US2019345141A1PendingUtilityA1
Aryl-substituted imidazoles
Assignee: ST JUDE CHILDRENS RES HOSPITALPriority: Sep 30, 2010Filed: Jul 23, 2019Published: Nov 14, 2019
Est. expirySep 30, 2030(~4.2 yrs left)· nominal 20-yr term from priority
Inventors:R. Kiplin GuyYiqun ZhangBrandon M. YoungMichael DyerKristin FinchDonald BashfordNagakumar BharathamRichard KriwackiGrace Roy-AppaLie MinJaeki MinAntonio Ferreira
A61P 35/00C07D 403/14C07D 403/06C07D 233/22
58
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Claims
Abstract
The compounds of the invention are antagonists of MDM2 and MDMX, with excellent specificity for MDM2 and MDMX over other proteins, and with selective binding affinity to MDMX over MDM2. The compounds can therefore regulate p53 activity and treat a variety of cancers. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the formula:
wherein Ar 1 and Ar 2 are independently selected from:
wherein each X is independently selected from N and CH;
wherein each Y is independently selected from S and O;
wherein each Q is independently selected from hydrogen, halogen, nitro, and C 1 -C 4 alkyl;
wherein Ar 1 and Ar 2 are different when both R 7 and R 8 are hydrogen;
wherein Ar 1 and Ar 2 have a cis relationship;
wherein R 1 is selected from hydrogen and C 1 -C 4 alkyl and substituted with 0-2 groups selected from halogen, alkoxy, carboxymethyl, carboxyethyl, trifluoromethyl, trifluoromethoxy, and —SO 2 Me;
wherein R 2 , R 3 , and R 5 are independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, n-propoxyl, i-propoxyl, n-butoxyl, i-butoxyl, and t-butoxyl;
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, alkoxy, and —SO 2 Me;
wherein R 6a and R 6b are independently selected from hydrogen and C 1 -C 4 alkyl, or wherein R 6a and R 6b together comprise ═O;
wherein R 7 and R 8 are independently selected from hydrogen, methyl, and ethyl;
wherein R 9 is selected from hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, carboxymethyl, and carboxyethyl;
wherein R 10 is selected from C 1 -C 4 alkyl and Ar 3 ; and
wherein Ar 3 is selected from:
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , having the formula:
wherein Ar 3 is selected from:
3 . The compound of claim 1 , wherein R 6a and R 6b are both hydrogen.
4 . The compound of claim 1 , wherein R 6a and R 6b together comprise ═O.
5 . The compound of claim 1 , wherein Ar 3 is:
6 . The compound of claim 1 , having the formula:
wherein Ar 1 and Ar 2 are independently selected from:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy;
wherein each X is independently N or CH; and wherein each Y is independently S or O;
wherein Q is hydrogen or C 1 -C 4 alkyl;
wherein Ar 1 and Ar 2 are different;
wherein R 1 is hydrogen or C 1 -C 4 alkyl;
wherein R 2 is hydrogen, halogen, —CH 3 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 ;
wherein R 3 is hydrogen, halogen, —CH 3 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 and
wherein the absolute stereochemistry at position 4 and 5 is R and S, respectively; or S and R, respectively; or
a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 , wherein each Ar 1 and Ar 2 is:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
8 . The compound of claim 1 , having the formula:
9 . The compound of claim 8 , wherein each Ar 1 and Ar 2 is:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
10 . The compound of claim 1 , selected from:
4-((4S,5R)-4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-5-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-((4R,5S)-4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-5-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-((4S,5R)-5-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; and 4-((4R,5 S)-5-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one.
11 . A method of treating a cell proliferative disorder in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a compound having the formula:
wherein Ar 1 and Ar 2 are independently selected from:
wherein each X is independently selected from N and CH;
wherein each Y is independently selected from S and O;
wherein each Q is independently selected from hydrogen, halogen, nitro, and C 1 -C 4 alkyl;
wherein Ar 1 and Ar 2 are different when both R 7 and R 8 are hydrogen;
wherein Ar 1 and Ar 2 have a cis relationship;
wherein R 1 is selected from hydrogen and C 1 -C 4 alkyl and substituted with 0-2 groups selected from halogen, alkoxy, carboxymethyl, carboxyethyl, trifluoromethyl, trifluoromethoxy, and —SO 2 Me;
wherein R 2 , R 3 , and R 5 are independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, n-propoxyl, i-propoxyl, n-butoxyl, i-butoxyl, and t-butoxyl;
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, alkoxy, and —SO 2 Me;
wherein R 6a and R 6b are independently selected from hydrogen and C 1 -C 4 alkyl, or wherein R 6a and R 6b together comprise ═O;
wherein R 7 and R 8 are independently selected from hydrogen, methyl, and ethyl;
wherein R 9 is selected from hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, carboxymethyl, and carboxyethyl;
wherein R 10 is selected from C 1 -C 4 alkyl and Ar 3 ; and
wherein Ar 3 is selected from:
or a pharmaceutically acceptable salt thereof.
12 . The method of claim 11 , wherein the compound has the formula:
wherein Ar 3 is selected from:
13 . The method of claim 11 , wherein the compound has the formula:
wherein Ar 1 and Ar 2 are independently selected from:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy;
wherein each X is independently N or CH; and wherein each Y is independently S or O;
wherein Q is hydrogen or C 1 -C 4 alkyl;
wherein Ar 1 and Ar 2 are different;
wherein R 1 is hydrogen or C 1 -C 4 alkyl;
wherein R 2 is hydrogen, halogen, —CH 3 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 ;
wherein R 3 is hydrogen, halogen, —CH 3 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 and
wherein the absolute stereochemistry at position 4 and 5 is R and S, respectively; or S and R, respectively; or
a pharmaceutically acceptable salt thereof.
14 . The method of claim 11 , wherein each Ar 1 and Ar 2 is independently:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
15 . The method of claim 11 , wherein the compound has the formula:
16 . The method of claim 11 , wherein each Ar 1 and Ar 2 is:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
17 . The method of claim 11 , wherein the compound is selected from:
4-((4S,5R)-4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-5-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-((4R,5S)-4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-5-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-((4S,5R)-5-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; and 4-((4R,5 S)-5-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one.
18 . A pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound having the formula:
wherein Ar 1 and Ar 2 are independently selected from:
wherein each X is independently selected from N and CH;
wherein each Y is independently selected from S and O;
wherein each Q is independently selected from hydrogen, halogen, nitro, and C 1 -C 4 alkyl;
wherein Ar 1 and Ar 2 are different when both R 7 and R 8 are hydrogen;
wherein Ar 1 and Ar 2 have a cis relationship;
wherein R 1 is selected from hydrogen and C 1 -C 4 alkyl and substituted with 0-2 groups selected from halogen, alkoxy, carboxymethyl, carboxyethyl, trifluoromethyl, trifluoromethoxy, and —SO 2 Me;
wherein R 2 , R 3 , and R 5 are independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, n-propoxyl, i-propoxyl, n-butoxyl, i-butoxyl, and t-butoxyl;
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, alkoxy, and —SO 2 Me;
wherein R 6a and R 6b are independently selected from hydrogen and C 1 -C 4 alkyl, or wherein R 6a and R 6b together comprise ═O;
wherein R 7 and R 8 are independently selected from hydrogen, methyl, and ethyl;
wherein R 9 is selected from hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, carboxymethyl, and carboxyethyl;
wherein R 10 is selected from C 1 -C 4 alkyl and Ar 3 ; and
wherein Ar 3 is selected from:
or a pharmaceutically acceptable salt thereof.
19 . The composition of claim 18 , wherein the compound has the formula:
wherein Ar 3 is selected from:
20 . The composition of claim 18 , wherein the compound has the formula:
wherein Ar 1 and Ar 2 are independently selected from:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy;
wherein each X is independently N or CH; and wherein each Y is independently S or O;
wherein Q is hydrogen or C 1 -C 4 alkyl;
wherein Ar 1 and Ar 2 are different;
wherein R 1 is hydrogen or C 1 -C 4 alkyl;
wherein R 2 is hydrogen, halogen, —CH 3 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 ;
wherein R 3 is hydrogen, halogen, —CH 3 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 and
wherein the absolute stereochemistry at position 4 and 5 is R and S, respectively; or S and R, respectively; or
a pharmaceutically acceptable salt thereof.
21 . The composition of claim 18 , wherein each Ar 1 and Ar 2 is:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
22 . The composition of claim 18 , wherein the compound has the formula:
23 . The composition of claim 18 , wherein each Ar 1 and Ar 2 is:
wherein R 4a -R 4e are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
24 . The composition of claim 18 , wherein each Ar 1 and Ar 2 is:
wherein R 4a and R 4e are each hydrogen; and
wherein R 4b -R 4d are independently selected from hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, and alkoxy.
25 . The composition of claim 18 , wherein the compound is selected from:
4-((4S,5R)-4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-5-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-((4R,5S)-4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-5-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-((4S,5R)-5-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; and 4-((4R,5 S)-5-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-(m-tolyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one.Join the waitlist — get patent alerts
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