Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
View Patent ↗This invention relates to urea compounds containing a pyridine, quinoline, or isoquinoline functionality which is oxidized at the nitrogen heteroatom and which are useful in the treatment of (i) raf mediated diseases, for example, cancer, (ii) p38 mediated diseases such as inflammation and osteoporosis, and (iii) VEGF mediated diseases such as angogenesis disorders.
1. A compound of formula (I) or a salt, prodrug or isolated stereoisomer thereof
M-L-B—NH—C(O)—NH-A I
wherein A is selected from the group consisting of:
(i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 C(O)R 2 halogen, cyano, and nitro;
(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 C(O)R 2 , halogen, cyano, and nitro;
(iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , halogen, cyano, and nitro; and
(iv) 8-10 membered bicyclic heteroaryl, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , halogen, cyano, and nitro;
B is selected from the group consisting of:
(i) phenylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro;
(ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro;
(iii) 5 and 6 membered monocyclic heteroaryl-ene, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro; and
(iv) 8-10 membered bicyclic heteroaryl-ene, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro;
L is selected from the group consisting of:
(a) —(CH 2 ) m —O—(CH 2 ) l —,
(b) —(CH 2 ) m —(CH 2 ) l —,
(c) —(CH 2 ) m —C(O)—(CH 2 ) l —,
(d) —(CH 2 ) m —NR 3a —(CH 2 ) l —,
(e) —(CH 2 ) m —NR 3a C(O)—(CH 2 ) l —,
(f) —(CH 2 ) m —S—(CH 2 ) l —,
(g) —(CH 2 ) m —C(O)NR 3a —(CH 2 ) l —,
(h) —(CH 2 ) m —CF 2 —(CH 2 ) l —,
(i) —(CH 2 ) m —CCl 2 —(CH 2 ) l —,
(j) —(CH 2 ) m —CHF—(CH 2 ) l —,
(k) —(CH 2 ) m —CR 3a (OH)—(CH 2 ) l —;
(l) —(CH 2 ) m —C≡C—(CH 2 ) l —;
(m) —(CH 2 ) m —C═C—(CH 2 ) l —;
(n) a single bond; and
(o) —(CH 2 ) m —CR 3a R 3b (CH 2 ) l —;
wherein m and 1 are integers independently selected from 0-4;
M is selected from the group consisting of:
(a) pyridine-1-oxide substituted 1 to 3 times by a substituent selected from the group consisting of —C(O)NR 4 R 5 , —C(NR 4 )R 5 , —C(O)R 4 , —SO 2 R 4 , and —SO 2 NR 4 R 5 ; which is optionally additionally substituted by Z r ;
(b) quinoline-1-oxide, which is optionally substituted by Z n ; and
(c) isoquinoline-1-oxide, which is optionally substituted by Z n ;
wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R 4 , halogen, cyano, —CO 2 R 4 , —C(O)R 4 , —C(O)NR 4 R 5 , —NO 2 , —OR 4 —, —NR 4 R 5 ,—NR 4 C(O)OR 5 , —NR 4 C(O)R 5 , —S(O) p R 4 , and —SO 2 NR 4 R 5
wherein each R 1 , R 2 , R 4 and R 5 is independently selected from the group consisting of:
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) 5-6 membered monocyclic heteroaryl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S or 8-10 membered bicyclic heteroaryl having 1-6 heteroatoms selected from the group consisting of O, N and S,
(e) C 1 -C 3 alkyl-phenyl,
(f) C 1 -C 3 alkyl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, said heteroaryl including 5-6 membered monocyclic and 8-10 membered bicyclic heteroaryl, and
(g) up to per-halo substituted C 1 -C 5 linear or branched alkyl; and
wherein each R 1 , R 2 , R 4 and R 5 , when not hydrogen or perhalo substituted C 1 -C 5 linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro;
wherein each R 3a and R 3b is hydrogen or C 1 -C 5 linear or branched alkyl;
and p and q are integers each independently selected from 0, 1, or 2
subject to the proviso that formula I does not include compounds of formula II:
wherein,
Y is OR 1 or NHR 2 ,
Hal is chlorine or bromine,
R 1 is H or C 1 -C 6 alkyl
R 2 is H, OH, CH 3 or CH 2 OH,
X 1 to X 7 are each, independently, H, OH or O(CO)C 1 -C 4 alkyl.
2. A compound as in claim 1 wherein A and B of formula I, are each independently:
a substituted or unsubstituted phenyl group,
a substituted or unsubstituted a naphthyl group,
a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or
a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.
3. A compound as in claim 1 wherein A of formula I is
a substituted or unsubstituted phenyl group,
a substituted or unsubstituted a naphthyl group,
a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or
a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl
and B of formula I is
a substituted or unsubstituted phenyl group,
a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or
a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl7 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.
