WO2008080938A1 - Use 2-substituted pyridines for cancer treatment - Google Patents

Use 2-substituted pyridines for cancer treatment Download PDF

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WO2008080938A1
WO2008080938A1 PCT/EP2007/064569 EP2007064569W WO2008080938A1 WO 2008080938 A1 WO2008080938 A1 WO 2008080938A1 EP 2007064569 W EP2007064569 W EP 2007064569W WO 2008080938 A1 WO2008080938 A1 WO 2008080938A1
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cio
alkyl
group
compounds
cyano
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PCT/EP2007/064569
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French (fr)
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Barbara Nave
Sven Harmsen
Bernd Müller
Thomas Grote
Joachim Rheinheimer
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Basf Se
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to 2-substituted pyridines of the formula I and the pharmaceutically acceptable salts of the 2-substituted pyridines of formula I for use in therapy, in particular in therapy or treatment of cancer or a cancerous diseases, respectively.
  • formula I 2-substituted pyridines of the formula I and the pharmaceutically acceptable salts of the 2-substituted pyridines of formula I for use in therapy, in particular in therapy or treatment of cancer or a cancerous diseases, respectively.
  • one of the two ring members is N, the other is C-H or C-halogen;
  • Y is a group -CH-R 1 -, -N-R 1 -, -O- or -S-;
  • R 1 , R 2 independently of one another are selected from the group consisting of Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Ci2-cycloalkyl and C4-Cio-cycloalkenyl, where the aliphatic and/or alicyclic groups of the radical definitions of R 1 and R 2 for their part may be partially or fully halogenated or may carry one, two, three or four radicals R v , which may be the same or different from each other:
  • m is 0, 1 or 2;
  • a 1 , A 2 , A 3 , A and A' independently of one another are hydrogen, d-Ce-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C3-C8-cycloalkenyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, nitro, cyanato, cyano and/or Ci-C4-alkoxy; or A 1 and A 2 , or A and A', respectively, together with the atoms to which they are attached are a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S;
  • R 1 may additionally be hydrogen
  • R 3 is selected from the group consisting of halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cs-C ⁇ -cycloalkyl, Ci-C4-alkoxy, C3-C4-alkenyloxy,
  • a 13 , A 14 and A 15 independently of one another have the meanings of A 1 , A 2 and A 3 as defined above;
  • R 1 aliphatic, alicyclic and/or aromatic groups of the radical definitions of R 1 for their part may be partially or fully halogenated or may carry one, two or three radicals R ta , which may be the same or different from each other and which have the meanings of R 1 as defined above;
  • R 4 is a five-, six-, seven-, eight-, nine- or ten-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle which comprises one, two, three or four heteroatoms as ring members, which are selected from the group consisting of O, N and S and where the heterocycle for its part may be partially or fully halogenated or may carry one, two, three or four radicals R u , which may be the same or different from each other:
  • q 0, 1 or 2;
  • a 4 , A 5 and A 6 independently of one another have the meanings of A 1 , A 2 and A 3 as defined above;
  • R u aliphatic, alicyclic and/or aromatic groups of the radical definitions of R u for their part may be partially or fully halogenated or may carry one, two or three radicals R ua , which may be the same or different from each other and which have the meanings of R u as defined above;
  • Z is O, S, NR a1 , NOR a1 or N-NR z1 R c1 ;
  • R a , R a1 , R b , R c , R c1 independently of one another are hydrogen, C r C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl or C 4 -C 6 -cycloalkenyl;
  • R b1 has the meanings of R b as defined above, except for hydrogen;
  • R z , R z1 independently of one another have the meanings of R a as defined above and may additionally be -CO-R a2 , where R a2 has the meanings of R a as defined above;
  • R a , R a1 , R b , R b1 , R c , R c1 , R z and R z1 for their part may be partially or fully halogenated or may carry one, two, three or four radicals R w , which may be the same or different from each other:
  • R w is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-C ⁇ -alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-C ⁇ -cycloalkyl, Cs-C ⁇ -cycloalkenyl, C3-C6-cycloalkoxy or Cs-C ⁇ -cycloalkenyloxy,
  • R a , R a1 , R b , R b1 , R c , R c1 , R z or R z1 together with the atoms, to which they are attached, may form a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S;
  • ( — ⁇ y > is phenyl or a five- or six-membered hetaryl which comprises 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S;
  • n 1 , 2, 3, 4 or 5;
  • L is selected from the group consisting of halogen, cyano, cyanato (OCN),
  • r is O, 1 or 2;
  • a 7 , A 8 , A 9 independently of one another have the meanings of A 1 , A 2 and A 3 as defined above;
  • R L is selected from the group consisting of halogen, cyano, Ci-Cio-alkyl,
  • s 0, 1 or 2;
  • a 10 , A 11 and A 12 independently of one another have the meanings of A 1 , A 2 and A 3 as defined above;
  • R L aliphatic, alicyclic and/or aromatic groups of the radical definitions of R L for their part may be partially or fully halogenated or may carry one, two, three or four radicals R LA , which may be the same or different from each other and which have the meanings of R L as defined above.
  • the invention in particular relates to the use of the compounds for the formula I and of their pharmaceutically acceptable salts in therapy or treatment of cancer or a cancerous disease, respectively.
  • the invention also relates to pharmaceutical compositions comprising a 2-substituted pyridine of the formula I as defined herein or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. Moreover the invention relates to the use of a 2-substituted pyridine of the formula I as defined herein and of their pharmaceutically acceptable salts in the manufacture of a medicament in particular a medicament for the therapy or treatment of cancer or a cancerous disease, respectively. The invention also provides a method for cancer treatment, which comprises administering to the subject in need thereof an effective amount of a 2-substituted pyridine of the formula I as defined herein or of their pharmaceutically acceptable salts.
  • cancer is still one of the leading causes of death.
  • cancer is the 2 nd most common reproductive cancer after breast cancer in women.
  • a large number of cytotoxic compounds are known to effectively inhibit the growth of tumor cells, including taxoides like paclitaxel (Taxole), docetaxel (Taxotere), the vinka alkaloids vinorelbine, vinblastine, vindesine and vincristine.
  • Taxoides like paclitaxel (Taxole), docetaxel (Taxotere), the vinka alkaloids vinorelbine, vinblastine, vindesine and vincristine.
  • these compounds are natural products having a complex structure and thus are difficult to produce.
  • an object of the present invention to provide compounds which effectively control or inhibit growth and/or progeny of tumor cells and thus are useful in the treatment of cancer. It is highly desirable that these compounds can be synthesized from simple starting compounds according to standard methods of organic chemistry.
  • 2-Substituted pyridines I have been described in WO 2006/000358.
  • the compounds disclosed therein are active against various phytopathogenic fungi. However, this document does not describe or suggest that these compounds may be effective in the treatment of diseases or even in the treatment of cancer.
  • 2-Substituted pyridines I can be prepared by the methods disclosed in
  • physiologically tolerated salts of the 2-substituted pyridines I especially acid addition salts with physiologically tolerated acids.
  • suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonic acids having from 1 to 12 carbon atoms, e.g.
  • Ci-C4-alkylsulfonic acids such as methanesulfonic acid, cycloaliphatic sulfonic acids such as S-(+)-10-camphorsulfonic acids and aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having from 2 to 10 carbon atoms such as oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lactic acid, tartaric acid, citric acid, glycolic acid and adipic acid, as well as cis- and trans- cinnamic acid, furoic acid and benzoic acid.
  • Other utilizable acids are described in
  • the physiologically tolerated salts of 2-substituted pyridines I may be present as the mono-, bis-, tris- and tetrakis-salts, that is, they may contain 1 , 2, 3 or 4 of the aforementioned acid molecules per molecule of formula I .
  • the acid molecules may be present in their acidic form or as an anion.
  • the acid addition salts are prepared in a customary manner by mixing the free base of a 2-substituted pyridine I with a corresponding acid, where appropriate in solution in water or an organic solvent as for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, an ether such as methyl tert-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.
  • Solvents, wherein the acid addition salt of I is insoluble might be added to precipitate the salt.
  • Suitable anti-solvents comprise
  • Ci-C4-alkylesters of Ci-C4-aliphatic acids such as ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc., di-Ci-C4-alkylethers such as methyl tert-butyl ether or diisopropyl ether.
  • halogen fluorine, chlorine, bromine or iodine
  • alkenyl and the alkenyl moieties of alkenyloxy unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 10, preferably 2 to 6, and in particular 2 to 4 carbon atoms, and a double bond in any position, especially C3-C4-alkenyl, for example ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,
  • - alkadienyl unsaturated straight-chain or branched hydrocarbon radicals having 4 to 8, in particular 4 to 6 carbon atoms and two double bonds in any position, for example butadiene, 1 ,3-pentadiene, 1 ,4-pentadiene, 1 ,3-hexadiene, 1 ,4-hexadiene and 1 ,5-hexadiene;
  • - alkynyl straight-chain or branched hydrocarbon radicals having 2 to 10, preferably 2 to 6, in particular 2 to 4 carbon atoms, and a triple bond in any position, especially
  • C3-C 4 -alkynyl for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1 ,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,
  • - cycloalkyl mono- or bicyclic hydrocarbon radicals having 3 to 10 carbon atoms; monocyclic groups having 3 to 8, especially 3 to 6 ring members, for example C3-C8-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
  • haloalkyl and the haloalkyl moieties of haloalkoxy straight-chain or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms (as mentioned above), where the hydrogen atoms in these groups may be partially or fully replaced by halogen atoms as mentioned above, for example
  • Ci-C4-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1 ,1 ,1-trichloroprop-1-yl, 1 ,1 ,1-trifluoroprop-1-yl, 1 ,1 ,1 -trichloroprop
  • - oxy-alkyleneoxy divalent straight-chain hydrocarbon radicals having 2 to 3 carbon atoms, e.g. OCH 2 CH 2 O or OCH 2 CH 2 CH 2 O;
  • heterocycle homo- or bicyclic hydrocarbon radicals containing one to four heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; unsaturated (heterocyclyl) includes partially unsaturated, e.g. mono-unsaturated, and aromatic (heteroaryl); said heterocycles in particular include:
  • 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom
  • 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, for example 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, thiophenyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1 ,2,4
  • 6-membered heteroaryl containing one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain one to three or one to four nitrogen atoms as ring members, for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazin-2-yl and 1 ,2,4-triazin-3-yl.
  • 9- or 10-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 9- or 10-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, in particular benzo-fused 5- or 6-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom (i. e.
  • 5- or 6-membered heteroaryl groups which, in addition to carbon atoms, contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1 ,3-dien-1 ,4-diyl group), for example benzothiazol-2-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 H-indazol-1-yl, 1 H-indazol-2-yl, benzofuran-2-yl and benzofuran-3-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, phthalazinyl, quinoxalinyl, quina
  • the scope of the present invention includes the (R) and (S) isomers of the formula I having chiral centers.
  • any mixture of the (R) and (S) isomer compounds in any ratio including the racemates is also within the scope of the present invention.
  • the 2-substituted pyridines I are generally useful both if Xi is N or if X2 is N. According to the present invention, only one of Xi and X2 is N, while the other ring member of the pyridine system is C-H or C-halogen, e. g. C-F, C-Cl and C-Br, in particular C-H.
  • 2-substituted pyridines of the formulae I and I' wherein R 1 and R 2 independently of one another are d-Cs-alkyl, d-Cs-haloalkyl, C2-C8-alkenyl, C2-C8-haloalkenyl, C2-C8-alkynyl, C2-C8-haloalkynyl, Cs-Cs-cycloalkyl or C3-C8-halocycloalkyl, more particularly Ci-Cs-alkyl, d-Cs-haloalkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two, especially one radical(s) R v which may be the same or different from each other and which are selected from the group consisting of Ci-C ⁇ -al
  • R 2 is Cs-Cs-alkyl or C3-Cs-haloalkyl, preferably Cs-Cs-alkyl, in each case branched in the ⁇ -position
  • R 2 is prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (2-methyl)-but-2-yl, (2,3-dimethyl)-but-2-yl, (3,3-dimethyl)-but-2-yl, (2-methyl)-pent-2-yl, (3-methyl)-pent-2-yl, (4-methyl)-pent-2-yl, (2,3-dimethyl)-pent-2-yl, (2,4-dimethyl)-pent-2-yl, (3,4-dimethyl)-pent-2-yl, (4,
  • R 2 is C3-C8-cycloalkyl or Cs-Cs-halocycloalkyl, preferably Cs-Cs-cycloalkyl, more preferably C3-C6-cycloalkyl
  • R v is attached to a cyclohexanyl ring, it is preferably in the ortho- or para-position, more preferably in the para-position.
  • R 2 being cyclopropanyl, cyclohexanyl, 2-methylcyclohexanyl, 4-methylcyclohexanyl, 2-phenylcyclohexanyl, 4-phenylcyclohexanyl, (2-tert-butyl)-cyclohexanyl and (4-tert-butyl)-cyclohexanyl.
  • R 2 has one of the aforementioned meanings
  • Y is NR 1 or CHR 1 and R 1 is hydrogen.
  • R 2 is Ci-C ⁇ -alkyl or Ci-C ⁇ -haloalkyl, preferably Ci-C4-alkyl, in particular methyl, ethyl, prop-2-yl and but-2-yl
  • R v selected from the group consisting of Cs-C ⁇ -cycloalkyl, particularly cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, and phenyl, where the phenyl moiety may carry one or two, preferably two radical(s) d-C ⁇ -alkoxy, preferably Ci-C4-alkoxy, in particular methoxy, ethoxy, propoxy and butoxy.
  • phenyl moiety carries two Ci-C6-alkoxy radicals, it is preferred that they are attached to adjacent carbon atoms of the phenyl ring.
  • Particular preference is given to 1-cyclopropyl-ethyl, 1-cyclohexyl-ethyl, 2-cyclopropyl-ethyl, 2-cyclohexyl-ethyl, 1-phenyl-ethyl, 2-phenyl-ethyl, 1-(3,4-dimethoxy)phenyl-ethyl and 2-(3,4-dimethoxy)phenyl-ethyl.
  • R 2 has one of the aforementioned meanings
  • Y is NR 1 or CHR 1 and R 1 is hydrogen.
  • R 1 and/or R 2 contain haloalkyl or haloalkenyl groups having a center of chirality, the (S)-isomers are preferred for these groups.
