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1. (WO2010072722) PIPERIDINE DERIVATIVES USEFUL AS OREXIN ANTAGONISTS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims

1. A compound of formula (I)


(I) where:

Ar is pyridinyl substituted with one, two or three groups independently selected from the group consisting of C1-4alkyl, halo, C^alkoxy, haloC^alkyl, haloC^alkoxy, cyano, phenyl or a 5 or 6 membered heterocyclyl group containing 1, 2 or 3 atoms selected from N, O or S, which phenyl or heterocyclyl group is optionally substituted with C1-4alkyl, halo, C^alkoxy, haloCi_4alkyl, haloC^alkoxy or cyano;

R1 is (C1_4)alkyl, halo, halo(C1_4)alkyl, (C1_4)alkoxy, halo(C1_4)alkoxy, (C1_4)alkyl-O-( C1.

4)alkyl, CN, NR5R6 wherein R5 is H or (C1.4)alkyl and R6 is H or (C1.4)alkyl;

R2 is (C1_4)alkyl, (C1_4)alkenyl, HO(C1_4)alkyl, halo, halo(C1_4)alkyl, (C1_4)alkoxy, halo(Ci_

4)alkoxy, (C1.4)alkyl-O-(C1.4)alkyl, CN, NR7R8 wherein R7 is H or (C1.4)-alkyl and R8 is H or (Ci_4)-alkyl;

R3 is (C1.4)alkyl, halo, halo(C1.4)alkyl, (C1.4)alkoxy, halo(C1.4)alkoxy, (C1.4)alkyl-O-( C1.

4)alkyl, CN, NR9R10 wherein R9 is H or (C1.4)-alkyl and R10 is H or (C1.4)-alkyl;

R4 is (C1.4)alkyl, halo, halo(C1.4)alkyl, (C1.4)alkoxy, halo(C1.4)alkoxy, (C1.4)alkyl-O-( C1.

4)alkyl, CN, NR11R12 wherein R11 is H or (C1.4)-alkyl and R12 is H or (C1.4)-alkyl; n is O or 1; p is 0 or 1; q is O or 1; r is 0 or 1 ; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein the pyridyl group is linked to the carbonyl group by means of a bond formed between the carbon at the 2 position of the pyridyl and the carbon of said carbonyl group, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or claim 2 where Ar is substituted with one (C1. 4)alkyl group and one (C1_4)alkoxy group, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 where Ar is substituted with one methyl group and one (C1_4)alkoxy group, or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 3 where Ar is substituted with one (Ci_4)alkyl group and one propoxy, ethoxy, methoxy, methylethoxy, methylpropoxy or cyclopropylmethoxy group, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 where Ar is substituted with one methyl group and one propoxy, ethoxy, methoxy, methylethoxy, methylpropoxy or cyclopropylmethoxy group, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 or claim 2 wherein Ar is substituted with one (C1. 4)alkyl group and one phenyl group, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 7 where Ar is substituted with one methyl group and one phenyl group, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 or claim 2 where n is 0, p is 1 , q is 1 , r is 0, R2 is alkyl, R3 is alkyl and Ar is substituted with one (C1_4)alkyl group and one (C1_4)alkoxy group, or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 9 where R2 is methyl, R3 is methyl and Ar is substituted with one methyl group and one propoxy group, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 or claim 2 where n is 0, p is 1 , q is 0, r is 1 , R2 is (Ci_4)alkyl, R4 is halo and Ar is substituted with one (Ci_4)alkyl group and one phenyl group, or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11 where R2 is methyl, R4 is fluoro and Ar is substituted with one methyl group and one phenyl group, or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 or claim 2 where n is 1, p is 1, q is 0, r is 0, R1 is halo, R2 is (Ci_4)alkyl and Ar is substituted with one (Ci_4)alkyl group and one cyclopropoxymethyl group, or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 13 where R1 is chloro, R2 is methyl and Ar is substituted with one methyl group and one cyclopropoxymethyl group, or a pharmaceutically acceptable salt thereof.

15. A compound selected from: 2-[((2S)- 1 - { [3-(ethyloxy)-6-methyl-2-pyridinyl]carbonyl} -2-piperidinyl)methyl]-6-fiuoro-8-methylimidazo [ 1 ,2-a]pyridine;

6-fluoro-8-methyl-2-{[(25)-l-({6-methyl-3-[(2-methylpropyl)oxy]-2-pyridinyl}carbonyl)-2-piperidinyl]methyl}imidazo[ 1 ,2-α]pyridine;

6,8-dimethyl-2- { [(2S)- 1 -( {6-methyl-3-[(2-methylpropyl)oxy]-2-pyridinyl} carbonyl)-2-piperidinyl]methyl}imidazo[ 1 ,2-α]pyridine;

8-methyl-2-[((2S)-l-{[6-methyl-3-(propyloxy)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]imidazo[l,2-a]pyridine; 2- { [(2S)- 1 -( {3-[(cyclopropylmethyl)oxy]-6-methyl-2-pyridinyl} carbonyl)-2-piperidinyljmethyl} -8-methylimidazo[ 1 ,2-a]pyridine;

8-methyl-2-{[(2S)-l-({6-methyl-3-[(l-methylethyl)oxy]-2-pyridinyl}carbonyl)-2-piperidinyl]methyl}imidazo[ 1 ,2-a]pyridine;

2-[((2S)-I- {[4-chloro-3-(ethyloxy)-6-methyl-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]-8-methylimidazo[l,2-a]pyridine;

7,8-dimethyl-2- { [(2S)- 1 -( {6-methyl-3-[(2-methylpropyl)oxy]-2-pyridinyl} carbonyl)-2-piperidinyl]methyl}imidazo[ 1 ,2-α]pyridine;

2-{[(25)-l-({3-[(cyclopropylmethyl)oxy]-6-methyl-2-pyridinyl}carbonyl)-2-piperidinyl]methyl}-7,8-dimethylimidazo[l,2-α]pyridine; 2-[((2S)- 1 - { [3-(ethyloxy)-6-methyl-2-pyridinyl]carbonyl} -2-piperidinyl)methyl]-7,8-dimethylimidazo [ 1 ,2-α]pyridine;

7,8-dimethyl-2-[((2S)-l-{[6-methyl-3-(propyloxy)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl] imidazo [ 1 ,2-a]pyridine;

8-fluoro-2-[((25)-l-{[6-methyl-3-(propyloxy)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl] imidazo [1 ,2-α]pyridine;

8-fluoro-2-{[(25)-l-({6-methyl-3-[(2-methylpropyl)oxy]-2-pyridinyl}carbonyl)-2-piperidinyljmethyl} imidazo [ 1 ,2-α]pyridine;

2- { [(2S)- 1 -( {3 -[(cyclopropylmethyl)oxy] -6-methyl-2-pyridinyl} carbonyl)-2-piperidinyl]methyl}-8-fluoroimidazo[l,2-α]pyridine; 6,7-dimethyl-2- { [(2S)- 1 -( {6-methyl-3-[(2-methylpropyl)oxy]-2-pyridinyl} carbonyl)-2-piperidinyljmethyl} imidazo [ 1 ,2-a]pyridine;

3-chloro-2-{[(2S)-l-({3-[(cyclopropylmethyl)oxy]-6-methyl-2-pyridinyl}carbonyl)-2-piperidinyljmethyl} -8-methylimidazo[ 1 ,2-a]pyridine;

3-chloro-2-[((2S)- 1 - { [3-(ethyloxy)-6-methyl-2-pyridinyl]carbonyl} -2-piperidinyl)methyl]-8-methylimidazo [ 1 ,2-a]pyridine;

2-{[(2S)-l-({3-[(cyclopropylmethyl)oxy]-6-methyl-2-pyridinyl}carbonyl)-2-piperidinyl]methyl} -3 ,8-dimethylimidazo[ 1 ,2-a]pyridine;

2-[((2S)-I- {[6-ethyl-3-(ethyloxy)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]-7,8-dimethylimidazo [ 1 ,2-a]pyridine; 6-fluoro-8-methyl-2-({(25)-l-[(6-methyl-3-phenyl-2-pyridinyl)carbonyl]-2-piperidinyl}methyl)imidazo[l,2-α]pyridine;

7,8-dimethyl-2-[((2S)-l-{[6-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-2-pyridinyl]carbonyl} -2-piperidinyl)methyl]imidazo[ 1 ,2-a]pyridine;

7,8-dimethyl-2-[((2S)-l-{[6-methyl-3-(5-methyl-l,3-oxazol-2-yl)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl] imidazo [ 1 ,2-a]pyridine;

2-[((2S)- 1 - { [3-(5-ethyl- 1 ,3-oxazol-2-yl)-6-methyl-2-pyridinyl]carbonyl} -2-piperidinyl)methyl]-7,8-dimethylimidazo[ 1 ,2-a]pyridine;

7,8-dimethyl-2-[((2S)-l-{[6-methyl-3-(2-pyrimidinyl)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]imidazo[ 1 ,2-a]pyridine;

7,8-dimethyl-2-[((2S)-l-{[6-methyl-3-(3-methyl-5-isoxazolyl)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]imidazo[l,2-a]pyridine; 7,8-dimethyl-2-[((2S)-l-{[6-methyl-3-(4-methyl-l,3-thiazol-2-yl)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]imidazo[l ,2-a]pyridine; and

6-fluoro-8-methyl-2-[((25)-l-{[6-methyl-3-(2-pyrimidinyl)-2-pyridinyl]carbonyl}-2-piperidinyl)methyl]imidazo[l,2-α]pyridine; or a pharmaceutically acceptable salt thereof.

16. The compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in therapy.

17. The compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder where an antagonist of a human orexin receptor is required.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a sleep disorder, a depression or mood disorder, an anxiety disorder, a substance-related disorder or a feeding disorder.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a sleep disorder.

20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein the sleep disorder is selected from the group consisting of Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; Sleep Apnea and Jet-Lag Syndrome.

21. Use of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder where an antagonist of a human orexin receptor is required.

22. Use according to claim 21 where the disease or disorder is a sleep disorder, a depression or mood disorder, an anxiety disorder, a substance-related disorder or a feeding disorder.

23. Use according to claim 22 wherein the disease or disorder is a sleep disorder.

24. Use according to claim 23 where the sleep disorder is selected from the group consisting of Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; Sleep Apnea and Jet-Lag Syndrome.

25. A method for the treatment of a disease or disorder where an antagonist of a human orexin receptor is required, in a subject in need thereof, comprising administering to said subject an effective amount of a compound as defined in any one claims 1 to 15, or a pharmaceutically acceptable salt thereof.

26. A method according to claim 25 where the disease or disorder is a sleep disorder, a depression or mood disorder, an anxiety disorder, a substance-related disorder or a feeding disorder.

27. A method according to claim 26 where the disease or disorder is a sleep disorder.

28. A method according to claim 27 where the sleep disorder is selected from the group consisting of Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; Sleep Apnea and Jet-Lag Syndrome.

29. A pharmaceutical composition comprising a) the compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers.