Diamine-containing, tetra-substituted piperazine compounds having identical 1- and 4-substituents

1. A compound having the formula of structure I:

or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein

one or two of R 1a , R 1b , R 2a , and R 2b are independently a C 1 to C 6 aliphatic linear or branched chain and the remaining of R 1a , R 1b , R 2a , and R 2b are hydrogen, provided that at least one of R 1a and R 1b and at least one of R 2a and R 2b are hydrogen;

or one of R 1a , R 1b , R 2a , and R 2b are

and the remaining of R 1a , R 1b , R 2a , and R 2b are hydrogen;

or R 1a and R 1b together form ═O and one of R 2a and R 2b is a C 1 to C 6 aliphatic linear or branched chain,

and the remaining of R 2a and R 2b is hydrogen;

y is in each instance an independent index value from 0 to 5;

W is a diamine heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor;

L 2 is a bond or (CH 2 ) z ;

z is an index value from 1 to 6;

X is CH 2 , C═O or C═S;

the groups —C(R 8 )(CH 2 ) v CH(R 9 )(CH 2 ) y -Q and —C(R 8 )(CH 2 ) v CH(R 9 )(CH 2 ) y -J are the same and, in those groups,

R 8 is H or ═O;

R 9 is hydrogen or N(R 10a )R 10b ;

R 10a and R 10b are independently hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butanoyl, pentanoyl, heptanoyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl, or polyethylene glycol;

v is an index value from 0 to 2; and

Q and J are the same and represent an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;

wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.

2. The compound as claimed in claim 1 , wherein R 8 is ═O.

3. The compound as claimed in claim 1 , wherein Q is:

where R 3a , R 3b and R 3c are optional ring substituents independently selected from hydroxyl, halogen, alkyl, —O-alkyl, aryl, and —O-aryl.

4. The compound as claimed in claim 3 , wherein at least one of R 3a , R 3b or R 3c is —CH 3 or —O—CH 3 .

5. The compound as claimed in claim 3 , wherein at least one of R 3a , R 3b or R 3c is —Cl or —CF 3 .

6. The compound as claimed in claim 1 wherein W is selected an amine, amide, alcohol, carboxylic acid, ether, ester, and urea.

7. A compound having the formula of structure II

or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein

one or two of R 1a , R 1b , R 2a , and R 2b are independently a C 1 to C 6 aliphatic linear or branched chain and the remaining of R 1a , R 1b , R 2a , and R 2b are hydrogen, provided that at least one of R 1a and R 1b and at least one of R 2a and R 2b are hydrogen;

or one of R 1a , R 1b , R 2a , and R 2b are

and the remaining of R 1a , R 1b , R 2a , and R 2b are hydrogen;

or R 1a and R 1b together form ═O and one of R 2a and R 2b is a C 1 to C 6 aliphatic linear or branched chain,

and the remaining of R 2a and R 2b is hydrogen;

R 4a is NH, N(—(CH 2 ) y —CH 3 ), NH—C(═O), or C(═O)—NH;

R 5a is NH 2 , NH—(CH 2 ) y —CH 3 , or N(—(CH 2 ) y —CH 3 ) 2 ;

y is in each instance independently an index value from 0 to 5;

the groups —C(R 8 )CH(R 9 )(CH 2 ) y -Q and —C(R 8 )CH(R 9 )(CH 2 ) y -J are the same and, in those groups

R 8 is H or ═O;

R 9 is hydrogen or N(R 10a )R 10b ;

R 10a and R 10b independently hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butanoyl, pentanoyl, heptanoyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl or cyclohexylmethyl;

Q and J are the same and represent an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl; and

z is an index value from 1 to 6;

wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.

