2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

1. A method of inhibiting a nitric oxide synthase, said method comprising:

(a) providing a compound of a formula

wherein Ar is selected from optionally-substituted aryl and heteroaryl moieties, where said substituents are selected from halo, alkyl, haloalkyl, cyano and amino substituents; L 1 is selected from optionally-substituted divalent C 1 -C 4 alkylene moieties, where said substituents are selected from halo, alkyl and divalent methylene substituents; R 1 is selected from H, alkyl and divalent alkylene substituents and amino protecting groups; L 2 is selected from optionally-substituted divalent C 1 -C 3 alkylene moieties, where said substituents are selected from halo, aza (—NH—) and substituted aza (—NR 2 ) moieties, where R 2 is selected from alkyl and divalent alkylene substituents; E 1 and E 3 are N, and E 2 is CH; and E 4 -E 7 are independently selected from CH, CR 3 and N, providing at least one of E 4 -E 7 is N, and where R 3 is selected from methyl and halo substituents, or a salt of a said compound; and

(b) contacting said compound with a nitric oxide synthase.

2. The method of claim 1 wherein Ar is selected from fluoro-, chloro- and cyano-substituted phenyl moieties; and E 5 is N.

3. The method of claim 2 wherein E 6 is a CCH 3 moiety.

4. A method of inhibiting a nitric oxide synthase, said method comprising:

(a) providing a compound of a formula

wherein X is selected from fluoro-, chloro- and cyano-substituents; L 1 is selected from optionally-substituted divalent C 1 -C 4 alkylene moieties, where said substituents are selected from halo, alkyl and divalent methylene substituents; and E 4 -E 7 are independently selected from CH, CR 3 and N, providing at least one of E 4 -E 7 is N, and where R 3 is selected from methyl and halo substituents, or a salt of a said compound; and

(b) contacting said compound with a nitric oxide synthase, thereby inducing coordination of said compound with hemoglobin iron in an active site of said nitric oxide synthase.

5. The method of claim 4 wherein E 5 is N.

6. The method of claim 5 wherein E 6 is a CCH 3 moiety.

7. The method of claim 4 wherein neuronal nitric oxide synthase is selectively inhibited over inducible and endothelial isoforms.

8. The method of claim 1 wherein L 1 is selected from (CH 2 ) n moieties, where n is an integer selected from 1-3, CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 is independently selected from H, fluoro, and alkyl substituents and moieties where R 4 and R 5 together and R 5 and R 6 together form methylene substituents and cyclopropyl moieties.

9. The method of claim 1 wherein L 2 is selected from (CH 2 ) m , CH(R 7 )CH(R 8 ), ( CH2 ) m NH and (CH 2 ) m NR 2 moieties, where m is an integer selected from 1-3 and each of R 7 -R 8 is independently selected from H and fluoro substituents, and moieties where R 1 and R 2 together form a divalent C 1 -C 2 alkylene substituent and a diazacycloalkyl moiety.

10. The method of claim 1 wherein L 1 is selected from (CH 2 ) n moieties, where n is an integer selected from 1-3, and CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 is independently selected from H and fluoro substituents.

11. The method of claim 1 wherein L 2 is selected from (CH 2 ) m and CH(R 7 )CH(R 8 ), moieties, where m is an integer selected from 1-3 and each of R 7 -R 8 is independently selected from H and fluoro substituents.

12. The method of claim 1 wherein said compound is an ammonium salt, and said salt has a counter ion that is a conjugate base of a protic acid.

13. The method of claim 4 wherein L 1 is selected from (CH 2 ) n moieties, where n is an integer selected from 1-3, and CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 is independently selected from H and fluoro substituents.

14. The method of claim 4 wherein said compound is an ammonium salt, and said salt has a counter ion that is a conjugate base of a protic acid.

15. A method of inhibiting a nitric oxide synthase, said method comprising:

(a) providing a compound of a formula

wherein Ar is selected from fluoro-, chloro- and cyano-substituted phenyl moieties, pyridinyl, methyl- and methyl- and amino-substituted pyridinyl moieties; L 1 is selected from optionally substituted divalent C 1 -C 4 alkylene moieties, where said substituents are selected from halo, alkyl and divalent methylene substituents; L 2 is selected from optionally fluoro-substituted divalent C 1 -C 3 alkylene moieties; and E 4 -E 7 are independently selected from CH, CR 3 and N, providing at least one of E 4 -E 7 is N, and where R 3 is selected from methyl and halo substituents, or a salt of a said compound; and

(b) contacting said compound with a nitric oxide synthase.

16. The compound of claim 15 wherein L 1 is selected from (CH 2 ) n moieties, where n is an integer selected from 1-3, CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 is independently selected from H and fluoro substituents, and moieties where R 4 and R 5 together and R 5 and R 6 together form methylene substituents and cyclopropyl moieties.

17. The compound of claim 15 wherein L 2 is selected from (CH 2 ) m , CH(R 7 )CH(R 8 ), ( CH2 ) m NH and (CH 2 ) m NR 2 moieties, where m is an integer selected from 1-3 and each of R 7 -R 8 is independently selected from H and fluoro substituents, and moieties where R 1 and R 2 together form a divalent C 1 -C 2 alkylene substituent and a diazacycloalkyl moiety.

18. The compound of claim 15 wherein E 5 is N.

19. The compound of claim 15 wherein L 1 is selected from (CH 2 ) n moieties, where n is an integer selected from 1-3, and CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 is independently selected from H and fluoro substituents;.

20. The compound of claim 15 wherein L 2 is selected from (CH 2 ) m and CH(R 7 )CH(R 8 ), moieties, where m is an integer selected from 1-3 and each of R 7 -R 8 is independently selected from H and fluoro substituents.