IP Library Granted Patent US 9,156,829
Granted Patent B2
US 9,156,829 · App. 14/625,812 · Granted Oct 13, 2015

Cycloalkyl and heterocycloalkyl compounds as orexin receptor antagonists

Inventors: Charlotte Fieldhouse (Cambridge, GB); Angela Glen (Cambridge, GB); Stephanie Maine (Cambridge, GB); Tatsuhiko Fujimoto (Kanagawa, JP); John Stephen Robinson (Cambridge, GB)
Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED
C07D413/12A61K31/44A61K31/4439A61K31/497A61K31/4965A61K31/505A61K31/506A61K45/06C07D213/74C07D239/42C07D241/20C07D401/12C07D403/12
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Quick Facts
Patent No.
US 9,156,829
App. No.
14/625,812
Granted
Oct 13, 2015
Kind
B2
Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein L, X, R a , R b , R 1 , R 2 and R 3 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Claims (284)

1. A compound of formula

wherein

R 1 represents a 5- or 6-membered heteroaryl group optionally substituted by at least one substituent selected from halogen, cyano, hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkoxycarbonylamino, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, —NR 4 R 5 , C 3 -C 6 cycloalkylamino, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkylcarbonylamino, sulphonamido, C 1 -C 3 alkylsulphonyl, C 1 -C 3 alkylsulphonylamino and —C(O)NR 6 R 7 ;

L represents a bond, CH 2 , O or NR 12 ;

R a represents a hydrogen atom or a C 1 -C 3 alkyl or C 1 -C 3 haloalkyl group;

R b represents a hydrogen atom or a C 1 -C 3 alkyl or C 1 -C 3 haloalkyl group;

X represents CH 2 , CHF or CF 2 ;

R 2 represents a hydrogen atom or a C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group;

R 3 represents a phenyl group or a 5- or 6-membered heteroaryl group, all optionally substituted by at least one substituent independently selected from halogen, hydroxyl, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyl, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, —NR 8 R 9 , —C(O)NR 10 R 11 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylmethyl or a 5- or 6-membered heteroaryl group, the heteroaryl group itself being optionally substituted by at least one substituent independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy;

R 4 and R 5 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 4 and R 5 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl and C 1 -C 3 alkoxy;

R 6 and R 7 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 6 and R 7 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen and hydroxyl;

R 8 and R 9 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 8 and R 9 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl and C 1 -C 3 alkoxy;

R 10 and R 11 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 10 and R 11 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen and hydroxyl; and

R 12 represents a hydrogen atom, methyl group or a C 2 -C 3 alkylene chain that links to R 1 to form a 5- or 6-membered ring;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R 1 represents a 5- or 6-membered heteroaryl group containing one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the heteroaryl group being optionally substituted by one or two substituents independently selected from halogen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl.

3. A compound according to claim 1 , wherein R 1 represents a 5- or 6-membered heteroaryl group selected from pyridinyl, pyrimidinyl and pyrazinyl, all optionally substituted as defined in claim 1 .

4. A compound according to claim 3 , wherein R 1 represents a group selected from:

(i) 4-(trifluoromethyl)pyridin-2-yl,

(ii) 5-(trifluoromethyl)pyridin-2-yl,

(iii) 5-(trifluoromethoxy)pyridin-2-yl,

(iv) 6-(trifluoromethyl)pyridin-2-yl,

(v) 6-(trifluoromethyl)pyridin-3-yl,

(vi) 5-chloropyridin-2-yl,

(vii) 5-bromopyridin-2-yl,

(viii) 3-fluoro-5-(trifluoromethyl)pyridin-2-yl,

(ix) 3-chloro-5-(trifluoromethyl)pyridin-2-yl,

(x) 3-bromo-5-(trifluoromethyl)pyridin-2-yl,

(xi) 5-bromo-3-methoxypyridin-2-yl,

(xii) 3-methyl-5-(trifluoromethyl)pyridin-2-yl,

(xiii) 5-(trifluoromethyl)pyrimidin-2-yl,

(xiv) 5-ethylpyrimidin-2-yl,

(xv) 5-(trifluoromethyl)pyrazin-2-yl,

(xvi) 5-chloropyrazin-2-yl,

(xvii) 5-(ethyl)pyrazin-2-yl,

(xviii) 5-(cyclopropyl)pyrazin-2-yl,

(xix) 5-(isopropyl)pyrazin-2-yl,

(xx) 3-methyl-5-(trifluoromethyl)pyrazin-2-yl,

(xxi) 3-ethyl-5-(trifluoromethyl)pyrazin-2-yl,

(xxii) 3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl, and

(xxiii) 3-isopropyl-5-(trifluoromethyl)pyrazin-2-yl.

5. A compound according to claim 1 , wherein X represents CH 2 .

6. A compound according to claim 1 , wherein L represents NH.

7. A compound according to claim 1 , wherein R 2 represents a hydrogen atom.

8. A compound according to claim 1 , wherein R 3 represents a 5- or 6-membered heteroaryl group selected from pyridinyl, pyrimidinyl and pyrazinyl, all optionally substituted as defined in claim 1 .

9. A compound according to claim 1 , wherein R 3 represents a phenyl group optionally substituted by at least one substituent independently selected from fluorine, chlorine, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or a 5- or 6-membered heteroaryl group, the heteroaryl group itself being optionally substituted by one or two substituents independently selected from C 1 -C 2 alkyl, C 1 -C 2 alkoxy and C 1 -C 2 haloalkoxy.

10. A compound according to claim 1 , wherein R 3 represents a group selected from:

(i) 2-fluorophenyl,

(ii) 2-chlorophenyl,

(iii) 2-methylphenyl,

(iv) 2-cyclopropylphenyl,

(v) 2-methoxyphenyl,

(vi) 2-ethoxyphenyl,

(vii) 2-(difluoromethoxy)phenyl,

(viii) 3-methylphenyl,

(ix) 3-methoxyphenyl,

(x) 2,6-difluorophenyl,

(xi) 2,6-dichlorophenyl,

(xii) 2,6-dimethoxyphenyl,

(xiii) 2,6-diethoxyphenyl,

(xiv) 2-ethoxy-5-methylphenyl,

(xv) 2,5-dimethoxyphenyl,

(xvi) 2-fluoro-6-methoxyphenyl,

(xvii) 5-fluoro-2-methoxyphenyl,

(xviii) 3-fluoro-2-methoxyphenyl,

(xix) 2-(1H-1,2,4-triazol-1-yl)phenyl,

(xx) 2-(2H-1,2,3-triazol-2-yl)phenyl,

(xxi) 5-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl,

(xxii) 5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,

(xxiii) 5-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl,

(xxiv) 5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,

(xxv) 2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,

(xxvi) 2-(pyrimidin-2-yl)phenyl,

(xxvii) 5-fluoro-2-(pyrimidin-2-yl)phenyl,

(xxviii) 2-(1H-pyrazol-1-yl)phenyl,

(xxix) 2-(1H-imidazol-1-yl)phenyl,

(xxx) 2-(1H-1,2,3-triazol-1-yl)phenyl,

(xxxi) 2-(pyrimidin-2-yl)-5-fluorophenyl,

(xxxii) 2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl,

(xxxiii) 2-methoxy-5-methylphenyl,

(xxxiv) 2-chloro-6-(2H-1,2,3-triazol-2-yl)phenyl,

(xxxv) 2-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl,

(xxxvi) 5-trifluoromethyl-2-(2H-1,2,3-triazol-2-yl)phenyl,

(xxxvii) 2-fluoro-6-(pyrazol-1-yl)phenyl,

(xxxviii) 5-fluoro-2-(pyrazol-1-yl)phenyl,

(xxxix) 5-methyl-2-(pyrazol-1-yl)phenyl,

(xl) 2-bromo-6-methoxyphenyl,

(xli) 2-methoxy-6-(pyrazol-1-yl)phenyl,

(xlii) 5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl,

(xliii) 3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,

(xliv) 5-trifluoromethyl-2-(1H-1,2,3-triazol-1-yl)phenyl,

(xlv) 5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl,

(xlvi) 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)phenyl,

(xlvii) 5-cyclopropyl-2-(2H-1,2,3-triazol-2-yl)phenyl,

(xlviii) 5-chloro-2-(pyrazol-1-yl)phenyl,

(xlix) 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,

(l) 2-(difluoromethyl)phenyl,

(li) 2-(trifluoromethyl)phenyl,

(lii) 3,6-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,

(liii) 2-cyclopropyl-6-fluorophenyl,

(liv) 2-(5-ethoxypyrimidin-2-yl)phenyl,

(lv) 3-(pyrimidin-2-yl)pyridin-2-yl,

(lvi) 3-ethoxy-6-methylpyridin-2-yl,

(lvii) 3-(pyrazol-1-yl)pyridin-2-yl,

(lviii) 3-(piperidin-1-yl)pyridin-2-yl,

(lix) 3-(trifluoromethoxy)pyridin-2-yl,

(lx) 3-(ethoxy)pyridin-2-yl,

(lxi) 3-(cyclopropyl)pyridin-2-yl,

(lxii) 3-chloropyridin-2-yl,

(lxiii) 3-bromopyridin-2-yl,

(lxiv) 3-methoxypyridin-2-yl,

(lxv) 3-(propan-2-yloxy)pyridin-2-yl,

(lxvi) 6-bromo-3-methoxypyridin-2-yl,

(lxvii) 3-methoxy-6-methylpyridin-2-yl, and

(lxviii) 3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl.

11. A compound of formula (I) as defined in claim 1 selected from the group consisting of:

2,6-Dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2,6-Dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]benzamide;

5-Methyl-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-[(5-Ethylpyrimidin-2-yl)amino]cyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-[(5-Chloropyridin-2-yl)amino]cyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

5-Methyl-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

5-Methyl-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-[(5-Chloropyrazin-2-yl)amino]cyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

5-Fluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2-(1H-Pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2-(Pyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

5-Fluoro-2-(pyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2R)-2-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[4-(trifluoromethyl)pyridin-2-yl]oxy}cyclopentyl]benzamide;

2,6-Dimethoxy-N-[(1S,2S)-2-{[4-(trifluoromethyl)pyridin-2-yl]oxy}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-(2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-(2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)benzamide;

5-Methyl-2-(2H-1,2,3-triazol-2-yl)-N-(2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)benzamide;

2,6-Dimethoxy-N-[(1S,2S)-2-{[6-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

3-Bromo-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

2-Ethoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-Ethoxy-6-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

2-(1H-Pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Fluoro-6-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2,6-Difluoro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2,6-Dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(1H-1,2,3-Triazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Fluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(Pyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Fluoro-2-(pyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Chloro-6-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Fluoro-2-(1H-1,2,3-triazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Methyl-2-(1H-1,2,3-triazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-(1H-Pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

2-(5-M ethyl-1,3,4-oxadiazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(2H-1,2,3-Triazol-2-yl)-5-(trifluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Fluoro-6-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Fluoro-2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Methyl-2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Bromo-6-methoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Methoxy-6-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-(Piperidin-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

5-Chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-Fluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(1H-1,2,3-Triazol-1-yl)-5-(trifluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Chloro-2-(1H-1,2,3-triazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2,3-Difluoro-6-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Cyclopropyl-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-(Trifluoromethoxy)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

5-Chloro-2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-Ethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

3,5-Difluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(Trifluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-Cyclopropyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

3,6-Difluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-(Difluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Cyclopropyl-6-fluoro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

5-Methyl-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[6-(trifluoromethyl)pyridin-3-yl]amino}cyclopentyl]benzamide;

N-Cyclobutyl-2,6-dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2-Chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2-Chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]benzamide;

2-Fluoro-6-methoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

2,6-Difluoro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-{Methyl[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

5-Fluoro-N-[(1S,2S)-2-{methyl[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

2-Fluoro-N-[(1S,2S)-2-{methyl[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-6-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(pyrimidin-2-yl)benzamide;

