WO2008080937A1 - 2-substituted pyrimidines i in therapy - Google Patents

2-substituted pyrimidines i in therapy Download PDF

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WO2008080937A1
WO2008080937A1 PCT/EP2007/064568 EP2007064568W WO2008080937A1 WO 2008080937 A1 WO2008080937 A1 WO 2008080937A1 EP 2007064568 W EP2007064568 W EP 2007064568W WO 2008080937 A1 WO2008080937 A1 WO 2008080937A1
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alkyl
formula
compounds
methyl
cyano
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PCT/EP2007/064568
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French (fr)
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Barbara Nave
Sven Harmsen
Bernd Müller
Thomas Grote
Frank Schieweck
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Basf Se
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings 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
    • 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

Definitions

  • the present invention relates to 2-substituted pyrimidines of the formula I
  • n 1 , 2, 3, 4 or 5;
  • L is halogen, cyano, cyanato (OCN), Ci-Cio-alkyl, C 2 -Ci 0 -alkenyl, C 2 -Ci 0 -alkynyl,
  • Ci-C 6 -alkoxy, C 2 -Ci 0 -alkenyloxy, C 2 -Ci 0 -alkynyloxy, C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -cycloalkyloxy, C 4 -C 6 -cycloalkenyloxy, nitro, -C( 0)-A 1 ,
  • n O, 1 or 2;
  • a 1 , A 2 , A 3 independently of one another are hydrogen, d-C 6 -alkyl,
  • v 0, 1 or 2;
  • a 4 , A 5 , A 6 independently of one another have the meanings of A 1 , A 2 and
  • 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 or three radicals R LA , which may be the same or different from each other and which have the meanings of R L as defined above;
  • R 1 , R 2 independently of one another are Ci-Cio-alkyl, C 2 -Ci 0 -alkenyl,
  • R v is halogen, cyano, Ci-C 8 -alkyl, C 2 -Ci 0 -alkenyl, C 2 -Ci 0 -alkynyl, C 3 -C 6 - cycloalkyl, C 4 -C 6 -cycloalkenyl, hydroxyl, Ci-C 6 -alkoxy, C 2 -Ci 0 -alkenyloxy,
  • r 0, 1 or 2;
  • a 7 , A 8 , A 9 , A and A' independently of one another have the meanings of
  • R 2 may additionally be hydrogen
  • 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 comprise O.
  • R 3 is halogen, cyano, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -cycloalkyl, Ci-C 4 -alkoxy, C 3 -C 4 -alkenyloxy, C 3 -C 4 -alkynyloxy, Ci-C 6 -alkylthio, di-(Ci-C6-alkyl)amino or Ci-C ⁇ -alkylamino, where the aliphatic and/or alicyclic groups of the radical definitions of R 3 for their part may be partially or fully halogenated or may carry one, two, three or four radicals R', which may be the same or different from each other:
  • w 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' aliphatic, alicyclic and/or aromatic groups of the radical definitions of R' 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' as defined above;
  • X is a group -CH-R 3 -, -N-R b -, -O- or -S-;
  • R a is hydrogen, halogen, d-C 6 -alkyl, d-C 6 -alkoxy, cyano or
  • Ci-C 6 -alkoxycarbonyl is hydrogen, d-C 6 -alkyl or C 3 -C 6 -cycloalkyl;
  • T is a group -CH-R a1 -;
  • R a1 has, independently from one another, the meanings of R a as defined above; q is 1 , 2, 3 or 4;
  • Y is a group -CH-R a2 - or -N-R b1 -; R a2 has the meanings of R a as defined above;
  • R b1 has the meanings of R b as defined above; o is O or i ;
  • Z is O, S or a group N(R C ); and R c is hydrogen, Ci-C 6 -alkyl or Ci-C 6 -alkoxy;
  • 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 pyrimidine 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 pyrimidine of the formula I as defined herein and of their pharmaceutically acceptable salts in the manufacture of a medicament in particular a medicament for therapy or treatment of cancer or a cancerous disease. 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 pyrimidine 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 still one of the leading causes of death.
  • ovarian 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 vincristine.
  • Pharmacologically active pyrimidines which may carry a piperazine or morpholine radical in the 2-position are known from EP-A 715 851.
  • pyrimidines for use in anticancer therapy which may be substituted in the 2-position by a large variety of different substituents including unsaturated heterocyclic rings have been described in WO 2006/079556.
  • 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 pyrimidines I have recently been described in WO 2005/113538.
  • 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 pyrimidines I can be prepared by the methods disclosed in WO 2005/113538 and in the literature cited therein as well as by standard methods of organic chemistry.
  • physiologically tolerated salts of the 2-substituted pyrimidines 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.
  • d-C 4 -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.
  • the physiologically tolerated salts of 2-substituted pyrimidines 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 pyrimidine 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 te/f-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-C 4 -alkylesters of Ci-C 4 -aliphatic acids such as ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc., di-CrC 4 -alkylethers such as methyl te/f-butyl ether or diisopropyl ether.
  • halogen fluorine, chlorine, bromine or iodine
  • - 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
  • C 3 -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,
  • 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 CrC 4 -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-,2-
  • - 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, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 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 ,
  • 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-t ⁇ azinyl, 1 ,3,5-triazin-2-yl and 1 ,2,4-triazin-3-yl.
  • 3-pyrazolidinyl 4-pyrazolidinyl, 5-pyrazolidinyl, 2-pyrrolidin-2-yl, 2-pyrrolidin-3-yl, 3- pyrrolidin-2-yl, 3-pyrrolidin-3-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 and thiomorpholin-4-yl.
  • 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 racemate is also within the scope of the present invention.
  • 2-substituted pyrimidines I wherein R 1 and R 2 independently of one another are Ci-C 8 -alkyl, CrC 8 -haloalkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -haloalkenyl, C 2 -C 8 -alkynyl, C 2 -C 8 -haloalkynyl, C 3 -C 8 -cycloalkyl or
  • C 3 -C 8 -halocycloalkyl more particularly Ci-C 8 -alkyl, Ci-C 8 -haloalkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -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 6 -alkyl, CrC 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -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, d-C 6
  • R 1 is CrC 6 -haloalkyl, particularly CrC 4 -haloalkyl, e. g. 2 ,2 ,2-trif luoroethy I , 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, preferably 2,2, 2-trifluoroethyl,
  • 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 and 2-methyl-2-propenyl, preferably 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl, more preferably 2-propenyl; or d-C 6 -alkyl, particularly C 2 -C 4 -alkyl, e. g.
  • R 1 is d-C ⁇ -alkyl or d-C ⁇ -haloalkyl
  • R 1 is Ci-C 2 -alkyl or Ci-C 2 -haloalkyl, especially methyl, ethyl, trichloromethyl, trifluoromethyl, 1 ,1 ,1 -trich loroethy I and 1 ,1 ,1-trifluoromethyl, preferably 1 ,1 ,1-trichloroethyl and 1 ,1 ,1-trifluoromethyl. More particular preference is given to compounds I in which R 1 has the aforementioned meanings and R 2 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.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a saturated or unsaturated five- or six- membered ring which may be interrupted by an oxygen atom and may carry one or two d-C 6 -alkyl, preferably d-d-alkyl substituents, e. g. methyl, ethyl, prop-1-yl, prop-2-yl and 1-methylethyl, more preferably d-C 2 -alkyl substituents, e. g. methyl, ethyl, especially methyl.
  • 2-substituted pyrimidines 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, and which is optionally substituted by one, two or three groups selected from halogen, d-C 4 -alkyl and d-C 4 -haloalkyl.
  • Preferred radicals of the formula NR 1 R 2 which are attached to the pyrimidine skeleton of the 2-substituted pyrimidines of formula I, include:
  • L 5 are selected from the group consisting of:
  • Ci-C 8 -alkyl in particular d-C 6 -alkyl, especially Ci-C 4 -alkyl, such as methyl, ethyl, propyl and butyl, preferably methyl;
  • C 2 -Ci 0 -alkenyl in particular C 2 -C 6 -alkenyl, especially C 2 -C 4 -alkenyl, such as ethenyl, propenyl and butenyl;
  • C 2 -Ci 0 -alkynyl in particular C 2 -C 6 -alkynyl, especially C 2 -C 4 -alkynyl, such as ethynyl, propynyl and butynyl;
  • d-C 6 -alkoxy in particular Ci-C 4 -alkoxy, preferably methoxy and ethoxy;
  • C 2 d-C 6 -alkoxy in particular Ci-C 4 -alkoxy, preferably
  • a 1 , A 2 independently of one another are hydrogen, d-C ⁇ -alkyl,
  • L may be partially or fully halogenated, e. g. where L may be CrC 6 -haloalkyl, especially Ci-C 2 -fluoroalkyl, such as trifluoromethyl.
  • n is preferably 1 , 2 or 3.
  • 2-substituted pyrimidines I wherein one or two radical(s) L is (are) attached to one (or two) of the ortho-position(s) of the phenyl ring.
  • 2-substituted pyrimidines I wherein n is 1 , 2 or 3.
  • L 1 is fluorine, chlorine, CH 3 or CF 3 , more preferably fluorine or chlorine;
  • L 2 , L 4 independently of one another are hydrogen, CH 3 or fluorine, more preferably hydrogen;
  • L 3 is hydrogen, fluorine, chlorine, bromine, cyano, CH 3 , SCH 3 , OCH 3 , SO 2 CH 3 , CO-NH 2 , CO-NHCH 3 , CO-NHC 2 H 5 , CO-N(CH 3 ) 2 , CS-NH 2 , CS-NHCH 3 ,
  • R 3 is chlorine.
  • the 2-substituted pyrimidines of the formula I have a substituent in the 2-position wherein q is 2, 3 or 4 and o is 0. In another particularly preferred embodiment of the present invention, the 2-substituted pyrimidines of the formula I have a substituent in the 2-position wherein q is 1 , 2 or 3 and o is 1.
  • these compounds particularly preferred are those wherein
  • X is a group -CH-R a - ;
  • R a is hydrogen, halogen, cyano or d-C 3 -alkyl, in particular hydrogen or Ci-C 3 -alkyl, such as methyl or ethyl, especially methyl;
  • T is a group -CH-R a1 - ;
  • R a1 is, independently from one another, hydrogen, halogen, cyano or
  • Ci-C 3 -alkyl in particular hydrogen or d-C 3 -alkyl, such as methyl or ethyl; especially R a1 is hydrogen or methyl; and q is 1 , 2,3 or 4, in particular 2, 3 or 4.
  • X is a group -CH-R 3 -;
  • R a is hydrogen, halogen, cyano or d-C 3 -alkyl, such as methyl or ethyl, especially methyl;
  • T is a group -CH-R a1 -;
  • R a1 is, independently from one another, hydrogen, halogen, cyano or
  • Ci-C 3 -alkyl in particular hydrogen or d-C 3 -alkyl, such as methyl or ethyl, especially methyl; q is 1 , 2, 3 or 4, in particular 1 , 2 or 3;
  • Y is a group -N-R b1 ;
  • R b1 is hydrogen or Ci-C 3 -alkyl, such as methyl or ethyl, especially methyl.
  • 2-substituted pyrimidines of the formula I in which at least one group R a1 of the moiety T, preferably the one adjacent to the ring nitrogen atom which is attached to the pyrimidine ring system of formula I, is Ci-C3-alkyl, preferably methyl or ethyl, especially methyl.
  • R a1 of the moiety T preferably the one adjacent to the ring nitrogen atom which is attached to the pyrimidine ring system of formula I
  • Ci-C3-alkyl preferably methyl or ethyl, especially methyl.
  • 2-substituted pyrimidines of the formula I in which X is a group -CH-R a - and R a is Ci-C 3 -alkyl, preferably methyl or ethyl, especially methyl.
  • X is a group -CH-R a - and R a is Ci-C 3 -alkyl, preferably methyl or ethyl, especially methyl.
  • R a1 of the moiety T are hydrogen.
  • n 1 , 2 or 3, where at least one substituent L is located in the ortho-position on the phenyl ring;
  • a 1 , A 2 independently of one another are hydrogen, Ci-C 6 -alkyl,
  • aliphatic 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;
  • R 1 , R 2 independently of one another are Ci-C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, d-C ⁇ -haloalkyl, C 2 -C 8 -haloalkenyl or C 2 -C 8 -haloalkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, where the aliphatic and/or alicyclic groups may carry one or two radicals R v which may be the same or different from each other and which are selected from the group consisting of Ci-C 6 -alkyl, CrC 6 -haloalkyl,
  • R 2 may additionally be hydrogen
  • R 1 , 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 d-C 6 -alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-C 6 -alkyl, d-C 6 -haloalkyl and oxy-d-C 3 -alkyleneoxy;
  • R 3 is halogen, cyano, d-d-alkyl, d-d-alkoxy or d-d-haloalkyl;
  • X is a group -CH-R 3 -, -N-R b -, -O- or -S-; particularly preferably -CH-R 3 -; and R 3 is hydrogen or Ci-C 3 -alkyl.
  • T is a group -CH-R 31 -;
  • R a1 is hydrogen, halogen, cyano or Ci-C 3 -alkyl, particularly preferably hydrogen or Ci-C 3 -alkyl; and q is 2, 3 or 4, if o is 0; or q is 1 , 2 or 3, if o is 1.
  • Z is O, S, NH, NCH 3 or NOCH 3 , and particularly preferably O or S, especially O.
  • n 1 , 2 or 3, where at least one substituent L is located in the ortho-position on the phenyl ring;
  • R 1 is Ci-C 6 -alkyl or CrC 6 -haloalkyl, preference is given to those wherein the chain of carbon atoms in the alkyl moiety of R 1 has at least 3 carbon atoms and is branched in the ⁇ -position, especially prop-2-yl, but-2-yl, pent-2-yl, 1 ,1 ,1-trichloroprop-2-yl and 1 ,1 ,1-trifluoroprop-2-yl, preferably but-2-yl and
  • R 1 is CrC 2 -alkyl or Ci-C 2 -haloalkyl, especially methyl, ethyl, trichloromethyl, trifluoromethyl, 1 ,1 ,1 -trich loroethy I and 1 ,1 ,1-trifluoromethyl, preferably 1 ,1 ,1 -trichloroethyl and 1 ,1 ,1-trifluoromethyl;
  • R 2 is hydrogen, or
  • R 1 , R 2 together with the nitrogen atom 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 pyrrolidinyl or 1-piperidinyl, and which is optionally substituted by one, two or three groups selected from halogen, Ci-C 4 -alkyl and Ci-C 4 -haloalkyl.
  • R 1 , R 2 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-methylpiperidine;
  • R 3 is halogen, cyano, CrC 4 -alkyl, d-C 4 -alkoxy or Ci-C 4 -haloalkyl, in particular R 3 is halogen or methyl, more preferably chlorine;
  • X is a group -CH-R 3 -, -N-R b -, -O- or -S-; particularly preferably -CH-R 3 -; and R 3 is hydrogen or d-C 3 -alkyl.
  • T is a group -CH-R 31 -;
  • R a1 is hydrogen, halogen, cyano or d-C 3 -alkyl, particularly preferably hydrogen or Ci-C 3 -alkyl; and q is 2, 3 or 4, if o is 0; or q is 1 , 2 or 3, if o is 1.
  • Z is O, S, NH, NCH 3 or NOCH 3 , and particularly preferably O or S, especially O.
  • Table 12 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro, R 3 is methyl and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 13 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro, R 3 is methyl and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 25 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,6-difluoro-4- cyano, R 3 is methyl and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 33 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,6-difluoro,4- methoxy, R 3 is methyl and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 46 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,6- chloro, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 51 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-methyl,4- fluoro, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 52 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,4- methoxycarbonyl, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 53 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,4-CN, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 58 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,4-difluoro, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 63 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,3,4-trifluoro, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 70 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,6-difluoro-4- cyano, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 81 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-methyl,4- cyano, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 82 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-methyl,4- bromo, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 83 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-methyl,5- fluoro, R 3 is chlorine and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 94 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,6- methyl, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 95 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,4,6-trifluoro, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 96 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,4,6-trifluoro, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 101 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-chloro, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 105 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-chloro-4- fflluuoi ro, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table
  • Table 114 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,4,6-trimethyl, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 115 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,4,6-trimethyl, R 3 is methoxy and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 136 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,6- chloro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 140 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,4,6-trifluoro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 141 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-methyl,4- fluoro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 147 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 150 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-chloro-4- fluoro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 151 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,3-difluoro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 156 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-methyl-4- chloro, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 160 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,6-difluoro-4- cyano, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 161 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,6-difluoro-4- methyl, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 169 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,3- methyl, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 170 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2,5-dimethyl, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • Table 177 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which L n is 2-fluoro,4- bromo, R 3 is cyano and R 1 , R 2 for each compound corresponds to one row of Table A.
  • 2-substituted pyrimidines I in particular the compounds of the formulae Ia, Ib, Ic and Ie 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 IC 50 values ⁇ 10 "6 mol/l (i.e. ⁇ 1 ⁇ M), preferably IC 50 values ⁇ 10 "7 mol/l (i.e. ⁇ 100 nM) for cell cycle inhibition in HeLa cells as determined by the test procedure outlined below.
  • substituted 2-substituted pyrimidines 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 pyrimidines 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.
  • 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 or 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.
  • RNase Buffer 10 mM NaCitrate, 0.1% Nonidet NP40, 50 ⁇ g/ml RNase, 10 ⁇ g/ml Propidium iodide
  • 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 1 the FACS Calibur:
  • the ratio of cells in G 0 /Gi-phase to G 2 /M phase is calculated and compared to the value for the controls (DMSO) only. Results are given in table 2 as the IC 5 O 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 tothe use of 2-substituted pyrimidines of the formulaI (I) or the pharmaceutically acceptable salts thereof in therapy. In formula Ithe indices and the substituents are as definedin the claims and the specification.

Description

2-Substituted pyrimidines I in therapy
Description
The present invention relates to 2-substituted pyrimidines of the formula I
Figure imgf000002_0001
z or the pharmaceutically acceptable salts thereof for use in therapy. In formula I the indices and the substituents are as defined below:
n is 1 , 2, 3, 4 or 5;
L is halogen, cyano, cyanato (OCN), Ci-Cio-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl,
Ci-C6-alkoxy, C2-Ci0-alkenyloxy, C2-Ci0-alkynyloxy, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C3-C6-cycloalkyloxy, C4-C6-cycloalkenyloxy, nitro, -C(=0)-A1,
-C(=0)-0-A1, -C(=O)-N(A2)A1, -C(=S)-N(A2)A1, -C(=NA2)-SA1, C(A2)(=N-0A1), N(A2)A1, N(A2)-C(=0)-A1, N(A3)-C(=O)-N(A2)A1, S(=O)m-A1, S(=O)m-O-A1 or S(=O)m-N(A2)A1, where
m is O, 1 or 2;
A1, A2, A3 independently of one another are hydrogen, d-C6-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 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 selected from the group consisting of O, N and S as ring members;
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 groups RL, which may be the same or different from each other: RL is halogen, cyano, Ci-Cio-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, hydroxyl, CrC6-alkoxy, C2-Ci0-alkenyloxy, C2-Ci0-alkynyloxy, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C3-C6-cycloalkoxy, C4-C6-cycloalkenyloxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, C(A5)(=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, N(A6)-C(=O)-N(A5)A4, S(=O)V-A4, S(=O)V-O-A4 or S(=O)V-N(A5)A4, it also being possible that two vicinal radicals RL together are (=0) or (=S), where
v is 0, 1 or 2;
A4, A5, 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 RL for their part may be partially or fully halogenated or may carry one, two or three radicals RLA, which may be the same or different from each other and which have the meanings of RL as defined above;
R1, R2 independently of one another are Ci-Cio-alkyl, C2-Ci0-alkenyl,
C2-Ci0-alkynyl, C3-Ci2-cycloalkyl or C4-Ci0-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 halogen, cyano, Ci-C8-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, C3-C6- cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, Ci-C6-alkoxy, C2-Ci0-alkenyloxy,
C2-Cio-alkynyloxy, C3-C6-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=0)-A7, -C(=0)-0-A7, -C(=O)-N(A8)A7, C(A8X=N-OA7), N(A8)A7, N(A8)-C(=O)-A7, N(A9)-C(=O)-N(A8)A7, S(=O)r-A7, S(=O)r-O-A7 or S(=O)r-N(A8)A7, 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, d-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, CrC6-haloalkyl, d-C6-alkoxy, cyano, nitro, -C(=0)-A, -C(=0)-0-A, -C(=O)-N(A')A, -C(A')(=N-0A) and -N(A')A; where
r is 0, 1 or 2;
A7, A8, A9, A and A' 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 Rv for their part may be partially or fully halogenated;
R2 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 comprise O. S. a carbonyl -(C=O)-, sulfoxyl -(-S[=O]-) or sulfonyl -(-SO2-) group or a further -(-N(RX)- group as a ring member, where Rx is hydrogen or d-C6-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-C6-alkyl, d-C6-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-alkoxy, C3-C4-alkenyloxy, C3-C4-alkynyloxy, Ci-C6-alkylthio, di-(Ci-C6-alkyl)amino or 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 R', which may be the same or different from each other:
R' is halogen, cyano, Ci-C8-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, hydroxyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, C2-Ci0-alkenyloxy, C2-Ci0-alkynyloxy, C4-C6-cycloalkenyl, C3-C6-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A10, -C(=O)-O-A10, -C(=O)-N(A11)A10, C(A11X=N-OA10), N(A11)A10, N(A11)-C(=O)-A10, N(A12)-C(=O)-N(A11)A10, S(=O)W-A10, S(=O)W-O-A10 or
S(=O)w-N(A11)A10, it also being possible that two vicinal radicals R' together are (=0) or (=S), where
w is 0, 1 or 2;
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 R' 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 R' as defined above;
X is a group -CH-R3-, -N-Rb-, -O- or -S-; Ra is hydrogen, halogen, d-C6-alkyl, d-C6-alkoxy, cyano or
Ci-C6-alkoxycarbonyl; Rb is hydrogen, d-C6-alkyl or C3-C6-cycloalkyl;
T is a group -CH-Ra1-;
Ra1 has, independently from one another, the meanings of Ra as defined above; q is 1 , 2, 3 or 4;
Y is a group -CH-Ra2- or -N-Rb1-; Ra2 has the meanings of Ra as defined above;
Rb1 has the meanings of Rb as defined above; o is O or i ;
Z is O, S or a group N(RC); and Rc is hydrogen, Ci-C6-alkyl or Ci-C6-alkoxy;
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 pyrimidine 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 pyrimidine of the formula I as defined herein and of their pharmaceutically acceptable salts in the manufacture of a medicament in particular a medicament for therapy or treatment of cancer or a cancerous disease. 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 pyrimidine 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. Pharmacologically active pyrimidines which may carry a piperazine or morpholine radical in the 2-position are known from EP-A 715 851.
Pyrimidines which carry an aryl, heteroaryl or a substituted amino group in the 2-position and which may be employed as anticancer agents have been described in WO 2005/030216 A1.
Furthermore, pyrimidines for use in anticancer therapy which may be substituted in the 2-position by a large variety of different substituents including unsaturated heterocyclic rings have been described in WO 2006/079556.
However, there is still a need to adapt such compounds by modification in order to increase their efficiency, to broaden or further specify their range of application and/or to minimize the side effects associated with their application.
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 pyrimidines of the formula I defined at the outset and by their pharmaceutically acceptable salts. 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 pyrimidine I as defined herein or of their pharmaceutically acceptable salts.
2-Substituted pyrimidines I have recently been described in WO 2005/113538. 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 pyrimidines I can be prepared by the methods disclosed in WO 2005/113538 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 pyrimidines 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. d-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 pyrimidines 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 pyrimidine 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 te/f-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-CrC4-alkylethers such as methyl te/f-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 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-methylpentyl, 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 CrC4-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 and haloalkynyl where the hydrogen atoms of the alkenyl and alkynyl 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- or 6-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, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 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-?-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-tιϊazinyl, 1 ,3,5-triazin-2-yl and 1 ,2,4-triazin-3-yl.
- 5- and 6-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, 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 and thiomorpholin-4-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 racemate is also within the scope of the present invention.
With regard to their activity to inhibit growth and progeny of tumor cells preference is given to 2-substituted pyrimidines I, wherein R2 is hydrogen.
Particular preference is given to 2-substituted pyrimidines I, wherein R1 and R2 independently of one another are Ci-C8-alkyl, CrC8-haloalkyl, C2-C8-alkenyl, C2-C8-haloalkenyl, C2-C8-alkynyl, C2-C8-haloalkynyl, C3-C8-cycloalkyl or
C3-C8-halocycloalkyl, more particularly Ci-C8-alkyl, Ci-C8-haloalkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C8-cycloalkyl, C3-C8-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-C6-alkyl, CrC6-haloalkyl, C3-C6-cycloalkyl, C3-C6-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, d-C6-alkyl, CrC6-haloalkyl, d-C6-alkoxy, cyano and nitro. More particular preference is given to compounds I in which R1 has one of the aforementioned meanings and R2 is hydrogen.
Very particular preference is given to 2-substituted pyrimidines I, wherein R1 is CrC6-haloalkyl, particularly CrC4-haloalkyl, e. g. 2 ,2 ,2-trif luoroethy I , 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, preferably 2,2, 2-trifluoroethyl,
2,2,2-trichloroethyl, 1 ,1 ,1 -trichloroprop-2-yl and 1 ,1 ,1 -trif I uoroprop-2-y I , more preferably 2,2, 2-trifluoroethyl and 1 ,1 ,1 -trifl uoroprop-2-yl ; C2-C6-alkenyl, particularly C2-C4-alkenyl, e. g. 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 and 2-methyl-2-propenyl, preferably 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl, more preferably 2-propenyl; or d-C6-alkyl, particularly C2-C4-alkyl, e. g. methyl, ethyl, prop-1-yl, prop-2-yl, 1-methylethyl, but-1-yl, but-2-yl, 1-methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pent-1-yl, pent-2-yl, pent-3-yl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl and 2,2-di-methylpropyl, preferably methyl, ethyl, prop-1-yl, prop-2-yl, but-1-yl, but-2-yl, pent-1-yl and pent-2-yl, more preferably but-2-yl. More particular preference is given to compounds I in which R1 has one of the aforementioned meanings and R2 is hydrogen.
Amongst 2-substituted pyrimidines I in which R1 is d-Cβ-alkyl or d-Cε-haloalkyl, preference is given to those wherein the chain of carbon atoms in the alkyl moiety of R1 has at least 3 carbon atoms and is branched in the α-position, especially prop-2-yl, but-2-yl, pent-2-yl, 1 ,1 ,1 -trichloroprop-2-yl and 1 ,1 ,1 -trifluoroprop-2-yl, preferably but-2-yl and 1 ,1 ,1 -trifluoroprop-2-yl. Preference is likewise given to 2-substituted pyrimidines I in which R1 is Ci-C2-alkyl or Ci-C2-haloalkyl, especially methyl, ethyl, trichloromethyl, trifluoromethyl, 1 ,1 ,1 -trich loroethy I and 1 ,1 ,1-trifluoromethyl, preferably 1 ,1 ,1-trichloroethyl and 1 ,1 ,1-trifluoromethyl. More particular preference is given to compounds I in which R1 has the aforementioned meanings and R2 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.
Preference is likewise given to 2-substituted pyrimidines I, wherein R1 and R2, 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-Cβ-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-C6-alkyl, d-C6-haloalkyl and oxy-d-C3-alkyleneoxy.
Particular preference is given to compounds 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 which may be interrupted by an oxygen atom and may carry one or two d-C6-alkyl, preferably d-d-alkyl substituents, e. g. methyl, ethyl, prop-1-yl, prop-2-yl and 1-methylethyl, more preferably d-C2-alkyl substituents, e. g. methyl, ethyl, especially methyl.
Amongst 2-substituted pyrimidines 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, and which is optionally substituted by one, two or three groups selected from halogen, d-C4-alkyl and d-C4-haloalkyl. Particular preference is given to the aforementioned 2-substituted pyrimidines I wherein the ring, which includes R1, R2 and the attached nitrogen atom, is methylated, in particular in the α-position, i. e. the carbon atom next to the nitrogen atom carries a methyl group, e. g. 2-methylpyrrolidine and 2-methylpiperidine. Particular preference is likewise given to the aforementioned 2-substituted pyrimidines 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-methylpiperidine.
