Nova Patents
EP1597251A2

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.

Term

Term ended

Projected expiry passed 11 February 2024, 2.6 years ago.

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43 claims: 34 independent, 9 dependent

  1. 1
    Claims of equivalent WO 2004074244 A2 CLAIMS 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 , -S(O) e N(R 9 ) 2 , -N(R 9 ) 2 , -N(R 9 )-S(O) e R 9 , -N(R 9 )-C(O)R 9 , -N(R 9 )-CO 2 R 9 , and -N(R 9 )-C(O)N(R 9 ) 2 , or Y, together with C-2 and C-3 form a fused ring system of formula A: wherein R >8 H 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, alkenyl, alkynyl, -(R 7 ) g -cycloalkyl, -(R 7 ) g -cycloalkenyl, -(R 7 ) g -Ay, -(R 7 ) g -Het, -(R 7 ) g -C(O)R 6 , -(R 7 ) g -C(O)Ay, -(R 7 ) g -C(O)Het, -(R 7 ) g -CO 2 R 6 , -(R 7 ) g -CO 2 Ay, -(R 7 ) g -CO 2 Het, -(R 7 ) g -C(O)N(R 6 ) 2 , -(R 7 ) g -OR 6 , -(R 7 ) g -OAy, -(R 7 ) g -OHet, -(R 7 ) g -OC(O)R 6 , -(R 7 ) g -OC(O)Ay, -(R 7 ) g -OC(O)Het, -(R 7 ) g -S(O) e R 6 , -(R 7 ) g -S(O) e Ay, -(R 7 ) g -S(O) e Het, -(R 7 ) g -S(O)eN(R 6 ) 2 , -(R 7 ) g -S(O) e N(R 6 )Ay, -(R 7 )g-S(O) e N(R 6 )Het, -(R 7 ) g -N(R 6 ) 2 , -(R 7 ) g -N(R 6 )Ay, -(R 7 ) g -N(R 6 )Het, -(R 7 ) g -N(R 6 )C(O)R 6 , -(R 7 ) g -N(R 6 )C(O)Ay, -(R 7 ) g -N(R 6 )C(O)Het, -(R 7 )g-N(R 6 )C(O)N(R 6 ) 2 , -(R 7 ) g -N(R 6 )S(O) e R 6 , -(R 7 ) g -N(R 6 )S(O) e Ay, -(R 7 )g-N(R 6 )S(O) e Het, -NO 2 , -CN, -SCN and -N 3 , or two adjacent R 4 groups together with the carbon atoms to which they are bonded form a phenyl or a 5- or 6-membered heterocycle or heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of O, N and S;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 n , or two adjacent R 5 groups are each the same or different and are independently selected from the group consisting of alkyl, alkenyl, -OR 6 , -S(O) e R 6 and -N(R 6 ) 2 and, together with the carbon atoms to which they are bonded, they form a C 5-6 cycloalkyl, Cs-βcycloalkenyl or a 5- or 6-membered heterocycle or heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S;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, cycloalkyl, cycloalkenyl, Ay, Het, -C(O)R 6 , -C(O)Ay, -C(O)Het, -CO 2 R 6 , -CO 2 Ay, -CO 2 Het, -C(O)-R 7 -OR 6 , -C(O)-R 7 -OAy, -C(O)-R 7 -OHet, -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 , -OC(O)R 6 , -O-(R 7 ) g -Ay, -OC(O)Ay, -O-(R 7 ) g -Het, -OC(O)Het, -O-R 7 -OR 6 , -O-R 7 -N(R 6 ) 2 , -S(O) e R 6 , -S(O) e -(R 7 ) g -Ay, -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 )Ay, -S(O) e -(R 7 ) g -N(R 6 )Het, -S(O) e N(R 6 )-(R 7 )g-C(O)R 6 , -S(O) e N(R 6 )-(R 7 ) g -C(O)Ay, -S(O)eN(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 -Ay, -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 )Ay, -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) -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 Ay, -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, -SCN, -NO 2 , and -N 3 ;and h is 1-20;wherein when R 1 is -CH , 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 or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  2. 8
    The compound according to any of claims 1-7, wherein Y is selected from the group consisting of -C(O)R 8 , -C(S)R 8 , -S(O) e R 9 , -S(O) e N(R 9 ) 2 , -N(R 9 ) 2 and -N(R 9 )-S(O) e R 9 .
  3. 9
    The compound according to any of claims 1-7, wherein Y is selected from the group consisting of -C(O)R 8 , -S(O) e R 9 , -S(O) e N(R 9 ) 2 , -N(R 9 ) 2 and -N(R 9 )-S(O) e R 9 .
  4. 10
    The compound according to any of claims 1-7, wherein Y is -C(O)R 8 .
  5. 11
    The compound according to any of claims 1-7, wherein Y together with C-2 and C-3 form a fused ring system of formula A.
  6. 12
    The compound according to any of claims 1-7, wherein Y together with C-2 and C-3 form a fused ring system of formula A and at least one of Z 1 , Z 2 , Z 3 and Z 4 is selected from the group consisting of N, O and S.
  7. 13
    The compound according to any of claims 1-7, wherein Y together with C-2 and C-3 form a fused ring system of formula A and d is 0 or 1.
  8. 14
    The compound according to any of claims 1-7, wherein Y together with C-2 and C-3 form a fused ring system of formula A, d is 1 or 2 and each R 10 is the same or different and is independently selected from halo and alkyl.
  9. 15
    The compound according to any of claims 1-14, wherein a is 0 or 1.
  10. 16
    The compound according to any of claims 1-15, wherein each R 4 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -(R 7 ) g -cycloalkyl, -(R 7 ) g -cycloalkenyl, -(R 7 ) g -Ay, -(R 7 ) g -Het, -(R 7 )g-C(O)R 6 , -(R 7 ) g -C(O)Ay, -(R 7 ) g -C(O)Het, -(R 7 ) g -CO 2 R 6 , -(R 7 ) g -CO 2 Ay, -(R 7 ) g -CO 2 Het, -(R 7 ) g -C(O)N(R 6 ) 2 , -(R 7 ) g -OR 6 , -(R 7 ) g -OAy, -(R 7 ) g -OHet, -(R 7 ) g -OC(O)R 6 , -(R 7 ) g -OC(O)Ay, -(R 7 ) g -OC(O)Het, -(R 7 ) g -S(O) e R 6 , -(R 7 ) g -S(O) e Ay, -(R 7 ) g -S(O) e N(R 6 ) 2 , -(R 7 ) g -S(O) e N(R 6 )Ay, -(R 7 ) g -S(O) e N(R 6 )Het, -(R 7 )g-N(R 6 ) 2 , -(R 7 ) g -N(R 6 )Ay, -(R 7 ) g -N(R 6 )Het, -(R 7 ) g -N(R 6 )C(O)R 6 , -(R 7 ) g -N(R 6 )C(O)N(R 6 ) 2 , -NO 2 , -CN, -SCN and -N 3 .