5-Fluoro-N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(pyrimidin-2-yl)benzamide;

N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1R,2R)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

5-Fluoro-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(1H-pyrazol-1-yl)pyridine-2-carboxamide;

3-Ethoxy-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide,

2-Chloro-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-6-(2H-1,2,3-triazol-2-yl)benzamide;

2,6-Difluoro-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

3-Cyclopropyl-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(trifluoromethoxy)pyridine-2-carboxamide;

N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(pyrimidin-2-yl)benzamide;

5-Chloro-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(2-Methyl-2-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

5-Chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

3-Fluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

3,5-Difluoro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

3-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

3-(1H-Pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide;

2-Fluoro-6-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

N-(2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}-2-methylcyclopentyl)-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Bromo-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-(Propan-2-yl)-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-[(5-Cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[5-(Propan-2-yl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-[(5-Ethylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclopentyl]benzamide;

5-Chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-[(5-Bromopyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-[(5-Bromo-3-methoxypyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

2-(2H-1,2,3-Triazol-2-yl)-N-[(1S,2S)-2-{[4-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-(4,4-Difluoro-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(4,4-Difluoro-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(4,4-Difluoro-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-4,4-Difluoro-2-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-4,4-Difluoro-2-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

2-Fluoro-6-methoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(pyrimidin-2-yl)benzamide;

5-Fluoro-N-[(1S,2S)-2-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(pyrimidin-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide;

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

N-[(1S,2S)-2-{[3-Cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

N-(2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}-2-methylcyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide;

N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(pyrimidin-2-yl)benzamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl)-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;

N-(2-Methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

N-[(1S,2S)-2-{[5-(Difluoromethoxy)pyridin-2-yl]amino}-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-5-fluoro-2-(pyrimidin-2-yl)benzamide;

N-[(1S,2S)-2-{[3-Methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide;

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide;

enantiomers thereof and pharmaceutically acceptable salts of any of the foregoing.

12. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 , which comprises

(i) reacting a compound of formula

wherein L, X, R a , R b , R 1 and R 2 are as defined in formula (I), with a compound of formula

wherein R 20 represents a halogen atom or a hydroxyl group and R 3 is as defined in formula (I), or a salt thereof; or

(ii) when L represents NH or N(CH 3 ), reacting a compound of formula

wherein R 25 represents a hydrogen atom or methyl group and X, R a , R b , R 2 and R 3 are as defined in formula (I), with a compound of formula (V), R 1 -LG 1 , wherein LG 1 represents a leaving group and R 1 is as defined in formula (I);

and optionally thereafter carrying out one or more of the following procedures:

converting a compound of formula (I) into another compound of formula (I)

removing any protecting groups

forming a pharmaceutically acceptable salt.

13. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 , in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

14. A composition according to claim 13 , wherein the one or more other therapeutic agents are selected from carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone and lithium.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in treating schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in treating post-traumatic stress disorder, panic disorders or addiction.

17. A compound of formula (I) as defined in claim 1 , wherein the compound is N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide, enantiomers thereof and pharmaceutically acceptable salts of any of the foregoing.

18. A compound of formula (I) as defined in claim 1 , wherein the compound is N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide, enantiomers thereof and pharmaceutically acceptable salts of any of the foregoing.

19. A compound of formula (I) as defined in claim 1 , wherein the compound is N-[(1S,2S)-2-Methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide and pharmaceutically acceptable salts thereof.

20. A compound of formula (I) as defined in claim 1 , wherein the compound is N-[(1S,2S)-2-{[3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide and pharmaceutically acceptable salts thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 6, 2015
From: FIELDHOUSE, CHARLOTTE; GLEN, ANGELA; MAINE, STEPHANIE; FUJIMOTO, TATSUHIKO; ROBINSON, JOHN STEPHEN
To: TAKEDA PHARMACEUTICAL COMPANY LIMITED
Reel/Frame 035100/0464 →
Priority Claims (1)
EP 14156011 · Feb 20, 2014 · regional
Continuity (1)
Related Publication 20150232460A1 · Aug 20, 2015