Isoquinoline derivatives and methods of use thereof

1. A method for making a compound of formula 13

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 5 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 11a

with a compound of formula 12

wherein 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 13.

2. A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein

R 1 , R 2 , R 3 , R 4 , R 7 , R 8 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;

R 9 is —SO 2 —B or —SO 2 NH—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.

3. A method for treating Parkinson's disease, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable hydrate or salt of a compound of claim 2 in amount sufficient to treat Parkinson's disease.

4. A method for treating an inflammatory disease, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable hydrate or salt of the compound of claim 2 in an amount sufficient to treat the inflammatory disease, wherein the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, or an inflammatory disease of the eye.

5. A method for treating a reperfusion disease, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable hydrate or salt of the compound of claim 2 in an amount sufficient to treat the reperfusion disease, wherein the reperfusion disease is myocardial infarction or stroke.

6. A method for treating diabetes, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable hydrate or salt of the compound of claim 2 in an amount sufficient to treat the diabetes.

7. A method for treating reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable hydrate or salt of the compound of claim 2 in an amount sufficient to treat the reoxygenation injury resulting from organ transplantation.

8. A composition comprising an effective amount of a compound or pharmaceutically acceptable salt or hydrate of the compound of claim 2 and a pharmaceutically acceptable carrier.

9. A compound of claim 2 having the formula:

or pharmaceutically acceptable salt thereof,

wherein:

R is —NHCH 2 CH 2 CN, —NHCH(NH)NH 2 , —NH[4-(1,2,4-triazole)], —NH[4-(N-morpholino)phenyl], —NHCH 2 CH 2 (4-N-benzylpiperidine), —NHCH 2 CH 2 (2-thienyl), —NH[1-(4-azabenzimidazole)], —NH[1-(4-(2′-pyridyl)piperazine)], —NHCH 2 CH 2 N(CH 2 CH 2 OH) 2 , —NH[1-(4-benzylpiperazine)], —NH 2 , —NHCH 2 CH 2 -phenyl, —NHCH 2 CH 2 (4-methoxyphenyl), —NHC(O)(N-morpholine), —NHCH((CH 2 ) 4 NH 2 )COOH, —NHCH(CH 2 COOH)COOH, —NH(CH 2 ) n COOH, —NHCH(CH 2 CH 2 COOH)COOH, or —NHCH(CH 2 OH)COOH; and

n is an integer ranging from 1 to 5.

10. A method for treating Parkinson's disease, the method comprising administering to a subject in need thereof the compound having the formula

or a pharmaceutically acceptable hydrate or salt thereof in an amount sufficient to treat Parkinson's disease.

11. A method for treating an inflammatory disease, the method comprising administering to a subject in need thereof the compound having the formula

or a pharmaceutically acceptable hydrate or salt thereof in an amount sufficient to treat an inflammatory disease, wherein the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, or an inflammatory disease of the eye.

12. A method for treating a reperfusion disease, the method comprising administering to a subject in need thereof the compound having the formula

or a pharmaceutically acceptable hydrate or salt thereof in an amount sufficient to treat a reperfusion disease, wherein the reperfusion disease is myocardial infarction or stroke.

13. A method for treating diabetes, the method comprising administering to a subject in need thereof the compound having the formula

or a pharmaceutically acceptable hydrate or salt thereof in an amount sufficient to treat diabetes.

14. A method for treating a reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound having the formula

or a pharmaceutically acceptable hydrate or salt thereof in an amount sufficient to treat a reoxygenation injury resulting from organ transplantation.

15. The pharmaceutically acceptable salt of the compound of claim 2 , wherein the salt is a mesylate salt.

16. A mesylate salt of the compound having the formula:

17. A method for treating Parkinson's disease, the method comprising administering to a subject in need thereof the mesylate salt of claim 16 in an amount sufficient to treat Parkinson's disease.

18. A method for treating an inflammatory disease, the method comprising administering to a subject in need thereof the mesylate salt of claim 16 in an amount sufficient to treat the inflammatory disease, wherein the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, or an inflammatory disease of the eye.

19. A method for treating a reperfusion disease, the method comprising administering to a subject in need thereof the mesylate salt of claim 16 in an amount sufficient to treat the reperfusion disease, wherein the reperfusion disease is myocardial infarction or stroke.

20. A method for treating diabetes, the method comprising administering to a subject in need thereof the mesylate salt of claim 16 in an amount sufficient to treat the diabetes.

21. A method for treating reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the mesylate salt of claim 16 in an amount sufficient to treat the reoxygenation injury resulting from organ transplantation.

22. A composition comprising an effective amount of the mesylate salt of claim 16 and a pharmaceutically acceptable carrier.