Modulators of 5-HT receptors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9879033-B2
Application number	US-201514887171-A
Country	US
Kind code	B2
Filing date	Oct 19, 2015
Priority date	May 22, 2009
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

The present application relates to aryl- and heteroaryl-fused decahydropyrroloazepine, octahydrooxepinopyrrole, octahydropyrrolothiazepine dioxide, decahydrocyclohepta[c]pyrrole, and octahydrocyclohepta[c]pyrrole derivatives of formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , A, Y 1 , Y 2 , and Y 3 are as defined in the specification. The present application also relates to compositions comprising such compounds, processes for making 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 (I):

or a pharmaceutically acceptable salt thereof, wherein
A is a group (i)

R 1 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, alkenyl, alkyl, haloalkyl, G 1 , G 2 , —(CR 4a R 5a ) m -G 1 , and —(CR 4a R 5a ) m -G 2 ;
R 4a and R 5a , at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl;
G 1 , at each occurrence, is independently aryl or heteroaryl, wherein each G 1 is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, cyano, —NO 2 , —OR 1b , —OC(O)R 1b ,—OC(O)N(R b )(R 3b ), —SR 1b , —S(O)R 2b , —S(O) 2 R 2b , —S(O) 2 N(R b )(R 3b ), —C(O)R 1b , —C(O)OR 1b , —C(O)N(R b )(R 3b ), —N(R b )(R 3b ), —N(R a )C(O)R 1b , —N(R a )C(O)O(R 1b ), —N(R a )C(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —NO 2 , —N(R b )S(O) 2 (R 2b ), —(CR 4b R 5b ) m —OR 1b , —C(OH)[(CR 4b R 5b ) m —R 4b ] 2 , —(CR 4b R 5b ) m —OC(O)R 1b , —(CR 4b R 5b ) m —OC(O)N(R b )(R 3b ),—(CR 4b R 5b ) m —SR 1b ,—(CR 4b R 5b ) m —S(O)R 2b ,—(CR 4b R 5b ) m —S(O) 2 R 2b , —CR 4b R 5b ) m —S(O) 2 N(R b )(R 3b ), —(CR 4b R 5b ) m —C(O)R 1b , —(CR 4b R 5b ) m —C(O)OR 1b , —(CR 4b R 5b ) m —C(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —N(R b )(R 3b ), —(CR 4b R 5b ) m —N(R a )C(O)R 1b , —(CR 4b R 5b ) m —N(R a )C(O)O(R 1b ), —(CR 4b R 5b ) m —N(R a )C(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —N(R b )S(O) 2 (R 2b ), cyanoalkyl, and haloalkyl;
G 2 is cycloalkyl, cycloalkenyl, or heterocycle unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, cyano, oxo, —SR 1b , —S(O)R 2b , —S(O) 2 R 2b , —S(O) 2 N(R b )(R 3b ), —C(O)R 1b , —C(O)OR 1b , —C(O)N(R b )(R 3b ), —N(R b )(R 3b ), —N(R a )C(O)R 1b , —N(R a )C(O)O(R 1b ), —N(R a )C(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —NO 2 , —N(R b )S(O) 2 (R 2b ), —(CR 4b R 5b ) m —OR 1b , —(CR 4b R 5b ) m —OC(O)R 1b , —(CR 4b R 5b ) m —OC(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —SR 1b , —(CR 4b R 5b ) m —S(O)R 2b , —(CR 4b R 5b ) m —S(O) 2 R 2b , —(CR 4b R 5b ) m —S(O) 2 N(R b )(R 3b ), —(CR 4b R 5b ) m —C(O)R 1b , —(CR 4b R 5b ) m —C(O)OR 1b , —(CR 4b R 5b ) m —C(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —N(R b )(R 3b ), —(CR 4b R 5b ) m —N(R a )C(O)R 1b , —(CR 4b R 5b ) m —N(R a )C(O)O(R 1b ), —(CR 4b R 5b ) m —N(R a )C(O)N(R b )(R 3b ), —(CR 4b R 5b ) m —N(R b )S(O) 2 (R 2b ), cyanoalkyl, and haloalkyl;
R a and R b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl;
R 1b and R 3b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl;
R 2b , at each occurrence, is independently alkyl or haloalkyl;
R 4b and R 5b , at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl;
m, at each occurrence, is independently 1, 2, 3, 4, or 5;

