US2017066778A1PendingUtilityA1
Solubility for target compounds
Est. expirySep 4, 2035(~9.1 yrs left)· nominal 20-yr term from priority
Inventors:Achyutharao Sidduri
A61K 31/519A61K 31/517A61K 31/513A61K 31/34A61K 31/4709A61K 31/506A61K 45/06C07D 493/04C07D 519/00
59
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Claims
Abstract
The present disclosure relates to compounds having an improved solubility thereby increasing their bioavailability, lower dosages, etc. The target compounds, may include but are not limited to, macrophage migration inhibitory factor (MIF) inhibitors, epidermal growth factor receptor (EGRF) inhibitors, kinase inhibitors and prodrugs of alpha4 beta1 and alpha4 beta7 integrin antagonists. An illustrative compound is shown below:
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound according to Formula I
wherein:
R 1 is -aryl, -heteroaryl, or C(O)R 3 , wherein
i) each of said aryl or heteroaryl may additionally be fused with an independently selected aryl or heteroaryl; and
ii) each of said aryl, heteroaryl, and alkyl is either unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of halo, hydroxyl, cyano, oxo, amino, aminoalkyl-, (amino)alkoxy-, -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, -alkylhydroxy, aryloxy-, -alkyl(aryl), (alkoxyalkyl)amino-, -aryl, -aryl(halo), -heteroaryl, C(O)OC n , —NR a R b ; deuterium, hydroxyl-alkyl-, hydroxyl-aryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —CH z F 3-z , —OCH z F 3-z , (alkoxyalkyl)amino-, —O(alkyl), —O(aryl), O(heteroaryl), —NH(SO 2 )alkyl, —NH(SO 2 )aryl, —NH(SO 2 )heteroaryl, (aryl)alkyl-, —S(O) 2 -alkyl, —S(O) 2 -aryl, —C(O)alkyl, —NHC(O)-alkyl, NH—, —NH—C(O)—R c —(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, —NH(R c )—C(O)-alkyl, —NH(R c )—C(O)-aryl, —S(O 2 )NH 2 , —S(O 2 )NH(alkyl), —S(O 2 )N(alkyl) 2 , —C(O)N(H)(alkyl), —CH z F 3-z , —OCH z F 3-z ;
R 2 is hydrogen, hydroxyl, OC(O)CH 3 , -oxy(aryl), or a group selected from -oxy(alkyl), -oxy(alkene), alkyl, -alkenyl, -oxy(alkyl)-aryl, -oxyalkynyl, OC(O)(alkyl), OC(O)(haloalkyl), and OC(O)(aryl) which is either substituted or non-substituted and straight or branched, where the substituents can be the same or different and are from the group consisting of oxo or halo;
R 3 is an alkyl, alkyl(benzyl), alkoxy(alkyl) all of which may be substituted or unsubstituted, or substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl, or alkyl(aryl), the substituted or unsubstituted monocyclic or bicyclic heteroaryl having 0, 1, 2 or 3 heteroatoms independently selected from N, O, or S;
R a is an alkyl, alkyl(benzyl), alkoxy(alkyl) all of which may be substituted or unsubstituted, or substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl, or alkyl(aryl), the substituted or unsubstituted monocyclic or bicyclic heteroaryl having 0, 1, 2 or 3 heteroatoms independently selected from N, O, or S;
R b is hydrogen or halo;
R c is hydrogen, halo, or alkyl;
-------- is an optional bond that is present only when R 2 is hydrogen;
n is 0, 1, 2, or 3; and
z is 0, 1, or 2.
2 . The compound of claim 1 wherein R 2 is hydrogen.
3 . The compound of claim 1 wherein,
R 1 is a substituted mono cyclic or bicyclic ring having 0, 1, 2, or 3 heteroatoms independently selected from N, O, or S; and
R 2 is hydroxyl or OC(O)C n R b .
4 . The compound of claim 1 wherein R 3 is
5 . A compound according to Formula II
wherein:
R 2 is hydrogen, hydroxyl, or a group substituted or non-substituted and straight or branched selected from -oxy(alkyl), -oxy(alkene), alkyl, -alkenyl, -alkynyl, —OC(O)(alkyl), —OC(O)(haloalkyl), and —OC(O)(aryl);
R 4 is cyano, amino, aminoalkyl-, alkyl, -alkyl(aryl), substituted or non-substituted aryl, if substituted then substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of halo, hydroxyl, cyano, oxo, amino, aminoalkyl-, alkyl(arylhalide), (amino)alkoxy-, -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, -alkylhydroxy, -alkyl(aryl), aryloxy-, -alkyl(aryl), (alkoxyalkyl)amino-, -aryl, -aryl(halo), -heteroaryl, C(O)OC n , —NR a R b ; deuterium, hydroxyl-alkyl-, hydroxyl-aryl-, amino, aminoalkyl;
R 5 is C(O)R c or cyano;
R a is an alkyl, alkoxy(alkyl), substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl, or alkyl(aryl), the substituted or unsubstituted monocyclic or bicyclic heteroaryl having 0, 1, 2 or 3 heteroatoms independently selected from N, O, or S;
R b is hydrogen or halo;
R c is hydrogen, or a group, substituted or unsubstituted, selected from straight or branched C1 to C 3 alkyl, CF 3 , alkoxy, cyano, aryl, and monocyclic or bicyclic heteroaryl having one to three heteroatoms independently selected from O, S, and N and if substituted then substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of halo, hydroxyl, cyano, oxo, amino, aminoalkyl-, ethoxy, (amino)alkoxy-, -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, -alkylhydroxy, -alkyl(aryl), aryloxy-, -alkyl(aryl), (alkoxyalkyl)amino-, -aryl, -aryl(halo), -heteroaryl, C(O)OC n , —NR a R b ; deuterium, hydroxyl-alkyl-, hydroxyl-aryl-, amino, aminoalkyl;
Y is S or O; and
n is 0, 1, 2, or 3.
6 . The compound of claim 5 wherein R 4 is selected from the group consisting of:
7 . The compound of claim 5 wherein,
R 4 is alkyl(aryl);
R 5 is C(O)OC n ; and
n is 0, 1, 2, or 3.
8 . The compound of claim 5 wherein R 5 is:
9 . A compound according to Formula III
wherein;
R 6 is hydrogen, halo, CN, alkyl, alkoxy, aryloxy, aryl, and SO 2 (alkyl);
R 7 is hydrogen, C(O)R c , alkyl, haloalkyl, alkenyl, alkynyl, and —CH 2 (aryl);
Ar is a substituted or non-substituted monocyclic or bicyclic heteroaryl, with one to four heteroatoms independently selected from O, S, and N, wherein the substituents are selected from the group consisting of halo, hydroxyl, oxy, cyano, amino, aminoalkyl-, (amino)alkoxy-, -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, NR a R b , OC n , —CH z F 3-z , —OCH z F 3-z , aryloxy-, (alkoxyalkyl)amino-, —O(alkyl), —O(aryl), —O(heteroaryl), —C(O)NH(alkyl), —C(O)N(aryl) 2 , —NH(SO 2 )alkyl, —NH(SO 2 )aryl, —NH(SO 2 )heteroaryl, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O) 2 -alkyl, —S(O) 2 -aryl, —C(O)N(alkyl) 2 , —C(O)alkyl, —NHC(O)-alkyl, —NH—C(O)—R c —(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, —NH(R c )—C(O)-alkyl, —NH(R c )—C(O)-aryl, —S(O 2 )NH 2 , —S(O 2 )NH(alkyl), —S(O 2 )N(alkyl) 2 , —C(O)N(H)(alkyl), —CH z F 3-z , —OCH z F 3-z , or -alkyl(aryl);
R c is hydrogen, or a group, substituted or unsubstituted, selected from straight or branched C 1 to C 3 alkyl, CF 3 , alkoxy, cyano, aryl, and monocyclic or bicyclic heteroaryl having one to three heteroatoms independently selected from O, S, and N and if substituted then substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of halo, hydroxyl, cyano, oxo, amino, aminoalkyl-, ethoxy, (amino)alkoxy-, -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, -alkylhydroxy, -alkyl(aryl), aryloxy-, -alkyl(aryl), (alkoxyalkyl)amino-, -aryl, -aryl(halo), -heteroaryl, C(O)OC n , —NR a R b ; deuterium, hydroxyl-alkyl-, hydroxyl-aryl-, amino, aminoalkyl;
R a is an alkyl, alkoxy(alkyl), substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl, or alkyl(aryl), the substituted or unsubstituted monocyclic or bicyclic heteroaryl having 0, 1, 2 or 3 heteroatoms independently selected from N, O, or S;
R b is hydrogen or halo;
n is 0, 1, 2, or 3; and
z is 0, 1, or 2.
10 . The compound of claim 9 wherein Ar is selected from the group consisting of:
11 . A compound according to Formula IV
wherein;
R 6 is hydrogen, halogen, CN, alkyl, alkoxy, aryloxy, aryl, and SO 2 (alkyl);
R 7 is hydrogen, C(O)R c , alkyl, alkenyl, alkynyl, and —CH 2 (aryl);
R 8 is substituted or non-substituted aryl or cycloalkyl or heterocycloalkyl, wherein the substituents are selected from the group consisting of straight or branched alkyl, halo, hydroxyl, oxy, cyano, amino, dimethylpropanone, aminoalkyl-, (amino)alkoxy-, -alkyl(arylhalide), -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, -alkylhydroxy, aryloxy-, -alkyl(aryl), —SO 2 (aryl), —SO 2 (alkyl), (alkoxyalkyl)amino-, -aryl, -heteroaryl, C(O)C n , C(O)OC n , —NR a R b , and deuterium;
R a is an alkyl, alkoxy(alkyl), substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl, or alkyl(aryl), the substituted or unsubstituted monocyclic or bicyclic heteroaryl having 0, 1, 2 or 3 heteroatoms independently selected from N, O, or S;
R b is hydrogen or halo;
R c is hydrogen, halo, aryl, or alkyl;
X is independently C, N, S, or O; and
n is 0, 1, or 2.
12 . The compound of claim 11 wherein R 7 is C(O)OC.
13 . A compound selected from the group consisting of:
Name
Ethyl 4-[[(3S,3aR,6S,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-
yl]oxy]-1-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-6-acetoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-
yl]oxy]-1-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-6-(2-chloroacetyl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-
b]furan-3-yl]oxy]-1-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aS,6aR)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-3-yl]oxy]-1-ethyl-2-oxo-
1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-
yl]oxy]-1-benzyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-6-acetoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-
yl]oxy]-1-benzyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-6-(2-chloroacetyl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-
b]furan-3-yl]oxy]-1-benzyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aS,6aR)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-3-yl]oxy]-1-benzyl-2-oxo-
1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-
yl]oxy]-1-[(4-fluorophenyl)methyl]-2-oxo-1,2-dihydroquinoline-3-carboxylate
Ethyl 4-[[(3S,3aR,6S,6aR)-6-(2-chloroacetyl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-
b]furan-3-yl]oxy]-1-[(4-fluorophenyl)methyl]-2-oxo-1,2-dihydroquinoline-3-
carboxylate
4-[[(3S,3aR,6S,6aR)-3-Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-1-
benzyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile
[(3S,3aR,6S,6aR)-3-[(1-Benzyl-3-cyano-2-oxo-4-quinolyl)oxy]-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[(1-Benzyl-3-cyano-2-oxo-4-quinolyl)oxy]-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-6-yl] 2-chloroacetate
4-[[(3S,3aR,6S,6aR)-3-Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-1-
[(4-fluorophenyl)methyl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile
[(3S,3aR,6S,6aR)-3-[[3-Cyano-1-[(4-fluorophenyl)methyl]-2-oxo-4-quinolyl]oxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[[3-Cyano-1-[(4-fluorophenyl)methyl]-2-oxo-4-quinolyl]oxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] benzoate
[(3S,3aR,6S,6aR)-3-[[3-Cyano-1-[(4-fluorophenyl)methyl]-2-oxo-4-quinolyl]oxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] 2-chloroacetate
4-[4-[[(3S,3aR,6S,6aR)-3-Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-
3-chloro-anilino]-1-benzyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile
Ethyl 4-[4-[[(3S,3aR,6S,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-
yl]oxy]-3-chloro-anilino]-1-benzyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
[(3S,3aR,6S,6aR)-3-[4-[(6,7-Dimethoxyquinazolin-4-yl)amino]phenoxy]-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-6-yl] acetate
N-[4-[[(3S,3aR,6S,6aR)-3-benzyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-
yl]oxy]phenyl]-6,7-dimethoxy-quinazolin-4-amine
N-[4-[[(3S,3aR,6S,6aR)-3-benzyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-3-
chloro-phenyl]-6,7-dimethoxy-quinazolin-4-amine
(3S,3aR,6S,6aR)-6-[2-Chloro-4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenoxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol
[(3S,3aR,6S,6aR)-3-[2-Chloro-4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenoxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[2-Chloro-4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenoxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] benzoate
[(3S,3aR,6S,6aR)-3-[4-(Thieno[3,2-d]pyrimidin-4-ylamino)phenoxy]-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-6-yl] acetate
(3S,3aR,6S,6aR)-6-[2-Chloro-4-(thieno[3,2-d]pyrimidin-4-ylamino)phenoxy]-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-3-ol
[(3S,3aR,6S,6aR)-3-[2-Chloro-4-(thieno[3,2-d]pyrimidin-4-ylamino)phenoxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[2-Chloro-4-(thieno[3,2-d]pyrimidin-4-ylamino)phenoxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] benzoate
(3S,3aR,6S,6aR)-6-[2-Chloro-4-[(2-methylsulfanylpyrimidin-4-yl)amino]phenoxy]-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol
[(3S,3aR,6S,6aR)-3-[2-[(1-Methylsulfonyl-4-piperidyl)amino]pyrimidin-4-yl]oxy-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[2-[(1-Tolylsulfonyl-4-piperidyl)amino]pyrimidin-4-yl]oxy-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[2-[[1-(2,2-Dimethylpropanoyl)-4-piperidyl]amino]pyrimidin-4-
yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[2-[(4-Fluorophenyl)methylamino]pyrimidin-4-yl]oxy-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-6-yl] acetate
[(3S,3aR,6S,6aR)-3-[2-[(1-Methylsulfonyl-4-piperidyl)amino]pyrimidin-4-yl]oxy-
2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] benzoate
[(3S,3aR,6S,6aR)-3-Acetoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] 5-bromo-2-[(1-
methylsulfonyl-4-piperidyl)amino]pyrimidine-4-carboxylate
(3S,3aR,6S,6aR)-6-[4-[[2-[4-[[(3S,3aR,6S,6aR)-3-Hydroxy-2,3,3a,5,6,6a-
hexahydrofuro[3,2-b]furan-6-yl]oxy]-3-chloro-anilino]pyrimidin-4-yl]amino]-2-chloro-
phenoxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol
[(3S,3aR,6S,6aR)-3-Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] (2S)-2-[(2-
chloro-6-methyl-benzoyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate
[(3S,3aR,6S,6aR)-3-Acetoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] (2S)-2-[(2-
chloro-6-methyl-benzoyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate
[(3S,3aR,6S,6aR)-3-Benzyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] (2S)-2-[(2-
chloro-6-methyl-benzoyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate
[(3S,3aR,6S,6aR)-3-Acetoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] (2S)-2-[(2-
chloro-6-methyl-benzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxo-pyrimidin-5-
yl)phenyl]propanoate
[(3S,3aR,6S,6aR)-3-Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] (2S)-2-[(2-
chloro-6-methyl-benzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxo-pyrimidin-5-
yl)phenyl]propanoate
14 . A pharmaceutical composition comprising therapeutically effective amounts of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
15 . The pharmaceutical composition of claim 9 , further comprising therapeutically effective amounts of one or more additional therapeutic agents.Join the waitlist — get patent alerts
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