SUBSTITUTED HYDROXYETHYLAMINE ASPARTYL PROTEASE INHIBITORS
First Claim
Patent Images
1. A 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;
L is selected from—
O—
,—
SO2—
,—
C(O)—
,—
C(R55)(R60)—
, and—
CH(NR55R60)—
;
R55 and R60 are each independently selected from hydrogen and alkyl;
R50, R50a, and R50b are independently selected from—
H,-halogen,—
OH,—
C(O)H,—
C(O)CH3,—
CH2OH,—
SH,—
S(O)0-2CH3,—
CN,—
NO2,—
NH2,—
NHCH3,—
N(CH3)2 —
C1—
C2 alkyl,—
OCH2,—
OCF3, and—
CF3;
R2 is selected from—
H,wherein when R1 is benzyl, and RC is 6-Isopropyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not —
H;
wherein, when R1 is 3,5-difluorobenzyl, and RC is 6-Ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not —
H;
wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2is not —
H;
—
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;
-alkyl, 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)0-1—
, 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,wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not methylcarbamoyl;
—
O—
C(O)—
N(R315)(R320),—
NH—
R400,—
R400,—
NH—
R500,—
R500 —
NH—
R600,—
R600, and—
NH—
R700;
R400 is wherein R405 is selected from —
H, —
N(R515)2, and O-alkyl;
R500 is a heteroaryl selected from III(a) and III(b), 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—
,—
N(R520)—
,—
S—
, and—
O—
;
M5 is selected from —
C— and
—
N—
;
R505 is independently selected from—
H,-alkyl,-halogen,—
NO2,—
CN,—
R200, andphenyl;
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 -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—
C(O)—
, -nitro, —
CN, -amino, —
NR220R225, -thioalkyl, —
CF3, —
OH, —
O-alkyl, and -heterocycloalkyl;
wherein when R1 is 3,5-difluoro-benzyl, and RC is 6-ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;
wherein when R1 is 3,5-difluoro-benzyl, and RC is 3-methoxy-benzyl, R2 is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino;
or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;
R700 is aryl optionally substituted with at least one R205;
RC is selected from—
(CH2)0-3-cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —
R205 and —
CO2-(alkyl),-alkyl optionally substituted with at least one group independently selected from R205,—
(CR245R250)0-4—
RX, wherein at least one —
(CR245R250)13 is optionally replaced with a group independently selected from —
O—
, —
N(R215)—
, —
C(O)1-2—
, —
C(O)N(R215)—
, and —
S(O)0-2—
, and-formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg);
RX is selected from-hydrogen,-aryl,-heteroaryl,-cycloalkyl,-heterocycloalkyl, andRXa—
RXb, wherein RXa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein each aryl or heteroaryl group attached directly or indirectly to —
(CR245R250)0-4—
is optionally substituted with at least one group independently selected from R200;
wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is optionally substituted with at least one group independently selected from R210 and —
(CR245R250)0-4—
R200;
wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is independently optionally replaced with a group selected from —
O—
, —
C(O)—
, —
N(R215)0-1—
, and —
S(O)0-2—
;
wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is independently optionally substituted with a group selected from—
(CO)0-1R215,—
(CO)0-1R220,—
S(O)0-2R200, and—
N(R200)—
S(O)0-2R200;
R245 and R250 at each occurrence are independently selected from—
H,—
(CH2)0-4C(O)—
OH,—
(CH2)0-4C(O)—
O—
alkyl,—
(CH2)0-4C(O)-alkyl,-alkyl,-hydroxyalkyl,—
O-alkyl,-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, 8, 9, or 10 carbon atoms,wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond,wherein the bicyclic ring system is optionally a fused or spiro ring system,wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from—
O—
,—
C(O)—
,—
S(O)0-2—
,—
C(═
N—
R255)—
,—
N—
,—
NR220—
,—
N((CO)0-1R200)—
, and—
N(SO2R200)—
,wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R245 and R250 are optionally substituted with at least one group independently selected from -halogen, -alkyl, —
N(R220)(R225), —
CN, and —
OH;
wherein the monocyclic and bicyclic groups included in R245 and R250 are optionally substituted with at least one group independently selected from halogen, —
(CH2)0-2—
OH, —
O-alkyl, alkyl, —
(CH2)0-2—
S-alkyl, —
CF3, aryl, —
N(R220)(R225), —
CN, —
(CH2)0-2—
NH2, —
(CH2)0-2—
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH-heteroaryl, —
NH-C(O)-alkyl, and —
NHS(O2)-alkyl;
formula (IVa) is wherein Q1 is selected from (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, and —
C(O)—
;
Q2 and Q3 each are independently selected from (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, —
O—
, —
C(O)—
, —
S—
, —
S(O)2—
, —
NH—
, and —
N(R7)—
;
Q4 is selected from a bond, (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, —
O—
, —
C(O)—
, —
S—
, —
S(O)2—
, —
NH—
, and —
N(R7); and
P1, P2, P3, and P4 each are independently selected from —
CH—
, —
C(R200)—
, and —
N—
;
formula (IVb) is wherein R4 is selected from —
H and -alkyl, and P1, P2, P3, and P4 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
;
formula (IVc) is wherein R4 is selected from —
H and -alkyl; and
P1, P2, P3, and P4 at each occurrence are independently selected from —
CH—
, —
CR200—
, and —
N—
;
formula (IVd) is wherein m is 0, 1, 2, 3, 4, 5, or 8;
Y′
is selected from —
H, —
CN, —
OH, —
O-alkyl, —
CO2H, —
C(O)OR215, -amino, -aryl, and -heteroaryl; and
P1 and P2 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
,or P1 and P2 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, P3 and P4 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
,or P3 and P4 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, P5 at each occurrence is independently selected from —
CH—
, —
C(R200)—
, and —
N—
,wherein at least one bond in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a double bond,wherein the bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a fused or spiro ring system,wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally replaced by a group independently selected from—
O—
,—
C(O)—
,—
S(O)0-2—
,—
C(═
N—
R255)—
,—
N—
,—
NR220—
,—
N((CO)0-1R200—
, and—
N(SO2R200)—
; and
P5 at each occurrence is independently selected from —
CH—
, —
C(R200)—
, and —
N—
, formula (IVe) is wherein U is selected from —
CH2—
CR100R101—
, —
CH2—
S—
, —
CH2S(O)—
, —
CH2—
S(O)2—
, —
CH2—
N(R100)—
, —
CH2—
C(O)—
, —
CH2—
O—
, —
C(O)—
C(R100)(R101)—
, —
SO2—
N(R100)—
, —
C(O)—
N(R55)—
, —
N(R55)—
C(O)—
N(R55)—
, —
O—
C(O)—
O—
, —
N(R55)—
C(O)—
O—
-, and —
C(O)—
O—
;
wherein R100 and R101 at each occurrence are independently selected from —
H, -alkyl, -aryl, —
C(O)-alkyl, —
(CO)0-1R215, —
(CO)0-1R220, and —
S(O)2-alkyl;
formula (IVf) is wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, —
N(R5)C(O)H, —
C(O)H, —
C(O)N(R5)(R6), —
NR5R6, R280, R285, -aryl, and -heteroaryl;
wherein R280 and R285, and the carbon to which they are attached form a C3—
C7 spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, -halogen, —
CF3, and —
CN;
wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R290 and R295;
wherein R290 and R295 at each occurrence are independently selected from -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
OH,—
NO2,-halogen,—
CO2H,—
CN,—
(CH2)0-4—
C(O)—
NR21R22,—
(CH2)0-4—
CO2R20,—
(CH2)0-4—
SO2—
NR21R22,—
(CH2)0-4S(O)-alkyl),—
(CH2)0-4—
S(O)2-(alkyl),—
(CH2)0-4-S(O)2-(cycloalkyl),—
(CH2)0-4—
N(H or R20)—
C(O)—
O—
R20,—
(CH2)0-4—
N(H or R20)—
C(O)—
N(R20)2,—
(CH2)0-4—
N—
C(S)—
N(R20)2,—
(CH2)0-4—
N(H or R20)—
CO—
R21,—
(CH2)0-4—
NR21R22,—
(CH2)0-4—
R11,—
(CH2)0-4—
O—
C(O)—
(alkyl),—
(CH2)0-4—
O—
P(O)—
(OR5)2,—
(CH2)0-4≧
O—
C(O)—
N(R20)2,—
(CH2)0-4—
O—
C(S)—
N(R20)2,—
(CH2)0-4—
O—
(R20)2,—
(CH2)0-4—
(R20)—
CO2H,—
(CH2)0-4—
S—
(R20),—
(CH2)0-4—
O-(alkyl optionally substituted with at least one halogen),-cycloalkyl,—
(CH2)0-4—
N(H or R20)—
S(O)2—
R21, and—
(CH2)0-4-cycloalkyl;
formula (IVg) is wherein a is 0 or 1;
b is 0 or 1;
S′
is selected from —
C(O)— and
—
CO2—
;
T′
is —
(CH2)0-4—
;
U′
is —
(CR245R250)—
;
V′
is selected from -aryl- and -heteroaryl-;
W′
is selected from-a bond,-alkyl-substituted with at least one group independently selected from R205,—
(CH2)0-4—
(CO)0-1—
N(R220)—
,—
(CH2)0-4—
(CO)0-1—
,—
(CH2)0-4—
CO2—
,—
(CH2)0-4—
SO2—
N(R220)—
,—
(CH2)0-4—
N(H or R215)—
CO2—
,—
(CH2)0-4—
N(H or R215)—
SO2—
,—
(CH2)0-4—
N(H or R215)—
C(O)—
N(R215)—
,—
(CH2)0-4—
N(H or R215)—
C(O)—
,—
(CH2)0-4—
N(R220)—
,—
(CH2)0-4—
O—
, and—
(CH2)0-4—
S—
;
X′
is selected from aryl and heteroaryl;
wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R205;
wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R200;
wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from—
(CO)0-1R215,—
(CO)0-1R220, and—
S(O)0-2R200;
R21 and R22 each independently are selected from—
H,-alkyl optionally substituted with at least one group independently selected from —
OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —
R17, and —
R18,—
(CH2)0-4—
C(O)-(alkyl),—
(CH2)0-4—
C(O)-(cycloalkyl),—
(CH2)0-4—
C(O)—
R17,—
(CH2)0-4—
C(O)—
R18,—
(CH2)0-4—
C(O)—
R19, and—
(CH2)0-4—
C(O)—
R11;
R17 at each occurrence is aryl optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
NR5R6, —
CN, —
CF3, and —
O-alkyl,-halogen,—
O-alkyl optionally substituted with at least one group independently selected from halogen, —
NR21R22, —
OH, —
CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)—
O—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);
R18 at each occurrence is heteroaryl optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,-halogen,—
O-alkyl optionally substituted with at least one group independently selected from -halogen, —
NR21R22, —
OH, and —
CN,-cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)2—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);
R19 at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —
C(O)—
, —
S(O)—
, and —
S(O)2—
, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,-halogen,—
O-alkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
CN, —
NR21R22, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)2—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);
R11 at each occurrence is heterocycloalkylwherein at least one carbon of the heterocycloalkyl is optionally replaced with —
C(O)—
, —
S(O)—
, and —
S(O)2—
,wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, and -halogen;
R20 is selected from -alkyl, -cycloalkyl, —
(CH2)0-2—
(R17), and —
(CH2)0-2—
(R18);
R200 at each occurrence is Independently selected from-alkyl optionally substituted with at least one group independently selected from R205,—
OH,—
NO2,—
NH2,-halogen,—
CN,—
CF3,—
OCF3,—
(CH2)0-4—
C(O)H,—
(CO)0-1R215,—
(CO)0-1R220,—
(CH2)0-4—
C(O)—
NR220R225,—
(CH2)0-4—
(C(O))0-1R215,—
(CH2)0-4—
(C(O))0-1—
R220,—
(CH2)0-4—
C(O)-alkyl,—
(CH2)0-4—
(C(O))0-1-cycloalkyl,—
(CH2)0-4—
(C(O))0-1-heterocycloalkyl,—
(CH2)0-4—
(C(O))0-1-aryl,—
(CH2)0-4—
(C(O))0-1-heteroaryl,—
(CH2)0-4—
C(O)—
O—
R215,—
(CH2)0-4—
S(O)0-2—
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)—
S(O)1-2—
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—
NR220R225,—
(CH2)0-4—
O—
C(O)-alkyl,—
(CH2)0-4—
O—
(R215),—
(CH2)0-4—
S—
(R215),—
(CH2)0-4—
C(O)H,—
(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—
R205,—
R210 , and-alkyl optionally substituted with at least one group independently selected from R205 and R210;
R205 at each occurrence is independently selected from-alkyl,-heteroaryl,-heterocycloalkyl,-aryl,-haloalkoxy,—
(CH2)0-3-cycloalkyl,-halogen,—
(CH2)0-6—
OH,—
O-phenyl,—
SH,—
(CH2)0-4—
C(O)CH3 —
(CH2)0-4—
C(O)H—
(CH2)0-4—
CO2H,—
(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,—
OCF3,—
C(O)2-benzyl,—
O-alkyl,—
C(O)2-alkyl, and—
NR235R240;
R210 at each occurrence is independently selected from—
OH,—
CN,—
(CH2)0-4—
C(O)H,-alkyl wherein a carbon atom is optionally replaced with —
C(O)—
, and a carbon atom is optionally substituted with at least one group independently selected from R205,—
S-alkyl,-halogen,—
O-alkyl,-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(O)2-alkyl;
R215 at each occurrence is independently selected from-alkyl,—
(CH2)0-2-aryl,—
(CH2)0-2-cycloalkyl,—
(CH2)0-2-heteroaryl, and—
(CH2)0-2-heterocycloalkyl;
wherein the aryl groups included within R215 are optionally substituted with at least one group independently selected from R205 or R210;
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,—
OH,-alkyl,—
(CH2)0-4—
C(O)H,-alkyl-OH,—
(CH2)0-4—
CO2-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,-aminoalkyl,—
S(O)2-alkyl,—
(CH2)0-4—
C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,—
(CH2)0-4—
C(O)—
NH2,—
(CH2)0-4—
C(O)—
NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R205,—
(CH2)0-4—
C(O)—
N(alkyl)(alkyl),-haloalkyl,—
(CH2)0-2-cycloalkyl,-alkyl-O-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;
R270 at each occurrence is independently selected fromR205,-alkyl optionally substituted with at least one group independently selected from R205,-phenyl,-halogen,—
O-alkyl,-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;
R235 and R240 at each occurrence are independently selected from—
H,-alkyl,—
C(O)-alkyl,—
OH,—
CF3,—
OCH3,—
NH—
CH3,—
N(CH3)2,—
(CH2)0-4—
C(O)—
(H or alkyl),—
SO2-alkyl, and-phenyl;
R255 is selected from -hydrogen, —
OH, —
N(R220)(R225), and —
O-alkyl;
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 is independently selected from—
H,-alkyl optionally substituted with at least one group independently selected from —
OH, amino, and halogen,-cycloalkyl, and-alkyl-O-alkyl.
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Abstract
The invention relates to novel compounds and also to methods of treating at least one disease, disorder, or condition associated with amyloidosis using such compounds. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
-
Citations
61 Claims
-
1. A 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; L is selected from —
O—
,—
SO2—
,—
C(O)—
,—
C(R55)(R60)—
, and—
CH(NR55R60)—
;R55 and R60 are each independently selected from hydrogen and alkyl; R50, R50a, and R50b are independently selected from —
H,-halogen, —
OH,—
C(O)H,—
C(O)CH3,—
CH2OH,—
SH,—
S(O)0-2CH3,—
CN,—
NO2,—
NH2,—
NHCH3,—
N(CH3)2—
C1—
C2 alkyl,—
OCH2,—
OCF3, and—
CF3;R2 is selected from —
H,wherein when R1 is benzyl, and RC is 6-Isopropyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not —
H;wherein, when R1 is 3,5-difluorobenzyl, and RC is 6-Ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not —
H;wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2is not —
H;—
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;-alkyl, 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)0-1—
, 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,wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not methylcarbamoyl; —
O—
C(O)—
N(R315)(R320),—
NH—
R400,—
R400,—
NH—
R500,—
R500—
NH—
R600,—
R600, and—
NH—
R700;R400 is wherein R405 is selected from —
H, —
N(R515)2, and O-alkyl;R500 is a heteroaryl selected from III(a) and III(b), 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—
,—
N(R520)—
,—
S—
, and—
O—
;M5 is selected from —
C— and
—
N—
;R505 is independently selected from —
H,-alkyl, -halogen, —
NO2,—
CN,—
R200, andphenyl; 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 -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—
C(O)—
, -nitro, —
CN, -amino, —
NR220R225, -thioalkyl, —
CF3, —
OH, —
O-alkyl, and -heterocycloalkyl;wherein when R1 is 3,5-difluoro-benzyl, and RC is 6-ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;wherein when R1 is 3,5-difluoro-benzyl, and RC is 3-methoxy-benzyl, R2 is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino;
or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;R700 is aryl optionally substituted with at least one R205; RC is selected from —
(CH2)0-3-cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —
R205 and —
CO2-(alkyl),-alkyl optionally substituted with at least one group independently selected from R205, —
(CR245R250)0-4—
RX, wherein at least one —
(CR245R250)13 is optionally replaced with a group independently selected from —
O—
, —
N(R215)—
, —
C(O)1-2—
, —
C(O)N(R215)—
, and —
S(O)0-2—
, and-formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg); RX is selected from -hydrogen, -aryl, -heteroaryl, -cycloalkyl, -heterocycloalkyl, and RXa—
RXb, wherein RXa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;wherein each aryl or heteroaryl group attached directly or indirectly to —
(CR245R250)0-4—
is optionally substituted with at least one group independently selected from R200;wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is optionally substituted with at least one group independently selected from R210 and —
(CR245R250)0-4—
R200;wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is independently optionally replaced with a group selected from —
O—
, —
C(O)—
, —
N(R215)0-1—
, and —
S(O)0-2—
;wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is independently optionally substituted with a group selected from—
(CO)0-1R215,—
(CO)0-1R220,—
S(O)0-2R200, and—
N(R200)—
S(O)0-2R200;R245 and R250 at each occurrence are independently selected from —
H,—
(CH2)0-4C(O)—
OH,—
(CH2)0-4C(O)—
O—
alkyl,—
(CH2)0-4C(O)-alkyl,-alkyl, -hydroxyalkyl, —
O-alkyl,-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, 8, 9, or 10 carbon atoms, wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from —
O—
,—
C(O)—
,—
S(O)0-2—
,—
C(═
N—
R255)—
,—
N—
,—
NR220—
,—
N((CO)0-1R200)—
, and—
N(SO2R200)—
,wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R245 and R250 are optionally substituted with at least one group independently selected from -halogen, -alkyl, —
N(R220)(R225), —
CN, and —
OH;wherein the monocyclic and bicyclic groups included in R245 and R250 are optionally substituted with at least one group independently selected from halogen, —
(CH2)0-2—
OH, —
O-alkyl, alkyl, —
(CH2)0-2—
S-alkyl, —
CF3, aryl, —
N(R220)(R225), —
CN, —
(CH2)0-2—
NH2, —
(CH2)0-2—
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH-heteroaryl, —
NH-C(O)-alkyl, and —
NHS(O2)-alkyl;formula (IVa) is wherein Q1 is selected from (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, and —
C(O)—
;
Q2 and Q3 each are independently selected from (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, —
O—
, —
C(O)—
, —
S—
, —
S(O)2—
, —
NH—
, and —
N(R7)—
;Q4 is selected from a bond, (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, —
O—
, —
C(O)—
, —
S—
, —
S(O)2—
, —
NH—
, and —
N(R7); andP1, P2, P3, and P4 each are independently selected from —
CH—
, —
C(R200)—
, and —
N—
;
formula (IVb) iswherein R4 is selected from —
H and -alkyl, andP1, P2, P3, and P4 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
;formula (IVc) is wherein R4 is selected from —
H and -alkyl; andP1, P2, P3, and P4 at each occurrence are independently selected from —
CH—
, —
CR200—
, and —
N—
;formula (IVd) is wherein m is 0, 1, 2, 3, 4, 5, or 8; Y′
is selected from —
H, —
CN, —
OH, —
O-alkyl, —
CO2H, —
C(O)OR215, -amino, -aryl, and -heteroaryl; andP1 and P2 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
,or P1 and P2 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, P3 and P4 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
,or P3 and P4 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, P5 at each occurrence is independently selected from —
CH—
, —
C(R200)—
, and —
N—
,wherein at least one bond in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a double bond, wherein the bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a fused or spiro ring system, wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally replaced by a group independently selected from —
O—
,—
C(O)—
,—
S(O)0-2—
,—
C(═
N—
R255)—
,—
N—
,—
NR220—
,—
N((CO)0-1R200—
, and—
N(SO2R200)—
; andP5 at each occurrence is independently selected from —
CH—
, —
C(R200)—
, and —
N—
, formula (IVe) iswherein U is selected from —
CH2—
CR100R101—
, —
CH2—
S—
, —
CH2S(O)—
, —
CH2—
S(O)2—
, —
CH2—
N(R100)—
, —
CH2—
C(O)—
, —
CH2—
O—
, —
C(O)—
C(R100)(R101)—
, —
SO2—
N(R100)—
, —
C(O)—
N(R55)—
, —
N(R55)—
C(O)—
N(R55)—
, —
O—
C(O)—
O—
, —
N(R55)—
C(O)—
O—
-, and —
C(O)—
O—
;wherein R100 and R101 at each occurrence are independently selected from —
H, -alkyl, -aryl, —
C(O)-alkyl, —
(CO)0-1R215, —
(CO)0-1R220, and —
S(O)2-alkyl;formula (IVf) is wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, —
N(R5)C(O)H, —
C(O)H, —
C(O)N(R5)(R6), —
NR5R6, R280, R285, -aryl, and -heteroaryl;wherein R280 and R285, and the carbon to which they are attached form a C3—
C7 spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, -halogen, —
CF3, and —
CN;wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R290 and R295; wherein R290 and R295 at each occurrence are independently selected from -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
