Methods of Treatment of Amyloidosis Using Subsituted Ethanolcyclicamine Aspartyl Protease Inhibitors

A method of preventing or treating at least one condition that benefits from inhibition of at least one aspartyl-protease, comprising:

• administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I),
• or at least one pharmaceutically acceptable salt thereof;
• wherein
• R1 is
• wherein
• n is 0 or 1;
• q is 0 or 1;
• r is 0, 1, or 2;
• K is selected from
• (CR3aR3b)—,
• —O—,
• —SO2—,
• —C(O)—, and
• —CH(NR55R60)—;
• R55 and R60 are each independently selected from hydrogen and alkyl;
• R3a and R3b are independently selected from
• -hydrogen,
• -halogen,
• —O-alkyl, and
• -alkyl optionally substituted with at least one group independently selected from halogen, —CN, —CF3, and —OH;
• W is selected from —(CH2)1-4—, —O—, —S(O)0-2—, —N(R55)—, and —C(O)—;
• E is a bond or alkyl;
• A is selected from
• -aryl optionally substituted with at least one group independently selected from R50,
• -cycloalkyl optionally substituted with at least one group independently selected from R50,
• -heteroaryl optionally substituted with at least one group independently selected from R50, and
• -heterocycle optionally substituted with at least one group independently selected from R50, wherein at least one atom of the heterocycle is optionally replaced with —C(O)— and —S(O)0-2—;
• wherein at least one heteroatom of the heteroaryl or heterocycle is optionally substituted with a group independently selected from —(CO)0-1R215, —(CO)0-1R220, —S(O)0-2R200, and —N(R200)—S(O)0-2R200;
• R50 is independently selected from
• —OH,
• -halogen,
• —OCF3,
• —NO2,
• —CN,
• —N(R)C(O)R,
• —CO2—R,
• —NH—CO2—R,
• —O-(alkyl)-CO2H,
• —NRR′,
• —SR,
• —CH2OH,
• —C(O)—R25,
• —C(O)NRR′,
• —SO2NRR′,
• —S(O)1-2R25,
• -alkyl optionally substituted with at least one group independently selected from —CF3, halogen, —O-alkyl, —OCF3, —NRR′, —OH, and —CN,
• -cycloalkyl optionally substituted with at least one group independently selected from —CF3, halogen, —O-alkyl, —OCF3, —NRR′, —OH, and —CN,
• —O-alkyl optionally substituted with at least one group independently selected from —CF3, halogen, —O-alkyl, —OCF3, —NRR′, —OH, and —CN,
• —O-benzyl optionally substituted with at least one group independently selected from —H, —OH, halogen, and alkyl,
• —O—(CH2)0-2—O—(CH2)1-2—O-alkyl, and
• —(CH2)0-2—O—(CH2)1-2—OH;
• R and R′ are each independently selected from hydrogen, alkyl, —(CH2)0-2-aryl and —(CH2)0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, —O-alkyl, amino, monoalkylamino, and dialkylamino;
• R25 is selected from alkyl, —(CH2)0-2-aryl and —(CH2)0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, —O-alkyl, amino, monoalkylamino, and dialkylamino;
• L is selected from a bond, —C(O)—, —S(O)1-2—, —O—, —C(R110)(R112)O—, —OC(R110)(R112)—, —N(R110)—, —C(O)N(R110)—, —N(R110)C(O)—, —C(R110)(R′)—, —C(OH)R110—, —SO2NR110—, —N(R110)SO2—, —N(R110)C(O)N(R112)—, —N(R110)C(S)N(R112)—, —OCO2—, —NCO2—, and —OC(O)N(R110)—;
• R110 and R112 are each independently selected from
• -hydrogen and
• -alkyl optionally substituted with at least one group independently selected from —OH, —O-alkyl, and halogen;
• G is selected from
• -alkyl (optionally substituted with at least one group independently selected from —CO2H, —CO2(alkyl), —O-alkyl, —OH, —NRR′, alkyl, -haloalkyl, -alkyl-O-alkyl), aryl (optionally substituted with at least one group independently selected from R50), and heteroaryl (optionally substituted with at least one group independently selected from R50);
• —(CH2)0-3-cycloalkyl wherein cycloalkyl is optionally substituted with at least one group independently selected from —CO2H, —CO2—(alkyl), —O-alkyl, —OH, —NH2, haloalkyl, alkyl, -alkyl-O-alkyl, mono(alkyl)amino, di(alkyl)amino, aryl (optionally substituted with at least one group independently selected from R50), and heteroaryl (optionally substituted with at least one group independently selected from R50);
• —(CRR)1-4-aryl wherein the aryl is optionally substituted with at least one group independently selected from R50,
• —(CH2)1-4-heteroaryl wherein the heteroaryl is optionally substituted with at least one group independently selected from R50,
• (CH2)0-4-heterocycle, wherein the heterocycle is optionally substituted with at least one group independently selected from R50, and
• —C(R10)(R12)—C(O)—NH—R14;
• R10 and R12 are each independently selected from
• —H,
• -alkyl,
• -(alkyl)0-1-aryl,
• -(alkyl)0-1-heteroaryl,
• -(alkyl)01-heterocycle,
• -aryl,
• -heteroaryl,
• -heterocycle,
• —(CH2)1-4—OH,
• —(CH2)1-4-Z-(CH2)1-4-aryl, and
• —(CH2)1-4-Z-(CH2)1-4-heteroaryl,
• wherein the heterocycle, aryl, and heteroaryl groups included within R10 and R12 are optionally substituted with at least one group independently selected from R50;
• Z is selected from —O—, —S—, and —NR16—;
• R14 is:
• —H,
• -alkyl,
• -aryl,
• -heteroaryl,
• -heterocycle,
• -(alkyl)-aryl,
• -(alkyl)-heteroaryl,
• -(alkyl)-, and
• —(CH2)0-2—O—(CH2)0-2—OH;
• wherein the heterocycle, aryl, and heteroaryl groups included within R14 are optionally substituted with at least one group independently selected from R50;
• R16 is selected from hydrogen and alkyl;
• or
• R1 is selected from
• wherein
• X, Y, and Z are independently selected from —C(H)0-2—, —O—, —C(O)—, —NH—, and —N—;
• wherein at least one bond of the (IIf) ring may optionally be a double bond;
• R50, R50a, and R50b are independently selected from —H, halogen, —OH, —SH, —CN, —C(O)-alkyl, —NR7R8, —NO2, —S(O)0-2-alkyl, alkyl, alkoxy, —O-benzyl (optionally substituted with at least one group independently selected from —H, —OH, and alkyl), —C(O)—NR7R8, alkyloxy, alkoxyalkoxyalkoxy, and cycloalkyl;
• wherein the alkyl, alkoxy, and cycloalkyl groups within R50, R50a, and R50b are optionally substituted with at least one group independently selected from alkyl, halogen, OH, NR5R6, CN, haloalkoxy, NR7R8, and alkoxy;
• R5 and R6 are independently selected from —H and alkyl, or
• R5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring;
• and
• R7 and R8 are independently selected from —H, alkyl optionally substituted with at least one group independently selected from —OH, —NH2, and halogen, -cycloalkyl, and -alkyl-O-alkyl;
• R2 is selected from
• —H,
• -alkyl optionally substituted with at least one group independently selected from R200,
• —OH,
• —O-alkyl optionally substituted with at least one group independently selected from R200,
• —O-aryl optionally substituted with at least one group independently selected from R200,
• —NH-alkyl optionally substituted with at least one group independently selected from R200,
• -heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —(CR245R250)—, —O—, —C(O)—, —C(O)C(O)—, —N(R200)0-2—, and —S(O)0-2—, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200),
• —NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —(CR245R250)—, —O—, —C(O)—, —C(O)C(O)—, —N(R200)0-2—, and —S(O)0-2—, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200,
• —C(O)—N(R315)(R320), wherein R315 and R320 are each independently selected from —H, alkyl, and phenyl,
• —NH—R400,
• —R400,
• —NH—R500,
• —R500,
• —NH—R600,
• —R600, and
• —R700;
• R400 is
• wherein R405 is selected from —H, —N(R515)2 and O-alkyl;
• R500 is a heteroaryl selected from (IIa) and (IIb)
• wherein
• M1 and M4 are independently selected from
• —C(R505)—,
• —N—,
• —N(R515)—,
• —S—, and
• —O—;
• M2 and M3 are independently selected from
• —C(R510)—,
• —N(R520)0-1—,
• —S—, and
• —O—;
• M5 is selected from —C— and —N—;
• R505 is independently selected from
• —H,
• -alkyl,
• -halogen,
• —NO2,
• —CN,
• R200, and
• -phenyl;
• R510 is independently selected from
• —H,
• -alkyl,
• -halogen,
• -amino,
• —CF3,
• R200, and
• -phenyl;
• R515 is independently selected from
• —H,
• -alkyl, and
• -phenyl;
• R520 is independently selected from
• —H,
• -alkyl,
• —(CH2)0-2-phenyl, and
• —C(Ph)3;
• R600 is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from —R605;
• R605 is selected from —H, -halogen, -alkyl, -phenyl, —CO2-alkyl, —NO2, —CN, —NH2, —NR220R225, -thioalkyl, —CF3, —OH, —O-alkyl, and -heterocycloalkyl;
• R700 is aryl optionally substituted with at least one —R205;
• RC is selected from formulae (IIIa), (IIIb), (IIIc), and (IIId)
• wherein
• A′ is —NH—;
• ring a′ is a 5, 6, or 7 membered cycloalkyl ring;
• ring b′ is a 5, 6, or 7 membered cycloalkyl ring;
• ring c′ is a 5 or 6 membered aromatic ring or a 5, 6, or 7 membered cycloalkyl ring;
• wherein at least one carbon of cycloalkyl rings a′, b′ and c′ of formulae (IIIa), (IIIb), (IIIc), and (IIId) is optionally replaced with a group independently selected from —C(O)—, —NH—, —N—, —N(R200)—, —O—, —S(O)0-2—, and —N(S(O)0-2—R200)—;
• wherein at least one carbon of aromatic ring c′ of formula (IIId) is optionally replaced with a group independently selected from —C(R200)—, —O—, —S(O)0-2—, —N—, —NH—, —N(S(O)0-2—R200)—, and —N(R200)—;
• wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl within RC is optionally substituted with at least one group independently selected from R200;
• and
• wherein each cycloalkyl and heterocycloalkyl within formulae (IIIa), (IIIb), (IIIc), and (IIId) optionally contains at least one double bond;
• R200 at each occurrence is independently selected from
• -alkyl optionally substituted with at least one group independently selected from R205,
• —OH,
• —NO2,
• -halogen,
• —CN,
• —(CH2)0-4—C(O)H,
• —(CO)0-1R215,
• (CO)0-1R220,
• —(CH2)0-4—(CO)0-1—NR220R225,
• —(CH2)0-4—(CO)0-1—NH(R215),
• —(CH2)0-4—C(O)-alkyl,
• —(CH2)0-4—(CO)0-1-cycloalkyl,
• —(CH2)0-4—(CO)0-1-heterocycloalkyl,
• —(CH2)0-4—(CO)0-1-aryl,
• —(CH2)0-4—(CO)0-1-heteroaryl,
• —(CH2)0-4—C(O)—O—R215,
• —(CH2)0-4—SO2—NR220R225,
• —(CH2)0-4—S(O)0-2-alkyl,
• —(CH2)0-4—S(O)0-2-cycloalkyl,
• —(CH2)0-4—N(H or R215)—C(O)—O—R215,
• —(CH2)0-4—N(H or R215)—SO2—R220,
