US 2007/0185056 A1 · Indane modulators of glucocorticoid receptor, AP-1, and/or NF/kB activity and use thereof

Abstract

Novel non-steroidal compounds are provided that are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including obesity, diabetes, inflammatory and immune diseases having the structure of formula (I): or enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, where X is -A1QA2-; Q is a bond, —C(═O)—, —OC(O)—, —C(═O)NR5—, —SOp—, —SOpNR5—, —C(O)O—, —NR5C(O)—, —OC(O)NR5—, —NR5C(O)O—, —S(O)pNR5C(O)—, —C(O)NR5S(O)p— —NR5S(O)p—, or —NR5C(═O)NR6—. Y is selected from hydrogen, C1-4alkyl, OR16, substituted C1-6alkyl, cycloalkyl, aryl, heterocyclo and heteroaryl. A1 and A2 are independently selected from a bond, C1-3alkylene, or C1-3alkenylene, and R1-R11 are defined herein. Also provided are pharmaceutical compositions, combinations, and methods of treating obesity, diabetes and inflammatory- or immune-associated diseases comprising said compounds.

A compound according to formula (IA):

or an enantiomer, diastereomer, or a pharmaceutically-acceptable salt thereof, in which:
R1, R2, R3, and R4 are independently selected from (i) hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, azide, cyano, OR12, NR12R13, —(O), —C(═O)R12, —(O)t—CO2R12, —(O)t—C(═O)NR12R13, NR12C(═O)R13, NR12C(O)OR13, NR12C(S)OR13, S(O)pR18qR18, NR13S(O)pR18, N(S(O)pR18)2, S(O)pNR12R13, cycloalkyl, heterocyclo, aryl, or heteroaryl;
and/or (ii) together with the atoms to which they are attached one of R1-R4 is combined with another one of R1-R4 located on an adjacent carbon atom to form a fused ring;
X is -A1QA2-;
Q is a bond, —C(═O)—, —OC(O)—, —C(═O)NR5—, —SOp—, —SOpNR5—, —C(O)O—, —NR5C(O)—, —OC(O)NR5—, —NR5C(O)O—, —S(O)pNR5C(O)—, —C(O)NR5S(O)p— —NR5S(O)p—, or —NR5C(═O)NR6—;
A1 and A2 are independently selected from a bond, C1-3alkylene, and C1-3alkenyleneA1 and A2 are
R5 and R6 are independently selected from hydrogen, alkyl, substituted alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, heterocyclo, aryl, and heteroaryl;
R7, R8, R9, R10, and R11 are independently selected from:
(i) hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano, OR14, SR14, NR14R15, C(═O)R14, CO2R14, C(═O)NR14R15, —O—C(═O)R14, NR14C(═O)R15, NR14C(═O)OR15, NR14C(═S)OR15, S(O)pR19, NR14S(O)pR19, S(O)pNR14R15, cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl, provided that:
(a) if X is N—R5C(O)— where Y is attached to the nitrogen atom, then R7 is selected from a group other than NR14R15 or —NR14C(═O)R15;
and/or
(b) if X is —NR5C(O)— where Y is attached to the nitrogen atom and if one or more of R7, R8, R9, R10, and/or R1 is a heterocyclo, then the heterocyclo is selected from a group other than maleimide;
and/or
(ii) R8 and R9, and/or R10 and R11 are taken together to form an oxo, alkenyl, substituted alkenyl or, together with the atom to which they are both attached R8 and R9, and/or R10 and R11 combine to form a spirocyclic group;
and/or
(iii) R7 is taken together with one of R8 or R11 to form a double bond;
Y is selected from hydrogen, C1-6-alkyl, OR16, substituted C1-6alkyl, cycloalkyl, aryl, heterocyclo and heteroaryl;
provided that if X is —NR5C(O)— where Y is attached to the nitrogen atom, then Y is selected from a group other than pyridine, pyrimidine, pyridone r pyrazole substituted with a phenyl ring;
R12, R13, R14, R15, and R16 at each occurrence are independently selected from (i) hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo;
or (ii) together with the atoms to which they are attached R12 is combined with R13 and/or R14 is combined with R15 to form a heteroaryl or heterocyclo ring;
R18 and R19 at each occurrence are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo;
t at each occurrence is 0 or 1;
and
p at each occurrence is 1 or 2.

21 more elements

Indane modulators of glucocorticoid receptor, AP-1, and/or NF/kB activity and use thereof

Life of this patent

Indane modulators of glucocorticoid receptor, AP-1, and/or NF/kB activity and use thereof

Life of this patent

Abstract

Claims20