R 2 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkylcarbonyl, haloalkyl, —(CR 4a R 5a ) m -G 1 , —(CR 4a R 5a ) p —O-G 1 , —C(O)-G 1 , —(CR 4a R 5a ) m -G 2 , —(CR 4a R 5a ) p —O-G 2 , —C(O)-G 2 , —S(O) 2 R 6 , and —C(O)NR 7 R 8 ;
p, at each occurrence, is independently 2, 3, 4, or 5;

R 6 and R 7 are independently selected from the group consisting of alkyl, haloalkyl, G 1 , —(CR 4a R 5a ) m -G 1 , G 2 , and —(CR 4a R 5a ) m -G 2 ;
R 8 is selected from the group consisting of hydrogen, alkyl, and haloalkyl; or
R 7 and R 8 taken together with the nitrogen to which they are attached form a heterocycle;
X 1 is CR 9 ;
X 2 is CR 10 ;
X 3 is CR 11 ;
X 4 is CR 12 ;
R 9 , R 10 , R 11 and R 12 are each independently hydrogen, alkyl, alkenyl, alkynyl, halogen, cyano, -G 1 , -G 2 , —NO 2 , —OR 1a , —OC(O)R 1a ,—OC(O)N(R b )(R 3a ), —SR 1a , —S(O)R 2a , —S(O) 2 R 2a , —S(O) 2 N(R b )(R 3a ), —C(O)R 1a , —C(O)G 3 , —C(O)OR 1a , —C(O)N(R b )(R 3a ), —N(R b )(R 3a ), —N(R a )C(O)R 1a , —N(R a )C(O)O(R 1a ), —N(R a )C(O)N(R b )(R 3a ), —N(R a )S(O) 2 (R 2a ), —(CR 4a R 5a ) m —NO 2 , —(CR 4a R 5a ) m —OR 1a , —(CR 4a R 5a ) m —OC(O)R 1a , —(CR 4a R 5a ) m —OC(O)N(R b )(R 3a ), —(CR 4a R 5a ) m —SR 1a , —(CR 4a R 5a ) m —S(O)R 2a , —(CR 4a R 5a ) m —S(O) 2 R 2a , —(CR 4a R 5a ) m —S(O) 2 N(R b )(R 3a ), —(CR 4a R 5a ) m —C(O)R 1a , —(CR 4a R 5a ) m —C(O)OR 1a , —(CR 4a R 5a ) m —C(O)N(R b )(R 3a ), —(CR 4a R 5a ) m —N(R b )(R 3a ), —(CR 4a R 5a ) m —N(R a )C(O)R 1a , —(CR 4a R 5a ) m —N(R a )C(O)O(R 1a ), —(CR 4a R 5a ) m —N(R a )C(O)N(R b )(R 3a ), —(CR 4a R 5a ) m -G 1 , —CR 4a ═CR 5a -G 1 , —(CR 4a R 5a ) m -G 2 , —CR 4a ═CR 5a -G 2 ,—CR 6a ═C(R 7a ) 2 , cyanoalkyl, haloalkyl, (v), (vi), (vii) or (vi); wherein

R 1a and R 3a , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, G 1 , —(CR 4a R 5a ) m -G 1 , G 2 , or —(CR 4a R 5a ) m -G 2 ;
R 2a , at each occurrence, is independently alkyl, haloalkyl, G 1 , or —(CR 4a R 5a ) m -G 1 ;
R 6a is alkyl or haloalkyl;
R 7a , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;
G 3 is a heterocyclic ring attached to the adjacent carbonyl moiety through a nitrogen atom contained within the heterocycle;
q is 1 or 2;

Y 1 is CR 18 R 19 ;
Y 2 is NR 20 ;
Y 3 is CR 18 R 19 ;
R 18 and R 19 are independently selected from the group consisting of hydrogen, alkyl, and haloalkyl; and
R 20 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, haloalkyl, —C(O)-G 1 , —C(O)NR a -G 1 , —S(O) n -G 1 -(CR 4a R 5a ) m -G 1 , —C(O)-G 2 , —C(O)NR a -G 2 , —S(O) n -G 2 , and —(CR 4a R 5a ) m -G 2 .

2. The compound of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, —(CR 4a R 5a ) m -G 1 , and —S(O) 2 R 6 .

3. The compound of claim 1 , wherein R 9 , R 10 , R 11 , and R 12 are each hydrogen, or
wherein one or two of R 9 , R 10 , R 11 , and R 12 are each independently alkyl, alkenyl, alkynyl, halogen, cyano, -G 1 , -G 2 , —NO 2 , —OR 1a , —OC(O)R 1a , —OC(O)N(R b )(R 3a ), —SR 1a , —S(O)R 2a , —S(O) 2 R 2a , —S(O) 2 N(R b )(R 3a ), —C(O)R 1a , —C(O)G 3 , —C(O)OR 1a , —C(O)N(R b )(R 3a ), —N(R b )(R 3a ), —N(R a )C(O)R 1a , —N(R a )C(O)O(R 1a ), —N(R a )C(O)N(R b )(R 3a ), —N(R a )S(O) 2 (R 2a ), —(CR 4a R 5a ) m —NO 2 , —(CR 4a R 5a ) m —OR 1a , —(CR 4a R 5a ) m —OC(O)R 1a , —(CR 4a R 5a ) m —OC(O)N(R b )(R 3a ), —(CR 4a R 5a ) m —SR 1a , —(CR 4a R 5a ,) S(O)R 2a , —(CR 4a R 5a ) m —S(O) 2 R 2a , —(CR 4a R 5a ) m —S(O) 2 N(R b )(R 3a ), —(CR 4a R 5a ) m —C(O)R 1a , —(CR 4a R 5a ) m —C(O)OR 1a , —(CR 4a R 5a ) m —C(O)N(R b )(R 3a ), —(CR 4a R 5a ) m —N(R b )(R 3a ), —(CR 4a R 5a ) m —N(R a )C(O)R 1a , —(CR 4a R 5a ) m —N(R a )C(O)O(R 1a ), —(CR 4a R 5a ) m N(R a )C(O)N(R b )(R 3a ), —(CR 4a R 5a ) m -G 1 , —CR 4a ═CR 5a -G 1 , —(CR 4a R 5a) m -G 2 , —CR 4a ═CR 5a -G 2 cyanoalkyl, haloalkyl, (v), (vi), (vii) or (viii), and the others of R 9 , R 10 , R 11 , and R 12 are hydrogen.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:
trans-2-benzyl-1,2,3,3a,4,5,6,10b-octahydrobenzo[c]pyrrolo[3,4-e]azepine;
trans-2-benzyl-5-(3-fluorophenylsulfonyl)-1,2,3,3a,4,5,6,10b -octahydrobenzo[c]pyrrolo[3,4-e]azepine;
trans-2-benzyl-5-(2,3-dichlorophenylsulfonyl)- 1,2,3,3a,4,5,6,10b -octahydrobenzo[c]pyrrolo[3,4-e]azepine;
trans-2-benzyl-5-(2,5-dichlorophenylsulfonyl)-1,2,3,3a,4,5,6,10b -octahydrobenzo

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Akritopoulou-Zanze Irini
• Braje Wilfried
• Djuric Stevan W
• Wilson Noel S
• Turner Sean C
• Kruger Albert W
• Relo Ana-Lucia
• Shekhar Shashank
• Welch Dennie S
• Zhao Hongyu
• Gandarilla Jorge
• Gasiecki Alan F
• Li Huanqiu
• Thompson Christina M
• Zhang Min

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P25/24

  Antidepressants · CPC title