US 7,582,673 B2Granted

Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use

AssigneeHigh Point Pharmaceuticals, LLC

InventorsAdnan M. M. Mjalli, Bapu Gaddam, Mohan Rao, Muralidhar Bondlela, Ramesh Gopalaswamy, Robert C. Andrews, Stephen Davis, Suvi Simila, Tan Ren

Life of this patent

Estimating the term…

Abstract

Embodiments of the present invention provide bissulfonamide compounds that are agonists of GalR1. The present invention further provides compositions comprising bissulfonamide compounds that are agonists of GalR1, and methods of use of such compounds and compositions.

Claims53

Dependent claims

A compound of Formula (I):

Ar2—SO2NH—Ar1—NHSO2—Ar3 (I)
wherein
Ar1 is a phenylene group optionally substituted 1 to 4 times, wherein the substituents of Ar1 are selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -perhaloalkyl;
I) -alkyl;
g) -aryl;
h) -heteroaryl;
i) -cycloalkyl;
j) -L-aryl;
k) -L-arylene-aryl;
l) -L-arylene-alkyl;
m) -Q-alkyl;
n) -Q-aryl;
o) -Q-alkylene-aryl;
p) -Q-arylene-alkyl;
q) -L-Q-alkylene-aryl;
r) -arylene-Q-alkyl;
s) -L-Q-alkyl;
t) -L-Q-aryl;
u) -L-Q-heteroaryl;
v) -L-Q-cycloalkyl;
w) -L-Q-arylene-alkyl;
x) -D4-alkylene-NR1R2;
y) -D4-NR1R2;
z) -D4-alkyl;
and
aa) -D4-H;
wherein
D4 comprises a direct bond, —CH2—, —O—, —N(R4)—, —C(O)—, —CON(R4)—, —N(R4)C(O)—, —N(R4)CON(R4′)—, —N(R4)C(O)O—, —OC(O)N(R4)—, —N(R4)SO2—, —SO2N(R4)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R4)SO2N(R4′)—, or —N═N—;
wherein
R4 and R4′ are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, and -alkylene-aryl;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and aryl, wherein R1 and R2 may be taken together to form a ring having the formula —(CH2)o-Z4-(CH2)p— bonded to the nitrogen atom to which R1 and R2 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o+p is less than or equal to 6,
Z4 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R31)—, —N(C(O)R31)—, —N(C(O)NHR31)—, —N(C(O)NR31R32)—, —N(S(O)2NHR31)—, —N(SO2R31)—, or —N(C(O)OR31)—;
wherein
R31 and R32 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
L is a direct bond, -alkylene, -alkenylene , or -alkynylene;
and
Q is a direct bond, —CH2—, —O—, or —S—;
Ar2 is a benzothiophene group;
Ar3 is selected from the group consisting of an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group,
wherein at least one of Ar2 and Ar3 has an oxygen atom or sulfur atom vicinal or geminal to the point of attachment to the —NHSO2— group, and
wherein Ar2 and Ar3 may be optionally substituted 1 to 5 times with a substituent selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -alkyl;
f) -aryl;
g) -cycloalkyl;
h) -heterocyclyl;
i) -alkylene-cycloalkyl;
j) -perhaloalkyl;
k) heteroaryl;
l) -alkylene-aryl;
m) -D1-H;
n) -D1-R3;
o) -D1-alkyl;
p) -D1-aryl;
q) -D1-perhaloalkyl;
r) -D1-alkylene-R3;
s) -D1-alkylene-aryl;
t) -D1-alkylene-D2-R3;
u) -D1-cycloalkyl;
v) -D1-heterocyclyl;
w) -D1-aryl;
x) -D1-heteroaryl;
y) -D1-arylene-D2-R3;
z) -D1-heteroarylene-D2-R3;
aa) -D1-alkylene-heteroaryl;
