Aryl and heteroaryl compounds, compositions, and methods of use
View Patent ↗This invention provides aryl and heteroaryl compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention may be useful as antagonists, or partial antagonist of factor IX and/or factor XI and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds may be useful in a variety of applications including the management, treatment and/or control of diseases caused in part by the intrinsic clotting pathway utilizing factor IX and/or XI.
1. A compound of Formula (X),
wherein
R 101 is selected from the group consisting of —H, or —CH 2 -thienyl wherein the thienyl group in —CH 2 -thienyl is optionally substituted with —Br or —CH 3 ;
R 102 is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)O-t-butyl,
—C(O)NH—OCH 2 -phenyl, —C(O)NHOH, and —C(O)NHSO 2 CH 3 ;
R 103 is selected from the group consisting of —H, —CH 2 -thienyl, —CH 2 -phenyl, —CH 2 -furanyl, -thienyl, and benzothienyl wherein each of the above possibilities for R 103 except —H are optionally substituted with one or more members selected from group consisting of
—H, —CH 3 , —CF 3 , —Cl, —Br, —F, —C(O)CH 3 , —CH 2 CH 3 , —CH═CH 2 , —CH 2 OH,
—CH(CH 3 ) 2 ,
—CH 2 CH 2 CH 3 ,
-propenyl, -3,3-dimethyl-butenyl, -isopropenyl, -phenyl, -phenylene-methyl, -phenylene-propyl, -phenylene-trifluoromethyl, -phenylene-chloride, -cyclopentyl, -cyclopentenyl, and -furanyl;
R 104 is selected from the group consisting of —O-cyclohexylene-ethyl, —O-cyclohexylene-t-butyl, —O-cyclohexylene-i-propyl, —O-phenylene-t-butyl, -phenylene-t-butyl, and
—C(O)-phenylene-t-butyl;
and Y is selected from the group consisting of —H, -methylene-cyclopentyl, -amino-cyclohexyl, -methylene-thienylene-methyl, methylene-thienylene-bromide, and tetrahydropyranyl;
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
2. A compound of Formula (X),
wherein R 101 , is selected from the group consisting of —H, or —CH 2 -thienyl wherein the thienyl group in —CH 2 -thienyl is optionally substituted with —Br or —CH 3 ;
R 102 is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)O-t-butyl,
—C(O)NH—OCH 2 -phenyl, —C(O)NHOH, and —C(O)NHSO 2 CH 3 ;
R 103 is selected from the group consisting of —H, —CH 2 -thienyl, —CH 2 -phenyl, —CH 2 -furanyl, thienyl, and benzothienyl wherein each of the above possibilities for R 103 except —H are optionally substituted with one or more members selected from group consisting of
—H, —CH 3 , —CF 3 , —Cl, —Br, —F, —C(O)CH 3 , —CH 2 CH 3 , —CH═CH 2 , —CH 2 OH,
—CH(CH 3 ) 2 , —CH 2 CH 2 CH 3 ,
R 104 is selected from the group consisting of
and Y is selected from the group consisting of H,
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
3. The compound according to claim 2 , wherein R 104 is
4. The compound according to claim 2 , wherein R 103 is optionally substituted —CH 2 -2-yl-thienyl or optionally substituted —CH 2 -phenyl.
5. The compound according to claim 2 , wherein R 103 is optionally substituted —CH 2 -2-yl-thienyl.
6. The compound according to claim 3 , wherein R 101 is —H.
7. The compound according to claim 3 , wherein Y is selected from the group consisting of
8. The compound according to claim 2 , wherein the compound of Formula (X) is selected from the group consisting of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-phenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid methyl ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid methyl ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-furan-3-yl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(4-isopropyl-phenyl)-thiophen-2-yl]-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-vinyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-p-tolyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(4-chloro-phenyl)-thiophen-2-yl]-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-ethyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-furan-2-yl-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(2-trifluoromethyl-phenyl)-propionic acid,
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid tert-butyl ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(3,5-difluorophenyl)-propionic acid,
[[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(5-methyl-thiophen-2-ylmethyl)-amino]-acetic acid,
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester,
{(4-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,
Benzo[b]thiophen-3-yl-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(4-fluoro-phenyl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-propenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-propyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(3,3-dimethyl-but-1-enyl)-thiophen-2-yl]-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid methyl ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-methyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid,
3-(5-Bromo-thiophen-2-yl)-2(R)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-chloro-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-chloro-furan-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(2,5-dichloro-thiophen-3-yl)-propionic acid,
(5-Bromo-thiophen-2-yl)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,
3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-furan-2-yl)-propionic acid,
2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[1-Cyclopentylmethyl-7-(4-trans-ethyl-cyclohexyloxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[6-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-benzoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
3-(5-Acetyl-thiophen-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-(5-isopropyl-thiophen-2-ylmethyl)-2(R)-methanesulfonylamino-2-oxo-ethyl]-amide,
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-(5-isopropyl-thiophen-2-ylmethyl)-2(S)-methanesulfonylamino-2-oxo-ethyl]-amide,
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-benzyloxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide, and
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-hydroxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide.
9. The compound according to claim 2 , wherein Y is -methylene-cyclopentyl.