Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
First Claim
1. A method for treating a raf-mediated tumor, a p38-mediated inflammation, or a disease which is mediated by the VEGF-induced signal transduction pathway that involves abnormal angiogenesis or hyperpermiability processes in a human or other mammal selected from the group consisting of tumor growth, optionally tumor growth wherein the tumor is a tumor of the lungs, thyroid, breast, gastrointestinal tract, kidney and bladder, ovary, cervix, angiosarcoma, or intracranial, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration, rheumatoid arthritis, psoriasis, a bullous disorder associated with subepidermal blister formation, bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, and diabetic retinopathy, comprising administering a compound of formula I or a salt or isolated stereoisomer thereof to a human or other mammal in need 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)1—
,(b) —
(CH2)m—
(CH2)1—
,(c) —
(CH2)m—
C(O)—
(CH2)1—
,(d) —
(CH2)m—
NR3a—
(CH2)1—
,(e) —
(CH2)m—
NR3aC(O)—
(CH2)1—
,(f) —
(CH2)m—
S—
(CH2)1—
,(g) —
(CH2)m—
C(O)NR3a—
(CH2)1—
,(h) —
(CH2)m—
CF2—
(CH2)1—
,(i) —
(CH2)m—
CCl2—
(CH2)1—
,(j) —
(CH2)m—
CHF—
(CH2)1—
,(k) —
(CH2)m—
C R3a(OH)—
(CH2)1—
;
(l) —
(CH2)m—
C≡
C—
(CH2)1—
;
(m) —
(CH2)m—
C═
C—
(CH2)1—
;
(n) a single bond; and
(o) —
(CH2)m—
CR3aR3b—
(CH2)1—
;
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;
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0 Petitions
Accused Products
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 angiogenesis disorders.
-
Citations
19 Claims
-
1. A method for treating a raf-mediated tumor, a p38-mediated inflammation, or a disease which is mediated by the VEGF-induced signal transduction pathway that involves abnormal angiogenesis or hyperpermiability processes in a human or other mammal selected from the group consisting of tumor growth, optionally tumor growth wherein the tumor is a tumor of the lungs, thyroid, breast, gastrointestinal tract, kidney and bladder, ovary, cervix, angiosarcoma, or intracranial, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration, rheumatoid arthritis, psoriasis, a bullous disorder associated with subepidermal blister formation, bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, and diabetic retinopathy, comprising administering a compound of formula I or a salt or isolated stereoisomer thereof to a human or other mammal in need 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)1—
,(b) —
(CH2)m—
(CH2)1—
,(c) —
(CH2)m—
C(O)—
(CH2)1—
,(d) —
(CH2)m—
NR3a—
(CH2)1—
,(e) —
(CH2)m—
NR3aC(O)—
(CH2)1—
,(f) —
(CH2)m—
S—
(CH2)1—
,(g) —
(CH2)m—
C(O)NR3a—
(CH2)1—
,(h) —
(CH2)m—
CF2—
(CH2)1—
,(i) —
(CH2)m—
CCl2—
(CH2)1—
,(j) —
(CH2)m—
CHF—
(CH2)1—
,(k) —
(CH2)m—
C R3a(OH)—
(CH2)1—
;(l) —
(CH2)m—
C≡
C—
(CH2)1—
;(m) —
(CH2)m—
C═
C—
(CH2)1—
;(n) a single bond; and (o) —
(CH2)m—
CR3aR3b—
(CH2)1—
;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 —
SO2NR4R5wherein 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; - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18, 19)
- NH—
-
15. A method for treating a raf-mediated tumor, a p38-mediated inflammation, or a disease which is mediated by the VEGF-induced signal transduction pathway that involves abnormal angiogenesis or hyperpermiability processes in a human selected from the group consisting of tumor growth, optionally tumor growth wherein the tumor is a tumor of the lungs, thyroid, breast, gastrointestinal tract, kidney and bladder, ovary, cervix, angiosarcoma, or intracranial, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration, rheumatoid arthritis, psoriasis, a bullous disorder associated with subepidermal blister formation, bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, and diabetic retinopathy, comprising administering a compound of formula I or a salt, or isolated stereoisomer thereof to a human or other mammal in need thereof,
M-L-B—- NH—
C(O)—
NH-A
Iwherein 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)1—
,(b) —
(CH2)m—
(CH2)1—
,(c) —
(CH2)m—
C(O)—
(CH2)1—
,(d) —
(CH2)m—
NR3a—
(CH2)1—
,(e) —
(CH2)m—
NR3aC(O)—
(CH2)1—
,(f) —
(CH2)m—
S—
(CH2)1—
,(g) —
(CH2)m—
C(O)NR3a—
(CH2)1—
,(h) —
(CH2)m—
CF2—
(CH2)1—
,(i) —
(CH2)m—
CCl2—
(CH2)1—
,(j) —
(CH2)m—
CHF—
(CH2)1—
,(k) —
(CH2)m—
C R3a(OH)—
(CH2)1—
;(l) —
(CH2)m—
C≡
C—
(CH2)1—
;(m) —
(CH2)m—
C═
C—
(CH2)1—
;(n) a single bond; and (o) —
(CH2)m—
CR3aR3b—
(CH2)1—
;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 —
SO2NR4R5wherein 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; - View Dependent Claims (16)
- NH—
Specification