Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds

A method for inhibiting β-amyloid peptide synthesis and/or release in a mammalian subject, thereby inhibiting onset of diseases mediated by β-amyloid peptide, which method comprises administering to said mammalian subject a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula IC:

• wherein R1 is selected from the group consisting of:
• A) alkyl of from 1 to 10 carbon atoms;
• B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of alkenyl unsaturation;
• C) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites of alkynyl unsaturation;
• D) cycloalkyl of from 3 to 12 carbon atoms;
• E) cycloalkenyl of from 4 to 8 carbon atoms;
• F) substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from:
• 1) alkoxy of from 1 to 10 carbon atoms;
• 2) substituted alkoxy of the formula substituted alkyl-O— where substituted alkyl is as defined in F herein;
• 3) cycloalkyl which is as defined in D herein;
• 4) substituted cycloalkyl is defined in I herein;
• 5) cycloalkenyl which is defined in E herein;
• 6) substituted cycloalkenyl which is defined in J herein;
• 7) acyl selected from alkyl-C(O)—, substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)— and heterocyclic-C(O)— wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein cycloalkyl is defined in D herein;
• wherein substituted cycloalkyl is defined in I herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• 8) acylamino having the formula —C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• 9) acyloxy selected from alkyl-C(O)O—, substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein cycloalkyl is defined in D herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• 10) amino;
• 11) aminoacyl having the formula —NRC(O)R wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic;
• wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• 12) aminoacyloxy having the formula —NRC(O)OR wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic;
• wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• 13) cyano;
• 14) halogen;
• 15) hydroxyl;
• 16) carboxyl;
• 17) carboxylalkyl having the formula “—C(O)Oalkyl” wherein alkyl is defined in A herein;
• 18) thiol;
• 19) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined in A herein;
• 20) substituted thioalkoxy having the formula —S-substituted alkyl, wherein substituted alkyl is defined in F herein;
• 21) aryl having from 6 to 14 ring carbon atoms, optionally substituted with from 1 to 5 substituents selected from the group consisting of:
• a) hydroxy;
• b) acyl as defined in F7 herein;
• c) acyloxy as defined in F9 herein;
• d) alkyl as defined in A herein;
• e) substituted alkyl as defined in F herein;
• f) alkoxy as defined in F1 herein;
• g) substituted alkoxy as defined in F2 herein;
• h) alkenyl as defined in B herein;
• i) substituted alkenyl as defined in G herein;
• j) alkynyl as defined in C herein;
• k) substituted alkynyl as defined in H herein;
• l) amino;
• m) aminoacyl as defined in F11 herein;
• n) acylamino as defined in F8 herein;
• o) alkaryl of the formula -alkylene-aryl having 8 carbon atoms in the alkylene moiety and aryl is defined in F21 herein;
• p) aryl as defined in F21 herein;
• q) aryloxy having the formula —O-aryl wherein aryl is defined in F21 herein;
• r) azido;
• s) carboxyl;
• t) carboxylalkyl having the formula “—C(O)Oalkyl” wherein alkyl is defined in A herein;
• u) cyano;
• v) halo selected from fluoro, chloro, bromo and iodo;
• w) nitro;
• x) heteroaryl as defined in F22 herein;
• y) heterocyclic as defined in F23 herein;
• z) aminoacyloxy as defined in F12 herein;
• aa) oxyacylamino having the formula —OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• bb) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined in A herein;
• cc) substituted thioalkoxy having the formula —S-substituted alkyl, wherein substituted alkyl is defined in F herein;
• dd) thioaryloxy having the formula —S-aryl wherein aryl is defined in F21 herein;
• ee) thioheteroaryloxy having the formula —S-heteroaryl wherein heteroaryl is defined F22 herein;
• ff) —SO-alkyl wherein alkyl is defined in A herein;
• gg) —SO-substituted alkyl wherein substituted alkyl is defined in F herein;
• hh) —SO-aryl wherein aryl is defined in F21 herein;
• ii) —SO-heteroaryl wherein heteroaryl is defined in F22 herein;
• jj) —SO2-alkyl wherein alkyl is defined in A herein;
• kk) —SO2-substituted alkyl wherein substituted alkyl is defined in F herein;
• ll) —SO2-aryl wherein aryl is defined in F21 herein;
• mm) —SO2-heteroaryl wherein heteroaryl is defined in F22 herein;
• nn) trihalomethyl wherein halo is defined in I20 herein;
• oo) mono- and dialkylamino wherein alkyl is defined in A herein;
• pp) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein;
• qq) mono- and di-arylamino wherein aryl is defined in F21 herein;
• rr) mono- and di-heteroarylamino wherein heteroaryl is defined in F22 herein;
• ss) mono- and di-heterocyclicamino wherein heterocyclic is defined in F23 herein;
• tt) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• 22) heteroaryl of from 1 to 15 ring carbon atoms and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and sulfur, optionally substituted with from 1 to 5 substituents selected from:
• a) alkyl as defined in A herein;
• b) substituted alkyl as defined in F herein;
• c) alkoxy as defined in F1 herein;
• d) substituted alkoxy as defined in F2 herein;
• e) aryl as defined in F21 herein;
• f) aryloxy having the formula —O-aryl wherein aryl is defined in F21 herein;
• g) halo selected from fluoro, chloro, bromo and iodo;
• h) nitro;
• i) heteroaryl as defined in F22 herein;
• j) thiol;
• k) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined in A herein;
• l) substituted thioalkoxy having the formula —S-substituted alkyl, wherein substituted alkyl is defined in F herein;
• m) thioaryloxy having the formula —S-aryl wherein aryl is defined in F21 herein;
• and
• n) trihalomethyl wherein halo is defined in I20 herein;
• 23) heterocyclic of from 1 to 15 ring carbon atoms and from 1 to 4 ring atoms selected from nitrogen, sulfur and oxygen, optionally substituted with from 1 to 5 substituents selected from:
• a) alkyl as defined in A herein;
• b) substituted alkyl as defined in F herein;
• c) alkoxy as defined in F1 herein;
• d) substituted alkoxy as defined in F2 herein;
• e) aryl as defined in F21 herein;
• f) aryloxy having the formula —O-aryl wherein aryl is defined in F21 herein;
• g) halo selected from fluoro, chloro, bromo and iodo;
• h) nitro;
• i) heteroaryl as defined in F22 herein;
• j) thiol;
• k) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined in A herein;
• l) substituted thioalkoxy having the formula —S-substituted alkyl, wherein substituted alkyl is defined in F herein;
• m) thioaryloxy having the formula —S-aryl wherein aryl is defined in F21 herein;
• and
• n) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo;
• 24) aryloxy of the formula —O-aryl wherein aryl is defined in F21 herein;
• 25) heteroaryloxy of the formula —O-heteroaryl wherein heteroaryl is defined in F22 herein;
• 26) hydroxyamino;
• 27) alkoxyamino wherein alkoxy is defined in F1 herein;
• 28) nitro;
• 29) —SO-alkyl wherein alkyl is defined in A herein;
• 30) —SO-substituted alkyl wherein substituted alkyl is defined in F herein;
• 31) —SO-aryl wherein aryl is defined in F21 herein;
• 32) —SO-heteroaryl wherein heteroaryl is defined in F22 herein;
• 33) —SO2-alkyl wherein alkyl is defined in A herein;
• 34) —SO2-substituted alkyl wherein substituted alkyl is defined in F herein;
• 35) —SO2-aryl wherein aryl is defined in F21 herein;
• 36) —SO2-heteroaryl wherein heteroaryl is defined in F22 herein;
• 37) mono- and dialkylamino wherein alkyl is defined in A herein;
• 38) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein;
• 39) mono- and di-arylamino wherein aryl is defined in F21 herein;
• 40) mono- and di-heteroarylamino wherein heteroaryl is defined in F22 herein;
• 41) mono- and di-heterocyclicamino wherein heterocyclic is defined in F23 herein;
