US 2011/0034526 A1Published application

Benzimidazole Compounds

AssigneeWyeth

InventorsRonald Charles Bernotas, Jeremy Mark Travins, Jay Edward Wrobel, David Harry Kaufman

Life of this patent

Estimating the term…

Abstract

This invention relates generally to benzimidazole-based modulators of Liver X receptors (LXRs) having formula (I) and related methods: wherein R2 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is: (i) substituted with 1 R7, and (ii) optionally substituted with from 1-5 Re; and R1, R3, R4, R5, R6, R7, and Re are defined herein.

Claims83

Dependent claims

A compound having formula (I):

wherein:
R1 is:
(i) hydrogen;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-10 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-10 Rb;
or
(iv) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, heterocycloalkenyl including 3-10 atoms, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-10 Rc;
or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-10 Rd;
R2 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is:
(i) substituted with 1 R7, and
(ii) optionally substituted with from 1-5 Re;
wherein:
R7 is WA, wherein:
W is a bond;
—O—;
—NR8—;
C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene;
—W1(C1-6 alkylene)-;
or —(C1-6 alkylene)W1—;
W1 at each occurrence is, independently, —O— or —NR8—;
R8 is hydrogen;
C1-C6 alkyl;
A is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is:
(i) substituted with 1 R9, and
(ii) optionally further substituted with from 1-5 Rg;
R9 is:
(i) —W2—S(O)nR10 or —W2—S(O)nNR11R12;
or
(ii) —W2—C(O)OR13;
or
(iii) —W2—C(O)NR11R12;
or
(iv) —W2—CN;
or
(v) C1-C12 alkyl or C1-C12 haloalkyl, each of which is:
(a) substituted with 1 Rh, and
(b) optionally further substituted with from 1-5 Ra;
or
(vi) —NR14R15;
wherein:
W2 at each occurrence is, independently, a bond;
C1-6 alkylene optionally substituted with from 1-3 Rf;
C2-6 alkenylene;
C2-6 alkynylene;
C3-6 cycloalkylene;
—O(C1-6 alkylene)-, or —NR8(C1-6 alkylene)-;
n at each occurrence is, independently, 1 or 2;
R10 is:
(i) C1-C6 alkyl or C1-C6haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(ii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(iv) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
R11 and R12 are each, independently:
(i) hydrogen;
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
or
(iv) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
or
(vi) heterocyclyl including 3-10 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or
R11 and R12 together with the nitrogen atom to which they are attached form a heterocyclyl including 3-10 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
R13 is:
(i) hydrogen;
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
or
(iv) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
one of R14 and R15 is hydrogen or C1-C3 alkyl;
and the other of R14 and R15 is:
(i) —S(O)nR10;
or
(ii) —C(O)OR13;
or
(iii) —C(O)NR11R12;
or
(iv) C1-C12 alkyl or C1-C12 haloalkyl, each of which is:
(a) substituted with 1 Rh, and
(b) optionally further substituted with from 1-5 Ra;
each of R3, R4, and R5 is, independently:
(i) hydrogen;
or
(ii) halo;
or
(iii) C1-C6 alkyl or C1-C6haloalkyl, each of which is optionally substituted with from 1-3 Ra;
R6 is:
(i) hydrogen;
or
(ii) halo;
or
(iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra;
or
(iv) nitro;
C1-C6 alkoxy;
C1-C6 haloalkoxy;
C1-C6 thioalkoxy;
C1-C6 thiohaloalkoxy;
or cyano;
Ra at each occurrence is, independently:
(i) NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
C7-C11 aralkoxy, heteroaralkoxy including 6-11 atoms, C3-C11 cycloalkoxy, C3-C11 cycloalkenyloxy, heterocyclyloxy including 3-10 atoms, or heterocycloalkenyloxy including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or cyano;
or
(ii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
Rb at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C60 alkoxy or C1-C6 haloalkoxy;
C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
C7-C11 aralkoxy, heteroaralkoxy including 6-11 atoms, C3-C10 cycloalkoxy, C3-C10 cycloalkenyloxy, heterocyclyloxy including 3-10 atoms, or heterocycloalkenyloxy including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or cyano;
or
(ii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(iii) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
Rc at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
or cyano;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
Rd at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
or cyano;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
Re at each occurrence is, independently, C1-C6 alkyl;
C1-C6 haloalkyl;
halo;
hydroxyl;
NRmRn;
C1-C6 alkoxy;
C1-C6 haloalkoxy;
C3-C6 cycloalkoxy;
or cyano;
or
Rg at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
or cyano;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl;
Rh at each occurrence is, independently, hydroxyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
C3-C10 cycloalkoxy or C3-C10 cycloalkenyloxy, each of which is optionally substituted with from 1-5 Rc;
or C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
each of Rm and Rn, at each occurrence is, independently, hydrogen;
or C1-C6 alkyl, or C1-C6 haloalkyl;
or an N-oxide and/or a pharmaceutically acceptable salt thereof;
provided that when:
(i) R2 is phenyl that is monosubstituted at the meta position with WA;
and
(ii) W is a bond;
and
(iii) A is phenyl that is monosubstituted at the meta position with R9;
and
(iv) R9 is —W2—C(O)OR13;
and
(v) R13 is CH2CH3;
then one of R1, R3, R4, R5, or R6 must be a substituent other than hydrogen.

