Indole and indoline derivatives and methods of use thereof

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 the step of reacting a compound of formula (IX) under alkylation conditions, cross-coupling conditions, or nucleophilic aromatic substitution conditions, to provide a compound of formula (X)

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (IV) according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, that is 6-((6-chloropyridin-3-yl)methyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole.

8. The compound according to claim 1 of formula (IV), wherein

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 oxadiazolyl and pyrazolyl; wherein the heterocycle is selected from the group consisting of piperidinyl, pyridazin-3(2H)-onyl, and pyrrolidinyl; wherein the heteroaryl and heterocycle are each independently unsubstituted or substituted with at least one alkyl.