IP Library › Granted Patent US 8,859,584

Granted Patent B2

US 8,859,584 · App. 13/716,837 · Granted Oct 14, 2014

TRPV1 antagonists

Inventors: Kevin R. Woller (Antioch, IL); Gregory A. Gfesser (Lindenhurst, IL); Huaqing Liu (Buffalo Grove, IL); Jerome F. Daanen (Racine, WI); Eric A. Voight (Pleasant Prairie, WI); Irene I. Drizin (Wadsworth, IL); Anurupa Shrestha (Gurnee, IL); Kathleen H. Mortell (Chicago, IL); Philip R. Kym (Libertyville, IL); Michael E. Kort (Lake Bluff, IL); Arthur Gomtsyan (Vernon Hills, IL)

Assignee: AbbVie, Inc.

C07D311/04 C07D215/46 C07D311/68 A61K45/06 C07D311/96 C07C275/30 A61K31/192 C07D311/70 A61K31/353 C07D491/052 A61K31/436 C07D215/42 A61K31/17 A61K31/47 C07C275/32

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Quick Facts

Patent No.: US 8,859,584
App. No.: 13/716,837
Granted: Oct 14, 2014
Kind: B2

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Abstract

Disclosed herein are compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein X 1 , L, R x , R y , R z , A, m, n, p, q, s, and positions a and b are as defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

Claims (203)

1. A compound of formula (I):

or a salt thereof, wherein:

L is a bond or CH 2 , and is bound to any one of the carbon atom of the monocyclic ring containing X 1 ;

X 1 is O;

n is 1 or 2;

A is CH;

m is 0, 1, or 2;

R x , at each occurrence, represents an optional substituent on any substitutable carbon atom of the ring containing A and each R x is independently alkyl, halogen, haloalkyl, OH, O(alkyl), O(haloalkyl), NH 2 , N(H)(alkyl), or N(alkyl) 2 ;

p is 0, 1, or 2;

R y , at each occurrence, represents an optional substituent on any substitutable carbon atom of the ring containing X 1 and each R y is independently alkyl, haloalkyl, —(C 1 -C 6 alkylenyl)-O(alkyl), G 1 , and —(C 1 -C 6 alkylenyl)-G 1 ; wherein G 1 , at each occurrence, is independently an aryl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, O(alkyl), and O(haloalkyl);

two R y groups that are attached to the same carbon atom, together with said carbon atom to which they are attached, optionally form a C 3 -C 6 monocyclic cycloalkyl ring, wherein the monocyclic cyclcoalkyl ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, oxo, halogen, and haloalkyl;

s is 0 or 1;

The alphabets a and b on the bicyclic ring independently represent the positions at which the —NH— of the urea moiety and a carbon atom of the ring are bound to each other, provided that when s is 1, the binding position for —NH— is at position a; and when s is 0, the binding position for —NH— is at position b;

R z , at each occurrence, represents an optional substituent on any substitutable position of the bicyclic ring and is independently halogen, haloalkyl, or alkyl; and

q is 0 or 1.

2. The compound or salt according to claim 1 , wherein n is 2.

3. The compound or salt according to claim 1 , wherein n is 1.

4. The compound or salt according to claim 1 , wherein L is CH 2 .

5. The compound or salt according to claim 1 , wherein L is a bond.

6. The compound or salt according to claim 2 , wherein L is a bond.

7. The compound or salt according to claim 2 , wherein L is CH 2 .

8. The compound or salt according to claim 1 having formula (I-a):

9. The compound or salt according to claim 8 , wherein:

n is 2; and

L is a bond.

10. The compound or salt according to claim 8 , wherein:

n is 2; and

L is CH 2 .

11. The compound or salt according to claim 8 , wherein:

n is 1; and

L is a bond.

12. The compound or salt according to claim 1 having formula (I-b):

13. The compound or salt according to claim 12 , wherein:

n is 2; and

L is a bond.

14. The compound or salt according to claim 1 , wherein the compound is selected from the group consisting of:

1-[(4R)-6,8-difluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7,8-difluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(2R,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-8-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-7,8-difluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-7-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]urea; and

1-[(4R)-7-bromo-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea.

15. The compound or salt according to claim 1 , wherein the compound is selected from the group consisting of:

1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-(5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-{[6-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]methyl}urea;

1-[(3S)-6-chloro-3,4-dihydro-2H-chromen-3-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(6-fluoro-3,4-dihydro-2H-chromen-3-yl)methyl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-2-(fluoromethyl)-2-methyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S,4R)-2-(fluoromethyl)-2-methyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-diethyl-8-fluoro-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-tert-butyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-diethyl-7-fluoro-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-diethyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7,8-dichloro-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-dipropyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-diethyl-6-fluoro-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-dipropyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-diethyl-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-fluoro-2,2,8-trimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6,8-difluoro-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-fluoro-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-8-fluoro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-bis(methoxymethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6,8-difluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(3R)-6-chloro-3,4-dihydro-2H-chromen-3-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S,4R)-7-chloro-8-fluoro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-(6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl)-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4S)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4S)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4S)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4S)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-(7-chloro-3,4-dihydro-2H-chromen-3-yl)-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4S)-6-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4S)-6-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4S)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4S)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(7-methoxy-3,4-dihydro-2H-chromen-4-yl)urea;

1-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(3-phenyl-3,4-dihydro-2H-chromen-4-yl)urea;

1-[3-(3,4-dimethoxybenzyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[2-(3-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-(3-benzyl-3,4-dihydro-2H-chromen-4-yl)-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[3-(3,4-dichlorobenzyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[2-(3,4-dimethoxyphenyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[3-(3,4-dichlorobenzyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[3-(4-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-[3-(4-methoxyphenyl)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[2-(4-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-phenyl-3,4-dihydro-2H-chromen-4-yl)urea;

1-[2-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[2-(2-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-{2-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-chromen-4-yl}urea;

1-[2-(4-chlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-(3,4-dihydrospiro[chromene-2,1′-cyclohexan]-4-yl)-3-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)urea;

1-[(2S,4R)-2-(difluoromethyl)-2-methyl-3,4-dihyd ro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-3,4-dihydrospiro[chromene-2,1′-cyclopentan]-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-(difluoromethyl)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-(8-hydroxybicyclo[4.2.0]octa-1,3,5-then-3-yl)urea;

1-[(2R,4R)-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-3-(8-hydroxybicyclo[4.2.0]octa-1,3,5-then-3-yl)urea;

1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6,8-difluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7,8-difluoro-2,2-di methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6,8-difluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-7-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-7,8-difluoro-2,2-di methyl-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(4R)-2,2-dimethyl-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea;

1-[(2R)-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]-3-[(4R)-8-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]urea;

1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2R)-5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea; and

1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-[(2S)-5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl]urea.

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

17. The pharmaceutical composition according to claim 16 further comprising an analgesic or a nonsteroidal anti-inflammatory drug, or a combination thereof.

18. A method for treating pain comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

19. The method according to claim 18 further comprising the step of co-administering with an analgesic or a nonsteroidal anti-inflammatory drug, or a combination thereof.

20. The method according to claim 19 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2013

From: WOLLER, KEVIN R.; GFESSER, GREGORY A.; LIU, HUAQING; DAANEN, JEROME F.; VOIGHT, ERIC A.; DRIZIN, IRENE I.; SHRESTHA, ANURUPA; MORTELL, KATHLEEN H.; KYM, PHILIP R.; KORT, MICHAEL E.; GOMTSIAN, ARTOUR R.

To: ABBVIE INC.

Reel/Frame 031445/0161 →

Continuity (3)

Provisional Application 61577360 · Dec 19, 2011

Provisional Application 61704787 · Sep 24, 2012

Related Publication 20130158067A1 · Jun 20, 2013