US 9,868,758 B2Granted

Betulinic proline imidazole derivatives as HIV inhibitors

AssigneeHetero Labs Limited

InventorsParthasaradhi Reddy Bandi, Rathnakar Reddy Kura, Panduranga Reddy Adulla, David Krupadanam Gazula Levi, Eswara Rao Bammidi, Ranga Reddy, Carl Thomas Wild, David Eugene Martin, Theodore John Nitz

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Abstract

The present invention relates to novel betulinic proline imidazole derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.

Claims13

Dependent claims

A Compound of the formula (1):

wherein,
R1 is substituted or unsubstituted alkyl,
wherein Rb is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;
R2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacids, substituted or unsubstituted alkoxy, or substituted or unsubstituted cycloalkyl;
X is absent, O, S, CH2 or NRa, wherein Ra is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or Ra is with their adjacent N and Carbon together form N-contained heterocycle;
R3 and R4 are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacids, or R3 and R4 are together with their adjacent carbons to form a bond or R3 and R4 are together with their adjacent carbons to form cyclopropyl or R3 and R4 are together with their adjacent carbons to form epoxide;
W is C(O), C(S), or CR9R10;
R6 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;
R7 is independently selected from substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R8 is independently selected from H, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
R5, R9 and R10 are independently selected from H, CO2Rd (wherein Rd is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;
R11 is H or substituted or unsubstituted alkyl;
alternatively R6 and R11 may be taken together with carbon atoms to which they are attached to form a substituted or unsubstituted aryl;
n is an integer from 1 to 3;
including pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, or combination thereof.

12 more elements

A compound selected from the group consisting of:

(1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(2-methoxyethoxy)ethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(1-(2-morpholinoethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclo butane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-methoxyethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-(pyridin-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(4-(pyridin-4-yl)-1-(2-(pyrrolidin-1-yl) ethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl) cyclobutane-1-carboxylic acid,
(1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(4-phenyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclo butane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1-(2-(dimethylamino)ethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid,
4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethyl amino)ethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid,
4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-methoxyethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid,
4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethyl amino)ethyl)-4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1-(2-(dimethylamino)ethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(diethoxyphosphoryl)ethyl)-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(4-phenyl-1-(2-phosphonoethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclo butane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(diethoxyphosphoryl)ethyl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(1-(2-(dimethylamino)ethyl)-4-phenyl-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(1-isopentyl-4-phenyl-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-phenyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy) pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, and
(1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b, 8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, or combination thereof.

27 more elements

Dependencies are inferred from the claim text.

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