JPWO2021080013A5

JPWO2021080013A5 -

Info

Publication number: JPWO2021080013A5
Application number: JP2022523359A
Authority: JP
Publication date: 2023-10-06

Claims

Formula (I):

[In the formula,
L is (1) bond, (2) C2-C4-alkynylene, (3) -(C1-C10-alkylene)-O-, (4) -O-(C1-C10-alkylene)-, (5) -(6- to 15-membered aryl)-, (6)-(5- to 15-membered heteroaryl)-, (7)-(3- to 15-membered heterocycle)-, and (8)-(C3 to C10 -cycloalkane)-;
W is selected from (1) CH, (2) CR ⁷ and (3) N;
Z is selected from (1) CH, (2) CR ⁸ and (3) N;
R ⁷ and R ⁸ each independently represent (1) cyano, (2) halogen, (3) pentahalosulfanyl, (4) C1-C10-thioalkyl, (5) C1-C10-alkoxy, (6) C1 ~C10-alkyl, (7) C2-C10-alkenyl, (8) C2-C10-alkynyl, (9) -OR ⁹ , (10) 6- to 15-membered aryl, (11) 5- to 15-membered heteroaryl , (12) C3-C10-cycloalkyl, (13) C2-C10-heteroalkyl, (14) 3- to 15-membered heterocycle, and (15) -(CR ¹⁰ R ¹¹ ) _n -Q,
Here, each of (4) to (8) of R ⁷ or R ⁸ may be optionally substituted with 1 to 10 halogens, and each of (10) to (14) of R ⁷ or R ⁸ may be optionally substituted with 1 to 10 halogens. each optionally substituted with 1 to 10 substituents selected from (1) halogen, (2) C1-C10-alkyl, and (3) C1-C10-haloalkyl,
R ⁹ is selected from (1) hydrogen, (2) C1-C10-alkyl, and (3) C1-C10-haloalkyl;
R ¹⁰ is selected from (1) hydrogen, (2) halogen, (3) C1-C10-alkyl and (4) C1-C10-haloalkyl,
R ¹¹ is selected from (1) hydrogen, (2) halogen, (3) C1-C10-alkyl and (4) C1-C10-haloalkyl,
or when R ¹⁰ and R ¹¹ are C1-C10-alkyl, R ¹⁰ and R ¹¹ may optionally form C3-C10-cycloalkyl together with the carbon atoms to which they are attached;
n is 0, 1, 2, 3 or 4,
Q is (1) halogen, (2) cyano, (3) -OR ¹⁰¹ , (4) -SR ¹⁰² , (5) -C(=O)R ¹⁰³ , (6) -C(=O)OR ¹⁰⁴ , (7)-S(=O)R ¹⁰⁵ , (8)-SO ₂ R ¹⁰⁶ , (9)-NR ¹⁰⁷ R ¹⁰⁸ , (10)-C(=O)NR ¹⁰⁹ R ¹¹⁰ , (11)-SO ₂ selected from NR ¹¹¹ NR ¹¹² , (12) 6- to 15-membered aryl, (13) 5- to 15-membered heteroaryl, (14) C3-C10-cycloalkyl, and (15) 3- to 15-membered heterocycle and each of (12) to (15) of Q is 1 to 10 substituents selected from (1) halogen, (2) C1-C10-alkyl, and (3) C1-C10-haloalkyl. May be substituted arbitrarily,
R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ , R ^{106 , R 107} ^, R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹¹ and R ¹¹² each independently represent (1) hydrogen, (2) selected from C1-C10-alkyl and (3) C1-C10-haloalkyl,
R ⁶ is selected from (1) hydrogen and (2) -NH ₂ ,
X is selected from (1) CH, (2) CR ¹² and (3) N;
R ¹² is selected from (1) halogen, (2) C1-C10-alkyl and (3) C1-C10-haloalkyl,
Y is selected from (1) CH, (2) CR ¹³ and (3) N;
R ¹³ is selected from (1) halogen, (2) C1-C10-alkyl and (3) C1-C10-haloalkyl,
R is selected from (1) 6- to 15-membered aryl and (2) 5- to 15-membered heteroaryl, each optionally substituted with 1 to 5 R ¹⁴ ;
Here, the plurality of R ^14s may be the same or different from each other,
R ¹⁴ is (1) halogen, (2) cyano, (3) pentahalosulfanyl, (4) C1-C10-alkyl, (5) C1-C10-thioalkyl, (6) C1-C10-alkoxy, (7 ) C2-C10-alkenyl, (8) C2-C10-alkynyl, (9) 6- to 15-membered aryl and (10) -OR ⁹ , where R ¹⁴ of (4)-(9) each may be optionally substituted with 1 to 10 halogens,
R ¹ is (1) C1-C10-alkyl, (2) halogen, (3) C1-C10-alkoxy, (4) C1-C10-haloalkyl, (5) C1-C10-haloalkoxy, and (6) selected from Cyano,
R ² is (1) hydrogen, (2) C1-C10-alkyl, (3) halogen, (4) C1-C10-alkoxy, (5) C1-C10-haloalkyl, (6) C1-C10-haloalkoxy , and (7) cyano,
R ³ is selected from (1) hydrogen and (2) C1-C10-alkyl;
R ⁴ is (1) hydrogen, (2) halogen, (3) C1-C10-alkyl, (4) C1-C10-haloalkyl, (5) cyano, and (6) (1) halogen (2) C1- selected from C3-C10-cycloalkyl optionally substituted with 1 to 10 substituents selected from C10-alkyl and (3) C1-C10-haloalkyl,
Or, R ³ and R ⁴ together form (1) -CR ⁴¹ R ⁴² -, (2) -CR ⁴³ R ⁴⁴ -CR ⁴⁵ R ⁴⁶ -, (3) -CR ⁴⁷ =CR ⁴⁸ -. It may be formed arbitrarily,
R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ and R ⁴⁸ are each independently selected from (1) hydrogen and (2) C1-C10-alkyl;
R ⁵ is (1) hydrogen, (2) cyano, (3) -NH ₂ , (4) C1-C10-alkyl, (5) C1-C10-alkoxy, (6) -NH-C(=O) -R ¹⁵ , (7) -NH-C(=O)-O-R ¹⁶ , (8) -O-R ¹⁷ , (9) -O-(C1-C10-alkylene)-R ¹⁸ , (10) -C(=O)-R ¹⁹ , (11) -C(=O)-NH-R ²⁰ , (12) -(C1-C10-alkylene)-(CR ²¹ R ²² ) _p -R ²³ , (13 ) 6- to 15-membered aryl, (14) 5- to 15-membered heteroaryl, (15) C3-C10-cycloalkyl, and (16) 3- to 15-membered heterocycle,
Each of (4), (5), (9) and (12) in R ⁵ is optionally represented by 1 to 10 substituents selected from (1) halogen, (2) cyano, and (3) -OH. Each of (13) to (16) of R ⁵ may be optionally substituted with 1 to 5 R ²⁴ ,
However, when R ⁵ is hydrogen, R ⁶ is -NH ₂ ,
R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ each independently represent (1) C1-C10-alkyl, (2) C1-C10-alkoxy, (3) 6- to 15-membered aryl, (4) 5- to 15-membered heteroaryl, (5) C3-C10-cycloalkyl, and (6) 3- to 15-membered heterocycle, R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R Each of (1) and (2) in ¹⁹ or R ²⁰ may be optionally substituted with 1 to 10 substituents selected from (1) halogen, (2) cyano, and (3) -OH. , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ (3) to (6) may be optionally substituted with 1 to 5 R ²⁵ ,
R ²¹ and R ²² are each independently selected from (1) hydrogen, (2) halogen, (3) C1-C10-alkyl, and (4) C1-C10-haloalkyl;
or when R ²¹ and R ²² are C1-C10-alkyl, R ²¹ and R ²² may optionally form C3-C10-cycloalkyl together with the carbon atoms to which they are attached;
p is 0, 1, 2, 3 or 4,
R ²³ is (1) halogen, (2) cyano, (3) -OR ²⁰¹ , (4) -SR ²⁰² , (5) -C(=O)R ²⁰³ , (6) -C(=O)OR ²⁰⁴ , (7)-S(=O)R ²⁰⁵ , (8)-SO ₂ R ²⁰⁶ , (9)-NR ²⁰⁷ R ²⁰⁸ , (10)-C(=O)NR ²⁰⁹ R ²¹⁰ , (11)- SO ₂ NR ²¹¹ R ²¹² , (12) 6- to 15-membered aryl, (13) 5- to 15-membered heteroaryl, (14) C3-C10-cycloalkyl, and (15) 3- to 15-membered heterocycle each of (12) to (15) of R ²³ is selected from 1 to 10 substituents selected from (1) halogen, (2) C1-C10-alkyl, and (3) C1-C10-haloalkyl. may be optionally substituted with a group,
R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ , R ²⁰⁵ , R ²⁰⁶ , R ²⁰⁷ , R ²⁰⁸ , R ²⁰⁹ , R ²¹⁰ , R ²¹¹ and R ²¹² each independently represent (1) hydrogen, (2) selected from C1-C10-alkyl and (3) C1-C10-haloalkyl,
R ²⁴ and R ²⁵ each independently represent (1) halogen, (2) cyano, (3) -OH, (4) oxo, (5) C1-C10-alkyl, (6) C1-C10-alkoxy, (7) -(C1-C10-alkylene)-NR ²⁶ R ²⁷ , (8) C3-C10-cycloalkyl, (9) 3- to 15-membered heterocycle and (10)-(C1-C10-alkylene)- (3- to 15-membered heterocycle), where each of (5) to (7) of R ²⁴ or R ²⁵ is selected from (1) halogen, (2) -OH, and (3) cyano. Each of (8) to (10) of R ²⁴ or R ²⁵ may be optionally substituted with 1 to 5 substituents, and each of (1) halogen, (2) -OH, (3) cyano , (4) C1-C10-alkyl and (5) C1-C10-haloalkyl, optionally substituted with 1 to 5 substituents selected from
R ²⁶ and R ²⁷ are each independently selected from (1) hydrogen and (2) C1-C10-alkyl;
A plurality of R ²⁴ and R ²⁵ may be the same or different]
or a pharmaceutically acceptable salt thereof.

Formula (Ia):

[wherein all symbols are as defined in claim 1]
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of.

R ⁵ is (1) cyano, (2) -NH ₂ , (3) -NH-C(=O)-R ¹⁵ , (4) -NH-C(=O)-O-R ¹⁶ , (5 )-O-R ¹⁷ , (6)-O-(C1-C10-alkylene)-R ¹⁸ , (7)-C(=O)-R ¹⁹ , (8)-C(=O)-NH-R ²⁰ , (9) 6- to 15-membered aryl, (10) 5- to 15-membered heteroaryl, (11) C3-C10-cycloalkyl, and (12) 3- to 15-membered heterocycle,
(6) in R ⁵ may be optionally substituted with 1 to 10 substituents selected from (1) halogen, (2) cyano, and (3) -OH, and (9) to R ⁵ Each of (12) may be optionally substituted with 1 to 5 ^R24 ,
3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the other symbols are as defined in claim 1.

Formula (Ia-1-1):

[In the formula,
R ^1a is selected from (1) hydrogen, (2) C1-C10-alkyl, and (3) C1-C10-haloalkyl,
R ^8a is selected from (1) hydrogen, (2) halogen, (3) C1-C10-alkyl, and (4) C1-C10-haloalkyl;
R ^5a is (1) cyano, (2) -NH ₂ , (3) -NH-C(=O)-R ¹⁵ , (4) -NH-C(=O)-O-R ¹⁶ , (5 )-O-R ¹⁷ , (6)-O-(C1-C10-alkylene)-R ¹⁸ , (7)-C(=O)-R ¹⁹ , (8)-C(=O)-NH-R ²⁰ , (9) 6- to 15-membered aryl, (10) 5- to 15-membered heteroaryl, (11) C3-C10-cycloalkyl, and (12) 3- to 15-membered heterocycle,
(6) of R ^5a may be optionally substituted with 1 to 10 substituents selected from (1) halogen, (2) cyano, and (3) -OH, and ( ⁹ ) to ( Each of 12) may be optionally substituted with 1 to 5 ^R24 ,
Other symbols are as defined in claim 1]
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

R ^5a is (1) -NH-C(=O)-(C3-C10-cycloalkyl), (2) -NH-C(=O)-(3- to 15-membered heterocycle), (3) -NH-C(=O)-O-(C1-C10-alkyl), (4) halogen, optionally substituted with 1 to 5 substituents selected from halogen, cyano and -OH; -O-(C1-C10-alkyl), (5) -O-(C1-C10-alkylene)-( optionally substituted with 1 to 5 substituents selected from cyano and -OH) (3 to 15 membered heterocycle), (6) -C(=O)-(C3-C10-cycloalkyl), (7) -C(=O)-(3 to 15 membered heterocycle), (8 )-C(=O)-NH-(C1-C10-alkyl) and (9) 5- to 15-membered heteroaryl,
Each of (1), (2) and (5) to (9) of R ^5a may be optionally substituted with 1 to 5 R ⁵¹ ,
A plurality of R ^51s may be the same or different from each other,
R ⁵¹ is independently (1) halogen, (2) cyano, (3) -OH, (4) C1-C10-alkyl, (5) C1-C10-alkoxy, (6) -(C1-C10- alkylene)-(3 to 15 membered heterocycle), (7) C3-C10-cycloalkyl, and (8) 3 to 15 membered heterocycle;
Each of (4) to (8) in R ⁵¹ is selected from (1) halogen, (2) -OH, (3) cyano, (4) C1-C10-alkyl and (5) C1-C10-haloalkyl. 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 10 substituents.

Formula (Ia-1-2):

[wherein all symbols are as defined in claim 1 or 4]
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

R ^5a is (1) -NH-C(=O)-(C3-C10-cycloalkyl), (2) -NH-C(=O)-(3- to 15-membered heterocycle), (3) -NH-C(=O)-O-(C1-C10-alkyl), (4) halogen, optionally substituted with 1 to 5 substituents selected from halogen, cyano and -OH; -O-(C1-C10-alkyl), (5) -O-(C1-C10-alkylene)-( optionally substituted with 1 to 5 substituents selected from cyano and -OH) (3 to 15 membered heterocycle), (6) -C(=O)-(C3-C10-cycloalkyl), (7) -C(=O)-(3 to 15 membered heterocycle), (8 )-C(=O)-NH-(C1-C10-alkyl) and (9) 5- to 15-membered heteroaryl,
Each of (1), (2) and (5) to (9) of R ^5a may be optionally substituted with 1 to 5 R ⁵¹ ,
A plurality of R ^51s may be the same or different from each other,
R ⁵¹ is independently (1) halogen, (2) cyano, (3) -OH, (4) C1-C10-alkyl, (5) C1-C10-alkoxy, (6) -(C1-C10- alkylene)-(3 to 15 membered heterocycle), (7) C3-C10-cycloalkyl, and (8) 3 to 15 membered heterocycle;
Each of (4) to (8) in R ⁵¹ is selected from (1) halogen, (2) -OH, (3) cyano, (4) C1-C10-alkyl and (5) C1-C10-haloalkyl. 7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 10 substituents.

Formula (Ib):

R is phenyl optionally substituted with 1 to 5 R ¹⁴ ;
^R4 is halogen;
R ⁵ is (1) C1-C10-alkyl, (2) C1-C10-alkoxy, (3) -NH-C(=O)-R ¹⁵ , (4) -NH-C(=O)-O -R ¹⁶ , (5) -O-R ¹⁷ , (6) -O-(C1-C10-alkylene)-R ¹⁸ , (7) -C(=O)-R ¹⁹ , (8) -C(= O) -NH-R ²⁰ , (9) -(C1-C10-alkylene)-(CR ²¹ R ²² ) _p -R ²³ , (10) 6- to 15-membered aryl, (11) 5- to 15-membered hetero aryl, (12) C3-C10-cycloalkyl, and (13) 3- to 15-membered heterocycle;
Each of (1), (2), (6) and (9) in R ⁵ is optionally represented by 1 to 10 substituents selected from (1) halogen, (2) cyano, and (3) -OH. each of (10) to (13) of R ⁵ may be optionally substituted with 1 to 5 R ²⁴ ;
9. A compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein the other symbols are as defined in claim 1.

Formula (Ic):

[wherein Ring B is selected from (1) 6- to 15-membered aryl and (2) 5- to 15-membered heteroaryl,
Other symbols are as defined in claim 1]
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of.

Ring B is

selected from
[In the formula, the right arrow is the bonding position with the 6-membered ring, the left arrow is the bonding position with R,
R is phenyl optionally substituted with 1 to 5 R ¹⁴ ;
^R4 is halogen;
R ⁵ is (1) C1-C10-alkyl, (2) C1-C10-alkoxy, (3) -NH-C(=O)-R ¹⁵ , (4) -NH-C(=O)-O -R ¹⁶ , (5) -O-R ¹⁷ , (6) -O-(C1-C10-alkylene)-R ¹⁸ , (7) -C(=O)-R ¹⁹ , (8) -C(= O) -NH-R ²⁰ , (9) -(C1-C10-alkylene)-(CR ²¹ R ²² ) _p -R ²³ , (10) 6- to 15-membered aryl, (11) 5- to 15-membered hetero aryl, (12) C3-C10-cycloalkyl, and (13) 3- to 15-membered heterocycle;
Here, each of (1), (2), (6) and (9) of R ⁵ is 1 to 10 substituents selected from (1) halogen, (2) cyano, and (3) -OH. each of (10) to (13) of R ⁵ may be optionally substituted with 1 to 5 R ²⁴ ,
Other symbols are as defined in claim 1]
11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

