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US 7,678,811 B2Granted
Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
AssigneeBayer HealthCare LLC
InventorsJacques Dumas, William J. Scott, Bernd Riedl
Life of this patent
Estimating the term…
Abstract
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.
Claims17
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 R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1C(O)R2 halogen, cyano, and nitro;
- (ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1C(O)R2, 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 R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1COR2, 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 R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1COR2, 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 C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 dialkylamino, halogen, cyano, and nitro;
- (ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 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 C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 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 C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 dialkylamino, halogen, cyano, and nitro;
- L is selected from the group consisting of:
- (a) —(CH2)m—O—(CH2)l—,
- (b) —(CH2)m—(CH2)l—,
- (c) —(CH2)m—C(O)—(CH2)l—,
- (d) —(CH2)m—NR3a—(CH2)l—,
- (e) —(CH2)m—NR3aC(O)—(CH2)l—,
- (f) —(CH2)m—S—(CH2)l—,
- (g) —(CH2)m—C(O)NR3a—(CH2)l—,
- (h) —(CH2)m—CF2—(CH2)l—,
- (i) —(CH2)m—CCl2—(CH2)l—,
- (j) —(CH2)m—CHF—(CH2)l—,
- (k) —(CH2)m—CR3a(OH)—(CH2)l—;
- (l) —(CH2)m—C≡C—(CH2)l—;
- (m) —(CH2)m—C═C—(CH2)l—;
- (n) a single bond;
- and
- (o) —(CH2)m—CR3aR3b(CH2)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)NR4R5, —C(NR4)R5, —C(O)R4, —SO2R4, and —SO2NR4R5;
- which is optionally additionally substituted by Zr;
- (b) quinoline-1-oxide, which is optionally substituted by Zn;
- and
- (c) isoquinoline-1-oxide, which is optionally substituted by Zn;
- wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R4, halogen, cyano, —CO2R4, —C(O)R4, —C(O)NR4R5, —NO2, —OR4—, —NR4R5,—NR4C(O)OR5, —NR4C(O)R5, —S(O)pR4, and —SO2NR4R5
- wherein each R1, R2, R4 and R5 is independently selected from the group consisting of:
- (a) hydrogen,
- (b) C1-C5 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) C1-C3 alkyl-phenyl,
- (f) C1-C3 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 C1-C5 linear or branched alkyl;
- and
- wherein each R1, R2, R4 and R5, when not hydrogen or perhalo substituted C1-C5 linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
- wherein each R3a and R3b is hydrogen or C1-C5 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 OR1 or NHR2,
- Hal is chlorine or bromine,
- R1 is H or C1-C6 alkyl
- R2 is H, OH, CH3 or CH2OH,
- X1 to X7 are each, independently, H, OH or O(CO)C1-C4 alkyl.
54 more elements
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 R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1C(O)R2, halogen, cyano, and nitro;
- (ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1C(O)R2, 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 R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1COR2, 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 R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, COR1, COOR1, CONR1R2, NR1COR2, 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 C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 dialkylamino, halogen, cyano, and nitro;
- (ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 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 C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 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 C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C3 dialkylamino, halogen, cyano, and nitro;
- L is selected from the group consisting of:
- (a) —(CH2)m—O—(CH2)l—,
- (b) —(CH2)m—(CH2)l—,
- (c) —(CH2)m—C(O)—(CH2)l—,
- (d) —(CH2)m—NR3a—(CH2)l—,
- (e) —(CH2)m—NR3aC(O)—(CH2)l—,
- (f) —(CH2)m—S—(CH2)l—,
- (g) —(CH2)m—C(O)NR3a—(CH2)l—,
- (h) —(CH2)m—CF2—(CH2)l—,
- (i) —(CH2)m—CCl2—(CH2)l—,
- (j) —(CH2)m—CHF—(CH2)l—,
- (k) —(CH2)m—CR3a(OH)—(CH2)l—;
- (l) —(CH2)m—C≡C—(CH2)l—;
- (m) —(CH2)m—C═C—(CH2)l—;
- (n) a single bond;
- and
- (o) —(CH2)m—CR3aR3b—(CH2)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)NR4R5, —C(NR4)R5, —C(O)R4, —SO2R4, and —SO2NR4R5;
- which is optionally additionally substituted by Zr;
- (b) quinoline-1-oxide, which is optionally substituted by Zn;
- and
- (c) isoquinoline-1-oxide, which is optionally substituted by Zn;
- wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R4, halogen, cyano, —CO2R4, —C(O)R4, —C(O)NR4R5, —NO2, —OR4—, —NR4R5, —NR4C(O)OR5, —N4C(O)R5, —S(O)pR4, and —SO2NR4R5
- wherein each R1, R2, R4 and R5 is independently selected from the group consisting of:
- (a) hydrogen,
- (b) C1-C5 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) C1-C3 alkyl-phenyl,
- (f) C1-C3 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 C1-C5 linear or branched alkyl;
- and
- wherein each R1, R2, R4 and R5, when not hydrogen or perhalo substituted C1-C5 linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
- wherein each R3a and R3b is hydrogen or C1-C5 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 OR1 or NHR2,
- Hal is chlorine or bromine,
- R1 is H or C1-C6 alkyl
- R2 is H, OH, CH3 or CH2OH,
- X1 to X7 are each, independently, H, OH or O(CO)C1-C4 alkyl.
54 more elements
Dependencies are inferred from the claim text.