4. A compound as in claim 1 wherein
A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isooxazolyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl,
B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, naphthylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene,
L is selected from the group consisting of —CH 2 O—, —OCH 2 —, —O—, a single bond, —CH 2 —, —NH—, —N(CH 3 )—, —N(CH 3 )CH 2 —, —NC 2 H 4 —, —C(O)—, —NHCH 2 —, —N(CH 3 )C(O)—, —NHC(O)—, —CH 2 N(Cl 3 )—, —C(O)NH—, —CH 2 S—, —SCH 2 —, —S—, —C(O)NCH 3 —, —CH 2 C(O)N(CH 3 )—, —C(O)N(CH 3 )CH 2 —, —CF 2 —, —CCl 2 —, —CHF— and —CH(OH)—, and
M is defined as in claim 1 .
5. A compound as in claim 1 wherein
A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl,
B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene,
L is selected from the group consisting of —CH 2 O—, —OCH 2 —, —O—, a single bond, —CH 2 —, —NH—, —N(CH 3 )—, —N(CH 3 )CH 2 —, —NC 2 H 4 —, —C(O)—, —NHCH 2 —, —N(CH 3 )C(O)—, —NHC(O)—, —CH 2 N(CH 3 )—, —C(O)NH—, —CH 2 S—, —SCH 2 —, —S—, —C(O)NCH 3 —, —CH 2 C(O)N(CH 3 )—, —C(O)N(CH 3 )CH 2 —, —CF 2 —, —CCl 2 —, —CHF— and —CH(OH)—, and
M is defined as in claim 1 .
6. A compound as in claim 4 wherein
A of formula I is a substituted group and the substituents are selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, t-butyl,
N(C 1 -C 5 alkyl)(C 1 -C 5 alkyl);
N(C 1 -C 5 alkyl)(phenyl);
N(C 1 - 5 alkyl)(pyridinyl);
S(O) 2 (C 1 -C 5 alkyl);
SO 2 NH(C 1 -C 5 alkyl);
SO 2 N(C 1 -C 5 alkyl)(C 1 -C 5 alkyl);
NHSO 2 (C 1 -C 5 alkyl);
N(C 1 -C 3 alkyl)SO 2 (C 1 -C 5 alkyl);
CO(C 1 -C 6 alkyl);
CO(phenyl);
CO(pyridinyl);
COO(C 1 -C 6 alkyl);
COO(phenyl);
COO(pyridinyl);
COOH;
CONH 2 ;
CONH(C 1 -C 6 alkyl);
CONH(phenyl);
CONH(pyridinyl);
CON(C 1 -C 6 alkyl);
CON(phenyl);
CON(pyridinyl);
NHCO(C 1 -C 5 alkyl);
NHCO(phenyl);
NHCO(pyridinyl); and
N(C 1 -C 5 alkyl)CO(C 1 -C 5 alkyl).
7. A compound as in claim 1 wherein
A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and
B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, naphthylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene.
8. A compound as in claim 1 wherein
A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and
B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, thienylene, furylene, pyridine-ene, isoquinoline-ene and indole-ene.
9. A compound as in claim 1 wherein
A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and
B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene and pyridine-ene.
10. A compound as in claim 7 wherein
A of formula I is a substituted group and the substituents are selected from the group consisting of:
NH(C 1 -C 5 alkyl);
NH(phenyl);
NH(pyridinyl);
A=phenyl, B=phenylene,
A=phenyl, B=pyridinyl-ene,
A=phenyl, B=isoquinolinyl-ene,
A=pyridinyl, B=phenylene,
A=pyridinyl, B=pyridinyl-ene,
A=pyridinyl, B=isoquinolinyl-ene,
A=naphthyl, B=phenylene,
A=naphthyl, B=pyridinyl-ene,
A=naphthyl, B=isoquinolinyl-ene,
A=isoquinolinyl, B=phenylene,
A=isoquinolinyl, B=pyridinyl-ene,
A=isoquinolinyl, B=isoquinolinyl-ene,
A=quinolinyl, B=phenylene,
A=quinolinyl, B=pyridinyl-ene,
A=quinolinyl, B=isoquinolinyl-ene,
A=pyrazolyl, B=phenylene,
A=pyrazolyl, B=pyridinyl-ene,
A=pyrazolyl, B=isoquinolinyl-ene,
A=isoxazolyl, B=phenylene,
A=isoxazolyl, B=pyridinyl-ene,
A=isoxazolyl, B=isoquinolinyl-ene.
A=indazolyl, B=phenylene,
A=indazolyl, B=pyridinyl-ene,
and
A=indazolyl, B=isoquinolinyl-ene.
11. A compound of formula I of claim 1 wherein in A, and B are one of the following combinations and M is as defined in claim 1 :
methylethyl, methyipropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, butyoxy, pentoxy, methyl sulfonyl, trifluoromethyl sulfonyl, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino and diethylamino.
12. A compound of formula I of claim 1 , wherein in A, and B are one of the following combinations and M is as defined in claim 1 :
A=phenyl, B=phenylene, and
A=phenyl, B=pyridinyl-ene.
13. A compound of formula (I) or a salt, or isolated stereoisomer thereof
M-L-B—NH—C(O)—NH-A I
wherein A is selected from the group consisting of:
(i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 C(O)R 2 , halogen, cyano, and nitro;
(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 C(O)R 2 , halogen, cyano, and nitro;
(iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , halogen, cyano, and nitro; and
(iv) 8-10 membered bicyclic heteroaryl, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , halogen, cyano, and nitro;
B is selected from the group consisting of:
(i) phenylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro;
(ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro;
(iii) 5 and 6 membered monocyclic heteroaryl-ene, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro; and
(iv) 8-10 membered bicyclic heteroaryl-ene, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, halogen, cyano, and nitro;
L is selected from the group consisting of:
(a) —(CH 2 ) m —O—(CH 2 ) l —,
(b) —(CH 2 ) m —(CH 2 ) l —,
(c) —(CH 2 ) m —C(O)—(CH 2 ) l —,
(d) —(CH 2 ) m —NR 3a —(CH 2 ) l —,
(e) —(CH 2 ) m —NR 3a C(O)—(CH 2 ) l —,
(f) —(CH 2 ) m —S—(CH 2 ) l —,
(g) —(CH 2 ) m —C(O)NR 3a —(CH 2 ) l —,
(h) —(CH 2 ) m —CF 2 —(CH 2 ) l —,
(i) —(CH 2 ) m —CCl 2 —(CH 2 ) l —,
(j) —(CH 2 ) m —CHF—(CH 2 ) l —,
(k) —(CH 2 ) m —CR 3a (OH)—(CH 2 ) l —;
(l) —(CH 2 ) m —C≡C—(CH 2 ) l —;
(m) —(CH 2 ) m —C═C—(CH 2 ) l —;
(n) a single bond; and
(o) —(CH 2 ) m —CR 3a R 3b —(CH 2 ) l —;
wherein m and l are integers independently selected from 0-4;
M is selected from the group consisting of:
(a) pyridine-1-oxide substituted 1 to 3 times by a substituent selected from the group consisting of —C(O)NR 4 R 5 , —C(NR 4 )R 5 , —C(O)R 4 , —SO 2 R 4 , and —SO 2 NR 4 R 5 ; which is optionally additionally substituted by Z r ;
(b) quinoline-1-oxide, which is optionally substituted by Z n ; and
(c) isoquinoline-1-oxide, which is optionally substituted by Z n ;
wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R 4 , halogen, cyano, —CO 2 R 4 , —C(O)R 4 , —C(O)NR 4 R 5 , —NO 2 , —OR 4 —, —NR 4 R 5 , —NR 4 C(O)OR 5 , —N 4 C(O)R 5 , —S(O) p R 4 , and —SO 2 NR 4 R 5
wherein each R 1 , R 2 , R 4 and R 5 is independently selected from the group consisting of:
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) 5-6 membered monocyclic heteroaryl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S or 8-10 membered bicyclic heteroaryl having 1-6 heteroatoms selected from the group consisting of O, N and S,
(e) C 1 -C 3 alkyl-phenyl,
(f) C 1 -C 3 alkyl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, said heteroaryl including 5-6 membered monocyclic and 8-10 membered bicyclic heteroaryl, and
(g) up to per-halo substituted C 1 -C 5 linear or branched alkyl; and
wherein each R 1 , R 2 , R 4 and R 5 , when not hydrogen or perhalo substituted C 1 -C 5 linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro;
wherein each R 3a and R 3b is hydrogen or C 1 -C 5 linear or branched alkyl;
and p and q are integers each independently selected from 0, 1, or 2
subject to the proviso that formula I does not include compounds of formula II:
wherein,
Y is OR 1 or NHR 2 ,
Hal is chlorine or bromine,
R 1 is H or C 1 -C 6 alkyl
R 2 is H, OH, CH 3 or CH 2 OH,
X 1 to X 7 are each, independently, H, OH or O(CO)C 1 -C 4 alkyl.
14. A compound as in claim 13 wherein A and B of formula I, are each independently:
a substituted or unsubstituted phenyl group,
a substituted or unsubstituted a naphthyl group,
a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or
a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzoxazolyl, 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzothiazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.
15. A pharmaceutical composition comprising
a) one or more compounds of formula I of claim 1 , or a isolated stereoisomer, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (I) and
b) at least one pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising
a) one or more compounds of formula I of claim 1 , or a salt, prodrug or isolated stereoisomer of a compound of formula I,
b) at least one other cytotoxic or cytostatic chemotherapeutic agent, wherein the amounts of a) and b) are jointly effective for treating a cancer, and
c) at least one pharmaceutically acceptable carrier.
17. A kit comprising a separate dose of a compound of formula I of claim 1 , or a salt, prodrug or isolated stereoisomer thereof, and a separate dose of a cytotoxic or cytostatic chemotherapeutic agent in separate containers.