Method of preparing poly(ADP-ribose) polymerases inhibitors

1. A method of preparing a compound of formula I

wherein R 1 is:

H;

cyano;

an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or

—C(O)—R 5 , where R 5 is: H; an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or OR 6 or NR 6 R 7 , where R 6 and R 7 are each independently H or an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;

R 2 is H;

R 3 is H or alkyl;

R 4 is H, halogen or alkyl,

the method comprising:

a) Sonogashira coupling of a compound of formula II, wherein X is halogen or CF 3 SO 2 —O—

with a compound of formula III

to form a compound of formula IV

b) reducing the compound of formula IV to generate a compound of formula V;

c) converting the compound of formula V into a compound of formula VI;

d) treating the compound of formula VI with N,N-dimethyl-2-nitroethylenamine to form a compound of formula VII

e) reducing the compound of formula VII to form a compound of formula VIII

f) converting the compound of formula VIII by reduction with Raney-Ni and subsequent cyclization with base into the compound of formula I.

2. The method of claim 1 , wherein the step c) comprises a CuI-promoted indole formation.

3. A method of preparing 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, the method comprising Sonogashira coupling of a compound of formula IX, wherein X is CF 3 SO 2 —O— or halogen,

with (4-ethynyl-benzyl)-methyl-carbamic acid methyl ester to form 5-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-3-nitro-benzoic acid methyl ester.

4. The method of claim 3 , wherein X is CF 3 SO 2 —O—.

5. The method of claim 3 , wherein X is bromine.

6. The method of claim 3 further comprising:

a) reducing 5-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-3-nitro-benzoic acid methyl ester into 3-amino-5-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-benzoic acid methyl ester;

b) converting 3-amino-5-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-benzoic acid methyl ester into 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-indole-4-carboxylic acid methyl ester;

c) treating 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-indole-4-carboxylic acid methyl ester with N,N-dimethyl-2-nitroethylenamine to generate 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-3-((E)-2-nitro-vinyl)-1H-indole-4-carboxylic acid methyl ester;

d) reducing 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-3-((E)-2-nitro-vinyl)-1H-indole-4-carboxylic acid methyl ester into 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-3-(2-nitro-ethyl)-1H-indole-4-carboxylic acid methyl ester;

e) converting 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-3-(2-nitro-ethyl)-1H-i ndole-4-carboxylic acid methyl ester into [4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzyl]-methyl-carbamic acid methyl ester; and

f) deprotecting [4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzyl]-methyl-carbamic acid methyl ester to produce 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

7. The method of claim 6 , wherein the step b) comprises a CuI-promoted indole formation.

8. The method of claim 6 , wherein the step e) comprises hydrogenation.