Indole and indoline derivatives and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9625475-B2
Application number	US-72772310-A
Country	US
Kind code	B2
Filing date	Mar 19, 2010
Priority date	Sep 29, 2008
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

The present application relates to indole and indoline derivatives of formula (I), (II), (III), (IV), (V), or (VI)

wherein a, R 1 , R 2 , R 3 , R 4 , R 5 , U, V, W, X, Y, and Z are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating disease conditions using such compounds and compositions, and methods for identifying such compounds.

First claim

What is claimed is:

1. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein
a is a single or double bond;
X is NR 6 ;
V is —CH 2 —;
Y is CH 2 CH 2 —;
Z is —CH 2 —;
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, halogen, —OR 1a , —S(O) 2 R 2a , or haloalkyl;
R 1a is independently alkyl or haloalkyl;
R 2a , at each occurrence, is independently alkyl;
R 6 is —(CR 4a R 5a ) m -G 1 wherein R 4a and R 5a are each hydrogen, and m is 1 or 2, or R 6 is —CR 4a ═CR 5a -G 1 wherein R 4a and R 5a are each hydrogen, and G 1 is phenyl or pyridinyl, unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, halogen, —OR 1b , —N(R b )(R 3b ), haloalkyl, heteroaryl, and heterocycle; wherein the heteroaryl is selected from the group consisting of furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl; wherein the heterocycle is selected from the group consisting of azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, thiopyranyl, and trithianyl; wherein the heteroaryl and heterocycle are each independently unsubstituted or substituted with at least one alkyl;
R b and R 1b , at each occurrence, are each independently alkyl; and
R 3b , at each occurrence, is independently alkoxyalkyl, or alkyl.

2. The compound according to claim 1 of formula (IV), wherein
a is a double bond; and
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, halogen, —OR 1a , or S(O) 2 R 2a .

3. The compound according to claim 1 of formula (IV), wherein
a is a single bond; and
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, or halogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[2-(6-chloropyridin-3-yl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-[(E)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-[(Z)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-[2-(2-methylphenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[2-(2-fluorophenyl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[2-(4-chlorophenyl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-{2-[3-(trifluoromethyl)phenyl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-methyl-6-[(Z)-2-(4-methylphenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
(5aR*,10bS*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;
(5aS,10bR)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;
(5aR,10bS)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-[2-(4-fluorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-(4-fluorobenzyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-(4-chlorobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-(4-bromobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-[3-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-(2,3-difluoro-4-methylbenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-[3-fluoro-4-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-bromo-6-[2-(4-chlorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[(E)-2-pyridin-3-ylvinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[2-(6-methylpyridin-3-yl)ethyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[2-(6-methylpyridin-3-yl)ethyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-(pyridin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-(pyridin-4-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[(pyridin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
6-[(pyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-[(2-fluoropyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-{[6-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-{[6-(piperidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-isopropyl-N-methylpyridin-2-amine;
N-(1,3-dioxolan-2-ylmethyl)-5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-methylpyridin-2-amine;
9-fluoro-6-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-(2-methoxyethyl)-N-methylpyridin-2-amine;
9-fluoro-6-[(5-fluoropyridin-3-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
2-{5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]pyridin-2-yl}pyridazin-3(2H)-one;
2-{4-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]phenyl}pyridazin-3(2H)-one; and
6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole.

5. A process for preparing a compound of formula (IV) according to claim 1 or a pharmaceutically acceptable salt thereof, the process comprising

Assignees

• Schrimpf Michael R
• Lee Chih-Hung
• Li Tao
• Gfesser Gregory A
• Mortell Kathleen H
• Faghih Ramin
• Nersesian Diana L
• Sippy Kevin B
• Bunnelle William H
• Scanio Marc
• Shi Lei
• Gopalakrishnan Murali
• Donnelly-Roberts Diana L
• Hu Min
• Abbvie Inc

Inventors

• Schrimpf Michael R
• Lee Chih-Hung
• Li Tao
• Gfesser Gregory A
• Mortell Kathleen H
• Faghih Ramin
• Nersesian Diana L
• Sippy Kevin B
• Bunnelle William H
• Scanio Marc
• Shi Lei
• Gopalakrishnan Murali
• Donnelly-Roberts Diana L
• Hu Min

Classifications

• G01N33/5058

  Neurological cells · CPC title

• A61P25/24

  Antidepressants · CPC title

• G01N2800/30

  Psychoses; Psychiatry · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• G01N2800/2814

  Dementia; Cognitive disorders · CPC title