US2010048513A1PendingUtilityA1
Novel inhibitors of chymase
Est. expiryAug 20, 2028(~2.1 yrs left)· nominal 20-yr term from priority
A61K 31/4535A61K 31/445A61K 31/662A61K 31/381A61P 11/06A61P 11/00
67
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Claims
Abstract
The present invention is directed to a compound of formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof, and methods for treating inflammatory and serine protease mediated disorders.
Claims
exact text as granted — not AI-modified1 . A method for treating or ameliorating a chymase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
wherein
R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl;
is selected from the group consisting of aryl, heteroaryl, benzo fused heterocyclyl, and cyclopropyl when n is 0 and one of R 2 or R 3 is phenyl, and benzo fused cycloalkyl, and ring A is optionally substituted with R 2 and R 3 ;
R 2 is one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, methoxy, C 2-6 alkoxy, C 1-6 alkylthio, —OCF 3 , —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro; furthermore, R 2 is optionally oxo when ring A is heteroaryl or benzo fused heterocyclyl; and, wherein any aryl-containing substituent of R 2 is optionally substituted with a substituent independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
and, wherein any of the foregoing C 1-6 alkyl or C 2-6 alkoxy containing substituents of R 2 are optionally substituted with a substituent independently selected from the group consisting of —NR 11 R 12 , aryl, heteroaryl, one to three halogens and hydroxy; wherein R 11 and R 12 are independently hydrogen; C 1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, or —NR 15 R 16 ; or aryl;
R 15 and R 16 are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, and said R 15 and R 16 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
R 3 is one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, —OCF 3 , —OCH 2 (C 2-6 )alkenyl, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, —NHC(═O)Cy, —N(C 1-6 alkyl)C(═O)Cy, —(NC(═O)) 2 NH 2 , —C(═O)C 1-4 alkoxy, —C(═O)NR 17 R 18 , —C(═O)NHcycloalkyl, —C(═O)N(C 1-6 alkyl)cycloalkyl, —C(═O)NHCy, —C(═O)N(C 1-6 alkyl)Cy, —C(═O)Cy, —OC(═O)C 1-6 alkyl, —OC(═O)NR 19 R 20 , —C(═O)Oaryl, —C(═O)Oheteroaryl, —CO 2 H, ureido, halogen, hydroxy, nitro, cyano, aryl, heteroaryl, heteroaryloxy, and aryloxy;
wherein any of the foregoing C 1-6 alkyl or C 1-6 alkoxy containing substituents of R 3 are optionally substituted with one to three substituents independently selected from the group consisting of —NR 21 R 22 , —NH(cycloalkyl), —N(C 1-6 alkyl)(cycloalkyl), —NHCy, —N(C 1-6 alkyl)Cy, aryl, heteroaryl, hydroxy, halogen, —C(═O)NR 23 R 24 , —OC(═O)NR 25 R 26 , —C(═O)C 1-4 alkoxy, and —C(═O)Cy;
wherein said R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, wherein C 1-6 alkyl is optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and R 17 and R 18 , R 19 and R 20 , R 21 and R 22 , R 23 and R 24 , and R 25 and R 26 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
Cy is a heterocyclyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkylC(═O)C 1-6 alkyl, —C 1-6 alkylC(═O)C 1-6 alkoxy, C 1-6 alkylC(═O)aryl, —C(═O)(C 1-6 )alkyl, —C(═O)(C 1-6 )alkoxy, —C(═O)aryl, —SO 2 aryl, aryl, heteroaryl, and heterocyclyl; wherein the aryl portion of any aryl-containing substituent of Cy is optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogen, hydroxy, NH 2 , NH(C 1-6 alkyl), and —N(C 1-6 )dialkyl; and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one to three oxo substituents; and heterocyclyl is optionally spiro-fused to said Cy;
and wherein the C 1-6 alkenyl and C 1-6 alkynyl substituents of R 3 are optionally substituted with aryl or —C(═O)NR 27 R 28 ; wherein said R 27 and R 23 are independently hydrogen; C 1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; or aryl; and R 27 and R 28 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
wherein the aryl, heteroaryl, and cycloalkyl substituents of R 3 are optionally substituted with one to three substituents independently selected from R 14 ;
wherein R 14 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
and any one of the foregoing C 1-6 alkyl- or C 1-6 alkoxy-containing substituents of R 14 is optionally substituted on a terminal carbon atom with a substituent selected from —NR 29 R 30 , aryl, heteroaryl, one to three halogen atoms, or hydroxy; wherein R 29 and R 30 are independently hydrogen; C 1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-16 )dialkyl; or aryl; and R 29 and R 30 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
