US2010075971A1PendingUtilityA1
Substituted pyridine derivatives useful in the treatment of cancer and other disorders
Est. expiryFeb 28, 2023(expired)· nominal 20-yr term from priority
Inventors:Jacques DumasWendy LeeYuanwei ChenLila AdnaneWilliam ScottSharad Kumar VermaJianqing ChenZhi ChenLin Yi
A61P 35/04A61P 43/00A61P 35/02A61P 9/14A61P 35/00A61P 19/02C07D 405/12C07D 401/12C07D 417/12C07D 213/84C07D 213/68
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Claims
Abstract
This invention relates to novel diaryl ureas, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and angiogenesis disorders, as a sole agent or in combination with cytotoxic therapies.
Claims
exact text as granted — not AI-modified1 ) A compound of formula (I)
or a pharmaceutically acceptable salt, wherein
A is phenyl, naphthyl, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzoxazole, indazole, quinoline, quinazoline, imidazopyrimidine, naphtyridine, or a group of the formula,
or a group of the formula
optionally substituted with 1-4 substituents which are independently R 1 , OR 1 , S(O) p R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , halogen, hydroxy, oxide, amino, cyano, or nitro;
B is phenyl, naphthyl, or pyridyl, optionally substituted with 1-4 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;
L is
(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 3 —(CH 2 ) l —,
(e) —(CH 2 ) m —NR 3 C(O)—(CH 2 ) l —,
(f) —(CH 2 ) m —S—(CH 2 ) l —,
(g) —(CH 2 ) m —C(O)NR 3 —(CH 2 ) l —, or
(h) a single bond;
m and l are integers independently selected from 0-4;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or
(10) a group of the formula
wherein each of R 1 , R 2 , R 3 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is a tetrahydropyrane, tetrahydrofurane, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofurane, dihydrothiophene, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine or; benzoxazole, indazole, quinoline, quinazoline, imidazopyrimidine or naphtyridine
R 4 and R 5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently 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, oxo, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) cyano,
(d) nitro,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —C(O)R 7 , where R 7 is C 1 -C 5 linear, branched, or cyclic alkyl;
R 7 is hydrogen or linear, branched, or cyclic C 1 -C 5 alkyl;
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
2 ) A compound of claim 1 wherein B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
3 ) (canceled)
4 ) (canceled)
5 ) A compound of claim 1 wherein A and B follow one of the following combinations:
A=phenyl and B=phenyl, A=indazolyl and B=phenyl, A=quinolinyl and B=phenyl, A=4H-benzo[1,3]dioxin-6-yl and B=phenyl; A=phenyl and B=pyridyl, A=indazolyl and B=pyridyl, A=quinolinyl and B=pyridyl, or A=4H-benzo[1,3]dioxin-6-yl and B=pyridyl.
6 ) A compound which is
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)urea N-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)-N′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[3-({2-[(2,2-dimethylhydrazino)carbonyl]pyridin-4-yl}oxy)phenyl]urea 4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-piperidin-1-ylpyridine-2-carboxamide N-piperidin-1-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide 4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-morpholin-4-ylpyridine-2-carboxamide N-morpholin-4-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide 4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-N-morpholin-4-ylpyridine-2-carboxamide N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(1H-tetrazol-5-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(4-methyl-1,3-thiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-quinolin-6-yl-N′-(4-{[2-(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)-N′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboximidamide 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carboximidamide N-methyl-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboximidamide N-methyl-4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carboximidamide 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carbothioamide 4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carbothioamide or 4-[4-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carbothioamide
7 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 1 and a physiologically acceptable carrier.
8 ) A method for treating or preventing a hyper-proliferative disorder in a human or other mammal comprising administering to a human or other mammal in need thereof a compound of claim 1 .
9 ) A method for treating or preventing a hyper-proliferative disorder in a human or other mammal comprising administering to a human or other mammal in need thereof a compound of claim 1 and an additional anti-proliferative agent.
10 ) A method for treating or preventing cancer in a human or other mammal comprising administering to a human or other mammal in need thereof a compound of claim 1 and a cytotoxic agent or cytostatic chemotherapeutic agent.
11 ) A method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase, associated with an aberration in the tyrosine kinase signal transduction pathway, comprising administering to a human or other mammal in need thereof a compound of claim 1 .
12 ) A method for treating or preventing a disease in a human or other mammal mediated by the VEGF-induced signal transduction pathway, comprising administering to a human or other mammal in need thereof a compound of claim 1 .
13 ) A method for treating or preventing a disease in a human or other mammal characterized by abnormal angiogenesis or hyperpermeability processes, comprising administering to a human or other mammal in need thereof a compound of claim 1 .
14 ) A method for treating or preventing a disease in a human or other mammal characterized by abnormal angiogenesis or hyperpermeability processes, comprising administering to a human or other mammal in need thereof a compound of claim 1 simultaneously with another angiogenesis inhibiting agent in the same formulation or in separate formulations.
15 ) A method for treating or preventing one or more of the following conditions in humans and/or other mammals: tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, a bolos disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis, comprising administering to a human or other mammal in need thereof a compound of claim 1 .
16 ) A method for treating or preventing one or more of the following conditions in humans and/or other mammals: tumor growth, retinopathy, diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, bullous disorder associated with subepidermal blister formation, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis, in combination with an infectious disease selected from the group consisting of: tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum , cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV),
said method comprising administering to a human or other mammal in need thereof a compound of claim 1 .
17 ) A method for treating or preventing diseases mediated by the VEGF-induced signal transduction pathway comprising administering a compound selected from the group consisting of:
4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carbothioic acid amide; 4-{3-[3-(2,2,4,4-Tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid (1-piperidyl)-amide; 4-{3-[3-(2,2,4,4-Tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid (4-morpholino)-amide; 4-{3-[3-(1-Methyl-1H-indazol-5-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid (4-morpholino)-amide; 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxamidine; 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{4-[2-(1H-tetrazol-5-yl)-pyridinyl-4-oxy]-phenyl}-urea; 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{4-[2-(4,5-dihydro-1H-imidazol-2-yl)-pyridinyl-4-oxy]-phenyl}-urea; 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-N-methyl-pyridine-2-carboxamidine; or a salt form, prodrug or metabolite thereof.
18 ) A method for treating or preventing cancer comprising administering a compound selected from the group consisting of:
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)urea N-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)-N′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[3-({2-[(2,2-dimethylhydrazino)carbonyl]pyridin-4-yl}oxy)phenyl]urea 4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-piperidin-1-ylpyridine-2-carboxamide N-piperidin-1-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide 4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-morpholin-4-ylpyridine-2-carboxamide N-morpholin-4-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide 4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-N-morpholin-4-ylpyridine-2-carboxamide N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(1H-tetrazol-5-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(4-methyl-1,3-thiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-quinolin-6-yl-N′-(4-{[2-(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea N-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)-N′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboximidamide 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carboximidamide N-methyl-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboximidamide N-methyl-4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carboximidamide 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carbothioamide 4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carbothioamide 4-[4-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carbothioamide, or a salt form, prodrug or metabolite thereof.
19 ) (canceled)
20 ) (canceled)
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 ) (canceled)
25 ) (canceled)
26 ) A compound of claim 1 wherein L is —O— and B is phenyl, optionally substituted with 1-4 halogen.
27 ) A compound of formula (I)
or a pharmaceutically acceptable salt, wherein A is phenyl, naphthyl, indazolyl, quinolinyl, pyridyl, benzo[1,3]dioxolan-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl or 4H-benzo[1,3]dioxin-6-yl, optionally substituted with 1-4 substituents which are independently R 1 and halogen,
L is —O— and B is phenyl, optionally substituted with 1-4 halogen;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or
(10) a group of the formula
wherein each of R 1 , R 2 , R 3 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is tetrahydropyrane, tetrahydrofurane, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofurane, dihydrothiophene, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine or benzoxazole, indazole, quinoline, quinazoline, imidazopyrimidine or naphtyridine;
R 4 and R 5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently 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, oxo, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) cyano,
(d) nitro,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —C(O)R 7 , where R 7 is C 1 -C 5 linear, branched, or cyclic alkyl;
R 7 is hydrogen or linear, branched, or cyclic C 1 -C 5 alkyl;
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
28 ) A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein
A is
wherein A is optionally substituted with 1-4 substituents which are independently R 1 , OR 1 , S(O) p R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , halogen, hydroxy, oxide, amino, cyano, or nitro;
B is phenyl, or pyridyl, optionally substituted with 1-4 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;
L is
(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 3 —(CH 2 ) l —,
(e) —(CH 2 ) m —NR 3 C(O)—(CH 2 ) l —,
(f) —(CH 2 ) m —S—(CH 2 ) l —,
(g) —(CH 2 ) m —C(O)NR 3 —(CH 2 ) l —, or
(h) a single bond;
m and l are integers independently selected from 0-4;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or
(10) a group of the formula
wherein each of R 1 , R 2 , R 3 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is a tetrahydropyrane, tetrahydrofurane, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofurane, dihydrothiophene, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine or benzoxazole, indazole, quinoline, quinazoline, imidazopyrimidine or naphtyridine;
R 4 and R 5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently 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, oxo, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) cyano,
(d) nitro,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —C(O)R 7 , where R 7 is C 1 -C 5 linear, branched, or cyclic alkyl;
R 7 is hydrogen or linear, branched, or cyclic C 1 -C 5 alkyl;
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
29 ) A compound of claim 28 wherein B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
30 ) A compound of claim 28 wherein L is —O— and B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
31 ) A compound as in claim 28 wherein B is phenyl or pyridyl, L is —O—, M a pyridine ring substituted only by Q, and Q is
C(S)NR 4 R 5 ; C(O)NR 7 —NR 4 R 5 ; or a group of the formula
with each of R 4 and R 5 , independently:
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where the substituent X is pyridinyl and the variable q is preferably an integer 0 or 1, and
R 6 is:
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl, or
(c) cyano.
32 ) A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein
A is
wherein A is optionally substituted with 1-4 substituents which are independently R 1 , OR 1 , or halogen
B is phenyl or pyridinyl, optionally substituted with 1-4 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro,
L is —O—,
M is a pyridine ring,
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or
(10) a group of the formula
wherein each of R 1 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is a tetrahydropyrane, tetrahydrofurane, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyrane, dihydrofurane, dihydrothiophene, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine or benzoxazole, indazole, quinoline, quinazoline, imidazopyrimidine or naphtyridine;
R 4 and R 5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently 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, oxo, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) cyano,
(d) nitro,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —C(O)R 7 , where R 7 is C 1 -C 5 linear, branched, or cyclic alkyl;
R 7 is hydrogen or linear, branched, or cyclic C 1 -C 5 alkyl;
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
33 ) A compound of claim 32 wherein B is phenyl or pyridinyl, substituted with 1-4 halogen.
34 ) A compound as in claim 32 wherein
M a pyridine ring substituted only by Q, and Q is C(S)NR 4 R 5 ; C(O)NR 7 —NR 4 R 5 ; or a group of the formula
with each of R 4 and R 5 , independently:
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where the substituent X is pyridinyl and the variable q is preferably an integer 0 or 1, and
R 6 is:
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl, or
(c) cyano.
35 ) An ester derivative of a compound of formula I of claim 1 .
36 ) An ester derivative of a compound of formula I of claim 10 .
37 ) A compound of formula (I)
or a pharmaceutically acceptable salt, wherein
A is phenyl;
optionally substituted with 1-4 substituents which are independently R 1 , OR 1 , S(O) p R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , halogen, hydroxy, oxide, amino, cyano, or nitro;
L is —O— and B is phenyl, optionally substituted with 1-4 halogen;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
or
(3) a group of the formula
wherein each of R 1 , R 2 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is pyridine;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl, or
(c) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
38 ) A compound of formula (I)
or a pharmaceutically acceptable salt, wherein
A is pyridine optionally substituted with 1-4 substituents which are independently R 1 , OR 1 , S(O) p R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , halogen, hydroxy, oxide, amino, cyano, or nitro;
L is —O— and B is phenyl, optionally substituted with 1-4 halogen;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
or
(3) a group of the formula
wherein each of R 1 , R 2 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is pyridine;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl, or
(c) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
39 ) A compound of formula (I)
or a pharmaceutically acceptable salt, wherein
A is pyrazole optionally substituted with 1-4 substituents which are independently R 1 , OR 1 , S(O) p R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , halogen, hydroxy, oxide, amino, cyano, or nitro;
L is —O— and B is phenyl, optionally substituted with 1-4 halogen;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, oxide, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR 4 R 5 ;
(2) C(O)NR 7 —NR 4 R 5 ;
or
(3) a group of the formula
wherein each of R 1 , R 2 , R 4 and R 5 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C 1 -C 3 phenyl-alkyl,
(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
(f) —(CH 2 ) q —X, where X is pyridine;
R 6 is independently
(a) hydrogen,
(b) C 1 -C 5 linear, branched, or cyclic alkyl, or
(c) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or
q is an integer 0, 1, 2, 3, or 4 and
p is an integer 0, 1, or 2.
40 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 27 and a physiologically acceptable carrier.
41 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 27 and a physiologically acceptable carrier.
42 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 28 and a physiologically acceptable carrier.
43 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 31 and a physiologically acceptable carrier.
44 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 32 and a physiologically acceptable carrier.
45 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 37 and a physiologically acceptable carrier.
46 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 38 and a physiologically acceptable carrier.
47 ) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 39 and a physiologically acceptable carrier.Cited by (0)
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