U.S. patent application number 11/075312 was filed with the patent office on 2005-10-27 for substituted hydroxyethylamine aspartyl protease inhibitors.
Invention is credited to Aquino, Jose, Bowers, Simeon, Brogley, Louis, Dressen, Darren, Jagodzinska, Barbara, John, Varghese, Maillard, Michel, Probst, Gary, Shah, Neerav, Tucker, John, Tung, Jay S..
Application Number | 20050239836 11/075312 |
Document ID | / |
Family ID | 34976289 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050239836 |
Kind Code |
A1 |
John, Varghese ; et
al. |
October 27, 2005 |
Substituted hydroxyethylamine aspartyl protease inhibitors
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.
Inventors: |
John, Varghese; (San
Francisco, CA) ; Maillard, Michel; (Redwood City,
CA) ; Tucker, John; (San Diego, CA) ; Aquino,
Jose; (Daly City, CA) ; Jagodzinska, Barbara;
(Redwood City, CA) ; Brogley, Louis; (Santa Cruz,
CA) ; Tung, Jay S.; (Belmont, CA) ; Bowers,
Simeon; (Oakland, CA) ; Dressen, Darren;
(Fremont, CA) ; Probst, Gary; (San Francisco,
CA) ; Shah, Neerav; (San Mateo, CA) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Family ID: |
34976289 |
Appl. No.: |
11/075312 |
Filed: |
March 9, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60619918 |
Oct 20, 2004 |
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60591918 |
Jul 29, 2004 |
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60575977 |
Jun 2, 2004 |
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60551052 |
Mar 9, 2004 |
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Current U.S.
Class: |
514/319 ;
514/320; 514/432; 546/202; 546/205; 549/23 |
Current CPC
Class: |
C07D 249/14 20130101;
C07C 2603/18 20170501; C07D 231/12 20130101; C07C 217/34 20130101;
C07D 233/88 20130101; C07D 275/02 20130101; C07C 311/24 20130101;
C07C 2601/14 20170501; C07D 405/12 20130101; C07C 217/48 20130101;
C07C 217/58 20130101; C07D 231/38 20130101; A61P 29/00 20180101;
C07C 2603/74 20170501; C07D 285/08 20130101; C07D 285/135 20130101;
C07D 207/323 20130101; C07D 233/54 20130101; C07D 233/64 20130101;
C07D 333/36 20130101; C07D 403/12 20130101; C07D 413/04 20130101;
C07C 323/30 20130101; C07D 495/04 20130101; C07C 229/60 20130101;
C07D 213/38 20130101; C07D 419/12 20130101; C07C 215/28 20130101;
C07C 225/20 20130101; C07D 309/14 20130101; A61P 25/00 20180101;
C07D 239/48 20130101; A61P 25/28 20180101; C07C 215/50 20130101;
C07C 237/20 20130101; C07C 317/28 20130101; C07C 225/06 20130101;
C07C 229/42 20130101; C07D 249/06 20130101; C07D 257/04 20130101;
C07D 409/12 20130101; C07D 271/113 20130101; C07C 323/32 20130101;
C07D 401/12 20130101; C07C 2602/04 20170501; C07C 2602/42 20170501;
C07D 239/42 20130101; C07D 277/42 20130101; C07D 335/06 20130101;
C07D 249/04 20130101; A61P 43/00 20180101; C07C 2601/02 20170501;
C07D 417/12 20130101; C07C 2602/10 20170501; C07D 307/52 20130101;
A61P 25/16 20180101; C07C 323/25 20130101; C07C 217/52 20130101;
C07D 207/325 20130101; C07C 229/16 20130101; C07D 215/42 20130101;
C07D 285/10 20130101; C07C 233/43 20130101; C07C 271/12 20130101;
C07D 311/74 20130101; C07D 413/12 20130101; C07D 263/34 20130101;
C07C 217/30 20130101; C07C 237/30 20130101 |
Class at
Publication: |
514/319 ;
514/320; 514/432; 546/202; 546/205; 549/023 |
International
Class: |
A61K 031/453; A61K
031/382; C07D 049/02 |
Claims
1. A compound of formula (I), 507or a pharmaceutically acceptable
salt thereof, wherein R.sub.1 is selected from 508wherein X, Y, and
Z are independently, selected from --C(H).sub.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--,
--SO.sub.2--, --C(O)--, --C(R.sub.55)(R.sub.60)--, and
--CH(NR.sub.55R.sub.60)--; R.sub.55 and R.sub.60 are each
independently selected from hydrogen and alkyl; R.sub.50,
R.sub.50a, and R.sub.50b are independently selected from --H,
-halogen, --OH, --C(O)H, --C(O)CH.sub.3, --CH.sub.2OH, --SH,
--S(O).sub.0-2CH.sub.3, --CN, --NO.sub.2, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2 --C.sub.1-C.sub.2 alkyl, --OCH.sub.3,
--OCF.sub.3, and --CF.sub.3; R.sub.2 is selected from --H, wherein
when R.sub.1 is benzyl, and R.sub.C is
6-Isopropyl-2,2-dioxo-2.lambda..sup.6-isothiochrom- an-4-yl,
R.sub.2 is not --H; wherein, when R.sub.1 is 3,5-difluorobenzyl,
and R.sub.C is
6-Ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl, R.sub.2 is
not --H; wherein when R.sub.1 is 3,5-difluorobenzyl, and R.sub.C is
7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R.sub.2 is not --H;
--OH, --O-alkyl, optionally substituted with at least one group
independently selected from R.sub.200; --O-aryl, optionally
substituted with at least one group independently selected from
R.sub.200; -alkyl, optionally substituted with at least one group
independently selected from R.sub.200; --NH-alkyl, optionally
substituted with at least one group independently selected from
R.sub.200; -heterocycloalkyl, (wherein at least one carbon is
optionally replaced with a group independently selected from
--(CR.sub.245R.sub.250)--, --O--, --C(O)--, --C(O)C(O)--,
--N(R.sub.200).sub.0-1--, and --S(O).sub.0-2--, and wherein the
heterocycloalkyl is optionally substituted with at least one group
independently selected from R.sub.200); --NH-heterocycloalkyl,
wherein at least one carbon is optionally replaced with a group
independently selected from --(CR.sub.245R.sub.250)--, --O--,
--C(O)--, --C(O)C(O)--, --N(R.sub.200).sub.0-2--, and
--S(O).sub.0-2--, and wherein the heterocycloalkyl is optionally
substituted with at least one group independently selected from
R.sub.200; --C(O)--N(R.sub.315)(R.sub.320), wherein R.sub.315 and
R.sub.320 are each independently selected from --H, -alkyl, and
phenyl, wherein when R.sub.1 is 3,5-difluorobenzyl, and R.sub.C is
7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R.sub.2 is not
methylcarbamoyl; --O--C(O)--N(R.sub.315)(R.sub.320),
--NH--R.sub.400, --R.sub.400, --NH--R.sub.500, --R.sub.500
--NH--R.sub.600, --R.sub.600, and --NH--R.sub.700; R.sub.400 is
509wherein R.sub.405 is selected from --H, --N(R.sub.515).sub.2,
and O-alkyl; R.sub.500 is a heteroaryl selected from III(a) and
III(b), 510wherein M.sub.1 and M.sub.4 are independently selected
from --C(R.sub.505)--, --N--, --N(R.sub.515)--, --S--, and --O--;
M.sub.2 and M.sub.3 are independently selected from
--C(R.sub.510)--, --N--, --N(R.sub.520)--, --S--, and --O--;
M.sub.5 is selected from --C-- and --N--; R.sub.505 is
independently selected from --H, -alkyl, -halogen, --NO.sub.2,
--CN, --R.sub.200, and phenyl; R.sub.510 is independently selected
from --H, -alkyl, -halogen, -amino, --CF.sub.3, --R.sub.200, and
-phenyl; R.sub.515 is independently selected from --H, -alkyl, and
-phenyl; R.sub.520 is independently selected from --H, -alkyl,
--(CH.sub.2).sub.0-2-phenyl, and --C(Ph).sub.3; R.sub.600 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 R.sub.605; R.sub.605 is
selected from -hydrogen, -halogen, -alkyl, -phenyl,
alkyl-O--C(O)--, -nitro, --CN, -amino, --NR.sub.220R.sub.225,
-thioalkyl, --CF.sub.3, --OH, --O-alkyl, and -heterocycloalkyl;
wherein when R.sub.1 is 3,5-difluoro-benzyl, and R.sub.C is
6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl, R.sub.2 is
not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino; wherein when
R.sub.1 is 3,5-difluoro-benzyl, and R.sub.C is 3-methoxy-benzyl,
R.sub.2 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; R.sub.700 is aryl
optionally substituted with at least one R.sub.205; R.sub.C is
selected from --(CH.sub.2).sub.0-3-cycloalkyl wherein the
cycloalkyl is optionally substituted with at least one group
independently selected from --R.sub.205 and --CO.sub.2-(alkyl),
-alkyl optionally substituted with at least one group independently
selected from R.sub.205, --(CR.sub.245R.sub.250).sub.0-4--R.sub.X,
wherein at least one --(CR.sub.245R.sub.256)-- is optionally
replaced with a group independently selected from --O--,
--N(R.sub.215)--, --C(O).sub.12--, --C(O)N(R.sub.215)--, and
--S(O).sub.0-2--, and -formulae (IVa), (IVb), (IVc), (IVd), (IVe),
(IVf), and (IVg); R.sub.X is selected from -hydrogen, -aryl,
-heteroaryl, -cycloalkyl, -heterocycloalkyl, and
--R.sub.Xa--R.sub.Xb, wherein R.sub.Xa and R.sub.Xb are
independently selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl; wherein each aryl or heteroaryl group attached
directly or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is
optionally substituted with at least one group independently
selected from R.sub.200; wherein each cycloalkyl or
heterocycloalkyl group attached directly or indirectly to
--(CR.sub.245R.sub.250).sub.0-4-- is optionally substituted with at
least one group independently selected from R.sub.210 and
--(CR.sub.245R.sub.250).sub.0-4--R.sub.200; wherein at least one
atom of the heteroaryl or heterocycloalkyl group attached directly
or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is independently
optionally replaced with a group selected from --O--, --C(O)--,
--N(R.sub.215).sub.0-1--, and --S(O).sub.0-2--; wherein at least
one heteroatom of the heteroaryl or heterocycloalkyl group attached
directly or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is
independently optionally substituted with a group selected from
--(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220,
--S(O).sub.0-2R.sub.200, and --N(R.sub.200)--S(O).sub.0-2R.sub.200;
R.sub.245 and R.sub.250 at each occurrence are independently
selected from --H, --(CH.sub.2).sub.0-4C(O)-- -OH,
--(CH.sub.2).sub.0-4C(O)--O-alkyl, --(CH.sub.2).sub.0-4C(O)-alkyl,
-alkyl, -hydroxyalkyl, --O-alkyl, -haloalkoxy,
--(CH.sub.2).sub.0-4-cyclo- alkyl, --(CH.sub.2).sub.0-4-aryl,
--(CH.sub.2).sub.0-4-heteroaryl, and
--(CH.sub.2).sub.0-4-heterocycloalkyl; or R.sub.245 and R.sub.250
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).sub.0-2--, --C(.dbd.N--R.sub.255)--,
--N--, --NR.sub.220--, --N((CO).sub.0-1R.sub.20- 0)--, and
--N(SO.sub.2R.sub.200)--; wherein the aryl, heteroaryl, and
heterocycloalkyl groups included in R.sub.245 and R.sub.250 are
optionally substituted with at least one group independently
selected from -halogen, -alkyl, --N(R.sub.220)(R.sub.225), --CN,
and --OH; wherein the monocyclic and bicyclic groups included in
R.sub.245 and R.sub.250 are optionally substituted with at least
one group independently selected from halogen,
--(CH.sub.2).sub.0-2--OH, --O-alkyl, alkyl,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3, aryl,
--N(R.sub.220)(R.sub.225- ), --CN, --(CH.sub.2).sub.0-2--NH.sub.2,
--(CH.sub.2).sub.0-2--NH(alkyl), --NHOH, --NH--O--alkyl,
--N(alkyl)(alkyl), --NH-heteroaryl, --NH--C(O)-alkyl, and
--NHS(O.sub.2)-alkyl; formula (IVa) is 511wherein Q.sub.1 is
selected from (--CH.sub.2--).sub.0-1, --CH(R.sub.200)--,
--C(R.sub.200).sub.2--, and --C(O)--; Q.sub.2 and Q.sub.3 each are
independently selected from (--CH.sub.2--).sub.0-1,
--CH(R.sub.200)--, --C(R.sub.200).sub.2--, --O--, --C(O)--, --S--,
--S(O).sub.2--, --NH--, and --N(R.sub.7)--; Q.sub.4 is selected
from a bond, (--CH.sub.2--).sub.0-1, --CH(R.sub.200)--,
--C(R.sub.200).sub.2--, --O--, --C(O)--, --S--, --S(O).sub.2--,
--NH--, and --N(R.sub.7); and P.sub.1, P.sub.2, P.sub.3, and
P.sub.4 each are independently selected from --CH--,
--C(R.sub.200)--, and --N--; formula (IVb) is 512wherein R.sub.4 is
selected from --H and -alkyl, and P.sub.1, P.sub.2, P.sub.3, and
P.sub.4 at each occurrence are independently selected from --CH--,
--C(R.sub.200)--, and --N--; formula (IVc) is 513wherein R.sub.4 is
selected from --H and -alkyl; and P.sub.1, P.sub.2, P.sub.3, and
P.sub.4 at each occurrence are independently selected from --CH--,
--CR.sub.200--, and --N--; formula (IVd) is 514wherein m is 0, 1,
2, 3, 4, 5, or 6; Y' is selected from --H, --CN, --OH, --O-alkyl,
--CO.sub.2H, --C(O)OR.sub.215, -amino, -aryl, and -heteroaryl; and
P.sub.1 and P.sub.2 at each occurrence are independently selected
from --CH--, --C(R.sub.200)--, and --N--, or P.sub.1 and P.sub.2
are optionally taken together to form a monocyclic or bicyclic ring
system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, P.sub.3 and
P.sub.4 at each occurrence are independently selected from --CH--,
--C(R.sub.200)--, and --N--, or P.sub.3 and P.sub.4 are optionally
taken together to form a monocyclic or bicyclic ring system of 3,
4, 5, 6, 7, 8, 9, or 10 carbon atoms, P.sub.5 at each occurrence is
independently selected from --CH--, --C(R.sub.200)--, and --N--,
wherein at least one bond in the monocyclic or bicyclic ring system
included in P.sub.1 and P.sub.2 or P.sub.3 and P.sub.4 is
optionally a double bond, wherein the bicyclic ring system included
in P.sub.1 and P.sub.2 or P.sub.3 and P.sub.4 is optionally a fused
or spiro ring system, wherein at least one carbon atom in the
monocyclic or bicyclic ring system included in P.sub.1 and P.sub.2
or P.sub.3 and P.sub.4 is optionally replaced by a group
independently selected from --O--, --C(O)--, --S(O).sub.0-2--,
--C(.dbd.N--R.sub.255)--- , --N--, --NR.sub.220--,
--N((CO).sub.0-1R.sub.200)--, and --N(SO.sub.2R.sub.200)--; and
P.sub.5 at each occurrence is independently selected from --CH--,
--C(R.sub.200)--, and --N--, formula (IVe) is 515wherein U is
selected from --CH.sub.2--CR.sub.100R.sub.101--, --CH.sub.2--S--,
--CH.sub.2--S(O)--, --CH.sub.2--S(O).sub.2--,
--CH.sub.2--N(R.sub.100)--, --CH.sub.2--C(O)--, --CH.sub.2--O--,
--C(O)--C(R.sub.100)(R.sub.101)--, --SO.sub.2--N(R.sub.100)--,
--C(O)--N(R.sub.55)--, --N(R.sub.55)--C(O)--N(R.sub.55)--,
--O--C(O)--O--, --N(R.sub.55)--C(O)--O--, and --C(O)--O--; wherein
R.sub.100 and R.sub.101 at each occurrence are independently
selected from --H, -alkyl, -aryl, --C(O)-alkyl,
--(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220, and
--S(O).sub.2-alkyl; formula (IVf) is 516wherein the B ring is
optionally substituted with at least one group independently
selected from -alkyl, -halogen, --OH, --SH, --CN, --CF.sub.3,
--O-alkyl, --N(R.sub.5)C(O)H, --C(O)H, --C(O)N(R.sub.5)(R.sub.6),
--NR.sub.5R.sub.6, R.sub.280, R.sub.285, -aryl, and -heteroaryl;
wherein R.sub.280 and R.sub.285, and the carbon to which they are
attached form a C.sub.3-C.sub.7 spirocycle which is optionally
substituted with at least one group independently selected from
-alkyl, --O-alkyl, -halogen, --CF.sub.3, and --CN; wherein the A
ring is aryl or heteroaryl, each optionally substituted with at
least one group independently selected from R.sub.290 and
R.sub.295; wherein R.sub.290 and R.sub.295 at each occurrence are
independently selected from -alkyl optionally substituted with at
least one group selected from -alkyl, -halogen, --OH, --SH, --CN,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, --OH, --NO.sub.2,
-halogen, --CO.sub.2H, --CN,
--(CH.sub.2).sub.0-4--C(O)--NR.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--CO.s- ub.2R.sub.20,
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.21R.sub.22,
--(CH.sub.2)0-4--S(O)-(alkyl),
--(CH.sub.2).sub.0-4--S(O).sub.2-(alkyl),
--(CH.sub.2).sub.0-4--S(O).sub.2-(cycloalkyl),
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--C(O)--O--R.sub.20,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--C(O)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--N--C(S)--N(R.su- b.20).sub.2,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--CO--R.sub.21,
--(CH.sub.2).sub.0-4--NR.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--R.sub.11,
--(CH.sub.2).sub.0-4--O--C(O)-(alkyl),
--(CH.sub.2).sub.0-4--O--P(O)--(OR- .sub.5).sub.2,
--(CH.sub.2).sub.0-4--O--C(O)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O--C(S)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O- --(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O--(R.sub.20)--CO.sub.2H,
--(CH.sub.2).sub.0-4--S--(R.sub.20), --(CH.sub.2).sub.0-4--O-(alkyl
optionally substituted with at least one halogen), -cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--S(O).sub.2--R.sub.21, and
--(CH.sub.2).sub.0-4-cycloalkyl; formula (IVg) is 517wherein a is 0
or 1; b is 0 or 1; S' is selected from --C(O)-- and --CO.sub.2--;
T' is --(CH.sub.2).sub.0-4--; U' is --(CR.sub.245R.sub.250)--; V'
is selected from -aryl- and -heteroaryl-; W' is selected from -a
bond, -alkyl-substituted with at least one group independently
selected from R.sub.205,
--(CH.sub.2).sub.0-4--(CO).sub.0-1--N(R.sub.220)--,
--(CH.sub.2).sub.0-4-(CO).sub.0-1--,
--(CH.sub.2).sub.0-4--CO.sub.2--,
--(CH.sub.2).sub.0-4--SO.sub.2--N(R.sub.220)--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO.sub.2--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--SO.sub.2--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--N(R.sub.215)--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--,
--(CH.sub.2).sub.0-4--N(R.sub.220)--, --(CH.sub.2).sub.0-4--O--,
and --(CH.sub.2).sub.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 R.sub.205; wherein each aryl or heteroaryl group
included in formula (IVg) is optionally substituted with at least
one group independently selected from R.sub.200; wherein at least
one heteroatom of the heteroaryl group included within formula
(IVg) is optionally substituted with a group selected from
--(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220, and
--S(O).sub.0-2R.sub.200; R.sub.21 and R.sub.22 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,
--R.sub.17, and --R.sub.18, --(CH.sub.2).sub.0-4--C(O)-(a- lkyl),
--(CH.sub.2).sub.0-4--C(O)-(cycloalkyl),
--(CH.sub.2).sub.0-4--C(O)- --R.sub.17,
--(CH.sub.2).sub.0-4--C(O)--R.sub.18, --(CH.sub.2).sub.0-4--C(-
O)--R.sub.19, and --(CH.sub.2).sub.0-4--C(O)--R.sub.11; R.sub.17 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, --NR.sub.5R.sub.6, --CN, --CF.sub.3, and
--O-alkyl, -halogen, --O-alkyl optionally substituted with at least
one group independently selected from halogen, --NR.sub.21R.sub.22,
--OH, --CN, and -cycloalkyl optionally substituted with at least
one group independently selected from -halogen, --OH, --SH, --CN,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, --C(O)-(alkyl),
--S(O)--O--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl); R.sub.18 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,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, -halogen, --O-alkyl
optionally substituted with at least one group independently
selected from -halogen, --NR.sub.21R.sub.22, --OH, and --CN,
-cycloalkyl optionally substituted with at least one group
independently selected from -halogen, --OH, --SH, --CN, CF.sub.3,
--O-alkyl, and --NR.sub.5R.sub.6, --C(O)-(alkyl),
--S(O).sub.2--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl); R.sub.19 at each occurrence is
heterocycloalkyl wherein at least one carbon is optionally replaced
with --C(O)--, --S(O)--, and --S(O).sub.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, --CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, -halogen,
--O-alkyl optionally substituted with at least one group
independently selected from -halogen, --OH, --CN,
--NR.sub.21R.sub.22, and -cycloalkyl optionally substituted with at
least one group independently selected from -halogen, --OH, --SH,
--CN, --CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, --C(O)-(alkyl),
--S(O).sub.2--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl); R.sub.11 at each occurrence is
heterocycloalkyl wherein at least one carbon of the
heterocycloalkyl is optionally replaced with --C(O)--, --S(O)--,
and --S(O).sub.2--, wherein the
heterocycloalkyl is optionally substituted with at least one group
independently selected from -alkyl, --O-alkyl, and -halogen;
R.sub.20 is selected from -alkyl, -cycloalkyl,
--(CH.sub.2).sub.0-2--(R.sub.17), and
--(CH.sub.2).sub.0-2--(R.sub.18); R.sub.200 at each occurrence is
independently selected from -alkyl optionally substituted with at
least one group independently selected from R.sub.205, --OH,
--NO.sub.2, --NH.sub.2, -halogen, --CN, --CF.sub.3, --OCF.sub.3,
--(CH.sub.2).sub.0-4--C(O)H, --(CO).sub.0-1R.sub.215,
--(CO).sub.0-1R.sub.220,
--(CH.sub.2).sub.0-4--C(O)--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1--R.sub.215,
--(CH.sub.2).sub.0-4--(C- (O)).sub.0-1--R.sub.220,
--(CH.sub.2).sub.0-4--C(O)-alkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-cycloalkyl,
--(CH.sub.2).sub.0-4--(C- (O)).sub.0-1-heterocycloalkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-aryl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-heteroaryl,
--(CH.sub.2).sub.0-4--C(- O)--O--R.sub.215,
--(CH.sub.2).sub.0-4--S(O).sub.0-2--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--S(O).sub.0-2-alkyl,
--(CH.sub.2).sub.0-4--S(O).sub.- 0-2-cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--O--R.sub.21- 5,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--S(O).sub.1-2--R.sub.220,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--R.sub.220,
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--O--C(O)-- alkyl,
--(CH.sub.2).sub.0-4--O--(R.sub.215),
--(CH.sub.2).sub.0-4--S--(R.s- ub.215),
--(CH.sub.2).sub.0-4--C(O)H, --(CH.sub.2).sub.0-4--O-(alkyl
optionally substituted with at least one halogen), and -adamantane,
wherein each aryl and heteroaryl group included within R.sub.200 is
optionally substituted with at least one group independently
selected from --R.sub.205, --R.sub.210, and -alkyl optionally
substituted with at least one group independently selected from
R.sub.205 and R.sub.210; wherein each cycloalkyl or
heterocycloalkyl group included within R.sub.200 is optionally
substituted with at least one group independently selected from
--R.sub.205, --R.sub.210, and -alkyl optionally substituted with at
least one group independently selected from R.sub.205 and
R.sub.210; R.sub.205 at each occurrence is independently selected
from -alkyl, -heteroaryl, -heterocycloalkyl, -aryl, -haloalkoxy,
--(CH.sub.2).sub.0-3-cycloalkyl, -halogen,
--(CH.sub.2).sub.0-6--OH, --O-phenyl, --SH,
--(CH.sub.2).sub.0-4--C(O)CH.sub.3 --(CH.sub.2).sub.0-4--C(O)H
--(CH.sub.2).sub.0-4--CO.sub.2H, --(CH.sub.2).sub.0-6--CN,
--(CH.sub.2).sub.0-6--C(O)--NR.sub.235R.sub.240- ,
--(CH.sub.2).sub.0-6--C(O)--R.sub.235, --(CH.sub.2).sub.0-4--N(H or
R.sub.215)--SO.sub.2--R.sub.235, --CF.sub.3, --CN, --OCF.sub.3,
--C(O).sub.2-benzyl, --O-alkyl, --C(O).sub.2-alkyl, and
--NR.sub.235R.sub.240; R.sub.210 at each occurrence is
independently selected from --OH, --CN,
--(CH.sub.2).sub.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
R.sub.205, --S-alkyl, -halogen, --O-alkyl, -haloalkoxy,
--NR.sub.220R.sub.225, -cycloalkyl optionally substituted with at
least one group independently selected from R.sub.205,
--C(O)-alkyl, --S(O).sub.2--NR.sub.235R.sub.240,
--C(O)--NR.sub.235R.sub.240, and --S(O).sub.2-alkyl; R.sub.215 at
each occurrence is independently selected from -alkyl,
--(CH.sub.2).sub.0-2-aryl, --(CH.sub.2).sub.0-2-cyc- loalkyl,
--(CH.sub.2).sub.0-2-heteroaryl, and --(CH.sub.2).sub.0-2-heteroc-
ycloalkyl; wherein the aryl groups included within R.sub.215 are
optionally substituted with at least one group independently
selected from R.sub.205 or R.sub.210; wherein the heterocycloalkyl
and heteroaryl groups included within R.sub.215 are optionally
substituted with at least one group independently selected from
R.sub.210; R.sub.220 and R.sub.225 at each occurrence are
independently selected from --H, --OH, -alkyl,
--(CH.sub.2).sub.0-4--C(O)H, -alkyl-OH,
--(CH.sub.2).sub.0-4--CO.sub.2-al- kyl, wherein alkyl is optionally
substituted with at least one group independently selected from
R.sub.205, -aminoalkyl, --S(O).sub.2-alkyl,
--(CH.sub.2).sub.0-4--C(O)-alkyl, wherein alkyl is optionally
substituted with at least one group independently selected from
R.sub.205, --(CH.sub.2).sub.0-4--C(O)--NH.sub.2,
--(CH.sub.2).sub.0-4--C(O)--NH(alky- l), wherein alkyl is
optionally substituted with at least one group independently
selected from R.sub.205, --(CH.sub.2).sub.0-4--C(O)--N(alky-
l)(alkyl), -haloalkyl, --(CH.sub.2).sub.0-2-cycloalkyl,
-alkyl-O-alkyl, --O-alkyl, -aryl, -heteroaryl, and
-heterocycloalkyl; wherein the aryl, heteroaryl and
heterocycloalkyl groups included within R.sub.220 and R.sub.225 are
each optionally substituted with at least one group independently
selected from R.sub.270; R.sub.270 at each occurrence is
independently selected from --R.sub.205, -alkyl optionally
substituted with at least one group independently selected from
R.sub.205, -phenyl, -halogen, --O-alkyl, -haloalkoxy,
--NR.sub.235R.sub.240, --OH, --CN, -cycloalkyl optionally
substituted with at least one group independently selected from
R.sub.205, --C(O)-alkyl, --S(O).sub.2--NR.sub.235R.sub.240,
--CO--NR.sub.235R.sub.240, --S(O).sub.2-alkyl, and
--(CH.sub.2).sub.0-4--C(O)H; R.sub.235 and R.sub.240 at each
occurrence are independently selected from --H, -alkyl,
--C(O)-alkyl, --OH, --CF.sub.3, --OCH.sub.3, --NH--CH.sub.3,
--N(CH.sub.3).sub.2, --(CH.sub.2).sub.0-4--C(O)--(H or alkyl),
--SO.sub.2-alkyl, and -phenyl; R.sub.255 is selected from
-hydrogen, --OH, --N(R.sub.220)(R.sub.225), and --O-alkyl; R.sub.5
and R.sub.6 are independently selected from --H and -alkyl, or
R.sub.5 and R.sub.6, and the nitrogen to which they are attached,
form a 5 or 6 membered heterocycloalkyl ring; and R.sub.7 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.
