US 2004/0110832 A1 · Aryl and heteroaryl compounds and methods to modulate coagulation

Abstract

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as antagonists, or more preferably, partial antagonist of factor IX and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds are 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. Such diseases or disease states include stroke, myocardial infarction, aneurysm surgery, and deep vein thrombosis associated with surgical procedures, long periods of confinement, and acquired or inherited pro-coagulant states.

The compound of Formula (I):

701
wherein
c is equal to 0, 1, or 2;
wherein the values of 0, 1, and 2 comprise a direct bond, —CH2—, and —CH2—CH2—, optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising:
-alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, or -hydroxyl.
G comprises:
-hydrogen, —CO2R1, —CH2OR1, —C(O)—R1, —C(R1)═N—O—R2, or an acid isostere;
wherein R1 and R2 independently comprise:
-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
V comprises:
—(CH2)b—O—(CH2)a—, —(CH2)b—N(R7)—(CH2)a—, —(CH2)b—O—, —(CH2)b—N(R7), —(CH2)a—, or a direct bond;
in which a is equal to 0, 1, or 2, b is equal to 1 or 2, and R7 comprises:
-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl;
wherein
the alkylene groups of V are optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising:
-alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, or -hydroxyl.
X comprises:
—N(R8)—, —CON(R8)—, —N(R8)CO—, —N(R8)CON(R9)—, —OC(O)N(R8)—, SO2N(R8)—, or —N(R8)SO2N(R9)—;
wherein
R8 and R9 independently comprise:
-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-cycloalkylene-C(O)-alkylene-aryl, -alkylene-heterocyclylene-C(O)-alkylene-aryl, -alkylene-C(H)(R10)(R11), or -alkylene-N—(R10)(R11),
wherein
R10 comprises H, alkyl, alkylene-aryl, alkylene-heteroaryl, aryl, or heteroaryl, and
R11 comprises H, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, -aryl, -heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkylene-aryl, —C(O)—O-alkylene-heteroaryl, —C(O)-alkyl, —C(O)-alkylene-aryl, —C(O)-alkylene-heteroaryl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-heteroaryl, —S(O)2-alkylene-aryl, S(O)2-alkylene-heteroaryl, —S(O)2—NH-alkyl , —S(O)2—NH-alkylene-aryl —S(O)2—NH-alkylene-heteroaryl, —S(O)2—NH-aryl, or —S(O)2—NH-heteroaryl;
R10 and R11 may be taken together to form a ring having the formula —(CH2)m-Z-(CH2)n— bonded to the nitrogen or carbon atom to which R10 and R11 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
Z independently comprises —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O2)—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O2)N(H)—, —(O)CO—, —NHS(O2)NH—, —OC(O)—, —N(R12)—, —N(C(O)R12)—, —N(C(O)NHR12)—, —N(S(O2)NHR12)—, —N(SO2R12)—, or —N(C(O)OR12)—;
wherein R12 comprises hydrogen, aryl, alkyl, or alkylene-aryl;
or
R10 and R11 may be taken together, with the nitrogen or carbon atom to which they are attached, to form a heterocyclyl or heteroaryl ring.
Ar1 comprises an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, or fused heterocyclylheteroaryl group optionally substituted 1 to 7 times, wherein the substituents independently comprise:
a) -fluoro;
b) -chloro;
c) -bromo;
d) -iodo;
e) -cyano;
f) -nitro;
g) -perfluoroalkyl;
h) -D1-R13;
i) -alkyl;
j) -aryl;
k) -heteroaryl;
l) -heterocyclyl;
m) -cycloalkyl;
n) -alkylene-aryl;
o) -alkylene-heteroaryl;
p) -alkylene-arylene-D1-R13;
q) -alkylene-heteroarylene-D1-R13;
r) -alkylene-arylene-aryl;
s) -alkylene-heteroarylene-aryl;
t) -alkylene-arylene-heteroaryl
u) -alkylene-arylene-arylene-D1-R13;
v) -alkylene-arylene-alkyl;
w) -alkylene-heteroarylene-alkyl;
x) -arylene-alkyl;
y) -arylene-cycloalkyl;
z) -heteroarylene-alkyl;
aa) -arylene-arylene-alkyl;
bb) -D1-alkyl;
cc) -D1-aryl;
dd) -D1-heteroaryl;
ee) -D1-arylene-D2-R14;
ff) -D1-heteroarylene-D2-R14;
gg) -D1-alkylene-heteroaryl;
hh) -D1-alkylene-aryl;
ii) -D1-alkylene-arylene-D2-R14
jj) -D1-alkylene-heteroarylene-D2-R14
kk) -D1-arylene-alkyl;
ll) -D1-heteroarylene-alkyl;
mm) -D1-alkylene-arylene-aryl;
nn) -D1-alkylene-heteroarylene-aryl;
oo) -D1-arylene-arylene-aryl;
pp) -D1-alkylene-arylene-alkyl;
qq) -D1-alkylene-heteroarylene-alky
ss) -alkylene-D1-alkylene-aryl;
tt) -alkylene-D1-alkylene-arylene-D2-R14
uu) -arylene-D1-alkyl;
vv) -arylene-D1-cycloalkyl;
ww) -arylene-D1-heterocyclyl;
xx) -alkylene-D1-aryl;
yy) -alkylene-D1-heteroaryl;
zz) -alkylene-D1-arylene-D2-R14
aaa) -alkylene-D1-heteroarylene-D2-R14
bbb) -alkylene-D1-heteroaryl;
ccc) -alkylene-D1-cycloalkyl;
ddd) -alkylene-D1-heterocyclyl;
eee) -alkylene-D1-arylene-alkyl;
fff) -alkylene-D1-heteroarylene-alkyl;
ggg) -alkylene-D1-alkylene-arylene-alkyl;
hh) -alkylene-D1-alkylene-heteroarylene-alkyl;
iii) -alkylene-D1-alkyl;
jjj) -alkylene-D1-R13;
kkk) -arylene-D1-R13;
lll) -heteroarylene-D1-R13;
or
mmm) -hydrogen;
wherein
D1 comprises —CH2—, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R15)—, —C(O)—, —CON(R15)—, —N(R15)C(O)—, —N(R15)CON(R16)—, —N(R15)C(O)O—, —OC(O)N(R15)—, —N(R15)SO2—, —SO2N(R15)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R15)SO2N(R16)—,
702
and
wherein R13, R15, R16, and R17 independently comprise:
-hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl;
D2 comprises —CH2—, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R25)—, —C(O)—, —CON(R25)—, —N(R18)C(O)—, —N(R18)CON(R19)—, —N(R18)C(O)O—, —OC(O)N(R18)—, —N(R18)SO2—, —SO2N(R18)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R18)SO2N(R19)—, and
wherein R18 and R19 independently comprise:
-hydrogen, -alkyl, -aryl, arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl;
and
R14 comprises -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl;
Ar2 comprises an aryl or heteroaryl group optionally substituted 1 to 7 times, wherein the substituents independently comprise:
a) -fluoro;
b) -chloro;
c) -bromo;
d) -iodo;
e) -cyano;
f) -nitro;
g) -perfluoroalkyl;
h) -T1-R20;
i) -alkyl;
j) -aryl;
k) -heteroaryl;
l) -heterocyclyl;
m) -cycloalkyl;
n) -alkylene-aryl;
o) -alkylene-arylene-aryl;
p) -alkylene-arylene-alkyl;
q) -arylene-alkyl;
r) -arylene-aryl;
s) -arylene-heteroaryl;
t) -heteroarylene-aryl;
u) -heteroarylene-heteroaryl;
v) -heteroarylene-heterocyclyl
w) -arylene-heterocyclyl
x) -arylene-arylene-alkyl;
y) -T1-alkyl;
z) -T1-aryl;
aa) -T1-alkylene-aryl;
bb) -T1-alkenylene-aryl;
cc) -T1-alkylene-heteroaryl;
dd) -T1-alkenylene-heteroaryl;
ee) -T1-cycloalkylene-aryl;
ff) -T1-cycloalkylene-heteroaryl;
gg) -T1-heterocyclylene-aryl;
hh) -T1-heterocyclylene-heteroaryl;
ii) -T1-arylene-alkyl;
jj) -T1-arylene-alkenyl;
kk) -T1-alkylene-arylene-aryl;
ll) -Ti-arylene-T2-aryl;
mm) -T1-arylene-arylene-aryl;
nn) -T1-alkylene-arylene-alkyl;
oo) -alkylene-T1-alkylene-aryl;
pp) -arylene-T1-alkyl;
qq) -arylene-T1-alkylene-aryl;
rr) -T1-alkylene-T2-aryl;
ss) -T1-alkylene-aryl;
tt) -alkylene-T1-heteroaryl;
uu) -alkylene-T1-cycloalkyl;
vv) -alkylene-T1-heterocyclyl;
ww) -alkylene-T-arylene-alkyl;
xx) -alkylene-T1-alkylene-arylene-alkyl;
yy) -alkylene-T1-alkyl;
zz) -alkylene-T1-R20;
aaa) -arylene-T1-R20;
or
bbb) -hydrogen;
wherein
T1 comprises —CH2—, —O—, —N(R21)—, —C(O)—, —CON(R21)—, —N(R21)C(O)—, —N(R21)CON(R22)—, —N(R21)C(O)O—, —OC(O)N(R21)—, —N(R21)SO2—, —SO2N(R21)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R21)SO2N(R22)—,
703
and
wherein R20, R21, R22 and R23, independently comprise:
-hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, -alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-arylene-aryl, -alkylene-arylene-alkylene-aryl, -alkylene-arylene-O-arylene, or alkylene-arylene-O-alkylene-aryl;
and
T2 comprises a direct bond, —CH2—, —O—, —N(R24)—, —C(O)—, —CON(R24)—, —N(R24)C(O)—, —N(R24)CON(R25)—, —N(R24)C(O)O—, —OC(O)N(R24)—, —N(R24)SO2—, —SO2N(R24)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R24)SO2N(R25)—,
wherein R24 and R25 independently comprise;
-hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl.
and wherein
the alkyl, aryl, heteroaryl, alkylene, and arylene groups in Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23 may be optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising:
a) -hydrogen;
b) -fluoro;
c) -chloro;
d) -bromo;
e) -iodo;
f) -cyano;
g) -nitro;
h) -perfluoroalkyl;
i) -Q-perfluoroalkyl
j) -Q-R24;
k) -Q-alkyl;
l) -Q-aryl;
m) -Q-alkylene-aryl;
n) -Q-alkylene-NR25R26;
or
o) -Q-alkyl-W—R27;
wherein
Q and W independently comprise:
—CH2—, —O—, —N(R28)—, —C(O)—, —CON(R28)—, —N(R28)C(O)—, —N(R28)CON(R29)—, —N(R28)C(O)O—, —OC(O)N(R28)—, —N(R28)SO2—, —SO2N(R28)—, —C(O)—O—, —O—C(O)—, or —N(R28)SO2N(R29)—,
wherein
R24, R25, R26, R27, R28, and R29 independently comprise:
-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.

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Aryl and heteroaryl compounds and methods to modulate coagulation

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Aryl and heteroaryl compounds and methods to modulate coagulation

Life of this patent

Abstract

Claims89