  • 2-substituted pyridines of the formulae I and I' wherein Y is NR 1 and wherein R 1 and R 2 , together with the nitrogen atom to which they are attached, form a saturated or unsaturated, preferably saturated five- or six- membered ring which may be interrupted by an ether -(-O-) or by a further amino -(-N(R X )- group, where R x is hydrogen or Ci-C ⁇ -alkyl, and/or where the ring formed may carry one or more, e. g.
  • substituent(s) from the group consisting of halogen, d-C ⁇ -alkyl, C-i-C ⁇ -haloalkyl and oxy-Ci-C3-alkyleneoxy, in particular halogen, Ci-C ⁇ -alkyl and C-i-C ⁇ -haloalkyl.
  • substituent(s) from the group consisting of halogen, d-C ⁇ -alkyl, C-i-C ⁇ -haloalkyl and oxy-Ci-C3-alkyleneoxy, in particular halogen, Ci-C ⁇ -alkyl and C-i-C ⁇ -haloalkyl.
  • those are especially preferred which correspond to the formula I'.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a saturated or unsaturated, preferably saturated five- or six-membered ring which may be interrupted by an oxygen atom and which may carry one or two Ci-C ⁇ -alkyl, preferably Ci-C4-alkyl substituents, e. g. methyl, ethyl, prop-1-yl and prop-2-yl, more preferably Ci-C2-alkyl substituents, e. g. methyl, ethyl, especially methyl.
  • 2-substituted pyridines of the formulae I and I' in which R 1 and R 2 , together with the nitrogen to which they are attached, form a saturated or unsaturated five- or six-membered ring especially preferred are those wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a saturated five- or six-membered ring which has no other heteroatom than the nitrogen atom attached to R 1 and R 2 , such as pyrrolidines and piperidines, e. g.
  • pyrrolidin-1-yl and piperidin-1-yl which is optionally substituted by one, two or three, preferably one group(s) selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl, preferably Ci-C4-alkyl.
  • More particular preference is given to the aforementioned 2-substituted pyridines I wherein the ring, which includes R 1 , R 2 and the attached nitrogen atom, is unsubstituted or is methylated, in particular in the ⁇ -position, i. e. the carbon atom next to the pyridine ring nitrogen atom carries a methyl group, e. g. 2-methylpyrrolidyl and 2-methylpiperidyl.
  • Preferred radicals of the formula NR 1 R 2 (i. e. where Y is -NR 1 ) which are attached to the pyridine skeleton of the 2-substituted pyridines of formula I, include: NH-C 2 H 5 , NH(CH(CHs) 2 ), NH-CH 2 CH 2 CH 3 , NH(CH(CH 3 )(C 2 H 5 ), (S)-NHCH(CH 3 )(C 2 H 5 ), NH-CH(CH 3 )(CH 2 CH 2 CH 3 ), (R)-NHCH(CH 3 )(C(CH 3 ) 3 ), NH-CH(CH 3 )CH(CHS) 2 , (R)-NHCH(CH 3 )(CH(CHS) 2 ), (S)-NHCH(CH 3 )(CH(CHS) 2 ), NH(cyclopentyl), NHCH 2 CF 3 , NHCH(CHs)(CF 3 ), (R)-NHCH
  • R 3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl or Ci-C4-alkoxy, such as chlorine, bromine, methyl, cyano, methoxy or ethoxy, especially chlorine, cyano, methyl or methoxy.
  • R 4 is pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl or benzothiazolyl, where the hetero
  • 2-substituted pyridines of the formulae I and I' wherein R 4 is pyrazol-1-yl, 3-amino-pyrazol-1-yl, [1 ,2,4]triazol-1-yl, 3-cyano-1 ,2,4-triazol-1-yl, [1 ,2,3]triazol-1-yl, 1 ,2,4-oxadiazol-3-yl, 5-methyl-1 ,2,4-oxadiazol-3-yl, pyridin-2-yl, (6-methyl)-pyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, (1 ,2-dihydro)-pyridin-2-on-1 -yl, pyrrolidin-2-on-1 -yl, piperidin-2-on-1 -yl, pyrrolidin-2-thion-1-yl, piperidin-2-thion-1-yl, piperidin-2-
  • R 4 is benzo-fused 5- or 6-membered heteroaryl which contains 1 , 2 or 3 nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom, in particular benzothiazol-2-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 H-indazol-1-yl, 1 H-indazol-3-yl, benzofuran-2-yl and benzofuran-3-yl; furthermore quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, phthalazinyl, quinoxalinyl, quinazolin-2-yl, quinazolin-4-yl, cinnolin-3
  • R a , R a1 , R b , R c and R c1 independently of one another are hydrogen, Ci-C ⁇ -alkyl, d-Ce-haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 4 -C 6 -cycloalkenyl or C 4 -C 6 -halocycloalkenyl, more preferably hydrogen, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl or C 3 -C 6 -cycl
  • those compounds I are preferred where R b1 has the preferred meanings of R b as defined above, except for hydrogen.
  • those compounds I are preferred where R z and R z1 independently of one another have the preferred meanings of R a as defined above or are -CO-R a2 , where R a2 has the preferred meanings of R a as defined above.
  • R a1 is hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, in particular methyl.
  • R a and/or R b especially both R a and R b are hydrogen.
  • R a and R a1 independently of one another are hydrogen or Ci-C4-alkyl, especially Ci-C 2 -alkyl, e. g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. More preferably R a is hydrogen, methyl, ethyl, n-propyl or iso-propyl. Likewise, more preferably R a1 is methyl. Furthermore, those compounds I are more particularly preferred where R b is hydrogen or Ci-C4-alkyl, especially Ci-C 2 -alkyl, e. g.
  • R b is hydrogen or methyl.
  • R z is hydrogen, Ci-C4-alkyl, e. g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl, in particular methyl, or -CO-R a2 , where R a2 is Ci-C4-alkyl, e. g. methyl or ethyl, in particular methyl. More preferably R z is hydrogen, methyl or -CO-R a2 , and R a2 is methyl.
  • L is selected from the group consisting of halogen, in particular fluorine, chlorine, bromine, preferably fluorine, chlorine; cyano; d-Cs-alkyl, in particular d-C ⁇ -alkyl, especially Ci-C4-alkyl, such as methyl, ethyl, propyl and butyl, preferably methyl; C2-Cio-alkenyl, in particular C2-C6-alkenyl, especially C2-C4-alkenyl, such as ethenyl, propenyl and butenyl; C2-Cio-alkynyl, in particular C2-C6-alkynyl, especially C2-C4-alkynyl, such as ethynyl, propynyl and butynyl;
  • a 7 , A 8 independently of one another are hydrogen, Ci-C ⁇ -alkyl,
  • aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated, e. g. where L may be
  • Ci-C 2 -fluoroalkyl such as trifluoromethyl.
  • those are especially preferred which correspond to the formula I'.
  • 2-substituted pyridines of the formulae I and I' wherein one or two radical(s) L is (are) attached to one (or two) of the ortho-position(s) of the hetaryl or phenyl ring system B.
  • the ring system B particularly preferably is five- membered hetaryl which comprises 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S or is pyridyl or phenyl, especially phenyl.
  • 2-substituted pyridines I wherein n is 1 , 2 or 3.
  • L 1 is fluorine, chlorine, CH3 or CF3, more preferably fluorine or chlorine;
  • L 2 , L 4 independently of one another are hydrogen, CH3 or fluorine, more preferably hydrogen;
  • L 5 is hydrogen, fluorine, chlorine or CH 3 , more preferably fluorine or chlorine.
  • pyridines of the formula I' and their salts are preferred, wherein the radical is a radical of the formula B as defined above.
  • Y is O, CHR 1 or NR 1 ,
  • R 1 , R 2 independently of one another are d-Cs-alkyl, C 2 -C8-alkenyl, C 2 -C8-alkynyl, d-Cs-haloalkyl, C 2 -C8-haloalkenyl or C 2 -C8-haloalkynyl, C 3 -C8-cycloalkyl, C 3 -C8-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two substituents R v which may be the same or different from each other and which are selected from the group consisting of Ci-C ⁇ -alkyl, C-i-C ⁇ -haloalkyl, C3-C6-cycloalkyl, Cs-C ⁇ -halocycloalkyl and phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen
  • Ci-C ⁇ -haloalkyl Ci-C ⁇ -haloalkyl, d-C ⁇ -alkoxy, cyano and nitro;
  • R 1 may additionally be hydrogen; or, if Y is NR 1 ,
  • R 1 and R 2 may also, together with the nitrogen atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may be interrupted by an ether (-O-) or by a further amino -(-N(R X ))- group, where R x is hydrogen or Ci-C ⁇ -alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, Ci-C ⁇ -alkyl, C-i-C ⁇ -haloalkyl and oxy-Ci-C3-alkyleneoxy;
  • R 3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;
  • R 4 is pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl or benzothiazolyl, where the heterocycle may be attached via C or N to the pyridine ring and may carry one, two or three radicals R
  • n 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring;
  • a 7 , A 8 independently of one another are hydrogen, Ci-C ⁇ -alkyl,
  • aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals R L , which may be the same or different from each other.
  • radical is a radical of the formula B as defined above.
  • Y is O, CHR 1 or NR 1 ,
  • R 1 , R 2 independently of one another are Ci-Cs-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, d-Cs-haloalkyl, C2-C8-haloalkenyl or C2-C8-haloalkynyl, Cs-Cs-cycloalkyl, C3-C8-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two substituents R v which may be the same or different from each other and which are selected from the group consisting of d-C ⁇ -alkyl, d-C ⁇ -haloalkyl, C3-C6-cycloalkyl, Cs-C ⁇ -halocycloalkyl and phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, d-C ⁇ -alkyl,
  • R 1 may additionally be hydrogen; or, if Y is NR 1 ,
  • R 1 and R 2 may also, together with the nitrogen atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may be interrupted by an ether (-O-) or by a further amino -(-N(R X ))- group, where R x is hydrogen or Ci-C ⁇ -alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-C ⁇ -alkyl, d-C ⁇ -haloalkyl and oxy-Ci-C3-alkyleneoxy;
  • R 3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;
  • n 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring;
  • L is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-C ⁇ -alkoxy,
  • a 7 , A 8 independently of one another are hydrogen, d-C ⁇ -alkyl,
  • aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals R L , which may be the same or different from each other.
  • radical is a radical of the formula B as defined above.
  • Y is CHR 1 or NR 1 ,
  • R 2 is Cs-Cs-alkyl or Cs-Cs-haloalkyl, preferably Cs-Cs-alkyl, in each case branched in the ⁇ -position, with preference given to those where R 2 is prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (2-methyl)-but-2-yl, (2,3-dimethyl)-but-2-yl, (3 ,3-d imethyl)-but-2-yl , (2-methyl)-pent-2-yl , (3-methyl)-pent-2-yl , (4-methyl)-pent-2-yl, (2,3-dimethyl)-pent-2-yl, (2,4-dimethyl)-pent-2-yl, (3,4-dimethyl)-pent-2-yl, (4,4-dimethyl)-pent-2-yl, 1 ,1
  • R 1 is hydrogen; or, if Y is NR 1 ,
  • R 1 and R 2 together with the nitrogen may also form a 5- or 6-membered saturated heterocycle, containing no further heteroatom such as pyrrolidin-1-yl and piperidin-1-yl, and which is optionally substituted by one, two or three, preferably one group(s) selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl, preferably Ci-C 4 -alkyl;
  • R 3 is halogen
  • R 4 is pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl or benzothiazolyl, where the heterocycle may be attached via C or N to the pyridine ring and may carry one, two or three radicals R
  • radical is a radical of the formula B as defined above.
  • Y is CHR 1 or NR 1 ,
  • R 2 is C3-Cs-alkyl or Cs-Cs-haloalkyl, preferably Cs-Cs-alkyl, in each case branched in the ⁇ -position, with preference given to those where R 2 is prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (2-methyl)-but-2-yl, (2,3-dimethyl)-but-2-yl, (3 ,3-d imethyl)-but-2-yl , (2-methyl)-pent-2-yl , (3-methyl)-pent-2-yl , (4-methyl)-pent-2-yl, (2,3-dimethyl)-pent-2-yl, (2,4-dimethyl)-pent-2-yl, (3,4-dimethyl)-pent-2-yl, (4,4-dimethyl)-pent-2-yl, 1 ,1
  • R 1 is hydrogen; or, if Y is NR 1 ,
  • R 1 and R 2 together with the nitrogen may also form a 5- or 6-membered saturated heterocycle, containing no further heteroatom such as pyrrolidin-1-yl and piperidin-1-yl, and which is optionally substituted by one, two or three, preferably one group(s) selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl, preferably Ci-C 4 -alkyl;
  • R 3 is halogen
  • radical is a radical of the formula B as defined above.
  • Table 9 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,4,5-trifluoro, R 3 is methyl and YR 2 for each compound corresponds to one row of Table A.
  • Table 17 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,5-difluoro, R 3 is methyl and YR 2 for each compound corresponds to one row of Table A.
  • Table 25 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,6-difluoro-4-cyano, R 3 is methyl and YR 2 for each compound corresponds to one row of Table A.
  • Table 33 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,6-difluoro,4-methoxy, R 3 is methyl and YR 2 for each compound corresponds to one row of Table A.
  • Table 41 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,5-dimethyl,4-bromo, R 3 is methyl and YR 2 for each compound corresponds to one row of Table A.
  • Table 49 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,6-difluoro, R 3 is chlorine and YR 2 for each compound corresponds to one row of Table A.
  • Table 57 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,4-dichloro, R 3 is chlorine and YR 2 for each compound corresponds to one row of Table A.
  • Table 65 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,3,4-trifluoro, R 3 is chlorine and YR 2 for each compound corresponds to one row of Table A.
  • Table 73 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,6-difluoro-4-methyl, R 3 is chlorine and YR 2 for each compound corresponds to one row of Table A.
  • Table 81 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-fluoro,3-methyl, R 3 is chlorine and YR 2 for each compound corresponds to one row of Table A.
  • Table 89 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-fluoro,4-bromo, R 3 is chlorine and YR 2 for each compound corresponds to one row of Table A.
  • Table 97 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,6-dichloro, R 3 is methoxy and YR 2 for each compound corresponds to one row of Table A.