• —(CH2)0-4—N(H or R215)—C(O)—N(R215)2,
• —(CH2)0-4—N(H or R215)—C(O)—R220,
• —(CH2)0-4—O—C(O)-alkyl,
• —(CH2)0-4—O—(R215),
• —(CH2)0-4—S—(R215),
• —(CH2)0-4—O-alkyl optionally substituted with at least one halogen, and
• -adamantane;
• wherein each aryl and heteroaryl group included within R200 is optionally substituted with at least one group independently selected from R205, R210, and alkyl (optionally substituted with at least one group independently selected from R205 and R210);
• wherein each cycloalkyl or heterocycloalkyl group included within R200 is optionally substituted with at least one group independently selected from R210;
• R205 at each occurrence is independently selected from
• -alkyl,
• -haloalkoxy,
• (CH2)0-3-cycloalkyl,
• -halogen,
• —(CH2)1-6—OH,
• —O-aryl,
• —OH,
• —SH,
• —(CH2)0-4—C(O)H,
• —(CH2)0-6—CN,
• —(CH2)0-6—C(O)—NR235R240,
• —(CH2)0-6—C(O)—R235,
• —(CH2)0-4—N(H or R215)—SO2—R235,
• —OCF3,
• —CF3,
• -alkoxy,
• -alkoxycarbonyl, and
• —NR235R240;
• R210 at each occurrence is independently selected from
• —(CH2)0-4—OH,
• —(CH2)0-4—CN,
• —(CH2)0-4—C(O)H,
• -alkyl optionally substituted with at least one group independently selected from R205,
• -alkanoyl,
• —S-alkyl;
• —S(O)2-alkyl,
• -halogen,
• -alkoxy,
• -haloalkoxy,
• —NR220R225,
• -cycloalkyl optionally substituted with at least one group independently selected from R205,
• -heterocycloalkyl,
• heteroaryl,
• —(CH2)0-4—NR235R240,
• —(CH2)0-4—NR235(alkoxy),
• —(CH2)0-4—S—(R215),
• —(CH2)0-4—NR235—C(O)H,
• —(CH2)0-4—NR235—C(O)-(alkoxy),
• —(CH2)0-4—NR235—C(O)—R240,
• —C(O)—NHR215,
• —C(O)-alkyl,
• —C(O)—NR235R240, and
• —S(O)2—NR235R240;
• R215 at each occurrence is independently selected from
• -alkyl,
• —(CH2)0-2-aryl,
• —(CH2)0-2-cycloalkyl,
• —(CH2)0-2-heteroaryl,
• —(CH2)0-2-heterocycloalkyl, and
• —CO2—CH2-aryl;
• wherein the aryl group included within R215 is optionally substituted with at least one group independently selected from R205 and R210, and
• wherein the heterocycloalkyl and heteroaryl groups included within R215 are optionally substituted with at least one group independently selected from R210;
• R220 and R225 at each occurrence are independently selected from
• —H,
• -alkyl,
• —(CH2)0-4—C(O)H,
• -alkylhydroxyl,
• -alkoxycarbonyl,
• -alkylamino,
• —S(O)2-alkyl,
• -alkanoyl optionally substituted with at least one halogen,
• —C(O)—NH2,
• —C(O)—NH(alkyl),
• —C(O)—N(alkyl)(alkyl),
• -haloalkyl,
• —(CH2)0-2-cycloalkyl,
• -(alkyl)-O-(alkyl),
• -aryl,
• -heteroaryl, and
• -heterocycloalkyl;
• wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within R220 and R225 are each optionally substituted with at least one group independently selected from R270;
• R270 at each occurrence is independently selected from
• —R205,
• -alkyl optionally substituted with at least one group independently selected from R205,
• -aryl,
• -halogen,
• -alkoxy,
• -haloalkoxy,
• —NR235R240,
• —OH,
• —CN,
• -cycloalkyl optionally substituted with at least one group independently selected from R205,
• —C(O)-alkyl,
• —S(O)2—NR235R240,
• —C(O)—NR235R240,
• —S(O)2-alkyl, and
• —(CH2)0-4—C(O)H;
• R235 and R240 at each occurrence are independently selected from
• —H,
• —OH,
• —CF3,
• —OCH3,
• —NHCH3,
• —N(CH3)2,
• —(CH2)0-4—C(O)(H or alkyl),
• -alkyl,
• -alkanoyl,
• —SO2-alkyl, and
• -aryl.