Substituted diazepan orexin receptor antagonists

• US 20080132490A1
• Filed: 11/30/2007
• Published: 06/05/2008
• Est. Priority Date: 12/01/2006
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Bergman, Jeffrey M., Breslin, Michael J., Cox, Christopher D., Coleman, Paul J., Mercer, Swati P., Roecker, Anthony J.
• Granted Patent: US 7,951,797 B2
• Time in Patent Office: Days
• US Class Current: 514/218
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Abstract

The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Claims

1. A compound of the formula I:

2. The compound of claim 1 of the formula Ia:

3. The compound of claim 1 of the formula Ie:

4. The compound of claim 1 wherein R¹ is phenyl, which is unsubstituted or substituted with one or more of:

(1) halogen,

(2) hydroxyl,

(3) —

O_n—

C_1-6alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(4) —

O_n-phenyl, where the phenyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(5) -heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³,

(6) —

NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected from the group consisting of;

(a) hydrogen,

(b) C_1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(7) —

S(O)₂—

NR¹⁰R¹¹,

(8) —

CO₂H,

(9) —

CN,

(10) —

NO₂, and

(11) —

B(OH)₂.

5. The compound of claim 4 wherein R¹ is phenyl, which is unsubstituted or substituted with one or more methyl, —

CF₃, halo, —

OCF₃, —

OCH₃, —

OCH₂CH₃, —

CO₂CH₃, —

CN, —

N(CH₃), —

NH(CH₂CH₃), —

NO₂, —

B(OH)₂, triazolyl or phenyl.

6. The compound of claim 5 wherein R¹ is phenyl, which is unsubstituted or substituted with one or more methyl or triazolyl.

7. The compound of claim 1 wherein R² is heteroaryl, which is unsubstituted or substituted with one or more of:

(1) halogen,

(2) hydroxyl,

(3) —

O_n—

C_1-6alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(4) —

O_n-phenyl, where the phenyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(5) -heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³,

(6) —

NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected from the group consisting of;

(a) hydrogen,

(b) C_1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(7) —

S(O)₂—

NR¹⁰R¹¹,

(8) —

CO₂H,

(9) —

CN, and

(10) —

NO₂,

with proviso that at least one of the substituents is halogen or C_1-6alkyl, or wherein two adjacent substituents are joined together to form a cycloalkyl ring.

8. The compound of claim 7 wherein R² is selected from the group consisting of:

(1) benzimidazolyl,

(2) benzothiazolyl,

(3) benzoxazolyl,

(4) cyclopentylpyrimidinyl,

(5) dihydrocyclopentapyrimidinyl,

(6) dihydroquinolinyl,

(7) furopyrimidinyl,

(8) pyrazolopyrimidinyl,

(9) pyridinyl,

(10) pyridopyrimidinyl,

(11) pyrimidinyl,

(12) quinazolinyl,

(13) quinolinyl,

(14) quinoxalinyl,

(15) tetrahydroquinazolinyl,

(16) thiadiazolyl, and

(17) thienopyrimidinyl,

which is substituted with halogen or C_1-6alkyl, and optionally substituted with hydroxyl, —

O—

C_1-6alkyl, keto, —

NH₂, or phenyl.

9. The compound of claim 8 wherein R² is selected from the group consisting of:

(1) 1,3-benzoxazol-2-yl,

(2) 2-(6,7-dihydro-5H-cyclopenta[d]pyrimidin)-yl,

(3) 2-(7,8-dihydroquinolin-5(6H)-on)-yl,

(4) 2-(furo[2,3]pyrimidine)-yl,

(5) 2-(pyrazolo[3,4]pyrimidine)-yl,

(6) 2-pyridinyl,

(7) 2-(pyrido[2,3-d]pyrimidin-7(8H)-on)-yl,

(8) 2-pyrimidinyl,

(9) 2-quinazolinyl,

(10) 2-quinoxalinyl,

(11) 2-(5,6,7,8-tetrahydroquinazolin)-yl,

(12) 2-(thieno[2,3-d]pyrimidin)-yl, and

(13) 2-(thieno[2,3]pyrimidin-4-amine)-yl,

which is substituted with methyl, chloro or fluoro.

10. The compound of claim 1 wherein one of R^2a, R^2b or R^2c is halogen or C_1-6alkyl, and the others of R^2a, R^2b and R^2c are hydrogen.

11. The compound of claim 1 wherein R³ is —

C_1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of;

(1) halogen,

(2) hydroxyl,

(3) —

C_1-6alkyl,

(4) —

(C_1-3)perfluoroalkyl,

(5) —

O—

(C_1-3)perfluoroalkyl,

(6) —

C_3-6cycloalkyl, and

(7) —

C_2-4alkenyl.

12. The compound of claim 11 wherein R³ is —

C_1-6alkyl.

13. The compound of claim 12 wherein R³ is methyl.

15. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. A method for treating a disease or disorder in which orexin receptors are involved in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 wherein the disease or disorder is selected from a sleep disorder, a sleep disturbance, decreased sleep maintenance, decreased quality of sleep, decreased REM sleep, decreased stage 2 sleep, increased fragmentation of sleep patterns, insomnia, decreased cognition, decreased memory retention, obesity, epilepsy, absence epilepsy, pain, neuropathic pain, Parkinson'"'"'s disease, psychosis and schizophrenia.

14. A compound which is selected from the group consisting of:

6-fluoro-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinazoline;

5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;

methyl 3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)benzoate;

3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)benzoic acid;

[3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)phenyl]methanol;

6,7-difluoro-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinoxaline;

5-methyl-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;

2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazoline;

2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopenta[d]pyrimidine;

2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-7,8-dihydroquinolin-5(6H)-one;

6-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}pyrido[2,3-d]pyrimidin-7(8H)-one;

5-methyl-2-(4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3]pyrimidin-4-amine;

5-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3]pyrimidine;

2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine;

(5R)-5-methyl-1-(5-methyl-4-propylpyrimidin-2-yl)-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;

(5R)-1-[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[5-methy 1-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;

(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1-[4-methyl-5-(trifluoromethyl)pyrimidin-2-yl]-1,4-diazepane;

(5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;

2-methyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}pyridin-3-yl)methanol;

4-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;

5-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;

2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazoline;

2-{(5R)-5-methyl-4-[S-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopenta[d]pyrimidine;

5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidine;

4-ethoxy-5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidine;

1,3-dimethyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;

5-bromo-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;

(5R)-5-methyl-1-[4-methyl-5-(trifluoromethyl)-pyrimidin-2-yl]-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;

(5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;

or a pharmaceutically acceptable salt thereof.

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