Modulators of 5-ht receptors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016096851-A1
Application number	US-201514887171-A
Country	US
Kind code	A1
Filing date	Oct 19, 2015
Priority date	May 22, 2009
Publication date	Apr 7, 2016
Grant date	—

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 or prodrug thereof, wherein
A is selected from the group consisting of

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 b ) 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 b , —(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 b ), —(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 N or CR 9 ;
X 2 is N or CR 10 ;
X 3 is N or CR 11 ;
X 4 is N or CR 12 ;
provided that only one or two of X 1 , X 2 , X 3 , or X 4 can be N;
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 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; or

R 9 and R 10 , R 10 and R 11 , R 11 and R 12 , or R 13 and R 14 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted phenyl, cycloalkyl, heterocycle, or heteroaryl ring;
Y 1 is NR 17 , CR 18 R 19 , C(O), S(O) n , or O;
Y 2 is NR 20 , CR 18 R 19 , C(O), or S(O) n ;
Y 3 is NR 17 , CR 18 R 19 , C(O), or S(O) n ; or
Y 1 and Y 2 together are CR 18 ═CR 19 , provided Y 3 is other than NR 17 ; or
Y 2 and Y 3 together are CR 18 ═CR 19 , provided Y is other than NR 17 or O;
n is 1 or 2;
provided that only one of Y and Y 3 can be NR 17 ; or Y 1 and Y 3 are other than NR 17 when Y 2 is NR 20 ; or only one of Y 1 , Y 2 , or Y 3 can be C(O) or S(O) n ; or Y 2 is other than NR 20 or S(O) n when Y 1 is O; or Y 3 is other than NR 17 when Y 1 is O;

R 17 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, haloalkyl, —C(O)-G 1 , —(CR 4a R 5a ) m -G 1 , —C(O)-G 2 , and —(CR 4a R 5a ) m -G 2 ;
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 A is (i).

3 . The compound of claim 1 , wherein A is (ii), (iii), or (iv).

4 . The compound of claim 1 , wherein Y 1 is C(O) or S(O) n , Y 2 is NR 20 , and Y 3 is CR 18 R 19 ; or wherein Y 1 is C(O), Y 2 and Y 3 are each CR 18 R 19 .

5 . The compound of claim 1 , wherein Y 1 is CR 18 R 19 , Y 2 is NR 20 , and Y 3 is C(O), or wherein Y 1 is CR 18 R 19 , Y 2 is C(O), and Y 3 is NR 20 .

6 . The compound of claim

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• 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

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/22

  Anxiolytics · CPC title