2. The compound according to claim 1, wherein R.sub.1 is selected
from --CH.sub.2-phenyl, wherein the phenyl ring is optionally
substituted with at least one group independently selected from
-halogen, --C.sub.1-C.sub.2 alkyl, --O-methyl, and --OH.
3. The compound according to claim 1, wherein R.sub.1 is selected
from 4-hydroxy-benzyl, 3-hydroxy-benzyl,
5-chloro-thiophen-2-yl-methyl,
5-chloro-3-ethyl-thiophen-2-yl-methyl,
3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl,
2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl,
5-hydroxy-6-oxo-6H-pyran-2-yl-meth- yl,
3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl,
3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and
3-fluoro-benzyl.
4. The compound according to claim 1, wherein R.sub.C is
--C(R.sub.245)(R.sub.250)--R.sub.Xwherein R.sub.245 and R.sub.250
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 atom within the monocyclic or bicyclic ring
system is optionally replaced by a group independently selected
from --O--, --C(O)--, --S(O).sub.0-2--, --C(.dbd.N--R.sub.255)--,
--N--, --NR.sub.220--, --N((CO).sub.0-1R.sub.20- 0)--, and
--N(SO.sub.2R.sub.200)--; and wherein the monocyclic or bicyclic
groups included within R.sub.245 and R.sub.250 are optionally
substituted with at least one group independently selected from
halogen, --(CH.sub.2).sub.0-2--OH, --(CH.sub.2).sub.0-2--S-alkyl,
--CF.sub.3, --O-alkyl, alkyl, aryl, --N(R.sub.220)(R.sub.225),
--CN, --(CH.sub.2).sub.0-2--NH.sub.2,
--(CH.sub.2).sub.0-2--NH(alkyl), --NHOH, --NH--O-alkyl,
--N(alkyl)(alkyl), --NH-heteroaryl, --NH--C(O)-alkyl, and
--NHS(O.sub.2)-alkyl; and wherein R.sub.X, R.sub.220, R.sub.225,
R.sub.255, and R.sub.200 are as defined in claim 1.
5. The compound according to claim 1, wherein R.sub.C is selected
from formulae (Va), (Vb), (Vc), and (Vd), 518wherein, A, B, and C
are independently selected from --CH.sub.2--, --O--, --C(O)--,
--S(O).sub.0-2--, --N((CO).sub.0-1R.sub.200)--,
--N(SO.sub.2R.sub.200)--, --C(.dbd.N--R.sub.255)--, and
--N(R.sub.220)--; A' at each occurence is independently selected
from --CH.sub.2-- and --O--; wherein (Va), (Vb), (Vc), and (Vd) are
each optionally substituted with at least one group independently
selected from -alkyl, --O-alkyl, --(CH.sub.2).sub.0-2--OH,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3, --CN, -halogen,
--(CH.sub.2).sub.0-2--NH.sub.2, --(CH.sub.2).sub.0-2--NH(alkyl),
--NHOH, --NH--O-alkyl, --N(alkyl)(alkyl), --NH--heteroaryl,
--NH--C(O)-alkyl, and --NHS(.sub.0-2)-alkyl; and R.sub.X,
R.sub.220, R.sub.255, and R.sub.200 are as defined in claim 1.
6. The compound according to claim 1, wherein R.sub.C is selected
from formulae (VIa) and (VIb) 519wherein at least one carbon of the
heterocycloalkyl of formula (VIa) and the cycloalkyl of formula
(VIb) is optionally replaced with a group independently selected
from --O--, --SO.sub.2--, and --C(O)--, wherein at least one carbon
of the heterocycloalkyl or cycloalkyl is optionally substituted
with at least one group independently selected from R.sub.205,
R.sub.245, and R.sub.250, wherein R.sub.100, R.sub.200, R.sub.205,
R.sub.245, and R.sub.250 are as defined in claim 1.
7. The compound according to claim 1, wherein R.sub.C is selected
from 6-isobutyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-yl,
6-Isopropyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl,
6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl,
7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl,
1-(3-tert-Butyl-phenyl)-cyclo- hexyl, and 3-methoxy-benzyl.
8. The compound according to claim 1, wherein R.sub.2 is selected
from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino,
[1,2,4]thiadiazol-5-ylamin- o,
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]th- iadiazol-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-ylami- no,
3,4-dioxo-cyclobut-1-enylamino,
2-methoxy-3,4-dioxo-cyclobut-1-enylami- no, and
2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
9. The compound according to claim 2, wherein R.sub.X 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)-cycl- ohexylamino,
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.
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), 520or pharmaceutically acceptable salts thereof,
wherein R.sub.1 is selected from 521wherein X, Y, and Z are
independently, selected from --C(H).sub.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--,
--SO.sub.2--, --C(O)--, --C(R.sub.55)(R.sub.60)--, and --CH(N
R.sub.55R.sub.60)--; R.sub.55 and R.sub.60 are each independently
selected from hydrogen and alkyl; R.sub.50, R.sub.50a, and
R.sub.50b are independently selected from --H, -halogen, --OH,
--C(O)H, --C(O)CH.sub.3, --CH.sub.2O, --SH, --S(O).sub.0-2CH.sub.3,
--CN, --NO.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2
--C.sub.1-C.sub.2 alkyl, --OCH.sub.3, --OCF.sub.3, and --CF.sub.3;
R.sub.2 is selected from --H, wherein when R.sub.1 is benzyl, and
R.sub.C is 6-Isopropyl-2,2-dioxo-2.lambda..sup.6-i-
sothiochroman-4-yl, R.sub.2 is not --H; wherein, when R.sub.1 is
3,5-difluorobenzyl, and R.sub.C is
6-Ethyl-2,2-dioxo-2.lambda..sup.6-isot- hiochroman-4-yl, R.sub.2 is
not --H; wherein when R.sub.1 is 3,5-difluorobenzyl, and R.sub.C is
7-ethyl-1,2,3,4-tetrahydro-naphthalen-- 1-yl, R.sub.2 is not --H;
--OH, --O-alkyl, optionally substituted with at least one group
independently selected from R.sub.200; --O-aryl, optionally
substituted with at least one group independently selected from
R.sub.200; -alkyl, optionally substituted with at least one group
independently selected from R.sub.200; --NH-alkyl, optionally
substituted with at least one group independently selected from
R.sub.200; -heterocycloalkyl, (wherein at least one carbon is
optionally replaced with a group independently selected from
--(CR.sub.245R.sub.250)--, --O--, --C(O)--, --C(O)C(O)--,
--N(R.sub.200).sub.0-1--, and --S(O).sub.0-2--, and wherein the
heterocycloalkyl is optionally substituted with at least one group
independently selected from R.sub.200); --NH-heterocycloalkyl,
wherein at least one carbon is optionally replaced with a group
independently selected from --(CR.sub.245R.sub.250)--, --O--,
--C(O)--, --C(O)C(O)--, --N(R.sub.200).sub.0-2--, and
--S(O).sub.0-2--, and wherein the heterocycloalkyl is optionally
substituted with at least one group independently selected from
R.sub.200; --C(O)--N(R.sub.315)(R.sub.320), wherein R.sub.315 and
R.sub.320 are each independently selected from --H, -alkyl, and
phenyl, wherein when R.sub.1 is 3,5-difluorobenzyl, and R.sub.C is
7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R.sub.2 is not
methylcarbamoyl; --O--C(O)--N(R.sub.315)(R.sub.320),
--NH--R.sub.400, --R.sub.400, --NH--R.sub.500, --R.sub.500
--NH--R.sub.600, --R.sub.600, and --NH--R.sub.700; R.sub.400 is
522wherein R.sub.405 is selected from --H, --N(R.sub.515).sub.2,
and O-alkyl; R.sub.500 is a heteroaryl selected from III(a) and
III(b), 523wherein M.sub.1 and M.sub.4 are independently selected
from --C(R.sub.505)--, --N--, --N(R.sub.515)--, --S--, and --O--;
M.sub.2 and M.sub.3 are independently selected from
--C(R.sub.510)--, --N--, --N(R.sub.520)--, --S--, and --O--;
M.sub.5 is selected from --C-- and --N--; R.sub.505 is
independently selected from --H, -alkyl, -halogen, --NO.sub.2,
--CN, --R.sub.200, and phenyl; R.sub.510 is independently selected
from --H, -alkyl, -halogen, -amino, --CF.sub.3, --R.sub.200, and
-phenyl; R.sub.515 is independently selected from --H, -alkyl, and
-phenyl; R.sub.520 is independently selected from --H, -alkyl,
--(CH.sub.2).sub.0-2-phenyl, and --C(Ph).sub.3; R.sub.600 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 R.sub.605; R.sub.605 is
selected from -hydrogen, -halogen, -alkyl, -phenyl,
alkyl-O--C(O)--, -nitro, --CN, -amino, --NR.sub.220R.sub.225,
-thioalkyl, --CF.sub.3, --OH, --O-alkyl, and -heterocycloalkyl;
wherein when R.sub.1 is 3,5-difluoro-benzyl, and R.sub.C is
6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl, R.sub.2 is
not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino; wherein when
R.sub.1 is 3,5-difluoro-benzyl, and R.sub.C is 3-methoxy-benzyl,
R.sub.2 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; R.sub.700 is aryl
optionally substituted with at least one R.sub.205; R.sub.C is
selected from --(CH.sub.2).sub.0-3-cycloalkyl wherein the
cycloalkyl is optionally substituted with at least one group
independently selected from --R.sub.205 and --CO.sub.2-(alkyl),
-alkyl optionally substituted with at least one group independently
selected from R.sub.205, --(CR.sub.245R.sub.250).sub.0-4--R.sub.X,
wherein at least one --(CR.sub.245R.sub.250)-- is optionally
replaced with a group independently selected from --O--,
--N(R.sub.215)--, --C(O).sub.1-2--, --C(O)N(R.sub.215)--, and
--S(O).sub.0-2--, and -formulae (IVa), (IVb), (IVc), (IVd), (IVe),
(IVf), and (IVg); R.sub.X is selected from -hydrogen, -aryl,
-heteroaryl, -cycloalkyl, -heterocycloalkyl, and
--R.sub.Xa--R.sub.Xb, wherein R.sub.Xa and R.sub.Xb are
independently selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl; wherein each aryl or heteroaryl group attached
directly or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is
optionally substituted with at least one group independently
selected from R.sub.200; wherein each cycloalkyl or
heterocycloalkyl group attached directly or indirectly to
--(CR.sub.245R.sub.250).sub.0-4-- is optionally substituted with at
least one group independently selected from R.sub.210 and
--(CR.sub.245R.sub.250).sub.0-4--R.sub.200; wherein at least one
atom of the heteroaryl or heterocycloalkyl group attached directly
or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is independently
optionally replaced with a group selected from --O--, --C(O)--,
--N(R.sub.215).sub.0-1--, and --S(O).sub.0-2--; wherein at least
one heteroatom of the heteroaryl or heterocycloalkyl group attached
directly or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is
independently optionally substituted with a group selected from
--(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220,
--S(O).sub.0-2R.sub.200, and --N(R.sub.200)--S(O).sub.0-2R.sub.200;
R.sub.245 and R.sub.250 at each occurrence are independently
selected from --H, --(CH.sub.2).sub.0-4C(O)-- -OH,
--(CH.sub.2).sub.0-4C(O)--O-alkyl, --(CH.sub.2).sub.0-4C(O)-alkyl,
-alkyl, -hydroxyalkyl, --O-alkyl, -haloalkoxy,
--(CH.sub.2).sub.0-4-cyclo- alkyl, --(CH.sub.2).sub.0-4-aryl,
--(CH.sub.2).sub.0-4-heteroaryl, and
--(CH.sub.2).sub.0-4-heterocycloalkyl; or R.sub.245 and R.sub.250
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).sub.0-2--, --C(.dbd.N--R.sub.255)--,
--N--, --NR.sub.220--, --N((CO).sub.0-1R.sub.20- 0)--, and
--N(SO.sub.2R.sub.200)--; wherein the aryl, heteroaryl, and
heterocycloalkyl groups included in R.sub.245 and R.sub.250 are
optionally substituted with at least one group independently
selected from -halogen, -alkyl, --N(R.sub.220)(R.sub.225), --CN,
and --OH; wherein the monocyclic and bicyclic groups included in
R.sub.245 and R.sub.250 are optionally substituted with at least
one group independently selected from halogen,
--(CH.sub.2).sub.0-2--OH, --O-alkyl, alkyl,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3, aryl,
N(R.sub.220)(R22.sub.5), --CN, --(CH.sub.2).sub.0-2--NH.sub.2,
--(CH.sub.2).sub.0-2--NH(alkyl), --NHOH, --NH--O-alkyl,
--N(alkyl)(alkyl), --NH--C(O)-alkyl, and --NHS(O.sub.2)-alkyl;
formula (IVa) is 524wherein Q.sub.1 is selected from
(--CH.sub.2--).sub.0-1, --CH(R.sub.200)--, --C(R.sub.200).sub.2--,
and --C(O)--; Q.sub.2 and Q.sub.3 each are independently selected
from (--CH.sub.2--).sub.0-1, --CH(R.sub.200)--,
--C(R.sub.200).sub.2--, --O--, --C(O)--, --S--, --S(O).sub.2--,
--NH--, and --N(R.sub.7)--; Q.sub.4 is selected from a bond,
(--CH.sub.2--).sub.0-1, --CH(R.sub.200)--, --C(R.sub.200).sub.2--,
--O--, --C(O)--, --S--, --S(O).sub.2--, --NH--, and --N(R.sub.7);
and P.sub.1, P.sub.2, P.sub.3, and P.sub.4 each are independently
selected from --CH--, --C(R.sub.200)--, and --N--; formula (IVb) is
525wherein R.sub.4 is selected from --H and -alkyl, and P.sub.1,
P.sub.2, P.sub.3, and P.sub.4 at each occurrence are independently
selected from --CH--, --C(R.sub.200)--, and --N--; formula (IVc) is
526wherein R.sub.4 is selected from --H and -alkyl; and P.sub.1,
P.sub.2, P.sub.3, and P.sub.4 at each occurrence are independently
selected from --CH--, --CR.sub.200--, and --N--; formula (IVd) is
527wherein m is 0, 1, 2, 3, 4, 5, or 6; Y' is selected from --H,
--CN, --OH, --O-alkyl, --CO.sub.2H, --C(O)OR.sub.215, -amino,
-aryl, and -heteroaryl; and P.sub.1 and P.sub.2 at each occurrence
are independently selected from --CH--, --C(R.sub.200)--, and
--N--, or P.sub.1 and P.sub.2 are optionally taken together to form
a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10
carbon atoms, P.sub.3 and P.sub.4 at each occurrence are
independently selected from --CH--, --C(R.sub.200)--, and --N--, or
P.sub.3 and P.sub.4 are optionally taken together to form a
monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10
carbon atoms, P.sub.5 at each occurrence is independently selected
from --CH--, --C(R.sub.200)--, and --N--, wherein at least one bond
in the monocyclic or bicyclic ring system included in P.sub.1 and
P.sub.2 or P.sub.3 and P.sub.4 is optionally a double bond, wherein
the bicyclic ring system included in P.sub.1 and P.sub.2 or P.sub.3
and P.sub.4 is optionally a fused or spiro ring system, wherein at
least one carbon atom in the monocyclic or bicyclic ring system
included in P.sub.1 and P.sub.2 or P.sub.3 and P.sub.4 is
optionally replaced by a group independently selected from --O--,
--C(O)--, --S(O).sub.0-2--, --C(.dbd.N--R.sub.255)--, --N--,
--NR.sub.220--, --N((CO).sub.0-1R.sub.20- 0)--, and
--N(SO.sub.2R.sub.200)--; formula (IVe) is 528wherein U is selected
from --CH.sub.2--CR.sub.100R.sub.101--, --CH.sub.2--S--,
--CH.sub.2--S(O)--, --CH.sub.2--S(O).sub.2--,
--CH.sub.2--N(R.sub.100)--, --CH.sub.2--C(O)--, --CH.sub.2--O--,
--C(O)--C(R.sub.100)(R.sub.101)--, --SO.sub.2--N(R.sub.100)--,
--C(O)--N(R.sub.55)--, --N(R.sub.55)--C(O)--N(R.sub.55)--,
--O--C(O)--O--, --N(R.sub.55)--C(O)--O--, and --C(O)--O--; wherein
R.sub.100 and R.sub.101 at each occurrence are independently
selected from --H, -alkyl, -aryl, --C(O)-alkyl,
--(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220, and
--S(O).sub.2-alkyl; formula (IVf) is 529wherein the B ring is
optionally substituted with at least one group independently
selected from -alkyl, -halogen, --OH, --SH, --CN, --CF.sub.3,
--O-alkyl, --N(R.sub.5)C(O)H, --C(O)H, --C(O)N(R.sub.5)(R.sub.6),
--NR.sub.5R.sub.6, R.sub.280, R.sub.285, -aryl, and -heteroaryl;
wherein R.sub.280 and R.sub.285, and the carbon to which they are
attached form a C.sub.3-C.sub.7 spirocycle which is optionally
substituted with at least one group independently selected from
-alkyl, --O-alkyl, -halogen, --CF.sub.3, and --CN; wherein the A
ring is aryl or heteroaryl, each optionally substituted with at
least one group independently selected from R.sub.290 and
R.sub.295; wherein R.sub.290 and R.sub.295 at each occurrence are
independently selected from -alkyl optionally substituted with at
least one group selected from -alkyl, -halogen, --OH, --SH, --CN,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, --OH, --NO.sub.2,
-halogen, --CO.sub.2H, --CN,
--(CH.sub.2).sub.0-4--C(O)--NR.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.20,
--(CH.sub.2).sub.0-4--SO.sub.2--N- R.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--S(O)-(alkyl),
--(CH.sub.2).sub.0-4--S(O).sub.2-(alkyl),
--(CH.sub.2).sub.0-4--S(O).sub.- 2-(cycloalkyl),
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--C(O)--O--R.sub.20,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--C(O)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--N--C(S)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--N- (H or R.sub.20)--CO--R.sub.21,
--(CH.sub.2).sub.0-4--NR.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--R.sub.11,
--(CH.sub.2).sub.0-4--O--C(O)-(alkyl),
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.5).sub.2,
--(CH.sub.2).sub.0-4--O-- -C(O)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O--C(S)--N(R.sub.20).sub.2- ,
--(CH.sub.2).sub.0-4--O--(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O--(R.s- ub.2O)--CO.sub.2H,
--(CH.sub.2).sub.0-4--S--(R.sub.20), --(CH.sub.2).sub.0-4--O-(alkyl
optionally substituted with at least one halogen), -cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--S(O).sub.2--R.sub.21, and
--(CH.sub.2).sub.0-4-cycloalkyl; formula (IVg) is 530wherein a is 0
or 1; b is 0 or 1; S' is selected from --C(O)-- and --CO.sub.2--;
T' is --(CH.sub.2).sub.0-4--; U' is --(CR.sub.245R.sub.250)--; V'
is selected from -aryl- and -heteroaryl-; W' is selected from -a
bond, -alkyl-substituted with at least one group independently
selected from R.sub.205, --(CH.sub.2).sub.0-4--(CO).sub.0-1-
--N(R.sub.220)--, --(CH.sub.2).sub.0-4--(CO).sub.0-1--,
--(CH.sub.2).sub.0-4--CO.sub.2--,
--(CH.sub.2).sub.0-4--SO.sub.2--N(R.sub- .220)--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO.sub.2--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--SO.sub.2--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--N(R.sub.215)--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--,
--(CH.sub.2).sub.0-4--N(- R.sub.220)--, --(CH.sub.2).sub.0-4--O--,
and --(CH.sub.2).sub.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 R.sub.205; wherein each aryl or heteroaryl group
included in formula (IVg) is optionally substituted with at least
one group independently selected from R.sub.200; wherein at least
one heteroatom of the heteroaryl group included within formula
(IVg) is optionally substituted with a group selected from
--(CO).sub.0-1R.sub.215- , --(CO).sub.0-1R.sub.220, and
--S(O).sub.0-2R.sub.200; R.sub.21 and R.sub.22 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,
--R.sub.17, and --R.sub.18, --(CH.sub.2).sub.0-4--C(O)-(a- lkyl),
--(CH.sub.2).sub.0-4--C(O)-(cycloalkyl),
--(CH.sub.2).sub.0-4--C(O)- --R.sub.17,
--(CH.sub.2).sub.0-4--C(O)--R.sub.18, --(CH.sub.2).sub.0-4--C(-
O)--R.sub.19, and --(CH.sub.2).sub.0-4--C(O)--R.sub.11; R.sub.17 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, --NR.sub.5R.sub.6, --CN, --CF.sub.3, and
--O-alkyl, -halogen, --O-alkyl optionally substituted with at least
one group independently selected from halogen, --NR.sub.21R.sub.22,
--OH, --CN, and -cycloalkyl optionally substituted with at least
one group independently selected from -halogen, --OH, --SH, --CN,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, --C(O)-(alkyl),
--S(O)--O--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl); R.sub.18 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,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, -halogen, --O-alkyl
optionally substituted with at least one group independently
selected from -halogen, --NR.sub.21R.sub.22, --OH, and --CN,
-cycloalkyl optionally substituted with at least one group
independently selected from -halogen, --OH, --SH, --CN, CF.sub.3,
--O-alkyl, and --NR.sub.5R.sub.6, --C(O)-(alkyl),
--S(O).sub.2--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl); R.sub.19 at each occurrence is
heterocycloalkyl wherein at least one carbon is optionally replaced
with --C(O)--, --S(O)--, and --S(O).sub.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, --CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, -halogen,
--O-alkyl optionally substituted with at least one group
independently selected from -halogen, --OH, --CN,
--NR.sub.21R.sub.22, and -cycloalkyl optionally substituted with at
least one group independently selected from -halogen, --OH, --SH,
--CN, --CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6, --C(O)-(alkyl),
--S(O).sub.2--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl); R.sub.11 at each occurrence is
heterocycloalkyl wherein at least one carbon of the
heterocycloalkyl is optionally
replaced with --C(O)--, --S(O)--, and --S(O).sub.2--, wherein the
heterocycloalkyl is optionally substituted with at least one group
independently selected from -alkyl, --O-alkyl, and -halogen;
R.sub.20 is selected from -alkyl, -cycloalkyl,
--(CH.sub.2).sub.0-2--(R.sub.17), and
--(CH.sub.2).sub.0-2--(R.sub.18); R.sub.200 at each occurrence is
independently selected from -alkyl optionally substituted with at
least one group independently selected from R.sub.205, --OH,
--NO.sub.2, --NH.sub.2, -halogen, --CN, --CF.sub.3, --OCF.sub.3,
--(CH.sub.2).sub.0-4--C(O)H, --(CO).sub.0-1R.sub.215,
--(CO).sub.0-1R.sub.220,
--(CH.sub.2).sub.0-4--C(O)--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1--R.sub.215,
--(CH.sub.2).sub.0-4--(C- (O)).sub.0-1--R.sub.220,
--(CH.sub.2).sub.0-4--C(O)-alkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-cycloalkyl,
--(CH.sub.2).sub.0-4--(C- (O)).sub.0-1-heterocycloalkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-aryl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-heteroaryl,
--(CH.sub.2).sub.0-4--C(- O)--O--R.sub.215,
--(CH.sub.2).sub.0-4--S(O).sub.0-2--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--S(O).sub.0-2-alkyl,
--(CH.sub.2).sub.0-4--S(O).sub.- 0-2-cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--O--R.sub.21- 5,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--S(O).sub.1-2--R.sub.220,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--R.sub.220,
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--O--C(O)-- alkyl,
--(CH.sub.2).sub.0-4--O--(R.sub.215),
--(CH.sub.2).sub.0-4--S--(R.s- ub.215),
--(CH.sub.2).sub.0-4--C(O)H, --(CH.sub.2).sub.0-4--O-(alkyl
optionally substituted with at least one halogen), and -adamantane,
wherein each aryl and heteroaryl group included within R.sub.200 is
optionally substituted with at least one group independently
selected from --R.sub.205, --R.sub.210, and -alkyl optionally
substituted with at least one group independently selected from
R.sub.205 and R.sub.210; wherein each cycloalkyl or
heterocycloalkyl group included within R.sub.200 is optionally
substituted with at least one group independently selected from
--R.sub.205, --R.sub.210, and -alkyl optionally substituted with at
least one group independently selected from R.sub.205 and
R.sub.210; R.sub.205 at each occurrence is independently selected
from -alkyl, -heteroaryl, -heterocycloalkyl, -aryl, -haloalkoxy,
--(CH.sub.2).sub.0-3-cycloalkyl, -halogen,
--(CH.sub.2).sub.0-6--OH, --O-phenyl, --SH,
--(CH.sub.2).sub.0-4--C(O)CH.sub.3 --(CH.sub.2).sub.0-4--C(O)H
--(CH.sub.2).sub.0-4--CO.sub.2H, --(CH.sub.2).sub.0-6--CN,
--(CH.sub.2).sub.0-6--C(O)--NR.sub.235R.sub.240- ,
--(CH.sub.2).sub.0-6--C(O)--R.sub.235, --(CH.sub.2).sub.0-4--N(H or
R.sub.215)--SO.sub.2--R.sub.235, --CF.sub.3, --CN, --OCF.sub.3,
--C(O).sub.2-benzyl, --O-alkyl, --C(O).sub.2-alkyl, and
--NR.sub.235R.sub.240; R.sub.210 at each occurrence is
independently selected from --OH, --CN,
--(CH.sub.2).sub.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
R.sub.205, --S-alkyl, -halogen, --O-alkyl, -haloalkoxy,
--NR.sub.220R.sub.225, -cycloalkyl optionally substituted with at
least one group independently selected from R.sub.205,
--C(O)-alkyl, --S(O).sub.2--NR.sub.235R.sub.240,
--C(O)--NR.sub.235R.sub.240, and --S(O).sub.2-alkyl; R.sub.215 at
each occurrence is independently selected from -alkyl,
--(CH.sub.2).sub.0-2-aryl, --(CH.sub.2).sub.0-2-cyc- loalkyl,
--(CH.sub.2).sub.0-2-heteroaryl, and --(CH.sub.2).sub.0-2-heteroc-
ycloalkyl; wherein the aryl groups included within R.sub.215 are
optionally substituted with at least one group independently
selected from R.sub.205 or R.sub.210; wherein the heterocycloalkyl
and heteroaryl groups included within R.sub.215 are optionally
substituted with at least one group independently selected from
R.sub.210; R.sub.220 and R.sub.225 at each occurrence are
independently selected from --H, --OH, -alkyl,
--(CH.sub.2).sub.0-4--C(O)H, -alkyl-OH,
--(CH.sub.2).sub.0-4CO.sub.2-alky- l, wherein alkyl is optionally
substituted with at least one group independently selected from
R.sub.205, -aminoalkyl, --S(O).sub.2-alkyl,
--(CH.sub.2).sub.0-4--C(O)-alkyl, wherein alkyl is optionally
substituted with at least one group independently selected from
R.sub.205, --(CH.sub.2).sub.0-4--C(O)--NH.sub.2,
--(CH.sub.2).sub.0-4--C(O)--NH(alky- l), wherein alkyl is
optionally substituted with at least one group independently
selected from R.sub.205, --(CH.sub.2).sub.0-4--C(O)--N(alky-
l)(alkyl), -haloalkyl, --(CH.sub.2).sub.0-2-cycloalkyl,
-alkyl-O-alkyl, --O-alkyl, -aryl, -heteroaryl, and
-heterocycloalkyl; wherein the aryl, heteroaryl and
heterocycloalkyl groups included within R.sub.220 and R.sub.225 are
each optionally substituted with at least one group independently
selected from R.sub.270; R.sub.270 at each occurrence is
independently selected from --R.sub.205, -alkyl optionally
substituted with at least one group independently selected from
R.sub.205, -phenyl, -halogen, --O-alkyl, -haloalkoxy,
--NR.sub.235R.sub.240, --OH, --CN, -cycloalkyl optionally
substituted with at least one group independently selected from
R.sub.205, --C(O)-alkyl, --S(O).sub.2--NR.sub.235R.sub.240,
--CO--NR.sub.235R.sub.240, --S(O).sub.2-alkyl, and
--(CH.sub.2).sub.0-4--C(O)H; R.sub.235 and R.sub.240 at each
occurrence are independently selected from --H, -alkyl,
--C(O)-alkyl, --OH, --CF.sub.3, --OCH.sub.3, --NH--CH.sub.3,
--N(CH.sub.3).sub.2, --(CH.sub.2).sub.0-4--C(O)--(H or alkyl),
--SO.sub.2-alkyl, and -phenyl; R.sub.255 is selected from
-hydrogen, --OH, --N(R.sub.220)(R.sub.225), and --O-alkyl; R.sub.5
and R.sub.6 are independently selected from --H and -alkyl, or
R.sub.5 and R.sub.6, and the nitrogen to which they are attached,
form a 5 or 6 membered heterocycloalkyl ring; and R.sub.7 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.
11. The method according to claim 10, wherein R, is selected from
--CH.sub.2-phenyl, wherein the phenyl ring is optionally
substituted with at least one group independently selected from
-halogen, --C.sub.1-C.sub.2 alkyl, --O-methyl, and --OH.
12. The method according to claim 10, wherein R.sub.1 is selected
from 4-hydroxy-benzyl, 3-hydroxy-benzyl,
5-chloro-thiophen-2-yl-methyl,
5-chloro-3-ethyl-thiophen-2-yl-methyl,
3,5-difluoro-2-hydroxy-benzyl, piperidin4-yl-methyl,
2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl,
5-hydroxy-6-oxo-6H-pyran-2-yl-meth- yl,
3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl,
3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and
3-fluoro-benzyl.
13. The method according to claim 10, wherein R.sub.C is
--C(R.sub.245)(R.sub.250)--R.sub.X, wherein R.sub.245 and R.sub.250
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 atom within the monocyclic or bicyclic ring
system is optionally replaced by a group independently selected
from --O--, --C(O)--, --S(O).sub.0-2--, --C(.dbd.N--R.sub.255)--,
--N--, --NR.sub.220--, --N((CO).sub.0-1R.sub.20- 0)--, and
--N(SO.sub.2R.sub.200)--; and wherein the monocyclic or bicyclic
groups included within R.sub.245 and R.sub.250 are optionally
substituted with at least one group independently selected from
halogen, --OH, --O-alkyl, alkyl, aryl, --N(R.sub.220)(R.sub.225),
--CN, --NH.sub.2, --NH(alkyl), --NHOH, --NH--O-alkyl,
--N(alkyl)(alkyl), --NH--C(O)-alkyl, and --NHS(O.sub.2)-alkyl; and
wherein R.sub.X, R.sub.220, R.sub.225, R.sub.255, and R.sub.200 are
as defined in claim 10.
14. The method according to claim 10, wherein R.sub.C is selected
from formulae (Va), (Vb), (Vc), and (Vd), 531wherein, A, B, and C
are independently selected from --CH.sub.2--, --O--, --C(O)--,
--S(O).sub.0-2--, --N((CO).sub.0-1R.sub.200)--,
--N(SO.sub.2R.sub.200)--, --C(.dbd.N--R.sub.255)--, and
--N(R.sub.220)--; A' at each occurence is independently selected
from --CH.sub.2-- and --O--; wherein (Va), (Vb), (Vc), and (Vd) are
each optionally substituted with at least one group independently
selected from -alkyl, --O-alkyl, --(CH.sub.2).sub.0-2--OH,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3, --CN, -halogen,
--(CH.sub.2).sub.0-2--NH.sub.2, --(CH.sub.2).sub.0-2--NH(alkyl),
--NHOH, --NH--O-alkyl, --N(alkyl)(alkyl), --NH-heteroaryl,
--NH--C(O)-alkyl, and --NHS(O.sub.2)-alkyl; and R.sub.X, R.sub.220,
R.sub.255, and R.sub.200 are as defined in claim 10.
15. The method according to claim 10, wherein R.sub.C is selected
from formulae (VIa) and (VIb), 532wherein at least one carbon of
the heterocycloalkyl of formula (VIa) and the cycloalkyl of formula
(VIb) is optionally replaced with a group independently selected
from --O--, --SO.sub.2--, and --C(O)--, wherein at least one carbon
of the heterocycloalkyl or cycloalkyl is optionally substituted
with at least one group independently selected from R.sub.205,
R.sub.245, and R.sub.250, wherein R.sub.100, R.sub.200, R.sub.205,
R.sub.245, and R.sub.250 are as defined in claim 10.
16. The method according to claim 10, wherein R.sub.C is selected
from 6-isobutyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-yl,
6-Isopropyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl,
6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl,
7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl,
1-(3-tert-Butyl-phenyl)-cyclo- hexyl, and 3-methoxy-benzyl.
17. The method according to claim 10, wherein R.sub.2 is selected
from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino,
[1,2,4]thiadiazol-5-ylamin- o,
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]th- iadiazol-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-ylami- no,
3,4-dioxo-cyclobut-1-enylamino,
2-methoxy-3,4-dioxo-cyclobut-1-enylami- no, and
2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
18. The method according to claim 11, wherein R.sub.X 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)-cycl- ohexylamino,
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.
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), 533or
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C 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), 534further
comprising-a composition including beta-secretase complexed with at
least one compound of formula (I), or pharmaceutically acceptable
salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are defined in
claim 10.
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), 535or a
pharmaceutically acceptable salt thereof to the patient, wherein
R.sub.1, R.sub.2, and R.sub.C are defined as in claim 1.
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): 536or
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C 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: 537or pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C 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: 538or pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C 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 (l) or a
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C 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 R.sub.1, R.sub.2,
and R.sub.C 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), 539or a pharmaceutically acceptable salt thereof,
wherein R.sub.1, R.sub.2, and R.sub.C 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), 540or a
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C are defined as in claim 1.
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), 541or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C 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; or between
Leu671 and Asp672 of the APP-770 Swedish Mutation.
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), 542or a pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are
defined as in claim 1.
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), 543or a pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are
defined as in claim 1.
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), 544or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are defined as in
claim 1.
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), 545or a
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C are defined as in claim 1.
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), 546or a pharmaceutically acceptable salt thereof,
wherein R.sub.1, R.sub.2, and R.sub.C are defined as in claim 1, to
the patient.
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), 547or a pharmaceutically acceptable salt thereof,
wherein R.sub.1, R.sub.2, and R.sub.C 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'.
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), 548or a pharmaceutically
acceptable salt, derivative or biologically active metabolite
thereof, to the patient, wherein R.sub.1, R.sub.2, and R.sub.C are
defined as in claim 1.
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), 549or a
pharmaceutically acceptable salt, derivative or biologically active
metabolite thereof, to the patient, wherein R.sub.1, R.sub.2, and
R.sub.C are defined as in claim 1.
48. An article of manufacture, comprising: (a) at least one dosage
form of at least one compound of formula (I), 550or a stereoisomer,
or pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, and R.sub.C 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) 551or a
stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R.sub.1, R.sub.2, and R.sub.C 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) 552or a
stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R.sub.1, R.sub.2, and R.sub.C 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) 553wherein
R.sub.1, R.sub.2, and R.sub.C 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)
554wherein R.sub.1, R.sub.2, and R.sub.C 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) 555wherein R.sub.1, R.sub.2, and R.sub.C 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 56, 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.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) to U.S. Provisional No. 60/619,918, filed Oct.
20, 2004, Provisional Application No. 60/591,918, filed Jul. 29,
2004, Provisional Application No. 60/575,977, filed Jun. 2, 2004,
and Provisional Application No. 60/551,052, filed Mar. 9, 2004, all
of which are expressly incorporated herein by reference in their
entirety.
FIELD OF THE PRESENT INVENTION
[0002] The present invention is directed to novel compounds and
also to methods of treating at least one condition, disorder, or
disease associated with amyloidosis using such compounds.
BACKGROUND OF THE PRESENT INVENTION
[0003] Amyloidosis refers to a collection of conditions, disorders,
and diseases associated with abnormal deposition of amyloidal
protein. For instance, Alzheimer's disease is believed to be caused
by abnormal deposition of amyloidal protein in the brain. These
amyloidal protein deposits, otherwise known as amyloid-beta
peptide, A-beta, or betaA4, are the result of proteolytic cleavage
of the amyloid precursor protein (APP).
[0004] The majority of APP molecules that undergo proteolytic
cleavage are cleaved by the aspartyl protease alpha-secretase.
Alpha-secretase cleaves APP between Lys687 and Leu688 producing a
large, soluble fragment, alpha-sAPP, which is a secreted form of
APP that does not result in beta-amyloid plaque formation. The
alpha-secretase cleavage pathway precludes the formation of A-beta,
thus providing an alternate target for preventing or treating
amyloidosis.
[0005] Some APP molecules, however, are cleaved by a different
aspartyl protease known as beta-secretase, which is also referred
to in the literature as BACE, BACE1, Asp2, and Memapsin2.
Beta-secretase cleaves APP after Met671, creating a C-terminal
fragment. See, for example, Sinha et al., Nature, (1999),
402:537-554 and published PCT application WO 00/17369. After
cleavage of APP by beta-secretase, an additional aspartyl protease,
gamma-secretase, may then cleave the C-terminus of this fragment,
at either Val711 or Ile713, found within the APP transmembrane
domain, generating an A-beta peptide. The A-beta peptide may then
proceed to form beta-amyloid plaques. A detailed description of the
proteolytic processing of APP fragments is found, for example, in
U.S. Pat. Nos. 5,441,870, 5,721,130, and 5,942,400.
[0006] The amyloidal disease Alzheimer's is a progressive
degenerative disease that is characterized by two major pathologic
observations in the brain which are (1) neurofibrillary tangles,
and (2) beta-amyloid (or neuritic) plaques. A major factor in the
development of Alzheimer's disease is A-beta deposits in regions of
the brain responsible for cognitive activities. These regions
include, for example, the hippocampus and cerebral cortex. A-beta
is a neurotoxin that may be causally related to neuronal death
observed in Alzheimer's disease patients. See, for example, Selkoe,
Neuron, 6 (1991) 487. Since A-beta peptide accumulates as a result
of APP processing by beta-secretase, inhibiting beta-secretase's
activity is desirable for the treatment of Alzheimer's disease.
[0007] Dementia-characterized disorders also arise from A-beta
accumulation in the brain including accumulation in cerebral blood
vessels (known as vasculary amyloid angiopathy) such as in the
walls of meningeal and parenchymal arterioles, small arteries,
capillaries, and venules. A-beta may also be found in cerebrospinal
fluid of both individuals with and without Alzheimer's disease.
Additionally, neurofibrillary tangles similar to the ones observed
in Alzheimer's patients can also be found in individuals without
Alzheimer's disease. In this regard, a patient exhibiting symptoms
of Alzheimer's due to A-beta deposits and neurofibrillary tangles
in their cerebrospinal fluid may in fact be suffering from some
other form of dementia. See, for example, Seubert et al., Nature,
359 (1992) 325-327. Examples of other forms of dementia where
A-beta accumulation generates amyloidogenic plaques or results in
vascular amyloid angiopathy include Trisomy 21 (Down's Syndrome),
Hereditary Cerebral Hemorrhage with amyloidosis of the Dutch-Type
(HCHWA-D), and other neurodegenerative disorders. Consequently,
inhibiting beta-secretase is not only desirable for the treatment
of Alzheimer's, but also for the treatment of other conditions
associated with amyloidosis.
[0008] Amyloidosis is also implicated in the pathophysiology of
stroke. Cerebral amyloid angiopathy is a common feature of the
brains of stroke patients exhibiting symptoms of dementia, focal
neurological syndromes, or other signs of brain damage. See, for
example, Corio et al., Neuropath Appl. Neurobiol., 22 (1996)
216-227. This suggests that production and deposition of A-beta may
contribute to the pathology of Alzheimer's disease, stroke, and
other diseases and conditions associated with amyloidosis.
Accordingly, the inhibition of A-beta production is desirable for
the treatment of Alzheimer's disease, stroke, and other diseases
and conditions associated with amyloidosis.
[0009] Presently there are no known effective treatments for
preventing, delaying, halting, or reversing the progression of
Alzheimer's disease and other conditions associated with
amyloidosis. Consequently, there is an urgent need for methods of
treatment capable of preventing and treating conditions associated
with amyloidosis including Alzheimer's disease.
[0010] Likewise, there is a need for methods of treatment using
compounds that inhibit beta-secretase-mediated cleavage of APP.
There is also a need for methods of treatment using compounds that
are effective inhibitors of A-beta production, and/or are effective
at reducing A-beta deposits or plaques, as well as methods of
treatment capable of combating diseases and conditions
characterized by amyloidosis, or A-beta deposits, or plaques.
[0011] There is also a need for methods of treating conditions
associated with amyloidosis using compounds that are efficacious,
bioavailable and/or selective for beta-secretase. An increase in
efficacy, selectivity, and/or oral bioavailability may result in
preferred, safer, less expensive products that are easier for
patients to use.
[0012] There is also a need for methods of treating conditions
associated with amyloidosis using compounds with characteristics
that would allow them to cross the blood-brain-barrier. Desirable
characteristics include a low molecular weight and a high log P
(increased log P=increased lipophilicity). Generally, known
aspartyl protease inhibitors are either incapable of crossing the
blood-brain barrier or do so with great difficulty. These compounds
are unsuitable for the treatment of the conditions described
herein. Accordingly, there is a need for methods of treating
conditions associated with amyloidosis using compounds that can
readily cross the blood-brain barrier and inhibit
beta-secretase.
[0013] There-is also a need for a method of finding suitable
compounds for inhibiting beta-secretase activity, inhibiting
cleavage of APP, inhibiting production of A-beta, and/or reducing
A-beta deposits or plaques.
[0014] The present invention is directed to novel compounds and
also to methods of treating conditions, disorders, and diseases
associated with amyloidosis using such compounds. An embodiment of
the present invention is administering at least one compound of
formula (I) wherein R.sub.1, R.sub.2, and R.sub.C are defined below
for treating at least one condition, disorder, or disease
associated with amyloidosis. Another embodiment of the present
invention is a method of administering at least one compound of
formula (I) wherein R.sub.1, R.sub.2, and R.sub.C are defined below
in treating conditions, disorders, and diseases associated with
amyloidosis. Another embodiment of the present invention is
directed to methods of treatment comprising administering at least
one compound of formula (I) wherein R.sub.1, R.sub.2, and R.sub.C
are defined below useful in preventing, delaying, halting, or
reversing the progression of Alzheimer's disease.
[0015] Another embodiment of the present invention is directed to
uses of beta-secretase inhibitors of at least one compound of
formula (I) wherein R.sub.1, R.sub.2, and R.sub.C are defined below
in treating or preventing conditions, disorders, and-diseases
associated with amyloidosis.
[0016] Another embodiment of the present invention is to administer
beta-secretase inhibitors of at least one compound of formula (I)
wherein R.sub.1, R.sub.2, and R.sub.C are defined below, exhibiting
at least one property chosen from improved efficacy, oral
bioavailability, selectivity, and blood-brain barrier penetrating
properties. The present invention accomplishes one or more of these
objectives and provides further related advantages.
BRIEF SUMMARY OF THE PRESENT INVENTION
[0017] The present invention is directed to novel compounds and
also to methods of treating at least one condition, disorder, or
disease associated with amyloidosis using such compounds. As
previously noted, amyloidosis refers to a collection of diseases,
disorders, and conditions associated with abnormal deposition of
A-beta protein.
[0018] Properties contributing to viable pharmaceutical
compositions of beta-secretase inhibitors are incorporated into the
present invention. These properties include improved efficacy,
bioavailability, selectivity, and/or blood-brain barrier
penetrating properties. They can be inter-related, though an
increase in any one of them correlates to a benefit for the
compound and its corresponding method of treatment. For example, an
increase in any one of these properties may result in preferred,
safer, less expensive products that are easier for patients to
use.
[0019] In an embodiment, the present invention provides a method of
preventing or treating conditions which benefit 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), 1
[0020] or pharmaceutically acceptable salts thereof, and wherein
R.sub.1, R.sub.2, and R.sub.C are as defined below.
[0021] In an embodiment, the present invention provides a method of
preventing or treating conditions which benefit 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 the inhibition is at least 10% for a dose
.ltoreq.100 mg/kg, and wherein R.sub.1, R.sub.2, and R.sub.C are as
defined below.
[0022] In another embodiment, the present invention provides a
method for preventing or treating conditions associated with
amyloidosis, comprising administering to a host a therapeutically
effective amount of at least one compound of formula (I), or a
pharmaceutically acceptable salt thereof, the compound having an F
value of at least 10%, wherein R.sub.1, R.sub.2, and R.sub.C are as
defined below.
[0023] In another embodiment, the present invention provides a
method of preventing or treating conditions associated with
amyloidosis, comprising administering to a host a composition
comprising a therapeutically effective amount of at least one
selective beta-secretase inhibitor of formula (I), or
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C are as defined below.
[0024] In another embodiment, the present invention provides a
method of preventing or treating Alzheimer's disease by
administering to a host an effective amount of at least one
compound of formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as defined
below.
[0025] In another embodiment, the present invention provides a
method of preventing or treating dementia by administering to a
host an effective amount of at least one compound of formula (I),
or pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, and R.sub.C are as defined below.
[0026] In another embodiment, the present invention provides a
method of inhibiting beta-secretase activity in a host, the method
comprising administering to the host an effective amount of at
least one compound of formula (I), or a pharmaceutically acceptable
salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as defined
below.
[0027] In another embodiment, the present invention provides a
method of inhibiting beta-secretase activity in a cell, the method
comprising administering to the cell an effective amount of at
least one compound of formula (I), or a pharmaceutically acceptable
salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as defined
below.
[0028] In another embodiment, the present invention provides a
method of inhibiting beta-secretase activity in a host, the method
comprising administering to the host an effective amount of at
least one compound of formula (I), or a pharmaceutically acceptable
salt thereof, wherein the host is a human, wherein R.sub.1,
R.sub.2, and R.sub.C are as defined below.
[0029] In another embodiment, the present invention provides 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
R.sub.1, R.sub.2, and R.sub.C are as defined below.
[0030] In-another embodiment, the present invention provides 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 R.sub.1, R.sub.2,
and R.sub.C are as defined below.
[0031] In another embodiment, the present invention provides 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 R.sub.1, R.sub.2, and R.sub.C are as defined
below.
[0032] In another embodiment, the present invention provides 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 R.sub.1, R.sub.2, and R.sub.C are as defined
below.
[0033] In another embodiment, the present invention provides 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 R.sub.1, R.sub.2, and R.sub.C are as defined
below.
[0034] In another embodiment, the A-beta deposits or plaques are in
a human brain.
[0035] In another embodiment, the present invention provides 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
R.sub.1, R.sub.2, and R.sub.C are as defined below.
[0036] In another embodiment, the at least one aspartyl protease is
beta-secretase.
[0037] In another embodiment, the present invention provides 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 R.sub.1, R.sub.2,
and R.sub.C are as defined below, and wherein the at least one
compound interacts with at least one beta-secretase subsite such as
S1, S1', or S2'.
[0038] In another embodiment, the present invention provides an
article of manufacture, comprising (a) at least one dosage form of
at least one compound of formula (I), or pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are
defined below, (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 disorders, conditions or diseases
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.
[0039] In another embodiment, the present invention provides a
packaged pharmaceutical composition for treating conditions 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 wherein R.sub.1, R.sub.2,
and R.sub.C are as defined below, and (b) instructions for using
the pharmaceutical composition.
Definitions
[0040] Throughout the specification and claims, including the
detailed description below, the following definitions apply.
[0041] It should be noted that, as used in this specification and
the appended claims, the singular forms "a," "an," and "the"
include plural referents unless the content clearly dictates
otherwise. Thus, for example, reference to a composition containing
"a compound" includes a mixture of two or more compounds. It should
also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates
otherwise.
[0042] Where multiple groups are indicated as being attached to a
structure, it is to be understood that the groups can be the same
or different.
[0043] APP, amyloid precursor protein, is defined as any APP
polypeptide, including APP variants, mutations, and isoforms, for
example, as disclosed in U.S. Pat. No. 5,766,846.
[0044] Beta-amyloid peptide (A-beta peptide) is defined as any
peptide resulting from beta-secretase mediated cleavage of APP,
including, for example, peptides of 39, 40, 41, 42, and 43 amino
acids, and extending from the beta-secretase cleavage site to amino
acids 39, 40, 41, 42, or 43.
[0045] Beta-secretase is an aspartyl protease that mediates
cleavage of APP at the N-terminus of A-beta. Human beta-secretase
is described, for example, in WO 00/17369.
[0046] The term. "complex" as used herein refers to an
inhibitor-enzyme complex, wherein the inhibitor is a compound of
formula (I) described herein, and wherein the enzyme is
beta-secretase or a fragment thereof.
[0047] The term "host" as used herein refers to a cell or tissue,
in vitro or in vivo, an animal, or a human.
[0048] The term "treating" refers to administering a compound or a
composition of formula (I) to a host having at least a tentative
diagnosis of disease or condition. The methods of treatment and
compounds of the present invention will delay, halt, or reverse the
progression of the disease or condition thereby giving the host a
longer and/or more functional life span.
[0049] The term "preventing" refers to administering a compound or
a composition of formula (I) to a host who has not been diagnosed
as having the disease or condition at the time of administration,
but who could be expected to develop the disease or condition or be
at increased risk for the disease or condition. The methods of
treatment and compounds of the present invention may slow the
development of disease symptoms, delay the onset of the disease or
condition, halt the progression of disease development, or prevent
the host from developing the disease or condition at all.
Preventing also includes administration of a compound or a
composition of the present invention to those hosts thought to be
predisposed to the disease or condition due to age, familial
history, genetic or chromosomal abnormalities, due to the presence
of one or more biological markers for the disease or condition,
such as a known genetic mutation of APP or APP cleavage products in
brain tissues or fluids, and/or due to environmental factors.
[0050] The term "halogen" in the present invention refers to
fluorine, bromine, chlorine, or iodine.
[0051] The term "alkyl" in the present invention refers to straight
or branched chain alkyl groups having 1 to 20 carbon atoms. An
alkyl group may optionally comprise at least one double bond and/or
at least one triple bond. The alkyl groups herein are unsubstituted
or substituted in one or more positions with various groups. For
example, such alkyl groups may be optionally substituted with
alkyl, alkoxy, --C(O)H, carboxy, alkoxycarbonyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, amido, alkanoylamino, amidino,
alkoxycarbonylamino, N-alkyl amidino, N-alkyl amido,
N,N'-dialkylamido, aralkoxycarbonylamino, halogen, alkylthio,
alkylsulfinyl, alkylsulfonyl, hydroxy, cyano, nitro, amino,
monoalkylamino, dialkylamino, halo alkyl, halo alkoxy, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, and the like. Additionally,
at least one carbon within any such alkyl may be optionally
replaced with --C(O)--.
[0052] Examples of alkyls include methyl, ethyl, ethenyl, ethynyl,
propyl, 1-ethyl-propyl, propenyl, propynyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, 3-methyl-butyl,
1-but-3-enyl, butynyl, pentyl, 2-pentyl, isopentyl, neopentyl,
3-methylpentyl, 1-pent-3-enyl, 1-pent-4-enyl, pentyl-2-yl, hexyl,
2-hexyl, 3-hexyl, 1-hex-5-enyl, formyl, acetyl, acetylamino,
trifluoromethyl, propionic acid ethyl ester, trifluoroacetyl,
methylsulfonyl, ethylsulfonyl, 1-hydroxy-1-methylethyl,
2-hydroxy-1,1,-dimethyl-ethyl, 1,1-dimethyl-propyl,
cyano-dimethyl-methyl, propylamino, and the like.
[0053] In an embodiment, alkyls may be selected from the group
comprising sec-butyl, isobutyl, ethynyl, 1-ethyl-propyl, pentyl,
3-methyl-butyl, pent-4-enyl, isopropyl, tert-butyl, 2-methylbutane,
and the like.
[0054] In another embodiment, alkyls may be selected from formyl,
acetyl, acetylamino, trifluoromethyl, propionic acid ethyl ester,
trifluoroacetyl, methylsulfonyl, ethylsulfonyl,
1-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethyl-ethyl,
1,1-dimethyl-propyl, cyano-dimethyl-methyl, propylamino, and the
like.
[0055] The term "alkoxy" in the present invention refers to
straight or branched chain alkyl groups, wherein an alkyl group is
as defined above, and having 1 to 20 carbon atoms, attached through
at least one divalent oxygen atom, such as, for example, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,
pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, allyloxy,
2-(2-methoxy-ethoxy)-ethoxy, benzyloxy, 3-methylpentoxy, and the
like.
[0056] In an embodiment, alkoxy groups may be selected from the
group comprising allyloxy, hexyloxy, heptyloxy,
2-(2-methoxy-ethoxy)-ethoxy, benzyloxy, and the like.
[0057] The term "--C(O)-alkyl" or "alkanoyl" refers to an acyl
radical derived from an alkylcarboxylic acid, a
cycloalkylcarboxylic acid, a heterocycloalkylcarboxylic acid, an
arylcarboxylic acid, an arylalkylcarboxylic acid, a
heteroarylcarboxylic acid, or a heteroarylalkylcarboxylic acid,
examples of which include formyl, acetyl, 2,2,2-trifluoroacetyl,
propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
[0058] The term "cycloalkyl" refers to an optionally substituted
carbocyclic ring system of one or more 3, 4, 5, 6, 7, or 8 membered
rings. A cycloalkyl can further include 9, 10, 11, 12, 13, and 14
membered fused ring systems. A cycloalkyl can be saturated or
partially unsaturated. The cycloalkyl may be monocyclic, bicyclic,
tricyclic, and the like. Bicyclic and tricyclic as used herein are
intended to include both fused ring systems, such as adamantyl,
octahydroindenyl, decahydro-naphthyl, and the like, substituted
ring systems, such as cyclopentylcyclohexyl and the like, and
spirocycloalkyls such as spiro[2.5]octane, spiro[4.5]decane,
1,4-dioxa-spiro[4.5]decane, and the like. A cycloalkyl may
optionally be a benzo fused ring system which is optionally
substituted as defined herein with respect to the definition of
aryl. At least one --CH.sub.2-- group within any such cycloalkyl
ring system may be optionally replaced with --C(O)--, --C(S)--,
--C(.dbd.N--OH)--, --C(.dbd.N-alkyl)-(optionally substituted as
defined herein with respect to the definition of alkyl), or
--C(.dbd.N--O-alkyl)-(optionally substituted as defined herein with
respect to the definition of alkyl).
[0059] Further examples of cycloalkyl radicals include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, octahydronaphthyl,
2,3-dihydro-1H-indenyl, and the like.
[0060] In one embodiment, a cycloalkyl may be selected from the
group comprising cyclopentyl, cyclohexyl, cycloheptyl, adamantenyl,
bicyclo[2.2.1]heptyl, and the like.
[0061] The cycloalkyl groups herein are unsubstituted or
substituted in at least one position with various groups. For
example, such cycloalkyl groups may be optionally substituted with
alkyl, alkoxy, --C(O)H, carboxy, alkoxycarbonyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, amido, alkanoylamino, amidino,
alkoxycarbonylamino, N-alkyl amidino, N-alkyl amido,
N,N'-dialkylamido, aralkoxycarbonylamino, halogen, alkylthio,
alkylsulfinyl, alkylsulfonyl, hydroxy, cyano, nitro, amino,
monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, and the like.
[0062] The term "cycloalkylcarbonyl" refers to an acyl radical of
the formula cycloalkyl-C(O)-- in which the term, "cycloalkyl" has
the significance given, above, such as cyclopropylcarbonyl,
cyclohexylcarbonyl, adamantylcarbonyl,
1,2,3,4-tetrahydro-2-naphthoyl,
2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,
1-hydroxy-1,2,3,4-tetrahydro-- 6-naphthoyl, and the like.
[0063] The term "heterocycloalkyl", "heterocycle", or
"heterocyclyl", refers to a monocyclic, bicyclic, or tricyclic
heterocycle radical, containing at least one nitrogen, oxygen or
sulfur atom ring member and having 3 to 8 ring members in each
ring, wherein at least one ring in the heterocycloalkyl ring system
may optionally contain at least one double bond. At least one
--CH.sub.2-- group within any such heterocycloalkyl ring system may
be optionally replaced with --C(O)--, --C(S)--, --C(.dbd.N--H)--,
--C(.dbd.N.dbd.OH)--, --(.dbd.N=alkyl)-(optionally substituted as
defined herein with respect to the definition of alkyl), or
--C(.dbd.N--O-alkyl) (optionally substituted as defined herein with
respect to the definition of alkyl).
[0064] The term "bicyclic" and "tricyclic" as used herein are
intended to include both fused ring systems, such as
2,3-dihydro-1H-indole, and substituted ring systems, such as
bicyclohexyl. At least one --CH.sub.2-- group within any such
heterocycloalkyl ring system may be optionally replaced with a
--C(O)--, --C(N)-- or --C(S)--. Heterocycloalkyl is intended to
include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring
members, and carbocyclic fused and benzo fused ring systems wherein
the benzo fused ring system is optionally substituted as defined
herein with respect to the definition of aryl. Such
heterocycloalkyl radicals may be optionally substituted on one or
more carbon atoms by halogen, alkyl, alkoxy, cyano, nitro, amino,
alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl,
haloalkyl, haloalkoxy, aminohydroxy, oxo, aryl, aralkyl,
heteroaryl, heteroaralkyl, amidino, N-alkylamidino,
alkoxycarbonylamino, alkylsulfonylamino, and the like, and/or on a
secondary nitrogen atom (i.e., --NH--) by hydroxy, alkyl,
aralkoxycarbonyl, alkanoyl, heteroaralkyl, phenyl, phenylalkyl, and
the like.
[0065] Examples of a heterocycloalkyl include morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl
S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,
pyrrolinyl, 2,5-dihydro-pyrrolyl, tetrahydropyranyl, pyranyl,
thiopyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,
imidazolidinyl, homopiperidinyl, 1,2-dihydro-pyridinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
1,4-dioxa-spiro[4.5]decyl, dihydropyrazinyl, dihydropyridinyl,
dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl
S-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl
S-oxide, 2-oxo-piperidinyl, 5-oxo-pyrrolidinyl,
2-oxo-1,2-dihydro-pyridinyl, 6-oxo-6H-pyranyl,
1,1-dioxo-hexahydro-thiopy- ranyl, 1-acetyl-piperidinyl,
1-methanesulfonylpiperidinyl, 1-ethanesulfonylpiperidinyl,
1-oxo-hexahydro-thiopyranyl, 1-(2,2,2-trifluoroacetyl)-piperidinyl,
1-formyl-piperidinyl, and the like.
[0066] In an embodiment, a heterocycloalkyl may be selected from
pyrrolidinyl, 2,5-dihydro-pyrrolyl, piperidinyl,
1,2-dihydro-pyridinyl, pyranyl, piperazinyl, imidazolidinyl,
thiopyranyl, tetrahydropyranyl, 1,4-dioxa-spiro[4.5]decyl, and the
like.
[0067] In another embodiment, a heterocycloalkyl may be selected
from 2-oxo-piperidinyl, 5-oxo-pyrrolidinyl,
2-oxo-1,2-dihydro-pyridinyl, 6-oxo-6H-pyranyl,
1,1-dioxo-hexahydro-thiopyranyl, 1-acetyl-piperidinyl,
1-methanesulfonyl piperidinyl, 1-ethanesulfonylpiperidinyl,
1-oxo-hexahydro-thiopyranyl, 1-(2,2,2-trifluoroacetyl)-piperidinyl,
1-formyl-piperidinyl, and the like.
[0068] The term "aryl" refers to an aromatic carbocyclic group
having a single ring (e.g., phenyl) or multiple condensed rings in
which at least one ring is aromatic. The aryl may be monocyclic
bicyclic, tricyclic, etc. Bicyclic and tricyclic as used herein are
intended to include both fused ring systems, such as naphthyl and
.beta.-carbolinyl, and substituted ring systems, such as biphenyl,
phenylpyridyl, diphenylpiperazinyl, tetrahydronaphthyl, and the
like. Preferred aryl groups of the present invention are phenyl,
1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl,
fluorenyl, tetralinyl or
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein
are unsubstituted or substituted in one or more positions with
various groups. For example, such aryl groups may be optionally
substituted with alkyl, alkoxy, --C(O)H, carboxy, alkoxycarbonyl,
aryl, heteroaryl, cycloalkyl, heterocyclalkyl, amido,
alkanoylamino, amidino, alkoxycarbonylamino, N-alkyl amidino,
N-alkyl amido, N,N'-dialkylamido, aralkoxycarbonylamino, halogen,
alkyl thio, alkylsulfinyl, alkylsulfonyl, hydroxy, cyano, nitro,
amino, monoalkylamino, dialkylamino, aralkoxycarbonylamino, halo
alkyl, halo alkoxy, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, and the like.
[0069] Examples of aryl radicals are phenyl, p-tolyl,
4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl,
4-CF.sub.3-phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl,
3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,
2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl,
3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,
2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl,
3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,
3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,
6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl,
and the like.
[0070] Further examples of aryl radicals include
3-tert-butyl-1-fluoro-phe- nyl, 1,3-difluorophenyl,
(1-hydroxy-1-methyl-ethyl)-phenyl,
1-fluoro-3-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl,
(1,1-dimethyl-propyl)-p- henyl, cyclobutyl-phenyl,
pyrrolidin-2-yl-phenyl, (5-oxo-pyrrolidin-2-yl)-- phenyl,
(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, (1H-pyrrol-2-yl)-phenyl,
(cyano-dimethyl-methyl)-phenyl, tert-butyl-phenyl,
1-fluoro-2-hydroxy-phenyl, 1,3-difluoro-4-propylamino-phenyl,
1,3-difluoro-4-hydroxy-phenyl, 1,3-difluoro-4-ethylamino-phenyl,
3-isopropyl-phenyl, (3H-[1,2,3]triazol-4-yl)-phenyl,
[1,2,3]triazol-1-yl-phenyl, [1,2,4]thiadiazol-3-yl-phenyl,
[1,2,4]thiadiazol-5-yl-phenyl, (4H-[1,2,4]triazol-3-yl)-phenyl,
[1,2,4]oxadiazol-3-yl-phenyl, imidazol-1-yl-phenyl,
(3H-imidazol-4-yl)-phenyl, [1,2,4]triazol-4-yl-phenyl,
[1,2,4]oxadiazol-5-yl-phenyl, isoxazol-3-yl-phenyl,
(1-methyl-cyclopropyl)-phenyl, isoxazol-4-yl-phenyl,
isoxazol-5-yl-phenyl, 1-cyano-2-tert-butyl-phenyl,
1-trifluoromethyl-2-tert-butyl-phenyl,
1-chloro-2-tert-butyl-phenyl, 1-acetyl-2-tert-butyl-phenyl,
1-tert-butyl-2-methyl-phenyl, 1-tert-butyl-2-ethyl-phenyl,
1-cyano-3-tert-butyl-phenyl, 1-trifluoromethyl-3-tert-butyl-phenyl,
1-chloro-3-tert-butyl-phenyl, 1-acetyl-3-tert-butyl-phenyl,
1-tert-butyl-3-methyl-phenyl, 1-tert-butyl-3-ethyl-phenyl,
4-tert-butyl-1-imidazol-1-yl-phenyl, ethylphenyl, isobutylphenyl,
isopropylphenyl, 3-allyloxy-1-fluoro-phenyl,
(2,2-dimethyl-propyl)-phenyl, ethynylphenyl,
1-fluoro-3-heptyloxy-phenyl,
1-fluoro-3-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl,
1-benzyloxy-3-fluoro-phe- nyl, 1-fluoro-3-hydroxy-phenyl,
1-fluoro-3-hexyloxy-phenyl, (4-methyl-thiophen-2-yl)-phenyl,
(5-acetyl-thiophen-2-yl)-phenyl, furan-3-yl-phenyl,
thiophen-3-yl-phenyl, (5-formyl-thiophen-2-yl)-phenyl,
(3-formyl-furan-2-yl)-phenyl, acetylamino-phenyl,
trifluoromethylphenyl, sec-butyl-phenyl, pentylphenyl,
(3-methyl-butyl)-phenyl, (1-ethyl-propyl)-phenyl,
cyclopentyl-phenyl, 3-pent-4-enyl-phenyl, phenyl propionic acid
ethyl ester, pyridin-2-yl-phenyl, (3-methyl-pyridin-2-yl)-- phenyl,
thiazol-2-yl-phenyl, (3-methyl-thiophen-2-yl)-phenyl,
fluoro-phenyl, adamantan-2-yl-phenyl,
1,3-difluoro-2-hydroxy-phenyl, cyclopropyl-phenyl,
1-bromo-3-tert-butyl-phenyl, (3-bromo-[1,2,4]thiadiaz-
ol-5-yl)-phenyl, (1-methyl-1H-imidazol-2-yl)-phenyl,
(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl,
(3,6-dimethyl-pyrazin-2-yl)-phenyl- ,
(3-cyano-pyrazin-2-yl)-phenyl, thiazol-4-yl-phenyl,
(4-cyano-pyridin-2-yl)-phenyl, pyrazin-2-yl-phenyl,
(6-methyl-pyridazin-3-yl)-phenyl, (2-cyano-thiophen-3-yl)-phenyl,
(2-chloro-thiophen-3-yl)-phenyl, (5-acetyl-thiophen-3-yl)-phenyl,
cyano-phenyl, and the like.
[0071] The term "heteroaryl" refers to an aromatic heterocycloalkyl
radical as defined above. The heteroaryl groups herein are
unsubstituted or substituted in at least one position with various
groups. For example, such heteroaryl groups may be optionally
substituted with, for example, alkyl, alkoxy, halogen, hydroxy,
cyano, nitro, amino, monoalkylamino, dialkylamino, haloalkyl,
haloalkoxy, --C(O)H, carboxy, alkoxycarbonyl, cycloalkyl,
heterocyclalkyl, aryl, heteroaryl, amido, alkanoylamino, amidino,
alkoxycarbonylamino, N-alkyl amidino, N-alkyl amido,
N,N'-dialkylamido, alkyl thio, alkylsulfinyl, alkylsulfonyl,
aralkoxycarbonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, and the like.
[0072] Examples of heteroaryl groups include
Benzo[4,5]thieno[3,2-d]-pyrim- idin-4-yl, pyridyl, pyrimidyl,
furanyl, imidazolyl, thienyl, oxazolyl, thiazolyl, pyrazinyl,
3-methyl-thienyl, 4-methyl-thienyl, 3-propyl-thienyl,
2-chloro-thienyl, 2-chloro-4-ethyl-thienyl, 2-cyano-thienyl,
5-acetyl-thienyl, 5-formyl-thienyl, 3-formyl-furanyl,
3-methyl-pyridinyl, 3-bromo-[1,2,4]thiadiazolyl,
1-methyl-1H-imidazole, 3,5-dimethyl-3H-pyrazolyl,
3,6-dimethyl-pyrazinyl, 3-cyano-pyrazinyl, 4-tert-butyl-pyridinyl,
4-cyano-pyridinyl, 6-methyl-pyridazinyl, 2-tert-butyl-pyrimidinyl,
4-tert-butyl-pyrimidinyl, 6-tert-butyl-pyrimidinyl,
5-tert-butyl-pyridazinyl, 6-tert-butyl-pyridazinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pyridazinyl, isoindolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl,
isoxazolyl, pyrazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl,
carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl
N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl
N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl
N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,
indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,
benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,
thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,
benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,
tetrahydrocarbazole, tetrahydrobetacarboline, and the like.
[0073] In an embodiment, a heteroaryl group may be selected from
pyridyl, pyrimidyl, furanyl, imidazolyl, thienyl, oxazolyl,
thiazolyl, pyrazinyl, and the like.
[0074] In another embodiment, a heteroaryl group may be selected
from 3-methyl-thienyl, 4-methyl-thienyl, 3-propyl-thienyl,
2-chloro-thienyl, 2-chloro-4-ethyl-thienyl, 2-cyano-thienyl,
5-acetyl-thienyl, 5-formyl-thienyl, 3-formyl-furanyl,
3-methyl-pyridinyl, 3-bromo-[1,2,4]thiadiazolyl,
1-methyl-1H-imidazole, 3,5-dimethyl-3H-pyrazolyl,
3,6-dimethyl-pyrazinyl, 3-cyano-pyrazinyl, 4-tert-butyl-pyridinyl,
4-cyano-pyridinyl, 6-methyl-pyridazinyl, 2-tert-butyl-pyrimidinyl,
4-tert-butyl-pyrimidinyl, 6-tert-butyl-pyrimidinyl,
5-tert-butyl-pyridazinyl, 6-tert-butyl-pyridazinyl, and the
like.
[0075] Further examples of heterocycloalkyls and heteroaryls may be
found in Katritzky, A. R. et al., Comprehensive Heterocyclic
Chemistry: The Structure, Reactions, Synthesis and Use of
Heterocyclic Compounds, Vol. 1-8, New York: Pergamon Press,
1984.
[0076] The term "aralkoxycarbonyl" refers to a radical of the
formula aralkyl-O--C(O)-- in which the term "aralkyl" is
encompassed by the definitions above for aryl and alkyl. Examples
of an aralkoxycarbonyl radical include benzyloxycarbonyl,
4-methoxyphenylmethoxycarbonyl, and the like.
[0077] The term "aryloxy" refers to a radical of the formula
--O-aryl in which the term aryl is as defined above.
[0078] The term "aralkanoyl" refers to an acyl radical derived from
an aryl-substituted alkanecarboxylic acid such as phenylacetyl,
3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl,
(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,
4-methoxyhydrocinnamoyl, and the like.
[0079] The term "aroyl" refers to an acyl radical derived from an
arylcarbdxylic acid, "aryl" having the meaning given above.
Examples of such aroyl radicals include substituted and
unsubstituted benzoyl or naphthoyl such as benzoyl,
4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,
1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl,
6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,
3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-- naphthoyl, and
the like.
[0080] The term "haloalkyl" refers to an alkyl radical having the
meaning as defined above wherein one or more hydrogens are replaced
with a halogen. Examples of such haloalkyl radicals include
chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, 1,1,1-trifluoroethyl, and the like.
[0081] The term "epoxide" refers to chemical compounds or reagents
comprising a bridging oxygen wherein the bridged atoms are also
bonded to one another either directly for indirectly. Examples of
epoxides include epoxyalkyl (e.g., ethylene oxide and
1,2-epoxybutane), epoxycycloalkyl (e.g., 1,2-epoxycyclohexane and
1,2-epoxy-1-methylcyclohexane), and the like.
[0082] The term "structural characteristics" refers to chemical
moieties, chemical motifs, and portions of chemical compounds.
These include R groups, such as those defined herein, ligands,
appendages, and the like. For example, structural characteristics
may be defined by their properties, such as, but not limited to,
their ability to participate in intermolecular interactions
including Van der Waal's interactions (e.g., electrostatic
interactions, dipole-dipole interactions, dispersion forces,
hydrogen bonding, and the like). Such characteristics may impart
desired pharmacokinetic properties and thus have an increased
ability to cause the desired effect and thus prevent or treat the
targeted diseases or conditions.
[0083] Compounds of formula (I) also comprise structural moieties
that participate in inhibitory interactions with at least one
subsite of beta-secretase. For example, moieties of the compounds
of formula (I) may interact with at least one of the S1, S1', and
S2' subsites, wherein S1 comprises residues Leu30, Tyr71, Phe108,
Ile110, and Trp115, S1' comprises residues Tyr198, Ile226; Val227,
Ser229, and Thr231, and S2' comprises residues Ser35, Asn37, Pro70,
Tyr71, Ile118, and Arg128. Such compounds and methods of treatment
may have an increased ability to cause the desired effect and thus
prevent or treat the targeted diseases or conditions.
[0084] The term "pharmaceutically acceptable" refers to those
properties and/or substances that are acceptable to the patient
from a pharmacological/toxicological point of view, and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance, and bioavailability.
[0085] The term "effective amount" as used herein refers to an
amount of a therapeutic agent administered to a host, as defined
herein, necessary to achieve a desired effect.
[0086] The term "therapeutically effective amount" as used herein
refers to an amount of a therapeutic agent administered to a host
to treat or prevent a condition treatable by administration of a
composition of the invention. That amount is the amount sufficient
to reduce or lessen at least one symptom of the disease being
treated or to reduce or delay onset of one or more clinical markers
or symptoms of the disease.
[0087] The term "therapeutically active agent" refers to a compound
or composition that is administered to a host, either alone or in
combination with another therapeutically active agent, to treat or
prevent a condition treatable by administration of a composition of
the invention.
[0088] The terms "pharmaceutically acceptable salt" and "salts
thereof" refer to acid addition salts or base addition salts of the
compounds in the present invention. A pharmaceutically acceptable
salt is any salt which retains the activity of the parent compound
and does not impart any deleterious or undesirable effect on the
subject to whom it is administered and in the context in which it
is administered. Pharmaceutically acceptable salts include salts of
both inorganic and organic acids. Pharmaceutically acceptable salts
include acid salts such as acetic, aspartic, benzenesulfonic,
benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium
edetate, camsylic, carbonic, chlorobenzoic, citric, edetic,
edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic,
gluconic, glutamic, glycolylarsanilic, hexamic, hexylresorcinoic,
hydrabamic, hydrobromic, hydrochloric, hydroiodic,
hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic,
malonic, mandelic, methanesulfonic, methyinitric, methylsulfuric,
mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic,
pamoic, pantothenic, phosphoric, monohydrogen phosphoric,
dihydrogen phosphoric, phthalic, polygalactouronic, propionic,
salicylic, stearic, succinic, sulfamic, sulfanilic, sulfonic,
sulfuric, tannic, tartaric, teoclic, toluenesulfonic, and the like.
Other acceptable salts may be found, for example, in Stahl et al.,
Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH;
1st edition (Jun. 15, 2002).
[0089] In an embodiment of the present invention, a
pharmaceutically acceptable salt is selected from the group
comprising hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,
phosphoric, citric, methanesulfonic,
CH.sub.3--(CH.sub.2).sub.0-4--COOH, HOOC--(CH.sub.2).sub.0-4--COOH,
HOOC--CH.dbd.CH--COOH, phenyl-COOH, and the like.
[0090] The term "unit dosage form" refers to physically discrete
units suitable as unitary dosages for human subjects or other
mammals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical vehicle. The
concentration of active compound, in the drug composition will
depend on absorption, inactivation, and/or excretion rates of the
active compound, the dosage schedule, the amount administered and
medium and method of administration, as well as other factors known
to those of skill in the art.
[0091] The term "modulate" refers to a chemical compound's activity
of either enhancing or inhibiting a functional property of
biological activity or process.
[0092] The terms "interact" and "interactions" refer to a chemical
compound's association and/or reaction with another chemical
compound, such as an interaction between an inhibitor and
beta-secretase. Interactions include, but are not limited to,
hydrophobic, hydrophilic, lipophilic, lipophobic, electrostatic,
and van der Waal's interactions including hydrogen bonding.
[0093] An "article of manufacture" as used herein refers to
materials useful for the diagnosis, prevention or treatment of the
disorders described above, such as a container with a label. The
label can be associated with the article of manufacture in a
variety of ways including, for example, the label may be on the
container or the label may be in the container as a package insert.
Suitable containers include, for example, blister packs, bottles,
bags, vials, syringes, test tubes, and the like. The containers may
be formed from a variety of materials such as glass, metal,
plastic, rubber, and/or paper, and the like. The container holds a
composition as described herein which is effective for diagnosing,
preventing, or treating a condition treatable by a compound or
composition of the present invention.
[0094] The article of manufacture may contain bulk quantities or
less of a composition as described herein. The label on, or
associated with, the container may provide instructions for the use
of the composition in diagnosing, preventing, or treating the
condition of choice, instructions for the dosage amount and for the
methods of administration. The label may further indicate that the
composition is to be used in combination with one or more
therapeutically active agents 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, an anti-A-beta
antibody, and/or a beta-secretase complex or fragment thereof. The
article of manufacture may further comprise multiple containers,
also referred to herein as a kit, comprising a therapeutically
active agent or a pharmaceutically-acceptable buffer, such as
phosphate-buffered saline, Ringer's solution and/or dextrose
solution. It may further include other materials desirable from a
commercial and user standpoint, including other buffers, diluents,
filters, needles, syringes, and/or package inserts with
instructions for use.
[0095] The compounds of formula (I), their compositions, and
methods of treatment employing them, can be enclosed in multiple or
single dose containers. The enclosed compounds and/or compositions
can be provided in kits, optionally including component parts that
can be assembled for use. For example, a compound inhibitor in
lyophilized form and a suitable diluent may be provided as
separated components for combination prior to use. A kit may
include a compound inhibitor and at least one additional
therapeutic agent for co-administration. The inhibitor and
additional, therapeutic agents may be provided as separate
component parts.
[0096] A kit may include a plurality of containers, each container
holding at least one unit dose of the compound of the present
invention. The containers are preferably adapted for the desired
mode of administration, including, for example, pill, tablet,
capsule, powder, gel or gel capsule, sustained-release capsule, or
elixir form, and/or combinations thereof, and the like, for oral
administration, depot products, pre-filled syringes, ampoules,
vials, and the like, for parenteral administration, and patches,
medipads, creams, and the like, for topical administration.
[0097] The term "C.sub.max" refers to the peak plasma concentration
of a compound in a host.
[0098] The term "T.sub.max" refers to the time at peak plasma
concentration of a compound in a host.
[0099] The term "half-life" refers to the period of time required
for the concentration or amount of a compound in a host to be
reduced to exactly one-half of a given concentration or amount.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0100] The present invention is directed to novel compounds and
also to methods of treating conditions, disorders, and diseases
associated with amyloidosis using such compounds. Amyloidosis
refers to a collection of diseases, disorders, and conditions
associated with abnormal deposition of amyloidal protein.
[0101] Accordingly, an embodiment of the present invention is to
provide a method of preventing or treating conditions which benefit
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), 2
[0102] or pharmaceutically acceptable salts thereof, wherein
[0103] R.sub.1 is selected from 3
[0104] wherein
[0105] X, Y, and Z are independently, selected from
--C(H).sub.0-2--, --O--, --C(O)--, --NH--, and --N--, wherein at
least one bond of the (IIf) ring may optionally be a double
bond;
[0106] L is selected from --O--, --SO.sub.2--, --C(O)--,
--C(R.sub.55)(R.sub.60)--, and --CH(NR.sub.55R.sub.60)--;
[0107] R.sub.55 and R.sub.60 are each independently selected from
hydrogen and alkyl;
[0108] R.sub.50, R.sub.50a, and R.sub.50b are independently
selected from --H, -halogen, --OH, --C(O)H, --C(O)CH.sub.3,
--CH.sub.2OH, --SH, --S(O).sub.0-2CH.sub.3, --CN, --NO.sub.2,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2--C.sub.1-C.sub.2
alkyl, --OCH.sub.3, --OCF.sub.3, and --CF.sub.3;
[0109] R.sub.2 is selected from --H, --OH, --O-alkyl (optionally
substituted with at least one group independently selected from
R.sub.200), --O-aryl, (optionally substituted with at least one
group independently selected from R.sub.200), -alkyl (optionally
substituted with at least one group independently selected from
R.sub.200), --NH-alkyl, (optionally substituted with at least one
group independently selected from R.sub.200), -heterocycloalkyl,
(wherein at least one carbon is optionally replaced with a group
independently selected from --(CR.sub.245R.sub.250)--, --O--,
--C(O)--, --C(O)C(O)--, --N(R.sub.200).sub.0-1--, and
--S(O).sub.0-2--, and wherein the heterocycloalkyl is optionally
substituted with at least one group independently selected from
R.sub.200), --NH-heterocycloalkyl, (wherein at least one carbon is
optionally replaced with a group independently selected from
--(CR.sub.245R.sub.250)--, --O--, --C(O)--, --C(O)C(O)--,
--N(R.sub.200).sub.0-2--, and --S(O).sub.0-2--, and wherein the
heterocycloalkyl is optionally substituted with at least one group
independently selected from R.sub.200),
--C(O)--N(R.sub.315)(R.sub.320),
--O--C(O)--N(R.sub.315)(R.sub.320), --NH--R.sub.400, --R.sub.400,
--NH--R.sub.500, --R.sub.500, --NH--R.sub.600, --R.sub.600, and
--NH--R.sub.700; wherein R.sub.315 and R.sub.320 are each
independently selected from --H, -alkyl, and phenyl;
[0110] R.sub.400 is 4
[0111] wherein R.sub.405 is selected from --H,
--N(R.sub.515).sub.2, and O-alkyl;
[0112] R.sub.500 is a heteroaryl selected from III(a) and III(b),
5
[0113] wherein
[0114] M.sub.1 and M.sub.4 are independently selected from
--C(R.sub.505)--, --N--, --N(R.sub.515)--, --S--, and --O--;
[0115] M.sub.2 and M.sub.3 are independently selected from
--C(R.sub.510)--, --N--, --N(R.sub.520)--, --S--, and --O--;
[0116] M.sub.5 is selected from --C-- and --N--;
[0117] R.sub.505 is independently selected from --H, -alkyl,
-halogen, --NO.sub.2, --CN, --R.sub.200, and -phenyl;
[0118] R.sub.510 is independently selected from --H, -alkyl,
-halogen, -amino, --CF.sub.3, --R.sub.200, and -phenyl;
[0119] R.sub.515 is independently selected from --H, -alkyl, and
-phenyl;
[0120] R.sub.520 is independently selected from --H, -alkyl,
--(CH.sub.2).sub.0-2-phenyl, and --C(Ph).sub.3;
[0121] R.sub.600 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
R.sub.605;
[0122] R.sub.605 is selected from -hydrogen, -halogen, -alkyl,
-phenyl, alkyl-O--C(O)--, -nitro, --CN, -amino,
--NR.sub.220R.sub.225, -thioalkyl, --CF.sub.3, --OH, --O-alkyl, and
-heterocycloalkyl;
[0123] R.sub.700 is aryl optionally substituted with at least one
R.sub.205;
[0124] R.sub.C is selected from
[0125] --(CH.sub.2).sub.03-cycloalkyl wherein the cycloalkyl is
optionally substituted with at least one group independently
selected from --R.sub.205 and --CO.sub.2-(alkyl),
[0126] -alkyl, optionally substituted with at least one group
independently selected from R.sub.205,
[0127] --(CR.sub.245R.sub.250).sub.0-4--R.sub.X, wherein at least
one --(CR.sub.245R.sub.250)-- is optionally replaced with a group
independently selected from --O--, --N(R.sub.215)--,
--C(O).sub.1-2--, --C(O)N(R.sub.215)-- and --S(O).sub.0-2--,
and
[0128] -formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and
(IVg);
[0129] R.sub.X is selected from -hydrogen, -aryl, -heteroaryl,
-cycloalkyl, -heterocycloalkyl, and --R.sub.Xa--R.sub.Xb, wherein
R.sub.Xa and R.sub.Xb are independently selected from aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl;
[0130] wherein each aryl or heteroaryl group attached directly or
indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is optionally
substituted with at least one group independently selected from
R.sub.200;
[0131] wherein each cycloalkyl or heterocycloalkyl group attached
directly or indirectly to --(CR.sub.245R.sub.250).sub.0-4-- is
optionally substituted with at least one group independently
selected from R.sub.210 and
--(CR.sub.245R.sub.250).sub.0-4--R.sub.200;
[0132] wherein at least one atom of the heteroaryl or
heterocycloalkyl group attached directly or indirectly to
--(CR.sub.245R.sub.250).sub.0-4-- - is independently optionally
replaced with a group selected from --O--, --C(O)--,
--N(R.sub.215).sub.0-1--, and --S(O).sub.0-2--;
[0133] wherein at least one heteroatom of the heteroaryl or
heterocycloalkyl group attached directly or indirectly to
--(CR.sub.245R.sub.250).sub.0-4-- is independently optionally
substituted with a group selected from --(CO).sub.0-1R.sub.215,
--(CO).sub.0-1R.sub.220, --S(O).sub.0-2R.sub.200, and
--N(R.sub.200)--S(O).sub.0-2R.sub.200;
[0134] R.sub.245 and R.sub.250 at each occurrence are independently
selected from --H, --(CH.sub.2).sub.0-4C(O)--OH,
--(CH.sub.2).sub.0-4C(O)- --O-alkyl,
--(CH.sub.2).sub.0-4C(O)-alkyl, -alkyl, -hydroxyalkyl, --O-alkyl;
-haloalkoxy; --(CH.sub.2).sub.0-4-cycloalkyl,
--(CH.sub.2).sub.0-4-aryl, --(CH.sub.2).sub.0-4-heteroaryl, and
--(CH.sub.2).sub.0-4-heterocycloalkyl; or
[0135] R.sub.245 and R.sub.250 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).sub.0-2--, --C(.dbd.N--R.sub.255)--, --N--, --NR.sub.220--,
--N((CO).sub.0-1R.sub.200)--, and --N(SO.sub.2R.sub.200)-- -;
[0136] wherein the aryl, heteroaryl, and heterocycloalkyl groups
included in R.sub.245 and R.sub.250 are optionally substituted with
at least one group independently selected from -halogen, -alkyl,
--N(R.sub.220)(R.sub.225), --CN, and --OH;
[0137] wherein the monocyclic and bicyclic groups included in
R.sub.245 and R.sub.250 are optionally substituted with at least
one group independently selected from halogen,
--(CH.sub.2).sub.0-2--OH, --O-alkyl, alkyl,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3, aryl,
--N(R.sub.220)(R.sub.225), --CN, --(CH.sub.2).sub.0-2--NH.sub.2,
--(CH.sub.2).sub.0-2--NH(alkyl), --NHOH, --NH--O-alkyl,
--N(alkyl)(alkyl), --NH-heteroaryl, --NH--C(O)-alkyl, and
--NHS(O.sub.2)-alkyl;
[0138] formula (IVa) is 6
[0139] wherein
[0140] Q.sub.1 is selected from (--CH.sub.2--).sub.0-1,
--CH(R.sub.200)--, --C(R.sub.200).sub.2--, and --C(O)--;
[0141] Q.sub.2 and Q.sub.3 each are independently selected from
(--CH.sub.2--).sub.0-1, --CH(R.sub.200)--, --C(R.sub.200).sub.2--,
--O--, --C(O)--, --S--, --S(O).sub.2--, --NH--, and
--N(R.sub.7)--;
[0142] Q.sub.4 is selected from a bond, (--CH.sub.2--).sub.0-1,
--CH(R.sub.200)--, --C(R.sub.200).sub.2--, --O--, --C(O)--, --S--,
--S(O).sub.2--, --NH--, and --N(R.sub.7)--; and
[0143] P.sub.1, P.sub.2, P.sub.3, and P.sub.4 each are
independently selected from --CH--, --C(R.sub.200)--, and
--N--;
[0144] formula (IVb) is 7
[0145] wherein
[0146] R.sub.4 is selected from --H and -alkyl; and
[0147] P.sub.1, P.sub.2, P.sub.3, and P.sub.4 at each occurrence
are independently selected from --CH--, --C(R.sub.200)--, and
--N--;
[0148] formula (IVc) is 8
[0149] wherein R.sub.4 is selected from --H and -alkyl; and
[0150] P.sub.1, P.sub.2, P.sub.3, and P.sub.4 at each occurrence
are independently selected from --CH--, --CR.sub.200--, and
--N--;
[0151] formula (IVd) is 9
[0152] wherein m is 0, 1, 2, 3, 4, 5, or 6;
[0153] Y' is selected from --H, --CN, --OH, --O-alkyl, --CO.sub.2H,
--C(O)OR.sub.215, -amino, -aryl, and -heteroaryl; and
[0154] P.sub.1 and P.sub.2 at each occurrence are independently
selected from --CH--, --C(R.sub.200)--, and --N--,
[0155] or P.sub.1 and P.sub.2 are optionally taken together to form
a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10
carbon atoms,
[0156] P.sub.3 and P.sub.4 at each occurrence are independently
selected from --CH--, --C(R.sub.200)--, and --N--,
[0157] or P.sub.3 and P.sub.4 are optionally taken together to form
a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10
carbon atoms,
[0158] P.sub.5 at each occurrence is independently selected from
--CH--, --C(R.sub.200)--, and --N--,
[0159] wherein at least one bond in the monocyclic or bicyclic ring
system included in P.sub.1 and P.sub.2 or P.sub.3 and P.sub.4 is
optionally a double bond,
[0160] wherein the bicyclic ring system included in P.sub.1 and
P.sub.2 or P.sub.3 and P.sub.4 is optionally a fused or spiro ring
system,
[0161] wherein at least one carbon atom in the monocyclic or
bicyclic ring system included in P.sub.1 and P.sub.2 or P.sub.3 and
P.sub.4 is optionally replaced by a group independently selected
from
[0162] --O--,
[0163] --C(O)--,
[0164] --S(O).sub.0-2--,
[0165] --C(.dbd.N--R.sub.255)--,
[0166] --N--,
[0167] --NR.sub.220--,
[0168] --N((CO).sub.0-1R.sub.200)--, and
[0169] --N(SO.sub.2R.sub.200)--;
[0170] formula (IVe) is 10
[0171] wherein
[0172] U is selected from --CH.sub.2--CR.sub.100R.sub.101--,
--CH.sub.2--S--, --CH.sub.2--S(O)--, --CH.sub.2--S(O).sub.2--,
--CH.sub.2--N(R.sub.100)--, --CH.sub.2--C(O)--, --CH.sub.2--O--,
--C(O)--C(R.sub.100)(R.sub.101)--, --SO.sub.2--N(R.sub.100)--,
--C(O)--N(R.sub.55)--, --N(R.sub.55)--C(O)--N(R.sub.55)--,
--O--C(O)--O--, --N(R.sub.55)--C(O)--O--, and --C(O)--O--;
[0173] wherein R.sub.100 and R.sub.100 at each occurrence are
independently selected from --H, -alkyl, -aryl, --C(O)-alkyl,
--(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220, and
--S(O).sub.2-alkyl;
[0174] formula (IVf) is 11
[0175] wherein the B ring is optionally substituted with at least
one group independently selected from -alkyl, -halogen, --OH, --SH,
--CN, --CF.sub.3, --O-alkyl, --N(R.sub.5)C(O)H, --C(O)H,
--C(O)N(R.sub.5)(R.sub.6), --NR.sub.5R.sub.6, --R.sub.280,
--R.sub.285, -aryl, and -heteroaryl;
[0176] wherein R.sub.280 and R.sub.285, and the carbon to which
they are attached form a C.sub.3-C.sub.7 spirocycle which is
optionally substituted with at least one group independently
selected from -alkyl, --O-alkyl, -halogen, --CF.sub.3, and
--CN;
[0177] wherein the A ring is aryl or heteroaryl, each optionally
substituted with at least one group independently selected from
R.sub.290 and R.sub.295;
[0178] wherein R.sub.290 and R.sub.295 at each occurrence are
independently selected from -alkyl (optionally substituted with at
least one group independently selected from -alkyl, -halogen, --OH,
--SH, --CN, --CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6), --OH,
--NO.sub.2, -halogen, --CO.sub.2H, --CN,
--(CH.sub.2).sub.0-4--C(O)--NR.sub.21R.sub.2- 2,
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.20,
--(CH.sub.2).sub.0-4--SO.sub.2-- -NR.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--S(O)-(alkyl),
--(CH.sub.2).sub.0-4--S(O).sub.2-(alkyl),
--(CH.sub.2).sub.0-4--S(O).sub.- 2-(cycloalkyl),
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--C(O)--O-R.sub.20,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--C(O)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--N--C(S)--N(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--N- (H or R.sub.20)--CO--R.sub.21,
--(CH.sub.2).sub.0-4--NR.sub.21R.sub.22,
--(CH.sub.2).sub.0-4--R.sub.11,
--(CH.sub.2).sub.0-4--O--C(O)-(alkyl),
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.5).sub.2,
--(CH.sub.2).sub.0-4--O-- -C(O)--N (R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O--C(S)--N(R.sub.20).sub.- 2,
--(CH.sub.2).sub.0-4--O--(R.sub.20).sub.2,
--(CH.sub.2).sub.0-4--O--(R.- sub.20)--CO.sub.2H,
--(CH.sub.2).sub.0-4--S--(R.sub.20), --(CH.sub.2).sub.0-4--O-(alkyl
optionally substituted with at least one halogen), -cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.20)--S(O).sub.2--R.sub.21, and
--(CH.sub.2).sub.0-4-cycloalkyl;
[0179] formula (IVg) is 12
[0180] wherein
[0181] a is 0 or 1;
[0182] b is 0 or 1;
[0183] S' is selected from --C(O)-- and --CO.sub.2--;
[0184] T' is --(CH.sub.2).sub.0-4--;
[0185] U' is --(CR.sub.245R.sub.250)--;
[0186] V' is selected from -aryl- and -heteroaryl-;
[0187] W' is selected from a bond, -alkyl-(optionally substituted
with at least one group independently selected from R.sub.205),
--(CH.sub.2).sub.0-4--(CO).sub.0-1--N(R.sub.220)--,
--(CH.sub.2).sub.0-4--(CO).sub.0-1--,
--(CH.sub.2).sub.0-4--CO.sub.2--,
--(CH.sub.2).sub.0-4--SO.sub.2--N(R.sub.220)--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO.sub.2--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--SO.sub.2--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--N(R.sub.215)--,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--,
--(CH.sub.2).sub.0-4--N(R.sub.220)--, --(CH.sub.2).sub.0-4--O--,
and --(CH.sub.2).sub.0-4--S--;
[0188] X' is selected from aryl and heteroaryl;
[0189] wherein each cycloalkyl included in formula (IVg) is
optionally substituted with at least one group independently
selected from R.sub.205;
[0190] wherein each aryl or heteroaryl group included in formula
(IVg) is optionally substituted with at least one group
independently selected from R.sub.200;
[0191] wherein at least one heteroatom of the heteroaryl group
included in formula (IVg) is optionally substituted with a group
selected from --(CO).sub.0-1R.sub.215, --(CO).sub.0-1R.sub.220, and
--S(O).sub.0-2R.sub.200;
[0192] R.sub.21 and R.sub.22 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), --R.sub.17,
and --R.sub.18), --(CH.sub.2).sub.0-4--C(O)-(alkyl),
--(CH.sub.2).sub.0-4--C(O)-(cycloalky- l),
--(CH.sub.2).sub.0-4--C(O)--R.sub.17,
--(CH.sub.2).sub.0-4--C(O)--R.su- b.18,
--(CH.sub.2).sub.0-4--C(O)--R.sub.19, and
--(CH.sub.2).sub.0-4--C(O)- --R.sub.11;
[0193] R.sub.17 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, --NR.sub.5R.sub.6,
--CN, --CF.sub.3, and --O-alkyl), -halogen, --O-alkyl (optionally
substituted with at least one group independently selected from
halogen, --NR.sub.21R.sub.22, --OH, and --CN), cycloalkyl
(optionally substituted with at least one group independently
selected from halogen, --OH, --SH, --CN, --CF.sub.3, --O-alkyl, and
--NR.sub.5R.sub.6), --C(O)-(alkyl), --S(O).sub.2--NR.sub.5R.sub.6,
--C(O)--NR.sub.5R.sub.6, and --S(O).sub.2-(alkyl);
[0194] R.sub.18 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,
--CF.sub.3, --O-alkyl, and --NR.sub.5R.sub.6), halogen, --O-alkyl
(optionally substituted with at least one group independently
selected from -halogen, --NR.sub.21R.sub.22, --OH, and --CN),
-cycloalkyl (optionally substituted with at least one group
independently selected from -halogen, --OH, --SH, --CN, CF.sub.3,
--O-alkyl, and --NR.sub.5R.sub.6), --C(O)-(alkyl),
--S(O).sub.2--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl);
[0195] R.sub.19 at each occurrence is heterocycloalkyl wherein at
least one carbon is optionally replaced with --C(O)--, --S(O)--,
and --S(O).sub.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, --CF.sub.3,
--O-alkyl, and --NR.sub.5R.sub.6), -halogen, --O-alkyl (optionally
substituted with at least one group independently selected from
-halogen, --OH, --CN, --NR.sub.21R.sub.22, and -cycloalkyl
optionally substituted with at least one group independently
selected from -halogen, --OH, --SH, --CN, --CF.sub.3, --O-alkyl,
and --NR.sub.5R.sub.6), --C(O)-(alkyl),
--S(O).sub.2--NR.sub.5R.sub.6, --C(O)--NR.sub.5R.sub.6, and
--S(O).sub.2-(alkyl);
[0196] R.sub.11 at each occurrence is heterocycloalkyl
[0197] wherein at least one carbon of the heterocycloalkyl is
optionally replaced with --C(O)--, --S(O)--, and
--S(O).sub.2--,
[0198] wherein the heterocycloalkyl is optionally substituted with
at least one group independently selected from -alkyl, --O-alkyl,
and -halogen;
[0199] R.sub.20 is selected from -alkyl, -cycloalkyl,
--(CH.sub.2).sub.0-2--(R.sub.17), and
--(CH.sub.2).sub.0-2--(R.sub.18);
[0200] R.sub.200 at each occurrence is independently selected from
-alkyl (optionally substituted with at least one group
independently selected from R.sub.205), --OH, --NO.sub.2,
--NH.sub.2, -halogen, --CN, --CF.sub.3, --OCF.sub.3,
--(CH.sub.2).sub.0-4--C(O)H, --(CO).sub.0-1R.sub.215,
--(CO).sub.0-1R.sub.220, (CH.sub.2).sub.0-4--C(O-
)--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1--R.sub.215,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1--R.sub.220,
(CH.sub.2).sub.0-4--C(O)- -alkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-cycloalkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-heterocycloalkyl,
--(CH.sub.2).sub.0-4--(C(O)).sub.0-1-aryl,
--(CH.sub.2).sub.0-4--(C(O)).s- ub.0-1-heteroaryl,
(CH.sub.2).sub.0-4--C(O)--O--R.sub.215,
--(CH.sub.2).sub.0-4--S(O).sub.0-2--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--S(O).sub.0-2-alkyl,
(CH.sub.2).sub.0-4--S(O).sub.0-- 2-cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--O--R.sub.215,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--S(O).sub.1-2--R.sub.220,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--C(O)--R.sub.220,
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--O--C(O)-- alkyl,
(CH.sub.2).sub.0-4--O--(R.sub.215),
--(CH.sub.2).sub.0-4--S--(R.sub- .215),
--(CH.sub.2).sub.0-4--C(O)H, --(CH.sub.2).sub.0-4--O-alkyl
optionally substituted with at least one halogen, and
-adamantane,
[0201] wherein each aryl and heteroaryl group included within
R.sub.200 is optionally substituted with at least one group
independently selected from --R.sub.205, --R.sub.210, and -alkyl
optionally substituted with at least one group independently
selected from R.sub.205 and R.sub.210;
[0202] wherein each cycloalkyl or heterocycloalkyl group included
within R.sub.200 is optionally substituted with at least one group
independently selected from --R.sub.205, --R.sub.210, and -alkyl
optionally substituted with at least one group independently
selected from R.sub.205 and R.sub.210;
[0203] R.sub.205 at each occurrence is independently selected from
-alkyl, -heteroaryl, -heterocycloalkyl, -aryl, haloalkoxy,
--(CH.sub.2).sub.0-3-cycloalkyl, -halogen,
--(CH.sub.2).sub.0-6--OH, --O-phenyl, --SH,
--(CH.sub.2).sub.0-4--C(O)CH.sub.3, --(CH.sub.2).sub.0-4--C(O)H,
--(CH.sub.2).sub.0-4--CO.sub.2H, --(CH.sub.2).sub.0-6--CN,
--(CH.sub.2).sub.0-6--C(O)--NR.sub.235R.sub.240- ,
--(CH.sub.2).sub.0-6--C(O)--
[0204] R.sub.235, --(CH.sub.2).sub.0-4--N(H or
R.sub.215)--SO.sub.2--R.sub- .235, --CF.sub.3, --CN, --OCF.sub.3,
--C(O).sub.2-benzyl, --O-alkyl, --C(O).sub.2-alkyl, and
--NR.sub.235R.sub.240;
[0205] R.sub.210 at each occurrence is independently selected from
--OH, --CN, --(CH.sub.2).sub.0-4--C(O)H, -alkyl (wherein a carbon
atom is optionally replaced with --C(O)--, and wherein a carbon
atom is optionally substituted with at least one group
independently selected from R.sub.205), --S-alkyl, -halogen,
--O-alkyl, -haloalkoxy, --NR.sub.220R.sub.225, -cycloalkyl
(optionally substituted with at least one group independently
selected from R.sub.205), --C(O)-alkyl,
--S(O).sub.2--NR.sub.235R.sub.240, --C(O)--NR.sub.235R.sub.240, and
--S(O).sub.2-alkyl;
[0206] R.sub.215 at each occurrence is independently selected from
-alkyl, --(CH.sub.2).sub.0-2-aryl, --(CH.sub.2).sub.0-2-cycloalkyl,
--(CH.sub.2).sub.0-2-heteroaryl, and
--(CH.sub.2).sub.0-2-heterocycloalky- l,
[0207] wherein the aryl groups included within R.sub.215 are
optionally substituted with at least one group independently
selected from R.sub.205 and R.sub.210,
[0208] wherein the heterocycloalkyl and heteroaryl groups included
within R.sub.215 are optionally substituted with at least one group
independently selected from R.sub.210;
[0209] R.sub.220 and R.sub.225 at each occurrence are independently
selected from --H, --OH, -alkyl, --(CH.sub.2).sub.0-4--C(O)H,
--(CH.sub.2).sub.0-4--C(O)CH.sub.3, -alkyl-OH,
--(CH.sub.2).sub.0-4--CO.s- ub.2-alkyl, (wherein alkyl is
optionally substituted with at least one group independently
selected from R.sub.205), -aminoalkyl, --S(O).sub.2-alkyl,
--(CH.sub.2).sub.0-4--C(O)-alkyl, (wherein alkyl is optionally
substituted with at least one group independently selected from
R.sub.205), --(CH.sub.2).sub.0-4--C(O)--NH.sub.2,
--(CH.sub.2).sub.0-4--C(O)--NH(alkyl), (wherein alkyl is optionally
substituted with at least one group independently selected from
R.sub.205), --(CH.sub.2).sub.0-4--C(O)--N(alkyl)(alkyl),
-haloalkyl, --(CH.sub.2).sub.0-2-cycloalkyl, -alkyl--O-alkyl,
-O-alkyl, -aryl, -heteroaryl, and -heterocycloalkyl,
[0210] wherein the aryl, heteroaryl and heterocycloalkyl groups
included within R.sub.220 and R.sub.225 are each optionally
substituted with at least one group independently selected from
R.sub.270;
[0211] R.sub.270 at each occurrence is independently selected from
--R.sub.205, -alkyl (optionally substituted with at least one group
independently selected from R.sub.205), -phenyl, -halogen,
--O-alkyl, -haloalkoxy, --NR.sub.235R.sub.240, --OH, --CN,
-cycloalkyl (optionally substituted with at least one group
independently selected from R.sub.205), --C(O)-alkyl,
--S(O).sub.2--NR.sub.235R.sub.240, --CO--NR.sub.235R.sub.240,
--S(O).sub.2-alkyl, and -(CH.sub.2).sub.0-4--C(O)H;
[0212] R.sub.235 and R.sub.240 at each occurrence are independently
selected from --H, -alkyl, --C(O)-alkyl, --OH, --CF.sub.3,
--OCH.sub.3, --NH--CH.sub.3, --N(CH.sub.3).sub.2,
--(CH.sub.2).sub.0-4--C(O)--(H or alkyl), --SO.sub.2-alkyl, and
-phenyl;
[0213] R.sub.255 is selected from -hydrogen, --OH,
--N(R.sub.220)(R.sub.22- 5), and --O-alkyl;
[0214] R.sub.5 and R.sub.6 are independently selected from --H and
-alkyl, or
[0215] R.sub.5 and R.sub.6, and the nitrogen to which they are
attached, form a 5 or 6 membered heterocycloalkyl ring; and
[0216] R.sub.7 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.
[0217] Exemplary R.sub.600 substituents of monocyclic, bicyclic, or
tricyclic heteroaryls include
Benzo[4,5]thieno[3,2-d]pyrimidin-4-yl,
4,6-Diamino-[1,3,5]triazin-2-yl, 3-nitro-pyridin-2-yl,
5-trifluoromethyl-pyridin-2-yl, 8-trifluoromethyl-quinolin-4-yl,
4-trifluoromethyl-pyrimidin-2-yl, 2-phenyl-quinazolin-4-yl,
6-Chloro-pyrazin-2-yl, pyrimidin-2-yl, quinolin-2-yl,
3-Chloro-pyrazin-2-yl, 6-Chloro-2,5-diphenyl-pyrimidin-4-yl,
3-Chloro-quinoxalin-2-yl, 5-ethyl-pyrimidin-2-yl,
6-Chloro-2-methylsulfan- yl-5-phenyl-pyrimidin-4-yl, quinolin-4-yl,
3-ethoxycarbonyl-pyridin-2yl, 5-Cyano-pyridin-2-yl,
2-phenyl-quinolin-4-yl, 7H-purin-6-yl, 3-Cyano-pyridin-2-yl,
4,6-dimethoxy-[1,3,5]triazin-2-yl, 3-Cyano-pyrazin-2-yl,
9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl, 2-Chloro-7H-purin-6-yl,
2-Amino-6-Chloro-pyrimidin-4-yl, 2-Chloro-6-methyl-pyrimidin-4-yl,
2-Amino-6-methyl-pyrimidin-4-yl, 4-Chloro-pyrimidin-2-yl,
2-Amino-7H-purin-6-yl, and 4-trifluoromethyl-pyrimidin-2-yl, and
the like.
[0218] Exemplary R.sub.2 substituents include
3-Allyl-5-benzyl-2-oxo-imida- zolidin-1-yl,
6-Benzyl-3,3-dimethyl-2-oxo-piperazin-1-yl,
3-Allyl-5-benzyl-2-oxo-pyrrolidin-1-yl,
5-Benzyl-3-isobutyl-2-oxo-imidazo- lidin-1-yl,
3-Benzyl-5-methyl-1,1-dioxo-1.lambda..sup.6-[1,2,5]thiadiazoli-
din-2-yl, 3-Benzyl-1,1-dioxo-1.lambda..sup.6-isothiazolidin-2-yl,
2-Benzyl-5-oxo-pyrrolidin-1-yl,
5-Benzyl-3-ethyl-2-oxo-pyrrolidin-1-yl,
3-Amino-5-benzyl-2-oxo-pyrrolidin-1-yl,
3-Acetylamino-5-benzyl-2-oxo-pyrr- olidin-1-yl,
5-Benzyl-3-[1,3]dioxolan-4-ylmethyl-2-oxo-pyrrolidin-1-yl,
3-Benzyl-5-oxo-morpholin-4-yl, 2-Benzyl-6-oxo-piperazin-1-yl,
8-Benzyl-6-methyl-10-oxo-6,9-diaza-spiro[4.5]dec-9-yl,
5-Benzyl-3-furan-2-ylmethylene-2-oxo-pyrrolidin-1-yl,
3-acetylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl,
3-acetylamino-3-(cyclopropylmethyl)-2-oxo-pyrrolidin-1-yl,
3-(2-amino-5-carboxypentanoylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl,
3-(2-methoxy-acetylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl,
3-ethoxycarbonylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl,
3-ethylureido-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, and
3-hydroxypropionylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl.
[0219] In another embodiment, compounds of formula (I) are used to
prevent or treat conditions associated with amyloidosis, wherein
R.sub.C, R.sub.1, and R.sub.2 are defined herein, excluding the
combinations wherein, R.sub.C is 3-methoxy-benzyl, R.sub.1, is
3,5-difluorobenzyl, and R.sub.2 is
4,6-Diamino-[1,3,5]triazin-2-ylamino, 3-nitro-pyridin-2-ylamin- o,
5-trifluoromethyl-pyridin-2-ylamino,
8-trifluoromethyl-quinolin-4-ylami- no,
4-trifluoromethyl-pyrimidin-2-ylamino,
2-phenyl-quinazolin-4-ylamino, 6-Chloro-pyrazin-2-ylamino,
pyrimidin-2-ylamino, quinolin-2-ylamino,
3-Chloro-pyrazin-2-ylamino,
6-Chloro-2,5-diphenyl-pyrimidin-4-ylamino,
3-Chloro-quinoxalin-2-ylamino, 5-ethyl-pyrimidin-2-ylamino,
6-Chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-ylamino,
quinolin-4-ylamino, 3-ethoxycarbonyl-pyridin-2ylamino,
5-Cyano-pyridin-2-ylamino, 2-phenyl-quinolin-4-ylamino,
7H-purin-6-ylamino, 3-Cyano-pyridin-2-ylamino,
4,6-dimethoxy-[1,3,5]triaz- in-2-ylamino,
3-Cyano-pyrazin-2-ylamino, 9-(tetrahydro-pyran-2-yl)-9H-puri-
n-6-ylamino, 2-Chloro-7H-purin-6-ylamino,
2-Amino-6-Chloro-pyrimidin-4-yla- mino,
2-Chloro-6-methyl-pyrimidin-4-ylamino,
2-Amino-6-methyl-pyrimidin-4-- ylamino,
4-Chloro-pyrimidin-2-ylamino, 2-Amino-7H-purin-6-ylamino, and the
like.
[0220] In another embodiment, compounds of formula (I) are used to
prevent or treat conditions associated with amyloidosis, wherein
R.sub.C, R.sub.1, and R.sub.2 are defined herein, excluding the
combinations wherein R.sub.C is
6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl, R.sub.1, is
3,5-difluorobenzyl, and R.sub.2 is 4-trifluoromethyl-pyrimidi-
n-2-ylamino.
[0221] In another embodiment, R.sub.1 is selected from
--CH.sub.2-phenyl, wherein the phenyl ring is optionally
substituted with at least one group independently selected from
-halogen, --C.sub.1-C.sub.2 alkyl, --O-methyl, and --OH.
[0222] In another embodiment, R.sub.1 is selected from
4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-Chloro-thiophen-2-yl-methyl,
5-Chloro-3-ethyl-thiophe- n-2-yl-methyl,
3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl,
2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl,
5-hydroxy-6-oxo-6H-pyran-2-yl-methyl,
3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl,
3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl- , and
3-fluoro-benzyl.
[0223] In another embodiment, R.sub.C is
--C(R.sub.245)(R.sub.250)--R.sub.- X, wherein R.sub.245 and
R.sub.250 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, and 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).sub.0-2--,
--C(.dbd.N--R.sub.255)--, --N--, --NR.sub.220--,
--N((CO).sub.0-1R.sub.200)--, and --N(SO.sub.2R.sub.200)-- -; and
wherein the monocyclic or bicyclic groups included within R.sub.245
and R.sub.250 are optionally substituted with at least one group
independently selected from halogen, --(CH.sub.2).sub.0-2--OH,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3,--O-alkyl, alkyl, aryl,
--N(R.sub.220)(R.sub.225), --CN, --(CH.sub.2).sub.0-2--NH.sub.2,
--(CH.sub.2).sub.0-2--NH(alkyl), --NHOH, --NH--O-alkyl,
--N(alkyl)(alkyl), --NH-heteroaryl, --NH--C(O)-alkyl, and
--NHS(O.sub.0-2)-alkyl.
[0224] In another embodiment, R.sub.C is selected from formulae
(Va), (Vb), (Vc), and (Vd), 13
[0225] wherein
[0226] A, B, and C are independently selected from --CH.sub.2--,
--O--, --C(O)--, --S(O).sub.0-2--, --N((CO).sub.0-1R.sub.200)--,
--N(SO.sub.2R.sub.200)--, --C(.dbd.N--R.sub.255)--, and
--N(R.sub.220)--;
[0227] A' at each occurence is independently selected from
--CH.sub.2-- and --O--;
[0228] wherein (Va), (Vb), (Vc), and (Vd) are each optionally
substituted with at least one group independently selected from
-alkyl, --O-alkyl, --(CH.sub.2).sub.0-2--OH,
--(CH.sub.2).sub.0-2--S-alkyl, --CF.sub.3, --CN, -halogen,
--(CH.sub.2).sub.0-2--NH.sub.2, --(CH.sub.2).sub.0-2--NH(- alkyl),
--NHOH, --NH--O-alkyl, --N(alkyl)(alkyl), --NH-heteroaryl,
--NH--C(O)-alkyl, and --NHS(O.sub.2)-alkyl.
[0229] In another embodiment, R.sub.C is selected from formulae
(VIa) and (VIb), 14
[0230] wherein at least one carbon of the heterocycloalkyl of
formula (VIa) and the cycloalkyl of formula (VIb) is optionally
replaced with a group independently selected from --O--,
--SO.sub.2--, and --C(O)--, wherein at least one carbon of the
heterocycloalkyl or cycloalkyl is optionally substituted with at
least one group independently selected from R.sub.205, R.sub.245,
and R.sub.250, wherein R.sub.100, R.sub.200, R.sub.205, R.sub.245,
and R.sub.250 are as defined herein.
[0231] In another embodiment, R.sub.C is selected from
6-isobutyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-yl,
6-Isopropyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl,
6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-yl,
7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl,
1-(3-tert-Butyl-phenyl)-cyclo- hexyl, and 3-methoxy-benzyl.
[0232] In another embodiment, R.sub.2 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]th- iadiazol-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-ylami- no,
3,4-dioxo-cyclobut-1-enylamino,
2-methoxy-3,4-dioxo-cyclobut-1-enylami- no, and
2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
[0233] In another embodiment, R.sub.X 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)-]cyc- lohexylamino,
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.
[0234] In another embodiment, the present invention encompasses
compounds of formula (I) wherein the hydroxyl substituent alpha to
the --(CHR.sub.1)-- group, as shown in formula (I), may optionally
be replaced by --NH.sub.2, --NH(R.sub.800),
--N(R.sub.800)(R.sub.800), --SH, and --SR.sub.800, wherein
--R.sub.800 is alkyl optionally substituted with at least one group
independently selected from R.sub.200, R.sub.205, R.sub.210,
R.sub.215, R.sub.220, and R.sub.225.
[0235] The present invention encompasses methods of treatment using
compounds with structural characteristics designed for interacting
with their target molecules. Such characteristics include at least
one moiety capable of interacting with at least one subsite of
beta-secretase. Such characteristics also include at least one
moiety capable of enhancing the interaction between the target and
at least one subsite of beta-secretase.
[0236] It is preferred that the compounds of formula (I) are
efficacious. For example, it is preferred that the compounds of
formula (I) decrease the level of beta-secretase using low dosages
of the compounds. Preferably, the compounds of formula (I) decrease
the level of A-beta by at least 10% using dosages of 100 mg/kg. It
is more preferred that the compounds of formula (I) decrease the
level of A-beta by at least 10% using dosages of less than 100
mg/kg. It is also more preferred that the compounds of formula (I)
decrease the level of A-beta by greater than 10% using dosages of
100 mg/kg. It is most preferred that the compounds of formula (I)
decrease the level of A-beta by greater than 10% using dosages of
less than 100 mg/kg.
[0237] Another embodiment of the present invention is to provide
methods of preventing or treating conditions associated with
amyloidosis using compounds with increased oral bioavailability
(increased F values).
[0238] Accordingly, an embodiment of the present invention is also
directed to methods for preventing or treating conditions
associated with amyloidosis, comprising administering to a host a
therapeutically effective amount of at least one compound of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sub.1, R.sub.2, and R.sub.C are as previously defined, and
wherein the compound has an F value of at least 10%.
[0239] Investigation of potential beta-secretase inhibitors
produced compounds with increased selectivity for beta-secretase
over other aspartyl proteases such as cathepsin, D (catD),
cathepsin E (catE), HIV protease, and renin. Selectivity was
calculated as a ratio of inhibition (IC50) values in which the
inhibition of beta-secretase was compared to the inhibition of
other aspartyl proteases. A compound is selective when the IC50
value (i.e., concentration required for 50% inhibition) of a
desired target (e.g., beta-secretase) is less than the IC50 value
of a secondary target (e.g., catD). Alternatively, a compound is
selective when its binding affinity is greater for its desired
target (e.g., beta-secretase) versus a secondary target (e.g.,
catD). Accordingly, methods of treatment include administering
selective compounds of formula (I) having a lower IC50 value for
inhibiting beta-secretase, or greater binding affinity for
beta-secretase, than for other aspartyl proteases such as catD,
catE, HIV protease, or renin. A selective compound is also capable
of producing a higher ratio of desired effects to adverse effects,
resulting in a safer method of treatment.
[0240] In an embodiment, the host is a cell.
[0241] In another embodiment, the host is an animal.
[0242] In another embodiment, the host is human.
[0243] In another embodiment, at least one compound of formula (I)
is administered in combination with a pharmaceutically acceptable
carrier or diluent.
[0244] In another embodiment, the pharmaceutical compositions
comprising compounds of formula (I) can be used to treat a wide
variety of disorders or conditions including 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 including dementias of mixed vascular
and degenerative origin, 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).
[0245] In another embodiment, the condition is Alzheimer's
disease.
[0246] In another embodiment, the condition is dementia.
[0247] When treating or preventing these diseases, the methods of
the present invention can either employ the compounds of formula
(I) individually or in combination, as is best for the patient.
[0248] In treating a patient displaying any of the conditions
discussed above, a physician may employ a compound of formula (I)
immediately and continue administration indefinitely, as needed. In
treating patients who are not diagnosed as having Alzheimer's
disease, but who are believed to be at substantial risk for it, the
physician may start treatment when the patient first experiences
early pre-Alzheimer's symptoms, such as memory or cognitive
problems associated with aging. In addition, there are some
patients who may be determined to be at risk for developing
Alzheimer's disease through the detection of a genetic marker such
as APOE4 or other biological indicators that are predictive for
Alzheimer's disease and related conditions.
[0249] In these situations, even though the patient does not have
symptoms of the disease or condition, administration of the
compounds of formula (I) may be started before symptoms appear, and
treatment may be continued indefinitely to prevent or delay the
onset of the disease. Similar protocols are provided for other
diseases and conditions associated with amyloidosis, such as those
characterized by dementia.
[0250] In an embodiment, the methods of preventing or treating
conditions associated with amyloidosis, comprising administering to
a host a composition comprising a therapeutically effective amount
of at least one compound of formula (I), may include beta-secretase
complexed with at least one compound of formula (I), or a
pharmaceutically acceptable salt thereof.
[0251] An embodiment of the present invention is a method of
preventing or treating the onset of Alzheimer's disease comprising
administering to a patient a therapeutically effective amount of at
least one compound of formula (I), or a pharmaceutically acceptable
salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as
previously defined.
[0252] Another embodiment of the present invention is 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, wherein R.sub.1, R.sub.2, and R.sub.C are as
previously defined.
[0253] Another embodiment of the present invention is a method of
preventing or treating conditions associated with amyloidosis by
administering to a host an effective amount of at least one
compound of formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as previously
defined.
[0254] Another embodiment of the present invention is a method of
preventing or treating Alzheimer's Disease by administering to a
host an effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, and R.sub.C are as previously defined.
[0255] Another embodiment of the present invention is a method of
preventing or treating dementia by administering to a host an
effective amount of at least one compound of formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2,
and R.sub.C are as previously defined.
[0256] Another embodiment of the present invention is a method of
inhibiting beta-secretase activity in a cell. This method comprises
administering to the cell an effective amount of at least one
compound of formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as previously
defined.
[0257] Another embodiment of the present invention is, a method of
inhibiting beta-secretase activity in a host. This method comprises
administering to the host an effective amount of at least one
compound of formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as previously
defined.
[0258] Another embodiment of the present invention is a method of
inhibiting beta-secretase activity in a host. This method comprises
administering to the host an effective amount of at least one
compound of formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as previously
defined, and wherein the host is a human.
[0259] Another embodiment of the present invention is 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 R.sub.1, R.sub.2,
and R.sub.C are as previously defined.
[0260] Another embodiment of the present invention is 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 R.sub.1, R.sub.2, and R.sub.C are as previously
defined.
[0261] Another embodiment of the present invention is 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
R.sub.1, R.sub.2, and R.sub.C are as previously defined, and
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, or between Leu671 and Asp672 of
the APP-770 Swedish Mutation.
[0262] Another embodiment of the present invention is 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 R.sub.1, R.sub.2, and R.sub.C are as previously
defined.
[0263] Another embodiment of the present invention is 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 R.sub.1, R.sub.2, and R.sub.C are as previously
defined.
[0264] Another embodiment of the present invention is 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
R.sub.1, R.sub.2, and R.sub.C are as previously defined.
[0265] In another embodiment, the A-beta deposits or plaques are in
a human brain.
[0266] Another embodiment of the present invention is 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 salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are
as previously defined.
[0267] Another embodiment of the present invention is 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 to the patient, wherein
R.sub.1, R.sub.2, and R.sub.C are as previously defined.
[0268] In another embodiment, the at least one aspartyl protease is
beta-secretase.
[0269] Another embodiment of the present invention is 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 R.sub.1, R.sub.2,
and R.sub.C are as previously defined, and wherein the at least one
compound interacts with at least one beta-secretase subsite such as
S1, S1', or S2'.
[0270] Another embodiment of the present invention is a method of
selecting a compound of formula (I) wherein the pharmacokinetic
parameters are adjusted for an increase in desired effect (e.g.,
increased brain uptake).
[0271] Another embodiment of the present invention is a method of
selecting a compound of formula (I) wherein C.sub.max, T.sub.max,
and/or half-life are adjusted to provide for maximum efficacy.
[0272] Another embodiment of the present invention is a method of
treating a 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
R.sub.1, R.sub.2, and R.sub.C are as previously defined.
[0273] In another embodiment, the condition is Alzheimer's
disease.
[0274] In another embodiment, the condition is dementia.
[0275] In another embodiment of the present invention, the
compounds of formula (I) are administered in oral dosage form. The
oral dosage forms are generally administered to the patient 1, 2,
3, or 4 times daily. It is preferred that the compounds be
administered either three or fewer times daily, more preferably
once or twice daily. It is preferred that, whatever oral dosage
form is used, it be designed so as to protect the compounds from
the acidic environment of the stomach. Enteric coated tablets are
well known to those skilled in the art. In addition, capsules
filled with small spheres, each coated to be protected from the
acidic stomach, are also well known to those skilled in the
art.
[0276] Therapeutically effective amounts include, for example, oral
administration from about 0.1 mg/day to about 1,000 mg/day,
parenteral, sublingual, intranasal, intrathecal administration from
about 0.2 mg/day to about 100 mg/day, depot administration and
implants from about 0.5 mg/day to about 50 mg/day, topical
administration from about 0.5 mg/day to about 200 mg/day, and
rectal administration from about 0.5 mg/day to about 500
mg/day.
[0277] When administered orally, an administered amount
therapeutically effective to inhibit beta-secretase activity, to
inhibit A-beta production, to inhibit A-beta deposition, or to
treat or prevent Alzheimer's disease is from about 0.1 mg/day to
about 1,000 mg/day.
[0278] In various embodiments, the therapeutically effective amount
may be administered in, for example, pill, tablet, capsule, powder,
gel, or elixir form, and/or combinations thereof. It is understood
that, while a patient may be started at one dose or method of
administration, that dose or method of administration may be varied
over time as the patient's condition changes.
[0279] Another embodiment of the present invention is a method of
prescribing a medication for preventing, delaying, halting, or
reversing disorders, conditions or diseases associated with
amyloidosis. The method includes identifying in a patient symptoms
associated with disorders, conditions or diseases associated with
amyloidosis, and prescribing at least one dosage form of at least
one compound of formula (I), or a pharmaceutically acceptable salt,
to the patient, wherein R.sub.1, R.sub.2, and R.sub.C are as
previously defined.
[0280] Another embodiment of the present invention is an article of
manufacture, comprising (a) at least one dosage form of at least
one compound of formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as previously
defined, (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 disorders, conditions or diseases
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.
[0281] Another embodiment of the present invention is a packaged
pharmaceutical composition for treating conditions 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, and (b) instructions for
using the pharmaceutical composition.
[0282] Another embodiment of the present invention is 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 R.sub.1, R.sub.2,
and R.sub.C are as previously defined, (b) a package insert
providing an oral dosage form should be administered to a patient
in need of therapy for disorders, conditions or diseases associated
with amyloidosis, and (c) at least one container comprising at
least one oral dosage form of at least one compound of formula
(I).
[0283] Another embodiment of the present invention is an article of
manufacture, comprising (a) at least one oral dosage form of at
least one compound of formula (I), or a pharmaceutically acceptable
salt thereof, wherein R.sub.1, R.sub.2, and R.sub.C are as
previously defined, 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 disorders,
conditions or diseases 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.
[0284] Another embodiment of the present invention is an article of
manufacture, comprising (a) 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 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 disorders,
conditions 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.
[0285] Another embodiment of the present invention is an article of
manufacture, comprising (a) 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, 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 disorders, conditions or diseases 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.
[0286] Another embodiment of the present invention is an article of
manufacture comprising (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 disorders, conditions or diseases 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
a therapeutically active and/or inactive agent is stored.
[0287] In another embodiment, 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/or an
anti-A-beta antibody.
[0288] Another embodiment of the present invention is a method of
producing a beta-secretase complex comprising exposing
beta-secretase to a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in a reaction mixture under conditions
suitable for the production of the complex.
[0289] Another embodiment of the present invention is 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) to a pharmaceutically acceptable
carrier.
[0290] Another embodiment of the present invention provides a
method of selecting a beta-secretase inhibitor comprising targeting
at least one moiety of at least one formula (I) compound, or a
pharmaceutically acceptable salt thereof, to interact with at least
one beta-secretase subsite such as, but not limited to, S1, S1', or
S2'.
[0291] The methods of treatment described herein include
administering the compounds of formula (I) orally, parenterally
(via intravenous injection (IV), intramuscular injection (IM),
depo-IM, subcutaneous injection (SC or SQ), or depo-SQ),
sublingually, intranasally (inhalation), intrathecally, topically,
or rectally. Dosage forms known to those skilled in the art are
suitable for delivery of the compounds of formula (I).
[0292] In treating or preventing the above diseases, the compounds
of formula (I) are administered using a therapeutically effective
amount. The therapeutically effective amount will vary depending on
the particular compound used and the route of administration, as is
known to those skilled in the art.
[0293] The compositions are preferably formulated as suitable
pharmaceutical preparations, such as for example but not limited
to, pill, tablet, capsule, powder, gel, or elixir form, and/or
combinations thereof, for oral administration or in sterile
solutions or suspensions for parenteral administration. Typically
the compounds described above are formulated into pharmaceutical
compositions using techniques and/or procedures well known in the
art.
[0294] For example, a therapeutically effective amount of a
compound or mixture of compounds of formula (I), or a
physiologically acceptable salt is combined with a physiologically
acceptable vehicle, carrier, binder, preservative, stabilizer,
flavor, and the like, in a unit dosage form as called for by
accepted pharmaceutical practice, and as defined herein. The amount
of active substance in those compositions or preparations is such
that a suitable dosage in the range indicated is obtained. The
compound concentration is effective for delivery of an amount upon
administration that lessens or ameliorates at least one symptom of
the disorder for which the compound is administered. For example,
the compositions can be formulated in a unit dosage form, each
dosage containing from about 2 mg to about 1000 mg.
[0295] The active ingredient may be administered in a single dose,
or may be divided into a number of smaller doses to be administered
at intervals of time. It is understood that the precise dosage and
duration of treatment is a function of the disease or condition
being treated and may be determined empirically using known testing
protocols or by extrapolation from in vivo or in vitro test data.
It is to be noted that concentrations and dosage values may also
vary with the severity of the condition to be alleviated. It is
also to be understood that the precise dosage and treatment
regimens may be adjusted over time according to the individual need
and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
compositions. A dosage and/or treatment method for any particular
patient also may depend on, for example, the age, weight, sex,
diet, and/or health of the patient, the time of administration,
and/or any relevant drug combinations or interactions.
[0296] To prepare compositions to be employed in the methods of
treatment, at least one compound of formula (I) is mixed with a
suitable pharmaceutically acceptable carrier. Upon mixing or
addition of the compound(s), the resulting mixture may be a
solution, suspension, emulsion, or the like. Liposomal suspensions
may also be suitable as pharmaceutically acceptable carriers. These
may be prepared according to methods known to those skilled in the
art. The form of the resulting mixture depends upon a number of
factors, including the intended mode of administration and the
solubility of the compound in the selected carrier or vehicle. An
effective concentration is sufficient for lessening or ameliorating
at least one symptom of the disease, disorder, or condition treated
and may be empirically determined.
[0297] Pharmaceutical carriers or vehicles suitable for
administration of the compounds provided herein include any such
carriers known to those skilled in the art to be suitable for the
particular mode of administration. Additionally, the active
materials can also be mixed with other active materials that do not
impair the desired action, or with materials that supplement the
desired action, or have another action. For example, the compounds
of formula (I) may be formulated as the sole pharmaceutically
active ingredient in the composition or may be combined with other
active ingredients.
[0298] Where the compounds exhibit insufficient solubility, methods
for solubilizing may be used. Such methods are known and include,
for example, using co-solvents (such as dimethylsulfoxide), using
surfactants (such as Tween.RTM.), and/or dissolution in aqueous
sodium bicarbonate. Derivatives of the compounds, such as salts,
metabolites, and/or pro-drugs, may also be used in formulating
effective pharmaceutical compositions. Such derivatives may improve
the pharmacokinetic properties of treatment administered.
[0299] The compounds of formula (I) may be prepared with carriers
that protect them against rapid elimination from the body, such as
time-release formulations or coatings. Such carriers include
controlled release formulations, such as, for example,
microencapsulated delivery systems and the like. The active
compound is included in the pharmaceutically acceptable carrier in
an amount sufficient to exert a therapeutically useful effect in
the absence of undesirable side effects on the patient treated.
Alternatively, the active compound is included in an amount
sufficient to exert a therapeutically useful effect and/or minimize
the severity and form of undesirable side effects. The
therapeutically effective concentration may be determined
empirically by testing the compounds in known in vitro and/or in
vivo model systems for the treated disorder.
[0300] The tablets, pills, capsules, troches, and the like may
contain a binder (e.g., gum tragacanth, acacia, corn starch,
gelatin, and the like); a vehicle (e.g., microcrystalline
cellulose, starch, lactose, and the like); a disintegrating agent
(e.g., alginic acid, corn starch, and the like); a lubricant (e.g.,
magnesium stearate, and the like); a gildant (e.g., colloidal
silicon dioxide, and the like); a sweetening agent (e.g., sucrose,
saccharin, and the like); a flavoring agent (e.g., peppermint,
methyl salicylate, and the like) or fruit flavoring; compounds of a
similar nature, and/or mixtures thereof.
[0301] When the dosage unit form is a capsule, it can contain, in
addition to material described above, a liquid carrier such as a
fatty oil. Additionally, dosage unit forms can contain various
other materials, which modify the physical form of the dosage unit,
for example, coatings of sugar or other enteric agents. A method of
treatment can also administer the compound as a component of an
elixir, suspension, syrup, wafer, chewing gum or the like. A syrup
may contain, in addition to the active compounds, sucrose as a
sweetening agent, flavors, preservatives, dyes and/or
colorings.
[0302] The methods of treatment may employ at least one carrier
that protects the compound against rapid elimination from the body,
such as time-release formulations or coatings. Such carriers
include controlled release formulations, such as, for example,
implants or microencapsulated delivery systems and the like, or
biodegradable, biocompatible polymers such as collagen, ethylene
vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters,
polylactic acid, and the like. Methods for preparation of such
formulations are known to those in the art.
[0303] When orally administered, the compounds of the present
invention can be administered in usual dosage forms for oral
administration as is well known to those skilled in the art. These
dosage forms include the usual solid unit dosage forms of tablets
and capsules as well as liquid dosage forms such as solutions,
suspensions, and elixirs. When solid dosage forms are used, it is
preferred that they be of the sustained release type so that the
compounds of the present invention need to be administered only
once or twice daily. When liquid oral dosage forms are used, it is
preferred that they be of about 10 mL to about 30 mL each. Multiple
doses may be administered daily.
[0304] The methods of treatment may also employ a mixture of the
active materials and other active or inactive materials that do not
impair the desired action, or with materials that supplement the
desired action.
[0305] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include a sterile diluent
(e.g., water for injection, saline solution, fixed oil, and the
like); a naturally occurring vegetable oil (e.g., sesame oil,
coconut oil, peanut oil, cottonseed oil, and the like); a synthetic
fatty vehicle (e.g., ethyl oleate, polyethylene glycol, glycerine,
propylene glycol, and the like, including other synthetic
solvents); antimicrobial agents (e.g., benzyl alcohol, methyl
parabens, and the like); antioxidants (e.g., ascorbic acid, sodium
bisulfite, and the like); chelating agents (e.g.,
ethylenediaminetetraacetic acid (EDTA), and the like); buffers
(e.g., acetates, citrates, phosphates, and the like); and/or agents
for the adjustment of tonicity (e.g., sodium chloride, dextrose,
and the like); or mixtures thereof.
[0306] Parenteral preparations can be enclosed in ampoules,
disposable syringes, or multiple dose vials made of glass, plastic,
or other suitable material. Buffers, preservatives, antioxidants,
and the like can be incorporated as required.
[0307] Where administered intravenously, suitable carriers include
physiological saline, phosphate buffered saline (PBS), and
solutions containing thickening and solubilizing agents such as
glucose, polyethylene glycol, polypropyleneglycol, and the like,
and mixtures thereof. Liposomal suspensions including
tissue-targeted liposomes may also be suitable as pharmaceutically
acceptable carriers. These may be prepared according to methods
known, for example, as described in U.S. Pat. No. 4,522,811.
[0308] The methods of treatment include delivery of the compounds
of the present invention in a nano crystal dispersion formulation.
Preparation of such formulations is described, for example, in U.S.
Pat. No. 5,145,684. Nano crystalline dispersions of HIV protease
inhibitors and their method of use are described in U.S. Pat. No.
6,045,829. The nano crystalline formulations typically afford
greater bioavailability of drug compounds.
[0309] The methods of treatment include administration of the
compounds parenterally, for example, by IV, IM, SC, or depo-SQ.
When administered parenterally, a therapeutically effective amount
of about 0.2 mg/mL to about 50 mg/mL is preferred. When a depot or
IM formulation is used for injection once a month or once every two
weeks, the preferred dose should be about 0.2 mg/mL to about 50
mg/mL.
[0310] The methods of treatment include administration of the
compounds sublingually. When given sublingually, the compounds of
the present invention should be given one to four times daily in
the amounts described above for IM administration.
[0311] The methods of treatment include administration of the
compounds intranasally. When given by this route, the appropriate
dosage forms are a nasal spray or dry powder, as is known to those
skilled in the art. The dosage of the compounds of the present
invention for intranasal administration is the amount described
above for IM administration.
[0312] The methods of treatment include administration of the
compounds intrathecally. When given by this route the appropriate
dosage form can be a parenteral dosage form as is known to those
skilled in the art. The dosage of the compounds of the present
invention for intrathecal administration is the amount described
above for IM administration.
[0313] The methods of treatment include administration of the
compounds topically. When given by this route, the appropriate
dosage form is a cream, ointment, or patch. When topically
administered, the dosage is from about 0.2 mg/day to about 200
mg/day. Because the amount that can be delivered by a patch is
limited, two or more patches may be used. The number and size of
the patch is not important. What is important is that a
therapeutically effective amount of a compound of the present
invention be delivered as is known to those skilled in the art. The
compounds can be administered rectally by suppository as is known
to those skilled in the art. When administered by suppository, the
therapeutically effective amount is from about 0.2 mg to about 500
mg.
[0314] The methods of treatment include administration of the
compounds by implants as is known to those skilled in the art. When
administering a compound of the present invention by implant, the
therapeutically effective amount is the amount described above for
depot administration.
[0315] Given a particular compound of the present invention and/or
a desired dosage form and medium, one skilled in the art would know
how to prepare and administer the appropriate dosage form and/or
amount.
[0316] The methods of treatment include use of the compounds of the
present invention, or acceptable pharmaceutical salts thereof, in
combination, with each other or with other therapeutic agents, to
treat or prevent the conditions listed above. Such agents or
approaches include acetylcholinesterase inhibitors such as tacrine
(tetrahydroaminoacridine, marketed as COGNEX.RTM.), donepezil
hydrochloride, (marketed as Aricept.RTM.) and rivastigmine
(marketed as Exelon.RTM.), gamma-secretase inhibitors,
anti-inflammatory agents such as cyclooxygenase II inhibitors,
anti-oxidants such as Vitamin E or ginkolides, immunological
approaches, such as, for example, immunization with A-beta peptide
or administration of anti-A-beta peptide antibodies, statins, and
direct or indirect neurotropic agents such as Cerebrolysin.RTM.,
AIT-082 (Emilien, 2000, Arch. Neurol. 57:454), and other
neurotropic agents, and complexes with beta-secretase or fragments
thereof.
[0317] Additionally, the methods of treatment also employ the
compounds of the present invention with inhibitors of
P-glycoprotein (P-gp). P-gp inhibitors and the use of such
compounds are known to those skilled in the art. See, for example,
Cancer Research, 53, 4595-4602 (1993), Clin. Cancer Res., 2, 7-12
(1996), Cancer Research, 56, 4171-4179 (1996), International
Publications WO 99/64001 and WO 01/10387. The blood level of the
P-gp inhibitor should be such that it exerts its effect in
inhibiting P-gp from decreasing brain blood levels of the compounds
of formula (I). To that end the P-gp inhibitor and the compounds of
formula (I) can be administered at the same time, by the same or
different route of administration, or at different times. Given a
particular compound of formula (I), one skilled in the art would
know whether a P-gp inhibitor is desirable for use in the method of
treatment, which P-gp inhibitor should be used, and how to prepare
and administer the appropriate dosage form and/or amount.
[0318] Suitable P-gp inhibitors include cyclosporin A, verapamil,
tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate,
progesterone, rapamycin, 10,11-methanodibenzosuberane,
phenothiazines, acridine derivatives such as GF120918, FK506,
VX-710, LY335979, PSC-833, GF-102,918, quinoline-3-carboxylic acid
(2-{4-[2-(6,7-dimethyl-3,4-dihydr-
o-1H-isoquinoline-2-yl)-ethyl]phenylcarbamoyl}-4,5-dimethylphenyl)-amide
(Xenova), or other compounds. Compounds that have the same function
and therefore achieve the same outcome are also considered to be
useful.
[0319] The P-gp inhibitors can be administered orally,
parenterally, (via IV, IM, depo-IM, SQ, depo-SQ), topically,
sublingually, rectally, intranasally, intrathecally or by
implant.
[0320] The therapeutically effective amount of the P-gp inhibitors
is from about 0.1 mg/kg to about 300 mg/kg daily, preferably about
0.1 mg/kg to about 150 mg/kg daily. It is understood that while a
patient may be started on one dose, that dose may have to be varied
over time as the patient's condition changes.
[0321] When administered orally, the P-gp inhibitors can be
administered in usual dosage forms for oral administration as is
known to those skilled in the art. These dosage forms include the
usual solid unit dosage forms of tablets or capsules as well as
liquid dosage forms such as solutions, suspensions or elixirs. When
the solid dosage forms are used, it is preferred that they be of
the sustained release type so that the P-gp inhibitors need to be
administered only once or twice daily. The oral dosage forms are
administered to the patient one through four times daily. It is
preferred that the P-gp inhibitors be administered either three or
fewer times a day, more preferably once or twice daily. Hence, it
is preferred that the P-gp inhibitors be administered in solid
dosage form and further it is preferred that the solid dosage form
be a sustained release form which permits once or twice daily
dosing. It is preferred that the dosage form used, is designed to
protect the P-gp inhibitors from the acidic environment of the
stomach. Enteric coated tablets are well known to those skilled in
the art. Capsules filled with small spheres, each coated to protect
from the acidic stomach, are also well known to those skilled in
the art.
[0322] In addition, the P-gp inhibitors can be administered
parenterally. When administered parehterally they can be
administered via IV, IM, depo-IM, SQ or depo-SQ.
[0323] The P-gp inhibitors can be given sublingually. When given
sublingually, the P-gp inhibitors should be given one through four
times daily in the same amount as for IM administration.
[0324] The P-gp inhibitors can be given intranasally. When given by
this route of administration, the appropriate dosage forms are a
nasal spray or dry powder as is known to those skilled in-the art.
The dosage of the P-gp inhibitors for intranasal administration is
the same as for IM administration.
[0325] The P-gp inhibitors can be given intrathecally. When given
by this route of administration the appropriate dosage form can be
a parenteral dosage form as is known to those skilled in the
art.
[0326] The P-gp inhibitors can be given topically. When given by
this route of administration, the appropriate dosage form is a
cream, ointment or patch. Because of the amount of the P-gp
inhibitors needed to be administered the patch is preferred.
However, the amount that can be delivered by a patch is limited.
Therefore, two or more patches may be required. The number and size
of the patch is not important; what is important is that a
therapeutically effective amount of the P-gp inhibitors be
delivered as is known to those skilled in the art.
[0327] The P-gp inhibitors can be administered rectally by
suppository or by implants, both of which are known to those
skilled in the art.
[0328] It should be apparent to one skilled in the art that the
exact dosage and frequency of administration will depend on the
particular compounds of the present invention administered, the
particular condition being treated, the severity of the condition
being treated, the age, weight, or general physical condition of
the particular patient, or any other medication the individual may
be taking as is well known to administering physicians who are
skilled in this art.
[0329] In another embodiment, the present invention provides a
method of preventing or treating conditions which benefit 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 the formula, 15
[0330] or pharmaceutically acceptable salts thereof, and wherein
R.sub.1, R.sub.2, and R.sub.C are as defined above and R.sub.0 is,
selected from --CH(alkyl)--, --C(alkyl).sub.2--,
--CH(cycloalkyl)--, --C(alkyl)(cycloalkyl)--, and
--C(cycloalkyl).sub.2--.
[0331] Exemplary compounds of formula (I) are provided in the
examples below. All compound names were generated using AutoNom
(AUTOmatic NOMenclature) version 2.1, ACD Namepro version 5.09,
Chemdraw Ultra (versions 6.0, 8.0, 8.03, and 9.0), or were derived
therefrom.
EXAMPLE 1
4-(3,5-difluoro-phenyl)-1-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naph-
thalen-1-ylamino]-3-pentazol-1-yl-butan-2-ol
[0332] 16
EXAMPLE 2
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-2,2-dioxo-2.lambda..sup-
.6-isothiochroman-4-ylamino]-3-pentazol-1-yl-butan-2-ol
[0333] 17
EXAMPLE 3
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-3-pe-
ntazol-1-yl-butan-2-ol
[0334] 18
EXAMPLE 4
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-pent-
azol-1-yl-butan-2-ol
[0335] 19
EXAMPLE 5
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(1-p-
henyl-1H-tetrazol-5-yl)-butan-2-ol
[0336] 20
EXAMPLE 6
4-(3,5-difluoro-phenyl)-1-[5-(2,2-dimethyl-propyl)-2-(1H-imidazol-2-yl)-be-
nzylamino]-3-tetrazol-1-yl-butan-2-ol
[0337] 21
EXAMPLE 7
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-pyrrol-1-yl-butan-2-ol
[0338] 22
EXAMPLE 8
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-imidazol-1-yl-butan-2-ol
EXAMPLE 9
4-(3,5-difluoro-phenyl)-1-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naph-
thalen-1-ylamino]-3-(1H-imidazol-2-yl)-butan-2-ol
[0339] 23
EXAMPLE 9
4-(3,5-difluoro-phenyl)-1-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naph-
thalen-1-ylamino]-3-(1H-imidazol-2-yl)-butan-2-ol
[0340] 24
EXAMPLE 10
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-2,2-dioxo-2.lambda..sup-
.6-isothiochroman-4-ylamino]-3-(1H-imidazol-2-yl)-butan-2-ol
[0341] 25
EXAMPLE 11
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-3-(1-
H-imidazol-2-yl)-butan-2-ol
[0342] 26
EXAMPLE 12
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-quin-
olin-4-ylamino]-3-(1H-imidazol-2-yl)-butan-2-ol
[0343] 27
EXAMPLE 13
4-(3,5-difluoro-phenyl)-1-[5-(2,2-dimethyl-propyl)-2-(1H-imidazol-2-yl)-be-
nzylamino]-3-(1H-imidazol-2-yl)-butan-2-ol
[0344] 28
EXAMPLE 14
4-(3,5-difluoro-phenyl)-1-(6-isobutyl-1,1-dioxo-1.lambda..sup.6-thiochroma-
n-4-ylamino)-butan-2-ol
[0345] 29
EXAMPLE 15
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-butan-2-ol
[0346] 30
EXAMPLE 16
3-(3-bromo-[1,2,4]thiadiazol-5-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethyl-
-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0347] 31
EXAMPLE 17
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-([1,2,4]thiadiazol-5-ylamino)-butan-2-ol
[0348] 32
EXAMPLE 18
3-(4-Chloro-[1,2,5]thiadiazol-3-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethy-
l-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0349] 33
EXAMPLE 19
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-([1,2,5]thiadiazol-3-ylamino)-butan-2-ol
[0350] 34
EXAMPLE 20
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(thiazol-2-ylamino)-butan-2-ol
[0351] 35
EXAMPLE 21
3-(5-bromo-[1,3,4]thiadiazol-2-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethyl-
-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0352] 36
EXAMPLE 22
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-([1,3,4]thiadiazol-2-ylamino)-butan-2-ol
[0353] 37
EXAMPLE 23
3-(5-amino-[1,3,4]thiadiazol-2-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethyl-
-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0354] 38
EXAMPLE 24
3-(2-bromo-thiazol-5-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-
-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0355] 39
EXAMPLE 25
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(thiazol-5-ylamino)-butan-2-ol
[0356] 40
EXAMPLE 26
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino)-butan-2-ol
[0357] 41
EXAMPLE 27
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
[0358] 42
EXAMPLE 28
3-(5-amino-[1,3,4]oxadiazol-2-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethyl--
2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0359] 43
EXAMPLE 29
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(1-trityl-1H-[1,2,4]triazol-3-ylamino)-butan-2-ol
[0360] 44
EXAMPLE 30
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(1H-[1,2,4]triazol-3-ylamino)-butan-2-ol
[0361] 45
EXAMPLE 31
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(oxazol-2-ylamino)-butan-2-ol
[0362] 46
EXAMPLE 32
3-(5-bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino)-4-(3,5-difluoro-phenyl)-1-
-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0363] 47
EXAMPLE 33
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(2-trityl-2H-[1,2,3]triazol-4-ylamino)-butan-2-ol
