US 7,253,195 B2Granted

Compounds for the treatment of neurodegenerative disorders

AssigneePfizer Inc.

InventorYuhpyng L. Chen

Life of this patent

Estimating the term…

Abstract

The present invention relates to compounds of the Formula wherein R3, R5, R7, 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.

Claims20

Dependent claims

A compound of the formula

wherein the ring containing X, Y, U is an aromatic ring in which one of the X, Y, U is a S and the other two of the X, Y, U are N as shown below I-A to I-C:
wherein Z is selected from —C(═O)CHR1R2, —C(═S)CHR1R2, —(C═NR8)CHR1R2, —C(═O)C(═O)R1 and —S(O)2—R1;
R1 is selected from —C1-C20 alkyl, —C2-C20 alkenyl, —C2-C20 alkynyl, —C1-C20 alkoxy, —C2-C20 alkenoxy, —C2-C20 alkynoxy, —C3-C20 cycloalkyl, —C4-C20 cycloalkenyl, (C10-C20)bi- or tricycloalkyl, (C10-C20)bi- or tricycloalkenyl, (4-20 membered) heterocycloalkyl, —C6-C20 aryl and (5-20 membered) heteroaryl;
wherein R1 is optionally independently substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R1a;
R1a is in each instance independently selected from —OH, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —CF3, —OCF3, —Cl, —Br, —I, —CN, —NO2, —NR9R10, —C(═O)NR9R10, —SO2—NR9R10, —C(═O)R11—C(═O)OR12, —S(O)n—R11, —C3-C15 cycloalkyl, —C4-C15 cycloalkenyl, —(C5-C11)bi- or tricycloalkyl, —(C7-C11)bi- or tricycloalkenyl,
-(4-20 membered) heterocycloalkyl, —C6-C15 aryl, -(5-15 membered) heteroaryl, —C6-C15 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 R1b;
R1b is in each instance independently selected from —OH, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —C1-C6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO2, —NR9R10, —C(═O)NR9R10, —C(═O)R11, —S(O)n—R11, —C6-C15 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 —C1-C4 alkoxy, or with a hydroxy group;
R9 and R10 are in each instance each independently selected from —H, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —CF3, —C(═O)R11, —S(O)n—R11, —C(═O)OR12,
—C(═O)NR11R12, —SO2—NR11R12, —(Czero-C4 alkylene)-(C3-C20 cycloalkyl), —(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), —(Czero-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), —(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), —(Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl), (Czero-C4 alkylene)-(C6-C10 aryl) and —(Czero-C4 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 substitutents independently selected from —C1-C4 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, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —C1-C6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO2, —CF3, —NH2, —C(═O)NH2, —SO2—NR9R10, —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 —C1-C4 alkoxy, or with a hydroxy group;
or NR9R10 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 NR9R10 are optionally independently substituted with from one to three substituents independently selected from —OH, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —F, —Cl, —Br, —I, —CF3, —NH2, —C(═O)NH2, —SO2—NH2, —C(═O)R11, —S(O)n—R11, (Czero-C4 alkylene)-(C6-C10 aryl), (Czero-C4 alkylene)-((5-10 membered heteroaryl), (Czero-C4 alkylene)-(C6-C10 cycloalkyl) and (Czero-C4 alkylene)-((5-10 membered) heterocycloakyl, and wherein the (Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl) substituent and the nitrogen atoms of said heterocycloalkyl moiety of NR9R10 are each optionally independently substituted with one substituent independently selected from —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C(═O)NH2, —SO2—NH2, C(═O)R11, —S(O)n—R11, (Czero-C4 alkylene)-(C6-C10 aryl), (Czero-C4 alkylene)-((5-10 membered) heteroaryl), (Czero-C4 alkylene)-(C6-C10 cycloalkyl) and (Czero-C4 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 —C1-C4 alkoxy, or with a hydroxy group;
R11 and R12 are in each instance each independently selected from —C1-C15 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —(Czero-C4 alkylene)-(C3-C15 cycloalkyl), —(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), —(Czero-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), —(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), —(Czero-C4 alkylene)-(C6-C15 aryl), —(Czero-C4 alkylene)-((5-15 membered) heterocycloalkyl) and —(Czero-C4 alkylene)-((5-15 membered) heteroaryl);
wherein R11 and R12 are each optionally independently substituted with from one to three substituents independently selected from the group consisting of:
—OH, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —C1-C6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO2, —C6-C15 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 —C1-C4 alkoxy, or with a hydroxy group;
R2 is selected from —H, —OH, —NH2, —CH2OH, —OC(═O)CH3, —C(CH3)2OH, —C(CH3)(CH2CH3)(OH), —C(OH)(Czero-C4 alkyl)(Czero-C4 alkyl), —OC(═O)R4 and —OC(═O)OR4, wherein said —OC(═O)R4 and —OC(═O)OR4 may optionally be a prodrug of the corresponding OH of R2;
R3 is selected from —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl and —(Czero-C4 alkylene)-(C3-C6 cycloalkyl), wherein when R3 is alkyl, alkenyl or alkynyl, R3 is optionally independently substituted with a substituent independently selected from —C1-C4 alkoxy, —OH, and —F;
R4 is selected from —C1-C4 alkyl, —CH(OH)(C1-C4 alkyl), —CH(OH)(C5-C6 aryl), —CH(OH)((5-6 membered) heteroaryl), —CH(OH)(C5-C6 cycloalkyl), —CH(OH)((5-6 membered) heterocycloalkyl);
R5 is selected from —H, —C1-C4 alkyl, —C2-C4 alkenyl, —C2-C4 alkynyl, —C(═O)(C1-C4 alkyl), —C6-C10aryl, -(5-20 membered) heteroaryl, —SO2—(C6-C10 aryl), —SO2-((5-20 membered) heteroaryl), —SO2—CH2—(C6-C20 aryl) and —SO2-CH2-((5-20 membered) heteroaryl);
R7 is selected from —(Czero-C4 alkylene)-(C3-C20 cycloalkyl), —(Czero-C4 alkylene)-(C4-C20 cycloalkenyl), —(Czero-C4 alkylene)-((C10-C20)bi- or tricycloalkyl), —(Czero-C4 alkylene)-((C10-C20)bi- or tricycloalkenyl), —(Czero-C4 alkylene)-((3-20 membered) heterocycloalkyl), —(Czero-C4 alkylene)-(C6-C15 aryl), and —(Czero-C4 alkylene)-((5-15 membered) heteroaryl), wherein said heterocycloalkyl optionally contains from one to four double or triple bonds;
wherein R7 is optionally substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R1a;
R8 is selected from —H and —C1-C6 alkyl;
or, when Z is —C(═NR8)CHR1R2, R8 and R1 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 R1b;
n is 0, 1, 2
or the pharmaceutically acceptable salts of such compounds.

20 more elements

A compound selected from the group consisting of:

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-phenyl-[1,3,4]thiadiazol-2-yl )-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(4-methoxy-phenyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3,4-dimethyl-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-adamantan-1-yl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-trifluoromethyl-benzylsulfanyl)-thiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-methoxy-benzylsulfanyl)-thiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(2-fluoro-benzylsulfanyl)-thiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-propylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[2-(3-trifluoromethyl-phenoxy)-ethylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3,4-dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-dipropylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-benzylsulfanyl-[1,3,4]thiadiazol-2-yl )-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1-(2,4-dichloro-phenoxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(4-phenoxy-butylsulfanyl)-thiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[2-(4-bromo-phenoxy)-ethylsulfanyl]-thiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-diethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-ethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-phenethylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl )-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(S)-hydroxy-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-(S)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-(R)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
Hydroxy-phenyl-acetic acid [1-(5-methyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butylcarbamoyl]-phenyl-methyl ester;
2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-formyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(2,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(2,4,4-trimethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(S)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(R)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(S)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(R)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(S)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(R)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(S)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-(R)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(S)-2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(R)-2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
3-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-yl-3-methyl-butyric acid;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxiranyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-3-oxy-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1,1-dimethyl-3-(2,2,2-trifluoro-ethylamino)-propyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-butyl)-1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3,3-dimethoxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-ethylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-ethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-dimethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-propylamino-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[3-(2-hydroxy-ethylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-tert-butylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-morpholin-4-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[3-(1-ethyl-propylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid [5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide
2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid (5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(2-chloro-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-2-methyl-propionic acid ethyl ester;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[(isopropyl-phenyl-carbamoyl)-methylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(3-fluoro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-allyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-propenyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-acetyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1-(3-methyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-butylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1-(3,3-dimethyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-cyclopropylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1-(4-methyl-piperazin-1-yl)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1-(4-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid {5-[1-(3-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(2-dimethylamino-ethylsulfanyl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-dimethylamino-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isobutyl-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenyl-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-butyramide;
N-(5-Benzyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;
N-[5-(3-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;
N-(5-Cyclobutyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]thiadiazol-2-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-methoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide;
2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid (5-cyclohexyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid (5-methylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;
2-(5-{2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-propionic acid ethyl ester;
2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid (5-phenethyl-[1,3,4]thiadiazol-2-yl)-amide;
2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid [5-(1-phenoxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[3-(toluene-4-sulfonylamino)-[1,2,4]thiadiazol-5-yl]-butyramide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (3-ethylsulfanyl-[1,2,4]thiadiazol-5-yl)-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (3-methanesulfonyl-[1,2,4]thiadiazol-5-yl)-amide;
and
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [3-(4-nitro-benzenesulfonylamino)-[1,2,4]thiadiazol-5-yl]-amide.

149 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/922,425Filed 20 Aug 2004 · us provisional application
Priority: 21 Aug 2003
Published: US 2005/0043372 A124 Feb 2005
Granted: 7 Aug 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 285/135
With oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical: nitrogen atoms
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61P 25/00
Drugs for disorders of the nervous system

Family

Application60/496,735Us provisional application · filed 21 Aug 2003
US 2005/0043372 A1Pre-grant publication · published 24 Feb 2005
US 7,253,195 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula

wherein the ring containing X, Y, U is an aromatic ring in which one of the X, Y, U is a S and the other two of the X, Y, U are N as shown below I-A to I-C:
wherein Z is selected from —C(═O)CHR1R2, —C(═S)CHR1R2, —(C═NR8)CHR1R2, —C(═O)C(═O)R1 and —S(O)2—R1;
R1 is selected from —C1-C20 alkyl, —C2-C20 alkenyl, —C2-C20 alkynyl, —C1-C20 alkoxy, —C2-C20 alkenoxy, —C2-C20 alkynoxy, —C3-C20 cycloalkyl, —C4-C20 cycloalkenyl, (C10-C20)bi- or tricycloalkyl, (C10-C20)bi- or tricycloalkenyl, (4-20 membered) heterocycloalkyl, —C6-C20 aryl and (5-20 membered) heteroaryl;
wherein R1 is optionally independently substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R1a;
R1a is in each instance independently selected from —OH, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —CF3, —OCF3, —Cl, —Br, —I, —CN, —NO2, —NR9R10, —C(═O)NR9R10, —SO2—NR9R10, —C(═O)R11—C(═O)OR12, —S(O)n—R11, —C3-C15 cycloalkyl, —C4-C15 cycloalkenyl, —(C5-C11)bi- or tricycloalkyl, —(C7-C11)bi- or tricycloalkenyl,
-(4-20 membered) heterocycloalkyl, —C6-C15 aryl, -(5-15 membered) heteroaryl, —C6-C15 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 R1b;
R1b is in each instance independently selected from —OH, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —C1-C6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO2, —NR9R10, —C(═O)NR9R10, —C(═O)R11, —S(O)n—R11, —C6-C15 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 —C1-C4 alkoxy, or with a hydroxy group;
R9 and R10 are in each instance each independently selected from —H, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —CF3, —C(═O)R11, —S(O)n—R11, —C(═O)OR12,
—C(═O)NR11R12, —SO2—NR11R12, —(Czero-C4 alkylene)-(C3-C20 cycloalkyl), —(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), —(Czero-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), —(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), —(Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl), (Czero-C4 alkylene)-(C6-C10 aryl) and —(Czero-C4 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 substitutents independently selected from —C1-C4 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, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —C1-C6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO2, —CF3, —NH2, —C(═O)NH2, —SO2—NR9R10, —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 —C1-C4 alkoxy, or with a hydroxy group;
or NR9R10 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 NR9R10 are optionally independently substituted with from one to three substituents independently selected from —OH, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —F, —Cl, —Br, —I, —CF3, —NH2, —C(═O)NH2, —SO2—NH2, —C(═O)R11, —S(O)n—R11, (Czero-C4 alkylene)-(C6-C10 aryl), (Czero-C4 alkylene)-((5-10 membered heteroaryl), (Czero-C4 alkylene)-(C6-C10 cycloalkyl) and (Czero-C4 alkylene)-((5-10 membered) heterocycloakyl, and wherein the (Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl) substituent and the nitrogen atoms of said heterocycloalkyl moiety of NR9R10 are each optionally independently substituted with one substituent independently selected from —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C(═O)NH2, —SO2—NH2, C(═O)R11, —S(O)n—R11, (Czero-C4 alkylene)-(C6-C10 aryl), (Czero-C4 alkylene)-((5-10 membered) heteroaryl), (Czero-C4 alkylene)-(C6-C10 cycloalkyl) and (Czero-C4 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 —C1-C4 alkoxy, or with a hydroxy group;
R11 and R12 are in each instance each independently selected from —C1-C15 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —(Czero-C4 alkylene)-(C3-C15 cycloalkyl), —(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), —(Czero-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), —(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), —(Czero-C4 alkylene)-(C6-C15 aryl), —(Czero-C4 alkylene)-((5-15 membered) heterocycloalkyl) and —(Czero-C4 alkylene)-((5-15 membered) heteroaryl);
wherein R11 and R12 are each optionally independently substituted with from one to three substituents independently selected from the group consisting of:
—OH, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 alkoxy, —C2-C6 alkenoxy, —C2-C6 alkynoxy, —C1-C6 hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO2, —C6-C15 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 —C1-C4 alkoxy, or with a hydroxy group;
R2 is selected from —H, —OH, —NH2, —CH2OH, —OC(═O)CH3, —C(CH3)2OH, —C(CH3)(CH2CH3)(OH), —C(OH)(Czero-C4 alkyl)(Czero-C4 alkyl), —OC(═O)R4 and —OC(═O)OR4, wherein said —OC(═O)R4 and —OC(═O)OR4 may optionally be a prodrug of the corresponding OH of R2;
R3 is selected from —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl and —(Czero-C4 alkylene)-(C3-C6 cycloalkyl), wherein when R3 is alkyl, alkenyl or alkynyl, R3 is optionally independently substituted with a substituent independently selected from —C1-C4 alkoxy, —OH, and —F;
R4 is selected from —C1-C4 alkyl, —CH(OH)(C1-C4 alkyl), —CH(OH)(C5-C6 aryl), —CH(OH)((5-6 membered) heteroaryl), —CH(OH)(C5-C6 cycloalkyl), —CH(OH)((5-6 membered) heterocycloalkyl);
R5 is selected from —H, —C1-C4 alkyl, —C2-C4 alkenyl, —C2-C4 alkynyl, —C(═O)(C1-C4 alkyl), —C6-C10aryl, -(5-20 membered) heteroaryl, —SO2—(C6-C10 aryl), —SO2-((5-20 membered) heteroaryl), —SO2—CH2—(C6-C20 aryl) and —SO2-CH2-((5-20 membered) heteroaryl);
R7 is selected from —(Czero-C4 alkylene)-(C3-C20 cycloalkyl), —(Czero-C4 alkylene)-(C4-C20 cycloalkenyl), —(Czero-C4 alkylene)-((C10-C20)bi- or tricycloalkyl), —(Czero-C4 alkylene)-((C10-C20)bi- or tricycloalkenyl), —(Czero-C4 alkylene)-((3-20 membered) heterocycloalkyl), —(Czero-C4 alkylene)-(C6-C15 aryl), and —(Czero-C4 alkylene)-((5-15 membered) heteroaryl), wherein said heterocycloalkyl optionally contains from one to four double or triple bonds;
wherein R7 is optionally substituted with from one to six fluorine atoms or with from one to three substituents independently selected from the group R1a;
R8 is selected from —H and —C1-C6 alkyl;
or, when Z is —C(═NR8)CHR1R2, R8 and R1 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 R1b;
n is 0, 1, 2
or the pharmaceutically acceptable salts of such compounds.

20 more elements

Facts

Application

10/922,425Filed 20 Aug 2004 · us provisional application

Priority

21 Aug 2003

Published

US 2005/0043372 A124 Feb 2005

Granted

7 Aug 2007

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 285/135
With oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical: nitrogen atoms
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61P 25/00
Drugs for disorders of the nervous system