bb) -D1-alkylene-heterocyclyl;
cc) -D1-alkylene-aryl;
aa) -D1-alkylene-arylene-D2-R3;
bb) -D1-alkylene-heteroarylene-D2-R3;
ff) -D1-alkylene-NR5R6;
gg) -D1-arylene-NR5R6;
and
hh) -acid isostere;
wherein
D1 is a direct bond, —CH2—, —O—, —N(R7)—, —C(O)—, —CON(R7)—, —N(R7)C(O)—, —N(R7)CON(R8)—, —N(R7)C(O)O—, —OC(O)N(R7)—, —N(R7)SO2—, —SO2N(R7)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R7)SO2N(R8)—, or —N═N—;
wherein
R7 and R8 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;
R3 is -hydrogen, -alkyl, -aryl, -heterocyclyl, or -heteroaryl;
and
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, and aryl, wherein R5 and R6 may be taken together to form a ring having the formula —(CH2)o-Z1-(CH2)p— bonded to the nitrogen atom to which R5 and R6 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o+p is less than or equal to 6,
Z1 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R9)—, —N(C(O)R9)—, —N(C(O)NHR9)—, —N(C(O)NR9R10)—, —N(S(O)2NHR9)—, —N(SO2R9)—, or —N(C(O)OR9)—;
wherein
R9 and R10 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
D2 is -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R11)—, —C(O)—, —CON(R11)—, —N(R11)C(O)—, —N(R11)CON(R12)—, —N(R11)C(O)O—, —OC(O)N(R11)—, —N(R11)SO2—, —SO2N(R11)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, or —N(R11)SO2N(R12)—,
wherein
R11 and R12 are independently selected from the group consisting of -hydrogen, -alkyl, and -aryl;
and wherein
the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, cycloalkylene, heterocyclylene, arylene, and heteroaryl in Ar2, Ar3, R1 through R32 may be optionally substituted independently 1 to 4 times with a substituent group selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -perhaloalkyl;
f) -A-perhaloalkyl;
g) -A-R40;
h) -A-alkyl;
i) -A-aryl;
j) -A-alkylene-aryl;
k) -A-alkylene-NR41R42;
and
l) -A-alkyl-E-R43;
wherein
A and E are independently selected from the group consisting of —CH2—, —O—, —N(R44)—, —C(O)—, —CON(R44)—, —N(R44)C(O)—, —N(R44)CON(R45)—, —N(R44)C(O)O—, —OC(O)N(R44)—, —N(R44)SO2—, —SO2N(R44)—, —C(O)—O—, —O—C(O)—, and —N(R44)SO2N(R45)—,
wherein R44 and R45 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;
R40 and R43 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;
and
R41 and R42 are independently selected from the group consisting of hydrogen, aryl, and alkyl, wherein R41 and R42 may be taken together to form a ring having the formula —(CH2)o-Z4-(CH2)p— bonded to the nitrogen atom to which R41 and R42 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o+p is less than or equal to 6,
Z4 is a direct bond a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R46)—, —N(C(O)R46)—, —N(C(O)NHR46)—, —N(C(O)NR46R47)—, —N(S(O)2NHR46)—, —N(SO2R46)—, or —N(C(O)OR46)—;
wherein
R46 and R47 are independently selected from the group consisting of hydrogen, aryl, alkyl, and -alkylene-aryl;
or a pharmaceutically acceptable salt or biohydrolyzable amide or biohydrolyzable ester thereof,
and
wherein the compound of Formula (I) is a GalR1 agonist.

