Methods of treatment of amyloidosis using bi-cyclic aspartyl protease inhibitors
First Claim
Patent Images
1. A method of preventing or treating at least one condition which 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 a pharmaceutically acceptable salt thereof;
wherein 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, —
S(O)0-2-alkyl, -alkyl, -alkoxy, —
O-benzyl optionally substituted with at least one substituent 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 substituent independently selected from alkyl, halogen, —
OH, —
NR5R6, —
NR7R8, —
CN, haloalkoxy, 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;
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 —
C(O)—
CH3, —
C(O)—
CH2(halogen), —
C(O)—
CH(halogen)2, wherein U is selected from —
C(O)—
, —
C(═
S)—
, —
S(O)0-2—
, —
C═
N—
R21—
, —
C═
N—
OR21—
, —
C(O)—
NR20—
, —
C(O)—
O—
, —
S(O)2—
NR20—
, and —
S(O)2—
O—
;
U′
is selected from —
C(O)—
, —
C═
N—
R21—
, —
C═
N—
OR21—
, —
C(O)—
NR20—
, and —
C(O)—
O—
;
V is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —
[C(R4)(R4′
)]1-3-D, and -(T)0-1-RN;
V′
is selected from -(T)0-1-RN′
;
wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V and V′
are optionally substituted with 1 or 2 RB groups;
wherein at least one carbon of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V and V′
are optionally replaced with —
N—
, —
O—
, —
NH—
, —
C(O)—
, —
C(S)—
, —
C(═
N—
H)—
, —
C(═
N—
OH)—
, —
C(═
N-alkyl)-, or —
C(═
N—
O-alkyl)-;
RB at each occurrence is independently selected from halogen, —
OH, —
CF3, —
OCF3, —
O-aryl, —
CN, —
NR101R′
101, -alkyl, -alkoxy, —
(CH2)0-4—
(C(O))0-1—
(O)0-1-alkyl, —
C(O)—
OH, —
(CH2)0-3-cycloalkyl, -aryl, -heteroaryl, and -heterocycloalkyl;
wherein, the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups included within RB are optionally substituted with 1 or 2 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, —
C1-C4 haloalkyl, —
C1-C4 haloalkoxy, -halogen, —
OH, —
CN, and —
NR101R′
101;
R101 and R′
101 are independently selected from —
H, -alkyl, —
(C(O))0-1—
(O)0-1-alkyl, —
C(O)—
OH, and -aryl;
R4 and R4 are independently selected from -hydrogen, -alkyl, —
(CH2)0-3-cycloalkyl, —
(CH2)0-3—
OH, -fluorine, —
CF3, —
OCF3, —
O-aryl, -alkoxy, —
C3-C7 cycloalkoxy, -aryl, and -heteroaryl, or R4 and R4 are taken together with the carbon to which they are attached to form a 3, 4, 5, 6, or 7 membered carbocyclic ring wherein 1, 2, or 3 carbons of the ring is optionally replaced with —
O—
, —
N(H)—
, —
N(alkyl)-, —
N(aryl)-, —
C(O)—
, or —
S(O)0-2;
D is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2 RB groups;
T is selected from —
NR20— and
—
O—
;
R20 is selected from H, —
CN, -alkyl, -haloalkyl, and -cycloalkyl;
R21 is selected from —
H, -alkyl, -haloalkyl, and -cycloalkyl;
RN is selected from —
OH, —
NH2, —
NH(alkyl), —
NH(cycloalkyl), —
N(alkyl)(alkyl), —
N (alkyl)(cycloalkyl), —
N (cycloalkyl)(cycloalkyl), —
R′
100, alkyl-R100, —
(CRR′
)1-6R′
100, —
(CRR′
)0-6R100, —
(CRR′
)1-6—
O—
R′
100, —
(CRR′
)1-6—
S—
R′
100, —
(CRR′
)1-6—
C(O)—
R100, —
(CRR′
)1-6—
SO2—
R100, and —
(CRR′
)1-6—
NR100—
R′
100, —
(CRR′
)1-6—
P(O)(O-alkyl)2, alkyl-O-alkyl-C(O)OH, and —
CH(RE1)—
(CH2)0-3-E1-E2-E3;
RN′
is —
SO2R′
100;
R and R′
are independently selected from -hydrogen, —
C1-C10 alkyl (optionally substituted with at least one group independently selected from —
OH, —
C1-C10 alkylaryl, and —
C1-C10 alkylheteroaryl);
R100 and R′
100 are independently selected from -cycloalkyl, -heterocycloalkyl, -aryl, -heteroaryl, -alkoxy, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocycloalkyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocycloalkyl, -heterocycloalkyl-W-aryl, -heterocycloalkyl-W-heteroaryl, -heterocycloalkyl-W-heterocycloalkyl, —
W—
R102, —
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-aryl, —
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-cycloalkyl, —
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-heterocycloalkyl, —
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-heteroaryl, —
C1-C10 alkyl optionally substituted with 1, 2, or 3 R115 groups, wherein 1, 2, or 3 carbons of the alkyl group are optionally replaced with a group independently selected from —
C(O)— and
—
NH—
, -alkyl-O-alkyl optionally substituted with 1, 2, or 3 R,115 groups, -alkyl-S-alkyl optionally substituted with 1, 2, or 3 R115 groups, and -cycloalkyl optionally substituted with 1, 2, or 3 R115 groups;
wherein the ring portions of each group included within R100 and R′
100 are optionally substituted with 1, 2, or 3 groups independently selected- from —
OR, —
NO2, -halogen, —
CN, —
OCF3, —
CF3, —
(CH2)0-4—
O—
P(═
O)(OR)(OR′
), —
(CH2)0-4—
C(O)—
NR105R′
105, —
(CH2)0-4—
O—
(CH2)0-4—
C(O)NR102R102′
, —
(CH2)0-4—
C(O)—
(C1-C12 alkyl), —
(CH2)0-4—
C(O)—
(CH2)0-4-cycloalkyl, —
(CH2)0-4—
R110, —
(CH2)0-4—
R120, —
(CH2)0-4—
R130, —
(CH2)0-4—
C(O)—
R110, —
(CH2)0-4—
C(O)—
R120, —
(CH2)0-4—
C(O)—
R130, —
(CH2)0-4—
C(O)—
R140, —
(CH2)0-4—
C(O)—
O—
R150, —
(CH2)0-4—
SO2—
NR105R′
105, —
(CH2)0-4—
SO—
(C1-C8 alkyl), —
(CH2)0-4—
SO2—
(C1-C12 alkyl), —
(CH2)0-4—
SO2—
(CH2)0-4-cycloalkyl, —
(CH2)-0-4—
N(R150)—
C(O)—
O—
R150, —
(CH2)0-4—
N(R150)—
C(O)—
N(R150)2, —
(CH2)0-4—
N(R150)—
CS—
N(R150)2, —
(CH2)0-4—
N(R150)—
C(O)—
R105, —
(CH2)0-4—
NR105R′
105, —
(CH2)0-4—
R140, —
(CH2)0-4—
O—
C(O)-(alkyl), —
(CH2)0-4—
O—
P(O)—
(O—
R110)2, —
(CH2)0-4—
O—
C(O)—
N(R150)2, —
(CH2)0-4—
O—
CS—
N(R150)2, —
(CH2)0-4—
O—
(R150), —
(CH2)0-4—
O—
R150′
—
C(O)OH, —
(CH2)0-4—
S—
(R150), —
(CH2)4-0—
N(R150)—
SO2—
R105, —
(CH2)0-4-cycloalkyl, and —
(C1-C10)-alkyl;
RE1 is selected from —
H, —
OH, —
NH2, —
NH—
(CH2)0-3—
RE2, —
NHRE8, —
NRE350C(O)RE5, —
C1-C4-alkyl-NHC(O)RE5, —
(CH2)0-4RE8, —
O—
(C1-C4 alkanoyl), —
C6-C10 (aryloxy optionally substituted with 1, 2, or 3 groups that are independently selected from halogen, —
C1-C4 alkyl, —
CO2H, —
C(O)—
C1-C4 alkoxy, and —
C1-C4 alkoxy), alkoxy, -aryl-(C1-C4 alkoxy), —
NRE350CO2RE351, —
C1-C4 alkyl-NRE350CO2RE351, —
CN, —
CF3, —
CF2-CF3, —
C≡
CH, —
CH2—
CH═
CH2, —
(CH2)1-4—
RE2, —
(CH2)1-4—
NH—
RE2, —
O—
(CH2)0-3—
RE2, —
S—
(CH2)0-3—
RE2, —
(CH2)0-4—
NHC(O)—
(CH2)0-6—
RE352, and —
(CH2)0-4—
(RE353)0-1—
(CH2)0-4—
RE354;
RE2 is selected from —
SO2—
(C1-C8 alkyl), —
SO—
(C1-C8 alkyl), —
S—
(C1-C8 alkyl), —
S—
C(O)-alkyl, —
SO2—
NRE3RE4, —
C(O)—
C1-C2 alkyl, and —
C(O)—
NRE4RE10;
RE3 and RE4 are independently selected from —
H, —
C1-C3 alkyl, and —
C3-C6 cycloalkyl;
RE10 is selected from alkyl, arylalkyl, alkanoyl, and arylalkanoyl;
RE5 is selected from cycloalkyl, alkyl (optionally substituted with 1, 2, or 3 groups that are independently selected from halogen, —
NRE6RE7, C1-C4 alkoxy, —
C5-C6 heterocycloalkyl, —
C5-C6 heteroaryl, —
C6-C10 aryl, —
C3-C7 cycloalkyl C1-C4 alkyl, —
S—
C1-C4 alkyl, —
SO2—
C1-C4 alkyl, —
CO2H, —
C(O)NRE6RE7, —
CO2—
C1-C4 alkyl, and —
C6-C10 aryloxy), heteroaryl (optionally substituted with 1, 2, or 3 groups that are independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
C1-C4 haloalkyl, and —
OH), heterocycloalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, and —
C2-C4 alkanoyl), aryl (optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —
OH, —
C1-C4 alkyl, —
C1-C4 alkoxy, and —
C1-C4 haloalkyl), and —
NRE6RE7;
RE6 and RE7 are independently selected from —
H, alkyl, alkanoyl, aryl, —
SO2—
C1-C4 alkyl, and -aryl-C1-C4 alkyl;
RE8 is selected from —
SO2-heteroaryl, —
SO2-aryl, —
SO2-heterocycloalkyl, —
SO2-C1-C10 alkyl, —
C(O)NHRE9, heterocycloalkyl, —
S—
alkyl, and —
S—
C2-C4 alkanoyl;
RE9 is selected from H, alkyl, and -aryl C1-C4 alkyl;
RE350 is selected from H and alkyl;
RE351 is selected from alkyl, -aryl-(C1-C4 alkyl), alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, cyano, heteroaryl, —
NRE6RE7, —
C(O)NRE6RE7, —
C3-C7 cycloalkyl, and —
C1-C4 alkoxy), heterocycloalkyl (optionally substituted with 1 or 2 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
C2-C4 alkanoyl, -aryl-(C1-C4 alkyl), and —
SO2—
(C1-C4 alkyl)), heteroaryl (optionally substituted with 1, 2, or 3 groups independently selected from —
OH, —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
NH2, —
NH(alkyl), and —
N(alkyl)(alkyl)), heteroarylalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
NH2, —
NH(alkyl), and —
N(alkyl)(alkyl)), aryl, heterocycloalkyl, —
C3-C8 cycloalkyl, and cycloalkylalkyl;
wherein the aryl, heterocycloalkyl, —
C3-C8 cycloalkyl, and cycloalkylalkyl groups included within RE351 are optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, —
CN, —
NO2, alkyl, alkoxy, alkanoyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, —
C1-C6 thioalkoxy, —
C1-C6 thioalkoxy-alkyl, and alkoxyalkoxy;
RE352 is selected from heterocycloalkyl, heteroaryl, aryl, cycloalkyl, —
S(O)0-2-alkyl, —
CO2H, —
C(O)NH2, —
C(O)NH(alkyl), —
C(O)N(alkyl)(alkyl), —
CO2-alkyl, —
NHS(O)0-2-alkyl, —
N(alkyl)S(O)0-2-alkyl, —
S(O)0-2-heteroaryl, —
S(O)0-2aryl, —
NH(arylalkyl), —
N(alkyl)(arylalkyl), thioalkoxy, and alkoxy;
wherein each group included within R352 is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently selected from alkyl, alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, —
NO2, —
CN, alkoxycarbonyl, and aminocarbonyl;
RE353 is selected from —
O—
, —
C(O)—
, —
NH—
, —
N(alkyl)-, —
NH—
S(O)0-2—
, —
N(alkyl)-S(O)0-2—
, —
S(O)0-2—
NH—
, —
S(O)0-2—
N(alkyl)-, —
NH—
C(S)—
, and —
N(alkyl)—
C(S)—
;
RE354 is selected from heteroaryl, aryl, arylalkyl, heterocycloalkyl, —
CO2H, —
CO2-alkyl, —
C(O)NH(alkyl), —
C(O)N(alkyl)(alkyl), —
C(O)NH2, —
C1-C8 alkyl, —
OH, aryloxy, alkoxy, arylalkoxy, —
NH2, —
NH(alkyl), —
N(alkyl)(alkyl), and -alkyl-CO2-alkyl;
wherein each group included within RE354 is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently selected from alkyl, alkoxy, —
CO2H, —
CO2-alkyl, thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, —
NO2, —
CN, alkoxycarbonyl, and aminocarbonyl;
E1 is selected from —
NRE11— and
—
C1-C6 alkyl- (optionally substituted with 1, 2, or 3 groups selected from —
C1-C4 alkyl), and RE11 is selected from —
H and alkyl;
or RE1 and RE11 combine to form —
(CH2)1-4-;
E2 is selected from a bond, —
SO2—
, —
SO—
, —
S—
, and —
C(O)—
; and
E3 is selected from —
H, —
C1-C4 haloalkyl, —
C5-C6 heterocycloalkyl, —
C6-C10 aryl, —
OH, —
N(E3a)(E3b), —
C1-C10 alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy), —
C3-C8 cycloalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —
C1-C3 alkyl and halogen), alkoxy, aryl (optionally substituted with at least one group selected from halogen, alkyl, alkoxy, —
CN and —
NO2), arylalkyl (optionally substituted with a group selected from halogen, alkyl, alkoxy, —
CN, and —
NO2);
E3a and E3b are independently selected from —
H, —
C1-C10 alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, —
C1-C4 alkoxy, —
C3-C8 cycloalkyl, and —
OH), —
C2-C6 alkyl, —
C2-C6 alkanoyl, aryl, —
SO2—
C1-C4 alkyl, -aryl-C1-C4 alkyl, and —
C3-C8 cycloalkyl C1-C4 alkyl;
or E3a, E3b, and the nitrogen to which they are attached may optionally form a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl;
wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently selected from alkyl, alkoxy, alkoxyalkyl, and halogen;
W is selected from —
(CH2)0-4—
, —
O—
, —
S(O)0-2—
, —
N(R135)—
, —
CR(OH)—
, and —
C(O)—
;
R102 and R102′
are independently selected from hydrogen, —
OH, and —
C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from -halogen, -aryl, and —
R110;
R105 and R′
105 are independently selected from —
H, —
R110, —
R120, -cycloalkyl, —
(C1-C2 alkyl)-cycloalkyl, -(alkyl)-O—
(C1-C3 alkyl), and -alkyl optionally substituted with at least one group independently selected from —
OH, -amine, and -halogen;
or R105 and R′
105 together with the atom to which they are attached form a 3, 4, 5, 6, or 7 membered carbocyclic ring, wherein one member is optionally a heteroatom selected from —
O—
, —
S(O)0-2—
, and —
N(R135)—
, wherein the carbocyclic ring is optionally substituted with 1, 2 or 3 R140 groups; and
wherein the at least one carbon of the carbocyclic ring is optionally replaced with —
C(O)—
;
R110 is aryl optionally substituted with 1 or 2 R125 groups;
R115 at each occurrence is independently selected from halogen, —
OH, —
C(O)—
O—
R102, —
C1-C6 thioalkoxy, —
C(O)—
O-aryl, —
NR105R′
105, —
SO2—
(C1-C8 alkyl), —
C(O)—
R180, R180, —
C(O)NR105R′
105, —
SO2NR105R′
105, —
NH—
C(O)-(alkyl), —
NH—
C(O) —
OH, —
NH—
C(O)—
OR, —
NH—
C(O)—
O-aryl, —
O—
C(O)-(alkyl), —
O-C(O)-amino, —
O—
C(O)-monoalkylamino, —
O—
C(O)-dialkylamino, —
O—
C(O)-aryl, —
O-(alkyl)-C(O)—
O—
H, —
NH—
SO2-(alkyl), -alkoxy, and -haloalkoxy;
R120 is -heteroaryl, optionally substituted with 1 or 2 R125 groups;
R125 at each occurrence is independently selected from -halogen, -amino, -monoalkylamino, -dialkylamino, —
OH, —
CN, —
SO2—
NH2, —
SO2—
NH-alkyl, —
SO2-N(alkyl)2, —
SO2—
(C1-C4 alkyl), —
C(O)—
NH2, —
C(O)—
NH-alkyl, —
C(O)—
N(alkyl)2, -alkyl optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkyl, halogen, —
OH, —
SH, —
CN, —
CF3, —
C1-C3 alkoxy, -amino, -monoalkylamino, and -dialkylamino, and -alkoxy optionally substituted with 1, 2, or 3-halogen;
R130 is heterocycloalkyl optionally substituted with 1 or 2 R125 groups;
R135 is independently selected from alkyl, cycloalkyl, —
(CH2)0-2-(aryl), —
(CH2)0-2-(heteroaryl), and —
(CH2)0-2-(heterocycloalkyl);
R140 at each occurrence is independently selected from heterocycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from -alkyl, -alkoxy, -halogen, -hydroxy, -cyano, -nitro, -amino, -monoalkylamino, -dialkylamino, -haloalkyl, -haloalkoxy, -amino-alkyl, -monoalkylamino-alkyl, and -dialkylaminoalkyl; and
wherein at least one carbon of the heterocycloalkyl is optionally replaced with —
C(O);
R150 is independently selected from -hydrogen, -cycloalkyl, —
(C1-C2 alkyl)-cycloalkyl, —
R110, R120, and -alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —
OH, —
NH2, —
C1-C3 alkoxy, —
R110, and -halogen;
R150′
is independently selected from -cycloalkyl, —
(C1-C3 alkyl)-cycloalkyl, R120, and -alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —
OH, —
NH2, —
C1-C3 alkoxy, —
R110, and -halogen; and
R180 is independently selected from -morpholinyl, -thiomorpholinyl, -piperazinyl, -piperidinyl, -homomorpholinyl, -homothiomorpholinyl, -homothiomorpholinyl S-oxide, -homothiomorpholinyl S,S-dioxide, -pyrrolinyl, and -pyrrolidinyl;
wherein each R180 is optionally substituted with 1, 2, 3, or 4 groups independently selected from -alkyl, -alkoxy, -halogen, -hydroxy, -cyano, -nitro, -amino, -monoalkylamino, -dialkylamino, -haloalkyl, -haloalkoxy, -aminoalkyl, -monoalkylamino-alkyl, -dialkylamino-alkyl and —
C(O); and
wherein at least one carbon of R180 is optionally replaced with —
C(O)—
;
Rc is selected from fused ring of formulae (IIIa) and (IIIb), wherein 1, 2, or 3 carbons of the cycloalkyl of formulae (IIIa) and (IIIb) are optionally replaced with —
C(O)—
, wherein at least one carbon of the fused heterocycloalkyl of IIIa and wherein at least one carbon of the fused cycloalkyl of IIIb is optionally substituted with one or two groups each independently selected from —
R205, —
R245, and —
R250;
R200, R200a, and R200b at each occurrence are independently selected from;
—
H, -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—
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—
CO2R215, —
(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)—
CO2R215, —
(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)0-6—
OH, -aryl, —
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, —
CF3, —
CN, -alkoxy, -alkoxycarbonyl, and —
NR235R240;
R210 at each occurrence is independently selected from —
OH, —
CN, —
(CH2)0-4—
C(O)H, -alkyl optionally substituted with at least one group independently selected from R205, —
S(O)2-alkyl, -halogen, -alkoxy, -haloalkoxy, —
NR220R225, -cycloalkyl optionally substituted with at least one group independently selected from R205, —
C(O)-alkyl, —
S(O)2—
NR235R240, —
C(O)—
NR235R240, and —
S-alkyl;
R215 at each occurrence is independently selected from -alkyl, —
(CH2)0-2-cycloalkyl, —
(CH2)0-2-aryl, —
(CH2)0-2-heteroaryl, —
(CH2)0-2-heterocycloalkyl, and —
CO2—
CH2-aryl;
wherein the aryl groups included within R215 are 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 R210;
R220 and R225 at each occurrence are independently selected from —
H, -alkyl, —
(CH2)0-4—
C(O)H, —
(CH2)0-4—
C(O)-alkyl, -alkylhydroxy, -alkoxycarbonyl, -alkylamino, —
S(O)2-alkyl, —
C(O)-alkyl 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 and heterocycloalkyl groups included within R220 and R225 are each optionally substituted with at least one group independently selected from R270;
R235 and R240 at each occurrence are independently selected from —
H, —
OH, —
CF3, —
OCH3, —
NH—
CH3, —
N(CH3)2, —
(CH2)0-4—
C(O)—
(H or alkyl), -alkyl, —
C(O)-alkyl, —
SO2-alkyl, and -aryl;
R245 and R250 at each occurrence are independently selected from —
H, —
OH, —
(CH2)0-4CO2-alkyl, —
(CH2)0=4—
C(O)-alkyl, -alkyl, -hydroxyalkyl, -alkoxy, -haloalkoxy, —
(CH2)0-4-cycloalkyl, —
(CH2)0-4-aryl, —
(CH2)0-4-heteroaryl, and —
(CH2)0-4-heterocycloalkyl;
or R245 and R250 are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, or 8 carbon atoms, wherein at least one carbon atom of the monocyclic or bicyclic ring system is optionally replaced by at least one group independently selected from —
O—
, —
S—
, —
SO2—
, —
C(O)—
, —
NR220—
, and —
N(alkyl)(alkyl); and
wherein the ring is optionally substituted with at least one group independently selected from -alkyl, -alkoxy, —
OH, —
NH2, —
NH(alkyl), —
N(alkyl)(alkyl), —
NH—
C(O)-alkyl, —
NH—
SO2-alkyl, and -halogen;
wherein the aryl, heteroaryl, or heterocycloalkyl groups included within R245 and R250 are optionally substituted with at least one group independently selected from halogen, alkyl, —
CN, and —
OH;
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, —
CO—
NR235R240, —
S(O)2-alkyl, and —
(CH2)0-4—
C(O)H;
R300 is selected from —
H, —
(CO)0-1R215, and —
(CO)0-1R220;
wherein at least one carbon of the aryl group of formulae (IIIa) or (IIIb) is optionally replaced by a heteroatom.
1 Assignment
0 Petitions
Accused Products
Abstract
The invention relates to novel compounds and methods of treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
-
Citations
60 Claims
-
1. A method of preventing or treating at least one condition which 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 a pharmaceutically acceptable salt thereof;
whereinR1 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,—
S(O)0-2-alkyl,-alkyl, -alkoxy, —
O-benzyl optionally substituted with at least one substituent 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 substituent independently selected from alkyl, halogen, —
OH, —
NR5R6, —
NR7R8, —
CN, haloalkoxy, and alkoxy;
R5 and R6 are independently selected from —
H and alkyl;
orR5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring;
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 —
C(O)—
CH3, —
C(O)—
CH2(halogen), —
C(O)—
CH(halogen)2,wherein U is selected from —
C(O)—
, —
C(═
S)—
, —
S(O)0-2—
, —
C═
N—
R21—
, —
C═
N—
OR21—
, —
C(O)—
NR20—
, —
C(O)—
O—
, —
S(O)2—
NR20—
, and —
S(O)2—
O—
;
U′
is selected from —
C(O)—
, —
C═
N—
R21—
, —
C═
N—
OR21—
, —
C(O)—
NR20—
, and —
C(O)—
O—
;
V is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —
[C(R4)(R4′
)]1-3-D, and -(T)0-1-RN;
V′
is selected from -(T)0-1-RN′
;
wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V and V′
are optionally substituted with 1 or 2 RB groups;
wherein at least one carbon of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V and V′
are optionally replaced with —
N—
, —
O—
, —
NH—
, —
C(O)—
, —
C(S)—
, —
C(═
N—
H)—
, —
C(═
N—
OH)—
, —
C(═
N-alkyl)-, or —
C(═
N—
O-alkyl)-;
RB at each occurrence is independently selected from halogen, —
OH, —
CF3, —
OCF3, —
O-aryl, —
CN, —
NR101R′
101, -alkyl, -alkoxy, —
(CH2)0-4—
(C(O))0-1—
(O)0-1-alkyl, —
C(O)—
OH, —
(CH2)0-3-cycloalkyl, -aryl,-heteroaryl, and -heterocycloalkyl;
wherein, the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups included within RB are optionally substituted with 1 or 2 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, —
C1-C4 haloalkyl, —
C1-C4 haloalkoxy, -halogen, —
OH, —
CN, and—
NR101R′
101;
R101 and R′
101 are independently selected from —
H, -alkyl, —
(C(O))0-1—
(O)0-1-alkyl, —
C(O)—
OH, and -aryl;
R4 and R4 are independently selected from -hydrogen, -alkyl, —
(CH2)0-3-cycloalkyl, —
(CH2)0-3—
OH, -fluorine, —
CF3, —
OCF3, —
O-aryl, -alkoxy, —
C3-C7 cycloalkoxy, -aryl, and -heteroaryl, orR4 and R4 are taken together with the carbon to which they are attached to form a 3, 4, 5, 6, or 7 membered carbocyclic ring wherein 1, 2, or 3 carbons of the ring is optionally replaced with —
O—
, —
N(H)—
, —
N(alkyl)-, —
N(aryl)-, —
C(O)—
, or —
S(O)0-2;
D is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2 RB groups;
T is selected from —
NR20— and
—
O—
;
R20 is selected from H, —
CN, -alkyl, -haloalkyl, and -cycloalkyl;
R21 is selected from —
H, -alkyl, -haloalkyl, and -cycloalkyl;
RN is selected from —
OH, —
NH2, —
NH(alkyl), —
NH(cycloalkyl), —
N(alkyl)(alkyl), —
N (alkyl)(cycloalkyl), —
N (cycloalkyl)(cycloalkyl), —
R′
100, alkyl-R100, —
(CRR′
)1-6R′
100, —
(CRR′
)0-6R100, —
(CRR′
)1-6—
O—
R′
100, —
(CRR′
)1-6—
S—
R′
100, —
(CRR′
)1-6—
C(O)—
R100, —
(CRR′
)1-6—
SO2—
R100, and —
(CRR′
)1-6—
NR100—
R′
100, —
(CRR′
)1-6—
P(O)(O-alkyl)2, alkyl-O-alkyl-C(O)OH, and —
CH(RE1)—
(CH2)0-3-E1-E2-E3;
RN′
is —
SO2R′
100;
R and R′
are independently selected from -hydrogen, —
C1-C10 alkyl (optionally substituted with at least one group independently selected from —
OH, —
C1-C10 alkylaryl, and —
C1-C10 alkylheteroaryl);
R100 and R′
100 are independently selected from-cycloalkyl, -heterocycloalkyl, -aryl, -heteroaryl, -alkoxy, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocycloalkyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocycloalkyl, -heterocycloalkyl-W-aryl, -heterocycloalkyl-W-heteroaryl, -heterocycloalkyl-W-heterocycloalkyl, —
W—
R102,—
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-aryl,—
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-cycloalkyl,—
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-heterocycloalkyl,—
CH[(CH2)0-2—
O—
R150]—
(CH2)0-2-heteroaryl,—
C1-C10 alkyl optionally substituted with 1, 2, or 3 R115 groups, wherein 1, 2, or 3 carbons of the alkyl group are optionally replaced with a group independently selected from —
C(O)— and
—
NH—
,-alkyl-O-alkyl optionally substituted with 1, 2, or 3 R,115 groups, -alkyl-S-alkyl optionally substituted with 1, 2, or 3 R115 groups, and -cycloalkyl optionally substituted with 1, 2, or 3 R115 groups;
wherein the ring portions of each group included within R100 and R′
100 are optionally substituted with 1, 2, or 3 groups independently selected- from —
OR, —
NO2, -halogen, —
CN, —
OCF3, —
CF3, —
(CH2)0-4—
O—
P(═
O)(OR)(OR′
), —
(CH2)0-4—
C(O)—
NR105R′
105, —
(CH2)0-4—
O—
(CH2)0-4—
C(O)NR102R102′
, —
(CH2)0-4—
C(O)—
(C1-C12 alkyl), —
(CH2)0-4—
C(O)—
(CH2)0-4-cycloalkyl, —
(CH2)0-4—
R110, —
(CH2)0-4—
R120, —
(CH2)0-4—
R130, —
(CH2)0-4—
C(O)—
R110, —
(CH2)0-4—
C(O)—
R120, —
(CH2)0-4—
C(O)—
R130, —
(CH2)0-4—
C(O)—
R140, —
(CH2)0-4—
C(O)—
O—
R150, —
(CH2)0-4—
SO2—
NR105R′
105, —
(CH2)0-4—
SO—
(C1-C8 alkyl), —
(CH2)0-4—
SO2—
(C1-C12 alkyl), —
(CH2)0-4—
SO2—
(CH2)0-4-cycloalkyl, —
(CH2)-0-4—
N(R150)—
C(O)—
O—
R150, —
(CH2)0-4—
N(R150)—
C(O)—
N(R150)2, —
(CH2)0-4—
N(R150)—
CS—
N(R150)2, —
(CH2)0-4—
N(R150)—
C(O)—
R105, —
(CH2)0-4—
NR105R′
105, —
(CH2)0-4—
R140, —
(CH2)0-4—
O—
C(O)-(alkyl), —
(CH2)0-4—
O—
P(O)—
(O—
R110)2, —
(CH2)0-4—
O—
C(O)—
N(R150)2, —
(CH2)0-4—
O—
CS—
N(R150)2, —
(CH2)0-4—
O—
(R150), —
(CH2)0-4—
O—
R150′
—
C(O)OH, —
(CH2)0-4—
S—
(R150), —
(CH2)4-0—
N(R150)—
SO2—
R105, —
(CH2)0-4-cycloalkyl, and —
(C1-C10)-alkyl;
RE1 is selected from —
H, —
OH, —
NH2, —
NH—
(CH2)0-3—
RE2, —
NHRE8, —
NRE350C(O)RE5, —
C1-C4-alkyl-NHC(O)RE5, —
(CH2)0-4RE8, —
O—
(C1-C4 alkanoyl), —
C6-C10 (aryloxy optionally substituted with 1, 2, or 3 groups that are independently selected from halogen, —
C1-C4 alkyl, —
CO2H, —
C(O)—
C1-C4 alkoxy, and —
C1-C4 alkoxy), alkoxy, -aryl-(C1-C4 alkoxy), —
NRE350CO2RE351, —
C1-C4 alkyl-NRE350CO2RE351, —
CN, —
CF3, —
CF2-CF3, —
C≡
CH, —
CH2—
CH═
CH2, —
(CH2)1-4—
RE2, —
(CH2)1-4—
NH—
RE2, —
O—
(CH2)0-3—
RE2, —
S—
(CH2)0-3—
RE2, —
(CH2)0-4—
NHC(O)—
(CH2)0-6—
RE352, and —
(CH2)0-4—
(RE353)0-1—
(CH2)0-4—
RE354;
RE2 is selected from —
SO2—
(C1-C8 alkyl), —
SO—
(C1-C8 alkyl), —
S—
(C1-C8 alkyl), —
S—
C(O)-alkyl, —
SO2—
NRE3RE4, —
C(O)—
C1-C2 alkyl, and —
C(O)—
NRE4RE10;
RE3 and RE4 are independently selected from —
H, —
C1-C3 alkyl, and —
C3-C6 cycloalkyl;
RE10 is selected from alkyl, arylalkyl, alkanoyl, and arylalkanoyl;
RE5 is selected from cycloalkyl, alkyl (optionally substituted with 1, 2, or 3 groups that are independently selected from halogen, —
NRE6RE7, C1-C4 alkoxy, —
C5-C6 heterocycloalkyl, —
C5-C6 heteroaryl, —
C6-C10 aryl, —
C3-C7 cycloalkyl C1-C4 alkyl, —
S—
C1-C4 alkyl, —
SO2—
C1-C4 alkyl, —
CO2H, —
C(O)NRE6RE7, —
CO2—
C1-C4 alkyl, and —
C6-C10 aryloxy), heteroaryl (optionally substituted with 1, 2, or 3 groups that are independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
C1-C4 haloalkyl, and —
OH), heterocycloalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, and —
C2-C4 alkanoyl), aryl (optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —
OH, —
C1-C4 alkyl, —
C1-C4 alkoxy, and —
C1-C4 haloalkyl), and —
NRE6RE7;
RE6 and RE7 are independently selected from —
H, alkyl, alkanoyl, aryl, —
SO2—
C1-C4 alkyl, and -aryl-C1-C4 alkyl;
RE8 is selected from —
SO2-heteroaryl, —
SO2-aryl, —
SO2-heterocycloalkyl, —
SO2-C1-C10 alkyl, —
C(O)NHRE9, heterocycloalkyl, —
S—
alkyl, and —
S—
C2-C4 alkanoyl;
RE9 is selected from H, alkyl, and -aryl C1-C4 alkyl;
RE350 is selected from H and alkyl;
RE351 is selected from alkyl, -aryl-(C1-C4 alkyl), alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, cyano, heteroaryl, —
NRE6RE7, —
C(O)NRE6RE7, —
C3-C7 cycloalkyl, and —
C1-C4 alkoxy), heterocycloalkyl (optionally substituted with 1 or 2 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
C2-C4 alkanoyl, -aryl-(C1-C4 alkyl), and —
SO2—
(C1-C4 alkyl)), heteroaryl (optionally substituted with 1, 2, or 3 groups independently selected from —
OH, —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
NH2, —
NH(alkyl), and —
N(alkyl)(alkyl)), heteroarylalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —
C1-C4 alkyl, —
C1-C4 alkoxy, halogen, —
NH2, —
NH(alkyl), and —
N(alkyl)(alkyl)), aryl, heterocycloalkyl, —
C3-C8 cycloalkyl, and cycloalkylalkyl;
wherein the aryl, heterocycloalkyl, —
C3-C8 cycloalkyl, and cycloalkylalkyl groups included within RE351 are optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, —
CN, —
NO2, alkyl, alkoxy, alkanoyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, —
C1-C6 thioalkoxy, —
C1-C6 thioalkoxy-alkyl, and alkoxyalkoxy;
RE352 is selected from heterocycloalkyl, heteroaryl, aryl, cycloalkyl, —
S(O)0-2-alkyl, —
CO2H, —
C(O)NH2, —
C(O)NH(alkyl), —
C(O)N(alkyl)(alkyl), —
CO2-alkyl, —
NHS(O)0-2-alkyl, —
N(alkyl)S(O)0-2-alkyl, —
S(O)0-2-heteroaryl, —
S(O)0-2aryl, —
NH(arylalkyl), —
N(alkyl)(arylalkyl), thioalkoxy, and alkoxy;
wherein each group included within R352 is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently selected from alkyl, alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, —
NO2, —
CN, alkoxycarbonyl, and aminocarbonyl;
RE353 is selected from —
O—
, —
C(O)—
, —
NH—
, —
N(alkyl)-, —
NH—
S(O)0-2—
, —
N(alkyl)-S(O)0-2—
, —
S(O)0-2—
NH—
, —
S(O)0-2—
N(alkyl)-, —
NH—
C(S)—
, and —
N(alkyl)—
C(S)—
;
RE354 is selected from heteroaryl, aryl, arylalkyl, heterocycloalkyl, —
CO2H, —
CO2-alkyl, —
C(O)NH(alkyl), —
C(O)N(alkyl)(alkyl), —
C(O)NH2, —
C1-C8 alkyl, —
OH, aryloxy, alkoxy, arylalkoxy, —
NH2, —
NH(alkyl), —
N(alkyl)(alkyl), and -alkyl-CO2-alkyl;
wherein each group included within RE354 is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently selected from alkyl, alkoxy, —
CO2H, —
CO2-alkyl, thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, —
NO2, —
CN, alkoxycarbonyl, and aminocarbonyl;
E1 is selected from —
NRE11— and
—
C1-C6 alkyl- (optionally substituted with 1, 2, or 3 groups selected from —
C1-C4 alkyl), and RE11 is selected from —
H and alkyl;
or RE1 and RE11 combine to form —
(CH2)1-4-;
E2 is selected from a bond, —
SO2—
, —
SO—
, —
S—
, and —
C(O)—
; and
E3 is selected from —
H, —
C1-C4 haloalkyl, —
C5-C6 heterocycloalkyl, —
C6-C10 aryl, —
OH, —
N(E3a)(E3b), —
C1-C10 alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy), —
C3-C8 cycloalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —
C1-C3 alkyl and halogen), alkoxy, aryl (optionally substituted with at least one group selected from halogen, alkyl, alkoxy, —
CN and —
NO2), arylalkyl (optionally substituted with a group selected from halogen, alkyl, alkoxy, —
CN, and —
NO2);
E3a and E3b are independently selected from —
H, —
C1-C10 alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, —
C1-C4 alkoxy, —
C3-C8 cycloalkyl, and —
OH), —
C2-C6 alkyl, —
C2-C6 alkanoyl, aryl, —
SO2—
C1-C4 alkyl, -aryl-C1-C4 alkyl, and —
C3-C8 cycloalkyl C1-C4 alkyl;
orE3a, E3b, and the nitrogen to which they are attached may optionally form a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl;
wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently selected from alkyl, alkoxy, alkoxyalkyl, and halogen;
W is selected from —
(CH2)0-4—
, —
O—
, —
S(O)0-2—
, —
N(R135)—
, —
CR(OH)—
, and —
C(O)—
;
R102 and R102′
are independently selected from hydrogen, —
OH, and —
C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from -halogen, -aryl, and —
R110;
R105 and R′
105 are independently selected from—
H,—
R110,—
R120,-cycloalkyl, —
(C1-C2 alkyl)-cycloalkyl,-(alkyl)-O—
(C1-C3 alkyl), and-alkyl optionally substituted with at least one group independently selected from —
OH, -amine, and -halogen;
orR105 and R′
105 together with the atom to which they are attached form a 3, 4, 5, 6, or 7 membered carbocyclic ring, wherein one member is optionally a heteroatom selected from —
O—
, —
S(O)0-2—
, and —
N(R135)—
, wherein the carbocyclic ring is optionally substituted with 1, 2 or 3 R140 groups; and
wherein the at least one carbon of the carbocyclic ring is optionally replaced with —
C(O)—
;
R110 is aryl optionally substituted with 1 or 2 R125 groups;
R115 at each occurrence is independently selected from halogen, —
OH, —
C(O)—
O—
R102, —
C1-C6 thioalkoxy, —
C(O)—
O-aryl, —
NR105R′
105, —
SO2—
(C1-C8 alkyl), —
C(O)—
R180, R180, —
C(O)NR105R′
105, —
SO2NR105R′
105, —
NH—
C(O)-(alkyl), —
NH—
C(O) —
OH, —
NH—
C(O)—
OR, —
NH—
C(O)—
O-aryl, —
O—
C(O)-(alkyl), —
O-C(O)-amino, —
O—
C(O)-monoalkylamino, —
O—
C(O)-dialkylamino, —
O—
C(O)-aryl, —
O-(alkyl)-C(O)—
O—
H, —
NH—
SO2-(alkyl), -alkoxy, and -haloalkoxy;
R120 is -heteroaryl, optionally substituted with 1 or 2 R125 groups;
R125 at each occurrence is independently selected from -halogen, -amino, -monoalkylamino, -dialkylamino, —
OH, —
CN, —
SO2—
NH2, —
SO2—
NH-alkyl, —
SO2-N(alkyl)2, —
SO2—
(C1-C4 alkyl), —
C(O)—
NH2, —
C(O)—
NH-alkyl, —
C(O)—
N(alkyl)2, -alkyl optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkyl, halogen, —
OH, —
SH, —
CN, —
CF3, —
C1-C3 alkoxy, -amino, -monoalkylamino, and -dialkylamino, and -alkoxy optionally substituted with 1, 2, or 3-halogen;
R130 is heterocycloalkyl optionally substituted with 1 or 2 R125 groups;
R135 is independently selected from alkyl, cycloalkyl, —
(CH2)0-2-(aryl), —
(CH2)0-2-(heteroaryl), and —
(CH2)0-2-(heterocycloalkyl);
R140 at each occurrence is independently selected from heterocycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from -alkyl, -alkoxy, -halogen, -hydroxy, -cyano, -nitro, -amino, -monoalkylamino, -dialkylamino, -haloalkyl, -haloalkoxy, -amino-alkyl, -monoalkylamino-alkyl, and -dialkylaminoalkyl; and
wherein at least one carbon of the heterocycloalkyl is optionally replaced with —
C(O);
R150 is independently selected from -hydrogen, -cycloalkyl, —
(C1-C2 alkyl)-cycloalkyl,—
R110,R120, and -alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —
OH, —
NH2, —
C1-C3 alkoxy, —
R110, and -halogen;
R150′
is independently selected from-cycloalkyl, —
(C1-C3 alkyl)-cycloalkyl,R120, and -alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —
OH, —
NH2, —
C1-C3 alkoxy, —
R110, and -halogen; and
R180 is independently selected from -morpholinyl, -thiomorpholinyl, -piperazinyl, -piperidinyl, -homomorpholinyl, -homothiomorpholinyl, -homothiomorpholinyl S-oxide, -homothiomorpholinyl S,S-dioxide, -pyrrolinyl, and -pyrrolidinyl;
wherein each R180 is optionally substituted with 1, 2, 3, or 4 groups independently selected from -alkyl, -alkoxy, -halogen, -hydroxy, -cyano, -nitro, -amino, -monoalkylamino, -dialkylamino, -haloalkyl, -haloalkoxy, -aminoalkyl, -monoalkylamino-alkyl, -dialkylamino-alkyl and —
C(O); and
wherein at least one carbon of R180 is optionally replaced with —
C(O)—
;
Rc is selected from fused ring of formulae (IIIa) and (IIIb), wherein 1, 2, or 3 carbons of the cycloalkyl of formulae (IIIa) and (IIIb) are optionally replaced with —
C(O)—
, wherein at least one carbon of the fused heterocycloalkyl of IIIa and wherein at least one carbon of the fused cycloalkyl of IIIb is optionally substituted with one or two groups each independently selected from —
R205, —
R245, and —
R250;
R200, R200a, and R200b at each occurrence are independently selected from;
—
H,-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—
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—
CO2R215,—
(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)—
CO2R215,—
(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)0-6—
OH,-aryl, —
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,—
CF3,—
CN,-alkoxy, -alkoxycarbonyl, and —
NR235R240;
R210 at each occurrence is independently selected from —
OH,—
CN,—
(CH2)0-4—
C(O)H,-alkyl optionally substituted with at least one group independently selected from R205, —
S(O)2-alkyl,-halogen, -alkoxy, -haloalkoxy, —
NR220R225,-cycloalkyl optionally substituted with at least one group independently selected from R205, —
C(O)-alkyl,—
S(O)2—
NR235R240,—
C(O)—
NR235R240, and—
S-alkyl;
R215 at each occurrence is independently selected from -alkyl, —
(CH2)0-2-cycloalkyl,—
(CH2)0-2-aryl,—
(CH2)0-2-heteroaryl,—
(CH2)0-2-heterocycloalkyl, and—
CO2—
CH2-aryl;
wherein the aryl groups included within R215 are 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 R210;
R220 and R225 at each occurrence are independently selected from —
H,-alkyl, —
(CH2)0-4—
C(O)H,—
(CH2)0-4—
C(O)-alkyl,-alkylhydroxy, -alkoxycarbonyl, -alkylamino, —
S(O)2-alkyl,—
C(O)-alkyl 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 and heterocycloalkyl groups included within R220 and R225 are each optionally substituted with at least one group independently selected from R270;
R235 and R240 at each occurrence are independently selected from —
H,—
OH,—
CF3,—
OCH3,—
NH—
CH3,—
N(CH3)2,—
(CH2)0-4—
C(O)—
(H or alkyl),-alkyl, —
C(O)-alkyl,—
SO2-alkyl, and-aryl;
R245 and R250 at each occurrence are independently selected from —
H,—
OH,—
(CH2)0-4CO2-alkyl,—
(CH2)0=4—
C(O)-alkyl,-alkyl, -hydroxyalkyl, -alkoxy, -haloalkoxy, —
(CH2)0-4-cycloalkyl,—
(CH2)0-4-aryl,—
(CH2)0-4-heteroaryl, and—
(CH2)0-4-heterocycloalkyl;
orR245 and R250 are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, or 8 carbon atoms, wherein at least one carbon atom of the monocyclic or bicyclic ring system is optionally replaced by at least one group independently selected from —
O—
, —
S—
, —
SO2—
, —
C(O)—
, —
NR220—
, and —
N(alkyl)(alkyl); and
wherein the ring is optionally substituted with at least one group independently selected from -alkyl, -alkoxy, —
OH,—
NH2,—
NH(alkyl),—
N(alkyl)(alkyl),—
NH—
C(O)-alkyl,—
NH—
SO2-alkyl, and-halogen;
wherein the aryl, heteroaryl, or heterocycloalkyl groups included within R245 and R250 are optionally substituted with at least one group independently selected from halogen, alkyl, —
CN, and —
OH;
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,—
CO—
NR235R240,—
S(O)2-alkyl, and—
(CH2)0-4—
C(O)H;
R300 is selected from —
H,—
(CO)0-1R215, and—
(CO)0-1R220;
wherein at least one carbon of the aryl group of formulae (IIIa) or (IIIb) is optionally replaced by a heteroatom. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60)
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42. An article of manufacture comprising:
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(a) a medicament comprising;
an effective amount of at least one compound of formula (I), in combination with active and/or inactive pharmaceutical agents;
(b) a package insert providing that an effective amount of at least one compound of formula (I) should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and
(c) a container in which a medicament comprising;
an effective amount of at least one compound of formula (I) in combination with active and/or inactive pharmaceutical agents is stored.
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Specification