Isoquinoline derivatives and methods of use thereof
The invention provides novel classes of Isoquinoline Derivatives. Pharmaceutical compositions and methods of making and using the compounds, are also described.
1. A process for preparing a compound of formula 37
wherein:
R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are independently -hydrogen, -halo, -hydroxy, -O-(C 1 -C 5 alkyl), C 1 –C 10 alkyl, -alkylhalo, —C 2 –C 10 alkenyl, —C 3 –C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 –C 5 alkyl), —OC(O)(C 1 –C 5 alkyl), NO 2 or —A—B;
A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 –C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;
B is —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, -heterocycle, —C 3 –C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 –C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 –C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 –C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —C(O)OH, —C 1 –C 5 alkylene-C(O)O—(C 1 –C 5 alkyl) or —C 1 –C 5 alkylene-OC(O) (C 1 –C 5 alkyl); and
Z 1 and Z 2 are independently —H or —C 1 –C 10 alkyl, which is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently, —H or —C 1 –C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z 1 and Z 2 are taken together to form a heterocyclic amine, comprising contacting a compound of formula 36
wherein
R c is C 1 –C 3 alkyl,
with a compound of formula 11a or a compound of formula 20
wherein
each occurrence of R a is independently C 1 –C 3 alkyl; and
R b is —Cl, —Br, —I, —OMs, —OTs or —OTf,
in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 37.
2. A method for treating Parkinson's disease, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable hydrate or salt of a compound having the formula:
wherein:
R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are independently -hydrogen, -halo, -hydroxy, —O—(C 1 –C 5 alkyl), —C 1 –C 10 alkyl, -alkylhalo, —C 2 –C 10 alkenyl, —C 3 –C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 –C 5 alkyl), —OC(O)(C 1 –C 5 alkyl), —NO 2 or —A—B;
A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 –C 4 alkyl)—, —NH—, —CH 2 —, —S— or —C(S)—;
B is —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, -heterocycle, —C 3 –C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 –C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 –C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 , any of which are unsubstituted or substituted with one or more of —O—(C 1 –C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, -aryl, -benzyl, -arylamido, -alkylcarboxy, —C(O)OH, —C 1 –C 5 alkylene-C(O)O—C 1 –C 5 alkyl or —C 1 –C 5 alkylene-OC(O)—C 1 –C 5 alkyl groups; and
Z 1 and Z 2 are independently —H or —C 1 –C 10 alkyl, which is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently, —H or —C 1 –C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z 1 and Z 2 are taken together to form a heterocyclic amine.
3. A pharmaceutical composition comprising an effective amount of a compound or pharmaceutically acceptable salt or hydrate of a compound having the formula:
wherein:
R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are independently -hydrogen, -halo, -hydroxy, —O—(C 1 –C 5 alkyl), —C 1 –C 10 alkyl, -alkylhalo, —C 2 –C 10 alkenyl, —C 3 –C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 –C 5 alkyl), —OC(O)(C 1 –C 5 alkyl), —NO 2 or —A—B;
A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 –C 4 alkyl)—, —NH—, —CH 2 —, —S— or —C(S)—;
B is —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, -heterocycle, —C 3 –C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 –C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 –C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 , any of which are unsubstituted or substituted with one or more of —O—(C 1 –C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, -aryl, -benzyl, -arylamido, -alkylcarboxy, —C(O)OH, —C 1 –C 5 alkylene-C(O)O—C 1 –C 5 alkyl or —C 1 –C 5 alkylene-OC(O)—C 1 –C 5 alkyl groups; and
Z 1 and Z 2 are independently —H or —C 1 –C 10 alkyl, which is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently, —H or —C 1 –C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z 1 and Z 2 are taken together to form a heterocyclic amine,
and a pharmaceutically acceptable carrier.
4. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
5. A method for treating Parkinson's disease, the method comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 4 .