n is 0 or 1;
W is O or S;
X is hydrogen or C 1-3 alkyl;
Y is independently selected from the group consisting of C 1-6 alkyl substituted with —OSO 2 NH 2 or hydroxy; SO 3 H, CO 2 H, heteroaryl, —OC(═O)NH 2 , and P(═O)OR 5 R 6 provided that when Y is CO 2 H, A and Z must both be bicyclic ring systems;
R 5 is selected from the group consisting of hydrogen; C 1-6 alkyl optionally substituted with NH 2 , —NH(C 1-16 )alkyl, —N(C 1-6 )dialkyl, 1,3-dioxolan-2-yl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6 alkylcarbonylthio, (C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogens, or hydroxy; and aryl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, —NH 2 , —NH(C 1-16 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R 5 is C 1-8 alkoxy, R 5 and R 6 are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
provided that R 5 is other than C 1-6 alkyl substituted with di(C 1-6 )alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl, n is 1, R 6 is OH, and Z-R 4 is 5-chloro-benzothiophen-3-yl; and provided that R 5 is other than C 1-6 alkyl substituted with C 1-6 alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R 6 is CH 3 , and Z-R 4 is 5-chloro-benzothiophen-3-yl;
R 6 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, heteroaryl, aryl, and hydroxy; wherein C 1-8 alkyl, C 1-8 alkoxy, and C 2-8 alkenyl are optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, aryl, heterocyclyl, heteroaryl, NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, C 1-6 alkyl-carbonyloxy, C 1-6 alkylcarbonylthio, C 1-6 alkoxycarbonyloxy, (C 1-6 )alkylamino-carbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogen atoms, and hydroxy; and when R 6 is C 1-8 alkyl, said C 1-8 alkyl is optionally substituted with one to four additional halogen atoms such that one to three halogen atoms are optionally chlorine and one to seven of the halogen atoms are optionally fluorine;
wherein the heteroaryl and aryl substituents of R 6 are optionally substituted with a substituent independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
Z is a seven to fifteen membered monocyclic or polycyclic ring system selected from the group consisting aryl, heteroaryl, benzo fused heterocyclyl, or benzo fused cycloalkyl;
R 4 is one to three substituents selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylthio, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, halogen, —C(═O)Cy, —C(═O)NR 31 R 32 , aryl, —CO 2 H, oxo, and cyano; wherein C 1-6 alkyl, C 1-6 alkenyl and C 1-6 alkoxy are optionally substituted with —NR 33 R 34 , aryl, heteroaryl, cycloalkyl, one to three halogen atoms, or hydroxy; and aryl and heteroaryl are each optionally substituted with a substituent independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, one to three halogen atoms, hydroxy, and nitro;
wherein said R 31 , R 32 , R 33 , and R 34 are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and R 31 with R 32 and R 33 with R 34 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
and pharmaceutically acceptable salts thereof.
2 . The method of claim 1 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
3 . The method of claim 2 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
4 . The method of claim 2 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
5 . The method of claim 2 wherein said kidney fibrosis is associated with glomerulonephritis.
6 . The method of claim 2 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
7 . The method of claim 6 wherein the chymase mediated disorder is asthma.
8 . The method of claim 6 wherein the chymase mediated disorder is allergic rhinitis.
9 . The method of claim 6 wherein the chymase mediated disorder is pulmonary fibrosis.
10 . The method of claim 1 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
11 . The method of claim 1 wherein Y is independently selected from SO 3 H and P(═O)OR 5 R 6 .
12 . The method of claim 11 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
13 . The method of claim 12 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
14 . The method of claim 12 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular-grafts.
15 . The method of claim 12 wherein said kidney fibrosis is associated with glomerulonephritis.
16 . The method of claim 12 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
17 . The method of claim 16 wherein the chymase mediated disorder is asthma.
18 . The method of claim 16 wherein the chymase mediated disorder is allergic rhinitis.
19 . The method of claim 16 wherein the chymase mediated disorder is pulmonary fibrosis.
