US 9,040,558 B2 · Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors

Abstract

The invention is directed to novel substituted benzylamino quinolines, compounds comprising substituted benzylamino quinolines, methods of making substituted benzylamino quinolines, the use of substituted benzylamino quinolines for treating or preventing a variety of conditions or diseases associated with lipoprotein metabolism, and the use of substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors.

A compound having the formula:

or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, or any combination thereof, wherein:
A is a substituted or an unsubstituted quinoline moiety having the formula:
wherein Ra, in each occurrence, is selected independently from:
1) a halogen;
a hydroxyl, or a cyano;
2) an alkyl or an alkoxy, any of which having up to 12 carbon atoms;
or 3) CO2R6;
and p is an integer from 0 to 3, inclusive;
R1 and R2 are selected independently from:
1) hydrogen;
2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
3) CO2R6, COR8, SO2R8, SO2NR6R7, or CONR6R7;
or 4) (CHRx)nR5 or (CH2)nRdCO2Re, wherein n, in each occurrence, is 1, 2, or 3;
Rx, in each occurrence, is selected independently from an alkyl or an alkoxy, either of which having up to 12 carbon atoms, or hydrogen;
Rd, in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
and Re, in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms, or hydrogen;
or R1 and R2 together with the diradical Z to which they are attached form a substituted or an unsubstituted monocyclic or bicyclic moiety comprising up to 12 carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms or heterogroups in addition to Z, selected independently from O, N, S, NR10, SO2, or CO;
R3 is selected from:
1) cyano;
2) a substituted alkyl having up to 12 carbon atoms;
3) a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from O, N, S, NR10, SO2, or CO;
or 4) CO2R6, COR8, SO2R8, SO2NR6R7, CONR6R7, C(S)NR6R7, C(S)NHC(O)OR8, or C(S)SR8;
or 5) a substituted or an unsubstituted group selected from 4,5-dihydro-oxazolyl, tetrazolyl, isoxazolyl, pyridyl, pyrimidinyl, oxadiazolyl, thiazolyl, or oxazolyl;
wherein any optional substituents is selected independently from a) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms;
or b) CO2R9, wherein R9 is an alkyl having up to 12 carbon atoms;
wherein when R3 is an aryl, a heterocyclyl, or a heteroaryl, R3 is optionally substituted with up to three substituents selected independently from a halide, a hydroxyl, a cyano, an alkoxy having up to 12 carbon atoms, or R11;
R4, in each occurrence, is selected independently from:
1) halogen, cyano, or hydroxy;
2) an alkyl, a cycloalkyl, a cycloalkoxy, an alkoxy, a haloalkyl, or a haloalkoxy, any of which having up to 12 carbon atoms;
3) a substituted or an unsubstituted aryl, aralkyl, aryloxy, heteroaryl, or heteroaryloxy, any of which having up to 12 carbon atoms, wherein any heteroaryl or heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from O, N, S, or NR10;
or 4) CO2R6, COR8, SO2R8, SO2NR6R7, CONR6R7, or (CH2)qNR6R7, wherein q is an integer from 0 to 5, inclusive;
m is an integer from 0 to 3, inclusive;
or R4m is a fused cyclic moiety comprising from 3 to 5 additional ring carbon atoms, inclusive, and optionally comprising at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
R5, in each occurrence, is selected independently from:
1) an alkoxy, a haloalkoxy, or a cycloalkyl, any of which having up to 12 carbon atoms;
2) a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
3) hydroxyl, NR6R7, CO2R6, COR8, or SO2R8;
or 4) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from O, N, S, NR10, SO2, or CO;
R6 and R7, in each occurrence, are selected independently from:
1) hydrogen;
2) an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms;
or 3) a substituted or an unsubstituted aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
or R6 and R7 together with the nitrogen atom to which they are attached form a substituted or an unsubstituted cyclic moiety having from 3 to 7 ring carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms in addition to the nitrogen atom to which R6 and R7 are bonded, selected independently from O, N, S, or NR10;
R8, in each occurrence, is selected independently from:
1) an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms;
or 2) a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
R10, in each occurrence, is selected independently from:
1) hydrogen;
or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
Z is N;
or the ZR1 moiety is S, CO, or SO2;
R11 is selected independently from:
1) an alkyl, a haloalkyl, a cycloalkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms;
2) a substituted or an unsubstituted heteroaryl or heterocyclyl, any of which having up to 12 carbon atoms, comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO, wherein any substituted heteroaryl or heterocyclyl is substituted with up to three substituents selected independently from an alkyl having up to 12 carbon atoms or a hydroxyl;
or
3) —CO—Z2—R13, —CO—R12, —CO—Z2—(CH2)r—CO—Z2—R13, —NR15R16, —Z2—CO—(CH2)r—Z2—R13, —Z2—CO—(CH2)r—CO—Z2—R13, —O—(CH2)r—CO—Z2—R13, —O—(CH2)r—R14, —O—R12—(CH2)r—R13, —O—R14—CO—O—R13, —O—(CH2)r—R12, —O—(CH2)r—NR′R″, —O—(CH2)r—CO2—(CH2)r—R13, —O—(CH2)r—CONR′R″, —O—(CH2)r—SR8, —O—(CH2)r—CO2—R13, —O—(CH2)r—O—(CH2)r—OR13, —O—(CH2)r—CONH—(CH2)r—OR13, —O—(CH2)r—SO2R8, —O—(CH2)r—R13, —O—(CH2)r—OR13, —S—(CH2)r—CONR′R″, —SO2—(CH2)r—OR13, —SO2—(CH2)r—CONR′R″, —(CH2)r—O—CO—R8, —(CH2)r—R12, —(CH2)r—R13, —(CH2)r—CO—Z2—R13, —(CH2)r—Z2—R13, or -alkenylene-CO2—(CH2)r—R13;
r, in each occurrence, is independently 1, 2, or 3;
R12, in each occurrence, is independently selected from a substituted or an unsubstituted heterocyclyl having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO, wherein any substituted heterocyclyl is substituted with up to three substituents selected independently from an acyl, an alkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms, or —COOH;
R13, in each occurrence, is independently selected from:
1) hydrogen;
or 2) a cycloalkyl, an aryl, a haloalkyl, a heterocyclyl, or an alkyl group optionally substituted with at least one hydroxyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
R14, in each occurrence, is independently selected from a heterocyclyl, a cycloalkyl, or an aryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
Z2, in each occurrence, is selected independently from NR10 or O;
R′ and R″, in each occurrence, are independently selected from hydrogen or an alkyl having up to 12 carbon atoms;
and
R15 and R16, in each occurrence, are independently selected from:
1) hydrogen;
2) an alkyl having up to 12 carbon atoms;
or 3) —(CH2)r—O—R13, —(CH2)r—R14, —COR13, —(CH2)r—CO—Z2—R13, —CO2R13, —CO2—(CH2)r—R13, —CO2—(CH2)r—R12, —CO2—(CH2)r—CO—Z2—R13, —CO2—(CH2)r—OR13, —CO—(CH2)r—O—(CH2)r—O—(CH2)r—R13, —CO—(CH2)r—O(CH2)r—OR13, or —CO—NH—(CH2)r—OR13;
or
R15 and R16 together with the nitrogen atom to which they are attached form a substituted or an unsubstituted cyclic moiety comprising up to 12 carbon atoms, optionally comprising at least one additional heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
wherein any substituted cyclic moiety is substituted with up to three substituents selected independently from:
1) hydroxyl;
2) an alkyl or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, or NR10;
or 3) COOR13, —Z2—(CH2)r—R13, —COR13, —CO2—(CH2)r—R13, —CO(CH2)r—O—R13, —(CH2)r—CO2—R13, —SO2R8, —SO2NR′R″, or —NR′R″;
wherein the —(CH2)r— linking moiety, in any occurrence, is optionally substituted with at least one group selected independently from hydroxyl, amino, or an alkyl having up to 3 carbon atoms;
when R1 and R2 do not form a monocyclic or bicyclic moiety, R1 and R2 are optionally substituted with 1 or 2 substituents, and when substituted, the substituents are selected independently from:
1) an alkyl, a cycloalkyl, a haloalkyl, an alkoxy, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR10, SO2, or CO;
or 2) halogen, cyano, or hydroxyl;
when R1 and R2 together with the diradical Z to which they are attached form a monocyclic or a bicyclic moiety, the cyclic moiety is optionally substituted with at least one substituent selected independently from:
1) halogen, cyano, or hydroxyl;
2) an alkyl, a haloalkyl, a cycloalkyl, an alkoxy, a cycloalkyl-substituted alkyl, an alkoxyalkyl, a cycloalkoxy, a haloalkoxy, an aryl, an aryloxy, an aralkyl, a heteroaryl or a heteroaryloxy, any of which having up to 12 carbon atoms, wherein any heteroaryl or heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from O, N, S, or NR10;
or 3) CO2R6, COR8, SO2R8, SO2NR6R7, or CONR6R7;
R4, R6, R7, and R8 are optionally substituted with at least one substituent, and when substituted, the substituents are selected independently from:
1) halide, hydroxy, cyano, or NR6R7;
or 2) an alkyl or an alkoxy, any of which having up to 12 carbon atoms;
and R5 is optionally substituted with at least one substituent, and when substituted, the substituents are selected independently from:
1) halide, hydroxy, cyano, or NR6R7;
or 2) an alkyl having up to 12 carbon atoms.

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Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors

Life of this patent

Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors

Life of this patent

Abstract

Claims28