183 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/809,873Filed 19 Dec 2008
Priority: 21 Dec 2007
Published: 10 Feb 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 235/08
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2: radicals containing only hydrogen and…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application61/016,070Us provisional application · filed 21 Dec 2007
US 2011/0034526 A1This patent

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

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Abstract

A compound having formula (I):

wherein:
R1 is:
(i) hydrogen;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-10 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-10 Rb;
or
(iv) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, heterocycloalkenyl including 3-10 atoms, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-10 Rc;
or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-10 Rd;
R2 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is:
(i) substituted with 1 R7, and
(ii) optionally substituted with from 1-5 Re;
wherein:
R7 is WA, wherein:
W is a bond;
—O—;
—NR8—;
C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene;
—W1(C1-6 alkylene)-;
or —(C1-6 alkylene)W1—;
W1 at each occurrence is, independently, —O— or —NR8—;
R8 is hydrogen;
C1-C6 alkyl;
A is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is:
(i) substituted with 1 R9, and
(ii) optionally further substituted with from 1-5 Rg;
R9 is:
(i) —W2—S(O)nR10 or —W2—S(O)nNR11R12;
or
(ii) —W2—C(O)OR13;
or
(iii) —W2—C(O)NR11R12;
or
(iv) —W2—CN;
or
(v) C1-C12 alkyl or C1-C12 haloalkyl, each of which is:
(a) substituted with 1 Rh, and
(b) optionally further substituted with from 1-5 Ra;
or
(vi) —NR14R15;
wherein:
W2 at each occurrence is, independently, a bond;
C1-6 alkylene optionally substituted with from 1-3 Rf;
C2-6 alkenylene;
C2-6 alkynylene;
C3-6 cycloalkylene;
—O(C1-6 alkylene)-, or —NR8(C1-6 alkylene)-;
n at each occurrence is, independently, 1 or 2;
R10 is:
(i) C1-C6 alkyl or C1-C6haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(ii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(iv) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
R11 and R12 are each, independently:
(i) hydrogen;
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
or
(iv) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
or
(vi) heterocyclyl including 3-10 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or
R11 and R12 together with the nitrogen atom to which they are attached form a heterocyclyl including 3-10 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
R13 is:
(i) hydrogen;
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
or
(iv) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
one of R14 and R15 is hydrogen or C1-C3 alkyl;
and the other of R14 and R15 is:
(i) —S(O)nR10;
or
(ii) —C(O)OR13;
or
(iii) —C(O)NR11R12;
or
(iv) C1-C12 alkyl or C1-C12 haloalkyl, each of which is:
(a) substituted with 1 Rh, and
(b) optionally further substituted with from 1-5 Ra;
each of R3, R4, and R5 is, independently:
(i) hydrogen;
or
(ii) halo;
or
(iii) C1-C6 alkyl or C1-C6haloalkyl, each of which is optionally substituted with from 1-3 Ra;
R6 is:
(i) hydrogen;
or
(ii) halo;
or
(iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra;
or
(iv) nitro;
C1-C6 alkoxy;
C1-C6 haloalkoxy;
C1-C6 thioalkoxy;
C1-C6 thiohaloalkoxy;
or cyano;
Ra at each occurrence is, independently:
(i) NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
C7-C11 aralkoxy, heteroaralkoxy including 6-11 atoms, C3-C11 cycloalkoxy, C3-C11 cycloalkenyloxy, heterocyclyloxy including 3-10 atoms, or heterocycloalkenyloxy including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or cyano;
or
(ii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
Rb at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C60 alkoxy or C1-C6 haloalkoxy;
C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
C7-C11 aralkoxy, heteroaralkoxy including 6-11 atoms, C3-C10 cycloalkoxy, C3-C10 cycloalkenyloxy, heterocyclyloxy including 3-10 atoms, or heterocycloalkenyloxy including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or cyano;
or
(ii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-5 Rc;
or
(iii) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
Rc at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
or cyano;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
Rd at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
or cyano;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-5 Ra;
or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-5 Rb;
Re at each occurrence is, independently, C1-C6 alkyl;
C1-C6 haloalkyl;
halo;
hydroxyl;
NRmRn;
C1-C6 alkoxy;
C1-C6 haloalkoxy;
C3-C6 cycloalkoxy;
or cyano;
or
Rg at each occurrence is, independently:
(i) halo;
NRmRn;
hydroxy;
C1-C6 alkoxy or C1-C6 haloalkoxy;
or cyano;
or
(ii) C1-C6 alkyl or C1-C6 haloalkyl;
Rh at each occurrence is, independently, hydroxyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
C3-C10 cycloalkoxy or C3-C10 cycloalkenyloxy, each of which is optionally substituted with from 1-5 Rc;
or C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-5 Rd;
each of Rm and Rn, at each occurrence is, independently, hydrogen;
or C1-C6 alkyl, or C1-C6 haloalkyl;
or an N-oxide and/or a pharmaceutically acceptable salt thereof;
provided that when:
(i) R2 is phenyl that is monosubstituted at the meta position with WA;
and
(ii) W is a bond;
and
(iii) A is phenyl that is monosubstituted at the meta position with R9;
and
(iv) R9 is —W2—C(O)OR13;
and
(v) R13 is CH2CH3;
then one of R1, R3, R4, R5, or R6 must be a substituent other than hydrogen.

183 more elements

Facts

Application

12/809,873Filed 19 Dec 2008

Priority

21 Dec 2007

Published

10 Feb 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 235/08
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2: radicals containing only hydrogen and…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents