Compounds for the reduction of beta-amyloid production

• US 8,637,525 B2
• Filed: 01/25/2011
• Issued: 01/28/2014
• Est. Priority Date: 07/31/2009
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Boy, Kenneth M., Guernon, Jason M., Macor, John E., Olson, Richard E., Shi, Jianliang, Thompson, Lorin A. III, Wu, Yong-Jin, Xu, Li, Zhang, Yunhui, Zuev, Dmitry S.
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US13/013,373
• Publication Number:
  US 20120028994A1
• Time in Patent Office: 1,099 Days
• Field of Search: 514/258.1, 514/383, 544/253
• US Class Current: 514/258.1
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/052 the oxygen-containing ring being six-membered
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 491/113 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The present disclosure provides a series of compounds of the formula (I)

• • which modulate β-amyloid peptide (β-AP) production and are useful in the treatment of Alzheimer'"'"'s Disease and other conditions affected by β-amyloid peptide (β-AP) production.

Claims

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

7-(4-fluorophenyl)-N2-(3-methoxy-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(2-methoxyphenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-fluorophenyl)-N2-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(2-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(2-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-chloro-2-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(3-methoxyphenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-(dimethylamino)phenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(2-fluoro-4-(trifluoromethyl)phenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(2-fluoro-4-(trifluoromethoxy)phenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(4-(6-chloropyrimidin-4-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; and

N2-(4-(2-chloropyridin-4-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine.

2. A pharmaceutical composition for treating disorders responsive to reduction of β

-amyloid peptide production comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or diluents, which is selected from the group consisting of;

7-(4-fluorophenyl)-N2-(3-methoxy-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(2-methoxyphenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-fluorophenyl)-N2-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(2-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(2-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-chloro-2-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(3-methoxyphenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(4-(dimethylamino)phenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(2-fluoro-4-(trifluoromethyl)phenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

7-(2-fluoro-4-(trifluoromethoxy)phenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;

N2-(4-(6-chloropyrimidin-4-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; and

N2-(4-(2-chloropyridin-4-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine.

3. A method for treating disorders responsive to reduction of β

-amyloid peptide production in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 wherein said disorder is selected from Alzheimer'"'"'s Disease (AD), Down Syndrome, mild cognitive impairment (MCI), cerebral amyloid angiopathy (CAA), dementia with Lewy bodies (DLB), amyotrophic lateral sclerosis (ALS-D), inclusion body myositis (IBM), age-related macular degeneration, and cancer.

5. The method of claim 4 wherein said disorder is selected from Alzheimer'"'"'s disease and Down Syndrome.