  11. 17
    The compound according to any of claims 1-15, wherein 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 and -(R 7 ) g -N(R 6 )C(O)R 6 .
  12. 18
    The compound according to any of claims 1-17, wherein b is 0, 1, 2 or 3.
  13. 19
    The compound according to any of claims 1-18, wherein 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)n-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 .
  14. 20
    The compound according to any of claims 1-19, wherein each R 11 is the same or different and is independently 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 .
  15. 21
    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;/\A(te/ -butyl)-2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4- yl}amino)benzamide hydrochloride;ΛA[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-l(2 V)-one hydrochloride;l-[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]-/\A methylbenzamide hydrochloride;/\^-(l indol-4-yl)-5-nitro-Λ ? -(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;Λ/^-(2,3-dihydro-l,4-benzodioxin-5-yl)-5-nitro-Λ 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;/V-[4-({4-[(2-Acetylphenyl)amino]-5-bromopyrimidin-2- yl}amino)phenyl]acetamide hydrochloride;/V-[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]-l,3- dihydro-2 benzimidazol-2-one hydrochloride;5-Bromo-Λ/ t -(2-morpholin-4-ylphenyl)-Λ 2 -(3,4,5-trimethoxyphenyl)pyrimidine- 2,4-diamine hydrochloride;ΛA[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;Λ £ -Cyclohexyl-2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4- yl}amino)benzamide hydrochloride;l-[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-(fe/ -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, solvates and physiologically functional derivatives thereof.
  16. 22
    A pharmaceutical composition comprising a compound according to any of claims 1-21.
  17. 24
    The pharmaceutical composition according to any of claims 22-23 further comprising a chemotherapeutic agent.
  18. 25
    A method for treating a condition mediated by PLK in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to any of claims 1-21.
  19. 26
    A method for treating a susceptible neoplasm in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to any of claims 1-21.
  20. 28
    A method for treating a condition characterized by inappropriate cellular proliferation in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to any of claims 1-21.
  21. 29
    A method for inhibiting proliferation of a cell, said method comprising contacting the cell with an amount of a compound according to any of claims 1-21 sufficient to inhibit proliferation of the cell.
  22. 30
    A method for inhibiting mitosis in a cell, said method comprising administering to the cell an amount of a compound according to any of claims 1-21 sufficient to inhibit mitosis in the cell.
  23. 31
    A process for preparing a compound according to any of claims 1-21, said process comprising reacting a compound of formula (IV):wherein R 15 is selected from the group consisting of halo and -S(O) e R 6 . with a compound of formula (V):
  24. 33
    The process according to any of claims 31-32 further comprising the step of converting a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof to another compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  25. 34
    A compound according to any of Claims 1-21 for use in therapy.
  26. 35
    A compound according to any of Claims 1-21 for use in the treatment of a condition mediated by PLK in an animal.
  27. 36
    A compound according to any of claims 1-21 for use in the treatment of a susceptible neoplasm in an animal.
  28. 37
    A compound according to any of claims 1-21 for use in the treatment of a condition characterized by inappropriate cellular proliferation in an animal.
  29. 38
    A compound according to any of claims 1-21 for use in inhibiting proliferation of a cell.
  30. 39
    A compound according to any of claims 1-21 for use in inhibiting mitosis in a cell.
  31. 40
    The use of a compound according to any of claims 1-21 for the preparation of a medicament for the treatment of condition mediated by PLK in an animal.
  32. 41
    The use of a compound according to any of claims 1-21 for the preparation of a medicament for the treatment of a susceptible neoplasm in an animal.
  33. 42
    The use of a compound according to any of claims 1-21 for the preparation of a medicament for the treatment of a condition characterized by inappropriate cellular proliferation.
  34. 43
    A pharmaceutical composition comprising a compound according to any of claims 1-21 for use in the treatment of a susceptible neoplasm in an animal.
Independent claims34