| US 7,354,933 B2 | ||
| Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors | ||
| Marcel Patek, Tucson, Ariz. (US); Anil Nair, Tucson, Ariz. (US); Augustin Hittinger, Igny (France); Conception Nemecek, Thiais (France); Daniel Bond, Tucson, Ariz. (US); Greg Harlow, Boulder, Colo. (US); Herve Bouchard, Thiais (France); Jacques Mauger, Tucson, Ariz. (US); Jean-Luc Malleron, Marcoussis (France); Mark Palermo, Rindge, N.H. (US); Fahad Al-Obeidi, Tucson, Ariz. (US); Thomas Faitg, Exton, Pa. (US); Hartmut Strobel, Liederbach (Germany); Sven Ruf, Floersheim (Germany); Kurt Ritter, Frankfurt Am Main (Germany); Youssef El-Ahmad, Creteil (France); Dominique Lesuisse, Montreuil (France); and Didier Bénard, Attainville (France) | ||
| Assigned to Aventis Pharma SA, Antony (France) | ||
| Filed on Feb. 02, 2004, as Appl. No. 10/770,382. | ||
| Claims priority of provisional application 60/468685, filed on May 07, 2003. | ||
| Claims priority of application No. 03 01098 (FR), filed on Jan. 31, 2003. | ||
| Prior Publication US 2004/0248884 A1, Dec. 09, 2004 | ||
| Int. Cl. C07D 401/06 (2006.01); C07D 403/06 (2006.01); A61K 31/41 (2006.01) | ||
| U.S. Cl. 514—314 [514/341; 514/389; 514/391; 546/172; 546/274.4; 548/319.1] | 58 Claims |
1. The compound of formula I:
![]() p is 0,
R and R1, which may be identical or different, are O or NH,
R2 and R3, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyphenylalkyl, thienylbenzothienylalkyl,
phenylalkyl, pyridylalkyl, benzothienylalkyl, aryl or heteroaryl, the phenylalkyl, pyridylalkyl, and benzothienylalkyl being
optionally substituted with one or more radicals chosen from halogen, hydroxyl, alkyl and alkoxy containing from one to four
carbon atoms,
A1 is single bond, alkyl, alkenyl or alkynyl,
Y and Y1, which may be identical or different, are such that one of Y and Y1 is —OCF3, —O—CF2—CHF2, —O—CHF2, —O—CH2—CF3, —SO2NR5R6, —SF5 or —S(O)n-alkyl and the other of Y and Y1 is —OCF3, —O—CF2—CHF2, —O—CHF2, —O—CH2—CF3, SO2NR5R6, —SF5, —S(O)n-alkyl, hydrogen, halogen, hydroxyl, alkoxy, nitro, —CN, —NR5R6, alkyl, aryl, heteroaryl, —CF3, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —S(O)n-alkenyl, —S(O)n-alkynyl, —S(O)n-cycloalkyl, —CONR5R6, or free, salified or esterified carboxyl,
or the
![]() ![]() that is optionally substituted with one or more alkyl that are optionally substituted,
q is 2, 3 or 4,
R5 and R6, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,
aryl or heteroaryl, or R5 and R6 taken together with the nitrogen atom to which they are attached form a 3- to 10-membered
heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7,
A2, which may be identical to or different from A1, is defined as A1 or is CO or SO2,
B2 is a saturated or unsaturated 3- to 10-membered monocyclic or bicyclic heterocyclyl containing one or more hetero atoms
chosen from O, S, N and NR7 that is optionally substituted with one or more identical or different substituents defined as
Y2,
R7 is hydrogen, alkyl, cycloalkyl, phenyl, acyl, —S(O)2Alk, —S(O)2Aryl, —S(O)2heteroaryl or —S(O)2NR5R6,
Y2 is hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, phenyl optionally substituted with
—NR5R6, heteroaryl, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —S(O)n-alkyl, —S(O)n-alkenyl, —S(O)n-alkynyl, —S(O)n-cycloalkyl, —COOR13, —COOR9, —OCOR13, —OCOR8, NR5R6, CONR5R6, —S(O)n—NR5R6, —NR10-CO—R13, —NHCOR8, —NHS(O)nR8, —NH—S(O)nCF3, —NR10-SO2—R13, NH—SO2—NR5R6, —NR10-CO—NR5R6, —NR10-CS—NR5R6 or —NR10-COOR13, all of which are optionally substituted,
all the alkyl, alkenyl, alkynyl and alkoxy above are linear or branched and contain not more than 6 carbon atoms,
all the cycloalkyl and heterocyclyl above contain not more than 7 carbon atoms,
all the aryl and heteroaryl above contain not more than 10 carbon atoms,
all the carbocyclyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl above, and also the ring
formed by R5 and R6 with the nitrogen atom to which they are attached, are optionally substituted with one or more substituents,
which may be identical or different, selected from the group consisting of halogen, cyano, hydroxyl, alkoxy, —CF3, nitro, aryl, heteroaryl, —C(═O)—OR9, —C(═O)—R8, —NR11R12, —C(═O)—NR11R12, —N(R10)-C(═O)—R8, —N(R10)-C(═O)—OR9, —N(R10)-C(═O)—NR11R12,
—N(R10)-S(O)n—R8, —S(O)n—R8, —N(R10)-S(O)n—NR11R12 and —S(O)n—NR11R12,
all the aryl and heteroaryl above are optionally substituted with one or more substituents selected from the group consisting
of alkyl, alkoxy and alkylenedioxy,
all the cyclic radicals above, and also the ring formed by R5 and R6 with the nitrogen atom to which they are attached, are
optionally substituted with one or more substituents selected from the group consisting of oxo and thioxo,
n is 0 to 2,
R8 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,
R9 is defined as R8 or is hydrogen,
R10 is hydrogen or alkyl,
R11 and R12, which may be identical or different, are hydrogen, C3-C6 cycloalkyl, cycloalkylalkyl, C1-C4 alkyl, phenyl, or phenylalkyl, optionally substituted with one or more substituents, which may be identical or different,
selected from the group consisting of C1-C4 alkyl, halogen, cyano, hydroxyl, alkoxy, —CF3, nitro, phenyl, and free, salified, esterified or amidated carboxyl,
or R11 and R12 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered cyclic radical containing
one or more hetero atoms chosen from O, S, N and NR7, and R13, which may be identical to or different from R5 or R6, is defined
as R5 or R6, or
a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral
or organic acid or with a mineral or organic base thereof,
with the proviso:
a) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least
one is —OCF3 or —S-alk, A2 is single bond or alkyl and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen
and the other imidazolylalkyl;
b) when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least
one is —S(O)n-alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not
selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl; or
c) when p is 0, R and R1 are oxygen, A1 is single bond, Y and Y1, which may be identical or different, are one is —SO2Alk or SO2NH2 and the other is NR5R6, A2 is single bond or alkylene and B2 is optionally substituted 5- to 10-membered heterocyclyl, then
R2 and R3 are not both hydrogen.
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