The compound is
(1) tert-butyl N-[4-chloro-3-[[3-fluoro-5-(2-phenylethynyl)-2-pyridyl]carbamoyl]phenyl]carbamate,
(2) 2-chloro-N-[3-fluoro-5-(2-phenylethynyl)-2-pyridyl]-5-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]benzamide,
(3) 2-chloro-N-[3-fluoro-5-(2-phenylethynyl)-2-pyridyl]-5-[(2-methylcyclopropanecarbonyl)amino]benzamide,
(4) 2-chloro-N-[3-fluoro-5-[2-(3-fluorophenyl)ethynyl]-2-pyridyl]-5-[[(1S,2S)-2-methylcyclopropanecarbonyl] Amino] benzamide,
(5) tert-butyl N-[4-chloro-3-[[5-[2-(3-fluorophenyl)ethynyl]-3-methyl-2-pyridyl]carbamoyl]phenyl]carbamate,
(6) 2-chloro-5-[(1-fluorocyclopropanecarbonyl)amino]-N-[3-fluoro-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(7) 2-chloro-5-(cyclopropanecarbonylamino)-N-[3-fluoro-5-[2-(4-fluorophenyl)ethynyl]-2-pyridyl]benzamide,
(8) tert-butyl N-[4-chloro-3-[[5-[2-(4-fluorophenyl)ethynyl]-3-methyl-2-pyridyl]carbamoyl]phenyl]carbamate,
(9) 2-chloro-5-(cyclopropanecarbonylamino)-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(10) N-[4-chloro-3-[[3-fluoro-5-(2-phenylethynyl)-2-pyridyl]carbamoyl]phenyl]-1,4-dioxane-2-carboxamide,
(11) tert-butyl N-[4-chloro-3-[[6-[2-(3-fluorophenyl)ethynyl]-2,4-dimethyl-3-pyridyl]carbamoyl]phenyl]carbamate,
(12) N-[4-chloro-3-[[5-[2-(4-fluorophenyl)ethynyl]-3-methyl-2-pyridyl]carbamoyl]phenyl]oxetane-2-carboxamide,
(13) N-[4-chloro-3-[[5-[2-(3-fluorophenyl)ethynyl]-3-methyl-2-pyridyl]carbamoyl]phenyl]-1,4-dioxane-2-carboxamide ,
(14) N-[4-chloro-3-[[5-[2-(4-fluorophenyl)ethynyl]-3-methyl-2-pyridyl]carbamoyl]phenyl]-1,4-dioxane-2-carboxamide ,
(15) tert-butyl N-[4-chloro-3-[[3-methyl-5-[2-(2-pyridyl)ethynyl]-2-pyridyl]carbamoyl]phenyl]carbamate,
(16) 2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(17) 4-chloro-N1-(2-hydroxy-1,1-dimethyl-ethyl)-N3-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzene-1,3-di carboxamide,
(18) 2-chloro-N-[5-[2-(3-fluorophenyl)ethynyl]-3-methyl-2-pyridyl]-5-(3-hydroxy-3-methyl-azetidine-1-carbonyl) benzamide,
(19) 2-chloro-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]-5-(5-tetrahydrofuran-3-yl-1,2,4-oxadiazole-3 -yl)benzamide,
(20) 2-chloro-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]-5-(tetrahydropyran-4-ylmethoxy)benzamide,
(21) 2-chloro-5-[[(2R)-1,4-dioxan-2-yl]methoxy]-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(22) 2-chloro-5-(1,4-dioxan-2-ylmethoxy)-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(23) 2-chloro-5-[[(2S)-1,4-dioxan-2-yl]methoxy]-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(24) 2-chloro-5-(2-methoxyethoxy)-N-[3-methyl-5-(2-phenylethynyl)-2-pyridyl]benzamide,
(25) tert-butyl (3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate,
(26) tert-butyl (4-chloro-3-((2-methyl-4-(phenoxymethyl)phenyl)carbamoyl)phenyl)carbamate,
A compound according to claim 1 or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13, which is an inhibitor of TREK1, TREK2, or both TREK1/TREK2.

An inhibitor of TREK1, TREK2, or both TREK1/TREK2, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, is therapeutically effective in a mammal. Pharmaceutical compositions for treating and/or preventing disorders associated with beneficial TREK1, TREK2 or both TREK1/TREK2 dysfunction.

Disorders associated with dysfunction of TREK1, TREK2, or both TREK1/TREK2 for which inhibitors of TREK1, TREK2, or both TREK1/TREK2 provide therapeutic benefit in mammals include 16. A pharmaceutical composition according to claim 15, wherein both inhibitors are neurological and/or psychiatric disorders associated with dysfunction of TREK1, TREK2 or both TREK1/TREK2 for therapeutic benefit in mammals.

Neurological and/or psychiatric disorders associated with dysfunction of TREK1, TREK2, or both TREK1/TREK2 for which inhibitors of TREK1, TREK2, or both TREK1/TREK2 provide therapeutic benefit in mammals include depression. , schizophrenia, anxiety disorder, bipolar depression, Alzheimer's disease, Parkinson's disease, Huntington 's disease, amyotrophic lateral sclerosis, neuropathic pain or cerebral infarction. Things .

A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and
(a) at least one agent known to decrease TREK1 channel activity; (b) at least one agent known to decrease TREK2 channel activity; (c) TREK1, TREK2, or TREK1/ (d) at least one agent known to prevent and/or treat disorders associated with TREK channel dysfunction in which both inhibitors of TREK2 provide therapeutic benefit in mammals, (d) TREK1, TREK2, or Instructions for preventing and/or treating disorders associated with TREK dysfunction in which both inhibitors of TREK1/TREK2 provide therapeutic benefit in mammals, and (e) said compounds in connection with cognitive behavioral therapy. A kit comprising one or more of instructions for administering.