OH,—
NO2,-halogen, —
CO2H,—
CN,—
(CH2)0-4—
C(O)—
NR21R22,—
(CH2)0-4—
CO2R20,—
(CH2)0-4—
SO2—
NR21R22,—
(CH2)0-4S(O)-alkyl),—
(CH2)0-4—
S(O)2-(alkyl),—
(CH2)0-4-S(O)2-(cycloalkyl),—
(CH2)0-4—
N(H or R20)—
C(O)—
O—
R20,—
(CH2)0-4—
N(H or R20)—
C(O)—
N(R20)2,—
(CH2)0-4—
N—
C(S)—
N(R20)2,—
(CH2)0-4—
N(H or R20)—
CO—
R21,—
(CH2)0-4—
NR21R22,—
(CH2)0-4—
R11,—
(CH2)0-4—
O—
C(O)—
(alkyl),—
(CH2)0-4—
O—
P(O)—
(OR5)2,—
(CH2)0-4≧
O—
C(O)—
N(R20)2,—
(CH2)0-4—
O—
C(S)—
N(R20)2,—
(CH2)0-4—
O—
(R20)2,—
(CH2)0-4—
(R20)—
CO2H,—
(CH2)0-4—
S—
(R20),—
(CH2)0-4—
O-(alkyl optionally substituted with at least one halogen),-cycloalkyl, —
(CH2)0-4—
N(H or R20)—
S(O)2—
R21, and—
(CH2)0-4-cycloalkyl;formula (IVg) is wherein a is 0 or 1; b is 0 or 1; S′
is selected from —
C(O)— and
—
CO2—
;T′
is —
(CH2)0-4—
;U′
is —
(CR245R250)—
;V′
is selected from -aryl- and -heteroaryl-;W′
is selected from-a bond, -alkyl-substituted with at least one group independently selected from R205, —
(CH2)0-4—
(CO)0-1—
N(R220)—
,—
(CH2)0-4—
(CO)0-1—
,—
(CH2)0-4—
CO2—
,—
(CH2)0-4—
SO2—
N(R220)—
,—
(CH2)0-4—
N(H or R215)—
CO2—
,—
(CH2)0-4—
N(H or R215)—
SO2—
,—
(CH2)0-4—
N(H or R215)—
C(O)—
N(R215)—
,—
(CH2)0-4—
N(H or R215)—
C(O)—
,—
(CH2)0-4—
N(R220)—
,—
(CH2)0-4—
O—
, and—
(CH2)0-4—
S—
;X′
is selected from aryl and heteroaryl;wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R205; wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R200; wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from —
(CO)0-1R215,—
(CO)0-1R220, and—
S(O)0-2R200;R21 and R22 each independently are selected from —
H,-alkyl optionally substituted with at least one group independently selected from —
OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —
R17, and —
R18,—
(CH2)0-4—
C(O)-(alkyl),—
(CH2)0-4—
C(O)-(cycloalkyl),—
(CH2)0-4—
C(O)—
R17,—
(CH2)0-4—
C(O)—
R18,—
(CH2)0-4—
C(O)—
R19, and—
(CH2)0-4—
C(O)—
R11;R17 at each occurrence is aryl optionally substituted with at least one group independently selected from -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
NR5R6, —
CN, —
CF3, and —
O-alkyl,-halogen, —
O-alkyl optionally substituted with at least one group independently selected from halogen, —
NR21R22, —
OH, —
CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)—
O—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);R18 at each occurrence is heteroaryl optionally substituted with at least one group independently selected from -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,-halogen, —
O-alkyl optionally substituted with at least one group independently selected from -halogen, —
NR21R22, —
OH, and —
CN,-cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)2—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);R19 at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —
C(O)—
, —
S(O)—
, and —
S(O)2—
, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,-halogen, —
O-alkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
CN, —
NR21R22, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)2—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);R11 at each occurrence is heterocycloalkyl wherein at least one carbon of the heterocycloalkyl is optionally replaced with —
C(O)—
, —
S(O)—
, and —
S(O)2—
,wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, and -halogen;R20 is selected from -alkyl, -cycloalkyl, —
(CH2)0-2—
(R17), and —
(CH2)0-2—
(R18);R200 at each occurrence is Independently selected from -alkyl optionally substituted with at least one group independently selected from R205, —
OH,—
NO2,—
NH2,-halogen, —
CN,—
CF3,—
OCF3,—
(CH2)0-4—
C(O)H,—
(CO)0-1R215,—
(CO)0-1R220,—
(CH2)0-4—
C(O)—
NR220R225,—
(CH2)0-4—
(C(O))0-1R215,—
(CH2)0-4—
(C(O))0-1—
R220,—
(CH2)0-4—
C(O)-alkyl,—
(CH2)0-4—
(C(O))0-1-cycloalkyl,—
(CH2)0-4—
(C(O))0-1-heterocycloalkyl,—
(CH2)0-4—
(C(O))0-1-aryl,—
(CH2)0-4—
(C(O))0-1-heteroaryl,—
(CH2)0-4—
C(O)—
O—
R215,—
(CH2)0-4—
S(O)0-2—
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)—
S(O)1-2—
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—
NR220R225,—
(CH2)0-4—
O—
C(O)-alkyl,—
(CH2)0-4—
O—
(R215),—
(CH2)0-4—
S—
(R215),—
(CH2)0-4—
C(O)H,—
(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 —
R205,—
R210 , and-alkyl optionally substituted with at least one group independently selected from R205 and R210; R205 at each occurrence is independently selected from -alkyl, -heteroaryl, -heterocycloalkyl, -aryl, -haloalkoxy, —
(CH2)0-3-cycloalkyl,-halogen, —
(CH2)0-6—
OH,—
O-phenyl,—
SH,—
(CH2)0-4—
C(O)CH3—
(CH2)0-4—
C(O)H—
(CH2)0-4—
CO2H,—
(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,—
OCF3,—
C(O)2-benzyl,—
O-alkyl,—
C(O)2-alkyl, and—
NR235R240;R210 at each occurrence is independently selected from —
OH,—
CN,—
(CH2)0-4—
C(O)H,-alkyl wherein a carbon atom is optionally replaced with —
C(O)—
, and a carbon atom is optionally substituted with at least one group independently selected from R205,—
S-alkyl,-halogen, —
O-alkyl,-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(O)2-alkyl;R215 at each occurrence is independently selected from -alkyl, —
(CH2)0-2-aryl,—
(CH2)0-2-cycloalkyl,—
(CH2)0-2-heteroaryl, and—
(CH2)0-2-heterocycloalkyl;wherein the aryl groups included within R215 are optionally substituted with at least one group independently selected from R205 or R210; 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,—
OH,-alkyl, —
(CH2)0-4—
C(O)H,-alkyl-OH, —
(CH2)0-4—
CO2-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,-aminoalkyl, —
S(O)2-alkyl,—
(CH2)0-4—
C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,—
(CH2)0-4—
C(O)—
NH2,—
(CH2)0-4—
C(O)—
NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R205,—
(CH2)0-4—
C(O)—
N(alkyl)(alkyl),-haloalkyl, —
(CH2)0-2-cycloalkyl,-alkyl-O-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; R270 at each occurrence is independently selected from R205, -alkyl optionally substituted with at least one group independently selected from R205, -phenyl, -halogen, —
O-alkyl,-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;R235 and R240 at each occurrence are independently selected from —
H,-alkyl, —
C(O)-alkyl,—
OH,—
CF3,—
OCH3,—
NH—
CH3,—
N(CH3)2,—
(CH2)0-4—
C(O)—
(H or alkyl),—
SO2-alkyl, and-phenyl; R255 is selected from -hydrogen, —
OH, —
N(R220)(R225), and —
O-alkyl;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; and R7 is independently selected from —
H,-alkyl optionally substituted with at least one group independently selected from —
OH, amino, and halogen,-cycloalkyl, and -alkyl-O-alkyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one atom within the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from —
O—
,—
C(O)—
,—
S(O)0-2—
,—
C(═
N—
R255)—
,—
N—
,—
NR220—
,N((CO)0-1R200)—
, and—
N(SO2R200)—
; andwherein the monocyclic or bicyclic groups included within R245 and R250 are optionally substituted with at least one group independently selected from halogen, —
(CH2)0-2—
OH, —
(CH2)0-2—
S-alkyl, —
CF3, —
O-alkyl, alkyl, aryl, —
N(R220)(R225), —
CN, —
(CH2)0-2—
NH2, —
(CH2)0-2—
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH-heteroaryl, —
NH—
C(O)-alkyl, and —
NHS(O2)-alkyl; and
wherein RX, R220, R225, R255, and R200 are as defined in claim 1.
- C(H)0-2—
-
5. The compound according to claim 1, wherein RC is selected from formulae (Va), (Vb), (Vc), and (Vd),
wherein, A, B, and C are independently selected from — - CH2—
,—
O—
,—
C(O)—
,—
S(O)0-2—
,—
N((CO)0-1R200)—
,—
N(SO2R200)—
,—
C(═
N—
R255)—
, and—
N(R220)—
;A′
at each occurence is independently selected from —
CH2— and
—
O—
;wherein (Va), (Vb), (Vc), and (Vd) are each optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, —
(CH2)0-2—
OH, —
(CH2)0-2—
S-alkyl, —
CF3, —
CN, -halogen, —
(CH2)0-2—
NH2, —
(CH2)0-2—
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH-heteroaryl, —
NH—
C(O)-alkyl, and —
NHS(O2)-alkyl; andRX, R220, R255, and R200 are as defined in claim 1.
- CH2—
-
6. The compound according to claim 1, wherein RC is selected from formulae (Vla) and (Vlb)
wherein at least one carbon of the heterocycloalkyl of formula (Vla) and the cycloalkyl of formula (Vlb) is optionally replaced with a group independently selected from — - O—
, —
SO2—
, and —
C(O)—
, wherein at least one carbon of the heterocycloalkyl or cycloalkyl is optionally substituted with at least one group Independently selected from R205, R245, and R250, wherein R100, R200, R205, R245, and R250 are as defined in claim 1.
- O—
-
7. The compound according to claim 1, wherein RC is selected from 6-isobutyl-1,1-dioxo-1λ
-
6-thiochroman-4-yl, 6-isopropyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, 1-(3-tert-Butyl-phenyl)-cyclohexyl, and 3-methoxy-benzyl.
-
6-thiochroman-4-yl, 6-isopropyl-2,2-dioxo-2λ
-
8. The compound according to claim 1, wherein R2 is selected from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
-
9. The compound according to claim 2, wherein RX is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′
- -Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.
-
25. A method of preventing or treating the onset of dementia comprising:
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof to the patient, wherein R1, R2, and RC are defined as in claim 1.
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),
-
26. A method of preventing or treating at least one condition associated with amyloidosis by administering to a host an effective amount of at least one compound of formula (I):
-
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
-
-
27. A method of preventing or treating Alzheimer'"'"'s disease by administering to a host an effective amount of at least one compound having the following structure:
-
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
-
-
28. A method of preventing or treating dementia by administering to a host an effective amount of at least one compound having the following structure:
-
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
-
-
29. A method of inhibiting beta-secretase activity in a cell, the method comprising the step of administering to the cell an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
-
30. A method of inhibiting beta-secretase activity in a host, the method comprising the step of administering to the host an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
-
31. The method according to claim 30, wherein the host is a human.
-
32. A method of affecting beta-secretase-mediated cleavage of amyloid precursor protein in a patient, comprising administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1. -
33. A method of inhibiting cleavage of amyloid precursor protein at a site between Met596 and Asp597 (numbered for the APP-695 amino acid isotype), or at a corresponding site of an isotype or mutant thereof, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
- administering a therapeutically effective amount of at least one compound of formula (I),
-
34. A method of inhibiting cleavage of amyloid precursor protein or mutant thereof at a site between amino acids, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2 and RC are defined as in claim 1, wherein the site between amino acids corresponds to between Met652 and Asp653 (numbered for the APP-751 isotype); between Met671 and Asp672 (numbered for the APP-770 isotype); between Leu596 and Asp597 of the APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation;
orbetween Leu671 and Asp672 of the APP-770 Swedish Mutation.
- administering a therapeutically effective amount of at least one compound of formula (I),
-
35. A method of inhibiting production of A-beta, comprising:
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),
-
36. A method of preventing or treating deposition of A-beta, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
- administering a therapeutically effective amount of at least one compound of formula (I),
-
37. A method of preventing, delaying, halting, or reversing a disease characterized by A-beta deposits or plaques, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.
- administering a therapeutically effective amount of at least one compound of formula (I),
-
38. The method in claim 37, wherein the A-beta deposits or plaques are in a human brain.
-
39. A method of preventing, delaying, halting, or reversing a condition associated with a pathological form of A-beta in a host comprising:
- administering to a patient in need thereof an effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable sail thereof, wherein R1, R2, and RC are defined as in claim 1.
- administering to a patient in need thereof an effective amount of at least one compound of formula (I),
-
40. A method of inhibiting the activity of at least one aspartyl protease in a patient in need thereof, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in. claim 1, to the patient.
- administering a therapeutically effective amount of at least one compound of formula (I),
-
41. The method according to claim 40 wherein the at least one aspartyl protease is beta-secretase.
-
42. A method of interacting an inhibitor with beta-secretase, comprising:
- administering to a patient In need thereof a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1, wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′
, and S2′
.
- administering to a patient In need thereof a therapeutically effective amount of at least one compound of formula (I),
-
43. A method of treating at least one condition in a patient, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R1, R2, and RC are defined as in claim 1.
- administering a therapeutically effective amount of at least one compound of formula (I),
-
44. The method according to claim 43, wherein the condition is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down'"'"'s syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease, and frontotemporal dementias with parkinsonism (FTDP).
-
45. The method according to claim 44, wherein the condition is Alzheimer'"'"'s disease.
-
46. The method according to claim 44, wherein the condition is dementia.
-
47. A method of prescribing a medication for preventing, delaying, halting, or reversing at least one disorder, condition or disease associated with amyloidosis comprising:
- identifying in a patient symptoms associated with at least one disorder, condition or disease associated with amyloidosis; and
prescribing at least one dosage form of at least one compound of formula (I),or a pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R1, R2, and RC are defined as in claim 1.
- identifying in a patient symptoms associated with at least one disorder, condition or disease associated with amyloidosis; and
-
48. An article of manufacture, comprising:
-
(a) at least one dosage form of at least one compound of formula (I), or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1; (b) a package insert providing that a dosage form comprising a 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) at least one container in which at least one dosage form of at least one compound of formula (I) is stored,
-
-
49. A packaged pharmaceutical composition for treating at least one condition related to amyloidosis, comprising:
-
(a) a container which holds an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1; and (b) instructions for using the pharmaceutical composition.
-
-
50. An article of manufacture, comprising:
-
(a) a therapeutically effective amount of at least one compound of formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1; (b) a package insert providing an oral dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and (c) at least one container comprising;
at least one oral dosage form of at least one compound of formula (I).
-
-
51. An article of manufacture, comprising:
-
(a) at least one oral dosage form of at least one compound of formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1; in a dosage amount ranging from about 2 mg to about 1000 mg;
associated with(b) a package insert providing that an oral dosage form comprising;
a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and(c) at least one container In which at least one oral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg is stored.
-
-
52. An article of manufacture, comprising:
-
(a) at least one oral dosage form of at least one compound of formula (I) wherein R1, R2, and RC are defined as in claim 1, in a dosage amount ranging from about 2 mg to about 1000 mg in combination with (b) at least one therapeutically active agent;
associated with(c) a package insert providing that an oral dosage form comprising;
a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with at least one therapeutically active agent should be administered to a patient in need of therapy for at least one disorder, condition or diseases associated with amyloidosis; and(d) at least one container in which at least one dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with a therapeutically active agent is stored.
-
-
53. The article of manufacture according to claim 52 wherein the therapeutically active agent, is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.
-
54. An article of manufacture, comprising:
-
(a) at least one parenteral dosage form of at least one compound of formula (I) wherein R1, R2, and RC are defined as in claim 1, in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL;
associated with(b) a package insert providing that a parenteral dosage form comprising;
a compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and(c) at least one container in which at least one parenteral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL is stored.
-
-
55. An article of manufacture comprising:
-
(a) a medicament comprising;
an effective amount of at least one compound of formula (I)wherein R1, R2, and RC are defined as in claim 1, 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.
-
-
56. A kit comprising:
-
(a) at least one dosage form of at least one compound according to claim 1; and (b) at least one container in which at least one dosage form of at least one compound according to claim 1 is stored,
-
-
57. A kit according to claim 58, further comprising a package insert:
-
a) containing information of the dosage amount and duration of exposure of a dosage form containing at least one compound of formula (I) as defined in claim 1, and b) providing that the dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis.
-
-
58. The kit according to claim 57 further comprising:
- at least one therapeutically active agent.
-
59. The kit according to claim 58 wherein the therapeutically active agent is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.
-
60. A method of producing A-beta-secretase complex comprising:
- exposing beta-secretase to a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in a reaction mixture under conditions suitable for the production of the complex.
-
61. A manufacture of a medicament for preventing, delaying, halting, or reversing Alzheimer'"'"'s disease, comprising:
- adding an effective amount of at least one compound of formula (I) as defined in claim 1, to a pharmaceutically acceptable carrier.
-
10. 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 pharmaceutically acceptable salts 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; L is selected from —
O—
,—
C(O)—
,—
C(R55)(R60)—
, and—
CH(NR55R60)—
;R55 and R60 are each independently selected from hydrogen and alkyl; R50, R50a, and R50b are independently selected from —
H-halogen, —
OH,—
C(O)H,—
C(O)CH3,—
CH2OH,—
SH,—
S(O)0-2CH3,—
CN,—
NO2,—
NH2,—
NHCH3,—
N(CH3)2—
C1—
C2 alkyl,—
OCH3,—
OCF3, and—
CF3;R2 is selected from —
H,wherein when R1 is benzyl, and RC is 6-Isopropyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not —
H;wherein, when R1 is 3,5-difluorobenzyl, and RC is 6-Ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not —
H;wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not —
H;—
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;-alkyl, 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)0-1, 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,wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not methylcarbamoyl; —
O—
C(O)—
N(R315)(R320),—
NH—
R400,—
R400,—
NH—
R500,—
R500—
NH—
R600,—
R600, and—
NH—
R700,R400 is wherein R405 is selected from —
H, —
N(R515)2, and O-alkyl;R500 is a heteroaryl selected from III(a) and III(b), 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—
,—
N(R520)—
,—
S—
, and—
O—
;M5 is selected from —
C— and
—
N—
;R505 is independently selected from —
H,-alkyl, -halogen, —
NO2,—
CN,—
R200, andphenyl; 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 -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—
C(O)—
, -nitro, —
CN, -amino, —
NR220R225, -thioalkyl, —
CF3, —
OH, —
O-alkyl, and -heterocycloalkyl;wherein when R1 is 3,5-difluoro-benzyl, and RC is 6-ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, R2 is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;wherein when R1 is 3,5-difluoro-benzyl, and RC is 3-methoxy-benzyl, R2 is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino;
or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;R700 is aryl optionally substituted with at least one R205; RC is selected from —
(CH2)0-3-cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —
R205 and —
CO2-(alkyl),-alkyl optionally substituted with at least one group independently selected from R205, —
(CR245R250)0-4—
RX, wherein at least one —
(CR245R250)—
is optionally replaced with a group independently selected from —
O—
, —
N(R215)—
, —
C(O)1-2—
, —
C(O)N(R215)—
, and —
S(O)0-2—
, and-formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg); RX is selected from -hydrogen, -aryl, -heteroaryl, -cycloalkyl, -heterocycloalkyl, and —
RXa—
RXb, wherein RXa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;wherein each aryl or heteroaryl group attached directly or indirectly to —
(CR245R250)0-4—
is optionally substituted with at least one group independently selected from R200;wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is optionally substituted with at least one group independently selected from R210 and —
(CR245R250)0-4—
R200;wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is independently optionally replaced with a group selected from —
O—
, —
C(O)—
, —
N(R215)0-1—
, and —
S(O)0-2—
;wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —
(CR245R250)0-4—
is independently optionally substituted with a group selected from—
(CO)0-1R215,—
(CO)0-1R220,—
S(O)0-2R200, and—
N(R200)—
S(O)0-2R200;R245 and R250 at each occurrence are independently selected from —
H,—
(CH2)0-4C(O)—
OH,—
(CH2)0-4C(O)—
O-alkyl,—
(CH2)0-4C(O)-alkyl,-alkyl, -hydroxyalkyl, —
O-alkyl,-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, 8, 9, or 10 carbon atoms, wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from —
O—
,—
C(O)—
,—
S(O)0-2—
,—
(═
N—
R255)—
,—
N—
,—
NR220—
,—
NR((CO)0-1R200)—
, and—
N(SO2R200)—
;wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R245 and R250 are optionally substituted with at least one group independently selected from -halogen, -alkyl, —
N(R220)(R225), —
CN, and —
OH;wherein the monocyclic and bicyclic groups included in R245 and R250 are optionally substituted with at least one group independently selected from halogen, —
(CH2)0-2—
OH, —
O-alkyl, alkyl, —
(CH2)0-2—
S-alkyl, —
CF3, aryl, —
N(R220)(R225), —
CN, —
(CH2)0-2—
NH2, —
(CH2)0-2—
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH—
C(O)-alkyl, and —
NHS(O2)-alkyl;formula (IVa) is wherein Q1 is selected from (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, and —
C(O)—
;Q2 and Q3 each are independently selected from (—
CH2—
)0-1, —
CH(R200)—
, —
C(R200)2—
, —
O—
, —
C(O)—
, —
S—
, —
S(O)2—
, —
NH—
, and —
N(R7)—
;Q4 is selected from a bond, (—
CH2—
)0-1, —
CH(R200)—
, 13 C(R200)2—
, —
O—
, —
C(O)—
, —
S—
, —
S(O)2—
, —
NH—
, and —
N(R7); andP1, P2, P3, and P4 each are independently selected from —
CH—
, —
C(R200)—
, and —
N—
;
formula (IVb) iswherein R4 is selected from —
H and -alkyl, andP1, P2, P3, and P4 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
;formula (IVc) is wherein R4 is selected from —
H and -alkyl; andP1, P2, P3, and P4 at each occurrence are independently selected from —
CH—
, —
CR200—
, and —
N—
;formula (IVd) is wherein m is 0, 1, 2, 3, 4, 5, or 6; Y′
is selected from —
H, —
CN, —
OH, —
O-alkyl, —
CO2H, —
C(O)OR215, -amino, -aryl, and -heteroaryl; andP1 and P2 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
,or P1 and P2 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, P3 and P4 at each occurrence are independently selected from —
CH—
, —
C(R200)—
, and —
N—
,or P3 and P4 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, P5 at each occurrence is independently selected from —
CH—
, —
C(R200)—
, and —
N—
,wherein at least one bond in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a double bond, wherein the bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a fused or spiro ring system, wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally replaced by a group independently selected from —
O—
,—
C(O)—
,—
S(O)0-2—
,—
C(═
N—
R255)—
,—
N—
,—
NR220—
,—
N((CO)0-1R200)—
, and—
N(SO2R200)—
;formula (IVe) is wherein U is selected from —
CH2—
CR100R101—
, —
CH2—
S—
, —
CH2—
S(O)—
, —
CH2—
S(O)2—
, —
CH2—
N(R100)—
, —
CH2—
C(O)—
, —
CH2—
O—
, —
C(O)—
C(R100)(R101)—
, —
SO2—
N(R100)—
, —
C(O)—
N(R55)—
, —
N(R55)—
C(O)—
N(R55)—
, —
O—
C(O)—
O—
, —
N(R55)—
C(O)—
O—
, and —
C(O)—
O—
;wherein R100 and R101 at each occurrence are independently selected from —
H, -alkyl, -aryl, —
C(O)-alkyl, —
(CO)0-1R215, —
(CO)0-1R220, and —
S(O)2-alkyl;formula (IVf) is wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, —
N(R5)C(O)H, —
C(O)H, —
C(O)N(R5)(R6), —
NR5R6, R280, R285, -aryl, and -heteroaryl;wherein R280 and R285, and the carbon to which they are attached form a C3—
C7 spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, -halogen, —
CF3, and —
CN;wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R290 and R295; wherein R290 and R295 at each occurrence are independently selected from -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
OH,—
NO2,-halogen, —
CO2H,—
CN,—
(CH2)0-4—
C(O)—
NR21R22,—
(CH2)0-4—
CO2R20,—
(CH2)0-4—
SO2NR21R22,—
(CH2)0-4S(O)-alkyl),—
(CH2)0-4—
S(O)2-(alkyl),—
(CH2)0-4—
S(O)2-(cycloalkyl),—
(CH2)0-4—
N(H or R20)—
C(O)—
O—
R20,—
(CH2)0-4—
N(H or R20)—
C(O)—
N(R20)2,—
(CH2)0-4—
N—
C(S)—
N(R20)2,—
(CH2)0-4—
N(H or R20)—
CO—
R21,—
(CH2)0-4—
NR21R22,—
(CH2)0-4—
R11,—
(CH2)0-4—
O—
C(O)-(alkyl),—
(CH2)0-4—
O—
P(O)—
(OR5)2,—
(CH2)0-4—
O—
C(O)—
N(R20)2,—
(CH2)0-4—
O—
C(S)—
N(R20)2,—
(CH2)0-4—
O—
(R20)2,—
(CH2)0-4—
O—
(R20)—
CO2H,—
(CH2)0-4—
S—
(R20),—
(CH2)0-4—
O-(alkyl optionally substituted with at least one halogen),-cycloalkyl, —
(CH2)0-4—
N(H or R20)—
S(O)2—
R21, and—
(CH2)0-4-cycloalkyl;formula (IVg) is wherein a is 0 or 1; b is 0 or 1; S′
is selected from —
C(O)— and
—
CO2—
;T′
is —
(CH2)0-4—
;U′
is —
(CR245R250)—
;V′
is selected from -aryl- and -heteroaryl-;W′
is selected from-a bond, -alkyl-substituted with at least one group independently selected from R205, —
(CH2)0-4—
(CO)0-1—
N(R220)—
,—
(CH2)0-4—
(CO)0-1—
,—
(CH2)0-4—
CO2—
,—
(CH2)0-4—
SO2—
N(R220)—
,—
(CH2)0-4—
N(H or R215)—
CO2—
,—
(CH2)0-4—
N(H or R215)—
SO2—
,—
(CH2)0-4—
N(H or R215)—
C(O)—
N(R215)—
,—
(CH2)0-4—
N(H or R215)—
C(O)—
,—
(CH2)0-4—
N(R220)—
,—
(CH2)0-4—
O—
, and—
(CH2)0-4—
S—
;X′
is selected from aryl and heteroaryl;wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R205; wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R200; wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from —
(CO)0-1R215,—
(CO)0-1R220, and—
S(O)0-2R200;R21 and R22 each independently are selected from —
H,-alkyl optionally substituted with at least one group independently selected from —
OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —
R17, and —
R18,—
(CH2)0-4—
C(O)-(alkyl),—
(CH2)0-4—
C(O)-(cycloalkyl),—
(CH2)0-4—
C(O)—
R17,—
(CH2)0-4—
C(O)—
R18,—
(CH2)0-4—
C(O)—
R19, and—
(CH2)0-4—
C(O)—
R11;R17 at each occurrence is aryl optionally substituted with at least one group independently selected from -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
NR5R6, —
CN, —
CF3, and —
O-alkyl,-halogen, —
O-alkyl optionally substituted with at least one group independently selected from halogen, —
NR21R22, —
OH, —
CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)—
O—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);R18 at each occurrence is heteroaryl optionally substituted with at least one group independently selected from -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,-halogen, —
O-alkyl optionally substituted with at least one group independently selected from -halogen, —
NR21R22, —
OH, and —
CN,-cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, CF3, —
O-alkyl, and —
NR5R6,—
C(O)-alkyl),—
S(O)2—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);R19 at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —
C(O)—
, —
S(O)—
, and —
S(O)2—
, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,-halogen, —
O-alkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
CN, —
NR21R22, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —
OH, —
SH, —
CN, —
CF3, —
O-alkyl, and —
NR5R6,—
C(O)-(alkyl),—
S(O)2—
NR5R6,—
C(O)—
NR5R6, and—
S(O)2-(alkyl);R11 at each occurrence is heterocycloalkyl wherein at least one carbon of the heterocycloalkyl is optionally replaced with —
C(O)—
, —
S—
(O)—
, and —
S(O)2—
,wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, and -halogen;R20 is selected from -alkyl, -cycloalkyl, —
(CH2)0-2—
(R17), and —
(CH2)0-2—
(R18);R200 at each occurrence is independently selected from -alkyl optionally substituted with at least one group independently selected from R205, —
OH,—
NO2,—
NH2,-halogen, —
CN,—
CF3,—
OCF3,—
(CH2)0-4—
C(O)H,—
(CO)0-1R215,—
(CO)0-1R220,—
(CH2)0-4—
C(O)—
NR220R225,—
(CH2)0-4—
(C(O))0-1—
R215,—
(CH2)0-4—
(C(O))0-1—
R220,—
(CH2)0-4—
C(O)-alkyl,—
(CH2)0-4—
(C(O))0-1-cycloalkyl,—
(CH2)0-4—
(C(O))0-1-heterocycloalkyl,—
(CH2)0-4—
C(O)0-1-aryl,—
(CH2)0-4—
(C(O)0-1-heteroaryl,—
(CH2)0-4—
C(O)—
O—
R215,—
(CH2)0-4—
S(O)0-2—
NR220R225,—
(CH2)0-4—
S(O)0-2-alkyl,—
(CH2)0-4S(O)0-2-cycloalkyl,—
(CH2)0-4—
N(H or R215)—
C(O)—
O—
R215,—
(CH2)0-4—
N(H or R215)—
S(O)1-2—
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—
NR220R225,—
(CH2)0-4—
O—
C(O)-alkyl,—
(CH2)0-4—
O—
(R215),—
(CH2)0-4—
S—
(R215),—
(CH2)0-4—
C(O)H,—
(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 —
R205,—
R210, and-alkyl optionally substituted with at least one group independently selected from R205 and R210; R205 at each occurrence is independently selected from -alkyl, -heteroaryl, -heterocycloalkyl, -aryl, -haloalkoxy, —
(CH2)0-3-cycloalkyl,-halogen, —
(CH2)0-6—
OH,—
O-phenyl,—
SH,—
(CH2)0-4—
C(O)CH3—
(CH2)0-4—
C(O)H—
(CH2)0-4—
CO2H,—
(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,—
OCF3,—
C(O)2-benzyl,—
O-alkyl,—
C(O)2-alkyl, and—
NR235R240;R210 at each occurrence is independently selected from —
OH,—
CN,—
(CH2)0-4—
C(O)H,-alkyl wherein a carbon atom is optionally replaced with —
C(O)—
, and a carbon atom is optionally substituted with at least one group independently selected from R205,—
S-alkyl,-halogen, —
O-alkyl,-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(O)2-alkyl;R215 at each occurrence is independently selected from -alkyl, —
(CH2)0-2-aryl,—
(CH2)0-2-cycloalkyl,—
(CH2)0-2-heteroaryl, and—
(CH2)0-2-heterocycloalkyl;wherein the aryl groups included within R215 are optionally substituted with at least one group independently selected from R205 or R210; 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,—
OH,-alkyl, —
(CH2)0-4—
C(O)H,-alkyl-OH, —
(CH2)0-4CO2-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,-aminoalkyl, —
S(O)2-alkyl,—
(CH2)0-4—
C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,—
(CH2)0-4—
C(O)—
NH2,—
(CH2)0-4—
C(O)—
NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R205,—
(CH2)0-4—
C(O)—
N(alkyl)(alkyl),-haloalkyl, —
(CH2)0-2-cycloalkyl,-alkyl-O-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; R270 at each occurrence is independently selected from —
R205,-alkyl optionally substituted with at least one group independently selected from R205, -phenyl, -halogen, —
O-alkyl,-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;R235 and R240 at each occurrence are independently selected from —
H,-alkyl, —
C(O)-alkyl,—
OH,—
CF3,—
OCH3,—
NH—
CH3,—
N(CH3)2,—
(CH2)0-4—
C(O)—
(H or alkyl),—
SO2-alkyl, and-phenyl; R255 is selected from -hydrogen, —
OH, —
N(R220)(R225), and —
O-alkyl;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; and R7 is independently selected from —
H,-alkyl optionally substituted with at least one group independently selected from —
OH, amino, and halogen,-cycloalkyl, and -alkyl-O-alkyl. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
wherein the monocyclic or bicyclic groups included within R245 and R250 are optionally substituted with at least one group independently selected from halogen, —
OH, —
O-alkyl, alkyl, aryl, —
N(R200(R225), —
CN, —
NH2, —
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH-C(O)-alkyl, and —
NHS(O2)-alkyl; and
wherein RX, R220 , R225, R255, and R200 are as defined in claim 10.
-
-
14. The method according to claim 10, wherein RC is selected from formulae (Va), (Vb), (Vc), and (Vd),
wherein, A, B, and C are independently selected from — - CH2—
,—
O—
,—
C(O)—
,—
S(O)0-2—
,—
N((CO)0-1R200)—
,—
N(SO2R200)—
,—
C(═
N—
R255)—
, and—
N(R220)—
;A′
at each occurence is independently selected from —
CH2— and
—
O—
;wherein (Va), (Vb), (Vc), and (Vd) are each optionally substituted with at least one group independently selected from -alkyl, —
O-alkyl, —
(CH2)0-2—
OH, —
(CH2)0-2—
S-alkyl, —
CF3, —
CN, -halogen, —
(CH2)0-2—
NH2, —
(CH2)0-2—
NH(alkyl), —
NHOH, —
NH—
O-alkyl, —
N(alkyl)(alkyl), —
NH-heteroaryl, —
NH—
C(O)-alkyl, and —
NHS(O2)-alkyl; andRX, R220, R255, and R200 are as defined in claim 10.
- CH2—
-
15. The method according to claim 10, wherein RC is selected from formulae (Vla) and (Vlb),
wherein at least one carbon of the heterocycloalkyl of formula (Vla) and the cycloalkyl of formula (Vlb) is optionally replaced with a group independently selected from — - O—
, —
SO2—
, and —
C(O)—
, wherein at least one carbon of the heterocycloalkyl or cycloalkyl is optionally substituted with at least one group independently selected from R205, R245, and R250, wherein R100, R200, R205, R245, and R250 are as defined in claim 10.
- O—
-
16. The method according to claim 10, wherein RC is selected from 6-isobutyl-1,1-dioxo-1λ
-
6-thiochroman-4-yl, 6-isopropyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, 1-(3-tert-Butyl-phenyl)-cyclohexyl, and 3-methoxy-benzyl.
-
6-thiochroman-4-yl, 6-isopropyl-2,2-dioxo-2λ
-
17. The method according to claim 10, wherein R2 is selected from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
-
18. The method according to claim 11, wherein RX is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl), 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′
- -Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.
-
19. The method according to claim 10, wherein at least one compound of formula (I) is administered in combination with a pharmaceutically acceptable carrier or diluent.
-
20. The method according to claim 10, wherein the condition is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome or Trisomy 21, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases, Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease, and frontotemporal dementias with parkinsonism.
-
21. The method according to claim 10, wherein the condition is Alzheimer'"'"'s disease.
-
22. The method according to claim 10, wherein the condition is dementia.
-
23. A method of preventing or treating at least one condition associated with amyloidosis, comprising:
-
administering to a host a composition comprising a therapeutically effective amount of at least one beta-secretase inhibitor of formula (I), or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined in claim 10.
-
-
24. A method of preventing or treating at least one condition associated with amyloidosis, comprising:
-
administering to a host a composition comprising a therapeutically effective amount of at least one beta-secretase inhibitor of formula (I), further comprising a composition including beta-secretase complexed with at least one compound of formula (I), or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined in claim 10.
-
Specification