded to the rest of the molecule via a nitrogen atom which constitutes a
  • X is Cl, Br, (as reflected in scheme 3), or a group selected from (CrC4-alkylsulfonyl)oxy, (Ci-C4-fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, the phenyl present in (phenylsulfonyl)oxy being optionally substituted with one, two, three, four or five substituents, each of them independently selected from halogen, nitro, cyano, Cr C4-alkyl and CrC4-alkoxy;
  • R 1 or R 2 are as defined supra but are different from Cl, Br, I, and
  • A is as defined supra, with boronic acids R x B(OH)2 (formula (Villa)), or boronic esters R x B(OR y )2 (formula (Vlllb)), or tetrafluoroborate salts R X BF4 (formula (Vlllc)), in the presence of
  • a base such as potassium carbonate or potassium acetate
  • a palladium catalyst such as dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(O), palladium(ll) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(ll) chloride, 1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1 ,4- naphthoquinone)palladium dimer, allyl(chloro)(1 ,3-dimesityl-1 ,3-dihydro-2H-imidazol-2- ylidene)palladium, palladium(ll) acetate/dicyclohexyl(2',4',6'-triisopropyl-biphenyl-2- yl
  • an additional ligand such as 2-(dicyclohexylphosphino)-2’,4’,6’- triisopropylbiphenyl,
  • a solvent such as dioxane, toluene, or water, or a mixture thereof, under nitrogen or argon atmosphere, at 80 °C-120 °C, for 2h-7d;
  • a methyl group which is subtituted one or more times with a group selected from a Cr C3-alkyl group, a Ci-C3-alkoxy group, a 4- to 6-membered heterocycloalkyl group, and an amino group which is substituted once or twice by a Ci-C3-alkyl group,
  • a C2-C6-alkenyl group which is optionally substituted with a Ci-C3-alkoxy group, a C5-C6-cycloalkenyl group,
  • a phenyl group which is substituted one or more times with a group independently selcted from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group,
  • a 5- to 10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluormethyl group, and a difluoromethyl group,
  • R y is Ci-C 6 -alkyl, or the two residues R y together are a C2-C6-alkylene group, preferably
  • compounds of general formula (la) prepared e.g. by a Suzuki coupling in which R 3 features a group comprising an olefinic double bond (e.g. if R 3 is alkenyl, cycloalkenyl or), can be readily converted into compounds in which R 3 features the corresponding saturated group (e.g. alkyl, cycloalkyl, heterocycloalkyl) by methods known to the person skilled in the art, such as catalytic hydrogenolysis using a suitable catalyst, such as palladium on carbon.
  • a suitable catalyst such as palladium on carbon.
  • R 3 is selected from -NR 5 R 6 , a N-linked 4- to 6-membered heterocycloalkyl group, and a N-linked heteroaryl group, whereby the term “N-linked” is to be understood as described in context of Scheme 3, and in which the terms “4- to 6-membered heterocycloalkyl”, and “heteroaryl” are constituted and optionally substituted as defined for R 3 , supra,
  • X is F, Cl, or Br (as reflected in scheme 3), and if X is Cl or Br, R 1 or R 2 can not be F; preferably X is F;
  • R 1 and R 2 have the meaning as defined supra, with the proviso that if X is Cl or Br, R 1 or R 2 can not be F, and with the proviso that at least one of R 1 and R 2 exerts an electron withdrawing effect; preferably, R 1 is selected from fluorine, and -CF 3 , and R 2 is hydrogen or fluorine; more preferably, R 1 is -CF 3 and R 2 is hydrogen;
  • a corresponding amine optionally as a free base or as a salt, such as a hydrochloride salt, selected from HNR 5 R 6 and a cyclic amine featuring one N-H as a ring atom, said cyclic amine being selected from a 4- to 6-membered heterocycloalkane, and a heteroarene containing one N-H as a ring atom, respectively,
  • a base such as triethylamine, DIPEA, or cesium carbonate
  • an inert solvent such as THF, CH 3 CN, DMF or DMSO
  • R 5 is H, and R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, a CrC3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a CrC3-hydroxyalkyl group, and
  • R 3 is selected from -NR 5 R 6 , a N-linked 4- to 6-membered heterocycloalkyl group, and a N-linked heteroaryl group, whereby the term “N-linked” is to be understood as described in context of Scheme 3, and in which the terms “4- to 6-membered heterocycloalkyl”, and “heteroaryl” are constituted and optionally substituted as defined for R 3 , supra,
  • X is Cl, Br, (as reflected in scheme 3), or a group selected from (CrC4-alkylsulfonyl)oxy, (Ci-C4-fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, the phenyl present in (phenylsulfonyl)oxy being optionally substituted with one, two, three, four or five substituents, each of them independently selected from halogen, nitro, cyano, Cr C4-alkyl and CrC4-alkoxy;
  • R 1 or R 2 are as defined supra but are different from Cl, Br; preferably, R 1 is -CF 3 and R 2 is hydrogen;
  • a corresponding amine optionally as a free base or as a salt, such as a hydrochloride salt, selected from HNR 5 R 6 and a cyclic amine featuring one N-H as a ring atom, said cyclic amine being selected from a 4- to 6-membered heterocycloalkane, and a heteroarene containing one N-H as a ring atom, respectively,
  • a base such as potassium phosphate or cesium carbonate
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a ligand such as 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1 , 1 '-biphenyl or 2,2'- bis(diphenylphosphino)-1 , T-binaphthalene
  • an inert solvent such as dioxane or toluene
  • R 5 is H, and R 6 is selected from
  • a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, a CrC3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a CrC3-hydroxyalkyl group, and
  • R 7 a CrC 6 -alkyl group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C4-C6- cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group, with the proviso that an unsubstituted methyl group is excluded; and Pg2 is a protecting group suitable for hydroxy groups, e.g. a benzyl group.
  • Scheme 5 Route for the preparation of compounds of general formula (lb) via formula (VI lb) in which R 1 , R 2 and A have the meaning as defined supra, in which R 3 in general formula (I) is a CrC 6 -alkoxy group which is optionally substituted with a group selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C4-C6-cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, and a 5- to 6-membered heteroaryl group, with the proviso that an unsubstituted methoxy group is excluded.
  • R 3 in general formula (I) is a CrC 6 -alkoxy group which is optionally substituted with a group selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C4-C6-cycloalkyl group, a 4- to 6-member
  • X is F or Cl (as reflected in scheme 5), and if X is CI, R 1 or R 2 can not be F; preferably X is F;
  • R 1 and R 2 have the meaning as defined supra, with the proviso that if X is Cl, R 1 or R 2 can not be F, and with the proviso that at least one of R 1 and R 2 exerts an electron withdrawing effect; preferably, R 1 is selected from fluorine and -CF 3 , and R 2 is hydrogen or fluorine; more preferably, R 1 is -CF 3 and R 2 is hydrogen;
  • R 7 -OH optionally as the alcohol or as an alkoxide salt, such as a sodium or potassium salt,
  • a strong base such as potassium tert-butoxide, or sodium hydride, or sodium metal
  • an inert solvent such as THF or DMF
  • a base such as cesium carbonate
  • a solvent such as DMSO
  • R 7 is a CrC 6 -alkyl group which is optionally substituted with a group independently selected from CrC3-haloalkyl group, a hydroxy group, a CrC3-alkyoxy group, a C4-C6- cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group, with the proviso that an unsubstituted methyl group is excluded.
  • X is Cl, Br, I, (as reflected in scheme 5), or a group selected from (CrC4-alkylsulfonyl)oxy, (Ci-C4-fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, the phenyl present in (phenylsulfonyl)oxy being optionally substituted with one, two, three, four or five substituents, each of them independently selected from halogen, nitro, cyano, CrC4-alkyl and CrC4-alkoxy;
  • R 1 or R 2 are as defined supra but are different from Cl, Br, I; preferably, R 1 is -CF 3 and R 2 is hydrogen;
  • a palladium catalyst such as [(2-Di-te/f-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl- 1 , 1 '-biphenyl)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate or [(2-Di -tert- butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1 , 1 '-biphenyl)-2-(2- aminobiphenyl)]palladium(ll) methanesulfonate, optionally a ligand, such as 2-Di(tert- butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl
  • R 7 is a CrC 6 -alkyl group which is optionally substituted with a group selected from a CrC3-haloalkyl group, a hydroxy group, a CrC3-alkyoxy group, a C4-C6-cycloalkyl group, a 4 to 6-membered heterocycloalkyl group, and a 5 to 6-membered heteroaryl group, with the proviso that an unsubstituted methyl group is excluded.
  • X is OPg2, where Pg2 is a protecting group suitable for hydroxy groups, e.g. a benzyl group;
  • R 1 , R 2 , and R 4 has the meaning as defined supra,
  • a palladium catalyst such as Palladium on carbon
  • a solvent such as ethanol
  • R 1 , R 2 , and A has the meaning as defined supra,
  • dialkylazodicarboxylate preferably diisopropylazodicarboxylate
  • a phosphine such as triphenylphosphine
  • inert solvent such as THF
  • R 7 is a CrC 6 -alkyl group which is optionally substituted with a group independently selected from CrC3-haloalkyl group, a hydroxy group, a CrC3-alkyoxy group, a C4-C6- cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, and a 5- to 6-membered heteroaryl group, with the proviso that an unsubstituted methyl group is excluded.
  • the present invention includes methods of preparing compounds of general formula (I) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (IV) :
  • R 1 , R 2 , R 3 and A are as defined for the compound of general formula (I) as defined supra or in anyone of claim 1-9, and potentially containing functional groups suitably protected
  • hydrazine hydrate in an alcoholic solution, e.g. EtOH, at a temperature range of about 50 °C - 80 °C, optionally removing protecting groups,
  • the present invention includes methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • the present invention includes intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.
  • the inventions includes the intermediate compounds of general formula (IV) :
  • the present invention includes the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
  • inventions includes the intermediate compounds of general formula (VII) which includes all compounds of formulae (Vila) and (Vllb):
  • R 1 , R 2 , X and A are as defined for the compound of general formula (I) and Compunds of formula (Vila) and (Vllb) supra as well as its use for the preparation of a compound of formula (I).
  • the present invention includes the intermediate compounds which are disclosed in the Example Section of this text, infra.
  • the present invention includes any sub-combination within any embodiment or aspect of the present invention of the intermediate compound of general formula (IV), supra.
  • the compounds of general formula (I) of the present invention can be converted to any salt, particularly pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to effectively inhibit cell proliferation and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative diseases in humans and animals.
  • the compounds of formula (I) are suitable for the treatment of a patient having a cancer that is sensitive to treatment with a phosphodiesterase 3A/B PDE3A- and/or PDE3B-SLF12 complex modulator by detecting co-expression of PDE3A and / or PDE3B and Schlafen 12 ( SLFN12 ) and / or SLFN12L mRNA, polynucleotides or polypeptides and/or a lack of decrease in expression of CREB3L1 mRNA, polynucleotides or polypeptides in a cancer cell derived from such patients.
  • the compounds of formula (I) are selective for cancer cell killing while minimizing enzymatic inhibition of PDE3A and PDE3B
  • Compounds of the present invention can be utilized to inhibit tumor growth by inducing a SLFN12 complex formation.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disease.
  • an alteration is meant a change (increase or decrease) in the expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein.
  • an alteration includes an about 10% change in expression levels, preferably an about 25% change, more preferably an about 40% change, and most preferably an about 50% or greater change in expression levels.
  • an alteration includes a 10% or less (including 10 %) change in expression levels, preferably a 25% or less (including 25%) change, more preferably a40% or less (including 40%) change, and most preferably a 50% or less (including 50%) or greater change in expression levels.
  • an alteration includes a 9% - 1 1 % (including 9% and 11 %) change in expression levels, preferably a 10%-25% (including 10% and 25%) change, more preferably a 25% - 40% (including 25% and 40%) change, and most preferably a 40%-50% (including 40% - 50%) or greater than 50% (including 50%) change in expression levels.
  • an alteration includes a 9% - 11 % (including 9% and 1 1 %) change in expression levels, preferably a 22%-28% (including 22% and 28%) change, more preferably a 35% - 45% (including 35% and 45%) change, and most preferably a 45%- 55% (including 45% - 55%) or a greater or equal to 55% change in expression levels
  • fragment is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% of the entire length of the reference nucleic acid molecule or polypeptide.
  • this portion contains, preferably, at least 9%-11 % (including 9% and 11 %), 18%-22% (including 18% ands 22%), 27%-33% (including 27% and 33%), 36%-44% (including 36% and 44%), 45%- 55% (including 45% and 55%), 54%-66% (including 54% and 66%), 63%-77% (including 63% and 77%), 72%-88%(including 72%and 88%), or 81 %-99% (including 81 % and 99%) of the entire length of the reference nucleic acid molecule or polypeptide
  • a fragment may contain about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 nucleotides or amino acids.
  • a fragment may contain 9-11 , about 18-22, 27-33, 36-44, 45-55, 54-66, 63- 77, 72-88, 81-99, 90-110, 180-220, 270-330, 360-440, 450-550, 540-660, 630-770, 720- 880, 810-990, or 900-1 100 nucleotides or amino acids (including for each the mentioned limitation e.g. for“9-11” means including 9 and 11.
  • modulator is meant any agent that binds to a polypeptide and alters a biological function or activity of the polypeptide.
  • a modulator includes, without limitation, agents that reduce or eliminate a biological function or activity of a polypeptide (e.g., an “inhibitor”). For example, a modulator may inhibit a catalytic activity of a polypeptide.
  • a modulator includes, without limitation, agents that increase or decrease binding of a polypeptide to another agent. For example, a modulator may promote binding of a polypeptide to another polypeptide.
  • the modulator of PDE3A and/or PDE3B polypeptide is a compound of formula (I).
  • hyperproliferative disease is meant a disease, such as cancer, associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both.
  • Hyperproliferative diseases include, but are not limited to, hematopoietic and benign hyperproliferative diseases.
  • Hematopoietic hyperproliferative diseases also known as myoproliferative diseases include e.g. polycythemia vera, essential thrombocytosis, thrombocytosis, primary myelofibrosis, and others.
  • “Benign hyperproliferative diseases” include for example, endometriosis, leiomyoma and benign prostate hyperplasia.
  • Hyperproliferative diseases include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the brain, breast, digestive tract, eye, head and neck, liver, respiratory tract, reproductive organs, skin, thyroid, parathyroid, urinary tract, and their distant metastases.
  • BPH benign prostate hyperplasia
  • solid tumours such as cancers of the brain, breast, digestive tract, eye, head and neck, liver, respiratory tract, reproductive organs, skin, thyroid, parathyroid, urinary tract, and their distant metastases.
  • Those diseases also include leukaemias, lymphomas, and sarcomas.
  • Solid tumours are such as e.g. cancers of the breast, brain, digestive tract, eye, head and neck, liver, parathyroid, reproductive organs, respiratory tract, skin, thyroid, urinary tract, and their distant metastases. Those diseases also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. More particularly Leucemias include, but are not limited to acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia (ALL) , acute monocytic leukemia (AML), acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia and also myelodysplastic syndrome (MDS), which can develop into an acute mye
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, chronic lymphocytic lymphoma (CLL), non-Hodgkin’s lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell lymphoma DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, hairy cell lymphoma, Hodgkin’s disease, mantle cell lymphoma (MCL), lymphoma of the central nervous system, small lymphocytic lymphoma and chronic lymphocytic lymphoma and Sezary syndrome.
  • CLL chronic lymphocytic
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • the term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disease, such as a carcinoma. These diseases have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. It will be appreciated that, although not precluded, treating a disease or condition does not require that the disease, condition or symptoms associated therewith be completely eliminated.
  • subject is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.
  • treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disease, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:
  • the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
  • the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention.
  • the cell is treated with at least one compound of general formula (I) of the present invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. n one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule générale (I) : (I), dans laquelle R1, R2, R3 et A sont tels que définis dans la description. L'invention concerne également des procédés de préparation desdits composés, des composés intermédiaires utiles pour préparer lesdits composés, des compositions et des combinaisons pharmaceutiques comprenant lesdits composés et l'utilisation desdits composés pour fabriquer des compositions pharmaceutiques destinées au traitement ou à la prophylaxie de maladies hyperprolifératives, en monothérapie ou en association avec d'autres principes actifs.
PCT/EP2020/052293 2019-02-01 2020-01-30 Composés dihydropyridazinone annelés utilisés en tant que composés anticancéreux WO2020157199A1 (fr)

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WO2024083545A1 (fr) 2022-10-17 2024-04-25 BASF Agro B.V. Procédé de préparation d'un composé de grignard 4-chloro-2-(trifluorométhyl)phényle et de ses dérivés

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024083545A1 (fr) 2022-10-17 2024-04-25 BASF Agro B.V. Procédé de préparation d'un composé de grignard 4-chloro-2-(trifluorométhyl)phényle et de ses dérivés

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