Nova Patents
EP1597251B1

Pyrimidine compounds

Abstract

The present invention provides compounds of formula (I): wherein all variables are as defined herein, pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

EP1597251B1, drawing sheet 1
Sheet 1 of 81

Term

Term ended

Expired 11 February 2024, 2.6 years ago.

  1. Priority
  2. Filed
  3. Granted
  4. Expired
  5. Today

34 claims: 17 independent, 17 dependent

  1. 1
    A compound of formula (I):wherein: R 1 is selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl;R 2 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -(R 7 ) g -C(O)R 6 , -(R 7 )g-CO 2 R 6 , -(R 7 ) g -C(O)N(R 6 ) 2 , -(R 7 ) g -OR 6 , -O-(R 7 ) g -Ay, -(R 7 ) g -S(O) e R 6 , -(R 7 ) g -N(R 6 ) 2 , -(R 7 ) g -N(R 6 )C(O)R 6 , -(R 7 ) g -CN, -(R 7 ) g -SCN, -NO 2 , -N 3 , Ay and 5- to 9-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S;each R 3 is the same or different and is independently H or alkyl;Y is selected from the group consisting of -C(O)R 8 , -C(S)R 8 , -S(O) e R 9 , -N(R 9 ) 2 , -N(R 9 )-S(O) e R 9 , and -N(R 9 )-C(O)R 9 , or Y, together with C-2 and C-3 form a fused ring system of formula A: wherein R 8 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR 6 , -O-(R 7 ) g -Ay, -O-(R 7 ) g -Het, -N(R 6 ) 2 , -N(R 6 )-(R 7 ) g -Ay, -N(R 6 )-(R 7 ) g -Het, -N(R 6 )-(R 7 ) g -OR 6 , -N(R 6 )-(R 7 ) g -C(O)R 6 , -N(R 6 )-(R 7 ) g -CO 2 R 6 , -N(R 6 )-(R 7 ) g -SO 2 R 6 , and -N(R 6 )-(R 7 ) g -N(R 6 ) 2 ;each R 9 is the same or different and is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay and Het;c is 0 or 1;Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of C, O, S and N, wherein when c is 0, at least one of Z 1 , Z 2 and Z 3 is C and wherein when c is 1, at least two of Z 1 , Z 2 , Z 3 and Z 4 are C;each dashed line represents an optional double bond;d is 0, 1 or 2;each R 10 is the same or different and is independently selected from the group consisting of halo, alkyl, oxo, hydroxy, mercapto and amino;a is 0, 1, 2 or 3;each R 4 is the same or different and is independently selected from the group consisting of halo, alkyl, , -(R 7 ) g -cycloalkyl, -(R 7 ) g -C(O)R 6 , -(R 7 ) g -CO 2 R 6 , , -(R 7 ) g -C(O)N(R 6 ) 2 , -(R 7 ) g -OR 6 , -(R 7 ) g -S(O) e R 6 , -(R 7 ) g -N(R 6 ) 2 , -(R 7 ) g -N(R 6 )C(O)R 6 , each e is the same or different and is independently 0, 1 or 2;b is 0, 1, 2, 3, 4 or 5;each R 5 is the same or different and is a group of formula (R 7 ) g -R 11 , each R 6 is the same or different and is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;g is 0 or 1;R 7 is alkylene or alkenylene;Ay is aryl;Het is a 5- or 6-membered heterocycle or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S;R 11 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, Ay, Het, -C(O)Het, -CO 2 R 6 , -CO 2 Ay, -CO 2 Het, -C(O)N(R 6 ) 2 , -C(O)N(R 6 )Ay, -C(O)N(R 6 )Het, -C(O)N(R 6 )-(R 7 ) g -N(R 6 ) 2 , -C(O)N(R 6 )-(R 7 ) g -CO 2 R 6 , -C(O)N(R 6 )-(R 7 ) g -S(O) e R 6 , -OR 6 , - -O-(R 7 ) g -Ay, -O-(R 7 ) g -Het, -O-R 7 -OR 6 , -O-R 7 -N(R 6 ) 2 , -S(O) e R 6 , -S(O) e -(R 7 ) g -Het, -S(O) e -(R 7 ) g -N(R 6 ) 2 , -S(O) e -(R 7 ) g -N(R 6 )Het, -S(O) e N(R 6 )-(R 7 ) g -C(O)Het, -N(R 6 ) 2 , -N(R 6 )-(R 7 ) g -Ay, -N(R 6 )-(R 7 ) g -Het, -N(R 6 )-(R 7 ) g -C(O)R 6 , -N(R 6 )-C(O)-(R 7 ) g -Het, -N(R 6 )-C(O)-(R 7 ) g -N(R 6 ) 2 , - -N(R 6 )-C(O)-(R 7 ) g -N(R 6 )Het, -N(R 6 )-C(O)-(R 7 ) g -N(R 6 )-(R 7 -O) h -N(R 6 )-CO 2 R 6 , -N(R 6 )-(R 7 ) g -S(O) e R 6 , -N(R 6 )-(R 7 ) g -S(O) e Het, -N(R 6 )-R 7 -N(R 6 ) 2 , -N(R 6 )-R 7 -OR 6 , -CN, , and -N 3 ;and h is 1-20;wherein when R 1 is -CH 3 , R 2 is Br or NO 2 , both R 3 are H, a is 0 and b is 0 or 1 wherein R 5 is -CO 2 H, then Y is not -CO 2 H, "alkyl" (and "alkylene") is "C1-8 straight or branched alkyl (and alkylene) (optionally substituted one or more times with halogen or cyano), "alkenyl" is C2-8 straight or branched alkenyl (optionally substituted one or more times with a halogen or cyano), "alkynyl" is C2-8 straight or branched alkynyl (optionally be substituted one or more times with a halogen or cyano), "cycloalkyl" is C3-8 cycloalkyl ( optionally be substituted on any available carbon with one or more substituents selected from the group consisting of halo, alkyl alkenyl, alkynyl, hydroxyl, oxo, carboxyl, alkyl carboxyl, alkylether, mercapto, sulfonyl, sulfinyl, alkylsulfonyl, sulfonamido, amino, alkylamino, dialkylamino, acetylamino, amino sulfonamide and cyano), "cycloalkenyl" Is C3 - 8 cycloalkenyl (optionally substituted on any available carbon with one or more substituents selected from the group consisting of halo, alkyl (including haloalkyl, e.g., perfluoroalkyl), alkenyl, alkynyl, hydroxyl, oxo, carboxyl, alkylcarboxyl, alkylether, mercapto, sulfonyl, sulfinyl, alkylsulfonyl, sulfonamido, amino, alkylamino, dialkylamino, acetylamino, amino sulfonamide and cyano), Ay is aryl which is monocyclic carbocyclic groups and fused bicyclic carbocyclic groups having from 6 to 13 carbon atoms and having at least one aromatic ring (optionally be substituted on any available carbon with one or more substituents selected from the group consisting of halo, alkyl, alkenyl, alkynyl, hydroxyl, carboxyl, alkylcarboxyl, alkylether, mercapto, sulfonyl, sulfinyl, alkylsulfonyl, sulfonamido, amino, alkylamino, dialkylamino, acetylamino, amino sulfonamido and cyano), "heterocycle and "heterocyclic" is monocyclic saturated or unsaturated non-aromatic groups and fused bicyclic saturated or unsaturated non-aromatic groups, having the specified number of members and containing 1, 2, 3 or 4 heteroatoms selected from N, O and S ( optionally be substituted on any available carbon or heteroatom with one or more substituents selected from the group consisting of halo, alkyl, alkenyl, alkynyl, oxo, hydroxyl, carboxyl, alkylcarboxyl, alkylether, mercapto, sulfonyl, sulfinyl, alkylsulfonyl, sulfonamido, amino, alkylamino, dialkylamino, acetylamino, amino sulfonamide and cyano), "heteroaryl is to aromatic monocyclic groups and fused bicyclic groups wherein at least one ring is aromatic, having the specified number of members and containing 1, 2, 3, or 4 heteroatoms selected from N, O and S (unless a different number of heteroatoms is specified (optionally be substituted on any available carbon or heteroatom with one or more substituents selected from the group consisting of halo, alkyl, alkenyl, alkynyl, oxo, hydroxyl, carboxyl, alkylcarboxyl, alkylether, mercapto, sulfonyl, sulfinyl, alkylsulfonyl, sulfonamido, amino, alkylamino, dialkylamino, acetylamino, amino sulfonamide and cyano). or a pharmaceutically acceptable salt or solvate thereof.
  2. 9
    The compound according to any of claims 1-8, wherein Y is selected from the group consisting of -C(O)R 8 , -C(S)R 8 , -S(O) e R 9 , -N(R 9 ) 2 and -N(R 9 )-S(O) e R 9 .
  3. 12
    The compound according to any of claims 1-8, wherein Y together with C-2 and C-3 form a fused ring system of formula A.
  4. 16
    The compound according to any of claims 1-15, wherein a is 0 or 1.
  5. 17
    The compound according to any of claims 1-16, wherein b is 0, 1, 2 or 3.
  6. 19
    A compound according to Claim 1 wherein:R 1 is H;R 2 is F or methyl;each R 3 is H;Y is -C(O)R 8 ;R 8 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, -OR 6 , -O-(R 7 ) g -Ay, -O-(R 7 ) g -Het, -N(R 6 ) 2 , -N(R 6 )-(R 7 ) g -Ay, -N(R 6 )-(R 7 ) g -Het, -N(R 6 )-(R 7 ) g -OR 6 , -N(R 6 )-(R 7 ) g -C(O)R 6 , -N(R 6 )-(R 7 ) g -CO 2 R 6 , -N(R 6 )-(R 7 ) g -SO 2 R 6 , and -N(R 6 )-(R 7 ) g -N(R 6 ) 2 ;a is 0;b is 0, 1, 2 or 3;each R 5 is the same or different and is a group of formula (R 7 ) g -R 11 ;each R 6 is the same or different and is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;g is 0 or 1;R 7 is alkylene or alkenylene;Ay is aryl;Het is a 5- or 6-membered heterocycle or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S;R 11 is selected from the group consisting of alkyl, Het, -OR 6 , -S(O) e R 6 , -S(O) e -(R 7 ) g -N(R 6 ) 2 , -N(R 6 ) 2 , -N(R 6 )-(R 7 ) g -C(O)R 6 and -N(R 6 )-C(O)-(R 7 ) g -N(R 6 ) 2 or a pharmaceutically acceptable salt thereof.
  7. 20
    A compound selected from the group consisting of:2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzoic acid hydrochloride;2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzamide hydrochloride;N -( tert -butyl)-2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzamide hydrochloride;N -[4-({4-[(2-benzoylphenyl)amino]-5-nitropyrimidin-2-yl}amino)phenyl]acetamide hydrochloride;8-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-3,4-dihydronaphthalen-1(2 H )-one hydrochloride;1-[2-({5-bromo-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)phenyl]ethanone hydrochloride;2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]- N- methylbenzamide hydrochloride;N 4 -(1 H -indol-4-yl)-5-nitro- N 2 -(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine hydrochloride;Methyl 2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzoate hydrochloride;N 4 -(2,3-dihydro-1,4-benzodioxin-5-yl)-5-nitro- N 2 -(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine hydrochloride;Cyclohexyl 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]benzoate hydrochloride;5-Hydroxy-2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzoic acid hydrochloride;2-[(2-{[4-(Acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]benzoic acid hydrochloride;N -[4-({4-[(2-Acetylphenyl)amino]-5-bromopyrimidin-2-yl}amino)phenyl]acetamide hydrochloride;N -[4-({5-Bromo-4-[(2-morpholin-4-ylphenyl)amino]pyrimidin-2-yl}amino)phenyl]acetamide hydrochloride;5-[(5-Bromo-4-{[2-(methylthio)phenyl]amino}pyrimidin-2-yl)amino]-1,3-dihydro-2 H -benzimidazol-2-one hydrochloride;5-Bromo- N 4 -(2-morpholin-4-ylphenyl)- N 2 -(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine hydrochloride;N -[4-({5-Bromo-4-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-2-yl}amino)phenyl]acetamide hydrochloride;Dimethyl 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]terephthalate hydrochloride;Benzyl 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]benzoate hydrochloride;Methyl 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]-6-methylbenzoate hydrochloride;Isobutyl 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]benzoate hydrochloride;2-[(2-{[4-(Acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]-6-methylbenzoic acid hydrochloride;N-Cyclohexyl-2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzamide hydrochloride;1-[2-({5-Nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)phenyl]ethanone hydrochloride;[5-Chloro-2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)phenyl](2-fluorophenyl)methanone hydrochloride;8-({5-Nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2-naphthol hydrochloride;N-( tert -butyl)-2-({5-methyl ketone-2-[(3,4,5- trimethoxyphenyl)amino] pyrimidin-4-yl} amino) benzamide;4-{[2-(4-Methylbenzoyl)phenyl]amino}-2-[(3,4,5-trimethoxyphenyl)amino]-pyrimidine-5-carbonitrile;and pharmaceutically acceptable salts and solvates thereof.
  8. 21
    A pharmaceutical composition comprising a compound according to any of claims 1-20.
  9. 24
    Use of a compound according to claims 1-20 in the manufacture of a medicament for treating a susceptible neoplasm in an animal.
  10. 26
    Use of a compound according to claims 1-20 in the manufacture of a medicament for treating a condition characterized by inappropriate cellular proliferation in an animal.
  11. 27
    Use of a compound according to claims 1-20 in the manufacture of a medicament for inhibiting proliferation of a cell.
  12. 28
    Use of a compound according to claims 1-20 in the manufacture of a medicament for inhibiting mitosis in a cell.
  13. 29
    A compound according to any of claims 1-20 for use in therapy.
  14. 30
    A compound according to any of claims 1-20 for use in the treatment of a susceptible neoplasm in an animal.
  15. 31
    A compound according to any of claims 1-20 for use in the treatment of a condition characterized by inappropriate cellular proliferation in an animal.
  16. 32
    A compound according to any of claims 1-20 for use in inhibiting proliferation of a cell.
  17. 33
    A compound according to any of claims 1-20 for use in inhibiting mitosis in a cell.
  18. 34
    The use of a compound according to any of claims 1-20 for the preparation of a medicament for the treatment of a susceptible neoplasm in an animal.
Independent claims18