Preferred radicals of the formula NR1R2, which are attached to the pyrimidine skeleton of the 2-substituted pyrimidines of formula I, include:
NH-C2H5, NH(CH(CHa)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(CH3)2, (R)-NHCH(CH3)(CH(CH3),), (S)-NHCH(CH3)(CH(CH3)2), NH(cyclopentyl), NHCH2CF3, NHCH(CH3)(CF3), (R)-NHCH(CH3)(CF3), (S)-NHCH(CH3)(CF3), NH-CH(CH3)CH2OCH3, NH-CH(CH3)CH2OH, NH-CH2C(CH3)=CH2, N(CH2CH3)2, N(CH3)(CH2CH=CH2), N(CH2CH3)(CH2CH=CH2), N((CH2)2CH3)(CH2CH=CH2), N(CH3)-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(CH3)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(CH3)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=CH2X -N(CN)(CH2CH=CH2X -NH-CH(CH3)CH2-OCHs, -NH-CH(CH3)CH2-C(O)-OCHS, 2-butoxycarbonyl-pyrrolidin-1-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 pyrimidines I, where the substituents L which are attached to the phenyl ring, hereinafter also referred to as substituents L1 to
L5, are selected from the group consisting of:
L halogen, in particular fluorine, chlorine, bromine, preferably fluorine, chlorine; cyano; Ci-C8-alkyl, in particular d-C6-alkyl, especially Ci-C4-alkyl, such as methyl, ethyl, propyl and butyl, preferably methyl; C2-Ci0-alkenyl, in particular C2-C6-alkenyl, especially C2-C4-alkenyl, such as ethenyl, propenyl and butenyl; C2-Ci0-alkynyl, in particular C2-C6-alkynyl, especially C2-C4-alkynyl, such as ethynyl, propynyl and butynyl; d-C6-alkoxy, in particular Ci-C4-alkoxy, preferably methoxy and ethoxy; C2-Ci0-alkenyloxy, in particular C2-C6-alkenyloxy, such as ethenyloxy; C2-Ci0-alkynyloxy, in particular C2-C6-alkynyloxy, such as ethynyloxy; nitro; -C(=0)-0-A1, in particular CrC4-alkoxycarbonyl, especially Ci-C2-alkoxycarbonyl, such as methoxycarbonyl; -C(=O)-N(A2)A1, in particular CO-NH2, Ci-C4-alkylaminocarbonyl, such as CO-NHCH3 and CO-NHC2H5, and di-(Ci-C4-alkyl)-aminocarbonyl, such as CO-N(CH3)2; -C(=S)-N(A2)A1, in particular CS-NH2, d-d-alkylaminothiocarbonyl, such as CS-NHCH3, and di-d-d-alkylaminothiocarbonyl, such as CS-N(CH3)2; C(A2)(=N-0A1), such as CH(=NOH) and CH(=NOCH3); N(A2)A1, in particular CrC4-alkylamino and di-Ci-C4-alkylamino; N(A2)-C(=0)-A1, in particular Ci-C4-alkylcarbonylamino, such as NH-C(=O)CH3, and N-(Ci-C4-alkylcarbonyl)-N-(CrC4-alkyl)-amino, such as N(CH3)-C(=O)CH3, and/or S(=0)m-A1, in particular -SH, CrC4-alkylthio, such as SCH3, and Ci-C4-alkylsulfonyl, such as SO2CH3; where
A1, A2 independently of one another are hydrogen, d-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 A1 and A2 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 CrC6-haloalkyl, especially Ci-C2-fluoroalkyl, such as trifluoromethyl.
L may be identical of different. The variable n is preferably 1 , 2 or 3.
Particular preference is given to 2-substituted pyrimidines I, wherein one or two radical(s) L is (are) attached to one (or two) of the ortho-position(s) of the phenyl ring. Moreover, particular preference is given to 2-substituted pyrimidines I, wherein n is 1 , 2 or 3.
Particular preference is furthermore given to 2-substituted pyrimidines I, wherein the substituents L are identical or different and selected from the group consisting of halogen, cyano, Ci-C8-alkyl, CrC8-haloalkyl, d-C6-alkoxy, -C(=0)-0-A1 and -C(=0)-N(A2)A1 and wherein A1 and A2 are as defined herein, and in particular hydrogen or Ci-C4-alkyl.
Particular preference is likewise given to 2-substituted pyrimidines I, wherein the phenyl ring, which is substituted by Ln, is of the formula B
Figure imgf000014_0001
in which # is the point of attachment to the pyrimidine skeleton and
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(CH3)2, CS-NH2, CS-NHCH3,
CS-N(CH3)2, NH-C(=O)CH3, N(CH3)-C(=O)CH3 or COOCH3, more preferably hydrogen, fluorine or chlorine; and L5 is hydrogen, fluorine, chlorine or CH3, more preferably fluorine or chlorine.
Preference is furthermore given to 2-substituted pyrimidines I in which R3 is halogen, cyano, Ci-C4-alkyl, d-C4-haloalkyl or Ci-C4-alkoxy, in particular chlorine, bromine, methyl, cyano, methoxy or ethoxy, especially chlorine, cyano, methyl or methoxy. Particularly preferred are compounds I in which R3 is chlorine.
Preference is furthermore given to 2-substituted pyrimidines of the formula I in which X is a group -CH-R3-, wherein Ra is hydrogen, halogen, cyano or Ci-C3-alkyl, in particular hydrogen or Ci-C3-alkyl, such as methyl or ethyl, especially methyl.
Preference is furthermore given to 2-substituted pyrimidines of the formula I in which T is a group -CH-Ra1-, wherein Ra1 is, independently from one another, hydrogen, halogen, cyano or Ci-C3-alkyl, in particular hydrogen or Ci-C3-alkyl, such as methyl or ethyl, especially hydrogen or methyl.
Preference is furthermore given to 2-substituted pyrimidines of the formula I in which Y iiss aa ggrroouupp --NN--RRbb11,, wwhheerreeiinn RRbb1 is hydrogen or Ci-C3-alkyl, such as methyl or ethyl, especially methyl; and o is 1.
Particularly preferred are likewise 2-substituted pyrimidines of the formula I in which o is O.
Preference is furthermore given to 2-substituted pyrimidines of the formula I in which Z is O, S or a group N(RC), in particular O, and Rc is hydrogen, Ci-C3-alkyl or Ci-C3-alkoxy, such as methyl, ethyl, methoxy and ethoxy, especially methyl or methoxy.
In one particularly preferred embodiment of the present invention, the 2-substituted pyrimidines of the formula I have a substituent in the 2-position wherein q is 2, 3 or 4 and o is 0. In another particularly preferred embodiment of the present invention, the 2-substituted pyrimidines of the formula I have a substituent in the 2-position wherein q is 1 , 2 or 3 and o is 1.
If q is 2, 3 or 4, particular preference is given to those compounds of formula I wherein all groups Ra1 present in the moiety T have identical meanings, e. g. hydrogen, methyl or ethyl, especially hydrogen. Furthermore, particular preference is given to those compounds of formula I wherein Ra and all groups Ra1 present in the moiety T have identical meanings, e. g. hydrogen, methyl or ethyl, especially hydrogen. Moreover, if o is 1 and if the moiety Y is a group -N-Rb1, it is particularly preferred that Rb1, Ra and all groups Ra1 have identical meanings, e. g. hydrogen, methyl or ethyl, especially hydrogen.
Very particularly preferred are 2-substituted pyrimidines of the formula I in which the substituent in the 2-position -N-[T]q-X-C(=Z)-[Y]0- is a lactam ring, i. e. o is 0 and Z is O. Among these compounds, particularly preferred are those wherein
X is a group -CH-Ra- ;
Ra is hydrogen, halogen, cyano or d-C3-alkyl, in particular hydrogen or Ci-C3-alkyl, such as methyl or ethyl, especially methyl;
T is a group -CH-Ra1- ;
Ra1 is, independently from one another, hydrogen, halogen, cyano or
Ci-C3-alkyl, in particular hydrogen or d-C3-alkyl, such as methyl or ethyl; especially Ra1 is hydrogen or methyl; and q is 1 , 2,3 or 4, in particular 2, 3 or 4.
Amongst the 2-substituted pyrimidines of the formula I in which the substituent in the 2-position -N-[T]q-X-C(=Z)-[Y]0- is a lactam ring, particular preference is given to those wherein Ra and Ra1 have identical meanings, especially hydrogen.
Very particular preference is furthermore given to 2-substituted pyrimidines of the formula I in which o is 1 and wherein the other variables of the substituent in the 2-position -N-Tq-X-C(=Z)-Y0- are as defined below:
X is a group -CH-R3-; Ra is hydrogen, halogen, cyano or d-C3-alkyl, such as methyl or ethyl, especially methyl;
T is a group -CH-Ra1-; Ra1 is, independently from one another, hydrogen, halogen, cyano or
Ci-C3-alkyl, in particular hydrogen or d-C3-alkyl, such as methyl or ethyl, especially methyl; q is 1 , 2, 3 or 4, in particular 1 , 2 or 3;
Y is a group -N-Rb1; and
Rb1 is hydrogen or Ci-C3-alkyl, such as methyl or ethyl, especially methyl.
Amongst the 2-substituted pyrimidines of the formula I mentioned directly above, more particular preference is given to those wherein Ra, Ra1 and Rb1 have identical meanings, especially hydrogen.
Very particular preference is furthermore given to 2-substituted pyrimidines of the formula I in which at least one group Ra1 of the moiety T, preferably the one adjacent to the ring nitrogen atom which is attached to the pyrimidine ring system of formula I, is Ci-C3-alkyl, preferably methyl or ethyl, especially methyl. Among the aforementioned 2-substituted pyrimidines of the formula I more particular preference is given to those wherein X is a group -CH-Ra- and Ra is hydrogen.
Very particular preference is furthermore given to 2-substituted pyrimidines of the formula I in which X is a group -CH-Ra- and Ra is Ci-C3-alkyl, preferably methyl or ethyl, especially methyl. Among the aforementioned 2-substituted pyrimidines of the formula I more particular preference is given to those wherein all groups Ra1 of the moiety T are hydrogen.
Especially preferred are 2-substituted pyrimidines of the formula I (embodiment A) where
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-C8-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, d-C6-alkoxy, C2-Cio-alkenyloxy, C2-Ci0-alkynyloxy, nitro, -C(=O)-O-A1, -C(=O)-N(A2)A1, -C(=S)-N(A2)A1, C(A2X=N-OA1), N(A2)A1, N(A2)-C(=O)-A1, or S(=O)m-A1, where
A1, A2 independently of one another are hydrogen, Ci-C6-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 d-C4-alkoxy; or A1 and A2 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 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;
R1, R2 independently of one another are Ci-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, d-Cβ-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 radicals Rv which may be the same or different from each other and which are selected from the group consisting of Ci-C6-alkyl, CrC6-haloalkyl,
C3-C6-cycloalkyl, C3-C6-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-C6-alkyl, CrC6-haloalkyl, d-C6-alkoxy, cyano and nitro;
R2 may additionally be hydrogen;
R1, 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-C6-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-C6-alkyl, d-C6-haloalkyl and oxy-d-C3-alkyleneoxy;
R3 is halogen, cyano, d-d-alkyl, d-d-alkoxy or d-d-haloalkyl;
X is a group -CH-R3-, -N-Rb-, -O- or -S-; particularly preferably -CH-R3-; and R3 is hydrogen or Ci-C3-alkyl.
Among the 2-substituted pyrimidines of embodiment A, more particular preference is given to those wherein additionally
T is a group -CH-R31-;
Ra1 is hydrogen, halogen, cyano or Ci-C3-alkyl, particularly preferably hydrogen or Ci-C3-alkyl; and q is 2, 3 or 4, if o is 0; or q is 1 , 2 or 3, if o is 1.
Among the 2-substituted pyrimidines mentioned of this embodiment, more particular preference is given to those wherein additionally
Z is O, S, NH, NCH3 or NOCH3, and particularly preferably O or S, especially O.
More preferred are 2-substituted pyrimidines of the formula I (embodiment B) where
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-C4-alkyl, CrC4-haloalkyl, d-C6-alkoxy, -C(=0)-0-A1 and -C(=0)-N(A2)A1 and wherein A1 and A2 are as defined herein, and in particular hydrogen or Ci-C4-alkyl; L is more preferably chlorine, fluorine, CH3 or CF3;
R1 is Ci-C6-alkyl or CrC6-haloalkyl, preference is given to those wherein the chain of carbon atoms in the alkyl moiety of R1 has at least 3 carbon atoms and is branched in the α-position, especially prop-2-yl, but-2-yl, pent-2-yl, 1 ,1 ,1-trichloroprop-2-yl and 1 ,1 ,1-trifluoroprop-2-yl, preferably but-2-yl and
1 ,1 ,1-trifluoroprop-2-yl. Preference is likewise given to 2-substituted pyrimidines I in which R1 is CrC2-alkyl or Ci-C2-haloalkyl, especially methyl, ethyl, trichloromethyl, trifluoromethyl, 1 ,1 ,1 -trich loroethy I and 1 ,1 ,1-trifluoromethyl, preferably 1 ,1 ,1 -trichloroethyl and 1 ,1 ,1-trifluoromethyl;
R2 is hydrogen, or
R1, R2 together with the nitrogen atom 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 pyrrolidinyl or 1-piperidinyl, and which is optionally substituted by one, two or three groups selected from halogen, Ci-C4-alkyl and Ci-C4-haloalkyl. Amongst these compounds preference is given to those, wherein the five- or six-membered ring in the α-position, i. e. the carbon atom next to the nitrogen atom, carries a methyl group, such as in. 2-methylpyrrolidine and 2-methylpiperidine. Particular preference is likewise given to the aforementioned 2-substituted pyrimidines 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-methylpiperidine; R3 is halogen, cyano, CrC4-alkyl, d-C4-alkoxy or Ci-C4-haloalkyl, in particular R3 is halogen or methyl, more preferably chlorine;
X is a group -CH-R3-, -N-Rb-, -O- or -S-; particularly preferably -CH-R3-; and R3 is hydrogen or d-C3-alkyl.
Among the 2-substituted pyrimidines of embodiment B, more particular preference is given to those wherein additionally
T is a group -CH-R31-;
Ra1 is hydrogen, halogen, cyano or d-C3-alkyl, particularly preferably hydrogen or Ci-C3-alkyl; and q is 2, 3 or 4, if o is 0; or q is 1 , 2 or 3, if o is 1.
Among the 2-substituted pyrimidines mentioned of this embodiment, more particular preference is given to those wherein additionally
Z is O, S, NH, NCH3 or NOCH3, and particularly preferably O or S, especially O.
In particular with a view to their use as anticancer agents, preference is given to the compounds I which are described by one of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii, wherein L, n, R1, R2 and R3 are as defined herein and wherein at least one of the variables, in particular all of the variables L, n, R1, R2 and R3 have the preferred or particularly preferred meanings, in particular the meanings given in embodiments A and B. Preferred examples for these compounds are given in the following tables 1 to 180. 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 imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
Table 1
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- chloro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 2
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A. Table 3
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dichloro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 4
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 5
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trifluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 6 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- fluoro, R3 is methyl and R1, R2for each compound corresponds to one row of Table A.
Table 7
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxycarbonyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 8
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4-CN, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 9
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,5-trifluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 10
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dichloro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 11
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 12 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A. Table 13
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-difluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 14
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- chloro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 15
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro-4- fluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 16 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3-difluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 17
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-difluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 18
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3,4-trifluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 19
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 20
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dimethyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 21 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl-4- chloro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 22
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A. Table 23
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dimethyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 24
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trimethyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 25 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- cyano, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 26
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 27
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methoxycarbonyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 28
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxy, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 29
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 30
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxycarbonyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 31
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- bromo, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 32 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- cyano, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 33 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro,4- methoxy, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 34 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,3- methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 35
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl, R3 is methyl and R1 , R2 for each compound corresponds to one row of Table A.
Table 36
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- cyano, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 37
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- bromo, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 38
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,5- fluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 39 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxy, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 40 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxycarbonyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 41 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl,4- bromo, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A. Table 42
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- bromo, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 43
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxy, R2 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 44
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,5- methyl, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 45
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is pentafluoro, R3 is methyl and R1, R2 for each compound corresponds to one row of Table A.
Table 46 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- chloro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 47 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 48
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dichloro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 49
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- methyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 50
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trifluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 51 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- fluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 52 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxycarbonyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 53 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4-CN, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 54
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,5-trifluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 55
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dichloro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 56
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 57
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 58 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-difluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 59
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- chloro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 60
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro-4- fluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A. Table 61
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3-difluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 62
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-difluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 63 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3,4-trifluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 64
Compoun iddss o of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 65
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dimethyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 66
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl-4- chloro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table
A.
Table 67
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- methyl, R2 is chlorine and R1, R2 for each compound corresponds to one row of Table
A.
Table 68
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dimethyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 69
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trimethyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 70 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- cyano, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 71
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 72
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methoxycarbonyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 73
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxy, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 74
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 75
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxycarbonyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 76
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- bromo, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 77
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- cyano, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 78 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro,4- mmeethoxy, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table
A.
Table 79
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,3- methyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 80
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 81 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- cyano, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 82 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- bromo, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 83 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,5- fluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 84
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxy, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 85
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxycarbonyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 86
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl, 4- bromo, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A. Table 87
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- bromo, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 88
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxy, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 89
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,5- methyl, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 90
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is pentafluoro, R3 is chlorine and R1, R2 for each compound corresponds to one row of Table A.
Table 91
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- chloro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table
A.
Table 92
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 93
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dichloro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 94 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 95 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trifluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A. Table 96
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- fluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 97
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxycarbonyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 98
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4-CN, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 99
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,5-trifluoro,
R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 100
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dichloro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 101 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 102
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 103
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-difluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 104
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- chloro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table
A.
Table 105 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro-4- fflluuoi ro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table
A.
Table 106
Compound Iss ooff V thre formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3-difluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 107
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-diflι is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 108
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3,4-trifluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 109
Compound Iss ooff the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 110
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dimethyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 11 1
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl-4- chloro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 112
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 113
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dimethyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 114 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trimethyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A. Table 115
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- cyano, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 116
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 117
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methoxycarbonyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 118
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxy, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 119
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 120
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxycarbonyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 121
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxy, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 122
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- cyano, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A. Table 123
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro,4- methoxy, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 124
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,3- methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 125
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 126
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- cyano, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 127
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- bromo, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 128
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,5- fluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 129
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxy, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 130
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxycarbonyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 131 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl,4- bbrrcomo, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table
A.
Table 132
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- bromo, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 133
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxy, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 134
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,5- methyl, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 135
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is pentafluoro, R3 is methoxy and R1, R2 for each compound corresponds to one row of Table A.
Table 136 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- chloro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 137
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 138
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dichloro, R is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 139
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,6- methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 140 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trifluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 141 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- fluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 142
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxycarbonyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 143
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4-CN, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 144
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,5-trifluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 145
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dichloro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 146
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 147 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 148
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-difluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 149
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- chloro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 150 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro-4- fluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 151 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3-difluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 152
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-difluoro, R3 is cyano and R1 , R2 for each compound corresponds to one row of Table A.
Table 153
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,3,4-trifluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 154
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 155
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4-dimethyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 156 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl-4- chloro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 157
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro-4- methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 158
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-dimethyl, R is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 159
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,4,6-trimethyl,
R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 160 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- cyano, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 161 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 162
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro-4- methoxycarbonyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 163
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxy, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 164
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 165
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- methoxycarbonyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 166
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- bromo, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 167
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-chloro,4- cyano, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 168
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,6-difluoro,4- methoxy, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 169 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,3- methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 170 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 171
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- cyano, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 172
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- bromo, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 173
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,5- fluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 174
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxy, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 175
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-methyl,4- methoxycarbonyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 176
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2,5-dimethyl, 4- bromo, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 177 Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- bromo, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 178
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,4- methoxy, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A. Table 179
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is 2-fluoro,5- methyl, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table 180
Compounds of the formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii in which Ln is pentafluoro, R3 is cyano and R1, R2 for each compound corresponds to one row of Table A.
Table A
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
The 2-substituted pyrimidines I, in particular the compounds of the formulae Ia, Ib, Ic and Ie 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, substituted 2-substituted pyrimidines 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 pyrimidines 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 or 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-27 given in table B were prepared according to the methods describes in WO2005/113538. They are representative compounds of this invention which are useful as anticancer agents. In table B the compounds are defined by formula I-A, wherein for the respective example HET, R1, R2, and (L)n are given in the rows of table B.
Figure imgf000045_0001
Table B: Compounds of the general formula I-A
Figure imgf000045_0002
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_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 1 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 Hn
Fl 3
FI 2 - A — l CN 1 Hn
Fl 2 - W — 3 Hn
DDM Parameter Fl 2
The ratio of cells in G0/Gi-phase to G2/M phase is calculated and compared to the value for the controls (DMSO) only. Results are given in table 2 as the IC5O 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.
