Substituted phenoxypropylcycloamine derivatives as histamine-3 (H

1. A compound of Formula I:

wherein:

R 1 is selected from pyrrolidin-1-yl, piperidin 1-yl, piperazin-1-yl, morpholin-4-yl, 1,3-dihydroisoindol-2-yl, hexahydro-pyrrolo[1,2-a]pyrazin-2-yl, or octahydro-pyrido[1,2-a]pyrazin-2-yl, wherein R 1 is optionally substituted with one to three R 20 groups;

R 2 at each occurrence is independently F, Cl, Br, I, OR 21 , NR 23 R 24 , NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C(═O)R 25 , CO 2 R 25 , or C(═O)NR 23 R 24 ;

R 3 is H or C 1 -C 6 alkyl;

R 4 is H or C 1 -C 6 alkyl;

R 5 is

wherein R 5 is para or meta to Y;

X is O;

Y is O;

R 10 is H, C 1 -C 4 alkyl, cycloalkyl, or arylalkyl;

R 11 is H, C 1 -C 6 alkyl, C(═O)R 25 , CO 2 R 25 ;

A is selected from pyrrolidin-1-yl; piperidin-1-yl; morpholin-4-yl; piperazin-1-yl; thiomorpholin-4-yl; 2,3-dihyro-indol-1-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 3,4-dihydro-1H-isoquinolin-2-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; indol-1-yl; and benzoimidazol-1-yl;

wherein A can be optionally substituted with one to three R 20 groups;

R 20 at each occurrence is independently, F, Cl, Br, I, OR 21 , OR 22 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl optionally substituted with OR 21 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5 or 6 membered heteroaryl, arylalkyl, (═O), C(═O)R 26 , CO 2 R 28 , OC(═O)R 25 , C(═O)NR 23 R 24 , NR 27 C(═O)R 25 , NR 27 C(═O)OR 25 , OC(═O)NR 23 R 24 , NR 27 C(═S)R 25 , or S(O) q R 25 , wherein said aryl groups are optionally substituted with one to three R 30 groups;

R 21 at each occurrence is independently H, C 1 -C 6 alkyl, aryl, or arylalkyl;

R 22 at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

R 23 and R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl, and aryl, or R 23 and R 24 , together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocyclic ring optionally substituted with ═O;

R 25 at each occurrence is independently C 1 -C 6 alkyl, aryl, or arylalkyl;

R 26 at each occurrence is independently NR 23 R 24 , CF 3 , C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-10 membered heteroaryl, or arylalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one to three R 30 groups;

R 27 at each occurrence is independently H or C 1 -C 6 alkyl;

R 28 at each occurrence is independently C 1 -C 6 alkyl, aryl, or arylalkyl, wherein said groups are optionally substituted with one to three R 30 groups;

R 30 at each occurrence is independently F, Cl, Br, I, OR 21 , OR 22 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, aryl, or arylalkyl;

n is 0, 1, 2, 3, or 4;

m is 3;

q is 0, 1, or 2;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is a pyrrolidin-1-yl, piperazin-1-yl or morpholin-4-yl group, wherein said groups are optionally substituted with 1 to 3 R 20 groups.

3. The compound of claim 2 wherein R 1 is a pyrrolidin-1-yl group, optionally substituted with 1 to 3 R 20 groups.

4. The compound of claim 3 wherein R 1 is 2-methyl-pyrrolidin-1-yl.

5. The compound of claim 1 wherein A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl wherein said groups are optionally substituted with 1 to 3 R 20 groups.

6. The compound of claim 1 wherein A is 3,4-dihydro-1H-isoquinolin-2-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; or 2-methyl-benzoimidazol-1-yl.

7. The compound of claim 1 wherein R 1 is 1,3-dihydro-isoindol-2-yl; hexahydro-pyrrolo[1,2-a]pyrazin-2-yl; or octahydro-pyrido[1,2-a]pyrazin-2-yl.

8. A compound of claim 1 having the structure of Formula Ic:

wherein:

R 1 is pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl, 1,3-dihydroisoindol-2-yl, hexahydro-pyrrolo[1,2-a]pyrazin-2-yl, or octahydro-pyrido[1,2-a]pyrazin-2-yl, wherein R 1 is optionally substituted with one to three R 20 groups;

R 2 at each occurrence is independently F, Cl, OR 21 , or C 1 -C 6 alkyl;

R 3 is H or C 1 -C 6 alkyl;

R 4 is H or C 1 -C 6 alkyl;

X is O;

R 10 is H, C 1 -C 4 alkyl, cycloalkyl, or arylalkyl;

A is selected from pyrrolidin-1-yl; piperidin-1-yl; morpholin-4-yl; piperazin-1-yl; thiomorpholin-4-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 3,4-dihydro-1H-isoquinolin-2-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; and benzoimidazol-1-yl;

wherein A can be optionally substituted with one to three R 20 groups;

R 20 at each occurrence is independently, F, CN, CF 3 , C 3 -C 6 alkyl optionally substituted with OR 21 , phenyl, 5 or 6 membered heteroaryl, (═O), C(═O)R 26 , CO 2 R 28 , C(═O)NR 23 R 24 , or S(O) 2 R 25 , wherein said phenyl group is optionally substituted with one to three R 30 groups;

R 21 at each occurrence is independently H, C 1 -C 6 alkyl, aryl, or arylalkyl;

R 23 and R 24 at each occurrence are each independently H or C 1 -C 6 alkyl;

R 25 at each occurrence is independently C 1 -C 6 alkyl, aryl, or arylalkyl;

R 26 at each occurrence is independently NR 23 R 24 , CF 3 , C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-10 membered heteroaryl, or arylalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one to three R 30 groups;

R 28 at each occurrence is independently C 1 -C 6 alkyl, aryl, or arylalkyl, wherein said groups are optionally substituted with one to three R 30 groups;

R 30 at each occurrence is independently F, Cl, CF 3 , C 1 -C 6 alkyl or phenyl;

n is 0, 1, or 2;

m is 3; or a stereoisomer or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein R 1 is a pyrrolidin-1-yl or group, wherein said group is optionally substituted with 1 to 3 R 20 groups.

10. The compound of claim 9 wherein A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl wherein said groups are optionally substituted with 1 to 3 R 20 groups.

11. The compound of claim 8 wherein R 1 is pyrrolidin-1-yl, piperazin-1-yl or morpholin-4-yl and A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl, wherein said R 1 and A are each optionally substituted with 1 to 3 R 20 groups.

12. The compound of claim 8 wherein R 1 is pyrrolidin-1-yl and A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or piperazin-1-yl, wherein said R 1 and A are each optionally substituted with 1 to 3 R 20 groups.

13. A compound of claim 1 having the structure of Formula Id:

wherein:

R 1 is pyrrolidin-1-yl, piperazin-1-yl, or morpholin-4-yl, wherein R 1 is optionally substituted with one to three R 20 groups;

R 2 at each occurrence is independently F, Cl, Br, I, OR 21 , NR 23 R 24 , NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C(═O)R 25 , CO 2 R 25 , or C(═O)NR 23 R 24 ;

R 3 is H or C 1 -C 6 alkyl;

R 4 is H or C 1 -C 6 alkyl;

X is O;

R 10 is H, C 1 -C 4 alkyl, cycloalkyl, or arylalkyl;

A is selected from pyrrolidin-1-yl; piperidin-1-yl; morpholin-4-yl; piperazin-1-yl; thiomorpholin-4-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 3,4-dihydro-1H-quinolin-1-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; and benzoimadazol-1-yl;

wherein A can be optionally substituted with one to three R 20 groups;

R 20 at each occurrence is independently, F, CN, CF 3 , C 1 -C 6 alkyl optionally substituted with OR 21 , phenyl, 5 or 6 membered heteroaryl, (═O), C(═O)R 26 , CO 2 R 28 , or S(O) 2 R 25 , wherein said phenyl group is optionally substituted with one to three R 30 groups;

R 21 at each occurrence is independently H, C 1 -C 6 alkyl, aryl, or arylalkyl;

R 23 and R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl, and aryl, or R 23 and R 24 , together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocyclic ring optionally substituted with ═O;

R 25 at each occurrence is independently C 1 -C 6 alkyl, aryl, or arylalkyl;

R 26 at each occurrence is independently NR 23 R 24 , CF 3 , C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-10 membered heteroaryl, or arylalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one to three R 30 groups;

R 28 at each occurrence is independently C 1 -C 6 alkyl, aryl, or arylalkyl, wherein said groups are optionally substituted with one to three R 30 groups;

R 30 at each occurrence is independently F, Cl, Br, I, OR 21 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, aryl, or arylalkyl;

n is 0, 1, or 2;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 wherein R 1 is a pyrrolidin-1-yl, wherein said group is optionally substituted with 1 to 3 R 20 groups.

15. The compound of claim 13 wherein A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl wherein said groups are optionally substituted with 1 to 3 R 20 groups.

16. The compound of claim 13 wherein R 1 is pyrrolidin-1-yl, piperazin-1-yl or morpholin-4-yl and A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl, wherein said R 1 and A are each optionally substituted with 1 to 3 R 20 groups.

17. A compound selected from the following:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

19. A pharmaceutical composition comprising a compound of claim 8 or a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

20. A pharmaceutical composition comprising a compound of claim 13 or a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

21. A pharmaceutical composition comprising a compound of claim 17 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.