  • Table 105 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-chloro, R 3 is methoxy and YR 2 for each compound corresponds to one row of Table A.
  • Table 113 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-methyl, R 3 is methoxy and YR 2 for each compound corresponds to one row of Table A.
  • Table 121 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,6-difluoro-4-methoxycarbonyl, R 3 is methoxy and YR 2 for each compound corresponds to one row of Table A.
  • Table 129 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is2,5-dimethyl, R 3 is methoxy and YR 2 for each compound corresponds to one row of Table A.
  • Table 137 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-fluoro,4-methoxy, R 3 is methoxy and YR 2 for each compound corresponds to one row of Table A.
  • Table 145 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-fluoro,6-methyl, R 3 is cyano and YR 2 for each compound corresponds to one row of Table A.
  • Table 153 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-fluoro, R 3 is cyano and YR 2 for each compound corresponds to one row of Table A.
  • Table 161 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2,4-dimethyl, R 3 is cyano and YR 2 for each compound corresponds to one row of Table A.
  • Table 169 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-chloro,4-methoxy, R 3 is cyano and YR 2 for each compound corresponds to one row of Table A.
  • Table 177 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-methyl,4-cyano, R 3 is cyano and YR 2 for each compound corresponds to one row of Table A.
  • Table 185 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which L n is 2-fluoro,5-methyl, R 3 is cyano and YR 2 for each compound corresponds to one row of Table A.
  • 2-substituted pyridines I in particular the compounds of the formulae Ia, Ic, Ie, If, Ig, Im, lo, Iq, Ir and Is effectively inhibit growth and/or progeny of tumor cells as can be shown by standard tests on tumor cell lines such as HeLa, MCF-7 and COLO 205.
  • 2-substituted pyrimidines I show in general IC50 values ⁇ 10 "6 mol/l (i.e. ⁇ 1 ⁇ M), preferably IC50 values ⁇ 10 "7 mol/l (i.e. ⁇ 100 nM) for cell cycle inhibition in HeLa cells as determined by the test procedure outlined below.
  • 2-substituted pyridines are useful as agents for treating, inhibiting or controlling the growth and/or progeny of cancerous tumor cells and associated diseases in a subject in need thereof. Therefore these compounds are useful in therapy of cancer in warm blooded vertebrates, i.e. mammals and birds, in particular human beings but also in other mammals of economic and/or social importance e.g. carnivores such as cats and dogs, swine (pigs, hogs and wild boars), ruminats (e.g.
  • treatment and “therapy” are synonyms.
  • 2-substituted pyridines I are useful in therapy of cancer or cancerous disease including cancer of breast, lung, colon, prostate, melanoma, epidermal, kidney bladder, mouth, larynx, esophagus, stomach, ovary, pancreas, liver, skin and brain.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and severity of the condition being treated. However, in general satisfactory results are obtained when the compounds of the invention are administered in amounts ranging from about 0.10 to about 100 mg/kg of body weight per day. A preferred regimen for optimum results would be from about 1 mg to about 20 mg/kg of body weight per day and such dosage units are employed that a total of from about 70 mg to about 1400 mg of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.
  • the dosage regimen for treating mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes.
  • the active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatine capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet.
  • these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.
  • Such compositions and preparations should contain at least 0.1 % of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 1000 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatine
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agent such
  • tablets, pills or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used.
  • these active compounds may be incorporated into sustained-release preparations and formulations. These active compounds may also be administered parenterally or intraperitoneal ⁇ . Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.
  • HeLa B cells are grown in DMEM (Life Technologies Cat No 21969-035) supplemented with 10% Fetal Calf Serum (FCS, Life Technologies Cat No 10270-106) in 180 cm 2 Flasks at 37°C, 92% humidity and 7% CO 2 .
  • FCS Fetal Calf Serum
  • Cells are seeded at 5x10 4 cells per well in a 24-well plate. Twenty hours later the compounds are added such that the final concentration is 1x10 "6 , 3.3x10 "7 , 1.1x10 "7 , 3.7x10 "8 , 1.2x10 "8 and 1 x10 "9 M in a final volume of 500 ⁇ l. DMSO alone is added to 6 wells as a control. Cells are incubated with the compounds as above for 20 h. Then cells are observed under the microscope to check for cell death, and the 24-well plate is then centrifuged at 1200 rpm for 5 min at 20 0 C, acceleration position 7 and break position 5 (Eppendorf centrifuge 5804R).
  • the supernatant is removed and the cells are lysed with 0.5 ml RNase Buffer (10 mM NaCitrate, 0.1 % Nonidet NP40, 50 ⁇ g/ml RNase, 10 ⁇ g/ml Propidium iodide) per well.
  • the plates are then incubated for at least 30 min in the dark at RT and the samples then transferred to FACS tubes. Samples are measured in a FACS machine (Beckton Dickinson) at the following settings:
  • the ratio of cells in Go/Gi-phase to G2/M phase is calculated and compared to the value for the controls (DMSO) only. Results are given in table C as the IC50 value calculated from the concentration curve plotted against the cell cycle ratio and indicate the compound concentration at which 50% of cells are in cell cycle arrest after treatment with the compound. Test on other cell lines (MCF-7 and COLO 205) were done in the same way except that they were incubated with the growth medium recommended by the American Tissue Culture collection for that cell type.

Abstract

The present invention relates to the use of 2-substituted pyridines of the formula (I) and the pharmaceutically acceptable salts of the 2-substituted pyridines of formula I in therapy, in particular in therapy or treatment of cancerous diseases. in which the indices and the substituents are as definedin the claims and the specification.

Description

USE 2-SUBSTITUTED PYRIDINES FOR CANCER TREATMENT
Description
The present invention relates to 2-substituted pyridines of the formula I and the pharmaceutically acceptable salts of the 2-substituted pyridines of formula I for use in therapy, in particular in therapy or treatment of cancer or a cancerous diseases, respectively. In formula I
Figure imgf000002_0001
the indices and the substituents are as defined below:
Xi, X2 in each case, one of the two ring members is N, the other is C-H or C-halogen;
Y is a group -CH-R1-, -N-R1-, -O- or -S-;
R1, R2 independently of one another are selected from the group consisting of Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Ci2-cycloalkyl and C4-Cio-cycloalkenyl, where the aliphatic and/or alicyclic groups of the radical definitions of R1 and R2 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Rv, which may be the same or different from each other:
Rv is selected from the group consisting of halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Ce-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1, C(A2X=N-OA1), N(A2)A1, N(A2)-C(=O)-A1, N(A3)-C(=O)-N(A2)A1, S(=O)m-A1, S(=O)m-O-A1 and S(=O)m-N(A2)A1, it also being possible that two vicinal radicals Rv together are (=0) or (=S), or Rv is phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C-i-Cβ-haloalkyl, Ci-Cβ-alkoxy, cyano, nitro, -C(=O)-A, -C(=O)-O-A, -C(=O)-N(A')A, C(A')(=N-OA) and N(A')A; where
m is 0, 1 or 2; A1, A2, A3, A and A' independently of one another are hydrogen, d-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, nitro, cyanato, cyano and/or Ci-C4-alkoxy; or A1 and A2, or A and A', respectively, together with the atoms to which they are attached are a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Rv for their part may be partially or fully halogenated;
R1 may additionally be hydrogen;
R1 and R2 may also, together with the nitrogen or carbon atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may comprise O, S, carbonyl (C=O), sulfoxyl (-S[=O]-), sulfonyl (-SO2-) or an -(-N(RX)- group as ring members, where Rx is hydrogen or C-i-Cβ-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, C-i-Cβ-alkyl, C-i-Cβ-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is selected from the group consisting of halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cs-Cβ-cycloalkyl, Ci-C4-alkoxy, C3-C4-alkenyloxy,
C3-C4-alkynyloxy, d-Cβ-alkylthio, di-(Ci-C6-alkyl)amino and Ci-Cβ-alkylamino, where the aliphatic and/or alicyclic groups of the radical definitions of R3 for their part may be partially or fully halogenated or may carry one, two, three or four radicals R1, which may be the same or different from each other:
R1 is selected from the group consisting of halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, d-Cβ-alkoxy, Cs-Cβ-cycloalkyl, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, C4-C6-cycloalkenyl, Cs-Ce-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A13, -C(=O)-O-A13, -C(=O)-N(A14)A13, C(A14X=N-OA13), N(A14)A13, N(A14)-C(=O)-A13,
N(A15)-C(=O)-N(A14)A13, S(=O)p-A13, S(=O)P-O-A13 and S(=O)P-N(A14)A13, it also being possible that two vicinal radicals Ru together are (=0) or (=S), where
p is O, 1 or 2; A13, A14 and A15 independently of one another have the meanings of A1, A2 and A3 as defined above;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of R1 for their part may be partially or fully halogenated or may carry one, two or three radicals Rta, which may be the same or different from each other and which have the meanings of R1 as defined above;
R4 is a five-, six-, seven-, eight-, nine- or ten-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle which comprises one, two, three or four heteroatoms as ring members, which are selected from the group consisting of O, N and S and where the heterocycle for its part may be partially or fully halogenated or may carry one, two, three or four radicals Ru, which may be the same or different from each other:
Ru is selected from the group consisting of halogen, cyano, Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, d-Cβ-alkoxy, Cs-Cβ-cycloalkyl, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, C4-C6-cycloalkenyl, Cs-Ce-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, -C(=S)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4,
N(A6)-C(=O)-N(A5)A4, S(=O)q-A4, S(=O)q-O-A4 and S(=O)q-N(A5)A4, it also being possible that two vicinal radicals Ru together are (=0) or (=S), where
q is 0, 1 or 2;
A4, A5 and A6 independently of one another have the meanings of A1, A2 and A3 as defined above;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Ru for their part may be partially or fully halogenated or may carry one, two or three radicals Rua, which may be the same or different from each other and which have the meanings of Ru as defined above;
R4 may furthermore be: cyano, C(=Z)ORa, C(=Z)NRzRb, C(=Z)NRz-ORa, C(=Z)NRa-NRzRb, C(=Z)Ra, CRaRb-ORz, CRaRb-NRzRc, ON(=CRaRb), O-C(=Z)Ra,
NRaRb1, NRa(C(=Z)Rb), NRa(C(=Z)ORb), NRa(C(=Z)-NRzRb), NRa(N=CRcRb), NRa-NRzRb or NRz-ORa, where
Z is O, S, NRa1, NORa1 or N-NRz1Rc1;
Ra, Ra1, Rb, Rc, Rc1 independently of one another are hydrogen, CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl or C4-C6-cycloalkenyl; Rb1 has the meanings of Rb as defined above, except for hydrogen;
Rz, Rz1 independently of one another have the meanings of Ra as defined above and may additionally be -CO-Ra2, where Ra2 has the meanings of Ra as defined above;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz and Rz1 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Rw, which may be the same or different from each other:
Rw is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, Cs-Cβ-cycloalkenyl, C3-C6-cycloalkoxy or Cs-Cβ-cycloalkenyloxy,
and where two of the radicals Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz or Rz1 together with the atoms, to which they are attached, may form a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S;
( —Λ y> is phenyl or a five- or six-membered hetaryl which comprises 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S;
n is 1 , 2, 3, 4 or 5;
L is selected from the group consisting of halogen, cyano, cyanato (OCN),
Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, nitro, -C(=O)-A7, -C(=O)-O-A7, -C(=O)-N(A8)A7,
-C(=S)-N(A8)A7, -C(=NA8)-SA7, C(A8X=N-OA7), N(A8)A7, N(A8)-C(=O)-A7, N(A9)-C(=O)-N(A8)A7, S(=0)rA7, S(=O)rO-A7 and S(=O)rN(A8)A7, where L may be identical or different, if n is 2, 3, 4 or 5, and where
r is O, 1 or 2;
A7, A8, A9 independently of one another have the meanings of A1, A2 and A3 as defined above;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals RL, which may be the same or different from each other: RL is selected from the group consisting of halogen, cyano, Ci-Cio-alkyl,
C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, Cs-Ce-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A10, -C(=O)-O-A10,
-C(=O)-N(A11)A10, C(A11)(=N-OA10), N(A11)A10, N(A11)-C(=O)-A10, N(A12)-C(=O)-N(A11)A10, S(=O)s-A10, S(=O)S-O-A10 and S(=O)S-N(A11)A10, it also being possible that two vicinal radicals RL together are (=0) or (=S), where
s is 0, 1 or 2; and
A10, A11 and A12 independently of one another have the meanings of A1, A2 and A3 as defined above;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of RL for their part may be partially or fully halogenated or may carry one, two, three or four radicals RLA, which may be the same or different from each other and which have the meanings of RL as defined above.
The invention in particular relates to the use of the compounds for the formula I and of their pharmaceutically acceptable salts in therapy or treatment of cancer or a cancerous disease, respectively.
The invention also relates to pharmaceutical compositions comprising a 2-substituted pyridine of the formula I as defined herein or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. Moreover the invention relates to the use of a 2-substituted pyridine of the formula I as defined herein and of their pharmaceutically acceptable salts in the manufacture of a medicament in particular a medicament for the therapy or treatment of cancer or a cancerous disease, respectively. The invention also provides a method for cancer treatment, which comprises administering to the subject in need thereof an effective amount of a 2-substituted pyridine of the formula I as defined herein or of their pharmaceutically acceptable salts.
Despite dramatic advances in research and novel treatment options, cancer is still one of the leading causes of death. Amongst the different types of cancer such as lung, breast, prostate and colon cancer as well as colon lymphomas, are most frequently diagnosed and ovarian cancer is the 2nd most common reproductive cancer after breast cancer in women. A large number of cytotoxic compounds are known to effectively inhibit the growth of tumor cells, including taxoides like paclitaxel (Taxole), docetaxel (Taxotere), the vinka alkaloids vinorelbine, vinblastine, vindesine and vincristine. However, these compounds are natural products having a complex structure and thus are difficult to produce.
It is, therefore, an object of the present invention to provide compounds which effectively control or inhibit growth and/or progeny of tumor cells and thus are useful in the treatment of cancer. It is highly desirable that these compounds can be synthesized from simple starting compounds according to standard methods of organic chemistry.
We have found that these and further objects are achieved by the 2-substituted pyridines I defined at the outset. Furthermore, we have found a method for treating cancer, which comprises administering to the subject in need thereof an effective amount of a 2-substituted pyridine I as defined herein or of their pharmaceutically acceptable salts.