124 more elements

A compound selected from the group consisting of:

Benzo[b]thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethylbenzenesulfonylamino)phenyl] amide;
Benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(propane-2-sulfonyl)benzenesulfonylamino]phenyl} amide;
3-[2-(Benzo[b]thiophene-2-sulfonylamino) -phenylsulfamoyl]-4-methoxy-benzoic acid methyl ester;
3-[2-(Benzo[b]thiophene-2-sulfonylamino) -phenylsulfamoyl]-4-methoxy-benzoic acid;
5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethane sulfonyl-benzenesulfonylamino) -phenyl]-amide;
Benzo[b]thiophene-2-sulfonic acid [2-(5-bromo-2-methoxy-benzene sulfonylamino)-phenyl]-amide;
Benzo[b]thiophene-2-sulfonic acid [2-(4-chloro-benzenesulfonylamino)phenyl] amide;
Benzo[b]thiophene-2-sulfonic acid [2-(4-methoxy-2-nitro-benzenesulfonylamino)phenyl]amide;
Benzo[b]thiophene-2-sulfonic acid [2-(4-methanesulfonyl-2-methoxy-benzenesulfonylamino) -phenyl] amide;
Benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-methylbenzenesulfonylamino)phenyl] amide;
Benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethylbenzenesulfonylamino)phenyl] amide;
Benzo[b]thiophene-2-sulfonic acid {2-[5-(2-dimethylaminoethanesulfonyl)-2-methoxy-benzenesulfonylamino]phenyl} amide;
Benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-tetrazol-2-yl-ethanesulfonyl)-benzenesulfonylamino]-phenyl}-amide;
Benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]-phenyl}-amide;
Benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]-phenyl}-amide;
Benzo[b]thiophene-2-sulfonic acid [2-(5-(1,1-Dichloro-2,2,2-trifluoroethyl)-2-methoxy-benzenesulfonylamino)phenyl] amide;
Benzo[b]thiophene-2-sulfonic acid [2-(4-imidazol-1-yl-2-methoxybenzenesulfonylamino)phenyl] amide;
N-[2-(Benzothiophene-2-sulfonyl)amino]phenylbenzothiophene-2-sulfonamide;
N-[2-(Benzothiophene-2-sulfonyl)amino]phenylbenzothiophene-2-sulfonamide;
N,N′-(4-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
N,N′-(4-cyano-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
2-[2-(Benzo[b]thiophene-2-sulfonylamino)-phenylsulfamoyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester;
N,N′-(4,5-dichloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
N,N′-(4-trifluoromethyl-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
N,N′-(4-chloro-5-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
N,N′-(4,5-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
Benzo[b]thiophene-2-sulfonic acid [2-(5-cyano-2-methoxy-benzenesulfonylamino)-phenyl]-amide;
Benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzenesulfonylamino]-phenyl}-amide;
N,N′-(4-chloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
N,N′-(4-bromo-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide);
and
N,N′-(4-methoxy-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide), or a pharmaceutically acceptable salts thereof.

29 more elements

A compound of Formula (Ia)

wherein
wherein J and K are independently selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -perhaloalkyl;
f) -alkyl;
g) -aryl;
h) -heteroaryl;
i) -cycloalkyl;
j) -L-aryl;
k) -L-arylene-aryl;
l) -L-arylene-alkyl;
m) -Q-alkyl;
n) -Q-aryl;
o) -Q-alkylene-aryl;
p) -Q-arylene-alkyl;
q) -L-Q-alkylene-aryl;
r) -arylene-Q-alkyl;
s) -L-Q-alkyl;
t) -L-Q-aryl;
u) -L-Q-heteroaryl;
v) -L-Q-cycloalkyl;
w) -L-Q-arylene-alkyl;
x) -D4-alkylene-NR1R2;
y) -D4-NR1R2;
z) -D4-alkyl;
and
aa) -D4-H;
wherein
D4 is a direct bond, —CH2—, —O—, —N(R4)—, —C(O)—, —CON(R4)—, —N(R4)C(O)—, —N(R4)CON(R4′)—, —N(R4)C(O)O—, —OC(O)N(R4)—, —N(R4)SO2—, —SO2N(R4)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R4)SO2N(R4′)—, or —N═N—;
wherein R4 and R4′ are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, and -alkylene-aryl;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and aryl, wherein R1 and R2 may be taken together to form a ring having the formula —(CH2)o-Z4-(CH2)p— bonded to the nitrogen atom to which R1 and R2 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o +p is less than or equal to 6,
Z4 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R31)—, —N(C(O)R31)—, —N(C(O)NHR31 )—, —N(C(O)NR31R32)—, —N(S(O)2NHR31)—, —N(SO2R31)—, or —N(C(O)OR31)—;
wherein
R31 and R32 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
L is a direct bond, -alkylene, -alkenylene , or -alkynylene;
Q is a direct bond, —CH2—, —O—, or —S—;
Ar2 is
and
Ar3 is either
wherein
R13 is alkyl, alkylene-cycloalkyl, haloalkyl, perhaloalkyl, or cycloalkyl;
R14 is
a) -halo;
b) -cyano;
c) -nitro;
d) -perhaloalkyl;
e) D1-R17;
f) -D1-alkyl;
g) -D1-alkylene-R17;
h) -D1-alkylene-D2-R17;
i) -D1-aryl;
j) -D1-heteroaryl;
k) -D1-arylene-D2-R17;
l) -D1-heteroarylene-D2-R17;
m) -D1-alkylene-heteroaryl;
n) -D1-alkylene-heterocyclyl;
o) -D1-alkylene-aryl;
p) -D1-alkylene-arylene-D2-R17;
q) -D1-alkylene-heteroarylene-D2-R17;
r) -D1-alkylene-NR18R19;
s) -D1-arylene-NR18R19;
t) -D1-perhalo C2-C6 alkyl;
or
u) -acid isostere;
wherein
D1 is a direct bond, —S(O)2—, —CON(R20)—, —SO2N(R20)—, —C(O)—O—, —S—, or —S(O)—;
wherein R20 is -hydrogen, -alkyl, -aryl, -heterocyclyl, or -heteroaryl;
R17 is -hydrogen, -alkyl, -aryl, -heterocyclyl, or -heteroaryl;
R18 and R19 are independently selected from the group consisting of hydrogen, aryl, and alkyl, wherein R18 and R19 may be taken together to form a ring having the formula —(CH2)o-Z2-(CH2)p— bonded to the nitrogen atom to which R18 and R19 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o +p is less than or equal to 6,
Z2 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R20)—, —N(C(O)R20)—, —N(C(O)NHR20)—, —N(C(O)NR20R21 )—, —N(S(O)2NHR20)—, —N(SO2R20)—, or —N(C(O)OR20)—;
wherein
R20 and R21 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
D2 is -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O—alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R22)—, —C(O)—, —CON(R22)—, —N(R22)C(O)—, —N(R22)CON(R23)—, —N(R22)C(O)O—, —OC(O)N(R22)—, —N(R22)SO2—, —SO2N(R22)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, or —N(R22)SO2N(R23)—,
wherein
R22 and R23 are independently selected from the group consisting of -hydrogen, -alkyl, and -aryl;
R15, R16 and R33 are independently selected from the group consisting of
a) -hydrogen;
b) -halogen;
c) -cyano;
d) -alkyl;
e) -aryl;
f) -alkylene-aryl;
g) -D3-H;
h) -D3-alkyl;
i) -D3-aryl;
j) -D3-alkylenearyl;
k) -Y-alkyl;
l) -Y-aryl;
m) -Y-alkylene-aryl;
n) -Y-alkylene-NR24R25;
and
o) -Y-alkylene-W—R26;
wherein
D3 is —O—, —C(O)—O—, —C(O)—NH—, —SO2—, —SO2—NH—, or —C(O)—;
Y and W are independently selected from the group consisting of —CH2—, —O—, —N(H), —S —, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, and —O—CO—,
R26 is aryl, alkyl, alkylene—aryl, alkoxy, or alkoxyaryl;
R24 and R25 are independently selected from the group consisting of hydrogen, aryl, and alkyl, wherein R24 and R25 may be taken together to form a ring having the formula —(CH2)o-Z3-(CH2)p— bonded to the nitrogen atom to which R24 and R25 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o +p is less than or equal to 6,
Z3 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R29)—, —N(C(O)R29)—, —N(C(O)NHR29)—, —N(C(O)NR29R30)—, —N(S(O)2NHR29)—, —N(SO2R29)—, or —N(C(O)OR29)—;
wherein
R29 and R30 are independently selected from the group consisting of hydrogen, aryl, alkyl, and -alkylaryl;
R26 is hydrogen, alkyl, aryl, or alkylene-aryl,
X is sulfur or oxygen;
and
m and n are independently 0, 1, or 2,
or a pharmaceutically acceptable salt thereof,
and
wherein the compound of Formula (I) is a GalR1 agonist.

113 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/255,000Filed 20 Oct 2005 · us provisional application
Priority: 21 Oct 2004
Published: US 2006/0106089 A118 May 2006
Granted: 1 Sep 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification32 codes

C07D 213/42
Radicals substituted by singly-bound nitrogen atoms: having hetero atoms attached to the substituent nitrogen atom
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/12
Drugs for disorders of the alimentary tract or the digestive system: antidiarrhoeals
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application60/620,699Us provisional application · filed 21 Oct 2004
Application60/670,752Us provisional application · filed 13 Apr 2005
US 2006/0106089 A1Pre-grant publication · published 18 May 2006
US 7,582,673 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of Formula (I):

Ar2—SO2NH—Ar1—NHSO2—Ar3 (I)
wherein
Ar1 is a phenylene group optionally substituted 1 to 4 times, wherein the substituents of Ar1 are selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -perhaloalkyl;
I) -alkyl;
g) -aryl;
h) -heteroaryl;
i) -cycloalkyl;
j) -L-aryl;
k) -L-arylene-aryl;
l) -L-arylene-alkyl;
m) -Q-alkyl;
n) -Q-aryl;
o) -Q-alkylene-aryl;
p) -Q-arylene-alkyl;
q) -L-Q-alkylene-aryl;
r) -arylene-Q-alkyl;
s) -L-Q-alkyl;
t) -L-Q-aryl;
u) -L-Q-heteroaryl;
v) -L-Q-cycloalkyl;
w) -L-Q-arylene-alkyl;
x) -D4-alkylene-NR1R2;
y) -D4-NR1R2;
z) -D4-alkyl;
and
aa) -D4-H;
wherein
D4 comprises a direct bond, —CH2—, —O—, —N(R4)—, —C(O)—, —CON(R4)—, —N(R4)C(O)—, —N(R4)CON(R4′)—, —N(R4)C(O)O—, —OC(O)N(R4)—, —N(R4)SO2—, —SO2N(R4)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R4)SO2N(R4′)—, or —N═N—;
wherein
R4 and R4′ are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, and -alkylene-aryl;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and aryl, wherein R1 and R2 may be taken together to form a ring having the formula —(CH2)o-Z4-(CH2)p— bonded to the nitrogen atom to which R1 and R2 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o+p is less than or equal to 6,
Z4 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R31)—, —N(C(O)R31)—, —N(C(O)NHR31)—, —N(C(O)NR31R32)—, —N(S(O)2NHR31)—, —N(SO2R31)—, or —N(C(O)OR31)—;
wherein
R31 and R32 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
L is a direct bond, -alkylene, -alkenylene , or -alkynylene;
and
Q is a direct bond, —CH2—, —O—, or —S—;
Ar2 is a benzothiophene group;
Ar3 is selected from the group consisting of an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group,
wherein at least one of Ar2 and Ar3 has an oxygen atom or sulfur atom vicinal or geminal to the point of attachment to the —NHSO2— group, and
wherein Ar2 and Ar3 may be optionally substituted 1 to 5 times with a substituent selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -alkyl;
f) -aryl;
g) -cycloalkyl;
h) -heterocyclyl;
i) -alkylene-cycloalkyl;
j) -perhaloalkyl;
k) heteroaryl;
l) -alkylene-aryl;
m) -D1-H;
n) -D1-R3;
o) -D1-alkyl;
p) -D1-aryl;
q) -D1-perhaloalkyl;
r) -D1-alkylene-R3;
s) -D1-alkylene-aryl;
t) -D1-alkylene-D2-R3;
u) -D1-cycloalkyl;
v) -D1-heterocyclyl;
w) -D1-aryl;
x) -D1-heteroaryl;
y) -D1-arylene-D2-R3;
z) -D1-heteroarylene-D2-R3;
aa) -D1-alkylene-heteroaryl;
bb) -D1-alkylene-heterocyclyl;
cc) -D1-alkylene-aryl;
aa) -D1-alkylene-arylene-D2-R3;
bb) -D1-alkylene-heteroarylene-D2-R3;
ff) -D1-alkylene-NR5R6;
gg) -D1-arylene-NR5R6;
and
hh) -acid isostere;
wherein
D1 is a direct bond, —CH2—, —O—, —N(R7)—, —C(O)—, —CON(R7)—, —N(R7)C(O)—, —N(R7)CON(R8)—, —N(R7)C(O)O—, —OC(O)N(R7)—, —N(R7)SO2—, —SO2N(R7)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R7)SO2N(R8)—, or —N═N—;
wherein
R7 and R8 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;
R3 is -hydrogen, -alkyl, -aryl, -heterocyclyl, or -heteroaryl;
and
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, and aryl, wherein R5 and R6 may be taken together to form a ring having the formula —(CH2)o-Z1-(CH2)p— bonded to the nitrogen atom to which R5 and R6 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o+p is less than or equal to 6,
Z1 is a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R9)—, —N(C(O)R9)—, —N(C(O)NHR9)—, —N(C(O)NR9R10)—, —N(S(O)2NHR9)—, —N(SO2R9)—, or —N(C(O)OR9)—;
wherein
R9 and R10 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
D2 is -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R11)—, —C(O)—, —CON(R11)—, —N(R11)C(O)—, —N(R11)CON(R12)—, —N(R11)C(O)O—, —OC(O)N(R11)—, —N(R11)SO2—, —SO2N(R11)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, or —N(R11)SO2N(R12)—,
wherein
R11 and R12 are independently selected from the group consisting of -hydrogen, -alkyl, and -aryl;
and wherein
the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, cycloalkylene, heterocyclylene, arylene, and heteroaryl in Ar2, Ar3, R1 through R32 may be optionally substituted independently 1 to 4 times with a substituent group selected from the group consisting of
a) -hydrogen;
b) -halo;
c) -cyano;
d) -nitro;
e) -perhaloalkyl;
f) -A-perhaloalkyl;
g) -A-R40;
h) -A-alkyl;
i) -A-aryl;
j) -A-alkylene-aryl;
k) -A-alkylene-NR41R42;
and
l) -A-alkyl-E-R43;
wherein
A and E are independently selected from the group consisting of —CH2—, —O—, —N(R44)—, —C(O)—, —CON(R44)—, —N(R44)C(O)—, —N(R44)CON(R45)—, —N(R44)C(O)O—, —OC(O)N(R44)—, —N(R44)SO2—, —SO2N(R44)—, —C(O)—O—, —O—C(O)—, and —N(R44)SO2N(R45)—,
wherein R44 and R45 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;
R40 and R43 are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;
and
R41 and R42 are independently selected from the group consisting of hydrogen, aryl, and alkyl, wherein R41 and R42 may be taken together to form a ring having the formula —(CH2)o-Z4-(CH2)p— bonded to the nitrogen atom to which R41 and R42 are attached,
wherein
o and p are, independently, 1, 2, 3, or 4 and o+p is less than or equal to 6,
Z4 is a direct bond a direct bond, —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O)2—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O)2N(H)—, —(O)CO—, —NHS(O)2NH—, —OC(O)—, —N(R46)—, —N(C(O)R46)—, —N(C(O)NHR46)—, —N(C(O)NR46R47)—, —N(S(O)2NHR46)—, —N(SO2R46)—, or —N(C(O)OR46)—;
wherein
R46 and R47 are independently selected from the group consisting of hydrogen, aryl, alkyl, and -alkylene-aryl;
or a pharmaceutically acceptable salt or biohydrolyzable amide or biohydrolyzable ester thereof,
and
wherein the compound of Formula (I) is a GalR1 agonist.

124 more elements

Facts

Application

11/255,000Filed 20 Oct 2005 · us provisional application

Priority

21 Oct 2004

Published

US 2006/0106089 A118 May 2006

Granted

1 Sep 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification32 codes

C07D 213/42
Radicals substituted by singly-bound nitrogen atoms: having hetero atoms attached to the substituent nitrogen atom
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/12
Drugs for disorders of the alimentary tract or the digestive system: antidiarrhoeals
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents