Substituted [1,4]-diazepanes as CXCR3 antagonists and their use in the treatment of inflammatory disorders
CXCR3 inhibitors of formula are disclosed. Inhibition of CXCR3 activation is useful for treating disorders resulting from CXCR3-associated T-cell mediated function, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and diabetes, as well as in the prevention of allograft rejection. N-ethyl-1,4-diazepane-1-carboxamides in which R 1 is substituted or unsubstituted arylalkyl and R 3 is substituted or unsubstituted aryl are particularly preferred.
1 . A compound of formula I
wherein:
R 1 is substituted or unsubstituted alkyl substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcycloalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted sulfur or oxygen heteroarylalkyl;
R 2 is H;
X is CO—, or (CO)—NH—;
R 3 is substituted or unsubstituted C2-C6 alkyl substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl;
Y is H, C(O)—, CON—, or C(O)NH—; and
R 4 is H, or substituted or unsubstituted alkyl
wherein R 3 is not pyridine when R 1 is alkyl.
2 . A 1,4-diazepane according to claim 1 of formula I
wherein
X is CO, Y is CONH—, and R 2 is H.
3 . A 1,4-diazepane carboxamide according to claim 2 , of formula II
wherein
R 4 is alkyl.
4 . A compound according to claim 3 of formula II:
wherein
R 1 is substituted or unsubstituted alkyl substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcycloalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted sulfur or oxygen heteroarylalkyl; and
R 3 is substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle; substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl;
wherein R 3 is not pyridine when R 1 is alkyl.
5 . A compound according to claim 4 of formula III
wherein
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcycloalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted sulfur or oxygen heteroarylalkyl;
R 3 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
wherein R 3 is not pyridine when R 1 is alkyl.
6 . A compound according to claim 4 of formula III
wherein R 1 is substituted or unsubstituted arylalkyl; and
R 3 is substituted or unsubstituted aryl or heteroaryl.
7 . A compound according to claim 1 chosen from:
4-(4-((4-fluorophenethyl)carbamoyl)-2-benzamidophenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(furan-4-carboxamido)phenyl)-N-ethyl-1,4-diazepane-1,7-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-cyclopropanecarboxamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
(+/−)-4-(2-(3-chlorobenzamido)-4-((2-phenylpropyl)carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-(isopropylcarbamoyl)phenyl)-acetyl-1,4-diazepane;
4-(4-(((+/−)trans-2-phenylcyclopropyl)carbamoyl)-2-(3,5-difluorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-((3-phenylpropyl)carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-chlorobenzyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-chlorophenethyl)carbamoyl)-2-benzamidophenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-((naphthalen-1-ylmethyl)-carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-isopropyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(4-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-chlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-chlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-(2,4-dichlorophenethyl)carbamoyl)-2-(3-methoxybenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-(benzylcarbamoyl-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(2-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(thiophene-2-carboxamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-methyl-1,4-diazepane-1-carboxamide;
4-(2-benzamido-4-(3-phenylpropyl)carbamoyl)phenyl-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-(3,4-dimethoxyphenethylcarbamoyl)phenyl)-acetyl-1,4-diazepane;
4-(4-(2,4-dichlorophenethyl)carbamoyl)-2-(3-cyanobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((3-chlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-chloro-2-methylphenethyl)carbamoyl)-2-(4-fluorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-(isopropylcarbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-isobutyramidophenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-benzamido-4-(4-methylphenethylcarbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-fluorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
1-(2-(4-(ethylcarbamoyl)-1,4-diazepan-1-yl)-5-(isopropylcarbamoyl)phenyl)-3-phenylurea,
4-(2-(3-chlorobenzamido)-4-((2,3-dihydro-1H-inden-1-yl)carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2-fluorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-propyl-1,4-diazepane-1-carboxamide;
4-(4-(((+/−)-trans-2-phenylcyclopropyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((3,4-dimethoxyphenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide,
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3,5-difluorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl-2-(2-fluorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-1,4-diazepane;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
(+/−)-4-(2-(3-chlorobenzamido)-4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-(((+/−)(-trans-)-2-phenylcyclopropyl)carbamoyl)-2-benzamidophenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(thiophene-4-carboxamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(thiophene-4-carboxamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((3-fluorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(furan-2-carboxamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(isonicotinamido phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-butyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-(phenethylcarbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-(3,4-difluorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((4-methylphenethyl)carbamoyl)-2-(3-chlorobenzamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((+/−)(trans-2-phenylcyclopropyl)carbamoyl)-2-(isonicotinamido)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-((2-(thio-2-yl)ethyl)carbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(2-(3-chlorobenzamido)-4-(isoquinolin-5-ylcarbamoyl)phenyl)-N-ethyl-1,4-diazepane-1-carboxamide;
4-(4-((2,4-dichlorophenethyl)carbamoyl)-2-benzamidophenyl)-ethyl-1,4-diazepane-1-carboxamide
8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 1 .
9 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 7 .
10 . A method for treating a disorder mediated by CXCR3 function comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I.
wherein:
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcycloalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted sulfur or oxygen heteroarylalkyl;
R 2 is H;
X is CO—, or (CO)—NH—;
R 3 is substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl;
Y is H, C(O)—, CON—, or C(O)NH—; and
R 4 is H, or substituted or unsubstituted alkyl,
wherein R 3 is not pyridine when R 1 is alkyl.
11 . The method of claim 10 wherein said compound is a 1,4-diazapene carboxamide of the formula
wherein
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcycloalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted sulfur or oxygen heteroarylalkyl;
R 3 is substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl;
and
R 4 is H, or substituted or unsubstituted alkyl,
wherein R 3 is not pyridine when R 1 is alkyl.
12 . The method of claim 10 wherein said disorder mediated by CXCR3 function is inflammation.
13 . The method of claim 10 wherein said disorder is inflammatory bowel disease.
14 . The method of claim 10 wherein said disorder is insulitis associated with diabetes.
15 . The method of claim 10 wherein said disorder is rheumatoid arthritis.
16 . The method of claim 10 wherein said disorder is multiple sclerosis.
17 . A method for treating inflammation comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 .