• 42) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• G) substituted alkenyl having from 1 to 3 substituents selected from the group consisting of:
• 1) alkoxy as defined in F1 herein;
• 2) substituted alkoxy as defined in F2 herein;
• 3) acyl as defined in F7 herein;
• 4) acylamino as defined in F8 herein;
• 5) acyloxy as defined in F9 herein;
• 6) amino;
• 7) aminoacyl as defined in F11 herein;
• 8) aminoacyloxy as defined in F12 herein;
• 9) cyano;
• 10) halogen selected from fluoro, chloro, bromo and iodo;
• 11) hydroxyl;
• 12) carboxyl;
• 13) carboxylalkyl as defined in F17 herein;
• 14) thiol;
• 15) thioalkoxy as defined in F19 herein;
• 16) substituted thioalkoxy as defined in F20 herein;
• 17) aryl as defined in F21 herein;
• 18) heteroaryl as defined in F22 herein;
• 19) heterocyclic as defined in F23 herein;
• 20) nitro;
• 21) —SO-alkyl wherein alkyl is defined in A herein;
• 22) —SO-substituted alkyl wherein substituted alkyl is defined in F herein;
• 23) —SO-aryl wherein aryl is defined in F21 herein;
• 24) —SO-heteroaryl wherein heteroaryl is defined in F22 herein;
• 25) —SO2-alkyl wherein alkyl is defined in A herein;
• 26) —SO2-substituted alkyl wherein substituted alkyl is defined in F herein;
• 27) —SO2-aryl wherein aryl is defined in F21 herein;
• 28) —SO2-heteroaryl wherein heteroaryl is defined in F22 herein;
• 29) mono- and dialkylamino wherein alkyl is defined in A herein;
• 30) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein;
• 31) mono- and di-arylamino wherein aryl is defined in F21 herein;
• 32) mono- and di-heteroarylamino wherein heteroaryl is defined in F22 herein;
• 33) mono- and di-heterocyclicamino wherein heterocyclic is defined in F23 herein;
• and
• 34) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• H) substituted alkynyl of from 1 to 3 substituents selected from:
• 1) alkoxy as defined in F1 herein;
• 2) substituted alkoxy as defined in F2 herein;
• 3) acyl as defined in F7 herein;
• 4) acylamino as defined in F8 herein;
• 5) acyloxy as defined in F9 herein;
• 6) amino;
• 7) aminoacyl as defined in F11 herein;
• 8) aminoacyloxy as defined in F12 herein;
• 9) cyano;
• 10) halogen selected from fluoro, chloro, bromo and iodo;
• 11) hydroxyl;
• 12) carboxyl;
• 13) carboxylalkyl as defined in F17 herein;
• 14) thiol;
• 15) thioalkoxy as defined in F19 herein;
• 16) substituted thioalkoxy as defined in F20 herein;
• 17) aryl as defined in F21 herein;
• 18) heteroaryl as defined in F22 herein;
• 19) heterocyclic as defined in F23 herein;
• 20) nitro;
• 21) —SO-alkyl wherein alkyl is defined in A herein;
• 22) —SO-substituted alkyl wherein substituted alkyl is defined in F herein;
• 23) —SO-aryl wherein aryl is defined in F21 herein;
• 24) —SO-heteroaryl wherein heteroaryl is defined in F22 herein;
• 25) —SO2-alkyl wherein alkyl is defined in A herein;
• 26) —SO2-substituted alkyl wherein substituted alkyl is defined in F herein;
• 27) —SO2-aryl wherein aryl is defined in F21 herein;
• 28) —SO2-heteroaryl wherein heteroaryl is defined in F22 herein;
• 29) mono- and dialkylamino wherein alkyl is defined in A herein;
• 30) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein;
• 31) mono- and di-arylamino wherein aryl is defined in F21 herein;
• 32) mono- and di-heteroarylamino wherein heteroaryl is defined in F22 herein;
• 33) mono- and di-heterocyclicamino wherein heterocyclic is defined in F23 herein;
• and
• 34) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein;
• wherein substituted alkyl is defined in F herein;
• wherein aryl is defined in F21 herein;
• wherein heteroaryl is defined in F22 herein;
• and wherein heterocyclic is defined in F23 herein;
• I) substituted cycloalkyl having 3 to 12 carbon atoms and from 1 to 5 substituents selected from the group consisting of:
• 1) hydroxy;
• 2) acyl as defined in F7 herein;
• 3) acyloxy as defined in F9 herein;
• 4) alkyl as defined in A herein;
• 5) substituted alkyl as defined in F herein;
• 6) alkoxy as defined in F1 herein;
• 7) substituted alkoxy as defined in F2 herein;
• 8) alkenyl as defined in B herein;
• 9) substituted alkenyl as defined in G herein;