2-Substituted pyridines I have been described in WO 2006/000358. The compounds disclosed therein are active against various phytopathogenic fungi. However, this document does not describe or suggest that these compounds may be effective in the treatment of diseases or even in the treatment of cancer.
2-Substituted pyridines I can be prepared by the methods disclosed in
WO 2006/000358 and in the literature cited therein as well as by standard methods of organic chemistry.
It is likewise possible to use physiologically tolerated salts of the 2-substituted pyridines I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonic acids having from 1 to 12 carbon atoms, e.g. Ci-C4-alkylsulfonic acids such as methanesulfonic acid, cycloaliphatic sulfonic acids such as S-(+)-10-camphorsulfonic acids and aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having from 2 to 10 carbon atoms such as oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lactic acid, tartaric acid, citric acid, glycolic acid and adipic acid, as well as cis- and trans- cinnamic acid, furoic acid and benzoic acid. Other utilizable acids are described in
Fortschritte der Arzneimittelforschung [Advances in Drug Research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966. The physiologically tolerated salts of 2-substituted pyridines I may be present as the mono-, bis-, tris- and tetrakis-salts, that is, they may contain 1 , 2, 3 or 4 of the aforementioned acid molecules per molecule of formula I . The acid molecules may be present in their acidic form or as an anion. The acid addition salts are prepared in a customary manner by mixing the free base of a 2-substituted pyridine I with a corresponding acid, where appropriate in solution in water or an organic solvent as for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, an ether such as methyl tert-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate. Solvents, wherein the acid addition salt of I is insoluble (anti-solvents), might be added to precipitate the salt. Suitable anti-solvents comprise
Ci-C4-alkylesters of Ci-C4-aliphatic acids such as ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc., di-Ci-C4-alkylethers such as methyl tert-butyl ether or diisopropyl ether.
In the symbol definitions given in formula I above, collective terms were used which generally represent the following substituents:
- halogen: fluorine, chlorine, bromine or iodine;
- alkyl and the alkyl moieties of alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylamino, di(alkyl)amino, alkylaminocarbonyl, di(alkyl)amincarbonyl, alkylcarbonylamino, alkylsulfinyl, alkylsulfonyl, alkylaminosulfonyl or di(alkyl)aminosulfonyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 10, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl,
1-methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-di-methylpropyl, 1-ethylpropyl, hexyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methyl pentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;
- alkenyl and the alkenyl moieties of alkenyloxy: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 10, preferably 2 to 6, and in particular 2 to 4 carbon atoms, and a double bond in any position, especially C3-C4-alkenyl, for example ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1 ,1-dimethyl-2-propenyl, 1 ,2-dimethyl-1-propenyl, 1 ,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1 ,1-dimethyl-2-butenyl, 1 ,1-dimethyl-3-butenyl, 1 ,2-dimethyl-1-butenyl, 1 ,2-dimethyl-2-butenyl, 1 ,2-dimethyl-3-butenyl, 1 ,3-dimethyl-1-butenyl, 1 ,3-dimethyl-2-butenyl, 1 ,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1 -ethyl-3-butenyl, 2-ethyl-1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,
1 ,1 ,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;
- alkadienyl: unsaturated straight-chain or branched hydrocarbon radicals having 4 to 8, in particular 4 to 6 carbon atoms and two double bonds in any position, for example butadiene, 1 ,3-pentadiene, 1 ,4-pentadiene, 1 ,3-hexadiene, 1 ,4-hexadiene and 1 ,5-hexadiene;
- alkynyl: straight-chain or branched hydrocarbon radicals having 2 to 10, preferably 2 to 6, in particular 2 to 4 carbon atoms, and a triple bond in any position, especially
C3-C4-alkynyl, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1 ,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,
2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1 ,1-dimethyl-2-butynyl, 1 ,1-dimethyl-3-butynyl, 1 ,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl;
- cycloalkyl: mono- or bicyclic hydrocarbon radicals having 3 to 10 carbon atoms; monocyclic groups having 3 to 8, especially 3 to 6 ring members, for example C3-C8-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
- haloalkyl and the haloalkyl moieties of haloalkoxy: straight-chain or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms (as mentioned above), where the hydrogen atoms in these groups may be partially or fully replaced by halogen atoms as mentioned above, for example
Ci-C4-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1 ,1 ,1-trichloroprop-1-yl, 1 ,1 ,1-trifluoroprop-1-yl, 1 ,1 ,1 -trichloroprop-2-yl and 1 ,1 ,1-trifluoroprop-2-yl; similar considerations apply to other halogenated groups such as haloalkenyl, haloalkynyl and halocycloalkyl where the hydrogen atoms of the alkenyl, alkynyl and cycloalkyl groups may be partially or fully replaced by halogen atoms as mentioned above;
- oxy-alkyleneoxy: divalent straight-chain hydrocarbon radicals having 2 to 3 carbon atoms, e.g. OCH2CH2O or OCH2CH2CH2O;
- 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle: homo- or bicyclic hydrocarbon radicals containing one to four heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; unsaturated (heterocyclyl) includes partially unsaturated, e.g. mono-unsaturated, and aromatic (heteroaryl); said heterocycles in particular include:
- 5-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, for example 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, thiophenyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,3-triazol-1-yl, 1 ,2,4-triazol-1-yl, 1 ,2,4-triazol-3-yl, tetrazolyl, 1 ,3,4-oxadiazol-2-yl, 1 ,3,4-thiadiazol-2-yl and 1 ,3,4-triazol-2-yl;
- 6-membered heteroaryl, containing one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain one to three or one to four nitrogen atoms as ring members, for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazin-2-yl and 1 ,2,4-triazin-3-yl.
- 9- or 10-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 9- or 10-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, in particular benzo-fused 5- or 6-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom (i. e. 5- or 6-membered heteroaryl groups which, in addition to carbon atoms, contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1 ,3-dien-1 ,4-diyl group), for example benzothiazol-2-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 H-indazol-1-yl, 1 H-indazol-2-yl, benzofuran-2-yl and benzofuran-3-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, phthalazinyl, quinoxalinyl, quinazolin-2-yl, quinazolin-4-yl, cinnolin-3-yl and cinnolin-4-yl.
- 5-, 6- and 7-membered heterocyclyl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-pyrrolidin-2-yl, 2-pyrrolidin-3-yl, 3-pyrrolidin-2-yl, 3-pyrrolidin-3-yl, pyrrolidon-1-yl, pyrrolidin-2-thion-1-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, pyridin(1 ,2-dihydro)-2-on-1-yl, 2-piperazinyl, 1-pyrimidinyl, 2-pyrimidinyl, morpholin-4-yl, thiomorpholin-4-yl, dihydrothiazol-2-yl, piperidin-2-on-1-yl, piperidin-2-thion-1-yl, dihydropyridinyl, hexahydroazepin-1-yl and hexahydroazepin-2-thion-1 -yl.
The scope of the present invention includes the (R) and (S) isomers of the formula I having chiral centers. Thus, it is to be understood that any mixture of the (R) and (S) isomer compounds in any ratio including the racemates is also within the scope of the present invention.
With regard to their activity to inhibit growth and progeny of tumor cells it has been found that the 2-substituted pyridines I are generally useful both if Xi is N or if X2 is N. According to the present invention, only one of Xi and X2 is N, while the other ring member of the pyridine system is C-H or C-halogen, e. g. C-F, C-Cl and C-Br, in particular C-H.
With regard to their activity to inhibit growth and progeny of tumor cells preference is given to 2-substituted pyridines I, wherein B is phenyl. These compounds correspond to the formula I'
Figure imgf000011_0001
wherein Xi, X2, Y, R2, R3, R4, L and n are as defined above.
Preference is furthermore given to 2-substituted pyridines of the formulae I and I', wherein Y is a group -CH-R1-, -N-R1- or -O-, particularly -CH-R1- or -N-R1-, and more particularly -N-R1-. If Y is a group -CH-R1- or -N-R1-, it is preferred that R1 is hydrogen. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Particular preference is given to 2-substituted pyridines of the formulae I and I', wherein R1 and R2 independently of one another are d-Cs-alkyl, d-Cs-haloalkyl, C2-C8-alkenyl, C2-C8-haloalkenyl, C2-C8-alkynyl, C2-C8-haloalkynyl, Cs-Cs-cycloalkyl or C3-C8-halocycloalkyl, more particularly Ci-Cs-alkyl, d-Cs-haloalkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two, especially one radical(s) Rv which may be the same or different from each other and which are selected from the group consisting of Ci-Cβ-alkyl, d-Cβ-haloalkyl, Cs-Cβ-cycloalkyl, Cs-Cβ-halocycloalkyl, and phenyl, where the phenyl moiety may carry one, two or three, especially one radical(s) which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl, d-Cβ-haloalkyl, Ci-Cβ-alkoxy, cyano and nitro. More particular preference is given to compounds I in which R2 has one of the aforementioned meanings, Y is NR1 or CHR1 and R1 is hydrogen. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Very particular preference is given to 2-substituted pyridines of the formulae I and I' wherein R2 is Cs-Cs-alkyl, Cs-Cs-alkenyl, Cs-Cs-alkynyl or Cs-Cs-haloalkyl, preferably C3-Cs-alkyl, in each case branched in the α-position; Cs-Cs-cycloalkyl or C3-Cs-halocycloalkyl, preferably Cs-Cs-cycloalkyl, which in each case may carry a radical Rv selected from the group consisting of Cs-Cβ-alkyl, Cs-Cβ-haloalkyl, preferably Cs-Cβ-alkyl, in each case branched in the α-position, and phenyl, where the phenyl moiety may carry one or two radical(s) which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-C6-alkyl, Ci-Cβ-haloalkyl, Ci-Cβ-alkoxy, cyano and nitro; Ci-Cβ-alkyl or d-Cβ-haloalkyl, preferably Ci-Cβ-alkyl, more preferably d-d-alkyl, in each case carrying a radical Rv selected from the group consisting of Cs-Cβ-cycloalkyl, Cs-Cβ-halocycloalkyl and phenyl, preferably Cs-Cβ-cycloalkyl and phenyl, where the phenyl moiety may carry one or two, preferably two radical(s) which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl, d-Cβ-haloalkyl, d-Cβ-alkoxy, cyano and nitro, preferably d-Cβ-alkoxy. More particular preference is given to compounds I in which R2 has one of the aforementioned meanings, Y is NR1 or CHR1 and R1 is hydrogen. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Amongst the 2-substituted pyridines of the formulae I and I' in which R2 is Cs-Cs-alkyl or C3-Cs-haloalkyl, preferably Cs-Cs-alkyl, in each case branched in the α-position, preference is given to those where R2 is prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (2-methyl)-but-2-yl, (2,3-dimethyl)-but-2-yl, (3,3-dimethyl)-but-2-yl, (2-methyl)-pent-2-yl, (3-methyl)-pent-2-yl, (4-methyl)-pent-2-yl, (2,3-dimethyl)-pent-2-yl, (2,4-dimethyl)-pent-2-yl, (3,4-dimethyl)-pent-2-yl, (4,4-dimethyl)-pent-2-yl, 1 ,1 ,1-trichloroprop-2-yl and 1 ,1 ,1-trifluoroprop-2-yl, more preferably prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (3,3-dimethyl)-but-2-yl and (4-methyl)-pent-2-yl, even more preferably prop-2-yl, but-2-yl, hept-2-yl, (3,3-dimethyl)-but-2-yl and (4-methyl)-pent-2-yl. More particular preference is given to compounds I in which R2 has one of the aforementioned meanings, Y is NR1 or CHR1 and R1 is hydrogen.
Amongst the 2-substituted pyridines of the formulae I and I' in which R2 is C3-C8-cycloalkyl or Cs-Cs-halocycloalkyl, preferably Cs-Cs-cycloalkyl, more preferably C3-C6-cycloalkyl, preference is given to those where R2 is cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl and cycloheptanyl, preferably cyclopropanyl and cyclohexanyl, which in each case may carry a group Rv which is selected from the group consisting of Cs-Cβ-alkyl branched in the α-position, preferably C3-C4-alkyl branched in the α-position, particularly the Cs-Cβ-alkyl and Cs-Cβ-alkyl radicals branched in the α-position mentioned above, and phenyl. If the group Rv is attached to a cyclohexanyl ring, it is preferably in the ortho- or para-position, more preferably in the para-position. Particular preference is given to R2 being cyclopropanyl, cyclohexanyl, 2-methylcyclohexanyl, 4-methylcyclohexanyl, 2-phenylcyclohexanyl, 4-phenylcyclohexanyl, (2-tert-butyl)-cyclohexanyl and (4-tert-butyl)-cyclohexanyl. More particular preference is given to compounds I in which R2 has one of the aforementioned meanings, Y is NR1 or CHR1 and R1 is hydrogen.
Amongst the 2-substituted pyridines of the formulae I and I' in which R2 is Ci-Cβ-alkyl or Ci-Cβ-haloalkyl, preferably Ci-C4-alkyl, in particular methyl, ethyl, prop-2-yl and but-2-yl, preference is given to those carrying a group Rv selected from the group consisting of Cs-Cβ-cycloalkyl, particularly cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, and phenyl, where the phenyl moiety may carry one or two, preferably two radical(s) d-Cβ-alkoxy, preferably Ci-C4-alkoxy, in particular methoxy, ethoxy, propoxy and butoxy. If the phenyl moiety carries two Ci-C6-alkoxy radicals, it is preferred that they are attached to adjacent carbon atoms of the phenyl ring. Particular preference is given to 1-cyclopropyl-ethyl, 1-cyclohexyl-ethyl, 2-cyclopropyl-ethyl, 2-cyclohexyl-ethyl, 1-phenyl-ethyl, 2-phenyl-ethyl, 1-(3,4-dimethoxy)phenyl-ethyl and 2-(3,4-dimethoxy)phenyl-ethyl. More particular preference is given to compounds I in which R2 has one of the aforementioned meanings, Y is NR1 or CHR1 and R1 is hydrogen.
If R1 and/or R2 contain haloalkyl or haloalkenyl groups having a center of chirality, the (S)-isomers are preferred for these groups. In the case of halogen-free alkyl or alkenyl groups having a center of chirality in R1 or R2, preference is given to the (R)-configured isomers.
Particular preference is likewise given to 2-substituted pyridines of the formulae I and I', wherein Y is NR1 and wherein R1 and R2, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, preferably saturated five- or six- membered ring which may be interrupted by an ether -(-O-) or by a further amino -(-N(RX)- group, where Rx is hydrogen or Ci-Cβ-alkyl, and/or where the ring formed may carry one or more, e. g. 1 , 2, 3 or 4, preferably 1 substituent(s) from the group consisting of halogen, d-Cε-alkyl, C-i-Cβ-haloalkyl and oxy-Ci-C3-alkyleneoxy, in particular halogen, Ci-Cβ-alkyl and C-i-Cβ-haloalkyl. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Very particular preference is given to compounds of the formulae I and I' in which R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated, preferably saturated five- or six-membered ring which may be interrupted by an oxygen atom and which may carry one or two Ci-Cβ-alkyl, preferably Ci-C4-alkyl substituents, e. g. methyl, ethyl, prop-1-yl and prop-2-yl, more preferably Ci-C2-alkyl substituents, e. g. methyl, ethyl, especially methyl.
Amongst 2-substituted pyridines of the formulae I and I' in which R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated five- or six-membered ring, especially preferred are those wherein R1 and R2, together with the nitrogen to which they are attached, form a saturated five- or six-membered ring which has no other heteroatom than the nitrogen atom attached to R1 and R2, such as pyrrolidines and piperidines, e. g. pyrrolidin-1-yl and piperidin-1-yl, and which is optionally substituted by one, two or three, preferably one group(s) selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl, preferably Ci-C4-alkyl. More particular preference is given to the aforementioned 2-substituted pyridines I wherein the ring, which includes R1, R2 and the attached nitrogen atom, is unsubstituted or is methylated, in particular in the α-position, i. e. the carbon atom next to the pyridine ring nitrogen atom carries a methyl group, e. g. 2-methylpyrrolidyl and 2-methylpiperidyl. More particular preference is likewise given to the aforementioned 2-substituted pyridines I wherein R1, R2, together with the nitrogen atom to which they are attached, form a six-membered saturated ring having a methyl group in the para-position (4-position), very particularly 4-methylpiperidyl.
Preferred radicals of the formula NR1R2 (i. e. where Y is -NR1) which are attached to the pyridine skeleton of the 2-substituted pyridines of formula I, include: NH-C2H5, NH(CH(CHs)2), NH-CH2CH2CH3, NH(CH(CH3)(C2H5), (S)-NHCH(CH3)(C2H5), NH-CH(CH3)(CH2CH2CH3), (R)-NHCH(CH3)(C(CH3)3), NH-CH(CH3)CH(CHS)2, (R)-NHCH(CH3)(CH(CHS)2), (S)-NHCH(CH3)(CH(CHS)2), NH(cyclopentyl), NHCH2CF3, NHCH(CHs)(CF3), (R)-NHCH(CHs)(CF3), (S)-NHCH(CHs)(CF3), NH-CH(CHS)CH2OCH3, NH-CH(CHS)CH2OH, NH-CH2C(CHS)=CH2, N(CH2CHS)2, N(CH3)(CH2CH=CH2), N(CHs)-CH2CH2CH=CH2, N(CH2CH=CH2)2, piperidin-1-yl, 2-methyl-piperidin-1-yl, 3-methyl-piperidin-1 -yl, 4-methyl-piperidin-1 -yl, 3,6-dihydro-2H-pyridin-1 -yl, 2-methyl-pyrrolidin-1-yl, (S)-NHCH(CH3)(C(CHs)3), -NH-n-butyl, -NH-tert-butyl, -NH-(sec-pentyl), -NH-2-methyl-cyclopentyl, 2-methyl-oxiranyl-methyl-amino, -N(ethyl)(isopropyl), -N(ethyl)(sec-butyl), -N(sec-butyl)2, NHCH(CH3)-isobutyl, NH-benzyl, -NHCH(CH3)CH2-CH(CHS)2, -NH-CH(CH3)CH2-C(O)-OH, N(CH2CH3)CH2C(CHs)=CH2, -N(n-Pr)(CH2CH=CH2), -NH-CH2CH2-CH2-OH, -N(CH3)(CH2CH2OH), -N(benzyl)(CH2CH2OH), -N(CH2CH2OH)(CH2CH=CH2)-, -N(CH2CH2OSiMe3)(CH2CH=CH2), -N(CN)(CH2CH=CH2), -NH-CH(CH3)CH2-OCH3, -NH-CH(CH3)CH2-C(O)-OCH3, 2-butoxycarbonyl-pyrrolidin-i-yl, 2,5-dimethyl-pyrrolidin-1-yl, 2,6-dimethyl-morpholin-4-yl and 1 ,1-dioxo-thiomorpholin-4-yl.
Preference is furthermore given to 2-substituted pyridines of the formulae I and I' in which R3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl or Ci-C4-alkoxy, such as chlorine, bromine, methyl, cyano, methoxy or ethoxy, especially chlorine, cyano, methyl or methoxy. Particularly preferred are compounds I in which R3 is chlorine. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Preference is furthermore given to 2-substituted pyridines of the formulae I and I' in which R4 is pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl or benzothiazolyl, where the heterocycle may be attached via C or N to the pyridine ring and may carry one, two or three substituents Ru, which may be the same or different from each other, it also being possible that two vicinal radicals Ru together are (=0) or (=S). More preferably, Ru is halogen, cyano, d-Cs-alkyl, Ci-Cβ-alkoxy, -C(=0)-A4, -C(=0)-0-A4, -C(=O)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, or two vicinal radicals Ru together are (=0) or (=S). Even more preferably, Ru is amino, amino, cyano or methyl, or two vicinal radicals Rw together are (=0) or (=S). Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Particular preference is given to 2-substituted pyridines of the formulae I and I', wherein R4 is pyrazol-1-yl, 3-amino-pyrazol-1-yl, [1 ,2,4]triazol-1-yl, 3-cyano-1 ,2,4-triazol-1-yl, [1 ,2,3]triazol-1-yl, 1 ,2,4-oxadiazol-3-yl, 5-methyl-1 ,2,4-oxadiazol-3-yl, pyridin-2-yl, (6-methyl)-pyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, (1 ,2-dihydro)-pyridin-2-on-1 -yl, pyrrolidin-2-on-1 -yl, piperidin-2-on-1 -yl, pyrrolidin-2-thion-1-yl, piperidin-2-thion-1-yl, [1 ,3]thiazol-2-yl,
(4,5-dimethyl)-[1 ,3]thiazol-2-yl, benzo-[1 ,3]thiazol-2-yl, hexahydro-2H-azepin-2-on-1 -yl, hexahydro-2H-azepin-2-thion-1-yl or 7-amino-indazol-1-yl; more particularly pyrazol-1-yl, [1 ,2,4]triazol-1-yl, pyridin-2-yl, (6-methyl)-pyridin-2-yl, pyrimidin-2-yl, pyridazin-3-yl, (1 ,2-dihydro)-pyridin-2-on-1-yl, pyrrolidon-1-yl, [1 ,3]thiazol-2-yl, (4,5-dimethyl)-[1 ,3]thiazol-2-yl or benzo-[1 ,3]thiazol-2-yl. More preference is given to compounds of the formula I and I', wherein R4 is 2-pyrimidinyl.
Preference is furthermore given to 2-substituted pyridines of the formulae I and I' in which R4 is benzo-fused 5- or 6-membered heteroaryl which contains 1 , 2 or 3 nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom, in particular benzothiazol-2-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 H-indazol-1-yl, 1 H-indazol-3-yl, benzofuran-2-yl and benzofuran-3-yl; furthermore quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, phthalazinyl, quinoxalinyl, quinazolin-2-yl, quinazolin-4-yl, cinnolin-3-yl and cinnolin-4-yl, especially benzothiazol-2-yl. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Preference is furthermore given to 2-substituted pyridines of the formulae I and I' in which R4 is cyano, C(=O)NRzRb, C(NRa1)NRzRb, C(=NORa1)NRzRb,
C(=N-NRz1Rc1)NRzRb, C(=S)NRzRb, C(=O)Ra, C(=NRa1)Ra, C(=NORa1)Ra, C(=N-NRz1Rc1)Ra, C(=O)ORa, C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)NRa-NRzRb, CRaRb-NRzRc or CRaRb-ORz. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Preference is likewise given to 2-substituted pyridines of the formulae I and I' in which R4 is cyano, O-C(=O)Ra or ON(=CRaRb). Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Preference is likewise given to 2-substituted pyridines of the formulae I and I' in which R4 is cyano, NRaRb1, NRa(C(=O)Rb), NRa(C(=NRa1)Rb), NRa(C(=NORa1)Rb), NRa(C(=O)ORb), NRa(C(=O)-NRzRb), NRa(C(=NRa1)-NRzRb), NRa(N=CRcRb), NRa-NRzRb or NRz-ORa. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Particular preference is given to 2-substituted pyridines of the formulae I and I', where R4 is cyano, C(=S)NRzRb, C(=O)NRzRb, C(=NORa1)NRzRb, C(NRa1)NRzRb, C(=O)Ra, C(=NORa1)Ra, C(=NRa1)Ra, C(=O)ORa, C(=NORa1)ORa, C(=NRa1)ORa, C(=O)NRz-ORa, C(=NORa1)NRz-ORa, C(=NRa1)NRz-ORa, C(=N-NRz1Rc1)Ra, CRaRb-NRzRc, ON(=CRaRb), NRa(C(=O)Rb), NRa(C(=O)ORb), NRa(N=CRcRb) or NRz-ORa.
Among the aforementioned compounds of the formulae I and I', those are preferred where Ra, Ra1, Rb, Rc and Rc1 independently of one another are hydrogen, Ci-Cβ-alkyl, d-Ce-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C4-C6-cycloalkenyl or C4-C6-halocycloalkenyl, more preferably hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl or C3-C6-cycloalkyl, especially hydrogen or d-C4-alkyl. Likewise, those compounds I are preferred where Rb1 has the preferred meanings of Rb as defined above, except for hydrogen. Likewise, those compounds I are preferred where Rz and Rz1 independently of one another have the preferred meanings of Ra as defined above or are -CO-Ra2, where Ra2 has the preferred meanings of Ra as defined above.
In one embodiment, very particular preference is given to 2-substituted pyridines of the formulae I and I', where R4 is cyano, C(=Z)ORa, C(=Z)NRzRb, C(=S)NRzRb, C(=Z)NRZ- ORa or C(=Z)Ra, preferably C(=Z)NRzRb, C(=S)NRzRb, or C(=Z)NRz-ORa, and where Z is O, NRa1 or NORa1, preferably NORa1, e. g. C(=O)ORa, C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRzRb, C(=NRa1)NRzRb, C(=NORa1)NRzRb, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)Ra, C(=NRa1)Ra and C(=NORa1)Ra. Among these compounds I, those are more particularly preferred where Ra1 is hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, in particular methyl. Likewise, those compounds I are more particularly preferred where Ra and/or Rb, especially both Ra and Rb are hydrogen. Likewise, those compounds I are more particularly preferred where Rz is hydrogen or -CO-Ra2, in particular C(=NH)N(CO-Ra2)Rb, where Ra2 and Rb independently from one another preferably are hydrogen or Ci-C4-alkyl such as methyl and ethyl. Very particular preference is given to 2-substituted pyridines I, where R4 is cyano, C(=NOCH3)NH2, C(=NH)NH2, C(=O)NH2, C(=S)NH2, C(=NH)NH-OH,
C(=O)NH-OH and C(=NH)NH-C(=O)CH3, especially cyano, C(=O)NH2, C(=S)NH2 or C(=NOCH3)NH2.
In another embodiment, very particular preference is given to 2-substituted pyridines of the formulae I and I', where R4 is cyano, C(=O)NRzRb, C(=NORa1)NRzRb, C(=NORa1)Ra, NRa(C(=O)ORb), NRz-ORa, ON(=CRaRb), NRa(C(=O)Rb), C(=S)NRzRb or CO2Ra. Among these compounds I, those are more particularly preferred where Ra and Ra1 independently of one another are hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, e. g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. More preferably Ra is hydrogen, methyl, ethyl, n-propyl or iso-propyl. Likewise, more preferably Ra1 is methyl. Furthermore, those compounds I are more particularly preferred where Rb is hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, e. g. methyl or ethyl, in particular methyl. More preferably Rb is hydrogen or methyl. Likewise, those compounds I are more particularly preferred where Rz is hydrogen, Ci-C4-alkyl, e. g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl, in particular methyl, or -CO-Ra2, where Ra2 is Ci-C4-alkyl, e. g. methyl or ethyl, in particular methyl. More preferably Rz is hydrogen, methyl or -CO-Ra2, and Ra2 is methyl. Very particular preference is given to 2-substituted pyrimidines I, where R3 is cyano, C(=O)NHCH3, C(=NOCH3)NH2, C(=NOCH3)CH3, NH(C(=O)OCH3), N(C(=O)CH3)-OCH3, ON(=C(CH3)2), NH(C(=O)CH3), C(=O)NH2, C(=S)NH2, C(=O)-O(CH3), C(=O)-O(CH2CH3), C(=O)-O(CH2CH2CH3) or
C(=O)-OCH(CH3)2, especially cyano, C(=NOCH3)NH2, C(=O)NH2 or C(=S)NH2. Preference is furthermore given to 2-substituted pyridines of the formulae I and I', where the substituents Ln (i. e. L1 to L4, if B is a five- or six-membered hetaryl; or L1 to L5, if B is phenyl) are as defined below:
L is selected from the group consisting of halogen, in particular fluorine, chlorine, bromine, preferably fluorine, chlorine; cyano; d-Cs-alkyl, in particular d-Cβ-alkyl, especially Ci-C4-alkyl, such as methyl, ethyl, propyl and butyl, preferably methyl; C2-Cio-alkenyl, in particular C2-C6-alkenyl, especially C2-C4-alkenyl, such as ethenyl, propenyl and butenyl; C2-Cio-alkynyl, in particular C2-C6-alkynyl, especially C2-C4-alkynyl, such as ethynyl, propynyl and butynyl;
Ci-Cβ-alkoxy, in particular Ci-C4-alkoxy, preferably methoxy and ethoxy; C2-Cio-alkenyloxy, in particular C2-C6-alkenyloxy, such as ethenyloxy; C2-Cio-alkynyloxy, in particular C2-C6-alkynyloxy, such as ethynyloxy; nitro; -C(=O)-O-A7, in particular Ci-C4-alkoxycarbonyl, especially Ci-C2-alkoxycarbonyl, such as methoxycarbonyl; -C(=O)-N(A8)A7, in particular CO-NH2,
Ci-C4-alkylaminocarbonyl, such as CO-NHCH3 and CO-NHC2H5, and di-(Ci-C4-alkyl)-aminocarbonyl, such as CO-N(CHs)2; -C(=S)-N(A8)A7, in particular CS-NH2, Ci-C4-alkylaminothiocarbonyl, such as CS-NHCH3, and di-Ci-C4-alkylaminothiocarbonyl, such as CS-N(CHs)2; C(A8X=N-OA7), such as CH(=NOH) and CH(=NOCH3); N(A8)A7, in particular Ci-C4-alkylamino and di-Ci-C4-alkylamino; N(A8)-C(=O)-A7, in particular Ci-C4-alkylcarbonylamino, such as NH-C(=O)CH3, and N-(Ci-C4-alkylcarbonyl)-N-(Ci-C4-alkyl)-amino, such as N(CH3)-C(=O)CH3, and/or S(=O)r-A7, in particular -SH, Ci-C4-alkylthio, such as SCH3, or Ci-C4-alkylsulfonyl, such as SO2CH3; where
A7, A8 independently of one another are hydrogen, Ci-Cβ-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, cyano and/or Ci-C4-alkoxy; or A7 and A8 together with the atoms to which they are attached are a five- or six-membered saturated heterocycle which comprises one or two heteroatoms from the group consisting of O, N and S;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated, e. g. where L may be
C-i-Cβ-haloalkyl, especially Ci-C2-fluoroalkyl, such as trifluoromethyl. Amongst the aforementioned compounds I, those are especially preferred which correspond to the formula I'.
