Aminoalkylazole derivatives as histamine-3 antagonists

1. A compound of formula (Ia)

wherein

X is (CH 2 ) 0 ;

m is 1, 2 or 3;

n is 0, 1, 2 or 3;

R is H, halogen or an optionally substituted C 1 -C 6 alkyl group;

R 1 and R 2 are each independently H or an optionally substituted C 1 -C 6 alkyl group or R 1 and R 2 may be taken together with the atom to which they are attached to form an optionally substituted 4- to 7-membered cycloheteroalkyl;

R 3 , R 4 , R 7 and R 8 are each independently H, or a C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or C 6 -C 10 aryl group each optionally substituted;

R 5 and R 6 are each independently H, halogen, OR 10 or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

R 10 is H or an optionally substituted C 1 -C 6 alkyl group; and

R 11 and R 12 are taken together with the atom to which they are attached to form an optionally substituted fused bicyclic 9- to 11-membered ring system optionally containing one to three additional heteroatoms selected from N, O or S; or

a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein the optionally substituted groups are selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, nitro, cyano, hydroxy, C 6 -C 10 aryl, a 3-10 membered heterocyclyl ring, a 5-10 membered heteroaryl ring, —N(R a ) 2 , —C(O)R b , —OR c and —S(O) p R d ; wherein each R a is independently H, C 1 -C 4 alkyl, —CHO, —C(O)(C 1 -C 4 alkyl), or —C(O)—O—(C 1 -C 4 alkyl); each R b is independently H, —OH, O(C 1 -C 4 alkyl), C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ; each R c is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO or —C(O)(C 1 -C 4 alkyl); each R d is independently C 1 -C 4 alkyl, or —OH; and p is 0, 1 or 2.

2. The compound of claim 1 , wherein m is 1;

or a stereoisomer or pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein n is 1;

or a stereoisomer or pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein n is 0;

or a stereoisomer or pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 3 , R 4 , R 7 and R 8 are each independently H or methyl optionally substituted with a group selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, nitro, cyano, hydroxy, C 6 -C 10 aryl, a 3-10 membered heterocyclyl ring, a 5-10 membered heteroaryl ring, —N(R a ) 2 , —C(O)R b , —OR c and —S(O) p R d ; wherein each R a is independently H, C 1 -C 4 alkyl, —CHO, —C(O)(C 1 -C 4 alkyl), or or —C(O)—O—(C 1 -C 4 alkyl); each R b is independently H, —OH, O(C 1 -C 4 alkyl), C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ; each R c is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO or —C(O)(C 1 -C 4 alkyl); each R d is independently C 1 -C 4 alkyl, or —OH; and p is 0, 1 or 2;

or a stereoisomer or pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 1 and R 2 are taken together with the atom to which they are attached to form a 5-membered cycloheteroalkyl ring optionally substituted with a group selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, nitro, cyano, hydroxy, C 6 -C 10 aryl, a 3-10 membered heterocyclyl ring, a 5-10 membered heteroaryl ring, —N(R a ) 2 , —C(O)R b , —OR c and —S(O) p R d ; wherein each R a is independently H, C 1 -C 4 alkyl, —CHO, —C(O)(C 1 -C 4 alkyl), or or —C(O)—O—(C 1 -C 4 alkyl); each R b is independently H, —OH, O(C 1 -C 4 alkyl), C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ; each R c is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO or —C(O)(C 1 -C 4 alkyl); each R d is independently C 1 -C 4 alkyl, or —OH; and p is 0, 1 or 2;

or a stereoisomer or pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R 11 and R 12 are taken together with the atom to which they are attached to form an indole, indazole or benzimidazole ring each independently optionally substituted with a group selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, nitro, cyano, hydroxy, C 6 -C 10 aryl, a 3-10 membered heterocyclyl ring, a 5-10 membered heteroaryl ring, —N(R a ) 2 , —C(O)R b , —OR c and —S(O) p R d ; wherein each R a is independently H, C 1 -C 4 alkyl, —CHO, —C(O)(C 1 -C 4 alkyl), or or —C(O)—O—(C 1 -C 4 alkyl); each R b is independently H, —OH, O(C 1 -C 4 alkyl), C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ; each R c is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO or —C(O)(C 1 -C 4 alkyl); each R d is independently C 1 -C 4 alkyl, or —OH; and p is 0, 1 or 2;

or a stereoisomer or pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 1 and R 2 are taken together with the atom to which they are attached to form an optionally substituted 5-membered cycloheteroalkyl ring; and R 11 and R 12 are taken together with the atom to which they are attached to form an optionally substituted benzimidazole ring;

or a stereoisomer or pharmaceutically acceptable salt thereof;

wherein the optionally substituted groups are selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, nitro, cyano, hydroxy, C 6 -C 10 aryl, a 3-10 membered heterocyclyl ring, a 5-10 membered heteroaryl ring, —N(R a ) 2 , —C(O)R b , —OR c and —S(O) p R d ; wherein each R a is independently H, C 1 -C 4 alkyl, —CHO, —C(O)(C 1 -C 4 alkyl), or or —C(O)—O—(C 1 -C 4 alkyl); each R b is independently H, —OH, O(C 1 -C 4 alkyl), C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ; each R c is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO or —C(O)(C 1 -C 4 alkyl); each R d is independently C 1 -C 4 alkyl, or —OH; and p is 0, 1 or 2.

9. The compound of claim 1 , wherein R is H;

or a stereoisomer or pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein NR 11 R 12 has the following structure:

wherein,

W and Z are each independently N or CR 16 ; and

R 15 and R 16 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl or C 3 -C 6 cycloalkyl;

with the proviso that W and Z are not both N;

or a stereoisomer or pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , wherein W is CR 16 and Z is N;

or a stereoisomer or pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , wherein R 16 is H and R 15 is H;

or a stereoisomer or pharmaceutically acceptable salt thereof.

13. The compound of claim 10 , wherein W is N and Z is CR 16 ;

or a stereoisomer or pharmaceutically acceptable salt thereof.

14. The compound of claim 10 , wherein both W and Z are independently CR 16 ;

or a stereoisomer or pharmaceutically acceptable salt thereof.

15. The compound of claim 10 , wherein R 15 is selected from the group consisting of H, 5-OCH 3 , 6-OCH 3 , 5-CH 3 and 6-CH 3 .

16. The compound of claim 10 , wherein R 16 is phenyl, H or CH 3 .

17. The compound of claim 1 , wherein NR 1 R 2 has the following structure:

v is 0, 1 or 2;

R 19 , R 20 and R 21 are each independently H, halo, nitro, cyano, hydroxy, S(O) q R d , —N(R a ) 2 , or C 1 -C 6 alkyl, C 1 -C 4 acyl, C 1 -C 4 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, or C 3 -C 6 cycloalkyl, each substituted with 0-4 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, nitro, cyano, hydroxy, phenyl, 3-10 membered heterocyclyl, —N(R a ) 2 , —C(O)R b , —OR c and —S(O) q R d ;

each R a is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO, —C(O)(C 1 -C 4 alkyl) or —C(O)—O—(C 1 -C 4 alkyl);

each R b is independently H, —OH, —O(C 1 -C 4 alkyl), C 1 -C 4 alkyl optionally substituted with halo, —NH 2 , —NH(C 1 -C 4 alkyl) or —N(C 1 -C 4 alkyl) 2 ;

each R c is independently H, C 1 -C 4 alkyl optionally substituted with halo, —CHO or —C(O)(C 1 -C 4 alkyl);

each R d is independently C 1 -C 4 alkyl optionally substituted with halo, or —OH; and

each q is independently 0, 1 or 2;

or a stereoisomer or pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , wherein v is 0;

or a stereoisomer or pharmaceutically acceptable salt thereof.

19. The compound of claim 17 , wherein v is 1 and R 21 is H;

or a stereoisomer or pharmaceutically acceptable salt thereof.

20. The compound of claim 17 , wherein v is 2 and R 21 is H;

or a stereoisomer or pharmaceutically acceptable salt thereof.

21. The compound of claim 17 , wherein R 19 and R 20 are independently H or methyl;

or a stereoisomer or pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , wherein —NR 1 R 2 is selected from the group consisting of piperidinyl, dimethylamino, methylethylamino, morpholin-4-yl, 4-methylpiperazinyl, diethylamino, 2-methylpyrrolidinyl, azepanyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, (R)-2-methylpyrrolidinyl, (S)-2-methylpyrrolidinyl, (R)-3-fluoropyrrolidinyl, (S)-3-fluoropyrrolidinyl, and pyrrolidinyl;

or a stereoisomer or pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , selected from the group consisting of:

1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-{4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-{2-[4-(1H-benzimidazol-1-ylmethyl)phenyl]-1,3-oxazol-4-yl}-N,N-dimethylmethanamine;

N-({2-[4-(1H-benzimidazol-1-ylmethyl)phenyl]-1,3-oxazol-4-yl}methyl)-N-methylethanamine;

1-{4-[4-(morpholin-4-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-(4-{4-[(4-methylpiperazin-1-yl)methyl]-1,3-oxazol-2-yl}benzyl)-1H-benzimidazole;

N-({2-[4-(1H-benzimidazol-1-ylmethyl)phenyl]-1,3-oxazol-4-yl}methyl)-N-ethylethanamine;

1-(4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl}benzyl)-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-(4-{4-[(2-methylpiperidin-1-yl)methyl]-1,3-oxazol-2-yl}benzyl)-1H-benzimidazole;

1-(4-{4-[(3-methylpiperidin-1-yl)methyl]-1,3-oxazol-2-yl}benzyl)-1H-benzimidazole;

1-(4-{4-[(4-methylpiperidin-1-yl)methyl]-1,3-oxazol-2-yl}benzyl)-1H-benzimidazole;

1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

1-[4-(4-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

1-[4-(4-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

1-{4-[5-methyl-4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-{4-[5-bromo-4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]phenyl}-1H-benzimidazole;

1-{4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-{2-[4-(1H-benzimidazol-1-yl)phenyl]-1,3-oxazol-4-yl}-N,N-dimethylmethanamine;

N-({2-[4-(1H-benzimidazol-1-yl)phenyl]-1,3-oxazol-4-yl}methyl)-N-methylethanamine;

1-{4-[4-(morpholin-4-ylmethyl)-1,3-oxazol-2-yl]phenyl}-1H-benzimidazole;

1-(4-{4-[(4-methylpiperidin-1-yl)methyl]-1,3-oxazol-2-yl}phenyl)-1H-benzimidazole;

N-({2-[4-(1H-benzimidazol-1-yl)phenyl]-1,3-oxazol-4-yl}methyl)-N-ethylethanamine;

1-(4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl}phenyl)-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]phenyl}-1H-benzimidazole;

1-(4-{4-[(2-methylpiperidin-1-yl)methyl]-1,3-oxazol-2-yl}phenyl)-1H-benzimidazole;

1-(4-{4-[(3-methylpiperidin-1-yl)methyl]-1,3-oxazol-2-yl}phenyl)-1H-benzimidazole;

1-(4-{4-[(4-methylpiperazin-1-yl)methyl]-1,3-oxazol-2-yl}phenyl)-1H-benzimidazole;

1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-indole;

6-fluoro-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-indazole;

1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-indazole;

1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-indazole;

5-fluoro-1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-indazole;

6-fluoro-1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-indazole;

5-fluoro-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-indazole;

6-fluoro-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-indazole;

1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-indazole;

1-(1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-indazol-5-yl)methanamine;

5-fluoro-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-indazole;

2-phenyl-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-2-(trifluoromethyl)-1H-benzimidazole;

1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-2-(trifluoromethyl)-1H-benzimidazole;

1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-2-phenyl-1H-benzimidazole;

1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-2-phenyl-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-2-(trifluoromethyl)-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-2-phenyl-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-5-methoxy-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-6-methoxy-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-5-methyl-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-6-methyl-1H-benzimidazole;

2-phenyl-1-{4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

1-{4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-2-(trifluoromethyl)-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-2,5-dimethyl-1H-benzimidazole;

1-{4-[4-(azepan-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-2,6-dimethyl-1H-benzimidazole;

2,5-dimethyl-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

2,6-dimethyl-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

2,5-dimethyl-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

2,6-dimethyl-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

5-methoxy-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

6-methoxy-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

5-methyl-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

6-methyl-1-{4-[4-(pyrrolidin-1-ylmethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole;

5-methoxy-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

6-methoxy-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

5-methyl-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

6-methyl-1-[4-(4-{[(2S)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole;

5-methoxy-1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole; and

6-methoxy-1-[4-(4-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-oxazol-2-yl)benzyl]-1H-benzimidazole; or

a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula (Ia) according to claim 1 ; or a stereoisomer or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25 , wherein the pharmaceutically acceptable salt is HCl.