Back to results
US 2007/0179142 A1Published application
Amido compounds and their use as pharmaceuticals
OwnerWenqing Yao, Jincong Zhuo +5inventors
InventorsWenqing Yao, Jincong Zhuo, Meizhong Xu, Brian Metcalf, Chunhong He, Ding-Quan Qian, Colin Zhang
Life of this patent
Estimating the term…
Abstract
The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.
Claims38
A compound of Formula I:
- or pharmaceutically acceptable salt or prodrug thereof, wherein:
- Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 —W—X—Y-Z;
- R1 and R2 together with the C atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R5;
- R3 and R4 together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 —W′—X′—Y′-Z′;
- R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
- W, W′ and W″ are each, independently, absent, C1-6 alkylenyl, C1-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, CS, COO, CONRe, OCONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- X, X′ and X″ are each, independently, absent, C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- Y, Y′ and Y″ are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, CS, COO, CONRe, OCONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- Z, Z′ and Z″ are each, independently, H, halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
- wherein two —W—X—Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″;
- wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″;
- wherein —W—X—Y-Z is other than H;
- wherein —W′—X′—Y′-Z′ is other than H;
- wherein —W″—X″—Y″-Z″is other than H;
- Ra is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, (C1-6 alkoxy)-C1-6 alkyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
- Rb is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
- Rc and Rd are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
- or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
- and
- Re and Rf are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
- or Re and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
- with the provisos:
- a) when R3 and R4 together with the N-atom to which they are attached form piperidinyl, said piperidinyl is unsubstituted or substituted by other than:
- wherein:
- V is CH2CH2, CH═CH, or CH2O;
- and
- R is H, halo or C1-5 alkyl;
- and
- b) when R3 and R4 together with the N-atom to which they are attached form piperazinyl, said Cy is substituted by at least one —W—X—Y-Z.
26 more elements
A method of modulating activity of 11βHSD1 or MR comprising contacting said 11βHSD1 or said MR with a compound of Formula I:
- or pharmaceutically acceptable salt or prodrug thereof, wherein:
- Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 —W—X—Y-Z;
- R1 and R2 together with the C atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R5;
- R3 and R4 together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 —W′—X′—Y′-Z′;
- R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
- W, W′ and W″ are each, independently, absent, C1-6 alkylenyl, C1-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, CS, COO, CONRe, OCONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- X, X′ and X″ are each, independently, absent, C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- Y, Y′ and Y″ are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, CS, COO, CONRe, OCONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- Z, Z′ and Z″ are each, independently, absent, H, halo, oxo, sulfido, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
- wherein two —W—X—Y-Z attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″;
- wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″;
- wherein —W—X—Y-Z is other than H;
- wherein —W′—X′—Y′-Z′ is other than H;
- wherein —W″—X″—Y″-Z″ is other than H;
- Ra is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, (C1-6 alkoxy)-C1-6 alkyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
- Rb is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
- Rc and Rd are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
- or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
- and
- Re and Rf are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
- or Re and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
18 more elements
A method of treating a disease in a patient, wherein said disease is associated with expression or activity of 11βHSD1 or MR, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
- or pharmaceutically acceptable salt or prodrug thereof, wherein:
- Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 —W—X—Y-Z;
- R1 and R2 together with the C atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R5;
- R3 and R4 together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 —W′—X′—Y′-Z′;
- R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRCRd,C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
- W, W′ and W″ are each, independently, absent, C1-6 alkylenyl, C1-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, CS, COO, CONRe, OCONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- X, X′ and X″ are each, independently, absent, C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- Y, Y′ and Y″ are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, CS, COO, CONRe, OCONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
- Z, Z′ and Z″ are each, independently, absent, H, halo, oxo, sulfido, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
- wherein two —W—X—Y-Z attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″;
- wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″;
- wherein —W—X—Y-Z is other than H;
- wherein —W′—X′—Y′-Z′ is other than H;
- wherein —W″—X″—Y″-Z″ is other than H;
- Ra is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, (C1-6 alkoxy)-C1-6 alkyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
- Rb is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
- Rc and Rd are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
- or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
- and
- Re and Rf are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
- or Re and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
18 more elements
Dependencies are inferred from the claim text.