Particular preference is given to 2-substituted pyridines of the formulae I and I', wherein one or two radical(s) L is (are) attached to one (or two) of the ortho-position(s) of the hetaryl or phenyl ring system B. The ring system B particularly preferably is five- membered hetaryl which comprises 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S or is pyridyl or phenyl, especially phenyl. Moreover, particular preference is given to 2-substituted pyridines I, wherein n is 1 , 2 or 3.
Particular preference is furthermore given to 2-substituted pyridines of the formulae I and I', wherein the substituents Ln are as defined below:
L is halogen, cyano, Ci-C8-alkyl, d-Ce-alkoxy, -C(=O)-O-A7 or -C(=O)-N(A8)A7.
Particular preference is furthermore given to 2-substituted pyridines I, wherein radical
is a radical of the following formula B:
Figure imgf000019_0001
in which # is the point of attachment to the pyrimidine skeleton and wherein
L1 is fluorine, chlorine, CH3 or CF3, more preferably fluorine or chlorine;
L2, L4 independently of one another are hydrogen, CH3 or fluorine, more preferably hydrogen; L3 is hydrogen, fluorine, chlorine, bromine, cyano, CH3, SCH3, OCH3, SO2CH3, CO-NH2, CO-NHCH3, CO-NHC2H5, CO-N(CHs)2, CS-NH2, CS-NHCH3, CS-N(CHs)2, NH-C(=O)CH3, N(CH3)-C(=O)CH3 Or COOCH3, more preferably hydrogen, fluorine or chlorine, even more preferably hydrogen; and
L5 is hydrogen, fluorine, chlorine or CH3, more preferably fluorine or chlorine.
Likewise pyridines of the formula I' and their salts are preferred, wherein the radical
Figure imgf000019_0002
is a radical of the formula B as defined above.
Furthermore, particularly preferred are 2-substituted pyridines of the formula I' where
Y is O, CHR1 or NR1,
R1, R2 independently of one another are d-Cs-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, d-Cs-haloalkyl, C2-C8-haloalkenyl or C2-C8-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two substituents Rv which may be the same or different from each other and which are selected from the group consisting of Ci-Cβ-alkyl, C-i-Cβ-haloalkyl, C3-C6-cycloalkyl, Cs-Cβ-halocycloalkyl and phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl,
Ci-Cβ-haloalkyl, d-Cβ-alkoxy, cyano and nitro;
R1 may additionally be hydrogen; or, if Y is NR1,
R1 and R2 may also, together with the nitrogen atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may be interrupted by an ether (-O-) or by a further amino -(-N(RX))- group, where Rx is hydrogen or Ci-Cβ-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, Ci-Cβ-alkyl, C-i-Cβ-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;
R4 is pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl or benzothiazolyl, where the heterocycle may be attached via C or N to the pyridine ring and may carry one, two or three radicals Ru, which may be the same or different from each other, where
Ru is halogen, cyano, Ci-C8-alkyl, d-Ce-alkoxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, or where two vicinal radicals Ru together are (=0) or (=S);
with particular preference given to compounds wherein R4 is 2-pyrimidinyl.
n is 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring;
L is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, nitro, -C(=O)-O-A7, -C(=O)-N(A8)A7, -C(=S)-N(A8)A7, C(A8X=N-OA7), N(A8)A7, N(A8)-C(=O)-A7 or S(=O)rA7, where
A7, A8 independently of one another are hydrogen, Ci-Cβ-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, cyano and/or Ci-C4-alkoxy; or A7 and A8 together with the atoms to which they are attached are a five- or six-membered saturated heterocycle which comprises one or two heteroatoms selected from the group consisting of O, N and S;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals RL, which may be the same or different from each other.
Amongst these, preference is given to those, wherein the radical
Figure imgf000021_0001
is a radical of the formula B as defined above.
Furthermore, particularly preferred are 2-substituted pyridines of the formula I' where
Y is O, CHR1 or NR1,
R1, R2 independently of one another are Ci-Cs-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, d-Cs-haloalkyl, C2-C8-haloalkenyl or C2-C8-haloalkynyl, Cs-Cs-cycloalkyl, C3-C8-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two substituents Rv which may be the same or different from each other and which are selected from the group consisting of d-Cε-alkyl, d-Cβ-haloalkyl, C3-C6-cycloalkyl, Cs-Cβ-halocycloalkyl and phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, d-Cβ-alkyl, C-i-Cε-haloalkyl, d-Cβ-alkoxy, cyano and nitro;
R1 may additionally be hydrogen; or, if Y is NR1,
R1 and R2 may also, together with the nitrogen atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may be interrupted by an ether (-O-) or by a further amino -(-N(RX))- group, where Rx is hydrogen or Ci-Cβ-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-Cβ-alkyl, d-Cβ-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;
R4 is cyano, C(=O)NRzRb, C(NRa1)NRzRb, C(=NORa1)NRzRb, C(=N-NRz1Rc1)NRzRb, C(=S)NRzRb, C(=O)Ra, C(=NRa1)Ra, C(=NORa1)Ra, C(=N-NRz1Rc1)Ra, C(=O)ORa, C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)NRa-NRzRb, CRaRb-NRzRc, CRaRb-ORz, O-C(=O)Ra, ON(=CRaRb), NRaRb1, NRa(C(=O)Rb), NRa(C(=NRa1)Rb), NRa(C(=NORa1)Rb), NRa(C(=O)ORb), NRa(C(=O)-NRzRb), NRa(C(=NRa1)-NRzRb), NRa(N=CRcRb), NRa-NRzRb or NRz-ORa, in particular R4 is cyano, C(=S)NRzRb, C(=O)NRzRb, C(=NORa1)NRzRb, C(NRa1)NRzRb, C(=O)Ra, C(=NORa1)Ra, C(=NRa1)Ra,
C(=O)ORa, C(=NORa1)ORa, C(=NRa1)ORa, C(=O)NRz-ORa, C(=NORa1)NRz-ORa, C(=NRa1)NRz-ORa, C(=N-NRz1Rc1)Ra, CRaRb-NRzRc, ON(=CRaRb), NRa(C(=O)Rb), NRa(C(=O)ORb), NRa(N=CRcRb) or NRz-ORa;
n is 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring;
L is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Cβ-alkoxy,
C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, nitro, -C(=O)-O-A7, -C(=O)-N(A8)A7, -C(=S)-N(A8)A7, C(A8)(=N-OA7), N(A8)A7, N(A8)-C(=O)-A7 or S(=O)rA7, where
A7, A8 independently of one another are hydrogen, d-Cε-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, cyano and/or Ci-C4-alkoxy; or A7 and A8 together with the atoms to which they are attached are a five- or six-membered saturated heterocycle which comprises one or two heteroatoms selected from the group consisting of O, N and S;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals RL, which may be the same or different from each other.
Amongst these, preference is given to those, wherein the radical
Figure imgf000022_0001
is a radical of the formula B as defined above.
Furthermore, especially preferred are 2-substituted pyridines of the formula I' where
Y is CHR1 or NR1,
R2 is Cs-Cs-alkyl or Cs-Cs-haloalkyl, preferably Cs-Cs-alkyl, in each case branched in the α-position, with preference given to those where R2 is prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (2-methyl)-but-2-yl, (2,3-dimethyl)-but-2-yl, (3 ,3-d imethyl)-but-2-yl , (2-methyl)-pent-2-yl , (3-methyl)-pent-2-yl , (4-methyl)-pent-2-yl, (2,3-dimethyl)-pent-2-yl, (2,4-dimethyl)-pent-2-yl, (3,4-dimethyl)-pent-2-yl, (4,4-dimethyl)-pent-2-yl, 1 ,1 ,1-trichloroprop-2-yl or 1 ,1 ,1-trifluoroprop-2-yl, more preferably prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (3,3-dimethyl)-but-2-yl and (4-methyl)-pent-2-yl, even more preferably prop-2-yl, but-2-yl, hept-2-yl, (3,3-dimethyl)-but-2-yl or (4-methyl)-pent-2-yl;
R1 is hydrogen; or, if Y is NR1,
R1 and R2 together with the nitrogen may also form a 5- or 6-membered saturated heterocycle, containing no further heteroatom such as pyrrolidin-1-yl and piperidin-1-yl, and which is optionally substituted by one, two or three, preferably one group(s) selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl, preferably Ci-C4-alkyl;
R3 is halogen;
R4 is pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl or benzothiazolyl, where the heterocycle may be attached via C or N to the pyridine ring and may carry one, two or three radicals Ru, which may be the same or different from each other, where
Ru is halogen, cyano, Ci-C8-alkyl, Ci-C6-alkoxy, -C(=O)-A4, -C(=O)-O-A4,
-C(=O)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, or where two vicinal radicals Ru together are (=0) or (=S);
with particular preference given to compounds wherein R4 is 2-pyrimidinyl.
and wherein the radical
Figure imgf000023_0001
is a radical of the formula B as defined above.
Furthermore, especially preferred are 2-substituted pyridines of the formula I' where
Y is CHR1 or NR1,
R2 is C3-Cs-alkyl or Cs-Cs-haloalkyl, preferably Cs-Cs-alkyl, in each case branched in the α-position, with preference given to those where R2 is prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (2-methyl)-but-2-yl, (2,3-dimethyl)-but-2-yl, (3 ,3-d imethyl)-but-2-yl , (2-methyl)-pent-2-yl , (3-methyl)-pent-2-yl , (4-methyl)-pent-2-yl, (2,3-dimethyl)-pent-2-yl, (2,4-dimethyl)-pent-2-yl, (3,4-dimethyl)-pent-2-yl, (4,4-dimethyl)-pent-2-yl, 1 ,1 ,1-trichloroprop-2-yl or 1 ,1 ,1-trifluoroprop-2-yl, more preferably prop-2-yl, but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, oct-2-yl, (3,3-dimethyl)-but-2-yl and (4-methyl)-pent-2-yl, even more preferably prop-2-yl, but-2-yl, hept-2-yl, (3,3-dimethyl)-but-2-yl or (4-methyl)-pent-2-yl;
R1 is hydrogen; or, if Y is NR1,
R1 and R2 together with the nitrogen may also form a 5- or 6-membered saturated heterocycle, containing no further heteroatom such as pyrrolidin-1-yl and piperidin-1-yl, and which is optionally substituted by one, two or three, preferably one group(s) selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl, preferably Ci-C4-alkyl;
R3 is halogen;
R4 is cyano, C(=O)NRzRb, C(NRa1)NRzRb, C(=NORa1)NRzRb, C(=N-NRz1Rc1)NRzRb, C(=S)NRzRb, C(=O)Ra, C(=NRa1)Ra, C(=NORa1)Ra, C(=N-NRz1Rc1)Ra, C(=O)ORa,
C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)NRa-NRzRb, CRaRb-NRzRc, CRaRb-ORz, O-C(=O)Ra, ON(=CRaRb), NRaRb1, NRa(C(=O)Rb), NRa(C(=NRa1)Rb), NRa(C(=NORa1)Rb), NRa(C(=O)ORb), NRa(C(=O)-NRzRb), NRa(C(=NRa1)-NRzRb), NRa(N=CRcRb), NRa-NRzRb or NRz-ORa, in particular R4 is cyano, C(=S)NRzRb, C(=O)NRzRb,
C(=NORa1)NRzRb, C(NRa1)NRzRb, C(=O)Ra, C(=NORa1)Ra, C(=NRa1)Ra, C(=O)ORa, C(=NORa1)ORa, C(=NRa1)ORa, C(=O)NRz-ORa, C(=NORa1)NRz-ORa, C(=NRa1)NRz-ORa, C(=N-NRz1Rc1)Ra, CRaRb-NRzRc, ON(=CRaRb), NRa(C(=O)Rb), NRa(C(=O)ORb), NRa(N=CRcRb) or NRz-ORa;
and wherein the radical
Figure imgf000024_0001
is a radical of the formula B as defined above.
In particular with a view to their use as anticancer agents, preference is given to the compounds of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, II, Im, In, lo, Ip, Ir, Is, It, Iu, Iv, Iw and Ix, wherein L, n, Y, R2 and R3 are as defined herein and preferably have the meanings given as preferred or particularly preferred meanings. Most preference is given to compounds If. Suitable examples are given in tables 1 to 188. Moreover, the groups mentioned for a substituent in the tables are per se, independently of the combination in which they are mentioned, a particularly preferred embodiment of the substituent in question.
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
Figure imgf000026_0004
Table 1
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-chloro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 2
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 3
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2,6-dichloro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 4
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 5
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trifluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 6
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-fluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 7
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxycarbonyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 8
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is,
It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-CN, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 9 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,5-trifluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 10
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dichloro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 11
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 12
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 13
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-difluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 14
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-chloro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 15
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro-4-fluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 16
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3-difluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 17 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-difluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 18
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3,4-trifluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 19
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 20
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dimethyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 21
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl-4-chloro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 22
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 23
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dimethyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 24
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trimethyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 25 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-cyano, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 26
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 27
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methoxycarbonyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 28
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxy, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 29
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 30
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxycarbonyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 31
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-bromo, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 32
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-cyano, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 33 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro,4-methoxy, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 34
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,3-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 35
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 36
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-cyano, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 37
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-bromo, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 38
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,5-fluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 39
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxy, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 40
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxycarbonyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 41 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl,4-bromo, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 42
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-bromo, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 43
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxy, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 44
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,5-methyl, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 45
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is pentafluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 46
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro,4-methoxy, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 47
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro, R3 is methyl and YR2 for each compound corresponds to one row of Table A.
Table 48
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-chloro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 49 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 50
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dichloro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 51
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-methyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 52
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trifluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 53
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-fluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 54
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxycarbonyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 55
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-CN, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 56
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,5-trifluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 57 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dichloro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 58
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 59
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 60
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-difluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 61
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-chloro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 62
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro-4-fluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 63
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3-difluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 64
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-difluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 65 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3,4-trifluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 66
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 67
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dimethyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 68
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl-4-chloro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 69
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-methyl, R2 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 70
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dimethyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 71
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trimethyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 72
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-cyano, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 73 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 74
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methoxycarbonyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 75
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxy, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 76
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 77
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxycarbonyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 78
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-bromo, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 79
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-cyano, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 80
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro,4-methoxy, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 81 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,3-methyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 82
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 83
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-cyano, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 84
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-bromo, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 85
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,5-fluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 86
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxy, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 87
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxycarbonyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 88
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl,4-bromo, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 89 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-bromo, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 90
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxy, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 91
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,5-methyl, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 92
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is pentafluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 93
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro,4-methoxy, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 94
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro, R3 is chlorine and YR2 for each compound corresponds to one row of Table A.
Table 95
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-chloro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 96
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 97 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dichloro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 98
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 99
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trifluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 100
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-fluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 101
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxycarbonyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 102
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-CN, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 103
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,5-trifluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 104
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dichloro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 105 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 106
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 107
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-difluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 108
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-chloro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 109
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro-4-fluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 110
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3-difluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 11 1
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-difluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 112
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3,4-trifluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 113 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 114
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dimethyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 115
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl-4-chloro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 116
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 117
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dimethyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 118
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trimethyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 119
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-cyano, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 120
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 121 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methoxycarbonyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 122
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxy, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 123
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 124
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is2-chloro,4-methoxycarbonyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 125
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is2-chloro,4-methoxy, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 126
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is2-chloro,4-cyano, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 127
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is2,6-difluoro,4-methoxy, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 128
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is2-fluoro,3-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 129 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is2,5-dimethyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 130
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-cyano, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 131
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-bromo, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 132
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,5-fluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 133
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxy, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 134
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxycarbonyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 135
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl,4-bromo, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 136
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-bromo, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 137 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxy, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 138
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,5-methyl, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 139
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is pentafluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 140
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro,4-methoxy, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 141
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro, R3 is methoxy and YR2 for each compound corresponds to one row of Table A.
Table 142
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-chloro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 143
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 144
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dichloro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 145 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,6-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 146
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trifluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 147
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-fluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 148
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxycarbonyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 149
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-CN, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 150
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,5-trifluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 151
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dichloro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 152
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 153 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 154
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-difluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 155
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-chloro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 156
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro-4-fluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 157
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3-difluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 158
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-difluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 159
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,3,4-trifluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 160
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 161 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4-dimethyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 162
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl-4-chloro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 163
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro-4-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 164
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-dimethyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 165
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,4,6-trimethyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 166
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-cyano, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 167
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 168
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro-4-methoxycarbonyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 169 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxy, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 170
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 171
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-methoxycarbonyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 172
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-bromo, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 173
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,4-cyano, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 174
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,6-difluoro,4-methoxy, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 175
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,3-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 176
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 177 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-cyano, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 178
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-Methyl,4-bromo, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 179
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,5-fluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 180
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxy, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 181
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-methyl,4-methoxycarbonyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 182
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2,5-dimethyl,4-bromo, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 183
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-bromo, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 184
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,4-methoxy, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 185 Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-fluoro,5-methyl, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 186
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is pentafluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 187
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro,4-methoxy, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table 188
Compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, IL, Im, In, lo, Ip, Iq, Ir, Is, It, Iu, Iv, Iw and Ix in which Ln is 2-chloro,5-fluoro, R3 is cyano and YR2 for each compound corresponds to one row of Table A.
Table A
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000054_0001
No. Y-R2
R2 Y [N-R1 , CH-R1]
A-140 (±) CH(CH3)CH(CH3)2
A-141 (R) CH(CH3)CH(CHs)2
A-142 (S) CH(CH3)CH(CHa)2
A-143 (CH2)5CH3
A-144 (±,±) CH(CH3)CH(CH3)CH2CH3
A-145 (±,R) CH(CH3)CH(CH3)CH2CH3
A-146 (±,S) CH(CH3)CH(CH3)CH2CH3
A-147 (±) CH2CH(CH3)CF3
A-148 (R) CH2CH(CH3)CF3
A-149 (S) CH2CH(CH3)CF3
A-150 (±) CH2CH(CF3)CH2CH3
A-151 (R) CH2CH(CF3)CH2CH3
A-152 (S) CH2CH(CF3)CH2CH3
A-153 (± +) CH(CH3)CH(CH3)CF3
A-154 (±,R) CH(CH3)CH(CH3)CF3
A-155 (±,S) CH(CH3)CH(CH3)CF3
A-156 (±,±) CH(CH3)CH(CF3)CH2CH3
A-157 (±,R) CH(CH3)CH(CF3)CH2CH3
A-158 (±,S) CH(CH3)CH(CF3)CH2CH3
A-159 CF3
A-160 CF2CF3
A-161 CF2CF2CF3
A-162 C-C3H5
A-163 (1 -CH3)-c-C3H4
A-164 C-C5H9
A-165 c-CβHii
A-166 (4-CH3)-c-C6H10
A-167 CH2C(CH3)=CH2
A-168 CH2CH2C(CHs)=CH2
A-169 CH2-C(CH3)3
A-170 CH2-Si(CH3)3
A-171 IvC6H13
A-172 (CH2)3-CH(CH3)2
A-173 (CH2)2-CH(CH3)-C2H5
A-174 CH2-CH(CH3)-n-C3H7 No. Y-R2
R2 Y [N-R1 , CH-R1]
A-175 CH(CH3)-n-C4H9
A-176 CH2-CH(C2Hs)2
A-177 CH(C2Hs)-Ii-C3H7
A-178 CH2-C-C5H9
A-179 CH2-CH(CH3)-CH(CH3)2
A-180 CH(CH3)-CH2CH(CH3)2
A-181 CH(CH3)-CH(CH3)-C2H5
A-182 CH(CH3)-C(CH3)3
A-183 (CH2)2-C(CH3)3
A-184 CH2-C(CH3)2-C2H5
A-185 2-CH3-C-C5H8
A-186 3-CH3-C-C5He
A-187 C(CH3)2-n-C3H7
A-188 (CH2)6-CH3
A-189 (CH2)4-CH(CH3)2
A-190 (CH2)3-CH(CH3)-C2H5
A-191 (CH2)2-CH(CH3)-n-C3H7
A-192 CH2-CH(CH3)-n-C4H9
A-193 CH(CH3)-n-C5Hn
A-194 (CH2)3C(CH3)3
A-195 (CH2)2CH(CH3)-CH(CH3)2
A-196 (CH2)CH(CH3)-CH2CH(CH3)2
A-197 CH(CH3)(CH2)2-CH(CH3)2
A-198 (CH2)2C(CH3)2C2H5
A-199 CH2CH(CH3)CH(CH3)C2H5
A-200 CH(CH3)CH2CH(CH3)C2H5
A-201 CH2C(CH3)2-n-C3H7
A-202 CH(CH3)CH(CH3)-n-C3H7
A-203 C(CH3)2-n-C4H9
A-204 (CH2)2CH(C2H5)2
A-205 CH2CH(C2H5)-n-C3H7
A-206 CH(C2H5)-n-C4H9
A-207 CH2CH(CH3)C(CH3)3
A-208 CH(CH3)CH2C(CH3)3
A-209 CH2C(CH3)2CH(CH3)2
A-210 CH2CH(C2H5)CH(CH3)2
A-21 1 CH(CH3)CH(CH3)CH(CH3)2
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
The 2-substituted pyridines I, in particular the compounds of the formulae Ia, Ic, Ie, If, Ig, Im, lo, Iq, Ir and Is effectively inhibit growth and/or progeny of tumor cells as can be shown by standard tests on tumor cell lines such as HeLa, MCF-7 and COLO 205. In particular, 2-substituted pyrimidines I show in general IC50 values < 10"6 mol/l (i.e. < 1 μM), preferably IC50 values < 10"7 mol/l (i.e. < 100 nM) for cell cycle inhibition in HeLa cells as determined by the test procedure outlined below.
Based on the results of these standard pharmacological test procedures, 2-substituted pyridines are useful as agents for treating, inhibiting or controlling the growth and/or progeny of cancerous tumor cells and associated diseases in a subject in need thereof. Therefore these compounds are useful in therapy of cancer in warm blooded vertebrates, i.e. mammals and birds, in particular human beings but also in other mammals of economic and/or social importance e.g. carnivores such as cats and dogs, swine (pigs, hogs and wild boars), ruminats (e.g. cattle, oxen, sheep, deer, goats, bison) and horses, or bird in particular poultry such as turkeys, chickens, ducks, geese, guinea fowl and the like. As used herein, the terms "treatment" and "therapy" are synonyms.
In particular, 2-substituted pyridines I are useful in therapy of cancer or cancerous disease including cancer of breast, lung, colon, prostate, melanoma, epidermal, kidney bladder, mouth, larynx, esophagus, stomach, ovary, pancreas, liver, skin and brain.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and severity of the condition being treated. However, in general satisfactory results are obtained when the compounds of the invention are administered in amounts ranging from about 0.10 to about 100 mg/kg of body weight per day. A preferred regimen for optimum results would be from about 1 mg to about 20 mg/kg of body weight per day and such dosage units are employed that a total of from about 70 mg to about 1400 mg of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.
The dosage regimen for treating mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decidedly practical advantage is that these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes. The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatine capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 1000 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations. These active compounds may also be administered parenterally or intraperitoneal^. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.
The following examples 1-1 to I-55 given in table B were prepared by the methods described in WO2006/000358. They are representative compounds of this invention which are useful as anticancer agents.
0000058741
Table B: Active compounds
Figure imgf000068_0001
0000058741
oo
Figure imgf000069_0001
0000058741
Figure imgf000070_0001
0000058741
O
Figure imgf000071_0001
0000058741
Figure imgf000072_0001
0000058741
K*
Figure imgf000073_0001
*) m.p. = melting point
Measurement of the cell cycle inhibition in HeLa cells - test procedure:
HeLa B cells are grown in DMEM (Life Technologies Cat No 21969-035) supplemented with 10% Fetal Calf Serum (FCS, Life Technologies Cat No 10270-106) in 180 cm2 Flasks at 37°C, 92% humidity and 7% CO2.
Cells are seeded at 5x104 cells per well in a 24-well plate. Twenty hours later the compounds are added such that the final concentration is 1x10"6, 3.3x10"7, 1.1x10"7, 3.7x10"8, 1.2x10"8 and 1 x10"9 M in a final volume of 500 μl. DMSO alone is added to 6 wells as a control. Cells are incubated with the compounds as above for 20 h. Then cells are observed under the microscope to check for cell death, and the 24-well plate is then centrifuged at 1200 rpm for 5 min at 200C, acceleration position 7 and break position 5 (Eppendorf centrifuge 5804R). The supernatant is removed and the cells are lysed with 0.5 ml RNase Buffer (10 mM NaCitrate, 0.1 % Nonidet NP40, 50 μg/ml RNase, 10 μg/ml Propidium iodide) per well. The plates are then incubated for at least 30 min in the dark at RT and the samples then transferred to FACS tubes. Samples are measured in a FACS machine (Beckton Dickinson) at the following settings:
Instrument Settings of the FACS Calibur: Run Modus: high
Parameter Voltage Amp Gain Mode
FSC E01 2,5 Hn
SSC 350 1 Hn
Fl 1
Fl 2 430 2 Hn
Fl 3
FI 2 - A — 1 Hn
Fl 2 - W — 3 Hn
DDM Parameter Fl 2
The ratio of cells in Go/Gi-phase to G2/M phase is calculated and compared to the value for the controls (DMSO) only. Results are given in table C as the IC50 value calculated from the concentration curve plotted against the cell cycle ratio and indicate the compound concentration at which 50% of cells are in cell cycle arrest after treatment with the compound. Test on other cell lines (MCF-7 and COLO 205) were done in the same way except that they were incubated with the growth medium recommended by the American Tissue Culture collection for that cell type.
Table C
Figure imgf000074_0001

Claims

We claim:
2-Substituted pyridine compounds of the formula I and the pharmaceutically acceptable salts of the 2-substituted pyridines of formula I for use in therapy
Figure imgf000075_0001
in which the indices and the substituents are as defined below:
Xi, X2 in each case, one of the two ring members is N, the other is C-H or
C-halogen;
Y is a group -CH-R1-, -N-R1-, -O- or -S-;
R1, R2 independently of one another are selected from the group consisting of Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Ci2-cycloalkyl and C4-Cio-cycloalkenyl, where the aliphatic and/or alicyclic groups of the radical definitions of R1 and R2 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Rv, which may be the same or different from each other:
Rv is selected from the group consisting of halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Ce-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1,
-C(=O)-N(A2)A1, C(A2)(=N-OA1), N(A2JA1, N(A2)-C(=O)-A1, N(A3)-C(=O)-N(A2)A1, S(=O)m-A1, S(=O)m-O-A1 and S(=O)m-N(A2)A1, it also being possible that two vicinal radicals Rv together are (=0) or (=S), or Rv is phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cβ-cycloalkyl, d-Ce-haloalkyl, Ci-C6-alkoxy, cyano, nitro, -C(=O)-A, -C(=O)-O-A, -C(=O)-N(A')A, C(A')(=N-OA) and N(A1JA; where
m is 0, 1 or 2;
A1, A2, A3, A and A' independently of one another are hydrogen, d-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, nitro, cyanato, cyano and/or Ci-C4-alkoxy; or A1 and A2, or A and A', respectively, together with the atoms to which they are attached are a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Rv for their part may be partially or fully halogenated;
R1 may additionally be hydrogen;
R1 and R2 may also, together with the nitrogen or carbon atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may comprise O, S, carbonyl (C=O), sulfoxyl (-S[=O]-), sulfonyl (-SO2-) or an N(Rx)-group as a ring member, where Rx is hydrogen or Ci-Cβ-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, Ci-Cβ-alkyl, d-Cε-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is selected from the group consisting of halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cs-Cβ-cycloalkyl, Ci-C4-alkoxy, C3-C4-alkenyloxy, C3-C4-alkynyloxy, C-i-Cβ-alkylthio, di-(Ci-C6-alkyl)amino and Ci-Cβ-alkylamino, where the aliphatic and/or alicyclic groups of the radical definitions of R3 for their part may be partially or fully halogenated or may carry one, two, three or four radicals R1, which may be the same or different from each other:
R1 is selected from the group consisting of halogen, cyano, d-Cs-alkyl,
C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, Ci-Cβ-alkoxy, C3-C6-cycloalkyl, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, C4-C6-cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A13, -C(=O)-O-A13, -C(=O)-N(A14)A13, C(A14X=N-OA13), N(A14)A13, N(A14)-C(=O)-A13, N(A15)-C(=O)-N(A14)A13, S(=O)P-A13,
S(=O)p-O-A13 and S(=O)P-N(A14)A13, it also being possible that two vicinal radicals Ru together are (=0) or (=S), where
p is O, 1 or 2;
A13, A14 and A15 independently of one another have the meanings of A1, A2 and A3 as defined above; and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of R1 for their part may be partially or fully halogenated or may carry one, two or three radicals Rta, which may be the same or different from each other and which have the meanings of R1 as defined above;
R4 is a five-, six-, seven-, eight-, nine- or ten-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S and where the heterocycle for its part may be partially or fully halogenated or may carry one, two, three or four radicals Ru, which may be the same or different from each other:
Ru is selected from the group consisting of halogen, cyano, Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, d-Cβ-alkoxy,
C3-C6-cycloalkyl, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, C4-C6-cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, -C(=S)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, N(A6)-C(=O)-N(A5)A4, S(=O)q-A4, S(=O)q-O-A4 and S(=O)q-N(A5)A4, it also being possible that two vicinal radicals Ru together are (=0) or (=S), where
q is O, 1 or 2;
A4, A5 and A6 independently of one another have the meanings of
A1, A2 and A3 as defined above;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Ru for their part may be partially or fully halogenated or may carry one, two or three radicals Rua, which may be the same or different from each other and which have the meanings of Ru as defined above;
R4 may furthermore be: cyano, C(=Z)ORa, C(=Z)NRzRb, C(=Z)NRz-ORa, C(=Z)NRa-NRzRb, C(=Z)Ra, CRaRb-ORz, CRaRb-NRzRc, ON(=CRaRb),
O-C(=Z)Ra, NRaRb1, NRa(C(=Z)Rb), NRa(C(=Z)ORb), NRa(C(=Z)-NRzRb), NRa(N=CRcRb), NRa-NRzRb or NRz-ORa, where
Z is O, S, NRa1, NORa1 or N-NRz1Rc1;
Ra, Ra1, Rb, Rc, Rc1 independently of one another are hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl or C4-C6-cycloalkenyl; Rb1 has the meanings of Rb as defined above, except for hydrogen; and
Rz, Rz1 independently of one another have the meanings of Ra as defined above and may additionally be -CO-Ra2, where Ra2 has the meanings of Ra as defined above;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz and Rz1 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Rw, which may be the same or different from each other:
Rw is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl,
C-i-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C3-C6-cycloalkenyl, Cs-Cβ-cycloalkoxy, Cs-Cβ-cycloalkenyloxy,
and where two of the radicals Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz or Rz1 together with the atoms, to which they are attached, may form a five- or six- membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms as ring members selected from the group consisting of O, N and S;
( —Λ y> is phenyl or a five- or six-membered hetaryl which comprises 1 , 2 or 3 heteroatoms as ring members selected from the group consisting of O, N and S;
n is 1 , 2, 3, 4 or 5;
L is selected from the group consisting of halogen, cyano, cyanato (OCN), Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, Cs-Ce-cycloalkyloxy, C4-C6-cycloalkenyloxy, nitro, -C(=O)-A7, -C(=O)-O-A7,
-C(=O)-N(A8)A7, -C(=S)-N(A8)A7, -C(=NA8)-SA7, C(A8X=N-OA7), N(A8)A7, N(A8)-C(=O)-A7, N(A9)-C(=O)-N(A8)A7, S(=O)rA7, S(=O)rO-A7 and S(=O)rN(A8)A7, where L may be identical or different, if n is 2, 3, 4 or 5, and where
r is 0, 1 or 2;
A7, A8, A9 independently of one another have the meanings of A1, A2 and
A3 as defined above;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals RL, which may be the same or different from each other:
RL is selected from the group consisting of halogen, cyano, Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, d-Cβ-alkoxy,
C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A10, -C(=O)-O-A10, -C(=O)-N(A11)A10, C(A11)(=N-OA10), N(A11)A10, N(A11)-C(=O)-A10, N(A12)-C(=O)-N(A11)A10, S(=O)S-A10, S(=O)s-O-A10 and S(=O)S-N(A11)A10, it also being possible that two vicinal radicals RL together are (=0) or (=S), where
s is 0, 1 or 2; and
A10, A11 and A12 independently of one another have the meanings of
A1, A2 and A3 as defined above;
and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of RL for their part may be partially or fully halogenated or may carry one, two, three or four radicals RLA, which may be the same or different from each other and which have the meanings of RL as defined above;
2. The compounds according to claim 1 where B in formula I is phenyl.
3. The compounds according to claim 2 which correspond to the formula I'
Figure imgf000079_0001
where
Y is a group -CH-R1-, -N-R1- or -O-;
R1, R2 independently of one another are selected from the group consisting of C-i-Cs-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Ci-C8-haloalkyl, C2-C8-haloalkenyl or C2-C8-haloalkynyl, Cs-Cs-cycloalkyl and
C3-C8-halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two radicals Rv which may be the same or different from each other and which are selected from the group consisting of d-Cε-alkyl, Ci-Cβ-haloalkyl, Cs-Cβ-cycloalkyl, Cs-Cβ-halocycloalkyl and phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, d-Cε-alkyl, d-Cε-haloalkyl, Ci-Cβ-alkoxy, cyano and nitro;
R1 may additionally be hydrogen;
R1 and R2 may also, together with the nitrogen atom to which they are attached, form a saturated or unsaturated five- or six-membered ring which may be interrupted by an ether (-O-) or by a further amino -(-N(RX))- group, where Rx is hydrogen or d-Cε-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, Ci-Cβ-alkyl, d-Cε-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;
R4 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,4-oxadiazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, pyrrolidinyl, piperidinyl, indazolyl, hexahydroazepinyl, dihydropyridinyl, dihydrothiazolyl and benzothiazolyl, where the heterocycle may be attached via C or N to the pyridine ring and may carry one, two or three radicals Ru, which may be the same or different from each other, where
Ru is halogen, cyano, Ci-C8-alkyl, d-Ce-alkoxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, or where two vicinal radicals Ru together are (=0) or (=S);
or R4 is selected from the group consisting of cyano, C(=O)NRzRb,
C(NRa1)NRzRb, C(=NORa1)NRzRb, C(=N-NRz1Rc1)NRzRb, C(=S)NRzRb, C(=O)Ra, C(=NRa1)Ra, C(=NORa1)Ra, C(=N-NRz1Rc1)Ra, C(=O)ORa, C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)NRa-NRzRb, CRaRb-NRzRc, CRaRb-ORz, O-C(=O)Ra, ON(=CRaRb), NRaRb1, NRa(C(=O)Rb), NRa(C(=NRa1)Rb),
NRa(C(=NORa1)Rb), NRa(C(=O)ORb), NRa(C(=O)-NRzRb), NRa(C(=NRa1)-NRzRb), NRa(N=CRcRb), NRa-NRzRb and NRz-ORa;
n is 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring;
L is selected from the group consisting of halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, nitro, -C(=0)-0-A7, -C(=O)-N(A8)A7, -C(=S)-N(A8)A7, C(A8)(=N-OA7), N(A8)A7, N(A8)-C(=O)-A7 and S(=O)rA7, where
A7, A8 independently of one another are hydrogen, d-Cε-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, cyano and/or Ci-C4-alkoxy; or A7 and A8 together with the atoms to which they are attached are a five- or six- membered saturated heterocycle which comprises one or two heteroatoms selected from the group consisting of O, N and S;
where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals RL, which may be the same or different from each other.
4. The compounds according to any of the preceding claims in which
R4 is selected from the group consisting of pyrazol-1-yl, 3-amino-pyrazol-1-yl, [1 ,2,4]triazol-1 -yl, 3-cyano-1 ,2,4-triazol-1 -yl, [1 ,2,3]triazol-1 -yl,
1 ,2,4-oxadiazol-3-yl, 5-methyl-1 ,2,4-oxadiazol-3-yl, pyridin-2-yl, (6-methyl)-pyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, (1 ,2-dihydro)-pyridin-2-on-1 -yl, pyrrolidin-2-on-1 -yl, piperidin-2-on-1 -yl, pyrrolidin-2-thion-1 -yl, piperidin-2-thion-1 -yl, [1 ,3]thiazol-2-yl, (4,5-dimethyl)-[1 ,3]thiazol-2-yl, benzo-[1 ,3]thiazol-2-yl,
(4,5-dimethyl)-(1 ,2-dihydro)-[1 ,3]thiazol-2-yl, hexahydro-2H-azepin-2-on-1-yl, hexahydro-2H-azepin-2-thion-1-yl and 7-amino-indazol-1 -yl.
5. The compounds according to claim 4 in which R4 is pyrimidin-2-yl.
6. The compounds according to any of claims 1 to 3 in which Xi is N and X2 is CH,
R4 is cyano, C(=Z)ORa, C(=Z)NRzRb, C(=S)NRzRb, C(=Z)NRz-ORa or C(=Z)Ra; and
Z is O, NRa1 or NORa1, where Ra, Rb, Rz and Ra1are as defined in claim 1.
7. The compounds according to any of the preceding claims in which
Y is a group -CHR1 or -NR1, where R1 is H; and R2 is selected from the group consisting of C3-C8-alkyl, C3-C8-alkenyl,
Cs-Cs-alkynyl or C3-C8-haloalkyl, in each case branched in the α-position; C3-C8-cycloalkyl or Cs-Cs-halocycloalkyl, which in each case may carry a radical Rv selected from the group consisting of C3-C6-alkyl, C3-C6-haloalkyl, in each case branched in the α-position, and phenyl;
Ci-Cβ-alkyl or C-i-Cβ-haloalkyl, in each case carrying a radical Rv selected from the group consisting of C3-C6-cycloalkyl, Cs-Cβ-halocycloalkyl and phenyl, where the phenyl moiety may carry one or two substituents which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl, C-i-Cβ-haloalkyl, d-Cβ-alkoxy, cyano and nitro.
8. The compounds according to any of claims 1 to 6 in which
Y is a group -NR1, where R1 and R2 together with the nitrogen atom to which they are attached, form a saturated five- or six-membered ring which may carry a substituent selected from the group consisting of halogen, C-i-Ce-alkyl and Ci-C6-haloalkyl.
9. The compounds according to any of the preceding claims in which Xi is N and X2 is CH.
10. The compounds according to any of the preceding claims in which the radical corresponds to the formula B:
Figure imgf000082_0001
where # is the point of attachment to the pyridine skeleton and
L1 is fluorine, chlorine, CH3 or CF3;
L2, L4 independently of one another are hydrogen, CH3 or fluorine; L3 is hydrogen, fluorine, chlorine, bromine, nitro, cyano, CH3, SCH3, OCH3,
SO2CH3, CO-NH2, CO-NHCH3, CO-NHC2H5, CO-N(CHs)2, CS-NH2, CS-NHCH3, CS-N(CHs)2, NH-C(=O)CH3, N(CH3)-C(=O)CH3 or COOCH3; and
L5 is hydrogen, fluorine, chlorine or CH3.
1 1. 2-substituted pyridine compounds of the formula I as defined in any of claims 1 to 10 and their pharmaceutically acceptable salts for use in therapy of cancer.
12. A pharmaceutical composition comprising a 2-substituted pyridine compound of the formula I as defined in any of the preceding claims or a pharmaceutically acceptable salt thereof.
13. The use of 2-substituted pyridine compounds of the formula I as defined in any of claims 1 to 10 and their pharmaceutically acceptable salt in therapy of a disease.
14. The use according to claim 13, wherein the disease is cancer.
15. The use of a 2-substituted pyridine compound of the formula I as defined in any of claims 1 to 10 and of their pharmaceutically acceptable salts in the manufacture of a medicament.
16. The use according to claim 15 in the manufacture of a medicament for the treatment of cancer.
17. A method for cancer treatment in animals, in particular humans, which comprises administering to the subject in need thereof an effective amount of a 2-substituted pyridine compound of the formula I as defined in any of claims 1 to 10 or of their pharmaceutically acceptable salts.
PCT/EP2007/064569 2006-12-28 2007-12-27 Use 2-substituted pyridines for cancer treatment WO2008080938A1 (en)

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EP2739680B1 (en) * 2011-08-05 2021-01-20 Saint-Gobain Isover Sizing composition for mineral wool containing a reducing saccharide and a hydrogenated saccharide, and resulting insulating products

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