• 10) alkynyl as defined in C herein;
• 11) substituted alkynyl as defined in H herein;
• 12) amino;
• 13) aminoacyl as defined in F11 herein;
• 14) alkaryl of the formula -alkylene-aryl having 8 carbon atoms in the alkylene moiety and aryl is defined in F21 herein;
• 15) aryl as defined in F21 herein;
• 16) aryloxy having the formula —O-aryl wherein aryl is defined in F21 herein;
• 17) carboxyl;
• 18) carboxylalkyl having the formula “—C(O)Oalkyl” wherein alkyl is defined in A herein;
• 19) cyano;
• 20) halo selected from fluoro, chloro, bromo and iodo;
• 21) nitro;
• 22) heteroaryl as defined in F22 herein;
• 23) thioalkoxy as defined in F19 herein;
• 24) substituted thioalkoxy as defined in F20 herein;
• and
• 25) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo;
• J) substituted cycloalkenyl having from 4 to 8 carbon atoms and from 1 to 5 substituents selected from the group consisting of:
• 1) hydroxy;
• 2) acyl as defined in F7 herein;
• 3) acyloxy as defined in F9 herein;
• 4) alkyl as defined in A herein;
• 5) substituted alkyl as defined in F herein;
• 6) alkoxy as defined in F1 herein;
• 7) substituted alkoxy as defined in F2 herein;
• 8) alkenyl as defined in B herein;
• 9) substituted alkenyl as defined in G herein;
• 10) alkynyl as defined in C herein;
• 11) substituted alkynyl as defined in H herein;
• 12) amino;
• 13) aminoacyl as defined in F11 herein;
• 14) alkaryl of the formula -alkylene-aryl having 8 carbon atoms in the alkylene moiety and aryl is defined in F21 herein;
• 15) aryl as defined in F21 herein;
• 16) aryloxy having the formula —O-aryl wherein aryl is defined in F21 herein;
• 17) carboxyl;
• 18) carboxylalkyl having the formula “—C(O)Oalkyl” wherein alkyl is defined in A herein;
• 19) cyano;
• 20) halo selected from fluoro, chloro, bromo and iodo;
• 21) nitro;
• 22) heteroaryl as defined in F22 herein;
• 23) thioalkoxy as defined in F19 herein;
• 24) substituted thioalkoxy as defined in F20 herein;
• and
• 25) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo;
• K) aryl as defined in F21 herein;
• L) heteroaryl as defined in F22 herein;
• and
• M) heterocyclic as defined in F23 herein;
• Z′ is represented by the formula —CX′X″—, —T—CH2— or —T—C(O)—, where T is selected from the group consisting of oxygen, sulfur, —NR5, where R5 is hydrogen, acyl as defined in F7 herein, alkyl as defined in A herein, aryl as defined in F21 herein, or heteroaryl as defined in F22 herein;
• X′ is hydrogen, hydroxy, or fluoro;
• X″ is hydrogen, hydroxy, or fluoro;
• or X′ and X″ together form an oxo group;
• wherein Q is selected from the group consisting of:
• Rb is selected from the group consisting of alkyl as defined in A herein, substituted alkyl as defined in F herein, alkenyl as defined in B herein, substituted alkenyl as defined in G herein, alkynyl as defined in C herein, substituted alkynyl as defined in H herein, acyl as defined in F7 herein, aryl as defined in F21 herein, heteroaryl as defined in F22 herein, and heterocyclic as defined in F23 herein;
• Rc is selected from the group consisting of alkyl as defined in A herein;
• substituted alkyl as defined in F herein;
• alkenyl as defined in B herein;
• substituted alkenyl as defined in G herein;
• aryl as defined in F21 herein;
• heteroaryl as defined in F22 herein;
• heterocyclic as defined in F23 herein;
• cycloalkyl as defined in D herein;
• and substituted cycloalkyl as defined in I herein;
• A—B is selected from a group of alkylene wherein alkylene is a divalent alkyl and alkyl is defined in A herein;
• alkenylene wherein alkenylene is a divalent alkenyl and alkenyl is defined in B herein;
• substituted alkylene wherein substituted alkylene is a divalent substituted alkyl as defined in F herein;
• substituted alkenylene wherein substituted alkenylene is a divalent substituted alkenyl as defined in G herein;
• and —N═CH—;
• V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl, thioalkoxy, substituted thioalkoxy and trihalomethyl;
• t is an integer from 0 to 4 or pharmaceutically acceptable salts thereof.