Carbonylamino-benzimidazole derivatives as androgen receptor modulators
View Patent ↗Compounds of structural formula (I) are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, arthritic condition and joint repair, HIV-wasting, prostate cancer, cancer cachexia, Alzheimer s disease, muscular dystrophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.
1. A compound of formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
R 1 is thiazolyl, optionally substituted with one or more R 4 groups;
R 2 is —(C═O)NR 5 R 6 ;
R 3 and R 4 are each independently selected from:
1) hydrogen,
2) halogen,
3) —(C═O) a O b (C 1-10 )alkyl,
4) —(C═O) a O b (C 2-8 )alkenyl,
5) —(C═O) a O b (C 2-8 )alkynyl,
6) —(C═O) a O b (C 3-10 )cycloalkyl,
7) —(C═O) a O b (C 3-8 )heterocyclyl,
8) —(C═O) a O b aryl,
9) —(C═O) a NR 5 R 6 ,
10) —O b (C═O)NR 5 R 6 ,
11) —NR 5 (C═O) a O b R b ,
12) —NR 5 (C═O)NR 5 R 6 ,
13) —NR 5 S(O) 2 R b ,
14) —(C═O)OH,
15) trifluoromethoxy,
16) trifluoroethoxy,
17) —O b (C 1-10 )perfluoroalkyl,
18) —S(O) 2 O b (C 1-10 )alkyl,
19) —S(O) 2 O b (C 2-8 )alkenyl,
20) —S(O) 2 O b (C 2-8 )alkynyl,
21) —S(O) 2 O b (C 3-10 )cycloalkyl,
22) —S(O) 2 O b (C 3-8 )heterocyclyl,
23) —S(O) 2 O b aryl,
24) —NR 5 S(O) 2 NR 5 R 6 ,
25) —CN
26) —NO 2 , and
27) OH,
wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more R Z groups;
R 5 is selected from:
1) hydrogen,
2) —(C═O) a O b (C 1-10 )alkyl,
3) —(C═O) a O b (C 2-8 )alkenyl,
4) —(C═O) a O b (C 2-8 )alkynyl,
5) —(C═O) a O b (C 3-10 )cycloalkyl,
6) —(C═O) a O b (C 3-8 )heterocyclyl,
7) —(C═O) a O b aryl,
8) —(C═O)N(R b ) 2 ,
9) trifluoromethoxy,
10) trifluoroethoxy,
11) —(C 1-10 )perfluoroalkyl,
12) —S(O) 2 N(R b ) 2 , and
13) —S(O) 2 O b R b ,
wherein said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl are each optionally substituted with one or more R Z groups,
R 6 is selected from:
1) —(C═O) a O b (C 1-10 )alkyl,
2) —(C═O) a O b (C 2-8 )alkenyl,
3) —(C═O) a O b (C 2-8 )alkynyl,
4) —(C═O) a O b (C 3-10 )cycloalkyl,
5) —(C═O) a O b (C 3-8 )heterocyclyl,
6) —(C═O) a O b aryl,
7) —(C═O)N(R b ) 2 ,
8) trifluoromethoxy,
9) trifluoroethoxy,
10) —(C 1-10 )perfluoroalkyl,
11) —S(O) 2 N(R b ) 2 , and
12) —S(O) 2 O b R b ,
wherein, said aryl, heterocyclyl, alkenyl, and alkynyl are optionally substituted with one or more R Z groups, and wherein said alkyl and cycloalkyl are substituted with one or more R Z groups,
with the proviso that R Z is other than hydrogen when R 6 is alkyl or cycloalkyl,
R Z is selected from:
1) hydrogen,
2) halogen,
3) —(C═O) a O b (C 2-8 )alkenyl,
4) —(C═O) a O b (C 2-8 )alkynyl,
5) —(C═O) a O b (C 3-10 )cycloalkyl,
6) —(C═O) a O b (C 3-8 )heterocyclyl,
7) —(C═O) a O b aryl,
8) —(C═O) a N(R b ) 2 ,
9) —O b (C═O)N(R b ) 2 ,
10) —NR b (C═O) a O b R b ,
11) —NR b (C═O)N(R b ) 2 ,
12) —NR b S(O) 2 R b ,
13) —(C═O)OH,
14) trifluoromethoxy,
15) trifluoroethoxy,
16) —O b (C 1-10 )perfluoroalkyl,
17) —S(O) 2 O b (C 1-10 )alkyl,
18) —S(O) 2 O b (C 2-8 )alkenyl,
19) —S(O) 2 O b (C 2-8 )alkynyl,
20) —S(O) 2 O b (C 3-10 )cycloalkyl,
21) —S(O) 2 O b (C 3-8 )heterocyclyl,
22) —S(O) 2 O b aryl,
23) —S(O) 2 N(R b ) 2
24) —NR b S(O) 2 N(R b ) 2
25) —CN,
26) —NO 2 ,
27) oxo, and
28) —OH,
wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more R a groups;
R a is selected from hydrogen, OH, (C 1-6 )alkoxy, halogen,
CO 2 H, CN, O(C═O)C 1-6 alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy,
—O b (C 1-10 )perfluoroalkyl, and NH 2 ; and
R b is hydrogen, —(C═O) a O b (C 1-10 )alkyl, —(C═O) a O b (C 2-8 )alkenyl,
—(C═O) a O b (C 2-8 )alkynyl, —(C═O) a O b (C 3-10 )cycloalkyl,
—(C═O) a O b (C 3-8 )heterocyclyl, —(C═O) a O b aryl,
—(C═O) a O b (C 1-10 )alkyl, —S(O) 2 N(R a ) 2 , —S(O) 2 O b R a , trifluoromethoxy,
trifluoroethoxy, or —O b (C 1-10 )perfluoroalkyl,
and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with up to three substituents selected from CO 2 H, NH 2 , OH, (C 1-6 )alkoxy, halogen, CN, O(C═O)C 1-6 alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy, —O b (C 1-10 )perfluoroalkyl and N(R a ) 2 .
2. A compound according to claim 1 , wherein R 1 is selected from thiazol-4-yl and thiazol-5-yl, wherein R 1 is optionally substituted with one or more R 4 groups.
3. A compound according to claim 2 , wherein:
R 3 and R 4 are each independently selected from:
1) hydrogen,
2) halogen,
3) —(C═O) a O b (C 1-10 )alkyl,
4) —(C═O) a O b (C 2-8 )alkenyl,
5) —(C═O) a O b (C 2-8 )alkynyl,
6) —(C═O) a O b (C 3-10 )cycloalkyl,
7) —(C═O) a O b (C 3-8 )heterocyclyl,
8) —(C═O) a O b aryl,
9) —(C═O) a NR 5 R 6 ,
10) —NR 5 S(O) 2 R b ,
11) trifluoroethoxy,
12) —O b (C 1-10 )perfluoroalkyl,
13) —S(O) 2 O b (C 1-10 )alkyl,
14) —S(O) 2 O b (C 3-10 )cycloalkyl,
15) —CN, and
16) OH,
wherein said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more R Z groups.
4. A compound according to claim 3 , wherein:
R 5 is selected from:
1) hydrogen,
2) —(C═O) a O b (C 1-10 )alkyl,
3) —(C═O) a O b (C 3-10 )cycloalkyl,
4) —(C═O) a O b (C 3-8 )heterocyclyl,
5) —(C═O) a O b aryl,
6) —(C═O) N(R b ) 2 , and
7) (C 1-10 )perfluoroalkyl
further wherein, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl are optionally substituted with one or more R Z groups,
R 6 is selected from:
1) —(C═O) a O b (C 1-10 )alkyl,
2) —(C═O) a O b (C 3-l0 )cycloalkyl,
3) —(C═O) a O b (C 3-8 )heterocyclyl,
4) —(C═O) a O b aryl,
5) —(C═O)N(R b ) 2 , and
6) (C 1-10 )perfluoroalkyl
further wherein said aryl, heterocyclyl, alkenyl, and alkynyl are optionally substituted with one or more R Z groups, and wherein said alkyl and cycloalkyl are substituted with one or more R Z groups (providing R Z is not hydrogen when R 6 is alkyl or cycloalkyl).
5. A compound according to claim 4 , wherein R b is selected from:
hydrogen, —(C═O) a O b (C 1-6 )alkyl, —(C═O) a O b (C 3-6 )cycloalkyl, —(C═O) a O b (C 3-6 )heterocyclyl, —(C═O) a O b aryl, and (C 1-3 )perfluoroalkyl, and wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with up to two substituents selected from NH 2 , OH, (C 1-6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1-6 alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy, —O b (C 1-10 )perfluoroalkyl and N(R a ) 2 .
6. A compound according to claim 1 , selected from:
N-isopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-[(1R)-1-phenylpropyl]-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(3,5-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-benzyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(2-phenylethyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(2-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(2-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(2-chlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-[(1S)-1-phenylethyl]-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(3-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(4-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;
N-(4-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;
N-(2,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;
N-(3,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;
N-(4-methoxyphenyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(3-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;
N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
N-(4-bromobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
N-(4-methoxybenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;
6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazole;
6-({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-[({[1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
N-methyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzinidazol-5-yl]urea;
N-benzyl-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroquinoline-1(2H)-carboxamide;
N-ethyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
6-({[methyl(2-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[methyl(4-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
N-(4-hydroxyphenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
N-(2-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
N-(1-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
N-(4-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
2-(1,3-thiazol-4-yl)-6[({[3(trifluoromethyl)benzyl]amino}carbonyl)amino]-3H-benzimidazole;
6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-{[(2-phenylpyrrolidin-1-yl)carbonyl]amino}-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[(5-isopropyl-2-methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-[({[(2-bromothien-3-yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
N-cyclopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
N-[4-(hydroxymethyl)phenyl]-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;
1-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea;
and pharmaceutically acceptable salts and stereoisomers thereof.
7. A compound according to claim 6 , selected from:
N-(3-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-(3,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
N-benzyl-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
N-ethyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;
6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[isopropyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;
6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;
N-cyclopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea; and
1-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea; and
pharmaceutically acceptable salts and stereoisomers thereof.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
9. A composition of claim 8 which further comprises an active ingredient selected from:
a) an estrogen or an estrogen derivative, alone or in combination with a progestin or progestin derivative;
b) a bisphosphonate;
c) an antiestrogen or a selective estrogen receptor modulator,
d) an αvβ3 integrin receptor antagonist,
e) a cathepsin K inhibitor,
f) an HMG-CoA reductase inhibitor,
g) an osteoclast vacuolar ATPase inhibitor,
h) an antagonist of VEGF binding to osteoclast receptors,
i) an activator of peroxisome proliferator-activated receptor γ,
j) calcitonin,
k) a calcium receptor antagonist,
l) parathyroid hormone or analog thereof,
m) a growth hormone secretagogue,
n) human growth hormone,
o) insulin-like growth factor,
p) a p38 protein kinase inhibitor,
q) bone morphogenetic protein,
r) an inhibitor of BMP antagonism,
s) a prostaglandin derivative,
t) vitamin D or vitamin D derivative,
u) vitamin K or vitamin K derivative,
v) ipriflavone,
w) fluoride salts,
x) dietary calcium supplement, and
y) osteoprotegerin.
10. A composition of claim 9 , wherein said bisphosphonate is alendronate.
11. A pharmaceutical composition made by combining a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. A process for making a pharmaceutical composition comprising combining a compound according to claim 1 and a pharmaceutically acceptable carrier.
13. A compound according to claim 1 , selected from:
6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-ium trifluoroacetate;
6-[({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({[(1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[methyl(2-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[methyl(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[methyl(4-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzinidazol-1-ium trifluoroacetate;
6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol- 1-ium trifluoroacetate;
6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate
6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
2-(1,3-thiazol-4-yl-6[({[3(trifluoromethyl)benzyl]amino}carbonyl)amino]-3H-benzimidazol-1-ium trifluoroacetate;
6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-{[(2-phenylpyrrolidin-1-yl)carbonyl]amino}-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(5-isopropyl-2-methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium bis(trifluoroacetate);
6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({[(2-bromothien-3-yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium bis(trifluoroacetate); and
6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
and stereoisomers thereof.
14. A compound according to claim 13 , selected from:
6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[isopropyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-([{(3chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
and stereoisomers thereof.
15. A compound selected from:
N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;
6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
N-(1-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea; and
N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;
16. A compound according to claim 15 which is: N-(1-phenylcyclopropyl)-N″-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea.
17. A compound according to claim 15 selected from:
N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;
6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;
6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; and
N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea.
18. A compound according to claim 1 wherein R Z is selected from:
1) —(C═O) a O b (C 2-8 )alkenyl,
2) —(C═O) a O b (C 2-8 )alkynyl,
3) —(C═O) a O b (C 3-8 )heterocyclyl,
4) —(C═O) a O b aryl,
5) —(C═O) a N(R b ) 2 ,
6) —O b (C═O)N(R b ) 2 ,
7) —NR b (C═O) a O b R b ,
8) —NR b (C═O)N(R b ) 2 ,
9) —NR b S(O) 2 R b ,
10) —(C═O)OH,
11) trifluoromethoxy,
12) trifluoroethoxy,
13) —O b (C 1-10 )perfluoroalkyl,
14) —S(O) 2 O b (C 1-10 )alkyl,
15) —S(O) 2 O b (C 2-8 )alkenyl,
16) —S(O) 2 O b (C 2-8 )alkynyl,
17) —S(O) 2 O b (C 3-10 )cycloalkyl,
18) —S(O) 2 O b (C 3-8 )heterocyclyl,
19) —S(O) 2 O b aryl,
20) —S(O) 2 N(R b ) 2
21) —NR b S(O) 2 N(R b ) 2
22) —CN,
23) —NO 2 ,
24) oxo, and
25) —OH,
wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more R a groups;
R a is selected from hydrogen, OH, (C 1-6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1-6 alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy, —O b (C 1-10 )perfluoroalkyl, and NH 2 ; and
R b is hydrogen, —(C═O) a O b (C 1-10 )alkyl, —(C═O) a O b (C 2-8 )alkenyl, —(C═O) a O b (C 2-8 )alkynyl, —(C═O) a O b (C 3-10 )cycloalkyl, —(C═O) a O b (C 3-8 )heterocyclyl, —(C═O) a O b aryl, —(C═O) a O b (C 1-10 )alkyl, —S(O) 2 N(R a ) 2 , —S(O) 2 O b R a , trifluormethoxy, trifluoroethoxy, or —O b (C 1-10 )perfluoroalkyl,
and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with up to three substituents selected from CO 2 H, NH 2 , OH, (C 1-6 )alkoxy, halogen, CN, O(C═O)C 1-6 alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy, —O b (C 1-10 )perfluoroalkyl and N(R a ) 2 .