20 . The method of claim 11 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
21 . A method for treating or ameliorating a chymase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (Ia):
wherein
is independently selected from the group consisting of aryl, heteroaryl, and benzo fused heterocyclyl, optionally substituted with R 2 and R 3 ;
R 2 is one to three substituents independently selected from the group consisting of C 1-4 alkyl, methoxy, C 2-6 alkoxy, NH 2 , NH(C 1-16 alkyl), —N(C 1-6 )dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro; wherein C 1-6 alkyl and C 2-6 alkoxy are optionally substituted with a substituent selected from the group consisting of —NR 11 R 12 , aryl, heteroaryl, one to three halogens and hydroxyl;
wherein C 1-4 alkyl and C 2-6 alkoxy substituents of R 2 are optionally substituted with a substituent independently selected from the group consisting of —NR 11 R 12 , aryl, heteroaryl, one to three halogens and hydroxy; wherein R 11 and R 12 are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl; wherein C 1-6 alkyl substituent of R 11 or R 12 is optionally substituted with substituent selected from the group consisting of hydroxy, aryl, —C(═O)C 1-4 alkoxy, and —NR 15 R 16 ;
wherein said R 15 and R 16 are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, and said R 15 and R 16 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
R 3 is one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —OCH 2 (C 2-6 )alkenyl, NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 )dialkyl, —NHC(═O)Cy, —N(C 1-6 alkyl)C(═O)Cy, —C(═O)C 1-4 alkoxy, —C(═O)NR 17 R 18 , —C(═O)NHcycloalkyl, —C(═O)N(C 1-6 alkyl)cycloalkyl, —C(═O)NHCy, —C(═O)N(C 1-6 alkyl)Cy, —C(═O)Cy, —OC(═O)NR 19 R 20 , halogen, hydroxy, nitro, cyano, aryl, and aryloxy; wherein alkyl and alkoxy are optionally substituted with one to three substituents independently selected from the group consisting of —NR 21 R 22 , —NHcycloalkyl, —N(C 1-6 alkyl)cycloalkyl, —NHCy, —N(C 1-6 alkyl)Cy, aryl, heteroaryl, halogen, —C(═O)NR 23 R 24 , —OC(═O)NR 25 R 26 , —C(═O)(C 1-4 )alkoxy, and —C(═O)Cy; wherein alkenyl is optionally substituted on a terminal carbon with aryl and —C(═O)NR 27 R 28 ; and, wherein aryl and cycloalkyl are optionally substituted with one to three substituents independently selected from R 14 ;
Cy is a heterocyclyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkylC(═O)C 1-6 alkyl, —C 1-6 alkylC(═O)C 1-6 alkoxy, C 1-6 alkylC(═O)aryl, —C(═O)(C 1-6 )alkyl, —C(═O)(C 1-6 )alkoxy, —C(═O)aryl, —SO 2 aryl, aryl, heteroaryl, and heterocyclyl; wherein aryl and the aryl portion of the C 1-6 alkylC(═O)aryl, —C(═O)aryl and —SO 2 aryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one to three oxo substituents; and, wherein heterocyclyl is optionally spiro-fused to said Cy;
R 5 is selected from the group consisting of hydrogen; C 1-3 alkyl optionally substituted with NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6 alkylcarbonylthio, (C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogens, or hydroxy; and aryl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R 6 is C 1-8 alkoxy, R 5 and R 6 are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
and provided that R 5 is other than C 1-3 alkyl substituted with di(C 1-6 )alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl, n is 1, R 6 is OH, and Z-R 4 is 5-chloro-benzothiophen-3-yl; and provided that R 5 is other than C 1-3 alkyl substituted with C 1-6 alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R 6 is CH 3 , and Z-R 4 is 5-chloro-benzothiophen-3-yl;
R 6 is selected from the group consisting of C 1-6 alkyl, C 1-8 alkoxy, heteroaryl, aryl, and hydroxy; wherein alkyl and C 1-8 alkoxy are optionally substituted on a terminal carbon atom with a substituent selected from C 1-3 alkoxy, aryl, or hydroxy; and alkoxy is optionally substituted on a terminal carbon with a substituent independently selected from the group consisting of C 1-6 alkylcarbonyloxy, and di(C 1-6 )alkylaminocarbonyl; and wherein heteroaryl and aryl are optionally substituted with one to three substituents independently selected from the group consisting of aryl, hydroxy, C 1-6 alkoxy, and halogen;
n is 0 or 1;
Z is a bicyclic aryl or bicyclic heteroaryl;
R 4 is one to three substituents selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, aryl(C 2-6 )alkenyl, halogen, —C(═O)Cy, —C(═O)NR 31 R 32 , aryl, —CO 2 H, oxo, and cyano; wherein the alkyl and alkoxy are optionally substituted with a substituent independently selected from the group consisting of —NR 33 R 34 , aryl, one to three halogen atoms, and hydroxy; wherein the aryl is optionally substituted with a substituent independently-selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, aryl, halogen, hydroxy, and nitro;
wherein said R 31 , R 32 , R 33 , and R 34 are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and R 31 with R 32 and R 33 with R 34 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
and pharmaceutically acceptable salts thereof.
22 . The method of claim 21 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
23 . The method of claim 22 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
24 . The method of claim 22 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
25 . The method of claim 22 wherein said kidney fibrosis is associated with glomerulonephritis.
26 . The method of claim 22 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
27 . The method of claim 26 wherein the chymase mediated disorder is asthma.
28 . The method of claim 26 wherein the chymase mediated disorder is allergic rhinitis.
29 . The method of claim 26 wherein the chymase mediated disorder is pulmonary fibrosis.
30 . The method of claim 21 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
31 . The method of claim 21 wherein, in the compound, R 1 , ring A, R 2 , R 3 , R 5 , R 6 , Z, and R 4 are dependently selected from the group consisting of:
R 5
R 6
n
W
Z-R 4
naphthalen-2-yl
H
CH 3
0
O
5-Cl-N-methyl-
indol-3-yl
3,4-difluoro-phenyl
H
OH
1
O
5-Cl-
benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
5-Cl-N-methyl-indol-3-yl
4-fluoro-phenyl
H
OH
1
O
5-Cl-N-methyl-indol-3-yl
naphthalen-2-yl
H
OH
0
O
5-Me-
benzothiophen-2-yl
3-fluoro-phenyl
H
CH 3
1
O
5-Cl-N-methyl-indol-3-yl
3,4-difluoro-phenyl
H
CH 3
1
O
5-Cl-N-methyl-indol-3-yl
4-{[1-(naphthalen-2-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-piperadin-4-
ylcarbonyl]-
amino}naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
5-F-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
5-F-N-methyl-indol-3-yl
4-amino-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
5-Br-N-methyl-indol-3-yl
Phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-fluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3,4-trifluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
phenyl
H
OH
1
O
5-Cl-benzothiophen-2-yl
4-fluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
CH 3
0
O
5-Cl-benzothiophen-3-yl
2-fluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
N-methyl-indol-3-yl
naphthalen-2-yl
H
OH
0
O
5-Br-benzothiophen-3-yl
4-fluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
pyridin-3-yl
H
OH
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
N-(3-phenyl-allyl)-indol-3-yl
naphthalen-2-yl
H
CH 2 CH 3
0
O
5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl
H
CH 2 CH 3
1
O
5-Cl-benzothiophen-3-yl
benzothiazol-6-yl
H
OH
0
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
H
CH 3
0
O
2-(4-phenyl-piperidin-1-
ylcarbonyl)-benzothiophen-3-yl
naphthalen-2-yl
H
CH 3
0
O
naphthalen-1-yl
naphthalen-2-yl
H
3-methoxy-
0
O
5-Cl-benzothiophen-3-yl
propyl
naphthalen-2-yl
H
CH 3
0
O
2-(4-(4-methoxyphenyl)-
piperidin-1-ylcarbonyl)-
benzothiophen-3-yl
naphthalen-2-yl
H
Phenethyl
0
O
5-Cl-benzothiophen-3-yl
phenyl
H
OH
1
O
naphthalen-1-yl
4-methoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
3-(Benzo
0
O
5-Cl-benzothiophen-3-yl
[1,3]dioxol-5-
yl)-propyl
naphthalen-2-yl
H
3-(naphthyl
0
O
5-Cl-benzothiophen-3-yl
en-1yl)
propyl
naphthalen-2-yl
H
CH 3
0
O
2-(4-Benzyloxycarbonyl)-
piperazin-1-ylcarbonyl))-
-benzothiophen-3-yl
4-methyl-phenyl
H
OH
1
O
5-Cl-benzothiophen-2-yl
naphthalen-2-yl
H
3-
0
O
5-Cl-benzothiophen-3-yl
(4-hydroxy
0
O
phenyl)
propyl
3-((N-Benzoyl-piperidin-4-
H
OH
0
O
naphthalen-1-yl
ylamino)-methyl)-
naphthalen-2-yl
naphthalen-2-yl
H
OH
0
S
5-Cl-benzothiophen-3-yl
3-[(4-phenyl-cyclohex-3-
H
OH
0
O
naphthalen-1-yl
enyl)-N-methyl-
aminocarbonyl]-naphthalen-
2-yl
naphthalen-2-yl
H
CH 3
0
O
2-((4-F-phenyl)-piperidin-1-
ylcarbonyl)-benzothiophen-3-yl
naphthalen-2-yl
H
(3-phenyl)
0
O
5-Cl-benzothiphen-3-yl
propyl
3,4-dimethoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
(4-phenyl)
0
O
5-Cl-benzothiphen-3-yl
butyl
naphthalen-2-yl
H
OH
0
O
6-Cl-N-methyl-indol-3-yl
naphthalen-2-yl
H
3-(4-methoxy
0
O
5-Cl-benzothiphen-3-yl
phenyl)
propyl
3-[4-((3-Phenethyl)-
H
OH
0
O
naphthalen-1-yl
pyrrolidin-1-ylcarbonyl)]-
naphthalen-2-yl
benzothiophen-5-yl
H
OH
0
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
5-carboxy-N-Me-indol-3-yl-
quinolin-3-yl
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
H
OH
0
O
7-Cl-N-methyl-indol-3-yl
benzo[b]thiophen-6-yl
H
OH
0
O
naphthalen-1-yl
3-[4-(6-Chloro-2-oxo-2,3-
H
OH
0
O
naphthalen-1-yl
dihydro-benzoimidazol-1-
yl)-piperidin-1-ylcarbonyl]-
naphthalen-2-yl
4-biphenyl
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
H
OH
0
O
N-cyclopropyl
methyl-indol-3-yl
naphthalen-2-yl
H
OH
0
O
4-Cl-N-methyl-indol-3-yl
benzothiophen-2-yl
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
H
OH
0
O
5-cyano-N-methyl-indol-3-yl
4-hydroxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
(6-Br)-naphthalen-2-yl
H
OH
0
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
Indol-3-yl
2-Amino-
H
OH
0
O
5-Cl-benzothiophen-3-yl
benzothiazol-5-yl
3-(Cyclohexylamino)
H
OH
0
O
naphthalen-1-yl
methyl-naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
5-Ph-benzothiophen-3-yl
3-(N-benzyl-
H
OH
0
O
naphthalen-1-yl
aminocarbonyloxy
methyl)
naphthalen-2-yl
3-(pyridin-4-yl-pyrrolidin-1-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
5-methoxy-N-methyl-
indol-3-yl
3-(methoxycarbonyl)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
6-Br-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
N-isopropyl-indol-3-yl
4-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
quinolin-6-yl
H
OH
0
O
naphthalen-1-yl
4-trifluoromethyl-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
N-phenyl-indol-3-yl
(4-(1H-indol-3-yl)-piperidin-
H
OH
0
O
naphthalen-1-yl
1-ylcarbonyl)-naphthalen-2-
yl
Indanyl
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
H
OH
0
O
5-Cl-1,1-dioxo-benzothiophen-
3-yl
((3-phenyl)pyrrolidin-1-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl
naphthalen-2-yl
H
Ph
0
O
5-Cl-benzothiophen-3-yl
((3-Methyl)-
H
OH
0
O
naphthalen-1-yl
cyclohexylamino)methyl-
naphthalen-2-yl
3-(cyclopentyl-N-
H
OH
0
O
naphthalen-1-yl
methylamino-carbonyl)-
naphthalen-2-yl
3-((5-methoxy
H
OH
0
O
naphthalen-1-yl
carbonyl)aminomethyl)-
naphthalen-2-yl
3-(4-(2-oxo-2,3-dihydro-
H
OH
0
O
naphthalen-1-yl
benzoimidazol-1-yl)-
piperidin-1-ylcarbonyl)-
naphthalen-2-yl
3-(phenyl-
H
OH
0
O
naphthalen-1-yl
aminocarbonyloxy)-methyl)-
naphthalen-2-yl
3-(N-phenyl-carbamoyloxy)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
quinolin-2-yl
H
OH
0
O
naphthalen-1-yl
3-((4-Phenoxy-phenyl)-
H
OH
0
O
naphthalen-1-yl
aminocarbonyloxy methyl)-
naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
5-(4-F-phenyl)-N-methyl-indol-
3-yl
naphthalen-2-yl
H
OH
0
O
4-Br-benzo
thiophen-3-yl
3-[(4-Benzotriazol-1-yl-
H
OH
0
O
naphthalen-1-yl
piperidin-1-ylcarbonyl)]-
naphthalen-2-yl
3-(4-phenyl)-piperidin-1-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl
3-((naphthalen-2-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-piperidin-4-
ylmethylamino-methyl)-
naphthalen-2-yl
3-((3-Benzenesulfonyl)-
H
OH
0
O
naphthalen-1-yl
pyrrolidin-1-ylcarbonyl)-
naphthalen-2-yl
3-(N-[3-(4-Oxo-1-phenyl-
H
OH
0
O
naphthalen-1-yl
1,3,8-triaza-spiro[4.5]
decane-8-carbonyl)-
naphthalen-2-yl
3-(naphthalen-2-
H
OH
0
O
naphthalen-1-yl
ylaminocarbonyloxy-
methyl)-naphthalen-2-yl
2-fluorenyl
H
OH
0
O
naphthalen-1-yl
3-(Benzylaminomethyl)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
(3-OH)naphthalen-2-yl
H
OH
0
O
naphthalen-1-yl
3-(N-Benzyl-3-
H
OH
0
O
naphthalen-1-yl
acrylamide)naphthalen-2-yl
3-((5-Phenyl)-pentylamino)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
3-(N-Benzyl-N-methyl-
H
OH
0
O
naphthalen-1-yl
aminocarbonyl)-naphthalen-
2-yl
3-[(5H-
H
OH
0
O
naphthalen-1-yl
Dibenzo[a,d]cyclohepten-5-
yl)-propyl]-methyl-amino-
methyl-naphthalen-2-yl
3-(4-(Benzothiazol-2-yl-
H
OH
0
O
naphthalen-1-yl
piperidin-1-ylcarbonyl))-
naphthalen-2-yl
1-(2-Oxo-2-(4-phenyl-
H
OH
0
O
naphthalen-1-yl
piperidin-1-yl)-ethoxy)-
naphthalen-2-yl
3-([2-(3,4-dimethoxy-
H
OH
0
O
naphthalen-1-yl
phenyl)-ethyl]-N-methyl-
aminocarbonyl)-
naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
1-Me-1H-pyrrolo[2,3-b]pyridine
3-((4-OH-cyclohexylamino)-
H
OH
0
O
naphthalen-1-yl
methyl)-naphthalen-2-yl
naphthalen-2-yl
H
CH 3
0
O
2-carboxy-
benzothiophen-3-yl
3-(Benzyl
H
OH
0
O
naphthalen-1-yl
aminocarbonyl)-naphthalen-
2-yl
3-(3-Phenyl-allyloxy)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
3-(Benzyloxy)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
3-(methoxycarbonyl-
H
OH
0
O
naphthalen-1-yl
methoxy)-nephthalen-2-yl
3-(Cyclopentylamino-
H
OH
0
O
naphthalen-1-yl
methyl)-nephthalen-2-yl
naphthalen-2-yl
H
OH
0
O
5-Cl-benzothiphen-23-yl
3-(Phenethyl-
H
OH
0
O
naphthalen-1-yl
methylaminomethyl)
naphthalen-2-yl
naphthalen-2-yl
H
CH 3
0
O
2-(benzylaminocarbonyl)-
benzothiophen-3-yl
naphthalen-2-yl
H
OH
0
O
N-phenyl-indol-4-yl
Indol-5-yl
H
OH
0
O
naphthalen-1-yl
3-(3-Phenyl-
H
OH
0
O
naphthalen-1-yl
propylcarbamoyl)-methoxy)-
naphthalen-2-yl
3-(2-phenyl-pyrrolidin-1-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl
3-amino-naphthalen-2-yl
H
OH
0
O
naphthalen-1-yl
3-((5-hydroxypentylamino)-
H
OH
0
O
naphthalen-1-yl
methyl)-naphthalen-2-yl
1-(methoxycarbonyl-
H
OH
0
O
naphthalen-1-yl
methoxy)-naphthalen-2-yl
benzo[1,3]dioxolyl
H
OH
0
O
naphthalen-1-yl
isoquinolin-3-yl
H
OH
0
O
naphthalen-1-yl
3-phenoxy-phenyl
H
OH
0
O
naphthalen-1-yl
3-(isopropyloxycarbonyl)-
H
OH
0
O
naphthalen-1-yl
naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
benzothiophen-2-yl
3-{[1-(naphthalen-2-
H
OH
0
O
naphthalen-1-yl
ylcarbonyl)-piperidin-4-
ylcarbonyl]-amino}-
naphthalen-2-yl
3-(benzylmethyl
H
OH
0
O
naphthalen-1-yl
aminomethyl)-
naphthalen-2-yl
naphthalen-2-yl
H
OH
0
O
6-(4-butylphenyl)-
benzothiophen-3-yl
trans-2-phenylcycloprop-1-
H
CH 3
0
O
5-Cl-benzothiophen-3-yl
yl
2-methoxy-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
benzofuran-2-yl
H
CH 3
0
O
5-Cl-benzothiophen-3-yl
2-nitro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-methylcarbonyloxy-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-hydroxy-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
pyridin-2-yl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-amino-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-trifluoromethyl-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-trifluoromethoxy-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-methoxy-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-methyl-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2,6-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
4-cyano-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-ureido-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-(NHC(═O)) 2 NH 2 -phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3,5-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2,3-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-bromo-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2,3-dimethoxy-phenyl
H
CH 3
1
O
5-Cl-benzothiphen-3-yl
3-nitro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-bromo-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3,5-dimethoxy-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2,5-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3,5-dichloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2,4-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-amino-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
phenyl
—CH 2 C(Me) 2 CH 2 O—
1
O
naphthalen-1-yl
phenyl
3-methoxy-
OH
1
O
naphthalen-1-yl
prop-1-yl
phenyl
3-methoxy-
3-methoxy-
1
O
naphthalen-1-yl
prop-1-yl
prop-1-yl-oxy
phenyl
2-(1,3-
OH
1
O
naphthalen-1-yl
dioxolan-2-yl)-
eth-1-yl
phenyl
—CH 2 OC(═O)
OH
1
O
naphthalen-1-yl
t-butyl
phenyl
—CH 2 CH 2 CH 2 O—
1
O
naphthalen-1-yl
phenyl
(2-dimethyl
2-dimethyl
1
O
naphthalen-1-yl
amino)-
amino-ethoxy
eth-1-yl
phenyl
—CH 2 C(═O)
—OCH 2
1
O
naphthalen-1-yl
NEt 2
C(═O)
NEt 2
phenyl
—(CH 2 ) 2 S
—O(CH 2 ) 2 S
1
O
naphthalen-1-yl
C(═O)
C(═O)
t-butyl
t-butyl
3,4-difluoro-phenyl
—CH 2 OC(═O)
CH 3
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3,4-difluoro-phenyl
(2-dimethyl
CH 3
1
O
5-Cl-benzothiophen-3-yl
amino)-
1
O
5-Cl-benzothiphen-3-yl
eth-1-yl
3,4-difluoro-phenyl
(2-amino)-
CH 3
1
O
5-Cl-benzothiophen-3-yl
eth-1-yl
3,4-difluoro-phenyl
—CH 2 C(═O)
CH 3
1
O
5-Cl-bezothiophen-3-yl
NEt 2
3,4-difluoro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3,4-difluoro-phenyl
—CH 2 C(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
NEt 2
C(═O)
NEt 2
3,4-difluoro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
methyl
3,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2-methoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
pyridin-2-yl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-trifluromethoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-methoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2,6-difluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2-chloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-chloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3,5-difluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2,3-difluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2-bromo-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2,3-dimethoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-nitro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-bromo-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3,5-dimethoxy-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2,5-difluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3,5-dichloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2,4-difluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-amino-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2-methoxy-phenyl
—CH 2 OC(═) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
pyridin-2-yl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-trifluoromethoxy-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-methoxy-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2,6-difluoro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2-chloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-chloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3,5-difluoro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2,3-difluoro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2-bromo-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2,3-dimethoxy-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-nitro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-bromo-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3,5-dimethoxy-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2,5-difluoro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3,5-dichloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2,4-difluoro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-amino-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2-methoxy-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
pyridin-2-yl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-trifluoromethoxy-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-methoxy-phenyl
—CH 2 OC(═)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2,6-difluoro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═)
t-butyl
2-chloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-chloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═)
t-butyl
3,5-difluoro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2,3-difluoro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2-bromo-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2,3-dimethoxy-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-nitro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-bromo-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3,5-dimethoxy-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2,5-difluoro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3,5-dichloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2,4-difluoro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-amino-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl′
t-butyl
OC(═O)
t-butyl
2-methoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
pyridin-2-yl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen--3yl
t-butyl
3-trifluoromethoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-methoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2,6-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3,5-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2,3-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2-bromo-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2,3-dimethoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-nitro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-bromo-phenyl
—CH 2 OC(═O)
H
1
O
5-Cl-benzothiphen-3-yl
t-butyl
3,5-dimethoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2,5-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiphen-3-yl
t-butyl
3,5-dichloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-amino-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2-methoxy-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
pyridin-2-yl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-trifluoromethoxy-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-methoxy-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2,6-difluoro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2-chloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-chloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3,5-difluoro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2,3-difluoro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2-bromo-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2,3-dimethoxy-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-nitro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-bromo-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3,5-dimethoxy-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2,5-difluoro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3,5-dichloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2,4-difluoro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-amino-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2-methoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
pyridin-2-yl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-trifluoromethoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-methoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2,6-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3,5-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2,3-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2-bromo-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2,3-dimethoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-nitro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isoproyloxy
3-bromo-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3,5-dimethoxy-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophne-3-yl
isopropyloxy
2,5-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3,5-dichloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-amino-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-fluoro-5-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-fluoro-3-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
4-fluoro-3-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-fluoro-5-chloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3,5-dibromo-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-cyano-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
2-cyano-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
3-fluoro-5-trifluoromethyl-
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
phenyl
3-fluoro-5-chloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2-fluoro-3-chloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
4-fluoro-3-chloro-phenyl
H
OH
1
O
5-Cl-benzothiophne-3-yl
2-fluoro-5-chloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3,5-dibromo-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-cyano-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
2-cyano-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
3-fluoro-5-trifluoromethyl-
H
OH
1
O
5-Cl-benzothiophne-3-yl
phenyl
3-fluoro-5-chloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2-fluoro-3-chloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
4-fluoro-3-chloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2-fluoro-5-chloro-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3,5-dibromo-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-cyano-pheyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
2-cyano-phenyl
—CH 2 OC(═O) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
butyl
3-fluoro-5-trifluoromethyl-
—CH 2 OC(═) t-
CH 3
1
O
5-Cl-benzothiophen-3-yl
phenyl
butyl
3-fluoro-5-chloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2-fluoro-3-chloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
4-fluoro-3-chloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2-fluoro-5-chloro-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3,5-dibromo-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-cyano-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
2-cyano-phenyl
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
t-butyl
OC(═O)
t-butyl
3-fluoro-5-trifluoromethyl-
—CH 2 OC(═O)
—OCH 2
1
O
5-Cl-benzothiophen-3-yl
phenyl
t-butyl
OC(═O)
t-butyl
3-fluoro-5-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2-fluoro-3-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
4-fluoro-3-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2-fluoro-5-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3,5-dibromo-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-cyano-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
2-cyano-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
3-fluoro-5-trifluoromethyl-
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
phenyl
t-butyl
3-fluoro-5-chloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2-fluoro-3-chloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
4-fluoro-3-chloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2-fluoro-5-chloro-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3,5-dibromo-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-cyano-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
2-cyano-phenyl
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
3-fluoro-5-trifluoromethyl-
—CH 2 CH 2 CH 2 O—
1
O
5-Cl-benzothiophen-3-yl
phenyl
3-fluoro-5-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2-fluoro-3-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
4-fluoro-3-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2-fluoro-5-chloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3,5-dibromo-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
3-cyano-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
2-cyano-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
and
3-fluoro-5-trifluoromethyl-
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
phenyl
isopropyloxy
32 . The method of claim 31 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
33 . The method of claim 32 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
34 . The method of claim 32 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
35 . The method of claim 32 wherein said kidney fibrosis is associated with glomerulonephritis.
36 . The method of claim 32 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
37 . The method of claim 36 wherein the chymase mediated disorder is asthma.
38 . The method of claim 36 wherein the chymase mediated disorder is allergic rhinitis.
39 . The method of claim 36 wherein the chymase mediated disorder is pulmonary fibrosis.
40 . The method of claim 1 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
41 . The method of claim 31 wherein the compounds have a formula selected from the group consisting of:
47 . The method of claim 46 wherein the chymase mediated disorder is asthma.
48 . The method of claim 46 wherein the chymase mediated disorder is allergic rhinitis.
49 . The method of claim 46 wherein the chymase mediated disorder is pulmonary fibrosis.
50 . The method of claim 41 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
51 . The method of claim 41 wherein the compound is selected from the group consisting of:
42 . The method of claim 41 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
43 . The method of claim 42 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
44 . The method of claim 42 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
45 . The method of claim 42 wherein said kidney fibrosis is associated with glomerulonephritis.
46 . The method of claim 42 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
52 . The method of claim 51 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
53 . The method of claim 52 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
54 . The method of claim 52 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
55 . The method of claim 52 wherein said kidney fibrosis is associated with glomerulonephritis.
56 . The method of claim 52 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
57 . The method of claim 56 wherein the chymase mediated disorder is asthma.
58 . The method of claim 56 wherein the chymase mediated disorder is allergic rhinitis.
59 . The method of claim 56 wherein the chymase mediated disorder is pulmonary fibrosis.
60 . The method of claim 51 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
61 . A method for treating or ameliorating a chymase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia selected from the group consisting of:
(Ia)
Cpd
R 5
R 6
n
W
Z-R 4
2
3,4-difluoro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
17
3,4-difluoro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
170
3,5-dichloro-phenyl
H
CH 3
1
O
5-Cl-benzothiophen-3-yl
187
3,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
191
3,4-difluoro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy
207
3,5-dichloro-phenyl
H
OH
1
O
5-Cl-benzothiophen-3-yl
261
3,5-dichloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
t-butyl
297
3,5-dichloro-phenyl
—CH 2 OC(═O)
OH
1
O
5-Cl-benzothiophen-3-yl
isopropyloxy.
62 . The method of claim 61 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
63 . The method of claim 62 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
64 . The method of claim 62 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
65 . The method of claim 62 wherein said kidney fibrosis is associated with glomerulonephritis.
66 . The method of claim 62 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
67 . The method of claim 66 wherein the chymase mediated disorder is asthma.
68 . The method of claim 66 wherein the chymase mediated disorder is allergic rhinitis.
69 . The method of claim 66 wherein the chymase mediated disorder is pulmonary fibrosis.
70 . The method of claim 61 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
71 . A method of claim 61 wherein the compound is:
72 . The method of claim 71 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
73 . The method of claim 72 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
74 . The method of claim 72 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
75 . The method of claim 72 wherein said kidney fibrosis is associated with glomerulonephritis.
76 . The method of claim 72 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
77 . The method of claim 76 wherein the chymase mediated disorder is asthma.
78 . The method of claim 76 wherein the chymase mediated disorder is allergic rhinitis.
79 . The method of claim 76 wherein the chymase mediated disorder is pulmonary fibrosis.
80 . The method of claim 71 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
81 . A method of claim 61 wherein the compound is:
82 . The method of claim 81 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
83 . The method of claim 82 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
84 . The method of claim 82 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
85 . The method of claim 82 wherein said kidney fibrosis is associated with glomerulonephritis.
86 . The method of claim 82 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
87 . The method of claim 86 wherein the chymase mediated disorder is asthma.
88 . The method of claim 86 wherein the chymase mediated disorder is allergic rhinitis.
89 . The method of claim 86 wherein the chymase mediated disorder is pulmonary fibrosis.
90 . The method of claim 81 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.
91 . A method of claim 61 wherein the compound is:
92 . The method of claim 91 wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
93 . The method of claim 92 wherein said acute lung injury is adult (acute) respiratory distress syndrome.
94 . The method of claim 92 wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts.
95 . The method of claim 92 wherein said kidney fibrosis is associated with glomerulonephritis.
96 . The method of claim 92 wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury.
97 . The method of claim 96 wherein the chymase mediated disorder is asthma.
98 . The method of claim 96 wherein the chymase mediated disorder is allergic rhinitis.
99 . The method of claim 96 wherein the chymase mediated disorder is pulmonary fibrosis.
100 . The method of claim 91 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 1000 mg/kg/day.Cited by (0)
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