8. A compound as claimed in claim 1 or claim 7 , wherein the compound is selected from:

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dichlorophenyl)propionyl]-5-[3-(2-aminoethylamino) propyl]-2-isobutylpiperazin-1-yl}-3-(2, 4-dichlorophenyl)propan-1-one;

(R)-2-Amino-1-[(2R, 5S)-5-[3-(2-aminoethylamino)propyl]-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutylpiperazin-1-yl]-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dimethylphenyl)propionyl]-5-[3-(2-aminoethylamino) propyl]-2-cyclohexylmethylpiperazin-1-yl}-3-(2, 4-dimethylphenyl)propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dichlorophenyl)propionyl]-5-[3-(2-aminoethylamino) propyl]-2-cyclohexylmethylpiperazin-1-yl}-3-(2, 4-dichloro-phenyl)-propan-1-one;

(R)-2-Amino-1-[(2R, 5S)-5-[3-(2-amino ethylamino)propyl]-4((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-cyclohexylmethylpiperazin-1-yl]-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(2, 4-dimethylphenyl)propionyl]-2-[3-(2-aminoethylamino) propyl]-5-isobutylpiperazin-1-yl}-3-(2, 4-dimethylpheny)-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dichlorophenyl)propionyl]-5-[4-(2-aminoethylamino) butyl]-2-isobutylpiperazin-1-yl}-3-(2, 4-dichlorophenyl)propan-1-one;

(R)-2-Amino-1-[(2R, 5S)-5-[4-(2-aminoethylamino)butyl]-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutylpiperazin-1-yl]-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dimethylphenyl)propionyl]-5-[4-(2-aminoethylamino) butyl]-2-isobutylpiperazin-1-yl}-3-(2, 4-dimethylphenyl)propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(3, 4-dichlorophenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-isobutylpiperazin-1-yl}-3-(3 ,4-dichloropheny)-propan-1-one;

(R)-2-Amino-1-[(2S, 5R)-2-[4-(2-aminoethylamino)butyl]-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-cyclohexylmethylpiperazin-1-yl]-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(2, 4-dichlorophenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-cyclohexylmethylpiperazin-1-yl}-3-(2, 4-dichloro-phenyl)propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dichlorophenyl)propionyl]-5-[3-(2-aminoethylamino) propyl]-2-methylpiperazin-1-yl}-3-(2, 4-dichlorophenyl)-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dimethylphenyl)propionyl]-5-[3-(2-aminoethylamino)propyl]-2-methylpiperazin-1-yl}-3-(2, 4-dimethylphenyl)propan-1-one;

(R)-2-Amino-1-[(2R, 5S)-5-[3-(2-aminoethylamino)propyl]-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-methylpiperazin-1-yl]-3-naphthalen-2-yl-propan-1-one; and

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(3, 4-dichlorophenyl)propionyl]-5-[3-(2-aminoethylamino) propyl]-2-methylpiperazin-1-yl}-3-(3, 4-dichlorophenyl)-propan-1-one, or a pharmaceutically acceptable salt thereof.

9. A compound as claimed in claim 1 or claim 7 , wherein the compound is selected from:

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(3, 4-dichlorophenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-methylpiperazin-1-yl}-3-(3, 4-dichlorophenyl)-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(2, 4-dimethylphenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-methylpiperazin-1-yl}-3-(2, 4-dimethylphenyl)-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-2-[4-(2-aminoethylamino)butyl]-4-[(R)-2-amino-3-(4-trifluoromethylphenyl)propionyl]-5-isobutylpiperazin-1-yl}-3-(4-trifluoromethyl-phenyl)propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(4-chlorophenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-isobutylpiperazin-1-yl}-3-(4-chlorophenyl)propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-5-[4-(2-aminoethylamino)butyl]-4-[(R)-2-amino-3-(3-trifluoromethylphenyl)propionyl]-2-isobutylpiperazin-1-yl}-3-(3-trifluoromethylphenyl)propan-1-one;

1-{(2R, 5S)-5-[4-(2-Aminoethylamino)butyl]-4-[3-(3, 4-dichlorophenyl)-propionyl]-2-isobutylpiperazin-1-yl}-3-(3, 4-dichlorophenyl)propan-1-one;

N 1 -(4-{(2S, 5R)-1,4-Bis-[3-(3, 4-dichlorophenyl)propyl]-5-isobutylpiperazin-2-yl}butyl)ethane-1, 2-diamine;

(R)-3-Amino-1-{(2R, 5S)-4-[(R)-3-amino-4-(2, 4-dichlorophenyl)butyl]-5-[4-(2-aminoethylamino) butyl]-2-isobutylpiperazin-1-yl}-4-(2, 4-dichlorophenyl)butan-1-one;

(R)-3-Amino-1-{(2S, 5R)-4-[(R)-3-amino-3-(2, 4-dichlorophenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-isobutylpiperazin-1-yl}-3-(2, 4-dichlorophenyl)-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(4-chloro-2-methylphenyl)-propionyl]2-[4-(2-aminoethylamino)butyl]-5-isobutylpiperazin-1-yl}-3-(4-chloro-2-methyl-phenyl)propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(2-chloro-4-methylphenyl)-propionyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutylpiperazin-1-yl}-3-(2-chloro-4-methyl-phenyl)propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(3, 4-difluorophenyl)propionyl]-2-[-4-(2-aminoethylamino) butyl]-5-isobutylpiperazin-1-yl}-3-(3 ,4-difluorophenyl)propan-1-one;

(R)-2-Amino-1-[(2R, 5S)-5-[4-(2-aminoethylamino)butyl]-4-((R)-2-amino-4-phenyl-butyryl)-2-isobutylpiperazin-1-yl]-4-phenylbutan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(4-tert-butylphenyl)priopionyl]-5-[4-(2-aminoethylamino) butyl]-2-isobutylpiperazin-1-yl}-3-(4-tert-butylphenyl)propan-1-one;

1-{(2R, 5S)-5-[4-(2-Aminoethylamino)butyl]-4-[3-(3 ,4-dimethylphenyl)-propionyl]-2-isobutylpiperazin-1 -yl}-3-(3 ,4-dimethylphenyl)propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-([1, 3, 4]thiadiazol-2-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(3, 4-dimethylphenyl)propionyl]-2-[4-(2-aminoethylamino) butyl]-5-isobutylpiperazin-1-yl}-3-(3, 4-dimethylphenyl)-propan-1-one;

(R)-2-Amino-1-{(2S, 5R)-4-[(R)-2-amino-3-(4-chloro-3-methylphenyl)-propionyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutylpiperazin-1-yl}-3-(4-chloro-3-methyl-phenyl)propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-5[4-(2-aminoethylamino)butyl]-4-[(R)-2-amino-3-(4-methoxyphenyl) propionyl]-2-isobutylpiperazin-1-yl}-3-(4-methoxyphenyl)propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-biphenyl-4-yl-propionyl)-5-[4-(2-amino-ethylamino) butyl]-2-isobutylpiperazin-1-yl}-3-biphenyl-4-yl-propan-1-one;

(R)-2-Amino-1-[(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-(3-[1, 2, 4]triazol-1-yl-propyl)piperazin-1- yl]-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-([1 , 2, 4]triazol-4-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(thiazol-2 -ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(5-methylthiazol-2-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(4-methylthiazol-2-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(5-methyl-[1, 3, 4]thiadiazol-2-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

N-{(R)-2-[(2S, 5R)-4-((R)-2-Acetylamino-3-naphthalen-2-yl-propionyl)-5-isobutyl-2-(3-[1, 2, 4]triazol-1-yl-propyl)piperazin-1-yl]-1-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(3-methylisoxazol-5-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(5-methylisoxazol-3-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(pyrimidin-4 -ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(isoxazol-3-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(pyrimidin-2-ylamino)propyl]piperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(R)-2-Amino-1-{(2R, 5S)-4-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-[2-(1H-imidazol-2-yl)ethyl]-2-isobutylpiperazin-1-yl}-3-naphthalen-2-yl-propan-1-one;

(S)-2-Amino-1-{(2R, 5S)-4-[(R)-2-amino-3-(2, 4-dichlorophenyl)priopionyl]-2-isobutyl-5-[3-([1 , 3, 4]thiadiazol-2-ylamino)propyl]piperazin-1-yl}-3-(2, 4-dichloro-phenyl)propan-1-one; and

(R)-2-Amino-1-[(2R, 5S)-5-[4-(2-aminoethylamino)butyl]-4-((R)-2-amino-3-p-tolyl-propionyl)-2-isobutylpiperazin-1-yl]-3-p-tolyl-propan-1-one, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound as defined in claim 1 or claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.