2-substituted Pyrimidines I In Therapy

  • Published: Jul 17, 2008
  • Earliest Priority: Jan 11 2007
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2-Substituted pyrimidines I in therapy

Description

The present invention relates to 2-substituted pyrimidines of the formula I

in which the indices and the substituents are as defined below:

R1 is C2-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Ci2-cycloalkyl, C4-Ci o- cycloalkenyl, phenyl or a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which is attached via carbon and which contains one, two, three or four heteroatoms selected from the group consisting of O, N and S; where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of R1 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Rv, which may be the same or different from each other:

Rv is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Cβ- cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1, 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, it also being possible that two vicinal radicals Rv together are (=0), (=S) or (=N-OA1), or Rv is phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl,

C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, d-Ce-haloalkyl, Ci-C6- alkoxy, cyano, nitro, -C(=O)-A, C(=O)-O-A, -C(=O)-N(A')A, C(A')(=N-OA) and N(A)A; where

m is O, 1 or 2;

A1, A2, A3, A and A' independently of one another are hydrogen, C-i-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, or A and A', respectively, together with the atoms to which they are attached are a five- or six- membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms selected from the group consisting of O, N and S;

and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Rv for their part may be partially or fully halogenated;

R2 is halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cs-Cβ-cycloalkyl, Ci-C4-alkoxy, C3-C4-alkenyloxy, C3-C4-alkynyloxy, d-Cε-alkylthio, di-(Ci-C6- alkyl)amino or Ci-Cβ-alkylamino, where the aliphatic and/or alicyclic groups of the radical definitions of R2 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Ru, which may be the same or different from each other:

Ru is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl,

C-i-Cβ-alkoxy, Cs-Cβ-cycloalkyl, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, C4-C6- cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A4, -C(=O)-O-A4, -C(=O)-N(A5)A4, C(A5X=N-OA4), N(A5)A4, N(A5)-C(=O)-A4, N(A6)-C(=O)-N(A5)A4, S(=O)q-A4, S(=O)q-O-A4 or S(=O)q-N(A5)A4, it also being possible that two vicinal radicals Ru together are (=0) or (=S), where

q is O, 1 or 2;

A4, A5 and A6 independently of one another have the meanings of A1, A2 and A3 as defined above;

and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Ru for their part may be partially or fully halogenated or may carry one, two or three radicals Rua, which may be the same or different from each other and which have the meanings of Ru as defined above;

R3 is selected from the group consisting of cyano, C(=Z)ORa, C(=Z)NRzRb, C(=Z)NRz-ORa, C(=Z)NRa-NRzRb, C(=Z)Ra, ON(=CRaRb), O-C(=Z)Ra, NRa(C(=Z)Rb), NRa(C(=Z)ORb), NRa(C(=Z)-NRzRb), NRa(N=CRcRb), NRa-NRzRb, NRz-ORa, and the radicals of the formulae R3a and R3b

wherein

Z is O, S, NRa1, NORa1 or N-NRz1Rc1;

Ra, Ra1, Rb, Rc, Rc1 independently of one another are hydrogen, Ci-Cβ- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cβ-cycloalkyl or C4-C6-cycloalkenyl;

Rb1 has the meanings of Rb as defined above, except for hydrogen; and Rz, Rz1 independently of one another have the meanings of Ra as defined above and may additionally be -CO-Ra2, where Ra2 has the meanings of Ra as defined above;

where the aliphatic and/or alicyclic groups of the radical definitions of Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz and Rz1 for their part may be partially or fully halogenated or may carry one, two, three or four groups R1, which may be the same or different from each other:

R1 is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, Cs-Cβ-cycloalkenyl,

C3-C6-cycloalkoxy or Cs-Cβ-cycloalkenyloxy,

and where two of the radicals Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz or Rz1 together with the atoms, to which they are attached, may form a five-, six- or seven-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;

and where # in the formulae R3a and R3b indicates the atom which is bond to the 2-position of the pyrimidine ring

x is O or i ;

Re, Rf, R9, Re# independently of one another are hydrogen, d-Cε-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl,

Rf, Ra together with the nitrogen atom to which they are attached may have the meaning Re-Z-C(Rh)=N;

Q is oxygen or N-Re#;

Q' is C(H)-Rk, C-Rk , N-N(H)-Re# or N-Re#; 1^- may be a double bond or a single bond;

Rh, Rk have the same meanings as Re and may additionally be halogen or cyano; or

Rh together with the carbon to which it is attached may be a carbonyl group;

where the aliphatic, alicyclic or aromatic groups of the radical definitions of Re, Re#, Rf, R9, Rh or Rk for their part may be partially or fully halogenated or may carry one to four groups Rw, which may be the same or different from each other:

Rw is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C3-C6-cycloalkenyl, Cs-Cβ-cycloalkoxy, Cs-Cβ-cycloalkenyloxy, and where two of the radicals Rf, Rs, Re or Re# together with the atoms to which they are attached may form a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S.

n is 1 , 2, 3, 4 or 5;

L is halogen, cyano, cyanato (OCN), Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6- cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, nitro, -C(=O)-A10, -C(=O)-O-A10, -C(=O)-N(A11)A10, -C(=S)-N(A11)A10, -C(=NA11)-SA10,

-C(A11)(=N-OA10), -N(A11)A10, -N(A11)-C(=O)-A10, -N(A12)-C(=O)-N(A11)A10, -S(=O)p-A10, -S(=O)p-O-A10 or -S(=O)p-N(A11)A10, where

p is 0, 1 or 2;

A10, A11, A12 independently of one another have the meanings of A1, A2 and A3 as defined above;

where L may be identical or different from each other and 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-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6- cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A13, -C(=O)-O-A13, -C(=O)-N(A14)A13, C(A14X=N-OA13), N(A14)A13, N(A14)-C(=O)-A13, N(A15)-C(=O)-N(A14)A13, S(=O)S-A13, S(=O)S-O-A13 or S(=O)s-N(A14)A13; it also being possible that two vicinal radicals RL together are (=0) or (=S), where

s is 0, 1 or 2; and

A13, A14 and A15 independently of one another have the meanings of A1, A2 and A3 as defined above;

and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of RL for their part may be partially or fully halogenated or may carry one, two, three or four groups RLA, which may be the same or different from each other and which have the meanings of RL as defined above;

and the pharmaceutically acceptable salts of the 2-substituted pyrimidines of formula I for use in therapy, i.e. in the therapy of a disease in an animal being in particular a humen being, in particular in therapy or treatment of cancer or a cancerous diseases, 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, respectively. The invention also provides a method for cancer treatment, which comprises administering to the subject in need thereof an effective amount of a 2-substituted 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. EP-A 715 851 discribes pharmacologically active 5-phenylpyrimidines which may carry, among other substituents, a piperazine or morpholine radical or an amino group which is mono- or disubstituted by alkyl and/or aryl in the 2-position, and which, among other radicals may carry an alkyl radical or certain substituted alkyl radicals in the 4-position

WO 2005/030216 describes pharmacologically active 5-phenylpyrimidines which carry an aryl, heteroaryl or a substituted amino group in the 2-position and a secondary amino group or cycloalkyl group in the 4-position. The compounds are mentioned to be usefull as anticancer agents.

Furthermore, WO 2006/079556 teaches 5-phenylpyrimidines which carry a substituted amino or alkoxy radical in the 4-postion and further radicals in the 2- and 6-positions of the pyrimidine ring to be useful in anticancer therapy.

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 accociated 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 I defined at the outset. Furthermore, we have found a method for treating cancer, which comprises administering to the subject in need thereof an effective amount of a 2-substituted pyrimidine I as defined herein or of their pharmaceutically acceptable salts.

2-Substituted pyrimidines of the formula I have been described in WO 2004/087678. The compounds disclosed therein are active against various phytopathogenic fungi. However, these documents do 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 2004/087678 as well as by analogy to the methods described in WO 2004/103978 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. Ci-C4-alkylsulfonic acids such as methanesulfonic acid, cycloaliphatic sulfonic acids such as S-(+)-10-camphorsulfonic acids and aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having from 2 to 10 carbon atoms such as oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lactic acid, tartaric acid, citric acid, glycolic acid and adipic acid, as well as cis- and trans- cinnamic acid, furoic acid and benzoic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in Drug Research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966. The physiologically tolerated salts of 2-substituted 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 tert-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate. Solvents, wherein the acid addition salt of I is insoluble (anti-solvents), might be added to precipitate the salt. Suitable anti-solvents comprise C1-C4- alkylesters of Ci-C4-aliphatic acids such as ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc., di-Ci-C4-alkylethers such as methyl tert-butyl ether or diisopropyl ether.

In the symbol definitions given in formula I above, collective terms were used which generally represent the following substituents:

- halogen: fluorine, chlorine, bromine or iodine, in particular chlorine or fluorine;

- alkyl and the alkyl moieties of alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylamino, di(alkyl)amino, alkylaminocarbonyl, di(alkyl)amincarbonyl, alkylcarbonylamino, alkylsulfinyl, alkylsulfonyl, alkylaminosulfonyl or di(alkyl)aminosulfonyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 10, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-di-methylpropyl, 1-ethylpropyl, hexyl, 1 ,1-dimethylpropyl,

1 ,2-dimethylpropyl, 1-methylpentyl, 2-methyl pentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;

- alkenyl and the alkenyl moieties of alkenyloxy: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 10, preferably 2 to 6, and in particular 2 to 4 carbon atoms, and a double bond in any position, especially C3-C4-alkenyl, for example ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,

1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1 ,1-dimethyl-2-propenyl, 1 ,2-dimethyl-1-propenyl, 1 ,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1 ,1-dimethyl-2-butenyl, 1 ,1-dimethyl-3-butenyl, 1 ,2-dimethyl-1-butenyl, 1 ,2-dimethyl-2-butenyl, 1 ,2-dimethyl-3-butenyl, 1 ,3-dimethyl-1-butenyl, 1 ,3-dimethyl-2-butenyl, 1 ,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1 ,1 ,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;

- alkadienyl: unsaturated straight-chain or branched hydrocarbon radicals having 4 to 8, in particular 4 to 6 carbon atoms and two double bonds in any position, for example butadiene, 1 ,3-pentadiene, 1 ,4-pentadiene, 1 ,3-hexadiene, 1 ,4-hexadiene and 1 ,5-hexadiene;

- alkynyl: straight-chain or branched hydrocarbon radicals having 2 to 10, preferably 2 to 6, in particular 2 to 4 carbon atoms, and a triple bond in any position, especially C3-C4-alkynyl, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1 ,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1 ,1-dimethyl-2-butynyl,

1 ,1-dimethyl-3-butynyl, 1 ,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1 -ethyl-1 -methyl-2-propynyl;

- cycloalkyl: mono- or bicyclic hydrocarbon radicals having 3 to 10 carbon atoms; monocyclic groups having 3 to 8, especially 3 to 6 ring members, for example C3-C8-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;

- haloalkyl and the haloalkyl moieties of haloalkoxy: straight-chain or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms (as mentioned above), where the hydrogen atoms in these groups may be partially or fully replaced by halogen atoms as mentioned above, for example Ci-C4-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl,

2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1 ,1 ,1-trichloroprop-1-yl, 1 ,1 ,1-trifluoroprop-1-yl, 1 ,1 ,1 -trichloroprop-2-yl and 1 ,1 ,1-trifluoroprop-2-yl; similar considerations apply to other halogenated groups such as haloalkenyl, haloalkynyl and halocycloalkyl where the hydrogen atoms of the alkenyl, alkynyl and cycloalkyl groups may be partially or fully replaced by halogen atoms as mentioned above;

- oxy-alkyleneoxy: divalent straight-chain hydrocarbon radicals having 2 to 3 carbon atoms, e.g. OCH2CH2O or OCH2CH2CH2O;

- 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle: homo- or bicyclic hydrocarbon radicals containing one to four heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; unsaturated (heterocyclyl) includes partially unsaturated, e.g. mono-unsaturated, and aromatic (heteroaryl); said heterocycles in particular include:

- 5-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, for example 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, thiophenyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,3-triazol-1 -yl, 1 ,2,4-triazol-1 -yl, 1 ,2,4-triazol-3-yl, tetrazolyl, 1 ,3,4-oxadiazol-2-yl, 1 ,3,4-thiadiazol-2-yl and 1 ,3,4-triazol-2-yl;

- 6-membered heteroaryl, containing one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain one to three or one to four nitrogen atoms as ring members, for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyτidazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazin-2-yl and 1 ,2,4-triazin-3-yl.

- 9- or 10-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 9- or 10-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, in particular benzo-fused 5- or 6-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom (i. e. 5- or 6-membered heteroaryl groups which, in addition to carbon atoms, contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1 ,3-dien-1 ,4-diyl group), for example benzothiazol-2-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 H-indazol-1-yl, 1 H-indazol-2-yl, benzofuran- 2-yl and benzofuran-3-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, phthalazinyl, quinoxalinyl, quinazolin-2-yl, quinazolin-4-yl, cinnolin-3-yl and cinnolin-4-yl.

- 5-, 6- and 7-membered heterocyclyl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 3-pyrazolidinyl, 4-pyrazolidinyl,

5-pyrazolidinyl, 2-pyrrolidin-2-yl, 2-pyrrolidin-3-yl, 3-pyrrolidin-2-yl, 3-pyrrolidin-3-yl, pyrrolidon-1-yl, pyrrolidin-2-thion-1-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, pyridin(1 ,2-dihydro)-2-on-1-yl, 2-piperazinyl, 1-pyrimidinyl, 2-pyrimidinyl, morpholin-4-yl, thiomorpholin-4-yl, dihydrothiazol-2-yl, piperidin-2-on-1-yl, piperidin-2-thion-1-yl, dihydropyridinyl, hexahydroazepin-1-yl and hexahydroazepin-2-thion-1 -yl.

The scope of the present invention includes the (R) and (S) isomers of the formula I having chiral centers. Thus, it is to be understood that any mixture of the (R) and (S) isomer compounds in any ratio including the racemates is also within the scope of the present invention.

With regard to their activity to inhibit growth and progeny of tumor cells preference is given to 2-substituted pyrimidines I, wherein R1 is different from C3-Cio-cycloalkyl or C3-Cio-cycloalkenyl. In particular R1 is C2-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, where the aliphatic groups of the radical definitions of R1 for their part may be unsubstituted, 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 as defined above and preferably selected from halogen, cyano, Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, hydroxyl (= OH), d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1, 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 and S(=O)m-N(A2)A1, it also being possible that two vicinal radicals Rv together are (=0), (=S) or (=N-OA1).

Particular preference is given to 2-substituted pyrimidines I wherein R1 is C2-C8-alkyl, C2-C8-haloalkyl, C2-C8-alkenyl, C2-C8-haloalkenyl, C2-Cs-alkynyl or C2-C8-haloalkynyl, more particularly d-Cs-alkyl, Ci-Cs-haloalkyl, d-Cs-alkenyl or C2-C8-haloalkenyl, where the aliphatic groups may carry one or two, especially one radical(s) Rv which may be the same or different from each other and which are preferably selected from the group consisting of Ci-Cβ-alkyl, d-drhaloalkyl, hydroxyl, Ci-Cβ-alkoxy, C3-C6- cycloalkyl, d.-drhalocycloalkyl, 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-Cβ-alkyl, d-Cβ- haloalkyl, d-Cβ-alkoxy, cyano and nitro. In particular, the radicals Rv, if present, are selected from the group consisting of hydroxyl and d-Cβ-alkoxy, preferably hydroxyl and d-d-alkoxy such as methoxy, ethoxy, propoxy and butoxy.

A preferred embodiment of the invention relates to 2-substituted pyrimidines I, wherein R1 is linear C2-C8-alkyl or C2-C8-haloalkyl, i.e. n-C2-C8-alkyl or n-C2-C8-haloalkyl, preferably n-C2-C6-alkyl and more preferably n-C2-d-alkyl, i. e. where the chain of carbon atoms of the alkyl radical is not branched but linear, e. g. ethyl, n-propyl and n-butyl, particularly methyl and ethyl.

A more preferred embodiment of the invention relates to 2-substituted pyrimidines I wherein R1 is d-Cs-alkyl or d-Cs-haloalkyl, preferably d-Cβ-alkyl, which in each case is branched but preferably not branched in the α-position (e. g. branched in the β- or γ-position), and which is unsubstituted or may carry one or two, especially one radical Rv selected from the group consisting of hydroxyl and d-d-alkoxy such as methoxy or ethoxy, e. g. (2-methyl)-but-1-yl, (3-methyl)-but-1-yl, (2,2-dimethyl)-but-1-yl, (2,3-dimethyl)-but-1 -yl, (3,3-dimethyl)-but-1 -yl, 2-hydroxy-(3-methyl)-but-1 -yl, 3-hydroxy-(3-methyl)-but-1 -yl, 4-hydroxy-(3-methyl)-but-1 -yl, 2-hydroxy-(2-methyl)-but-1 -yl, 3-hydroxy-(2-methyl)-but-1 -yl, 4-hydroxy-(2-methyl)-but-1-yl and (2-methyl)-prop-1-yl, more preferably (2-methyl)-but-1 -yl, 2-hydroxy-(3-methyl)-but-1 -yl and (2-methyl)-prop-1 -yl.

Another preferred embodiment of the invention relates to 2-substituted pyrimidines I wherein R1 is d-Cs-alkenyl or d-Cs-haloalkenyl, preferably d-Cs-alkenyl, e. g. but-1-en-4-yl (= but-3-en-1-yl), but-2-en-1-yl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 2-methyl-but-2-en-1-yl and 3-methyl-but-2-en-1-yl, more preferably but-1-en-4-yl and 3-methyl-but-1 -enyl. If R1 is branched or carries a halogen atom or a subsitutend Rv, R1 may have a center of chirality. If R1 carries a halogen atom creating 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, preference is given to the (R)-configured isomers.

Another preferred embodiment of the invention relates to 2-substituted pyrimidines I, wherein R1 is a saturated, partially unsaturated or aromatic, preferably saturated five- or six-membered carbocycle, i.e. C3-Ci2-cycloalkyl, C3-Cio-cycloalkenyl or phenyl, or a C-bound heterocycle which may carry an oxygen atom (-O-), an imino nitrogen (=N-) or an amino -(-N(RX)- group as ring member, where Rx is hydrogen or d-Cε-alkyl, and/or where the ring formed may carry one or more, e. g. 1 , 2, 3 or 4, preferably 1 substituent(s) from the group consisting of halogen, d-Cε-alkyl, d-Cε-haloalkyl and oxy-Ci-C3-alkyleneoxy, in particular halogen, d-Cε-alkyl and C-i-Cε-haloalkyl. Amongst these, particular preference is given to compounds I, wherein R1 is a saturated or unsaturated, preferably saturated five- or six-membered C-bound heterocycle which carries an oxygen atom or a nitrogen atom or an amino -(-N(RX)- group as ring member, examples including tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl, e. g. pyrrolidin-2-yl and piperidin-2-yl, and which may carry one or two Ci-Cβ-alkyl, preferably Ci-C4-alkyl substituents, e. g. methyl, ethyl, prop-1-yl and prop- 2-yl, more preferably Ci-C2-alkyl substituents, e. g. methyl, ethyl, especially methyl. Very particular preference is given to the aforementioned 2-substituted pyrimidines I wherein the heterocycle which includes R1 is unsubstituted or is methylated, e. g. 5-methylpyrrolidin-2-yl, 6-methylpiperidin-2-yl and 4-methylpiperidin-2-yl.

With regard to their activity to inhibit growth and progeny of tumor cells preference is furthermore given to 2-substituted pyrimidines I in which R2 is halogen, cyano, C1-C4- alkyl, Ci-C4-haloalkyl or Ci-C4-alkoxy, in particular fluorine, chlorine, bromine, methyl, cyano, methoxy or ethoxy, more preferably fluorine, chlorine, cyano, methyl or methoxy. Particularly preferred are compounds of the formula I, wherein R2 is chlorine, cyano or methyl.

Preference is furthermore given to 2-substituted pyrimidines I in which R3 is cyano, C(=O)NRzRb, C(=NRa1)NRzRb, C(=NORa1)NRzRb, C(=N-NRz1Rc1)NRzRb, C(=S)NRzRb, C(=O)Ra, C(=NRa1)Ra, C(=NORa1)Ra, C(=N-NRz1Rc1)Ra, C(=O)ORa, C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, or C(=O)NRa-NRzRb.

Preference is likewise given to 2-substituted pyrimidines I in which R3 is O-C(=O)Ra or ON(=CRaRb). Preference is likewise given to 2-substituted pyrimidines I in which R3 is NRa(C(=0)Rb), NRa(C(=S)Rb), NRa(C(=NRa1)Rb), NRa(C(=N0Ra1)Rb), NRa(C(=0)0Rb), NRa(C(=0)-NRzRb), NRa(C(=NRa1)-NRzRb), NRa(N=CRcRb), NRa-NRzRb or NRz-ORa.

Particular preference is given to 2-substituted pyrimidines I, where R3 is cyano,

C(=S)NRzRb, C(=O)NRzRb, C(=NORa1)NRzRb, C(=NRa1)NRzRb, C(=O)Ra, C(=NORa1)Ra, C(=NRa1)Ra, C(=O)ORa, C(=NORa1)ORa, C(=NRa1)ORa, C(=O)NRz-ORa, C(=NORa1)NRz-ORa, C(=NRa1)NRz-ORa, C(=N-NRz1Rc1)Ra, ON(=CRaRb), NRa(C(=O)Rb), NRa(C(=O)ORb), NRa(N=CRcRb) or NRz-ORa.

Among the aforementioned compounds I, those are preferred where Ra, Ra1, Rb, Rc and Rc1 independently of one another are hydrogen, d-Cε-alkyl, d-Cε-haloalkyl, C2-C6- alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C6-cycloalkyl, C3-C6- halocycloalkyl, C4-C6-cycloalkenyl or C4-C6-halocycloalkenyl, more preferably hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl or C3-C6- cycloalkyl, especially hydrogen or Ci-C4-alkyl. Likewise, those compounds I are preferred where Rb1 has the preferred meanings of Rb as defined above, except for hydrogen. Likewise, those compounds I are preferred where Rz and Rz1 independently of one another have the preferred meanings of Ra as defined above or are -CO-Ra2, where Ra2 has the preferred meanings of Ra as defined above.

A particular preferred embodiment of the invention relates to 2-substituted pyrimidines I, where R3 is selected from the croup consisting of cyano, C(=O)NRzRb, C(=NORa1)NRzRb, C(=NORa1)Ra, NRa(C(=O)ORb), ON(=CRaRb), NRa(C(=O)Rb), NRa(C(=S)Rb) and C(=S)NRzRb. Among these compounds I, those are more preferred where Ra and Ra1 independently of one another are hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, e. g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. More preferably Ra is hydrogen, methyl, ethyl, n-propyl or iso-propyl. Likewise, more preferably Ra1 is methyl. Furthermore, those compounds I are more particularly preferred where Rb is hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, e. g. methyl or ethyl, in particular methyl. More preferably Rb is hydrogen or methyl. Likewise, those compounds I are more particularly preferred where Rz is hydrogen, Ci-C4-alkyl, e. g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl, in particular methyl, or -CO-Ra2, where Ra2 is Ci-C4-alkyl, e. g. methyl or ethyl, in particular methyl. More preferably Rz is hydrogen, methyl or -CO-Ra2, and Ra2 is methyl. Very particular preference is given to 2-substituted pyrimidines I, where R3 is selected from the group consisting of cyano, C(=O)NHCH3, C(=NOCH3)NH2, C(=NOH)NH2, C(=NOCH3)CH3, C(=NOH)CH3, NH(C(=O)OCH3), N(C(=O)CH3)-OCH3, ON(=C(CH3)2), NH(C(=O)CH3), C(=O)NH2, C(=S)NH2, C(=O)-O(CH3), C(=O)-O(CH2CH3), C(=O)-O(CH2CH2CH3) and C(=O)-OCH(CH3)2, with most preference given to R3 being selected from the group consisting of cyano, C(=NOCH3)NH2, C(=NOH)NH2,C(=O)NH2 and C(=S)NH2. In another embodiment of the invention R3 is selected from C(=Z)ORa, C(=Z)NRz-ORa or C(=Z)Ra, preferably C(=O)ORa, C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)Ra, C(=NRa1)Ra and C(=NORa1)Ra. Among these compounds I, those are more particularly preferred where Ra1 is hydrogen or Ci-C4-alkyl, especially Ci-C2-alkyl, in particular methyl. Likewise, those compounds I are more particularly preferred where Ra and/or Rb, especially both Ra and Rb are hydrogen. Likewise, those compounds I are more particularly preferred where Rz is hydrogen or -CO-Ra2, a particular preferred radical R3 being C(=NH)N(CO-Ra2)Rb, where Ra2 and Rb independently from one another preferably are hydrogen or Ci-C4-alkyl such as methyl and ethyl.

Very particular preference is given to 2-substituted pyrimidines I, where R3 is selected from the group consisting of cyano, C(=NOCH3)NH2, C(=NOH)NH2, C(=NH)NH2, C(=O)NH2, C(=S)NH2, C(=NH)NH-OH, C(=O)NH-OH and C(=NH)NH-C(=O)CH3, especially cyano, C(=NOCH3)NH2, C(=NOH)NH2, C(=O)NH2 and C(=S)NH2.

In a further preferred embodiment of the invention the radical R3 is selected from NRa(C(=O)Rb) and NRa(C(=S)Rb), wherein Ra and Rb together form a C2-C5-alkylene or C3-C5-alkenylene moiety. In this embodiment particular preference is given to compounds, wherein R3 is pyrrolidin-2-on-1-yl, piperidin-2-on-1-yl, azepin-2-on1-yl, pyrrolidin-2-thion-1-yl, piperidin-2-thion-1-yl or azepin-2-thion-1-yl.

In a further preferred embodiment of the invention the radical R3 is a radical of the formulae R3a or R3b as defined above. Preferably, the radical R3b corresponds one of the following formulae:

wherein Re#, Rs and Rh are as defined above. In these formulae Re#, R9 and Rh are preferably independently of one another hydrogen, d-Cε-alkyl, C2-C6-alkenyl,

C2-C6-alkynyl or Cs-Cβ-cycloalkyl, in particular are hydrogen, methyl or ethyl. Amongst these preference is given to radicals R3b of the formulae:

wherein Re#, Rs and Rh are as defined above. Examples for these radicals include radicals of the following formulae:

Likewise, preference is given to 5-phenyl pyrimidines I, wherein the radical R3 in the 2-position is of the formula R3a:

wherein Q, Re, Rf and Rs are as deffned above. Preferably Q is oxygen. Preferably Re, Rf and Rs are independently of one another hydrogen, d-Cε-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or Cs-Cβ-cycloalkyl, in particular hydrogen, methyl or ethyl or Rf and Rs together with the nitrogen are a radical Re-Q-C(Rh)=N, wherein Q, Re and Rh are as defined above. In particular Q is oxygen and Re and Rh are H or d-Cε-alkyl. Examples of this type of radical R3a include:

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 independently of each other selected from the group consisting of:

L halogen, in particular fluorine, chlorine, bromine, preferably fluorine, chlorine; cyano; Ci-Cs-alkyl, in particular d-Cε-alkyl, especially Ci-C4-alkyl, such as methyl, ethyl, propyl and butyl, preferably methyl; C2-Cio-alkenyl, in particular

C2-C6-alkenyl, especially C2-C4-alkenyl, such as ethenyl, propenyl and butenyl; C2-Cio-alkynyl, in particular C2-C6-alkynyl, especially C2-C4-alkynyl, such as ethynyl, propynyl and butynyl; d-Cβ-alkoxy, in particular Ci-C4-alkoxy, preferably methoxy and ethoxy; C2-Cio-alkenyloxy, in particular C2-C6-alkenyloxy, such as ethenyloxy; C2-Cio-alkynyloxy, in particular C2-C6-alkynyloxy, such as ethynyloxy; nitro; -C(=O)-O-A10, in particular Ci-C4-alkoxycarbonyl, especially Ci-C2-alkoxycarbonyl, such as methoxycarbonyl; -C(=O)-N(A11)A10, in particular CO-NH2, Ci-C4-alkylaminocarbonyl, such as CO-NHCH3 and CO-NHC2H5, and di-(Ci-C4-alkyl)-aminocarbonyl, such as CO-N(CHs)2; -C(=S)-N(A11)A10, in particular CS-NH2, C-i-d-alkylaminothiocarbonyl, such as CS-NHCH3, and di-d-Gralkylaminothiocarbonyl, such as CS-N(CHs)2; C(A11X=N-OA10), such as CH(=NOH) and CH(=NOCH3); N(A11)A10, in particular Ci-C4-alkylamino and di-Ci-C4-alkylamino; N(A11)-C(=O)-A10, in particular d-d-alkylcarbonylamino, such as NH-C(=O)CH3, and N-(Ci-C4-alkylcarbonyl)-N-(Ci-C4-alkyl)-amino, such as N(CH3)-C(=O)CH3, and/or S(=O)P-A10, in particular -SH, Ci-C4-alkylthio, such as SCH3, or Ci-C4-alkylsulfonyl, such as SO2CH3; where

A10, A11 independently of one another are hydrogen, Ci-Cβ-alkyl, C2-Cβ- 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 A10 and A11 together with the atoms to which they are attached are a five- or six-membered saturated heterocycle which comprises one or two heteroatoms from the group consisting of O, N and S;

where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated, e. g. where L may be C-i-Cβ- haloalkyl, especially Ci-C2-fluoroalkyl, such as trifluoromethyl.

