Back to results
US 7,605,264 B2Granted
Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
AssigneeBristol-Myers Squibb Company
InventorsDavid S. Weinstein, James Sheppeck, John L. Gilmore
Life of this patent
Estimating the term…
Abstract
Novel non-steroidal compounds are provided which 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, and have the structure of formula (I) or stereoisomers or prodrugs or solvates or pharmaceutically acceptable salts thereof, wherein A, B, J, K, Z, R, Ra, Rb, Rc, and Rd, are defined herein. Also provided are pharmaceutical compositions and methods of treating obesity, diabetes and inflammatory or immune associated diseases comprising said compounds.
Claims15
A compound of formula I:
- including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein
- J and K are the same or different and are independently selected from —C═ or —N—;
- R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, hydroxyaryl and NR1R2, wherein R1 and R2 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl, hydroxyalkyl, and a heterocyclic ring;
- Ra is hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano, heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO2 alkyl, CONReRf, CH2NRgRh, CO2H, CH2OH, CH2NRH, NRgRh, NHCH2Rg, NHCHRgRh, NHCORe, NHCONReRf or NHSO2ReRf;
- Rb is hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano, halo, heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO2 alkyl, hydroxyaryl, aryloxyalkyl, CONRiRj, CH2NRkRl, CO2H, CH2OH, CH2NHRk, NHCH2Rk, NRkRl, NHCHRkRl, NHCORi, NHCONRiRj or NHSO2Ri,
- where Re and Rf are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl;
- or Re and Rf can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
- Rg and Rh are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl;
- or Rg and Rh can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
- Ri and Rj are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl;
- or Ri and Rj can be taken together with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
- Rk and Rl are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl;
- or Rk and Rl can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, or S;
- Rc and Rd are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, hydroxyaryl, and aryloxyalkyl;
- or
- Rc and Rd are taken together with the carbon to which they are attached to form a 3- to 7-membered ring which may optionally include an O atom or an N atom;
- Z is independently selected from the group consisting of CONR1R2, CH2NR1R2, SONR1R2 and SO2NR1R2, wherein R1 and R2 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl, hydroxyalkyl, or a heterocyclic ring;
- one of A and B is an optionally substituted 5-membered heterocyclic ring and the other is selected from an optionally substituted carbocyclic or heterocyclic ring;
- and
- wherein heteroaryl is unsubstituted or is substituted by one to four substituents selected from:
- halo, (including F, Br, Cl or I), CF3, alkoxy, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, HO—N═, cycloheteroalkyl, alkyloxycarbonyl, alkoxyoximyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, hydroxyalkyl (alkyl)amino carbonyl, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl, alkylthio, alkyl, haloalkoxy, trifluoromethoxy, alkynyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, carboxy, cycloalkyl, arylalkoxy, aryloxycarbonyl, cycloalkylaminocarbonyl, cycloalkylalkylaminocarbonyl, alkoxycarbonylalkyl, alkoxyalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, arylalkylaminocarbonyl, N-hydroxyalkyl(N-alkyl)aminocarbonyl, cycloheteroalkylaminocarbonyl, cycloheteroalkylalkylaminocarbonyl, N-aryl(N-alkyl)aminocarbonyl, N-arylalkyl(N-cyanoalkyl)aminocarbonyl, dialkylaminoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl-, arylalkyl- or aryl-cycloheteroalkylaminocarbonyl, N-dialkylaminoalkyl(N-alkyl or N-arylalkyl)aminocarbonyl, N-heteroarylalkyl(N-alkyl)aminocarbonyl, N-arylalkyl(N-alkyl)aminocarbonyl, N-dialkylamino(N-arylalkyl)aminocarbonyl, N-hydroxyalkyl(N-arylalkyl)aminocarbonyl, aminoalkyloxycarbonyl, cycloheteroalkylcarbonyl, N═N═N, alkylsulfonyl, aminosulfonyl, and heteroarylaminosulfonyl;
- provided that when both J and K are C═;
- R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl;
- Z is CONR1R2 or CH2NR1R2 wherein R1 and R2 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl or hydroxyalkyl.
21 more elements
A compound having the structure
- including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where R is alkyl;
- Rb1 is hydrogen or alkyl;
- X2 is N or CR16;
- R16 is the same or different and is independently hydrogen, hydroxy or alkyl;
- and X is aryl, arylalkyl, alkyl, heteroaryl, or heteroarylalkyl;
- or
- including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where R is alkyl;
- Rb2 is hydrogen or alkyl;
- X2 is N or CR16;
- R16 is the same or different and is independently hydrogen, hydroxy or alkyl;
- and Xa is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl or halo;
- or
- including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where R is alkyl;
- Rb3 is hydrogen or alkyl;
- X2 is N or CR16;
- R16 is the same or different and is independently hydrogen, hydroxy or alkyl;
- and Xb is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl or halo;
- or
- including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where R is alkyl;
- Rb4 is hydrogen, CO2 alkyl, nitro, cyano, formyl, cycloheteroalkylcarbonyl, alkylaminoalkyl or amino;
- X2 is N or CR16;
- Xc is fluoro;
- R16 is the same or different and is independently hydrogen, hydroxy or alkyl;
- and
- X is hydrogen, alkyl or halo;
- or
- including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where W is S or NH;
- Rb5 is hydrogen, CO2 alkyl, nitro, cyano, formyl, cycloheteroalkylcarbonyl, alkylaminoalkyl or amino;
- X2 is N or CR16;
- R16 is the same or different and is independently hydrogen, hydroxy or alkyl;
- T is a cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl ring, each ring substituted by 0-4 R5 and 0-1 R6;
- R3 and R4 are independently at each occurrence hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cyano, nitro, or CHO;
- or R3 and R4 combine to form ═O or a ═C, wherein the C of ═C is substituted by hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, substituted amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl;
- and
- R5 and R6 are, independently at each occurrence, hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano, heteroarylaminocarboyl, cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl, nitro, oxo, CHO, CO2 alkyl, hydroxyaryl, aryloxyalkyl, CO2H, or CH2OH;
- or R5 and R6 located on adjacent atoms can be taken together to form an optionally substituted cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl ring.
33 more elements
Dependencies are inferred from the claim text.