Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed 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
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention also relates to the use of these compounds for the therapy of hyperproliferative diseases, in particular human cancer.
• a subgroup of proapoptotic anticancer agents target cells preferentially in mitosis. In general these agents do not induce apoptosis in non-dividing cells, arrested in the GO, G1 or G2 phase of the cell division cycle. In contrast, dividing cells going through mitosis (M-phase of the cell division cycle), are killed efficiently by induction of apoptosis by this subgroup agents. Therefore, this subgroup or class of anti-cancer agents is described as cell-cycle specific or cell-cycle dependent.
• Tubulin inhibitors with Taxol (Paclitaxel®) as a prominent example, belong to this class of cell-cycle specific, apoptosis inducing anti-cancer agents.
• Ra is -C(O)RI , in which
• Q is optionally substituted by Rea and/or Reb, and is 3-7C-cycloalkyl
• each R2 may be the same or different and is independently selected from the group consisting of: 3-7C-cycloalkyl, phenyl, Har, Het, halogen, trifluoromethyl, nitro, cyano,
• each R3, R4, R5 and R6 may be the same or different and is each independently selected from the group consisting of: hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, phenyl, and phenyl-1-4C-alkyl,
• each R7 may be the same or different and is independently selected from the group consisting of: hydrogen, 1-7C-alkyl, and 3-7C-cycloalkyl,
• each R8 and R9 may be the same or different and is each independently selected from the group consisting of: hydrogen, and 1-4C-alkyl,
• each R10 may be the same or different is independently selected from the group consisting of: 1-4C-alkyl, phenyl, halogen, trifluoromethyl, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl, and phenoxy, wherein each of said phenyl and phenoxy radicals can be unsubstituted or optionally substituted by up to four halogen radicals and up to two 1-4C-alkyl, hydroxyl, trifluoromethyl or cyano radicals,
• each y is 1 , 2, 3 or 4,
• each Rba, Rbb, Rbc, Rca, Rcb, Rda, Rdb, Rea and Reb may be the same or different and is each independently selected from the group consisting of: 1-4C-alkyl, phenyl, halogen, trifluoromethyl, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl, and phenoxy, wherein each of said phenyl and phenoxy can be unsubstituted or optionally substituted by up to four halogen radicals and up to two 1-4C-alkyl, hydroxyl, trifluoromethyl or cyano radicals,
• each Har is the same or different and is independently any fully aromatic or partially aromatic mono- or fused bicyclic ring or ring system made up of a first constituent being a 5- or 6-membered monocyclic unsaturated, aromatic heteroaryl ring A, which heteroaryl ring A comprises one to four heteroatoms independently selected from nitrogen, oxygen and sulfur, and, optionally, fused to said first constituent, a second constituent being a benzene ring, a 5-6C-cycloalkane ring, an additional heteroaryl ring A as defined herein afore, or a heterocyclic ring B as defined herein below, whereby said Har ring or ring system is attached to the parent molecular group via a substitutable ring carbon or ring nitrogen atom,
• 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, and, particularly, the ethyl and methyl radicals.
• 3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclopentyl and cyclohexyl are to be emphasized.
• 3-7C-Cycloalkane stands for cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, of which cyclohexane and cyclopentane are to be emphasized.
• 5-6C-Cycloalkane stands for cyclohexane and cyclopentane.
• Phenyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals, which is substituted by a phenyl radical. Examples which may be mentioned are the phenethyl and the benzyl radicals.
• 2-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy radical.
• fluorine-substituted 1-4C-alkoxy for example, the 2,2,3, 3,3-penta- fluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals may be mentioned.
• "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy radicals are replaced by fluorine atoms.
• Pyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
• 1-4C-Alkylcarbonyloxy stands for a carbonyloxy group to which one of the abovementioned 1-4C-alkyl radicals is bonded.
• An example is the acetoxy radical (CH 3 C(O)-O-).
• quinazolinyl quinoxalinyl, cinnolinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, benzoxazolyl, benzothiazolyl or benzimidazolyl, as well as naphthyridinyl, indolizinyl or purinyl.
• Har When R2 is Har, a more detailed example for Har includes imidazolyl.
• R2 is Har
• another more detailed example for Har includes pyridinyl.
• a further more detailed example for Har includes pyridin-2-yl.
• another further more detailed example for Har includes pyridin-3-yl.
• another further more detailed example for Har includes pyridin-4-yl.
• each definition is independent.
• Q is attached via a carbon atom of the benzene ring to the parent molecular group, and is benzofuranyl, or
• Q is optionally substituted by Rba and/or Rbb and/or Rbc, and is phenyl, or
• Q is optionally substituted by Rca and/or Rcb, and is Har, or Q is attached via a carbon atom of the benzene ring to the parent molecular group, and is 1 ,3- benzodioxolyl, 2,2-difluoro-1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3- dihydrobenzofuranyl, chromenyl or chromanyl, or
• each Har is the same or different and is independently either a 5-membered monocyclic heteroaryl radical comprising one to four heteroatoms independently selected from nitrogen, oxygen and sulphur, such as e.g. any one selected from furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl and oxadiazolyl, whereby said Har radical is attached to the parent molecular group via a ring carbon or ring nitrogen atom, or a 6-membered monocyclic heteroaryl radical comprising one or two nitrogen atoms, such as e.g. any one selected from pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, whereby said Har radical is attached to the parent molecular group via a ring carbon atom,
• R1 is 1-4C-alkyl, 1-4C-alkyl substituted by one substituent selected from R2, or 3-4C-alkyl substituted by two hydroxyl radicals on different carbon atoms, and either
• Q is optionally substituted by Rba and/or Rbb, and is phenyl, or Q is optionally substituted by Rca and/or Rcb, and is pyridinyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl or imidazolyl, or Q is attached via a carbon atom of the benzene ring to the parent molecular group, and is 1 ,3- benzodioxolyl, 2,2-difluoro-1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3- dihydrobenzofuranyl, chromenyl or chromanyl, or
• R3 is 1-4C-alkyl such as e.g. methyl
• each R4 may be the same or different and is independently selected from the group consisting of: hydrogen, and 1-4C-alkyl such as e.g. methyl or ethyl
• R201 is 1-4C-alkyl such as e.g. methyl or ethyl
• R202 is 1-4C-alkyl such as e.g.
• each Rba and Rbb may be the same or different and is each independently selected from the group consisting of: methyl, ethyl, fluorine, chlorine, bromine, and trifluoromethyl
• each Rca and Rcb may be the same or different and is each independently selected from the group consisting of: methyl, ethyl, fluorine, chlorine, and trifluoromethyl
• each R2 may be the same or different and is independently selected from the group consisting of: pyridinyl, morpholino, imidazol-1-yl, pyrazol-1-yl,
• Rca is methyl
• R1 is 2,3-dihydroxypropyl, and either
• Q is unsubstituted, and is phenyl, or
• Rca is methyl or chlorine
• Q is 5-(Rca)-4-(Rcb)-furan-3-yl, or, especially, 5-(Rca)-4-(Rcb)-furan-2-yl, in which Rca is methyl or chlorine, Rcb is methyl,
• Q is unsubstituted, and is pyridin-2-yl or pyridin-3-yl,
• Q is substituted by Rca and/or Rcb, and is pyridinyl, furanyl or thiophenyl, or
• Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, especially pyridin- 2-yl or pyridin-3-yl,
• R1 is 2,3-dihydroxypropyl, and either
• Q is unsubstituted, and is phenyl, or
• each R2 may be the same or different and is independently selected from the group consisting of: pyridinyl, methoxycarbonyl, methylcarbonyloxy, methoxy, ethoxy, and 2-methoxyethoxy,
• each Rba and Rbb may be the same or different and is each independently selected from the group consisting of: methyl, ethyl, fluorine, bromine, and chlorine;
• Rba is methyl, ethyl, chlorine or fluorine
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl, especially furan-2-yl, or
• Rca is methyl or chlorine
• Ra is -C(O)RI , in which either
• R2 is pyridyl, or R1 is (R2)-methyl, in which
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• R2 is hydroxyl or methoxy
• R1 is (2-methoxyethoxy)-methyl, or
• Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl, especially furan-2-yl, or
• Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or thiophen-3-yl, especially thiophen-2-yl, or
• Rba is methyl, ethyl, chlorine or fluorine, or
• Rcb is methyl
• Q is cyclohexyl or cyclopentyl; in a particular subembodiment
• Q is unsubstituted, and is phenyl
• Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl, especially furan-2-yl, or
• Rca is methyl or chlorine
• Rca is methyl or chlorine
• Rcb is methyl
• Q is unsubstituted, and is thiophen-2-yl
• subembodiment Q is unsubstituted, and is furan-2-yl; and the salts thereof.
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl, especially furan-2-yl, or
• Rca is methyl or chlorine
• Rcb is methyl
• Q is unsubstituted, and is phenyl, in another particular subembodiment Q is unsubstituted, and is pyridin-2-yl,
• Q is unsubstituted, and is thiophen-2-yl
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• Q is unsubstituted, and is phenyl, or
• Q is unsubstituted, and is pyridin-2-yl, or
• Q is unsubstituted, and is pyridin-3-yl, or
• R1 is (R2)-methyl, or 2-(R2)-ethyl, in which
• Q is cyclohexyl
• Q is unsubstituted, and is pyridin-2-yl, or
• Q is unsubstituted, and is furan-2-yl, or
• Ra is -C(O)RI , in which R1 is 1-4C-alkyl, such as e.g. methyl, ethyl, propyl or butyl.
• Ra is -C(O)RI , in which
• a further subdetail (detail b2) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• a further subdetail (detail b3) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which R2 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, hydroxyl, 1- 4C-alkoxycarbonyl, phenyl-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, or carboxyl.
• R2 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, hydroxyl, 1- 4C-alkoxycarbonyl, phenyl-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, or carboxyl.
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which R2 is 1-2C-alkoxy, 1-2C-alkoxy-ethoxy, (1-2C-alkoxy-ethoxy)-ethoxy, hydroxyl, 1-2C- alkoxycarbonyl, 1-2C-alkylcarbonyloxy, or carboxyl.
• a further subdetail (detail b5) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• R2 is Har, in which
• a further subdetail (detail b7) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which R2 is Har, in which
• Har is optionally substituted by one or two substituents independently selected from R10 as defined in the compounds mentioned above, and is pyridinyl.
• a further subdetail (detail b9) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• R2 is Har, in which
• Har is optionally mono-substituted by R10, and is pyridinyl, imidazolyl (e.g. imidazol-1-yl) or pyrazolyl (e.g. pyrazol-1-yl), in which R10 is 1-4C-alkyl, such as e.g. Har is pyridinyl, imidazol-1-yl, pyrazol-1-yl, 1 N-(methyl)-imidazolyl or 1 N-(methyl)-pyrazolyl.
• a further subdetail (detail b10) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• Har is unsubstituted, and is pyridinyl.
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• a further subdetail (detail b12) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• R2 is 1-4C-alkoxy, such as e.g. methoxy or ethoxy, or hydroxyl.
• R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is mono-substituted by R2, in which
• a further subdetail (detail b13) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is (R2)-methyl, 2-(R2)-ethyl, or 3-(R2)-propyl, in which R2 is methoxy, ethoxy, hydroxyl, methylcarbonyloxy, or 2-methoxyethoxy.
• a further subdetail (detail b14) of the compounds according to detail b of this invention include those compounds of formula I, in which
• a further subdetail (detail b15) of the compounds according to detail b of this invention include those compounds of formula I, in which
• a further subdetail (detail b16) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is 2-methoxyethyl.
• Raa is pyridinyl
• a further subdetail (detail b23) of the compounds according to detail b of this invention include those compounds of formula I, in which
• a further subdetail (detail b25) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is (R2)-methyl, 2-(R2)-ethyl or 3-(R2)-propyl, in which
• R201 is methyl
• R202 is methyl
• R2 is imidazol-1-yl.
• a further subdetail (detail b27) of the compounds according to detail b of this invention include those compounds of formula I, in which
• R1 is (R2)-methyl, 2-(R2)-ethyl or 3-(R2)-propyl, in which
• Raa is 1 N-methyl-imidazolyl.
• Raa is 1 N-methyl-imidazolyl, such as e.g. 1-methyl-imidazol-2-yl or 1-methyl-imidazol-5-yl.
• a further subdetail (detail b34) of the compounds according to detail b of this invention include those compounds of formula I, in which
• a further subdetail (detail b35) of the compounds according to detail b of this invention include those compounds of formula I, in which
• a third embodimental detail (detail c) of the compounds of formula I according to this invention includes those compounds of formula Ia, in which R1 is any one of the meanings indicated in Table 1 given below.
• a fifth embodimental detail (detail e) of the compounds of formula I according to this invention includes those compounds of formula Ic**, in which R1 is any one of the meanings indicated in Table 1 given below.
• a first embodimental variant (variant a) of the compounds of formula I according to this invention includes those compounds of formula I, which are from formula Ia
• one subvariant of variant b includes compounds of formula Ib, in which the radicals -N(H)-C(O)- and Q are located at the opposite side of the plane defined by the cyclopropane ring.
• a more precise subvariant of variant b includes compounds of formula Ib*
• another more precise subvariant of variant b includes compounds of formula Ib**
• a fourth embodimental variant (variant d) of the compounds of formula I according to this invention includes those compounds of formula I, which are from formulae Id or Id'
• a fifth embodimental variant (variant e) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Rbb has one of the meanings as defined in the compounds mentioned above,
• Rbc has one of the meanings as defined in the compounds mentioned above.
• Q is optionally substituted by Rba and/or Rbb, and is phenyl, in which Rba is 1-4C-alkyl, halogen, trifluoromethyl, or hydroxyl, Rbb is 1-4C-alkyl, halogen, trifluoromethyl, or hydroxyl.
• a further subvariant (variant e2) of the compounds according to variant e of this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is optionally substituted by Rba, and is phenyl, in which
• Rba is methyl, ethyl, fluorine or chlorine; especially, methyl, fluorine or chlorine.
• a further subvariant (variant e3) of the compounds according to variant e of this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• a further subvariant (variant e4) of the compounds according to variant e of this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is unsubstituted, and is phenyl.
• Rba is methyl, ethyl, fluorine or chlorine.
• Rba is methyl, ethyl, fluorine or chlorine.
• a further subvariant (variant e7) of the compounds according to variant e of this invention includes those compounds of formula Ia, Ib or Ic, in which
• Rba is chlorine, methyl or ethyl.
• a further subvariant (variant e8) of the compounds according to variant e of this invention includes those compounds of formula Ia, Ib or Ic, in which
• Rba is chlorine, methyl or ethyl
• Rbb is fluorine, chlorine or methyl.
• a further subvariant (variant e9) of the compounds according to variant e of this invention includes those compounds of any of the formulae Ia, Ib and Ic, in which
• Rba is methyl, ethyl, fluorine or chlorine; especially, methyl, fluorine or chlorine.
• a further subvariant (variant e10) of the compounds according to variant e of this invention includes those compounds of any of the formulae Ia, Ib and Ic, in which
• Rba is methyl, ethyl, fluorine or chlorine; especially, methyl, fluorine or chlorine.
• a further subvariant (variant e11 ) of the compounds according to variant e of this invention includes those compounds of any of the formulae Ia, Ib and Ic, in which
• Q is unsubstituted, and is phenyl.
• a further subvariant (variant e13) of the compounds according to variant e of this invention includes those compounds of formula Ib, in which
• Q is unsubstituted, and is phenyl.
• a further subvariant (variant e14) of the compounds according to variant e of this invention includes those compounds of formula Ic, in which
• a sixth embodimental variant (variant f) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Har is a 5-membered monocyclic heteroaryl radical comprising one to four heteroatoms independently selected from nitrogen, oxygen and sulphur, such as e.g. any one selected from furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl and oxadiazolyl, whereby said Har radical is attached to the parent molecular group via a ring carbon or ring nitrogen atom,
• Rca has one of the meanings as defined in the compounds mentioned above,
• Rcb has one of the meanings as defined in the compounds mentioned above.
• a subvariant (variant f1 ) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Har is furanyl, thiophenyl, imidazol-1-yl or pyrazol-1-yl,
• Rcb is 1-4C-alkyl.
• a further subvariant (variant f2) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• a further subvariant (variant f4) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• a further subvariant (variant f6) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is a radical of the following formula
• Rca is methyl or chlorine.
• a further subvariant (variant f7) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is a radical of the following formula
• Rca is methyl or chlorine
• Rcb is attached to any possible ring carbon atom, and is methyl.
• Q is a radical of the following formula
• Rca is methyl or chlorine.
• a further subvariant (variant f9) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Rca is methyl or chlorine
• a further subvariant (variant f11 ) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib and Ic, in which
• a further subvariant (variant f12) of the compounds according to variant f of this invention include those compounds of any of the formulae Ia, Ib and Ic, in which
• a seventh embodimental variant (variant g) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is optionally substituted by Rca and/or Rcb, and is Har, in which
• Har is a 6-membered monocyclic heteroaryl radical comprising one or two nitrogen atoms, such as e.g. any one selected from pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, whereby said Har radical is attached to the parent molecular group via a ring carbon atom,
• Rcb has one of the meanings as defined in the compounds mentioned above.
• a subvariant (variant g1) of the compounds according to variant g of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is optionally substituted by Rca and/or Rcb, and is Har, in which
• Rcb has one of the meanings as defined in the compounds mentioned above.
• a further subvariant (variant g2) of the compounds according to variant g of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Har is pyridinyl.
• a further subvariant (variant g3) of the compounds according to variant g of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• a further subvariant (variant g4) of the compounds according to variant g of this invention include those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is pyridin-2-yl.
• a further subvariant (variant g5) of the compounds according to variant g of this invention include those compounds of any of the formulae Ia, Ib and Ic, in which
• a further subvariant (variant g6) of the compounds according to variant g of this invention include those compounds of any of the formulae Ia, Ib and Ic, in which
• a further subvariant (variant g7) of the compounds according to variant g of this invention include those compounds of formula Ia, in which
• Q is unsubstituted Har, in which Har is pyridin-2-yl.
• a further subvariant (variant g8) of the compounds according to variant g of this invention include those compounds of formula Ib, in which
• Har is pyridin-2-yl.
• a further subvariant (variant g9) of the compounds according to variant g of this invention include those compounds of formula Ic, in which
• Har is pyridin-2-yl.
• a further subvariant (variant g10) of the compounds according to variant g of this invention include those compounds of formula Ia, in which
• Har is pyridin-3-yl.
• a further subvariant (variant g12) of the compounds according to variant g of this invention include those compounds of formula Ic, in which
• An eighth embodimental variant (variant h) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is optionally substituted by Rda, and is Het, in which
• Het is a 3- to 7-membered monocyclic fully saturated heterocyclic ring comprising one or two heteroatoms independently selected from nitrogen, oxygen and sulphur, such as e.g. any one selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomorpholinyl, whereby said Het radical is attached to the parent molecular group via a ring carbon or ring nitrogen atom, Rda has one of the meanings as defined in the compounds mentioned above.
• a ninth embodimental variant (variant i) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is unsubstituted, and is cyclohexyl or cyclopentyl.
• Q is unsubstituted, and is cyclohexyl.
• a further subvariant (variant i4) of the compounds according to variant i of this invention include those compounds of formula Ic, in which
• Q is unsubstituted, and is cyclohexyl.
• a tenth embodimental variant (variant j) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which Q is attached via a carbon atom of the benzene ring to the parent molecular group, and is 1 ,3- benzodioxolyl, 2,2-difluoro-1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3- dihydrobenzofuranyl, chromenyl or chromanyl.
• An eleventh embodimental variant (variant k) of the compounds of formula I according to this invention includes those compounds of any of the formulae Ia, Ib, Ic, Id and Id', in which
• Q is any one selected from the group consisting of phenyl, 2-chlorophenyl, 2-methylphenyl, 2- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,
• furanyl, thiophenyl or dimethylfuranyl such as e.g. furan-2-yl, thiophen-2-yl or 3,4- dimethylfuran-2-yl, methyl-pyrazol-1-yl, such as e.g. 5-methyl-pyrazol-1-yl, pyridinyl, such as e.g. pyridin-3-yl, tetrahydrofuranyl, such as e.g. tetrahydrofuran-2-yl, and cyclohexyl.
• a thirteenth embodimental variant (variant m) of the compounds of formula I according to this invention includes those compounds of formula Ia, in which Q is any one of the meanings indicated in Table 1 given below.
• a fourteenth embodimental variant (variant n) of the compounds of formula I according to this invention includes those compounds of formula Ic*, in which Q is any one of the meanings indicated in Table 1 given below.
• a fifteenth embodimental variant (variant o) of the compounds of formula I according to this invention includes those compounds of formula Ic**, in which Q is any one of the meanings indicated in Table 1 given below.
• a sixteenth embodimental variant (variant p) of the compounds of formula I according to this invention includes those compounds of formula Ib*, in which Q is any one of the meanings indicated in Table 1 given below.
• a seventeenth embodimental variant (variant q) of the compounds of formula I according to this invention includes those compounds of formula Ia, in which R1 is any one of the meanings indicated in Table 1 given below.
• An eighteenth embodimental variant (variant r) of the compounds of formula I according to this invention includes those compounds of formula Ic*, in which R1 is any one of the meanings indicated in Table 1 given below.
• a twenth embodimental variant (variant t) of the compounds of formula I according to this invention includes those compounds of formula Ib*, in which R1 is any one of the meanings indicated in Table 1 given below.
• the invention refers to all conceivable stereoisomers, like e.g. diastereomers and enantiomers, in substantially pure form as well as in any mixing ratio, including the racemates, as well as the salts thereof.
• stereoisomers of formula Ic* and of formula Ic** and the salts thereof are part of the invention.
• stereoisomers of formula Ib* and of formula Ib** and the salts thereof are part of the invention.
• enantiomerically pure compounds of this invention may be prepared according to art- known processes, such as e.g. via asymmetric syntheses, for example, by preparation and separation of appropriate diastereoisomeric compounds/intermediates, which can be separated by known methods (e.g.
• Exemplary compounds according to the present invention may include, without being restricted thereto, any compound selected from those compounds of formula I mentioned in the following examples, the enantiomers (e.g., when the compound is from formula Ic, in one special embodiment, the enantiomer having the formula Ic* and, in another special embodiment, the enantiomer having the formula Ic**, or when the compound is from formula Ib, in one special embodiment, the enantiomer having the formula Ib* and, in another special embodiment, the enantiomer having the formula Ib**) as well as the salts of these compounds and enantiomers.
• the enantiomers e.g., when the compound is from formula Ic, in one special embodiment, the enantiomer having the formula Ic* and, in another special embodiment, the enantiomer having the formula Ic**
• the enantiomers e.g., when the compound is from formula Ic, in one special embodiment, the enantiomer having the formula Ic* and,
• any or all of the following compounds of formula Ic, in which Ra is -C(O)RI are more worthy to be mentioned by means of the substituent meanings for R1 and Q in the Table 1 given below, as well as the enantiomers and the salts of these compounds and enantiomers.
• a compound of formula III in which Ra has the meanings given above, can be condensed with malonitrile in the presence of sulfur and a suitable base, such as for example an amine (e.g. diethyl amine or morpholine) to give corresponding compounds of formula Il in a manner known to the person skilled in the art (e.g. according to a Gewald reaction) or as described in the following examples.
• a suitable base such as for example an amine (e.g. diethyl amine or morpholine) to give corresponding compounds of formula Il in a manner known to the person skilled in the art (e.g. according to a Gewald reaction) or as described in the following examples.
• compounds of the formula I can also be prepared from the corresponding compounds of formula Il and corresponding compounds of formula Rb-C(O)-X, in which X is hydroxyl, by reaction with amide bond linking reagents known to the person skilled in the art.
• amide bond linking reagents known to the person skilled in the art which may be mentioned are, for example, the carbodi- imides (e.g. dicyclohexylcarbodiimide or, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate), uronium salts [e.g.
• preferred amide bond linking reagents are uronium salts and, particularly, carbodiimides, preferably, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC).
• Acid derivatives of formula Rb-C(O)-X are known, commercially available or can be prepared as it is known for the skilled person, e.g. from the corresponding carboxylic acids.
• Carboxylic acids of formula Rb-C(O)-OH are known, commercially available or can be obtained as it is habitual for the skilled person, e.g. analogously or similarly to standard procedures.
• carboxylic acids of formula Rb-C(O)-OH in which Rb is -T-Q, in which T is 1-6C- alkylene, as defined above, especially those, in which Rb is -CH 2 -CH 2 -Q or -CH 2 -CH(CH 3 )-Q, in which Q has the meanings given above, can be obtained via CC-coupling reactions, such as e.g.
• carboxylic acids of formula Rb-C(O)-OH in which Rb is -T-Q, in which T is 1 ,2-cyclopropylene and Q has the meanings given above, can be obtained, starting from aldehydes of the formula Q-CHO, via Knoevenagel or Horner-Wadsworth-Emmons reaction, and then cyclopropanation reaction of the double bond (e.g. by Simmons-Smith reaction or, in particular, by Corey-Chaykovsky cyclopropanation reaction using dimethylsulfoxonium methylide) and, if necessary, hydrolysis of the corresponding esters obtained.
• cyclopropanation reaction of the double bond e.g. by Simmons-Smith reaction or, in particular, by Corey-Chaykovsky cyclopropanation reaction using dimethylsulfoxonium methylide
• MIRC Michael-initiated ring closure
• Aldehydes of the formula Har-CHO are known or can be obtained as it is known for the skilled person, such as e.g. from the corresponding heteroaromatic compounds by formylation reaction. Some aldehydes can be obtained as described e.g. for 4-methoxy-pyridin-2-carbaldehyde in Ashimori et al, Chem Pharm Bull 38, 2446-2458 (1990) or analogously or similarly thereto.
• Har-substituted carboxylic acids e.g. propionic acids
• Har in which Har has the meanings given above (e.g. substituted or unsubstituted pyridyl)
• Har-substituted carboxylic acids in which Har has the meanings given above (e.g. substituted or unsubstituted pyridyl)
• Har-substituted carboxylic acids in which Har has the meanings given above (e.g. substituted or unsubstituted pyridyl)
• Har e.g. substituted or unsubstituted pyridyl
• 3-(4-methoxypyridin-2-yl)propionic acid is described as compound A1 in WO03080607, or analogously or similarly thereto.
• the substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
• the present invention also relates to intermediates, including their salts, methods and processes useful in synthesizing compounds according to this invention.
• MS stands for mass spectrum
• M is the molecular ion in mass spectroscopy, calc. for calculated, fnd. for found, Boc for the tertbutoxycarbonyl group, EDC or EDCI for 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride and other abbreviations have their meanings customary per se to the skilled person.
• (RS) characterizes a racemate comprising the one enantiomer having the configuration R and the other enantiomer having the configuration S; each of these enantiomers in pure form as well as their mixtures including the racemic mixtures is part of this invention.
• the symbols RS and SR are used to denote the specific configuration of each of the chiral centers of a racemate.
• (1 RS, 2RS) stands for a racemate (racemic mixture) comprising the one enantiomer having the configuration (1 R,2R) and the other enantiomer having the configuration (1S.2S); each of these enantiomers in pure form as well as their mixtures including the racemic mixtures is part of this invention.
• reaction mixture is a solution, it is extracted by three portions of 5% sodium hydrogencarbonate (10 ml each) and once by water (10 ml), the organic layer is evaporated and the residue subjected to purification.
• the title compound is prepared from Example 7 by art-known saponification reaction (e.g. using 1 N

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