US 7,087,636 B2Granted

Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function

AssigneeBristol-Myers Squibb Company

InventorsMark E. Salvati, James Aaron Balog, Dacia A. Pickering, Hong Zhu

Life of this patent

Estimating the term…

Abstract

Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.

Claims25

Dependent claims

A compound of the following formula, or a salt thereof:

wherein the symbols have the following meanings and are, for each occurrence, independently selected:
G is an aryl or heteroaryl group, where said group is mono- or polycyclic and is optionally substituted at one or more positions;
A1 is CR7;
A2 is CR7;
Y is O, S, or (CR7R7′)n wherein n=1 or 2;
W is CR7R7′—CR7R7′ or CR8═CR8′;
Q1 is H, alkyl or substituted alkyl;
Q2 is H, alkyl or substituted alkyl;
R1 and R1′ are each independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, and/or arylalkyl or substituted arylalkyl;
R2 is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl;
R4 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C═O, R1NHC═O, R1OC═O;
SO2OR1, or SO2NR1R1′;
R5 is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C═O, R1NHC═O, SO2R1, SO2OR1, or SO2NR1R1′;
R7 and R7′ are at each occurrence independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, N3, CN, OR1, O(C═O)R1, O(C═O)NHR1, O(C═O)OR1, nitro, hydroxylamine, hydroxylamide, amino, SR1, SeR1, NHR4, NR2R5, NOR1, thiol, alkylthio or substituted alkylthio, R1C═O, R1OC═O, R1NHC═O, SO2R1, SOR1, PO3R1R1′, R1R1′NC═O, C═OSR1, SO2R1, SO2OR1, SO2NR1R1′, OSO2-aryl, OSO2-(substituted aryl), OSO2-heterocyclo, OSO2-(substituted heterocyclo), and/or COCl;
R8 and R8′ are each independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, nitro, halo, CN, OR1, amino, NHR4, NR2R5, NOR1, alkylthio or substituted alkylthio, C═OSR1, R1OC═O, R1C═O, R1NHC═O, R1R1′NC═O, SO2OR1, S═OR1, SO2R1, PO3R1R1′, and/or SO2NR1R1′;
with the proviso that when A1 and A2 are CH;
Y is O or CH2;
W is CH2—CH2 or CH═CH;
Q2 is H or CH2OH;
and Q2 is H or CH2OH, then (i) G is not pyridinyl, phenyl, dichlorophenyl, bromophenyl or methoxyphenyl when R7a or R7a′ is OH or OCH3 and (ii) G is not methoxyphenyl or phenyl substituted with —OCH2CH2-SB where SB is dimethylamino, diethylamino, piperidinyl, morpholinyl, or pyrrolidinyl when R7a and R7a′ are both hydrogen.

17 more elements

A compound of selected from the group consisting of (i):

(3aα,4α,7α,7aα)-Octahydro-3-hydroxy-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one (2);
(3aα,4α,7α,7aα)-Octahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one (3);
(3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-3-hydroxy-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one (4);
(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-3-methoxy-4,7-methano-1H-isoindol-1-one (5);
(3aα,4α,7α,7aα)-Octahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-3-(2-propenyl)-4,7-methano-1H-isoindol-1-one (6);
(3aα,4β,7β,7aα)-Octahydro-3-hydroxy-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindol-1-one (7);
(3aα,4β,7β,7aα)-Octahydro-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindol-1-one (8);
(3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-3-hydroxy-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-isoindol-1-one (9);
(3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-isoindol-1-one (10);
(1α,3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-2-(4-nitro-1-naphthalenyl)-3-oxo-4,7-methano-1H-isoindole-1-carbonitrile (12B);
(3aα,4β,7β,7aα)-2,3,3a,4,7,7a-Hexahydro-3-hydroxy-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindol-1-one (13B);
(3aα,4β,7β,7aα)-Octahydro-3-hydroxy-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindol-1-one (14);
(3aα,4α,7α,7aα)-2-(1,2-Dihydro-4-methyl-2-oxo-7-quinolinyl)-2,3,3a,4,7,7a-hexahydro-3-methoxy-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-Octahydro-3-methoxy-2-(1-naphthalenyl)-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-Octahydro-2-(1-naphthalenyl)-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2-(1,2-Dihydro-4-methyl-2-oxo-7-quinolinyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2-(3,5-Dichlorophenyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2-(4-Bromo-1-naphthalenyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-3-hydroxy-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one;
(3aα,4α,7α,7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-3-hydroxy-5-methyl-4,7-methano-1H-isoindol-1-one;
(1α,3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-3-oxo-4,7-methano-1H-isoindole-1-carbonitrile;
and
(3aα,4α,7α,7aα)-2,3,3a,4,7,7a-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-methano-1H-isoindol-1-one;
and (ii) a pharmaceutically acceptable salt.

23 more elements

A compound having the formula,

wherein,
Y is —O—, —S—, —CR7′R7′—, or —(CR7′R7′)2—;
W is —CR7R7′—CR7R7′— or —CR8═CR8′—;
R7 and R8 are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, N3, CN, OR1, O(C═O)R1, O(C═O)NHR1, O(C═O)OR1, nitro, hydroxylamine, hydroxylamide, amino, SR1, NR4R5, alkylthio or substituted alkylthio, R1C═O, R1OC═O, R1NHC═O, SO2R1, SOR1, SO2NR1R1′, OSO2-aryl, OSO2-(substituted aryl), OSO2-heterocyclo, OSO2-(substituted heterocyclo), or COCl;
R7′ and R8′ are at each occurrence independently selected from H, alkyl, substituted alkyl, OH, O(alkyl), alkenyl, and/or cyano;
R1 and R1′ are independently selected from H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, and arylalkyl or substituted arylalkyl;
R4 and R5 are independently selected from H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C═O, R1NHC═O, R1OC═O;
SO2OR1, and SO2NR1R1′;
X is selected from trifluoromethyl, halogen, cyano, nitro, and/or alkyl;
and
y is 0, 1, 2, or 3;
or a pharmaceutically-acceptable salt.

9 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/322,276Filed 18 Dec 2002 · us provisional application
Priority: 19 Dec 2001
Published: US 2003/0181728 A125 Sep 2003
Granted: 8 Aug 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 209/74
4,7-Endo-alkylene-iso-indoles: with an oxygen atom in position 1
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/26
Of the sex hormones: androgens

Family

Application60/341,962Us provisional application · filed 19 Dec 2001
US 2003/0181728 A1Pre-grant publication · published 25 Sep 2003
US 7,087,636 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of the following formula, or a salt thereof:

wherein the symbols have the following meanings and are, for each occurrence, independently selected:
G is an aryl or heteroaryl group, where said group is mono- or polycyclic and is optionally substituted at one or more positions;
A1 is CR7;
A2 is CR7;
Y is O, S, or (CR7R7′)n wherein n=1 or 2;
W is CR7R7′—CR7R7′ or CR8═CR8′;
Q1 is H, alkyl or substituted alkyl;
Q2 is H, alkyl or substituted alkyl;
R1 and R1′ are each independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, and/or arylalkyl or substituted arylalkyl;
R2 is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl;
R4 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C═O, R1NHC═O, R1OC═O;
SO2OR1, or SO2NR1R1′;
R5 is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C═O, R1NHC═O, SO2R1, SO2OR1, or SO2NR1R1′;
R7 and R7′ are at each occurrence independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, N3, CN, OR1, O(C═O)R1, O(C═O)NHR1, O(C═O)OR1, nitro, hydroxylamine, hydroxylamide, amino, SR1, SeR1, NHR4, NR2R5, NOR1, thiol, alkylthio or substituted alkylthio, R1C═O, R1OC═O, R1NHC═O, SO2R1, SOR1, PO3R1R1′, R1R1′NC═O, C═OSR1, SO2R1, SO2OR1, SO2NR1R1′, OSO2-aryl, OSO2-(substituted aryl), OSO2-heterocyclo, OSO2-(substituted heterocyclo), and/or COCl;
R8 and R8′ are each independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, nitro, halo, CN, OR1, amino, NHR4, NR2R5, NOR1, alkylthio or substituted alkylthio, C═OSR1, R1OC═O, R1C═O, R1NHC═O, R1R1′NC═O, SO2OR1, S═OR1, SO2R1, PO3R1R1′, and/or SO2NR1R1′;
with the proviso that when A1 and A2 are CH;
Y is O or CH2;
W is CH2—CH2 or CH═CH;
Q2 is H or CH2OH;
and Q2 is H or CH2OH, then (i) G is not pyridinyl, phenyl, dichlorophenyl, bromophenyl or methoxyphenyl when R7a or R7a′ is OH or OCH3 and (ii) G is not methoxyphenyl or phenyl substituted with —OCH2CH2-SB where SB is dimethylamino, diethylamino, piperidinyl, morpholinyl, or pyrrolidinyl when R7a and R7a′ are both hydrogen.

17 more elements

Facts

Application

10/322,276Filed 18 Dec 2002 · us provisional application

Priority

19 Dec 2001

Published

US 2003/0181728 A125 Sep 2003

Granted

8 Aug 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 209/74
4,7-Endo-alkylene-iso-indoles: with an oxygen atom in position 1
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/26
Of the sex hormones: androgens