Substituted benzimidazole compounds with dual NOS inhibitory activity and mu opioid agonist activity

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein,

R 1 is substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, optionally substituted C 1-4 alkheterocyclyl, or optionally substituted C 2-9 heterocyclyl;

R 2 is H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C 1-4 bridged alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 3 and R 4 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

R 5 is H, R 5A C(NH)NH(CH 2 ) r5 —, R 5A NHC(NH)NH(CH 2 ) r5 —, or R 5B NHC(S)NH(CH 2 ) r5 —, where r5 is an integer from 0 to 2; R 5A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-6 thioalkyl, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, optionally substituted C 1-4 thioalkheterocyclyl, or nitro; R 5B is optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-6 thioalkyl, optionally substituted aryloyl, optionally substituted C 1-4 thioalkaryl, optionally substituted C 1-4 thioalkheterocyclyl, or nitro; and

R 6 is H, R 6A C(NH)NH(CH 2 ) r6 —, R 6A NHC(NH)NH(CH 2 ) r6 —, or R 6A NHC(S)NH(CH 2 ) r6 —, where r6 is an integer from 0 to 2 and R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, optionally substituted C 1-4 thioalkheterocyclyl, or nitro;

where one, but not both, of R 5 and R 6 is H, and wherein

when R 1 is substituted C 1-6 alkyl, said substituted C 1-6 alkyl is substituted with one, two, three or, in the case of substituted C 2-6 alkyl groups, four substituents independently selected from the group consisting of: (1) C 1-6 alkoxy; (2) C 1-6 alkylsulfinyl; (3) C 1-6 alkylsulfonyl; (4) C 6-10 aryl; (5) C 6-10 aryl-C 1-6 alkoxy; (6) aryloyl; (7) azido; (8) carboxaldehyde; (9) C 3-8 cycloalkyl; (10) halo; (11) C 2-9 heterocyclyl; (12) (C 2-9 heterocycle)oxy; (13) (C 2-9 heterocycle)oyl; (14) hydroxyl; (15) N-protected amino; (16) nitro; (17) oxo; (18) C 3-8 spiroalkyl; (19) C 1-6 thioalkoxy; (20) C 6-10 aryl-C 1-6 thioalkoxy; (21) thiol; (22) —CO 2 R A , where R A is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6-10 aryl and (c) C 1-6 alkaryl; (23) —C(O)NR B R C , where each of R B and R C is, independently, selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-10 aryl and (d) C 1-6 alkaryl; (24) —SO 2 R D , where R D is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6-10 aryl and (c) C 1-6 alkaryl; (25) —SO 2 NR E R F , where each of R E and R F is, independently, selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-10 aryl and (d) C 1-6 alkaryl; and (26) —NR G R H , where each of R G and R H is, independently, selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) optionally substituted C 1-6 alkyl; (d) C 2-6 alkenyl; (e) C 2-6 alkynyl; (f) optionally substituted C 6-10 aryl; (g) optionally substituted C 1-6 alkaryl; (h) optionally substituted C 3-8 cycloalkyl; (i) C 1-10 alk-C 3-8 cycloalkyl; (j) C 2-9 heterocyclyl, or (k) optionally substituted C 1-4 alkheterocyclyl, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

2. The compound of claim 1 , wherein,

R 1 is substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1-4 alkheterocyclyl;

R 2 is, independently, H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 3 and R 4 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

R 5 is H or R 5A C(NH)NH(CH 2 ) r5 —, wherein r5 is an integer from 0 to 2, R 5A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl; and

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 —, wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

3. The compound of claim 1 , wherein R 1 is optionally substituted C 1-4 alkheterocyclyl, or an alkylamine-substituted C 1-6 alkyl.

4. The compound of claim 3 , wherein said alkylamine-substituted C 1-6 alkyl is selected from the group consisting of 2-(N,N-dimethylamino)-ethyl, and 2-(N,N-diethylamino)-ethyl.

5. The compound of claim 3 , wherein said C 1-4 alkheterocyclyl is selected from the group consisting of 2-(N-aziridinyl)-ethyl, 2-(N-azetidanyl)-ethyl, 2-(N-pyrrolidinyl)-ethyl, 2-(N-piperidinyl)-ethyl, 2-(N-methyl-2-pyrrolidinyl)-ethyl, 2-(N-methyl-4-piperidinyl)-ethyl, and 2-(N-morpholinyl)-ethyl.

6. The compound of claim 1 , wherein r5 or r6 is 0.

7. The compound of claim 1 , wherein R 5A is methyl, fluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, thiomethoxy, thioethoxy, thio-n-propyloxy, thio-1-propyloxy, thio-n-butyloxy, thio-1-butyloxy, thio-t-butyloxy, phenyl, benzyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole.

8. The compound of claim 1 , wherein R 6A is methyl, fluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, thiomethoxy, thioethoxy, thio-n-propyloxy, thio-1-propyloxy, thio-n-butyloxy, thio-1-butyloxy, thio-t-butyloxy, phenyl, benzyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole.

9. The compound of claim 1 , wherein one or both of R 1 and R 2 is not H.

10. The compound of claim 1 , wherein R 1 is (CH 2 ) m1 X 1 , wherein X 1 is selected from the group consisting of:

wherein

each of R 1A and R 1B is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 1C and R 1D is, independently, H, OH, CO 2 R 1E , or NR 1F R 1G , wherein each of R 1E , R 1F , and R 1G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 1C and R 1D together with the carbon they are bonded to are C═O;

Z 1 is NR 1H , NC(O)R 1H , NC(O)OR 1H , NC(O)NHR 1H , NC(S)R 1H , NC(S)NHR 1H , NS(O) 2 R 1H , O, S(O), S(O) 2 , or S, wherein R 1H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, with the proviso that when Z 1 is NC(O)OR 1H , R 1H is not H;

m1 is an integer of 2 to 6;

n1 is an integer of 1 to 4;

p1 is an integer of 0 to 2; and

q1 is an integer of 0 to 5.

11. The compound of claim 1 , wherein R 2 is (CH 2 ) m2 X 2 , wherein X 2 is selected from the group consisting of:

wherein

each of R 2A and R 2B is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 2C and R 2D is, independently, H, OH, CO 2 R 2E , or NR 2F R 2G , wherein each of R 2E , R 2F , and R 2G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 2C and R 2D together with the carbon they are bonded to are C═O;

Z 2 is NR 2 H, NC(O)R 2H , NC(O)OR 2H , NC(O)NHR 2H , NC(S)R 2H , NC(S)NHR 2H , NS(O) 2 R 2H , O, S(O), S(O) 2 , or S, wherein R 2H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, with the proviso that when Z 2 is NC(O)OR 2H , R 2H is not H;

m2 is an integer of 2 to 6;

n2 is an integer of 1 to 4;

p2 is an integer of 0 to 2; and

q2 is an integer of 0 to 5.

12. The compound of claim 1 or 2 , wherein R 1 is (CH 2 ) m1 X 1 , wherein X 1 is selected from the group consisting of:

wherein

each of R 3C and R 3D is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 3C and R 3D together with the carbon they are bonded to are C═O;

Z 3 is NC(NH)R 3H , wherein R 3H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

m1 is an integer of 0 to 6;

n3 is an integer of 1 to 4;

p3 is an integer of 0 to 2; and

q3 is an integer of 0 to 5.

13. The compound of claim 1 or 2 , wherein R 2 is (CH 2 ) m2 X 2 , wherein X 2 is selected from the group consisting of:

wherein

each of R 3C and R 3D is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 3C and R 3D together with the carbon they are bonded to are C═O;

Z 3 is NC(NH)R 3H , wherein R 3H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

m2 is an integer of 0 to 6;

n3 is an integer of 1 to 4;

p3 is an integer of 0 to 2; and

q3 is an integer of 0 to 5.

14. The compound of claim 1 , wherein R 1 or R 2 is

wherein Z is NR Z , o is an integer from 0-3, p is an integer from 1 to 2, q is an integer from 0 to 2, r is an integer from 0 to 1, s is an integer from 0 to 3, u is an integer from 0 to 1, t is an integer from 2 to 7, w is an integer from 0 to 2; and wherein said R Z is independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl.

15. The compound of claim 1 , wherein R 2 is

wherein each of R 2J2 , R 2J3 , R 2J4 , R 2J5 , and R 2J6 is, independently, H, C 1-6 alkyl; OH; C 1-6 alkoxy; SH; C 1-6 thioalkoxy; Halo; NO 2 ; CN; CF 3 ; OCF 3 ; NR where each of R 2Ja and R 2Jb is, independently, H or C 1-6 alkyl; C(O)R 2k , where R 2Jc is H or C 1-6 alkyl; CO 2 R 2Jd , where R 2Jd is H or C 1-6 alkyl; tetrazolyl; C(O)NR 2Je R 2Jf , where each of R 2Je and R 2Jf is, independently, H or C 1-6 alkyl; OC(O)R 2Jg , where R 2Jg is C 1-6 alkyl; NHC(O)R 2Jh , where R 2Jh is H or C 1-6 alkyl; SO 3 H; S(O) 2 NR 2Ji R 2Jj , where each of R 2Ji and R 2Jj is, independently, H or C 1-6 alkyl; S(O)R 2Jk , where R 2Jk is C 1-6 alkyl; and S(O) 2 R 2Jl , where R 2Jl is C 1-6 alkyl,

r2 is an integer of 0 to 2, and

each of R 2K1 and R 2K2 is, independently H or C 1-6 alkyl.

16. The compound of claim 15 , wherein r2 is 1, and R 2J2 , R 2J3 , R 2J5 , R 2J6 , R 2K1 , and R 2K2 are H.

17. The compound of claim 16 , wherein R 2J4 is methoxy, ethoxy, n-propyloxy, isopropyloxy, dimethylamino, diethylamino, thiomethoxy, thioethoxy, n-propyl, isopropyl, or cyclopropyl.

18. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

19. The compound of claim 1 , wherein said compound selectively inhibits neuronal nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS).

20. The compound of claim 1 , wherein said compound is active in an in vitro opioid receptor assay with an EC 50 of 2 μM or less.

21. The compound of claim 20 , wherein said opioid receptor is the mu opioid receptor.

22. The compound of claim 21 , wherein said compound is a mu opioid receptor agonist.

23. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

24. The compound of claim 1 , wherein R 5B is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole.