Compounds for the treatment of neurodegenerative disorders
The present invention relates to compounds of the Formula wherein R 3 , R 5 , R 7 , U, X, Y and Z are as defined. Compounds of the Formula I have activity inhibiting production of Aβ-peptide. This invention also relates to pharmaceutical compositions and methods of treating diseases, for example, neurodegenerative diseases, e.g., Alzheimer's disease, in a mammal comprising compounds of the Formula I.
1. A compound of the formula I-A
wherein Z is selected from —C(═O)CHR 1 R 2 , —C(═S)CHR 1 R 2 , —(C═NR 8 )CHR 1 R 2 , —C(═O)C(═O)R 1 and —S(O) 2 —R 1 ;
R 1 is selected from —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 1 -C 20 alkoxy, —C 2 -C 20 alkenoxy, —C 2 -C 20 alkynoxy, —C 3 -C 20 cycloalkyl, —C 4 -C 20 cycloalkenyl, (C 10 -C 20 )bi- or tricycloalkyl, (C 10 -C 20 )bi- or tricycloalkenyl, (4-20 membered) heterocycloalkyl, —C 6 -C 20 aryl and (5-20 membered) heteroaryl;
wherein R 1 is optionally independently substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R 1a ;
R 1a is in each instance independently selected from —OH, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —CF 3 , —OCF 3 , —Cl, —Br, —I, —ON, —NO 2 , —NR 9 R 10 , —C(═O)NR 9 R 10 , —SO 2 —NR 9 R 10 , —C(═O)R 11 , —S(O) n —R 11 , —C 3 -C 15 cycloalkyl, —C 4 -C 15 cycloalkenyl, —(C 5 -C 11 )bi- or tricycloalkyl, —(C 7 -C 11 )bi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl, —C 6 -C 15 aryl, -(5-15 membered) heteroaryl, —C 6 -C 15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy are each optionally independently substituted with from one to three substituents independently selected from the group R 1b ;
R 1b is in each instance independently selected from —OH, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —C 1 -C 6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —NR 9 R 10 , —C(═O)NR 9 R 10 , —C(═O)R 11 , —S(O) n —R 11 , —C 6 -C 15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl are each optionally independently substituted with from one to six fluorine atoms or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group;
R 9 and R 10 are in each instance each independently selected from —H, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2-C 12 alkynyl, —CF 3 , —C(═O)R 11 , —S(O) n —R 11 , —C(═O)OR 12 , —C(═O)NR 11 R 12 , —SO 2 —NR 11 R 12 , —(C zero -C 4 alkylene)-(C 3 -C 20 cycloalkyl), —(C zero -C 4 alkylene)-(C 4 -C 8 cycloalkenyl), —(C zero -C 4 alkylene)-((C 5 -C 11 )bi- or tricycloalkyl), —(C zero -C 4 alkylene)-((C 7 -C 11 )bi- or tricycloalkenyl), —(C zero -C 4 alkylene)-((5-10 membered) heterocycloalkyl), (C zero -C 4 alkylene)-(C 6 -C 10 aryl) and —(C zero -C 4 alkylene)-((5-10 membered) heteroaryl), wherein said aryl, heteroaryl, alkyl, alkenyl and alkynyl are each optionally independently substituted with from one to six fluorine atoms or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group, and wherein said cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl are each optionally independently substituted with from one to three substituents independently selected from —OH, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —C 1 -C 6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —NH 2 , —C(═O)NH 2 , —SO 2 —NR 9 R 10 , —C(═O)H and —C(═O)OH, wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group;
or NR 9 R 10 may in each instance independently optionally form a heterocycloalkyl moiety of from four to ten ring members, said heterocycloalkyl moiety optionally containing one to two further heteroatoms independently selected from N, O and S, and optionally containing from one to three double bonds, wherein the carbon atoms of the heterocycloalkyl moiety of NR 9 R 10 are optionally independently substituted with from one to three substituents independently selected from —OH, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —F, —Cl, —Br, —I, —CF 3 , —NH 2 , —C(═O)NH 2 , —SO 2 —NH 2 , —C(═O)R 11 , —S(O) n —R 11 , (C zero -C 4 alkylene)-(C 6 -C 10 aryl), (C zero -C 4 alkylene)-((5-10 membered heteroaryl), (C zero -C 4 alkylene)-(C 6 -C 10 cycloalkyl) and (C zero -C 4 alkylene)-((5-10 membered) heterocycloakyl, and wherein the (C zero -C 4 alkylene)-((5-10 membered) heterocycloalkyl) substituent and the nitrogen atoms of said heterocycloalkyl moiety of NR 9 R 10 are each optionally independently substituted with one substituent independently selected from —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C(═O)NH 2 , —SO 2 NH 2 , C(═O)R 11 , —S(O) n —R 11 , (C zero -C 4 alkylene)-(C 6 -C 10 aryl), (C zero -C 4 alkylene)-((5-10 membered) heteroaryl), —(C zero -C 4 alkylene)-(C 6 -C 10 cycloalkyl) and (C zero -C 4 alkylene)-((5-10 membered) heterocycloalkyl), and wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms, or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group;
R 11 and R 12 are in each instance each independently selected from —C 1 -C 15 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —(C zero -C 4 alkylene)-(C 3 -C 15 cycloalkyl), —(C zero -C 4 alkylene)-(C 4 -C 8 cycloalkenyl), —(C zero -C 4 alkylene)-((C 5 -C 11 )bi- or tricycloalkyl), —(C zero -C 4 alkylene)-((C 7 -C 11 )bi- or tricycloalkenyl), —(C zero -C 4 alkylene)-(C 6 -C 15 aryl), —(C zero -C 4 alkylene)-((5-15 membered) heterocycloalkyl) and —(C zero -C 4 alkylene)-((5-15 membered) heteroaryl);
wherein R 11 and R 12 are each optionally independently substituted with from one to three substituents independently selected from the group consisting of: —OH, C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —C 1 -C 6 hydroxyalkyl, —F, ——Cl, —Br, —I, —CN, NO 2 , C 6 -C 15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl, are each optionally independently substituted with from one to six fluorine atoms or with from one to two substituents independently selected from C 1 -C 4 alkoxy, or with a hydroxy group;
R 2 is selected from —H, —OH, —NH 2 , —CH 2 OH, —OC(═O)CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 )(CH 2 OH 3 )(OH), —C(OH)(C zero -C 4 alkyl)(C zero -C 4 alkyl), —OC(═O)R 4 and —OC(═O)OR 4 , wherein said —OC(═O)R 4 and —OC(═O)OR 4 may optionally be a prod rug of the corresponding OH of R 2 ;
R 3 is selected from —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl and —(C zero -C 4 alkylene)-(C 3 -C 6 cycloalkyl), wherein when R 3 is alkyl, alkenyl or alkynyl, R 3 is optionally independently substituted with a substituent independently selected from —C 1 -C 4 alkoxy, —OH and —F;
R 4 is selected from —C 1 -C 4 alkyl, —CH(OH)(C 1 -C 4 alkyl), —CH(OH)(C 5 -C 6 aryl), —CH(OH)((5-6 membered) heteroaryl), —CH(OH)(C 5 -C 6 cycloalkyl), and —CH(OH)((5-6 membered) heterocycloalkyl);
R 5 is selected from —H, —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —C 2 -C 4 alkynyl, —C(═O)(C 1 -C 4 alkyl), —C 6 -C 10 aryl, -(5-20 membered) heteroaryl, —SO 2 -(C 6 -C 10 aryl), —SO 2 -((5-20 membered) heteroaryl), —SO 2 —CH 2 -(C 6 -C 20 aryl) and —SO 2 —CH 2 -((5-20 membered) heteroaryl);
R 7 is selected from C 1 -C 20 alkyl, —(C zero -C 4 alkylene)-(C 3 -C 20 cycloalkyl), —(C zero -C 4 alkylene)-(C 4 -C 20 cycloalkenyl), —(C zero -C 4 alkylene)-((C 10 -C 20 )bi- or tricycloalkyl), —(C zero -C 4 alkylene)-((C 10 -C 20 )bi- or tricycloalkenyl), —(C zero -C 4 alkylene)-((3-20 membered) heterocycloalkyl), —(C zero -C 4 alkylene)-(C 6 -C 15 aryl) and —(C zero -C 4 alkylene)-((5-15 membered) heteroaryl), wherein said heterocycloalkyl optionally contains from one to four double or triple bonds;
wherein R 7 optionally substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R 1a ;
R 8 is selected from —H and —C 1 -C 6 alkyl;
or, when Z is —C(═NR 8 )CHR 1 R 2 , R 8 and R 1 may together with the nitrogen and carbon atoms to which they are respectively attached optionally form a five to fourteen membered heteroaryl ring or a five to eight membered heterocycloalkyl ring, wherein said heteroaryl or heterocycloalkyl ring optionally contains from one to two further heteroatoms selected from N, O and S, and wherein said heterocycloalkyl ring optionally contains from one to three double bonds, and wherein said heteroaryl or heterocycloalkyl ring is optionally substituted with from one to three substituents independently selected from the group R 1b ; and
n is 0, 1, 2; or
a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R is —H, —OH, or —OC(═O)CH 3 , or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 , wherein R 2 is —OH, or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 , wherein R is selected from —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 20 cycloalkyl, (4-20 membered) heterocycloalkyl, —C 6 -C 20 aryl and (5-20 membered) heteroaryl; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 , wherein:
Z is —C(═O)CHR 1 R 2 ;
R 1 is —C 1 -C 20 alkyl; and
R 2 is —H, —OH or OC(═O)CH 3 ; or
a pharmaceutically acceptable salt thereof.
6. A compound according to claim 5 , wherein R 2 is —H or —OH; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 6 , wherein R 2 is —OH; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , wherein:
Z is —C(═O)CHR 1 R 2 ;
R 1 is —C 1 -C 20 alkyl;
R 2 is —H, —OH or OC(═O)CH 3 ;
R 3 is —C 1 -C 6 alkyl;
R 5 is —H; and
R 7 is —C 1 -C 20 alkyl; or
a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 , wherein R 2 is —OH; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 8 , wherein:
R 1 is —C(CH 3 ) 3 ;
R 2 is —OH;
R 3 is —CH 2 CH 2 CH 3 ; and
R 7 is —C(CH 3 ) 3 ; or
a pharmaceutically acceptable salt thereof.
11. A compound of formula
wherein Z is selected from —C(═O)CHR 1 R 2 , —C(═S)CHR 1 R 2 , —(C═NR 8 )CHR 1 R 2 , —C(═O)C(═O)R 1 and —S(O) 2 —R 1 ;
R 1 is selected from —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 1 -C 20 alkoxy, —C 2 -C 20 alkenoxy, —C 2 -C 20 alkynoxy, —C 3 -C 20 cycloalkyl, —C 4 -C 20 cycloalkenyl, (C 10 -C 20 )bi- or tricycloalkyl, (C 10 -C 20 )bi- or tricycloalkenyl, (4-20 membered) heterocycloalkyl, —C 6 -C 20 aryl and (5-20 membered) heteroaryl;
wherein R 1 is optionally independently substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R 1a ;
R 1a is in each instance independently selected from —OH, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —CF 3 , —OCF 3 , —Cl, —Br, —I, —ON, —NO 2 , —NR 9 R 10 , —C(═O)NR 9 R 10 , —SO 2 —NR 9 R 10 , —C(═O)R 11 , —S(O) n —R 11 , —C 3 -C 15 cycloalkyl, —C 4 -C 15 cycloalkenyl, —(C 5 -C 11 )bi- or tricycloalkyl, —(C 7 -C 11 )bi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl, —C 6 -C 15 aryl, -(5-15 membered) heteroaryl, —C 6 -C 15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy are each optionally independently substituted with from one to three substituents independently selected from the group R 1b ;
R 1b is in each instance independently selected from —OH, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —C 1 -C 6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —NR 9 R 10 , —C(═O)NR 9 R 10 , —C(═O)R 11 , —S(O) n —R 11 , —C 6 -C 15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl are each optionally independently substituted with from one to six fluorine atoms or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group;
R 9 and R 10 are in each instance each independently selected from —H, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2-C 12 alkynyl, —CF 3 , —C(═O)R 11 , —S(O) n —R 11 , —C(═O)OR 12 , —C(═O)NR 11 R 12 , —SO 2 —NR 11 R 12 , —(C zero -C 4 alkylene)-(C 3 -C 20 cycloalkyl), —(C zero -C 4 alkylene)-(C 4 -C 8 cycloalkenyl), —(C zero -C 4 alkylene)-((C 5 -C 11 )bi- or tricycloalkyl), —(C zero -C 4 alkylene)-((C 7 -C 11 )bi- or tricycloalkenyl), —(C zero -C 4 alkylene)-((5-10 membered) heterocycloalkyl), (C zero -C 4 alkylene)-(C 6 -C 10 aryl) and —(C zero -C 4 alkylene)-((5-10 membered) heteroaryl), wherein said aryl, heteroaryl, alkyl, alkenyl and alkynyl are each optionally independently substituted with from one to six fluorine atoms or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group, and wherein said cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl are each optionally independently substituted with from one to three substituents independently selected from —OH, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —C 1 -C 6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —NH 2 , —C(═O)NH 2 , —SO 2 —NR 9 R 10 , —C(═O)H and —C(═O)OH, wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group;
or NR 9 R 10 may in each instance independently optionally form a heterocycloalkyl moiety of from four to ten ring members, said heterocycloalkyl moiety optionally containing one to two further heteroatoms independently selected from N, O and S, and optionally containing from one to three double bonds, wherein the carbon atoms of the heterocycloalkyl moiety of NR 9 R 10 are optionally independently substituted with from one to three substituents independently selected from —OH, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —F, —Cl, —Br, —I, —CF 3 , —NH 2 , —C(═O)NH 2 , —SO 2 —NH 2 , —C(═O)R 11 , —S(O) n —R 11 , (C zero -C 4 alkylene)-(C 6 -C 10 aryl), (C zero -C 4 alkylene)-((5-10 membered heteroaryl), (C zero -C 4 alkylene)-(C 6 -C 10 cycloalkyl) and (C zero -C 4 alkylene)-((5-10 membered) heterocycloakyl, and wherein the (C zero -C 4 alkylene)-((5-10 membered) heterocycloalkyl) substituent and the nitrogen atoms of said heterocycloalkyl moiety of NR 9 R 10 are each optionally independently substituted with one substituent independently selected from —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C(═O)NH 2 , —SO 2 —NH 2 , C(═O)R 11 , —S(O) n —R 11 , (C zero -C 4 alkylene)-(C 6 -C 10 aryl), (C zero -C 4 alkylene)-((5-10 membered) heteroaryl), —(C zero -C 4 alkylene)-(C 6 -C 10 cycloalkyl) and (C zero -C 4 alkylene)-((5-10 membered) heterocycloalkyl), and wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms, or with from one to two substituents independently selected from —C 1 -C 4 alkoxy, or with a hydroxy group;
R 11 and R 12 are in each instance each independently selected from —C 1 -C 15 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —(C zero -C 4 alkylene)-(C 3 -C 15 cycloalkyl), —(C zero -C 4 alkylene)-(C 4 -C 8 cycloalkenyl), —(C zero -C 4 alkylene)-((C 5 -C 11 )bi- or tricycloalkyl), —(C zero -C 4 alkylene)-((C 7 -C 11 )bi- or tricycloalkenyl), —(C zero -C 4 alkylene)-(C 6 -C 15 aryl), —(C zero -C 4 alkylene)-((5-15 membered) heterocycloalkyl) and —(C zero -C 4 alkylene)-((5-15 membered) heteroaryl);
wherein R 11 and R 12 are each optionally independently substituted with from one to three substituents independently selected from the group consisting of: —OH, C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenoxy, —C 2 -C 6 alkynoxy, —C 1 -C 6 hydroxyalkyl, —F, ——Cl, —Br, —I, —CN, NO 2 , C 6 -C 15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl, are each optionally independently substituted with from one to six fluorine atoms or with from one to two substituents independently selected from C 1 -C 4 alkoxy, or with a hydroxy group;
R 2 is selected from —H, —OH, —NH 2 , —CH 2 OH, —OC(═O)CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 )(CH 2 COH 3 )(OH), —C(OH)(C zero -C 4 alkyl)(C zero -C 4 alkyl), —OC(═O)R 4 and —OC(═O)OR 4 , wherein said —OC(═O)R 4 and —OC(═O)OR 4 may optionally be a prod rug of the corresponding OH of R 2 ;
R 3 is selected from —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl and —(C zero -C 4 alkylene)-(C 3 -C 6 cycloalkyl), wherein when R 3 is alkyl, alkenyl or alkynyl, R 3 is optionally independently substituted with a substituent independently selected from —C 1 -C 4 alkoxy, —OH and —F;
R 4 is selected from —C 1 -C 4 alkyl, —CH(OH)(C 1 -C 4 alkyl), —CH(OH)(C 5 -C 6 aryl), —CH(OH)((5-6 membered) heteroaryl), —CH(OH)(C 5 -C 6 cycloalkyl), and —CH(OH)((5-6 membered) heterocycloalkyl);
R 5 is selected from —H, —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —C 2 -C 4 alkynyl, —C(═O)(C 1 -C 4 alkyl), —C 6 -C 10 aryl, -(5-20 membered) heteroaryl, —SO 2 -(C 6 -C 10 aryl), —SO 2 -((5-20 membered) heteroaryl), —SO 2 —CH 2 —(C 6 -C 20 aryl) and —SO 2 —CH 2 -((5-20 membered) heteroaryl);
R 7 is selected from C 1 -C 20 alkyl, —(C zero -C 4 alkylene)-(C 3 -C 20 cycloalkyl), —(C zero -C 4 alkylene)-(C 4 -C 20 cycloalkenyl), —(C zero -C 4 alkylene)-((C 10 -C 20 )bi- or tricycloalkyl), —(C zero -C 4 alkylene)-((C 10 -C 20 )bi- or tricycloalkenyl), —(C zero -C 4 alkylene)-((3-20 membered) heterocycloalkyl), —(C zero -C 4 alkylene)-(C 6 -C 15 aryl) and —(C zero -C 4 alkylene)-((5-15 membered) heteroaryl), wherein said heterocycloalkyl optionally contains from one to four double or triple bonds;
wherein R 7 optionally substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R 1a ;
R 8 is selected from —H and —C 1 -C 6 alkyl;
or, when Z is —C(═NR 8 )CHR 1 R 2 , R 8 and R 1 may together with the nitrogen and carbon atoms to which they are respectively attached optionally form a five to fourteen membered heteroaryl ring or a five to eight membered heterocycloalkyl ring, wherein said heteroaryl or heterocycloalkyl ring optionally contains from one to two further heteroatoms selected from N, O and S, and wherein said heterocycloalkyl ring optionally contains from one to three double bonds, and wherein said heteroaryl or heterocycloalkyl ring is optionally substituted with from one to three substituents independently selected from the group R 1b ; and
n is 0, 1, 2; or
a pharmaceutically acceptable salt thereof.
12. A compound according to claim 11 , wherein R 2 is —H, —OH, or —OC(═O)CH 3 , or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 12 , wherein R 2 is —OH, or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 11 , wherein R 1 is selected from —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 20 cycloalkyl, (4-20 membered) heterocycloalkyl, —C 6 -C 20 aryl and (5-20 membered) heteroaryl; or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 11 , wherein:
Z is —C(═O)CHR 1 R 2 ;
R 1 is —C 1 -C 20 alkyl; and
R 2 is —H, —OH or OC(═O)CH 3 ; or
a pharmaceutically acceptable salt thereof.
16. A compound according to claim 15 , wherein R 2 is —H or —OH; or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 16 , wherein R 2 is —OH; or a pharmaceutically acceptable salt thereof.
18. A compound according to claim 11 , wherein:
Z is —C(═O)CHR 1 R 2 ;
R 1 is —C 1 -C 20 alkyl;
R 2 is —H, —OH or OC(═O)CH 3 ;
R 3 is —C 1 -C 6 alkyl;
R 5 is —H; and
R 7 is —C 1 -C 20 alkyl; or
a pharmaceutically acceptable salt thereof.
19. A compound according to claim 18 , wherein:
R 1 is —C(CH 3 ) 3 ;
R 2 is —OH;
R 3 is —CH 2 CH 2 CH 3 ; and
R 7 is —C(CH 3 ) 3 ; or
a pharmaceutically acceptable salt thereof.