SPIROPIPERIDINE BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

• US 20100069419A1
• Filed: 10/29/2007
• Published: 03/18/2010
• Est. Priority Date: 10/30/2006
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Nomland, Ashley, Hills, Ivory D., Stauffer, Shaun R.
• Granted Patent: US 8,293,759 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present invention is directed to spiropiperidine compounds of formula (I)

which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer'"'"'s disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

Claims

1. A compound of formula (I):

2. A compound of claim 1, wherein X¹ is N.

3. A compound of claim 1, wherein X² is NR^1AR^1B, wherein R^1A and R^1B are linked together with the nitrogen to which they are attached to form a ring structure comprising three to nine ring carbon atoms, wherein one or more of said ring carbon atoms is optionally substituted with one or more

(a) halo,

(b) —

C_1-10 alkyl

(c) —

C_3-12 cycloalkyl,

(d) —

O—

C_1-10 alkyl,

(e) —

C_0-6 alkyl-aryl,

wherein said alkyl, cycloalkyl or aryl moiety is optionally substituted with one or more

(i) halo,

(ii) —

C_1-6 alkyl,

(iii) —

OC_1-6 alkyl, or

(iv) —

C_1-6 haloalkyl.

4. A compound of claim 1, wherein X² is NR^1AR^1B, wherein R^1A and R^1B are each optionally substituted C_1-10 alkyl , or R^1A is aryl and R^1B is optionally substituted C_1-10 alkyl.

5. A compound of claim 1, wherein R² is aryl, which is optionally substituted with one or more

(a) halo,

(b) —

OH,

(c) —

CN,

(d) —

C_1-10 alkyl,

(e) —

C_3-12 cycloalkyl,

(f) —

O—

C_1-10 alkyl, and

(g) —

C_0-6 alkyl-aryl, wherein said aryl is optionally substituted with one or more

(i) halo, and

(ii) —

OH, and

(h) —

C_0-6 alkyl-heteroaryl.

6. A compound of claim 1, wherein Q is —

CH₂—

, and R³ is selected from the group consisting of

(1) —

C_1-10 alkyl,

(2) —

C_2-10 alkynyl,

(3) —

C_3-12 cycloalkyl,

(4) aryl, and

(5) heteroaryl,

wherein said alkyl, cycloalkyl, alkynyl, aryl or heteroaryl R³ moiety is optionally substituted with one or more

(a) halo,

(b) —

OH,

(c) —

C_1-10 alkyl,

(d) —

C_3-12 cycloalkyl, or

(e) —

O—

C_1-10 alkyl.

7. A compound of claim 1, wherein R⁴ is —

C_1-10 alkyl or —

C_3-4 alkenyl.

8. A compound of claim 7, wherein R⁴ is methyl.

9. A compound of claim 1, wherein the compound of formula (I) is a compound of formula (II):

10. A compound of claim 9, wherein X¹ is N.

11. A compound of claim 9, wherein R^1A and R^1B are linked together with the nitrogen to which they are attached to form a ring structure comprising four to nine ring carbon atoms, wherein one or more of said ring carbon atoms is optionally substituted with one or more

(a) halo,

(b) —

C_1-10 alkyl

(c) —

C_3-12 cycloalkyl,

(d) —

O—

C_1-10 alkyl,

(e) —

C_0-6 alkyl-aryl,

wherein said alkyl, cycloalkyl or aryl moiety is optionally substituted with one or more

(i) halo,

(ii) —

C_1-6 alkyl,

(iii) —

OC_1-6 alkyl, or

(iv) —

C_1-6 haloalkyl.

12. A compound of claim 1, which is selected from the group consisting of

trans-4-azetidin-1-yl-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-4-azetidin-1-yl-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-pyrrolidin-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-(2-methylpyrrolidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-piperidin-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-4-(3,3-difluoroazetidin-1-yl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-(2-phenylazetidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-pyrrolidin-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-(3-methylpyrrolidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-4-[3-(fluoromethyl)pyrrolidin-1-yl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-4-(3-cyclohexylpyrrolidin-1-yl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-(3-phenylpyrrolidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-4-(3-benzylpyrrolidin-1-yl)-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-4-(1,3-dihydro-2H-isoindol-2-yl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-(2-methylpyrrolidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-(2-propylpyrrolidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-(2-phenylpyrrolidin-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-4-(2-benzylpyrrolidin-1-yl)-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-[2-(2-phenylethyl)pyrrolidin-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-4-piperidin-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-4-(2-azabicyclo[2.2.1]hept-2-yl)-8-but-2-ynyl-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-4-[2RS-(3-methoxyphenyl)pyrrolidin-1-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-but-2-yn-1-yl-1-(3-fluorophenyl)-4-[2RS-(3-methoxyphenyl)pyrrolidin-1-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-4-[2RS-(3-isobutylphenyl)pyrrolidin-1-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one; and

(5R,7S)-8-but-2-yn-1-yl-1-(3-fluorophenyl)-4-[2RS-(3-isobutylphenyl)pyrrolidin-1-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-4-pyrrolidin-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-(4,4-difluoropiperidin-1-yl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(2-benzylpyrrolidin-1-yl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(2-benzylpyrrolidin-1-yl)-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

Trans-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-4-[2-(2-methylbenzyl)pyrrolidin-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-4-[2-(3-chlorobenzyl)pyrrolidin-1-yl]-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-4-[2-(3-methoxybenzyl)pyrrolidin-1-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-4-[2-(4-chlorobenzyl)pyrrolidin-1-yl]-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-(cyclobutylmethyl)-4-[2-(2-fluorobenzyl)pyrrolidin-1-yl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[2-(2-chlorobenzyl)pyrrolidin-1-yl]-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(2-benzylpyrrolidin-1-yl)-1-(3-bromophenyl)-8-(cyclobutylmethyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(2-benzylpyrrolidin-1-yl)-1-(3-chlorophenyl)-8-(cyclobutylmethyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

trans-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-4-phenyl-1,8-diazaspiro[4.5]dec-3-en-2-one;

or a pharmaceutically acceptable salt thereof

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method of treating Alzheimer'"'"'s disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, and a pharmaceutically acceptable carrier.

15. A method for the manufacture of a medicament or a composition for treating Alzheimer'"'"'s Disease in a patient in need thereof, comprising combining a compound of claim 1 or a pharmaceutically acceptable salt thereof, with a pharmaceutical carrier or diluent.