Cyclohexyl piperazinyl methanone derivatives

Abstract

The present invention relates to compounds of formula I

Description

Claims

1. A compound of formula I:

2. The compound according to claim 1 of formula I-A:

3. The compound according to claim 1, wherein R3 is selected from the group consisting of —(CH2)m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenalkylsulfonyl, lower halogenalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl,—(CH2)n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenalkylsulfonyl, lower halogenalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl,indanyl and 1-oxo-indanyl.

4. The compound according to claim 1, wherein R3 is —(CH2)m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenalkylsulfonyl, lower halogenalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl.

5. The compound according to claim 1, wherein R3 is —(CH2)n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenalkylsulfonyl, lower halogenalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl.

6. The compound according to claim 1, wherein R3 is —(CH2)n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is pyridyl or isoxazolyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenalkylsulfonyl, lower halogenalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl.

7. The compound according to claim 1, wherein R3 is selected from the group consisting of —CO—(C3-C8)-alkyl,—CO—(CH2)p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl, and—CO—(CH2)q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl.

8. The compound according to claim 1, wherein R3 is —CO—(CH2)p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl.

9. The compound according to claim 1, wherein R3 is -CO-NR4R5 and wherein R4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl;R5 is selected from the group consisting of lower alkyl,aryl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzyoyl, lower halogenalkoxy and lower hydroxyalkyl, andlower arylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl; orR4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

10. The compound according to claim 1, wherein R3 is —CO—NR4R5 and wherein R4 is hydrogen or lower alkyl; andR5 is selected from the group consisting of lower alkyl,phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzyoyl, lower halogenalkoxy and lower hydroxyalkyl, andlower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl.

11. The compound according to claim 1, wherein R5 is phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzyoyl, lower halogenalkoxy and lower hydroxyalkyl, orlower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl.

12. The compound according to claim 1, wherein R3 is -CO-NR4R5 and wherein R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

13. The compound according to claim 1, wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, pyrrolidine, azepane, piperazine, azetidine and thiomorpholine, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

14. The compound according to claim 1, wherein R4 and R5 together with the nitrogen atom to which they are attached form a group selected from 2-methylpyrrolidine, piperidine, 4-methoxypiperidine, 4,4-difluoropiperidine, morpholine, 4-phenylpiperazine, 1,3-dihydro-isoindole and 3,4-dihydro-2H-quinoline.

15. The compound according to claim 1, wherein R1 is lower alkyl.

16. The compound according to claim 1, wherein R1 is cycloalkyl.

17. The compound according to claim 1, wherein R2 is hydrogen or lower alkyl.

18. The compound according to claim 1, wherein R2 and R3 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that is condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

19. The compound according to claim 1, selected from the group consisting of (4-isopropyl-piperazin-1-yl)-(4-p-tolylamino-cyclohexyl)-methanone,[4-(4-fluoro-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,[4-(1,3-dihydro-isoindol-2-yl)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,(4-isopropyl-piperazin-1-yl)-[4-(6-methoxy-pyridin-3-ylamino)-cyclohexyl]-methanone,[4-(3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,[4-(indan-1-ylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,(4-isopropyl-piperazin-1-yl)-[4-(1-phenyl-propylamino)-cyclohexyl]-methanone,(4-isopropyl-piperazin-1-yl)-{4-[2-(3-methoxy-phenyl)-ethylamino]-cyclohexyl]-methanone,[4-(4-difluoromethoxy-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-isobutyramide,N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-4-methoxy-benzamide,2,4-difluoro-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-benzamide, 2,4-dichloro-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-benzamide, 1-benzyl-1-isopropyl-3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-urea, 1,1-diethyl-3-[cis-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-urea,4-phenyl-piperazine-1-carboxylic acid[cis-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,1-(4-chloro-phenyl)-3-[cis-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-1-methyl-urea,1-benzyl-1-ethyl-3-[cis-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-urea,3,4-dihydro-2H-quinoline-1-carboxylic acid[cis-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,1-(3-fluoro-phenyl)-3-[cis-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-1-methyl-urea,2-methyl-pyrrolidine-1-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,1-benzyl-1-isopropyl-3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-urea,1,1-diethyl-3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-urea,piperidine-1-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,morpholine-4-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,4-methoxy-piperidine-1-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,4-phenyl-piperazine-1-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,1-(4-chloro-phenyl)-3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-1-methyl-urea,1-benzyl-1-ethyl-3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-urea,3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-1-phenyl-1-propyl-urea,3,4-dihydro-2H-quinoline-1-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,1-(3-fluoro-phenyl)-3-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-1-methyl-urea,4,4-difluoro-piperidine-1-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,1,3-dihydro-isoindole-2-carboxylic acid[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,(4-cyclopentyl-piperazin-1-yl)-[4-(2-fluoro-phenylamino)-cyclohexyl]-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(3-fluoro-phenylamino)-cyclohexyl]-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(4-fluoro-phenylamino)-cyclohexyl]-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(2,4-difluoro-phenylamino)-cyclohexyl]-methanone,3-[4-(4-cyclopentyl-piperazine-1-carbonyl)-cyclohexylamino]-benzonitrile,(4-cyclopentyl-piperazin-1-yl)-[4-(2-methoxy-phenylamino)-cyclohexyl]-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(4-methoxy-phenylamino)-cyclohexyl]-methanone,1-{4-[4-(4-cyclopentyl-piperazine-1-carbonyl)-cyclohexylamino]-phenyl}-ethanone,[4-(4-benzoyl-phenylamino)-cyclohexyl]-(4-cyclopentyl-piperazin-1-yl)-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(pyrazin-2-ylamino)-cyclohexyl]-methanone,(4-cyclopentyl-piperazin-1-yl)-{4-[(3-fluoro-phenyl)-methyl-amino]-cyclohexyl}-methanone,(4-cyclopentyl-piperazin-1-yl)-{4-[(4-fluoro-phenyl)-methyl-amino]-cyclohexyl}-methanone,[4-(2-fluoro-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,[4-(2,4-difluoro-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,3-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexylamino]-benzonitrile,(4-isopropyl-piperazin-1-yl)-[4-(4-methoxy-phenylamino)-cyclohexyl]-methanone,1-{4-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexylamino]-phenyl}-ethanone,[4-(4-benzoyl-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,2-[4-(4-cyclopentyl-piperazine-1-carbonyl)-cyclohexylamino]-benzonitrile,and pharmaceutically acceptable salts thereof.

20. The compound according to claim 1, selected from the group consisting of [4-(1,3-dihydro-isoindol-2-yl)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,(4-isopropyl-piperazin-1-yl)-[4-(6-methoxy-pyridin-3-ylamino)-cyclohexyl]-methanone,[4-(indan-1-ylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,(4-isopropyl-piperazin-1-yl)-[4-(1-phenyl-propylamino)-cyclohexyl]-methanone,(4-isopropyl-piperazin-1-yl)-{4-[2-(3-methoxy-phenyl)-ethylamino]-cyclohexyl}-methanone,[4-(4-difluoromethoxy-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(4-fluoro-phenylamino)-cyclohexyl]-methanone,(4-cyclopentyl-piperazin-1-yl)-[4-(2,4-difluoro-phenylamino)-cyclohexyl]-methanone,3-[4-(4-cyclopentyl-piperazine-1-carbonyl)-cyclohexylamino]-benzonitrile,[4-(4-benzoyl-phenylamino)-cyclohexyl]-(4-cyclopentyl-piperazin-1-yl)-methanone,(4-isopropyl-piperazin-1-yl)-[4-(4-methoxy-phenylamino)-cyclohexyl]-methanone,[4-(4-benzoyl-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,trans-(4-cyclobutyl-piperazin-1-yl)-[4-(4-fluoro-phenylamino)-cyclohexyl]-methanone,[4-(2,4-dichloro-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,trans-[4-(6-chloro-pyridin-3-ylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone,trans-6-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexylamino]-nicotinonitrile,trans-(4-isopropyl-piperazin-1-yl)-[4-(5-methanesulfonyl-pyridin-2-ylamino)-cyclohexyl]-methanone,and pharmaceutically acceptable salts thereof.

21. A process for the manufacture of a compound according to claim 1, comprising the steps of: a) coupling a compound of formula II

22. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 as well as a pharmaceutically acceptable carrier and/or adjuvant.

23. A method for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors, comprising the step of administering a therapeutically active amount of a compound according to claim 1 to a human being or animal in need thereof.

24. A method for the treatment or prevention of obesity in a human being or animal, which method comprises administering a therapeutically effective amount of a compound of formula I according to claim 1 in combination or association with a therapeutically effective amount of a compound selected from the group consisting of a lipase inhibitor, an anorectic agent, a selective serotonin reuptake inhibitor, and an agent that stimulates metabolism of body fat, to said human being or animal in need thereof.

25. A method of treatment or prevention of type II diabetes in a human being or animal, which comprises administering a therapeutically effective amount of a compound according to claim 1 in combination or association with a therapeutically effective amount of an anti-diabetic agent to said human or animal in need thereof.