AZACYCLYLISOQUINOLINONE AND ISOINDOLINONE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS

• US 20090069370A1
• Filed: 09/11/2008
• Published: 03/12/2009
• Est. Priority Date: 09/12/2007
• Status: Abandoned Application

• Current Assignee: Wyeth LLC (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Gross, Jonathan Laird, Robichaud, Albert Jean, Zhou, Dahui
• Application Number:
  US12/208,780
• Publication Number:
  US 20090069370A1
• Time in Patent Office: Days
• US Class Current: 514/308
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

Claims

1. A compound of formula I

2. The compound of claim 1 wherein n is 1 or 2.

3. The compound of claim 1 wherein R¹ is optionally substituted cycloalkyl.

4. The compound of claim 1 wherein R¹ is C₁-C₄ alkyl.

5. The compound of claim 1 wherein R¹ is a C₃-C₆ cycloalkyl.

6. The compound of claim 1 having the structure of formula Ix:

7. The compound of claim 1 having the structure of formula Ia

8. The compound of claim 1 wherein the azacyclic ring is attached at the 3-position of said azacyclic ring.

9. The compound of claim 1 wherein m is 1.

10. The compound of claim 7 wherein the azacyclic ring is attached at the 3-position of said azacyclic ring;

R⁷ is CONR⁹R¹⁰; and

R⁸ is H.

11. The compound of claim 1 wherein R² is an optionally substituted aminocarbonylphenyl or cycloheteroalkylcarbonylphenyl group.

12. The compound of claim 1 wherein X is (CR³R⁴)_p and p is 0.

13. The compound of claim 1 wherein R² is selected from the group consisting of methyloxycarbonylphenyl, carboxyphenyl, aminocarbonylphenyl, alkylaminocarbonylphenyl, cycloalkylaminocarbonylphenyl, N,N-dialkylaminocarbonylphenyl, carboxyphenylalkyl, aminocarbonylphenylalkyl, alkylaminocarbonylphenylalkyl, N,N-dialkylaminocarbonylphenylalkyl, cycloalkylaminocarbonylphenylalkyl, cyanophenyl, cycloheteroalkylcarbonylphenyl, aminocarbonylhalophenyl, alkylaminocarbonylhalophenyl, N,N-dialkylaminocarbonylhalophenyl, cycloheteroalkylcarbonylhalophenyl, halophenyl, phenyl, dihalophenyl, alkylaminocarbonylhalophenyl, pyrrolidine-1-carbonylphenyl, and aminoalkoxyalkyl.

14. The compound of claim 1 selected from the group consisting essentially of:

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}benzoic acid;

Methyl 4-{[2-(1-cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}benzoate;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}benzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N-methylbenzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N-ethylbenzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N-isopropylbenzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N-cyclopropylbenzamide;

N-Cyclobutyl-4-{[2-(1-cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}benzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N-cyclopentylbenzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N,N-dimethylbenzamide;

4-{[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}-N,N-diethylbenzamide;

2-(1-Cyclobutylpiperidin-4-yl)-6-[4-(pyrrolidin-1-ylcarbonyl)phenoxy]-3,4-dihydroisoquinolin-1(2H)-one;

Methyl 4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)benzoate;

4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)benzoic acid;

4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)benzamide;

4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)-N-methylbenzamide;

4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)-N-ethylbenzamide

4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)-N,N-dimethylbenzamide;

N-Cyclobutyl-4-({[2-(1-cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)benzamide;

2-(1-Cyclobutylpiperidin-4-yl)-6-{[4-(pyrrolidin-1-ylcarbonyl)benzyl]oxy}-3,4-dihydroisoquinolin-1(2H)-one;

4-({[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]oxy}methyl)-N-cyclopentylbenzamide;

4-(1-Oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindol-5-yl)benzonitrile;

4-[2-(1-Methylpiperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]benzonitrile;

4-[2-(1-Ethylpiperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]benzonitrile;

4-[1-Oxo-2-(1-propylpiperidin-4-yl)-2,3-dihydro-1H-isoindol-5-yl]benzonitrile;

4-{2-[1-(Cyclopropylmethyl)piperidin-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}benzonitrile;

4-{2-[1-(Cyclopentylmethyl)piperidin-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}benzonitrile;

4-[2-(1-Cyclobutylpiperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]benzonitrile;

4-[2-(1-Cyclopentylpiperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]benzonitrile;

4-[2-(1-Cyclohexylpiperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]benzonitrile;

4-({2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}oxy)benzoic acid;

4-({2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}oxy)-N-methylbenzamide;

4-({2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}oxy)-N-ethylbenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenoxy]-3,4-dihydroisoquinolin-1(2H)-one;

4-({2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}oxy)benzoic acid;

4-({2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}oxy)-N-methylbenzamide;

4-({2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}oxy)-N-ethylbenzamide;

2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenoxy]-3,4-dihydroisoquinolin-1(2H)-one;

4-{2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-methylbenzamide;

4-{2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-ethylbenzamide;

2-[(3R)-1-cyclopentylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-methylbenzamide;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-ethylbenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-(cyclopentylmethyl)pyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-methylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-(cyclopropylmethyl)pyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-(furan-3-ylmethyl)pyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclohexylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-(furan-2-ylmethyl)pyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-2-[(3R)-1-(thiophen-2-ylmethyl)pyrrolidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-(1-methylethyl)pyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-(1-cyclobutylpiperidin-4-yl)-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-piperidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-(1-cyclopentylpiperidin-4-yl)-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclopentylpiperidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpiperidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-(2-fluoro-4-{[(2S)-2-methylpyrrolidin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquinolin-1(2H)-one;

N-cyclobutyl-4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-3-fluorobenzamide;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-3-fluoro-N-methylbenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-(2-fluoro-4-{[(2R)-2-methylpyrrolidin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquinolin-1(2H)-one;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-ethyl-3-fluorobenzamide;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-3-fluoro-N,N-dimethylbenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-cyclopentyl-3-fluorobenzamide;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-cyclopropyl-3-fluorobenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-[4-fluoro-3-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-[3-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

6-[3-chloro-4-(pyrrolidin-1-ylcarbonyl)phenyl]-2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one;

2-(1-isopropylpiperidin-4-yl)-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-isopropylpiperidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-[3-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N,N-dimethylbenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-N-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-(pyrrolidin-1-ylcarbonyl)-3,4-dihydroisoquinolin-1(2H)-one;

N-ethyl-3-fluoro-4-{2-[(3R)-1-isopropylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}benzamide;

3-fluoro-4-{2-[(3R)-1-isopropylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-methylbenzamide;

N-ethyl-4-{2-[(3R)-1-isopropylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}benzamide;

6-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl]-2-[(3R)-1-isopropylpyrrolidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-phenyl-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-6-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]isoindolin-1-one;

4-{2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-methylbenzamide;

2-[(3R)-1-cyclobutylpyrrolidin-3-yl]-3,3′

,4,4′

-tetrahydro-6,6′

-biisoquinoline-1,1′

(2H,2′

H)-dione;

2-[(3R)-1-benzylpyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(³R)-pyrrolidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

4-{2-[(3S)-1-cyclobutylpyrrolidin-3-yl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-N-methylbenzamide;

2-(1-benzylpiperidin-4-yl)-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

2-[(3R)-1-benzylpiperidin-3-yl]-6-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-3,4-dihydroisoquinolin-1(2H)-one;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-isopropylbenzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-cyclopropylbenzamide;

(R)—

N-cyclobutyl-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide;

(R)-6-(4-(azetidine-1-carbonyl)phenyl)-2-(1-cyclobutylpyrrolidin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(2-fluoroethyl)benzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(2-methoxyethyl)benzamide;

4-(2-((R)-1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N—

((S)-1-methoxypropan-2-yl)benzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(2-isopropoxyethyl)benzamide;

(R)-2-(1-cyclobutylpyrrolidin-3-yl)-6-(4-(morpholine-4-carbonyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;

(R)-2-(1-cyclobutylpyrrolidin-3-yl)-6-(4-(piperidine-1-carbonyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;

(R)-2-(1-cyclobutylpyrrolidin-3-yl)-6-(2-fluoro-4-(piperidine-1-carbonyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;

(R)-2-(1-cyclobutylpyrrolidin-3-yl)-6-(2-fluoro-4-(morpholine-4-carbonyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-fluoro-N-(2-isopropoxyethyl)benzamide;

4-(2-((R)-1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-fluoro-N—

((S)-1-methoxypropan-2-yl)benzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-fluoro-N-(2-methoxyethyl)benzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-fluoro-N-(2-fluoroethyl)benzamide;

(R)—

N-cyclobutyl-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-fluorobenzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-cyclopropyl-3-fluorobenzamide;

(R)-4-(2-(1-cyclobutylpyrrolidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-fluoro-N-isopropylbenzamide;

(R)-6-(4-(azetidine-1-carbonyl)-2-fluorophenyl)-2-(1-cyclobutylpyrrolidin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one;

a stereoisomer thereof; and

a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1.

15. A method for the treatment of a patient suffering from a cognitive disorder related to or affected by the Histamine-3 (H₃) receptor comprising administering to the patient a compound of formula I

16. The method of claim 15, wherein said disorder is a neurodegenerative disorder.

18. The method of claim 15, wherein said disorder is selected from the group consisting of:

Alzheimer'"'"'s disease, attention deficit disorder, schizophrenia, cognitive dysfunction in schizophrenia, Parkinsons'"'"' disease, frontal temporal dementia or depression.

17. The method of 15, wherein said disorder is mild cognitive impairment (MCI), dementia, delirium, amnestic disorder, Alzheimer'"'"'s disease (AD), Parkinson'"'"'s disease (PD), Huntington'"'"'s disease (HD), memory disorder, memory deficits associated with depression, schizophrenia, a psychotic disorder, paranoia, mano-depressive illness, attention deficit hyperactivity disorder (ADHD), dyslexia, developmental disorders, Down'"'"'s syndrome, Fragile X syndrome, loss of executive function, loss of learned information, vascular dementia, cognitive decline, neurodegenerative disorder, HIV-induced dimentia, head trauma, Pick'"'"'s disease, Creutzfeldt-Jakob disease, Body dementia, vascular dementia, surgical procedure-induced cognitive dysfunction, traumatic brain injury or stroke.

20. A process for the preparation of a compound of formula Ia′