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 system. Moreover, particular preference is given to 2-substituted pyrimidines I, wherein n is 1 , 2 or 3, i. e. the phenyl ring attached to the pyrimidine skeleton carries 1 , 2 or 3 substituents RL which are different from hydrogen.

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:

L halogen, cyano, d-Cβ-alkyl, Ci-C6-alkoxy, -C(=O)-O-A10 or -C(=O)-N(A11)A10 and wherein A10 and A11 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 group substituted by Ln is B 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(CHs)2, CS-NH2, CS-NHCH3, CS-N(CHs)2, NH-C(=O)CH3, N(CH3)-C(=O)CH3 Or COOCH3, more preferably hydrogen, fluorine or chlorine, even more preferably hydrogen; and

L5 is hydrogen, fluorine, chlorine or CH3, more preferably fluorine or chlorine.

Furthermore, particularly preferred are 2-substituted pyrimidines of the formula I where

R1 is C2-Cio-alkyl, C2-Cio-alkenyl or C2-Cio-alkynyl, where the aliphatic groups of the radical definitions of R1 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-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Cβ- cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyloxy, C4-C6-cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1, C(A2X=N-OA1), N(A2)A1, N(A2)-C(=O)-A1, N(A3)-C(=O)-N(A2)A1, S(=0)m-A1, S(=O)m-O-A1 or S(=O)m-N(A2)A1, it also being possible that two vicinal radicals Rv together are (=0) or (=S);

R2 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;

R3 has the meanings given in claim 1 but does not carry any group Rwa;

n is 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring and wherein L are identical or different and selected from the group consisting of:

L halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ-alkoxy, C2-C10- alkenyloxy, C2-Cio-alkynyloxy, nitro, -C(=O)-O-A10, -C(=O)-N(A11)A10, -C(=S)-N(A11)A10, C(A11X=N-OA10), N(A11)A10, N(A11)-C(=O)-A10 and S(=O)P-A10, where

A10, A11 independently of one another are hydrogen, d-Cε-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 A10 and A11 together with the atoms to which they are attached are a five- or six-membered partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms selected from the group consisting of O, N and S;

and 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.

More 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-C4-alkyl, Ci-C4-haloalkyl, Ci-C6-alkoxy, -C(=O)-O-A1 and - C(=O)-N(A11)A10 and wherein A10 and A11 are as defined herein, and in particular hydrogen or Ci-C4-alkyl; L is more preferably chlorine, fluorine, CH3 or CF3;

R1 is C4-C8-alkyl or C4-C8-haloalkyl, preferably C4-C6-alkyl, which in each case is branched but preferably not branched in the α-position (e. g. branched in the β- or γ-position), and which is unsubstituted or may carry one or two, especially one radical Rv selected from the group consisting of hydroxyl and Ci-C4-alkoxy such as methoxy or ethoxy, e. g. (2-methyl)-but-1-yl, (3-methyl)-but-1-yl, (2,2-dimethyl)-but-1-yl, (2,3-dimethyl)-but-1-yl, (3,3-dimethyl)-but-1-yl, 2-hydroxy- (3-methyl)-but-1 -yl, 3-hydroxy-(3-methyl)-but-1 -yl, 4-hydroxy-(3-methyl)-but-1 -yl,

2-hydroxy-(2-methyl)-but-1 -yl, 3-hydroxy-(2-methyl)-but-1 -yl, 4-hydroxy-(2-methyl)-but-1-yl and (2-methyl)-prop-1-yl, more preferably (2-methyl)-but-1-yl, 2-hydroxy-(3-methyl)-but-1-yl and (2-methyl)-prop-1-yl;

R2 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl, in particular chlorine, fluorine, cyano, methyl, ethyl, methoxy or ethoxy;

R3 is selected from the group consisting of cyano, C(=O)NHCH3, C(=NOCH3)NH2,

C(=NOH)NH2, C(=NOCH3)CH3, C(=NOH)CH3, NH(C(=O)OCH3), N(C(=O)CH3)-OCH3, ON(=C(CH3)2), NH(C(=O)CH3), C(=O)NH2, C(=S)NH2,

C(=O)-O(CH3), C(=O)-O(CH2CH3), C(=O)-O(CH2CH2CH3) and C(=O)-OCH(CH3)2, with most preference given to R3 being selected from the group consisting of cyano, C(=NOCH3)NH2, C(=NOH)NH2,C(=O)NH2 and C(=S)NH2.

Likewise 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, Ci-C4-haloalkyl, d-Cβ-alkoxy, -C(=O)-O-A1 and - C(=O)-N(A11)A10 and wherein A10 and A11 are as defined herein, and in particular hydrogen or Ci-C4-alkyl; L is more preferably chlorine, fluorine, CH3 or CF3;

R1 is C2-Cs-alkenyl or C2-C8-haloalkenyl, preferably C2-C8-alkenyl, e. g. but-1-en-4-yl

(= but-3-en-1-yl), but-2-en-1-yl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 2- methyl-but-2-en-1-yl and 3-methyl-but-2-en-1-yl, more preferably but-1-en-4-yl and 3-methyl-but-1-enyl;

R2 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl, in particular chlorine, fluorine, cyano, methyl, ethyl, methoxy or ethoxy;

R3 is selected from the group consisting of cyano, C(=O)NHCH3, C(=NOCH3)NH2, C(=NOH)NH2, C(=NOCH3)CH3, C(=NOH)CH3, NH(C(=O)OCH3), N(C(=O)CH3)-OCH3, ON(=C(CH3)2), NH(C(=O)CH3), C(=O)NH2, C(=S)NH2, C(=O)-O(CH3), C(=O)-O(CH2CH3), C(=O)-O(CH2CH2CH3) and C(=O)-OCH(CH3)2, with most preference given to R3 being selected from the group consisting of cyano, C(=NOCH3)NH2, C(=NOH)NH2,C(=O)NH2 and C(=S)NH2.

Likewise preferred are 2-substituted pyrimidines of the formula I (embodiment C) and their salts, 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, Ci-C4-haloalkyl, Ci-Cβ-alkoxy, -C(=O)-O-A1 and - C(=O)-N(A11)A10 and wherein A10 and A11 are as defined herein, and in particular hydrogen or Ci-C4-alkyl; L is more preferably chlorine, fluorine, CH3 or CF3;

R1 is C3-Ci2-cycloalkyl, C3-Cio-cycloalkenyl, phenyl, or a C-bound heterocycle which may carry an oxygen atom (-O-), an imino nitrogen (=N-) or an amino -(-N(RX)- group as ring member, where Rx is hydrogen or C-i-Cβ-alkyl, and/or where the ring formed may carry one or more, e. g. 1 , 2, 3 or 4, preferably 1 substituent(s) from the group consisting of halogen, d-Cε-alkyl, d-Cε-haloalkyl and oxy-Ci-C3- alkyleneoxy, in particular halogen, d-Cε-alkyl and C-i-Cε-haloalkyl. Amongst these, particular preference is given to compounds I, wherein R1 selected from cyclopentyl, cyclohexyl, pyrrolidin-2-yl and piperidin-2-yl, and which may carry one or two d-Cε-alkyl, preferably Ci-C4-alkyl substituents, e. g. methyl, ethyl, prop-1-yl and prop-2-yl, more preferably Ci-C2-alkyl substituents, e. g. methyl, ethyl, especially methyl;

R2 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl, in particular chlorine, fluorine, cyano, methyl, ethyl, methoxy or ethoxy;

R3 is selected from the group consisting of cyano, C(=O)NHCH3, C(=NOCH3)NH2, C(=NOH)NH2, C(=NOCH3)CH3, C(=NOH)CH3, NH(C(=O)OCH3), N(C(=O)CH3)-OCH3, ON(=C(CH3)2), NH(C(=O)CH3), C(=O)NH2, C(=S)NH2, C(=O)-O(CH3), C(=O)-O(CH2CH3), C(=O)-O(CH2CH2CH3) and

C(=O)-OCH(CH3)2, with most preference given to R3 being selected from the group consisting of cyano, C(=NOCH3)NH2, C(=NOH)NH2,C(=O)NH2 and C(=S)NH2.

In particular with a view to their use as anticancer agents, preference is given to the compounds I of the formulae I.A, I. B, I.C, I. D, I. E, I. F, I.G, I. H, IJ, I. K, I. L, I. M, I.N, I.N, I.O, I.Q, I. R, I.S, IT, I. U, I.V, I.W and I.X as defined below, wherein L, n, R1 and R2 are as defined herein and wherein at least one of the variables, in particular all of the variables L, n, R1 and R2 have the preferred or particulary preferred meanings; specific examples of these compounds being compiled in the tables below. 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.

I. D

Table 1

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-chloro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 2

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 3

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dichloro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 4

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A Table 5

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trifluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 6

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 7

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxycarbonyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 8

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-CN, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 9

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,5-trifluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 10

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dichloro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 11

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chlorine, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 12

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluorine, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 13 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-difluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 14

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-chloro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A Table 15 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro-4-fluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 16 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3-difluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 17 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-difluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 18 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3,4-trifluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 19 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 20 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dimethyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 21 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl-4-chloro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A Table 22

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 23

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dimethyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 24

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN,

LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trimethyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A Table 25

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-cyano, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 26

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 27

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methoxycarbonyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 28

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxy, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 29

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 30 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxycarbonyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 31

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-bromo, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 32

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-cyano, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 33

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro,4-methoxy, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 34

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,3-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 35

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 36

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-cyano, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 37

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-bromo, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 38 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 39

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxy, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 40

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxycarbonyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 41

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl,4-bromo, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 42

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-bromo, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 43

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxy, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 44

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,5-methyl, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 45

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is pentafluoro, R2 is methyl and R1 for a compound corresponds in each case to one row of Table A

Table 46 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-chloro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 47

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 48

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dichloro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 49

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 50

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trifluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 51

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 52

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxycarbonyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 53

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-CN, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 54 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,5-trifluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 55

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dichloro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 56

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 57

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 58

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-difluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 59

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-chloro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 60

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro-4-fluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 61

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3-difluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 62 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-difluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 63

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3,4-trifluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 64

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 65

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dimethyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 66

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl-4-chloro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 67

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 68

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dimethyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 69

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trimethyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 70 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-cyano, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 71

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 72

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methoxycarbonyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 73

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxy, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 74

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 75

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxycarbonyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 76

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-bromo, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 77

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-cyano, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 78 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro,4-methoxy, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 79

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,3-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 80

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 81

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-cyano, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 82

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-bromo, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 83

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 84

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxy, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 85

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxycarbonyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 86 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl,4-bromo, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 87

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-bromo, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 88

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxy, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 89

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,5-methyl, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 90

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is pentafluoro, R2 is chloro and R1 for a compound corresponds in each case to one row of Table A

Table 91

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-chloro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 92

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 93

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dichloro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 94 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 95

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trifluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 96

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 97

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxycarbonyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 98

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-CN, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 99

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,5-trifluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 100

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dichloro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 101

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 102 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 103

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-difluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 104

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-chloro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 105

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro-4-fluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 106

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3-difluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 107

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-difluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 108

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3,4-trifluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 109

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 110 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dimethyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 11 1

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl-4-chloro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 112

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 113

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dimethyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 114

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trimethyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 115

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-cyano, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 116

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 117

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methoxycarbonyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 118 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxy, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 119

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 120

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxycarbonyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 121

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-bromo, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 122

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-cyano, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 123

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro,4-methoxy, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 124

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,3-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 125

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 126 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-cyano, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 127

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-bromo, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 128

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 129

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxy, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 130

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxycarbonyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 131

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl,4-bromo, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 132

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-bromo, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 133

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxy, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 134 Compounds of the formulae I .A, LB, I.C, I.D, I.E, I.F, I.G, I.H, I.J, I.K, I.L, I.M, I.N, I.N, 1.0, I.Q, I. R, I.S, IT, I. U, I.V, I.W and I.X, in which Ln is 2-fluoro,5-methyl, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 135

Compounds of the formulae I. A, I. B, I.C, I.D, I.E, I.F, I.G, I.H, I.J, I.K, I.L, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is pentafluoro, R2 is methoxy and R1 for a compound corresponds in each case to one row of Table A

Table 136

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-chloro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 137

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 138

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dichloro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 139

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,6-methyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 140

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trifluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 141

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 142 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-methoxycarbonyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 143

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,4-CN, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 144

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,5-trifluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 145

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dichloro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 146

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 147

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 148

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-difluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 149

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-chloro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 150 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro-4-fluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 151

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3-difluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 152

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-difluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 153

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,3,4-trifluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 154

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 155

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4-dimethyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 156

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl-4-chloro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 157

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro-4-methyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 158 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-dimethyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 159

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,4,6-trimethyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 160

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-cyano, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 161

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 162

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro-4-methoxycarbonyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 163

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxy, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 164

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 165

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-methoxycarbonyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A Table 166

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-bromo, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 167

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-chloro,4-cyano, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 168

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,6-difluoro,4-methoxy, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 169

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-fluoro,3-methyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 170

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2,5-dimethyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 171

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-cyano, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 172

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-bromo, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 173

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-fluoro, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 174 Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxy, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 175

Compounds of the formulae LA, LB, LC, LD, LE, LF, LG, LH, LJ, LK, LL, LM, LN, LN, LO, LQ, LR, LS, LT, LU, LV, LW and LX, in which Ln is 2-methyl,4-methoxycarbonyl, R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 176

Compounds of the formulae LA, LB, LC, LD, LE1 LF1 LG, LH1 LJ1 LK1 LL1 LM1 LN1 LN1 LO1 LQ1 LR1 LS1 LT1 LU1 LV1 LW and LX1 in which Ln is 215-dimethyl,4-bromo1 R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 177

Compounds of the formulae LA1 LB1 LC1 LD1 LE1 LF1 LG1 LH1 LJ1 LK1 LL1 LM1 LN1 LN1 LO1 LQ1 LR1 LS1 LT1 LU1 LV1 LW and LX1 in which Ln is 2-fluoro,4-bromo1 R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 178

Compounds of the formulae LA1 LB1 LC1 LD1 LE1 LF1 LG1 LH1 LJ1 LK1 LL1 LM1 LN1 LN1 LO1 LQ1 LR1 LS1 LT1 LU1 LV1 LW and LX1 in which Ln is 2-fluoro,4-methoxy1 R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 179

Compounds of the formulae LA1 LB1 LC1 LD1 LE1 LF1 LG1 LH1 LJ1 LK1 LL1 LM1 LN1 LN1 LO1 LQ1 LR1 LS1 LT1 LU1 LV1 LW and LX1 in which Ln is 2-fluoro,5-methyl1 R2 is cyano and R1 for a compound corresponds in each case to one row of Table A

Table 180

Compounds of the formulae LA1 LB1 LC1 LD1 LE1 LF1 LG1 LH1 LJ1 LK1 LL1 LM1 LN1 LN1 LO1 LQ1 LR1 LS1 LT1 LU1 LV1 LW and LX1 in which Ln is pentafluoro, R2 is cyano

Table A

The 2-substituted pyrimidines of the formula I, in particular the compounds of the formulae I .A, I.J, I. K and I. P 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 < 5x10"7 mol/l (i.e. < 500 nM) for cell cycle inhibition in HeLa cells as determined by the test procedure outlined below.

Based on the results of these standard pharmacological test procedures, 2-substituted 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.

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 of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.

The following examples 1-1 to I-7 given in table B are representative compounds of this invention which are useful as anticancer agents.

Table B: Active compounds

*) 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 1 x10"6, 3.3x10"7, 1.1x10"7, 3.7x10"8, 1.2x10"8 and 1 x10"9 M in a final volume of 500 μl. DMSO alone is added to 6 wells as a control. Cells are incubated with the compounds as above for 20 h. Then cells are observed under the microscope to check for cell death, and the 24-well plate is then centrifuged at 1200 rpm for 5 min at 200C, acceleration position 7 and break position 5 (Eppendorf centrifuge 5804R). The supernatant is removed and the cells are lysed with 0.5 ml RNase Buffer (10 mM NaCitrate, 0.1 % Nonidet NP40, 50 μg/ml

RNase, 10 μg/ml Propidium iodide) per well. The plates are then incubated for at least 30 min in the dark at RT and the samples then transferred to FACS tubes. Samples are measured in a FACS machine (Beckton Dickinson) at the following settings:

Instrument Settings of the FACS Calibur: Run Modus: high

Parameter Voltage Amp Gain Mode

FSC E01 2,5 Hn

SSC 350 1 Hn

Fl 1

Fl 2 430 2 Hn

Fl 3

FI 2 - A — 1 Hn

Fl 2 - W — 3 Hn

DDM Parameter Fl 2

The ratio of cells in Go/Gi-phase to G2/M phase is calculated and compared to the value for the controls (DMSO) only. Results are given in table C as the IC50 value calculated from the concentration curve plotted against the cell cycle ratio and indicate the compound concentration at which 50% of cells are in cell cycle arrest after treatment with the compound.

Test on other cell lines (MCF-7 and COLO 205) were done in the same way except that they were incubated with the growth medium recommended by the American Tissue Culture collection for that cell type. Table C

We claim:

1. 2-substituted 5-phenylpyrimidines of the formula I and their pharmaceutically acceptable salts for use in therapy:

in which the indices and the substituents are as defined below:

R1 is C2-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Ci2-cycloalkyl, C3-Ci0- cycloalkenyl, phenyl or a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which is attached via carbon and which contains one, two, three or four heteroatoms selected from the group consisting of O, N and S; where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of R1 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Rv, which may be the same or different from each other:

Rv is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-Cβ- cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, d-Cβ-alkoxy, C2-Ci0- alkenyloxy, C2-Ci0-alkynyloxy, C3-C6-cycloalkyloxy, C4-C6- cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1, C(A2)(=N-OA1), N(A2JA1, N(A2)-C(=O)-A1, N(A3)-C(=O)-N(A2)A1, S(=0)m-A1, S(=0)m-0-A1 or S(=O)m-N(A2)A1, it also being possible that two vicinal radicals Rv together are (=0), (=S) or (=N-OA1), or Rv is phenyl, where the phenyl moiety may carry one, two or three radicals which may be the same or different from each other and which are selected from the group consisting of: halogen, Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ci-C6-haloalkyl, CrC6- alkoxy, cyano, nitro, -C(=O)-A, C(=O)-O-A, -C(=O)-N(A')A, C(A')(=N-OA) and N(A')A; where

m is 0, 1 or 2;

A1, A2, A3, A and A' independently of one another are hydrogen, d-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl,

C3-C8-cycloalkenyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, nitro, cyanato, cyano and/or Ci-C4-alkoxy; or A1 and A2, or A and A', respectively, together with the atoms to which they are attached are a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms selected from the group consisting of O, N and S;

and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Rv for their part may be partially or fully halogenated;

R2 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-Cβ- alkylthio, di-(Ci-C6-alkyl)amino or Ci-Cβ-alkylamino, where the aliphatic and/or alicyclic groups of the radical definitions of R2 for their part may be partially or fully halogenated or may carry one, two, three or four radicals Ru, which may be the same or different from each other:

Ru is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, Ci-C6-alkoxy, Cs-Cβ-cycloalkyl, C2-Cio-alkenyloxy, C2-C10- alkynyloxy, C4-C6-cycloalkenyl, Cs-Cβ-cycloalkyloxy, 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)q-A4, S(=O)q-O-A4 or S(=O)q-N(A5)A4, it also being possible that two vicinal radicals Ru together are (=0) or (=S), where

q is O, 1 or 2;

A4, A5 and A6 independently of one another have the meanings of

A1, A2 and A3 as defined above;

and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of Ru for their part may be partially or fully halogenated or may carry one, two or three radicals Rua, which may be the same or different from each other and which have the meanings of Ru as defined above;

R3 is selected from the group consisting of cyano, C(=Z)ORa, C(=Z)NRzRb, C(=Z)NRz-ORa, C(=Z)NRa-NRzRb, C(=Z)Ra, ON(=CRaRb), O-C(=Z)Ra,

NRa(C(=Z)Rb), NRa(C(=Z)ORb), NRa(C(=Z)-NRzRb), NRa(N=CRcRb), NRa-NRzRb, NRz-ORa, and the radicals of the formulae R3a and R3b

where

Z is O, S, NRa1, NORa1 or N-NRz1Rc1;

Ra, Ra1, Rb, Rc, Rc1 independently of one another are hydrogen, Ci-Cβ- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cβ-cycloalkyl or C4-C6- cycloalkenyl;

Rb1 has the meanings of Rb as defined above, except for hydrogen; and

Rz, Rz1 independently of one another have the meanings of Ra as defined above and may additionally be -CO-Ra2, where Ra2 has the meanings of Ra as defined above;

where the aliphatic and/or alicyclic groups of the radical definitions of Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz and Rz1 for their part may be partially or fully halogenated or may carry one, two, three or four groups R1, which may be the same or different from each other:

R1 is halogen, cyano, Ci-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ- alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C3-C6- cycloalkenyl, Cs-Cβ-cycloalkoxy or Cs-Cβ-cycloalkenyloxy,

and where two of the radicals Ra, Ra1, Rb, Rb1, Rc, Rc1, Rz or Rz1 together with the atoms, to which they are attached, may form a five-, six- or seven- 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,

and where # in the formulae R3a and R3b indicates the atom which is bond to the 2-position of the pyrimidine ring

x is O or i ;

Re, Rf, R9, Re# independently of one another are hydrogen, d-Cε-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl,

Rf, Ra together with the nitrogen atom to which they are attached may have the meaning Re-Z-C(Rh)=N;

Q is oxygen or N-Re#; Q' is C(H)-Rk, C-Rk , N-N(H)-Re# or N-Re#;

ilii may be a double bond or a single bond;

Rh, Rk have the same meanings as Re and may additionally be halogen or cyano; or

Rh together with the carbon to which it is attached may be a carbonyl group;

where the aliphatic, alicyclic or aromatic groups of the radical definitions of Re, Re#, Rf, R9, Rh or Rk for their part may be partially or fully halogenated or may carry one to four groups Rw, which may be the same or different from each other:

Rw is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C3-C6-cycloalkenyl, Cs-Cβ-cycloalkoxy, Cs-Cβ-cycloalkenyloxy, and where two of the radicals Rf, Rs, Re or Re# together with the atoms to which they are attached may form a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S;

n is 1 , 2, 3, 4 or 5;

L are independently of each other selected from halogen, cyano, cyanato (OCN), Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, d-Ce-alkoxy, C2-Ci0- alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyl, C4-C6-cycloalkenyl, C3-C6- cycloalkyloxy, C4-C6-cycloalkenyloxy, nitro, -C(=O)-A10, -C(=O)-O-A10, - C(=O)-N(A11)A10, -C(=S)-N(A11)A10, -C(=NA11)-SA10, C(A11)(=N-OA10),

N(A11)A10, N(A11)-C(=O)-A10, N(A12)-C(=O)-N(A11)A10, S(=O)P-A10, S(=O)p-O-A10 or S(=O)p-N(A11)A10, where

p is O, 1 or 2;

A10, A11, A12 independently of one another have the meanings of A1, A2 and A3 as defined above;

where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of L for their part may be partially or fully halogenated or may carry one, two, three or four radicals RL, which may be the same or different from each other: RL is halogen, cyano, Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, hydroxyl, Ci-C6-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, C3-C6- cycloalkyl, C4-C6-cycloalkenyl, Cs-Cβ-cycloalkyloxy, C4-C6- cycloalkenyloxy, -C(=O)-A13, -C(=O)-O-A13, -C(=O)-N(A14)A13, C(A14X=N-OA13), N(A14)A13, N(A14)-C(=O)-A13,

N(A15)-C(=O)-N(A14)A13, S(=O)s-A13, S(=O)S-O-A13 or S(=O)s-N(A14)A13; it also being possible that two vicinal radicals RL together are (=0) or (=S), where

s is 0, 1 or 2; and

A13, A14 and A15 independently of one another have the meanings of A1, A2 and A3 as defined above;

and where the aliphatic, alicyclic and/or aromatic groups of the radical definitions of RL for their part may be partially or fully halogenated or may carry one, two, three or four groups RLA, which may be the same or different from each other and which have the meanings of RL as defined above.

2. The compounds according to claim 1 , where

R1 is C2-Cio-alkyl, C2-Cio-alkenyl or C2-Cio-alkynyl where the aliphatic groups of the radical definitions of R1 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-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, C3-C6- cycloalkyl, C4-C6-cycloalkenyl, hydroxyl, Ci-Cβ-alkoxy, C2-C10- alkenyloxy, C2-Cio-alkynyloxy, Cs-Cβ-cycloalkyloxy, C4-C6- cycloalkenyloxy, -C(=O)-A1, -C(=O)-O-A1, -C(=O)-N(A2)A1, C(A2X=N-OA1), N(A2)A1, N(A2)-C(=O)-A1, N(A3)-C(=O)-N(A2)A1, S(=0)m-A1, S(=0)m-0-A1 or S(=O)m-N(A2)A1, it also being possible that two vicinal radicals Rv together are (=0), (=S) or (=N-OA1);

R2 is halogen, cyano, Ci-C4-alkyl, Ci-C4-alkoxy or Ci-C4-haloalkyl;

n is 1 , 2 or 3 where at least one substituent L is located in the ortho-position on the phenyl ring;

L is halogen, cyano, d-Cs-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cβ-alkoxy, C2-Cio-alkenyloxy, C2-Cio-alkynyloxy, nitro, -C(=O)-O-A10, -C(=O)-N(A11)A10, -C(=S)-N(A11)A10, C(A11)(=N-OA10), N(A11)A10, N(A11)-C(=O)-A10 or S(=O)P-A10, where

A10, A11 independently of one another are hydrogen, d-Cε-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl or phenyl, where the organic radicals may be partially or fully halogenated or may be substituted by halogen, cyano and/or Ci-C4-alkoxy; or A10 and A11 together with the atoms to which they are attached are a five- or six-membered partially unsaturated or aromatic heterocycle which comprises one, two, three or four heteroatoms selected from the group consisting of O, N and S;

and 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.

3. The compounds according to any of claims 1 or 2, wherein

R3 is selected from the group consisting of cyano, C(=O)NRzRb,

C(=NRa1)NRzRb, C(=NORa1)NRzRb, C(=N-NRz1Rc1)NRzRb, C(=S)NRzRb, C(=O)Ra, C(=NRa1)Ra, C(=NORa1)Ra, C(=N-NRz1Rc1)Ra, C(=O)ORa,

C(=NRa1)ORa, C(=NORa1)ORa, C(=O)NRz-ORa, C(=NRa1)NRz-ORa, C(=NORa1)NRz-ORa, C(=O)NRa-NRzRb, O-C(=O)Ra, O-N(=CRaRb), NRa(C(=O)Rb), NRa(C(=S)Rb), NRa(C(=NRa1)Rb), NRa(C(=NORa1)Rb), NRa(C(=O)ORb), NRa(C(=O)-NRzRb), NRa(C(=NRa1)-NRzRb), NRa(N=CRcRb), NRa-NRzRb and NRz-ORa.

4. The compounds according to claim 3, wherein

R3 is selected from the group consisting of cyano, C(=O)NRzRb, C(=NORa1)NRzRb, C(=S)NRzRb, C(=O)NRz-ORa, C(=NORa1)Ra and

C(=N-NRz1Rc1)Ra.

5. The compounds according to claim 3, in which

R3 is selected from the group consisting of ON(=CRaRb), NRa(C(=O)Rb),

NRa(C(=O)ORb), NRa(N=CRcRb) and NRz-ORa.

6. The compounds according to any of the preceding claims, wherein

R1 is C2-C8-alkyl, C2-C8-haloalkyl, C2-Cs-alkenyl or C2-C8-haloalkenyl, which in each case may carry one or two radicals Rv selected from the group consisting of hydroxyl and Ci-C4-alkoxy.

7. The compounds according to any of the preceding claims, wherein the phenyl group substituted by Ln is given by the formula B

where # is the point of attachment to the pyridine skeleton and

L1 is fluorine, chlorine, CH3 or CF3;

L2, L4 independently of one another are hydrogen, CH3 or fluorine; L3 is hydrogen, fluorine, chlorine, bromine, nitro, cyano, CH3, SCH3, OCH3,

SO2CH3, CO-NH2, CO-NHCH3, CO-NHC2H5, CO-N(CH3)2, CS-NH2, CS-NHCH3, CS-N(CHs)2, NH-C(=O)CH3, N(CH3)-C(=O)CH3 or COOCH3; and

L5 is hydrogen, fluorine, chlorine or CH3.

8. A pharmaceutical composition comprising a 2-substituted 5-phenylpyrimidine compound of the formula I as defined in any of the preceding claims or a pharmaceutically acceptable salt thereof.

9. 2-substituted 5-phenylpyrimidine compounds of the formula I as defined in any of claims 1 to 7 and their pharmaceutically acceptable salts for use in therapy of cancer.

10. A pharmaceutical composition comprising a 2-substituted 5-phenylpyrimidine compound of the formula I as defined in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

1 1. The use of 2-substituted 5-phenylpyrimidine compounds of the formula I as defined in any of claims 1 to 7 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 5-phenylpyrimidine compound of the formula I as defined in any of claims 1 to 7 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 5-phenylpyrimidine compound of the formula I as defined in any of claims 1 to 7 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 5-phenylpyrimidine compound of the formula I as defined in any of claims 1 to 7 or of their pharmaceutically acceptable salts.

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