Figure imgf000049_0001

Claims

We claim:
1. 2-substituted pyrimidine compounds of the formula I and their pharmaceutically acceptable salts for use in therapy:
Figure imgf000050_0001
in which the indices and the substituents are as defined below:
n is 1 , 2, 3, 4 or 5;
L is halogen, cyano, cyanato (OCN), Ci-Cio-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, d-C6-alkoxy, C2-Ci0-alkenyloxy, C2-Ci0-alkynyloxy, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C3-C6-cycloalkyloxy, C4-C6-cycloalkenyloxy, nitro, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1,
-C(=S)-N(A2)A1, -C(=NA2)-SA1, C(A2)(=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 or S(=O)m-N(A2)A1, where
m is 0, 1 or 2;
A1, A2, A3 independently of one another are hydrogen, Ci-Cβ-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 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 selected from the group consisting of O, N and S as ring members;
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 halogen, cyano, Ci-Cio-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, hydroxyl, CrC6-alkoxy, C2-Ci0-alkenyloxy, C2-Ci0-alkynyloxy, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C3-C6-cycloalkoxy, C4-C6-cycloalkenyloxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, C(A5)(=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, N(A6)-C(=O)-N(A5)A4,
S(=O)V-A4, S(=O)V-O-A4 or S(=O)V-N(A5)A4, it also being possible that two vicinal radicals RL together are (=0) or (=S), where
v is O, 1 or 2;
A4, A5, 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 RL for their part may be partially or fully halogenated or may carry one, two or three radicals RLA, which may be the same or different from each other and which have the meanings of RL as defined above;
R1, R2 independently of one another are Ci-Cio-alkyl, C2-Ci0-alkenyl,
C2-Ci0-alkynyl, C3-Ci2-cycloalkyl or C4-Ci0-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 halogen, cyano, Ci-C8-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, Ci-C6-alkoxy, C2-Cio-alkenyloxy, C2-Ci0-alkynyloxy, C3-C6-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=0)-A7, -C(=0)-0-A7, -C(=O)-N(A8)A7, C(A8X=N-OA7), N(A8)A7, N(A8)-C(=O)-A7, N(A9)-C(=O)-N(A8)A7,
S(=O)r-A7, S(=O)r-O-A7 or S(=O)r-N(A8)A7, 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, d-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C3-C6-cycloalkyl, CrC6-haloalkyl, d-C6-alkoxy, cyano, nitro, -C(=0)-A, -C(=0)-0-A, -C(=O)-N(A')A, -C(A)(=N-OA) and -N(A')A; where
r is O, 1 or 2; A7, A8, A9, A and A' 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 Rv for their part may be partially or fully halogenated;
R2 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 comprise O, S, a carbonyl -(C=O)-, sulfoxyl
-(-S[=O]-), a sulfonyl -(-SO2-) group or a further (-N(RX)- group as ring member, where Rx is hydrogen or d-C6-alkyl, and/or where the ring formed may comprise one or more substituents selected from the group consisting of halogen, d-C6-alkyl, d-C6-haloalkyl and oxy-Ci-C3-alkyleneoxy;
R3 is halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl,
C3-C6-cycloalkyl, Ci-C4-alkoxy, C3-C4-alkenyloxy, C3-C4-alkynyloxy, C-i-Cβ-alkylthio, di-(C-i-C6-alkyl)amino or Ci-C6-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 R', which may be the same or different from each other:
R' is halogen, cyano, Ci-C8-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, hydroxyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, C2-Ci0-alkenyloxy,
C2-Cio-alkynyloxy, C4-C6-cycloalkenyl, C3-C6-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A10, -C(=O)-O-A10, -C(=O)-N(A11)A10, C(A11X=N-OA10), N(A11)A10, N(A11)-C(=O)-A10, N(A12)-C(=O)-N(A11)A10, S(=O)W-A10, S(=O)W-O-A10 or S(=O)w-N(A11)A10, it also being possible that two vicinal radicals R' together are (=0) or (=S), where
w is 0, 1 or 2;
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 R' 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 R' as defined above;
X is a group -CH-R3-, -N-Rb-, -O- or -S-; Ra is hydrogen, halogen, d-C6-alkyl, d-C6-alkoxy, cyano or
Ci-C6-alkoxycarbonyl; Rb is hydrogen, d-C6-alkyl or C3-C6-cycloalkyl;
T is a group -CH-Ra1-; Ra1 has, independently from one another, the meanings of Ra as defined above; q is 1 , 2, 3 or 4;
Y is a group -CH-Ra2- or -N-Rb1-; Ra2 has the meanings of Ra as defined above;
Rb1 has the meanings of Rb as defined above; o is O or i ;
Z is O, S or a group N(RC); and Rc is hydrogen, CrC6-alkyl or CrC6-alkoxy.
2. The compounds according to claim 1 where
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-C8-alkyl, C2-Ci0-alkenyl, C2-Ci0-alkynyl, d-C6-alkoxy, C2-do-alkenyloxy, C2-do-alkynyloxy, nitro, -C(=0)-0-A1, -C(=O)-N(A2)A1, -C(=S)-N(A2)A1, C(A2)(=N-0A1), N(A2)A1, N(A2)-C(=0)-A1, and S(=O)m-A1, where
A1, A2 independently of one another are hydrogen, d-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 d-d-alkoxy; or A1 and A2 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 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.
3. The compounds according to any of claims 1 or 2, where
R1, R2 independently of one another are Ci-C8-alkyl, C2-C8-alkenyl,
C2-C8-alkynyl, CrC8-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 radicals Rv which may be the same or different from each other and which are selected from the group consisting of Ci-C6-alkyl, CrC6-haloalkyl, C3-C6-cycloalkyl, C3-C6-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-C6-alkyl, CrC6-haloalkyl, d-C6-alkoxy, cyano and nitro;
R2 may additionally be hydrogen;
R1, 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 comprise O or a further amino -(-N(RX)- group as ring members, 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-C6-alkyl, d-C6-haloalkyl and oxy-d-Cs-alkyleneoxy.
4. The compounds according to any of the preceding claims where
R3 is halogen, cyano, d-d-alkyl, d-d-alkoxy or d-d-haloalkyl.
5. The compounds according to any of the preceding claims where X is a group -CH-R3-;
Ra is hydrogen or d-C3-alkyl; q is 2, 3 or 4; and o is 0.
6. The compounds according to any of claims 1 to 4 where X is a group -CH-R3-;
Ra is hydrogen, halogen, cyano or Ci-C3-alkyl; Y is a group -N-Rb1;
Rb1 is hydrogen or Ci-C3-alkyl; q is 1 , 2 or 3; and o is 1.
7. The compounds according to claim 5 or 6 where Ra, Ra1 and, if appropriate, Rb1 have the same meaning.
8. The compounds according to any of claims 1 to 7 in which the phenyl group substituted by Ln is defined by the formula B:
Figure imgf000055_0001
where # is the point of attachment to the pyrimidine skeleton and where
L1 is fluorine, chlorine, CH3 or CF3;
L2, L4 independently of one another are hydrogen, CH3 or fluorine;
L3 is hydrogen, fluorine, chlorine, bromine, cyano, nitro, CH3, SCH3, OCH3, SO2CH3, CO-NH2, CO-NHCH3, CO-NHC2H5, CO-N(CH3)2, CS-NH2,
CS-NHCH3, CS-N(CH3)2, NH-C(=O)CH3, N(CH3)-C(=O)CH3 or COOCH3; and L5 is hydrogen, fluorine, chlorine or CH3.
9. 2-substituted pyrimidine compounds of the formula I as defined in any of claims 1 to 8 and their pharmaceutically acceptable salts for use in therapy of cancer.
10. A pharmaceutical composition comprising a 2-substituted pyrimidine compound of the formula I as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
1 1. The use of 2-substituted pyrimidine compounds of the formula I as defined in any of claims 1 to 8 and their pharmaceutically acceptable salt in therapy of a disease.
12. The use according to claim 11 , wherein the disease is cancer.
13. The use of a 2-substituted pyrimidine compound of the formula I as defined in any of claims 1 to 8 and of their pharmaceutically acceptable salts in the manufacture of a medicament.
14. The use according to claim 13, where the medicament is for the treatment of cancer.
15. The use of a 2-substituted pyrimidine compound of the formula I as defined in any of claims 1 to 8 and of their pharmaceutically acceptable salts for the treatment of cancer in animals, in particular humans.
16. 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 pyrimidine compound of the formula I as defined in any of claims 1 to 8 or of their pharmaceutically acceptable salts.
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