IP Library › Granted Patent US 7,786,153

Granted Patent B2

US 7,786,153 · App. 11/366,172 · Granted Aug 31, 2010

Compounds that are useful for improving pharmacokinetics

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Quick Facts

Patent No.: US 7,786,153
App. No.: 11/366,172
Granted: Aug 31, 2010
Kind: B2

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Abstract

Novel compounds of formula 1 or a pharmaceutically acceptable salt thereof inhibit cytochrome P450 monooxygenase.

Claims (349)

1. A compound, prodrug of the compound, pharmaceutically acceptable salt of the compound or prodrug, or combination thereof, wherein:

the compound corresponds in structure to formula I:

R 1 is selected from the group consisting of heteroaryl and heterocycle;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxyalkyl, alkynyl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, aryloxycarbonyl, arylthioalkoxyalkyl, arylthioalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, di(alkoxycarbonyl)alkyl, heteroarylalkoxyalkyl, heteroarylalkoxycarbonyl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroaryloxycarbonyl, heteroarylthioalkoxyalkyl, heteroarylthioalkyl, heterocyclealkoxyalkyl, heterocyclealkoxycarbonyl, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxycarbonyl, heterocyclethioalkoxyalkyl, heterocyclethioalkyl, hydroxyalkyl, and (NR C R D )alkyl;

R 4 is selected from the group consisting of heteroaryl and heterocycle;

R 5 and R 6 are each independently selected from the group consisting of hydrogen, lower alkyl, and arylalkyl;

m is 0-3;

n is 0-3;

A 1 is O;

A 2 is O;

X 1 and X 2 are each independently selected from the group consisting of O and S;

L is

R 7 is selected from the group consisting of hydrogen, alkenyl, alkenylcarbonyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxyalkyl, alkynyl, alkynylcarbonyl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, arylthioalkoxyalkyl, arylthioalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, di(alkoxycarbonyl)alkyl, heteroarylalkoxyalkyl, heteroarylalkoxycarbonyl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylthioalkoxyalkyl, heteroarylthioalkyl, heterocyclealkoxyalkyl, heterocyclealkoxycarbonyl, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclethioalkoxyalkyl, heterocyclethioalkyl, hydroxyalkyl, (NR C R D )alkyl, and

R 10 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxyalkyl, alkynyl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, aryloxycarbonyl, arylthioalkoxyalkyl, arylthioalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, di(alkoxycarbonyl)alkyl, heteroarylalkoxyalkyl, heteroarylalkoxycarbonyl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroaryloxycarbonyl, heteroarylthioalkoxyalkyl, heteroarylthioalkyl, heterocyclealkoxyalkyl, heterocyclealkoxycarbonyl, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxycarbonyl, heterocyclethioalkoxyalkyl, heterocyclethioalkyl, hydroxyalkyl, and (NR A R B )alkyl;

R 11 is selected from the group consisting of hydrogen, lower alkyl, and arylalkyl;

R 12 is selected from the group consisting of aryl, heteroaryl, and heterocycle;

q is 0-3;

X 3 is selected from the group consisting of O and S;

A 3 is absent or selected from the group consisting of O and NR A3 , wherein R A3 is selected from the group consisting of hydrogen and lower alkyl;

R A and R B are independently selected from the group consisting of hydrogen and lower alkyl;

R C and R D are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, arylalkoxycarbonyl, arylsulfonyl, formyl, (NR E R F )carbonyl, and (NR E R F )sulfonyl;

R E and R F are each independently selected from the group consisting of hydrogen and lower alkyl; and

wherein any one of the

aryl,

heteroaryl,

heterocycle,

cycloalkyl,

cycloalkyl moiety of cycloalkylalkyl,

aryl moieties of arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, aryloxycarbonyl, arylthioalkoxyalkyl, and arylthioalkyl,

heteroaryl moieties of heteroarylalkoxyalkyl, heteroarylalkoxycarbonyl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroaryloxycarbonyl, heteroarylthioalkoxyalkyl, and heteroarylthioalkyl, and

heterocycle moieties of heterocyclealkoxyalkyl, heterocyclealkoxycarbonyl, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxycarbonyl, heterocyclethioalkoxyalkyl, and heterocyclethioalkyl,

at each occurrence, is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkynyl, benzyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, nitro, phenoxy, thioalkoxy, thioalkoxyalkyl, —NR A R B , (NR A R B )alkoxy, and (NR A R B )alkyl.

2. The compound, prodrug, salt, or combination according to claim 1 , wherein:

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, arylalkoxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl;

R 7 is selected from the group consisting of hydrogen, alkenyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, arylalkyl, arylcarbonyl, carboxyalkyl, cycloalkylalkyl, di(alkoxycarbonyl)alkyl, heteroarylalkoxycarbonyl, heterocyclealkoxycarbonyl, heteroarylalkyl, heterocyclealkyl, (NR C R D )alkyl, and

R 10 is selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, arylalkoxyalkyl, arylalkyl, and cycloalkylalkyl; and

R C and R D are each independently selected from the group consisting of hydrogen, alkyl, and alkoxycarbonyl.

3. The compound, prodrug, salt, or combination according to claim 1 , wherein:

R 1 is heteroaryl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, arylalkoxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl;

R 4 is heteroaryl;

R 10 is selected from the group consisting of hydrogen, alkyl, and arylalkyl;

R 12 is heteroaryl; and

R C and R D are each independently selected from the group consisting of hydrogen, alkyl, and alkoxycarbonyl.

4. The compound, prodrug, salt, or combination according to claim 1 , wherein:

R 1 is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, arylalkoxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl;

R 4 is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl;

R C and R D are independently selected from the group consisting of hydrogen, alkyl, and alkoxycarbonyl;

R 10 is selected from the group consisting of hydrogen and arylalkyl; and

R 12 is heteroaryl.

5. The compound, prodrug, salt, or combination according to claim 1 , wherein:

R 1 is selected from the group consisting of imidazolyl, oxazolyl, pyrazolyl, pyridinyl, thiazolyl, and thienyl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is selected from the group consisting of imidazolyl, oxazolyl, pyrazolyl, pyridinyl, thiazolyl, and thienyl;

R 7 is selected from the group consisting of

hydrogen,

alkenyl,

alkoxycarbonylalkyl,

alkyl,

alkylcarbonyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl,

arylcarbonyl, wherein the aryl portion of arylcarbonyl is selected from the group consisting of phenyl and naphthyl,

carboxyalkyl,

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl,

di(alkoxycarbonyl)alkyl,

heteroarylalkoxycarbonyl, wherein the heteroaryl portion of heteroarylalkoxycarbonyl is thiazolyl,

heteroarylalkyl, wherein the heteroaryl portion of heteroarylalkyl is selected from the group consisting of imidazolyl, pyridinyl, pyrrolyl, and quinolinyl,

heterocycloalkyl, wherein the heterocycle portion of heterocyclealkyl is tetrahydrofuranyl,

(NR C R D )alkyl, and

R c and R D are independently selected from the group consisting of hydrogen, alkyl, and alkoxycarbonyl;

R 10 is selected from the group consisting of hydrogen and phenylmethyl; and

R 12 is selected from the group consisting of imidazolyl, oxazolyl, pyrazolyl, pyridinyl, thiazolyl, and thienyl.

6. The compound according to claim 1 , wherein the compound corresponds in structure to formula II:

7. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, arylalkoxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl;

R c and R D are independently selected from the group consisting of hydrogen, alkyl, and alkoxycarbonyl;

R 10 is selected from the group consisting of hydrogen and arylalkyl; and

R 12 is heteroaryl selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.

8. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is selected from the group consisting of imidazolyl, oxazolyl, pyrazolyl, pyridinyl, thiazolyl, and thienyl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is selected from the group consisting of imidazolyl, oxazolyl, pyrazolyl, pyridinyl, thiazolyl, and thienyl;

R 5 and R 6 are each independently selected from the group consisting of

hydrogen,

lower alkyl, and

phenylmethyl;

R 7 is selected from the group consisting of

hydrogen,

alkenyl,

alkoxycarbonylalkyl,

alkyl,

alkylcarbonyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl,

arylcarbonyl, wherein the aryl portion of arylcarbonyl is selected from the group consisting of phenyl and naphthyl,

carboxyalkyl,

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl,

di(alkoxycarbonyl)alkyl,

heteroarylalkoxycarbonyl, wherein the heteroaryl portion of heteroarylalkoxycarbonyl is thiazolyl,

heteroarylalkyl, wherein the heteroaryl portion of heteroarylalkyl is selected from the group consisting of imidazolyl, pyridinyl, pyrrolyl, and quinolinyl,

heterocycloalkyl, wherein the heterocycle portion of the heterocyclealkyl is tetrahydrofuranyl,

(NR C R D )alkyl, and

R c and R D are independently selected from the group consisting of hydrogen, alkyl, and alkoxycarbonyl;

R 10 is selected from the group consisting of hydrogen and phenylmethyl; and

R 12 is selected from the group consisting of imidazolyl, oxazolyl, pyrazolyl, pyridinyl, thiazolyl, and thienyl.

9. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is thiazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is thiazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is selected from the group consisting of hydrogen, alkenyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkylalkyl, di(alkoxycarbonyl)alkyl, and (NR C R D )alkyl; and

R C and R D are independently selected from the group consisting of hydrogen and alkoxycarbonyl.

10. The compound, prodrug, salt, or combination according to claim 9 , wherein the compound is selected from the group consisting of

N-ethyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethylpropyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethylpropyl)-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethylpropyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N,N-bis[2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-ethyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-4-methylpentyl]amine;

N-ethyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)propyl]amine;

N-ethyl-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)propyl]amine;

N-ethyl-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)propyl]-N-((2S)-2-thiazol-5-ylmethoxy carbonylamino)propyl]amine;

N-ethyl-N,N-bis[2-(thiazol-5-ylmethoxycarbonylamino)ethyl]amine;

N-ethyl-N,N-bis[2-(thiazol-5-ylmethoxycarbonylamino)-3-cyclohexylpropyl]amine;

N-ethyl-N,N-bis[2-(thiazol-5-ylmethoxycarbonylamino)-3-(methoxycarbonyl)propyl]amine;

N-ethyl-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-(phenylmethoxy)propyl]-N-[2-(thiazol-5-ylmethoxycarbonylamino)-3-(phenylmethoxy)propyl]amine;

N-ethyl-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-[4-(phenylmethoxy)phenyl]propyl]-N-[2-(thiazol-5-ylmethoxycarbonylamino)-3-[4-(phenylmethoxy)phenyl]propyl]amine;

N-ethyl-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propyl]-N-[2-(thiazol-5-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propyl]amine;

N-ethyl-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-N-[2-(thiazol-5-ylmethoxycarbonylamino)-3-(4-methoxyphenyl)propyl]amine;

N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxy carbonylamino)-3-phenylpropyl]amine;

N-(2-methylpropyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3-methylbutyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N,N-bis-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2-methylpropyl)-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3-methylbutyl)-N,N-bis[(2R)-2-thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-acetyl-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2-methylpropyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(4-pentenyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3-carboxypropyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-butyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-octyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(cyclopropylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3,5,5-trimethylhexyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethyl-4-pentenyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenyl propyl]amine;

N-[2-((tert-butoxycarbonyl)amino)ethyl]-N,N-bis-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(6-methoxy-6-oxohexyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino) 3 -phenyl propyl]amine;

N-[4-ethoxy-2-(ethoxycarbonyl)-4-oxobutyl]-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonyl amino)-3-phenylpropyl]amine;

N-(3-methylbutyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(cyclohexylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-ethyl-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine; and

N-ethyl-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine.

11. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is thiazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of the cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is thiazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is selected from the group consisting of

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

arylcarbonyl, wherein the aryl portion of arylcarbonyl is selected from the group consisting of phenyl and naphthyl.

12. The compound, prodrug, salt, or combination according to claim 11 , wherein the compound is selected from the group consisting of

N-benzyl-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-benzyl-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-benzoyl-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-((2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2-phenylethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-[3-(1,3-benzodioxol-5-yl)-2-methylpropyl]-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonyl amino)-3-phenylpropyl]amine;

N-(3,5-ditert-butyl-2-hydroxybenzyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2-naphthylmethyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3-phenoxybenzyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)]amine;

N-(3-methoxybenzyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3,4-dimethoxybenzyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-[4-(3-(dimethylamino)propoxy)benzyl]-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(4-dimethylaminobenzyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-[(6-methoxy-2-naphthyl)methyl]-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine; and

N-benzyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine.

13. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is thiazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and or cyclohexyl;

R 4 is thiazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is selected from the group consisting of

heteroarylalkoxycarbonyl, wherein the heteroaryl portion of heteroarylalkoxycarbonyl is thiazolyl,

heteroarylalkyl, wherein the heteroaryl portion of heteroarylalkyl is selected from the group consisting of imidazolyl, pyridinyl, pyrrolyl, and quinolinyl, and

heterocycloalkyl, wherein the heterocycle portion of heterocyclealkyl is tetrahydrofuranyl.

14. The compound, prodrug, salt, or combination according to claim 13 , wherein the compound is selected from the group consisting of

N-(thiazol-5-ylmethoxycarbonyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(1H-imidazol-4-ylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenyl propyl]amine;

N-(3-pyridinylmethyl)-N,N-bis[(2S)-2-thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(4-pyridinylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(1H-pyrrol-2-ylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenyl propyl]amine;

N-[(2,5-dimethoxytetrahydro-3-furanyl)methyl]-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonyl amino)-3-phenylpropyl]amine; and

N-(3-quinolinylmethyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N [(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine.

15. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is thiazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 1 is thiazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is

R 10 is selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is phenyl,

arylalkyl, wherein the aryl portion of arylalkyl is phenyl, and

cycloalkylalkyl; and

R 12 is heteroaryl.

16. The compound, prodrug, salt, or combination according to claim 6 , wherein;

R 1 is thiazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is thiazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is

R 10 is phenylmethyl; and

R 12 is thiazol-5-yl.

17. The compound, prodrug, salt, or combination according to claim 16 , wherein the compound is tris-N-[2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl].

18. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is oxazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is oxazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is alkyl.

19. The compound, prodrug, salt, or combination according to claim 18 , wherein the compound is N-ethyl-N,N-bis[(2S)-2-(oxazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine.

20. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is thien-2-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl, wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl, wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl, wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is thien-2-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is alkyl.

21. The compound, prodrug, salt, or combination according to claim 20 , wherein the compound is N-ethyl-N,N-bis[(2S)-2-(thien-2-ylmethoxy carbonylamino)-3-phenylpropyl]amine.

22. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is pyridin-3-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 1 is pyridin-3-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is alkyl.

23. The compound, prodrug, salt, or combination according to claim 22 , wherein the compound is N-ethyl-N,N-bis[(2S)-2-(pyridin-3-ylmethoxy carbonylamino)-3-phenylpropyl]amine.

24. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is imidazol-4-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is imidazol-4-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is alkyl.

25. The compound, prodrug, salt, or combination according to claim 24 , wherein the compound is N-ethyl-N,N-bis[(2S)-2-(1H-imidazol-4-yl methoxycarbonyl amino)-3-phenyl propyl]amine.

26. The compound, prodrug, salt, or combination according to claim 6 , wherein:

R 1 is pyrazol-5-yl;

R 2 and R 3 are independently selected from the group consisting of

hydrogen,

alkoxycarbonylalkyl,

alkyl,

arylalkoxyalkyl wherein the aryl portion of arylalkoxyalkyl is selected from the group consisting of phenyl and naphthyl,

arylalkyl wherein the aryl portion of arylalkyl is selected from the group consisting of phenyl and naphthyl, and

cycloalkylalkyl wherein the cycloalkyl portion of cycloalkylalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R 4 is pyrazol-5-yl;

R 5 is hydrogen;

R 6 is hydrogen; and

R 7 is alkyl.

27. The compound, prodrug, salt, or combination according to claim 26 , wherein the compound is N-ethyl-N,N-bis[(2S)-2-(pyrazol-5-ylmethoxy carbonylamino)-3-phenylpropyl]amine.

28. A compound, prodrug of the compound, pharmaceutically acceptable salt of the compound or prodrug, or combination thereof, wherein the compound is selected from the group consisting of

N-ethyl-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethylpropyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethylpropyl)-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(2,2-dimethylpropyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N,N-bis[2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3-methylbutyl)-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-benzyl-N,N-bis[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(4-pyridinylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(cyclopropylmethyl)-N,N-bis[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine;

N-(3-methoxybenzyl)-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine; and

N-ethyl-N-[(2R)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]-N-[(2S)-2-(thiazol-5-ylmethoxycarbonylamino)-3-phenylpropyl]amine.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 10, 2013

From: ABBOTT LABORATORIES

To: ABBVIE INC.

Reel/Frame 030185/0141 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 30, 2007

From: KEMPF, DALE J.; FLENTGE, CHARLES A.; RANDOLPH, JOHN T.; HUANG, PEGGY; KLEIN, LARRY L.

To: ABBOTT LABORATORIES

Reel/Frame 020180/0224 →