[0364] 48
EXAMPLE 34
3-(5-bromo-2H-[1,2,3]triazol-4-ylamino)-4-(3,5-difluoro-phenyl)-1-(6-ethyl-
-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylamino)-butan-2-ol
[0365] 49
EXAMPLE 35
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(2H-[1,2,3]triazol-4-ylamino)-butan-2-ol
[0366] 50
EXAMPLE 36
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(thiophen-2-ylamino)-butan-2-ol
[0367] 51
EXAMPLE 37
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(3-methyl-5-nitro-3H-imidazol-4-ylamino)-butan-2-ol
[0368] 52
EXAMPLE 38
3-[1-(3,5-difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochr-
oman-4-ylamino)-2-hydroxy-propylamino]-5-phenyl-isothiazole-4-carbonitrile
[0369] 53
EXAMPLE 39
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroma-
n-4-ylamino)-3-(4-phenyl-[1,2,5]thiadiazol-3-ylamino)-butan-2-ol
[0370] 54
EXAMPLE 40
3-[1-(3,5-difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochr-
oman-4-ylamino)-2-hydroxy-propylamino]-cyclobut-3-ene-1,2-dione
[0371] 55
EXAMPLE 41
3-[1-(3,5-difluoro-benzyl-3-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochro-
man-4-ylamino)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione
[0372] 56
EXAMPLE 42
3-[1-(3,5-difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochr-
oman-4-ylamino)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-di-
one
[0373] 57
EXAMPLE 43
3-(3-bromo-[1,2,4]thiadiazol-5-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-
-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0374] 58
EXAMPLE 44
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-([1,2,4]thiadiazol-5-ylamino)-butan-2-ol
[0375] 59
EXAMPLE 45
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0376] 60
EXAMPLE 46
3-(4-chloro-[1,2,5]thiadiazol-3-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethy-
l-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0377] 61
EXAMPLE 47
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-([1,2,5]thiadiazol-3-ylamino)-butan-2-ol
[0378] 62
EXAMPLE 48
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(thiazol-2-ylamino)-butan-2-ol
[0379] 63
EXAMPLE 49
3-(5-bromo-[1,3,4]thiadiazol-2-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-
-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0380] 64
EXAMPLE 50
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-([1,3,4]thiadiazol-2-ylamino)-butan-2-ol
[0381] 65
EXAMPLE 51
3-(5-amino-[1,3,4]thiadiazol-2-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-
-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0382] 66
EXAMPLE 52
3-(2-bromo-thiazol-5-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-t-
etrahydro-naphthalen-1-ylamino)-butan-2-ol
[0383] 67
EXAMPLE 53
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(thiazol-5-ylamino)-butan-2-ol
[0384] 68
EXAMPLE 54
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino)-butan-2-ol
[0385] 69
EXAMPLE 55
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
[0386] 70
EXAMPLE 56
3-(5-amino-[1,3,4]oxadiazol-2-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl--
1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0387] 71
EXAMPLE 57
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(1-trityl-1H-[1,2,4]triazol-3-ylamino)-butan-2-ol
[0388] 72
EXAMPLE 58
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(1H-[1,2,4]triazol-3-ylamino)-butan-2-ol
[0389] 73
EXAMPLE 59
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(oxazol-2-ylamino)-butan-2-ol
[0390] 74
EXAMPLE 60
3-(5-bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino)-4-(3,5-difluoro-phenyl)-1-
-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0391] 75
EXAMPLE 61
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(2-trityl-2H-[1,2,3]triazol-4-ylamino)-butan-2-ol
[0392] 76
EXAMPLE 62
3-(5-bromo-2H-[1,2,3]triazol-4-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-
-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0393] 77
EXAMPLE 63
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(2H-[1,2,3]triazol-4-ylamino)-butan-2-ol
[0394] 78
EXAMPLE 64
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(thiophen-2-ylamino)-butan-2-ol
[0395] 79
EXAMPLE 65
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(3-methyl-5-nitro-3H-imidazol-4-ylamino)-butan-2-ol
[0396] 80
EXAMPLE 66
3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylam-
ino)-2-hydroxy-propylamino]-5-phenyl-isothiazole-4-carbonitrile
[0397] 81
EXAMPLE 67
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(4-phenyl-[1,2,5]thiadiazol-3-ylamino)-butan-2-ol
[0398] 82
EXAMPLE 68
3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylam-
ino)-2-hydroxy-propylamino]-cyclobut-3-ene-1,2-dione
[0399] 83
EXAMPLE 69
3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylam-
ino)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione
[0400] 84
EXAMPLE 70
3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylam-
ino)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione
[0401] 85
EXAMPLE 71
{3-[1-(3,5-difluoro-benzyl-3-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylam-
ino)-2-hydroxy-propylamino]-phenyl}-acetic acid
[0402] 86
EXAMPLE 72
3-(2-chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,-
4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0403] 87
EXAMPLE 73
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-([1,-
2,4]thiadiazol-5-ylamino)-butan-2-ol
[0404] 88
EXAMPLE 74
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(4-chloro-[1,2,5]thiadiazol--
3-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol
[0405] 89
EXAMPLE 75
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-([1,-
2,5]thiadiazol-3-ylamino)-butan-2-ol
[0406] 90
EXAMPLE 76
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(thi-
azol-2-ylamino)-butan-2-ol
[0407] 91
EXAMPLE 77
3-(5-bromo-[1,3,4]thiadiazol-2-ylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohe-
xylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0408] 92
EXAMPLE 78
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-([1,-
3,4]thiadiazol-2-ylamino)-butan-2-ol
[0409] 93
EXAMPLE 79
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(5-m-
ethyl-[1,3,4]thiadiazol-2-ylamino)-butan-2-ol
[0410] 94
EXAMPLE 80
3-(5-amino-[1,3,4]thiadiazol-2-ylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohe-
xylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0411] 95
EXAMPLE 81
3-(2-bromo-thiazol-5-ylamino)-1-[-1-(3-tert-butyl-phenyl)-cyclohexylamino]-
-4-(3,5-difluoro-phenyl-butan-2-ol
[0412] 96
EXAMPLE 82
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(thi-
azol-5-ylamino)-butan-2-ol
[0413] 97
EXAMPLE 83
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(5-t-
rifluoromethyl-[1,3,4]thiadiazol-2-ylamino)-butan-2-ol
[0414] 98
EXAMPLE 84
3-(3-bromo-[1,2,4]thiadiazol-5-ylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohe-
xylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0415] 99
EXAMPLE 85
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(5-t-
rifluorom ethyl-[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
[0416] 100
EXAMPLE 86
3-(5-amino-[1,3,4]oxadiazol-2-ylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohex-
ylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0417] 101
EXAMPLE 87
1-[-1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(5--
methyl-[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
[0418] 102
EXAMPLE 88
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(5-p-
henyl-[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
[0419] 103
EXAMPLE 89
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(5-p-
yridin-4-yl-[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
[0420] 104
EXAMPLE 90
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(1-t-
rityl-1H-[1,2,4]triazol-3-ylamino)-butan-2-ol
[0421] 105
EXAMPLE 91
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(1H--
[1,2,4]triazol-3-ylamino)-butan-2-ol
[0422] 106
EXAMPLE 92
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(oxa-
zol-2-ylamino)-butan-2-ol
[0423] 107
EXAMPLE 93
3-(5-bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino)-1-[1-(3-tert-butyl-phenyl-
)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0424] 108
EXAMPLE 94
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2-t-
rityl-2H-[1,2,3]triazol-4-ylamino)-butan-2-ol
[0425] 109
EXAMPLE 95
3-(5-bromo-2H-[1,2,3]triazol-4-ylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohe-
xylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0426] 110
EXAMPLE 96
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]4-(3,5-difluoro-phenyl)-3-(2H-[-
1,2,3]triazol-4-ylamino)-butan-2-ol
[0427] 111
EXAMPLE 97
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(thi-
ophen-3-ylamino)-butan-2-ol
[0428] 112
EXAMPLE 98
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(thi-
ophen-2-ylamino)-butan-2-ol
[0429] 113
EXAMPLE 99
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(3-n-
itro-thiophen-2-ylamino)-butan-2-ol
[0430] 114
EXAMPLE 100
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(3-m-
ethyl-5-nitro-3H-imidazol-4-ylamino)-butan-2-ol
[0431] 115
EXAMPLE 101
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2,5-
-dimethyl-4-nitro-2H-pyrazol-3-ylamino)-butan-2-ol
[0432] 116
EXAMPLE 102
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-5-phenyl-isothiazole-4-carbonitrile
[0433] 117
EXAMPLE 103
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(4-p-
henyl-[1,2,5]thiadiazol-3-ylamino)-butan-2-ol
[0434] 118
EXAMPLE 104
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(1-m-
ethyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0435] 119
EXAMPLE 105
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]4-(3,5-difluoro-phenyl)-3-(pyri-
midin-4-ylamino)-butan-2-ol
[0436] 120
EXAMPLE 106
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(2-chloro-pyrimidin-4-ylamin-
o)-4-(3,5-difluoro-phenyl)-butan-2-ol
[0437] 121
EXAMPLE 107
2-{4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)--
2-hydroxy-propylamino]-pyrimidin-2-ylamino}-N,N-dipropyl-acetamide
[0438] 122
EXAMPLE 108
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-pyridin-4-ol
[0439] 123
EXAMPLE 109
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-5-iodo-pyridin-4-ol
[0440] 124
EXAMPLE 110
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-5-iodo-1-methyl-1H-pyridin-4-one
[0441] 125
EXAMPLE 111
3-(benzo[4,5]thieno[3,2-D]pyrimidin-4-ylamino)-1-[1-(3-tert-butyl-phenyl)--
cyclohexylamino]-4-3,5-difluoro-phenyl)-butan-2-ol
[0442] 126
EXAMPLE 112
5-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-4-chloro-isothiazole-3-carboxylic acid methyl
ester
[0443] 127
EXAMPLE 113
5-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-3-methanesulfinyl-isothiazole-4-carbonitrile
[0444] 128
EXAMPLE 114
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2-f-
luoro-4-trifluoromethyl-thiazol-5-ylamino)-butan-2-ol
[0445] 129
EXAMPLE 115
3-(1-benzyl-1H-pyrazol-4-ylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohexylami-
no]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0446] 130
EXAMPLE 116
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-cyclobut-3-ene-1,2-dione
[0447] 131
EXAMPLE 117
3-[3-[1-(3-tert-butyl-phenyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hy-
droxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione
[0448] 132
EXAMPLE 118
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione
[0449] 133
EXAMPLE 119
4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-benzoic acid
[0450] 134
EXAMPLE 120
4-[3-[1-(3-tert-butyl-phenyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hy-
droxy-propylamino]-benzamide
[0451] 135
EXAMPLE 121
4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-N-methyl-benzamide
[0452] 136
EXAMPLE 122
{4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2--
hydroxy-propylamino]-phenyl}-acetic acid
[0453] 137
EXAMPLE 123
3-{4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)--
2-hydroxy-propylamino]-phenyl}-propionic acid
[0454] 138
EXAMPLE 124
2-{3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)--
2-hydroxy-propylamino]-phenyl}--N,N-dipropyl-acetamide
[0455] 139
EXAMPLE 125
2-{3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-y-
lamino)-2-hydroxy-propylamino]-phenyl}--N,N-dipropyl-acetamide
[0456] 140
EXAMPLE 126
1-(6-bromo-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-3-(3,5-difluor-
o-phenoxy)-propan-2-ol
[0457] 141
EXAMPLE 127
1-(3,5-difluoro-phenoxy)-3-(6-isobutyl-1,1-dioxo-1.lambda..sup.6-thiochrom-
an-4-ylamino)-propan-2-ol
[0458] 142
EXAMPLE 128
1-(6-tert-butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-3-(3,5-di-
fluoro-phenoxy)-propan-2-ol
[0459] 143
EXAMPLE 129
1-[1-(3-bromo-phenyl)-cyclohexylamino]-3-(3,5-difluoro-phenoxy)-propan-2-o-
l
[0460] 144
EXAMPLE 130
1-(3,5-difluoro-phenoxy)-3-[1-(3-isobutyl-phenyl)-cyclohexylamino]-propan--
2-ol
[0461] 145
EXAMPLE 131
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(3,5-difluoro-phenoxy)-propa-
n-2-ol
[0462] 146
EXAMPLE 132
1-(6-bromo-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-3-(3,5-difluor-
o-benzenesulfonyl)-propan-2-ol
[0463] 147
EXAMPLE 133
1-(3,5-difluoro-benzenesulfonyl)-3-(6-isobutyl-1,1-dioxo-1.lambda..sup.6-t-
hiochroman-4-ylamino)-propan-2-ol
[0464] 148
EXAMPLE-134
1-(6-tert-butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-3-(3,5-di-
fluoro-benzenesulfonyl)-propan-2-ol
[0465] 149
EXAMPLE 135
1-[1-(3-bromo-phenyl)-cyclohexylamino]-3-(3,5-difluoro-benzenesulfonyl)-pr-
opan-2-ol
[0466] 150
EXAMPLE 136
1-(3,5-difluoro-benzenesulfonyl)-3-[1-(3-isobutyl-phenyl)-cyclohexylamino]-
-propan-2-ol
[0467] 151
EXAMPLE 137
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(3,5-difluoro-benzenesulfony-
l)-propan-2-ol
[0468] 152
EXAMPLE 138
4-(6-bromo-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-1-(3,5-difluor-
o-phenyl)-3-hydroxy-butan-1-one
[0469] 153
EXAMPLE 139
1-(3,5-difluoro-phenyl)-3-hydroxy-4-(6-isobutyl-1,1-dioxo-1.lambda..sup.6--
thiochroman-4-ylamino)-butan-1-one
[0470] 154
EXAMPLE 140
4-(6-tert-butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-1-(3,5-di-
fluoro-phenyl)-3-hydroxy-butan-1-one
[0471] 155
EXAMPLE 141
4-[1-(3-bromo-phenyl)-cyclohexylamino]-1-(3,5-difluoro-phenyl)-3-hydroxy-b-
utan-1-one
[0472] 156
EXAMPLE 142
1-(3,5-difluoro-phenyl)-3-hydroxy-4-[1-(3-isobutyl-phenyl)-cyclohexylamino-
]-butan-1-one
[0473] 157
EXAMPLE 143
4-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-phenyl)-3-hydr-
oxy-butan-1-one
[0474] 158
EXAMPLE 144
1-(6-bromo-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-4-(3,5-difluor-
o-phenyl)-pentan-2-ol
[0475] 159
EXAMPLE 145
1-(6-bromo-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-4-(3,5-difluor-
o-phenyl)-4-methylamino-butan-2-ol
[0476] 160
EXAMPLE 146
1-[(1-(3-tert-butyl-phenyl-cyclohexylamino]-4-(3,5-difluoro-phenyl)-pentan-
-2-ol
[0477] 161
EXAMPLE 147
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-4-meth-
ylamino-butan-2-ol
[0478] 162
EXAMPLE 148
1-(6-tert-butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-4-(3,5-di-
fluoro-phenyl)-pentan-2-ol
[0479] 163
EXAMPLE 149
1-(6-tert-butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-4-(3,5-di-
fluoro-phenyl)-4-methylamino-butan-2-ol
[0480] 164
EXAMPLE 150
1-[1-(3-bromo-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-pentan-2-ol
[0481] 165
EXAMPLE 151
1-[1-(3-bromo-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-4-methylami-
no-butan-2-ol
[0482] 166
EXAMPLE 152
2-(3,5-difluoro-benzyl)-4-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naph-
thalen-1-ylamino]-3-hydroxy-N-methyl-butyramide
[0483] 167
EXAMPLE 153
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-2,2-dioxo-2.lambda..sup-
.6-isothiochroman-4-ylamino]-3-hydroxy-N-methyl-butyramide
[0484] 168
EXAMPLE 154
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-1,1-dioxo-1.lambda..sup-
.6-thiochroman-4-ylamino]-3-hydroxy-N-methyl-butyramide
[0485] 169
EXAMPLE 155
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-3-hy-
droxy-N-methyl-butyramide
[0486] 170
EXAMPLE 156
2-(3,5-difluoro-benzyl)-4-[6-2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-quino-
lin-4-ylamino]-3-hydroxy-N-methyl-butyramide
[0487] 171
EXAMPLE 157
2-(3,5-difluoro-benzyl)-4-[5-(2,2-dimethyl-propyl)-2-(1H-imidazol-2-yl)-be-
nzylamino]-3-hydroxy-N-methyl-butyramide
[0488] 172
EXAMPLE 158
2-(3,5-difluoro-benzyl)-4-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naph-
thalen-1-ylamino]-3-hydroxy-N-phenyl-butyramide
[0489] 173
EXAMPLE 159
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-2,2-dioxo-2.lambda..sup-
.6-isothiochroman-4-ylamino]-3-hydroxy-N-phenyl-butyramide
[0490] 174
EXAMPLE 160
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-1,1-dioxo-1.lambda..sup-
.6-thiochroman-4-ylamino]-3-hydroxy-N-phenyl-butyramide
[0491] 175
EXAMPLE 161
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-3-hy-
droxy-N-phenyl-butyramide
[0492] 176
EXAMPLE 162
2-(3,5-difluoro-benzyl)-4-[6-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-quin-
olin-4-ylamino]-3-hydroxy-N-phenyl-butyramide
[0493] 177
EXAMPLE 163
2-(3,5-difluoro-benzyl)-4-[5-(2,2-dimethyl-propyl)-2-(1H-imidazol-2-yl)-be-
nzylamino]-3-hydroxy-N-phenyl-butyramide
[0494] 178
EXAMPLE 164
4-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydr-
oxy-N-methyl-butyramide
[0495] 179
EXAMPLE 165
4-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydr-
oxy-N-phenyl-butyramide
[0496] 180
EXAMPLE 166
4-[4-(3-tert-butyl-phenyl)-tetrahydro-pyran-4-ylamino]-2-(3,5-difluoro-ben-
zyl)-3-hydroxy-N-methyl-butyramide
[0497] 181
EXAMPLE 167
4-[4-(3-tert-butyl-phenyl)-tetrahydro-pyran-4-ylamino]-2-(3,5-difluoro-ben-
zyl)-3-hydroxy-N-phenyl-butyramide
[0498] 182
EXAMPLE 168
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-ethy-
lamino-butan-2-ol
[0499] 183
EXAMPLE 169
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-prop-
ylamino-butan-2-ol
[0500] 184
EXAMPLE 170
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(2,2-difluoro-ethylamino)-4--
(3,5-difluoro-phenyl-butan-2-ol
[0501] 185
EXAMPLE 171
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2,2-
,2-trifluoro-ethylamino)-butan-2-ol
[0502] 186
EXAMPLE 172
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(cyclopropylmethyl-amino)-4--
(3,5-difluoro-phenyl)-butan-2-ol
[0503] 187
EXAMPLE 173
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2-h-
ydroxy-ethylamino)-butan-2-ol
[0504] 188
EXAMPLE 174
3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-propane-1,2-diol
[0505] 189
EXAMPLE 175
3-(2-amino-ethylamino)-1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5--
difluoro-phenyl)-butan-2-ol
[0506] 190
EXAMPLE 176
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(3-m-
ethylsulfanyl-propylamino)-butan-2-ol
[0507] 191
EXAMPLE 177
1-[1-(3-tert-butyl-phenyl-cyclohexylamino]4-(3,5-difluoro-phenyl)-3-(3-hyd-
roxy-2,2-dimethyl-propylamino)-butan-2-ol
[0508] 192
EXAMPLE 178
6-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propylamino]-hexanoic acid methyl ester
[0509] 193
EXAMPLE 179
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-[(py-
rrolidin-3-ylmethyl)-amino]-butan-2-ol
[0510] 194
EXAMPLE 180
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-[(pi-
peridin-4-ylmethyl-amino]-butan-2-ol
[0511] 195
EXAMPLE 181
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2-p-
iperidin-4-yl-ethylamino)-butan-2-ol
[0512] 196
EXAMPLE 182
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-[(1--
phenyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-butan-2-ol
[0513] 197
EXAMPLE 183
1-[1-(3-tert-butyl-phenyl-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-[(1H--
pyrazol-3-ylmethyl)-amino]-butan-2-ol
[0514] 198
EXAMPLE 184
1-[1-(3-tert-butyl-phenyl-cyclohexylamino]-3-[(4-chloro-1-methyl-1H-pyrazo-
l-3-ylmethyl)-amino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0515] 199
EXAMPLE 185
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-[(fu-
ran-2-ylmethyl)-amino]-butan-2-ol
[0516] 200
EXAMPLE 186
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-[1,2-
,3]triazol-1-yl-butan-2-ol
[0517] 201
EXAMPLE 187
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]4-(3,5-difluoro-phenyl)-3-(1-me-
thyl-1H-pyrazol-4-yl)-butan-2-ol
[0518] 202
EXAMPLE 188
3-benzylamino-1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro--
phenyl)-butan-2-ol
[0519] 203
EXAMPLE 189
2-{[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2--
hydroxy-propylamino]-methyl}-phenol
[0520] 204
EXAMPLE 190
4-{[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2--
hydroxy-propylamino]-methyl}-benzene-1,3-diol
[0521] 205
EXAMPLE 191
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(pyridin-4-ylamino)-butan-2-ol
[0522] 206
EXAMPLE 192
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-3-(1-
-methyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0523] 207
EXAMPLE 193
4-(3,5-difluoro-phenyl)-1-[5-(2,2-dimethyl-propyl)-2-imidazol-1-yl-benzyla-
mino]-butan-2-ol
[0524] 208
EXAMPLE 194
4-(3,5-difluoro-phenyl)-1-[5-(2,2-dimethyl-propyl)-2-(4-hydroxymethyl-imid-
azol-1-yl)-benzylamino]-butan-2-ol
[0525] 209
EXAMPLE 195
4-(3,5-difluoro-phenyl)-1-(3,4,5-trimethoxy-benzylamino)-butan-2-ol
[0526] 210
EXAMPLE 196
4-(3,5-difluoro-phenyl)-1-[2-(2-hydroxymethyl-phenylsulfanyl)-benzylamino]-
-butan-2-ol
[0527] 211
EXAMPLE 197
N-(4-{[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-methyl}-phenyl-N-meth-
yl-acetamide
[0528] 212
EXAMPLE 198
4-(3,5-difluoro-phenyl)-1-(3-iodo-benzylamino)-butan-2-ol
[0529] 213
EXAMPLE 199
1-(4-amino-benzylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol
[0530] 214
EXAMPLE 200
4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-3-(1-methy-
l-1H-pyrazol-4-ylamino)-butan-2-ol
[0531] 215
EXAMPLE 201
4-(3,5-difluoro-phenyl)-1-(3-ethyl-benzylamino)-3-(1-methyl-1H-pyrazol-4-y-
lamino)-butan-2-ol
[0532] 216
EXAMPLE 202
3-(2-chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1-(3-ethyl-benzyl-
amino)butan-2-ol
[0533] 217
EXAMPLE 203
4-(3,5-difluoro-phenyl)-1-[(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethy-
l)-amino]-butan-2-ol
[0534] 218
EXAMPLE 204
4-(3,5-difluoro-phenyl)-1-[(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethy-
l)-amino]-butan-2-ol
[0535] 219
EXAMPLE 205
4-(3,5-difluoro-phenyl)-1-[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-amino-
]-butan-2-ol
[0536] 220
EXAMPLE 206
4-(3,5-difluoro-phenyl)-1-[(7,7-dimethyl-bicyclo[3.1.1]hept-6-ylmethyl)-am-
ino]-butan-2-ol
[0537] 221
EXAMPLE 207
3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-5-phenyl-1,3-dihydro-benz-
o[e][1,4]diazepin-2-one
[0538] 222
EXAMPLE 208
4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-butan-2-ol
[0539] 223
EXAMPLE 209
3-(2-chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phe-
nyl)-cyclopropylamino]-butan-2-ol
[0540] 224
EXAMPLE 210
4-(3,5-difluoro-phenyl)-1-(1,1-dioxo-1.lambda..sub.6-thiochroman-4-ylamino-
)-butan-2-ol
[0541] 225
EXAMPLE 211
1-(6-bromo-1,1-dioxo-1.lambda..sub.6-thiochroman-4-ylamino)-4-(3,5-difluor-
o-phenyl)-butan-2-ol
[0542] 226
EXAMPLE 212
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-buta-
n-2-ol
[0543] 227
EXAMPLE 213
[4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-6-(2,2-dimethyl-propyl)--
chroman-7-yl]-carbamic acid benzyl ester
[0544] 228
EXAMPLE 214
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-butan-2-ol
[0545] 229
EXAMPLE 215
4-(3,5-difluoro-phenyl)-1-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naph-
thalen-1-ylamino]-butan-2-ol
[0546] 230
EXAMPLE 216
1-(2-bromo-9H-fluoren-9-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol
[0547] 231
EXAMPLE 217
4-(3,5-difluoro-phenyl)-1-(2-isobutyl-9H-fluoren-9-ylamino)-butan-2-ol
[0548] 232
EXAMPLE 218
1-[2-bromo-5-(2,2-dimethyl-propyl-benzylamino]-4-(3,5-difluoro-phenyl)-but-
an-2-ol
[0549] 233
EXAMPLE 219
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-butan--
2-ol
[0550] 234
EXAMPLE 220
1-[1-(3-tert-butyl-phenyl)-4-methyl-cyclohexylamino]-4-(3,5-difluoro-pheny-
l)-butan-2-ol
[0551] 235
EXAMPLE 221
1-[1-(3-tert-butyl-phenyl)-4-hydroxymethyl-cyclohexylamino]-4-(3,5-difluor-
o-phenyl)-butan-2-ol
[0552] 236
EXAMPLE 222
1-[1-(3-tert-butyl-phenyl)-3-methyl-cyclohexylamino]-4-(3,5-difluoro-pheny-
l)-butan-2-ol
[0553] 237
EXAMPLE 223
1-[1-(3-tert-butyl-phenyl)-2-methyl-cyclohexylamino]-4-(3,5-difluoro-pheny-
l)-butan-2-ol
[0554] 238
EXAMPLE 224
2-(3-tert-butyl-phenyl-2-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cy-
clohexanol
[0555] 239
EXAMPLE 225
1-[1-(3-tert-butyl-5-fluoro-phenyl)-cyclohexylamino]-4-(3,5-difluoro-pheny-
l)-butan-2-ol
[0556] 240
EXAMPLE 226
1-[1-(3-tert-butyl-phenyl)-4-methylsulfanyl-cyclohexylamino]-4-(3,5-difluo-
ro-phenyl)-butan-2-ol
[0557] 241
EXAMPLE 227
1-[1-(3-tert-butyl-phenyl-4-methoxy-cyclohexylamino]-4-(3,5-difluoro-pheny-
l)-butan-2-ol
[0558] 242
EXAMPLE 228
4-(3-tert-butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-c-
yclohexanone
[0559] 243
EXAMPLE 229
1-[1-(3-tert-butyl-phenyl)-4-(thiazol-2-ylamino)-cyclohexylamino]-4-(3,5-d-
ifluoro-phenyl)-butan-2-ol
[0560] 244
EXAMPLE 230
1-[1-(3-tert-butyl-phenyl-4-3-methyl-isoxazol-5-ylamino)-cyclohexylamino]--
4-(3,5-difluoro-phenyl)-butan-2-ol
[0561] 245
EXAMPLE 231
1-[1-(3-tert-butyl-phenyl)-4-(1H-pyrazol-3-ylamino)-cyclohexylamino]-4-(3,-
5-difluoro-phenyl)-butan-2-ol
[0562] 246
EXAMPLE 232
1-[1-(3-tert-butyl-phenyl)-4-(isoxazol-3-ylamino)-cyclohexylamino]-4-(3,5--
difluoro-phenyl)-butan-2-ol
[0563] 247
EXAMPLE 233
1-[1-(3-tert-butyl-phenyl)-4-(5-methyl-isoxazol-3-ylamino)-cyclohexylamino-
]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0564] 248
EXAMPLE 234
1-[1-(3-tert-butyl-phenyl)-4-(pyridin-3-ylamino)-cyclohexylamino]-4-(3,5-d-
ifluoro-phenyl)-butan-2-ol
[0565] 249
EXAMPLE 235
1-[1-(3-tert-butyl-phenyl)-4-(pyridin-2-ylamino)-cyclohexylamino]-4-(3,5-d-
ifluoro-phenyl)-butan-2-ol
[0566] 250
EXAMPLE 236
1-[1-(3-tert-butyl-phenyl-4-trifluoromethyl-cyclohexylamino]-4-(3,5-difluo-
ro-phenyl)-butan-2-ol
[0567] 251
EXAMPLE 237
1-[1-(3-tert-butyl-phenyl)-4,4-difluoro-cyclohexylamino]-4-(3,5-difluoro-p-
henyl)-butan-2-ol
[0568] 252
EXAMPLE 238
1-[1-(6-tert-butyl-pyrimidin-4-yl)-cyclohexylamino]-4-(3,5-difluoro-phenyl-
)-butan-2-ol
[0569] 253
EXAMPLE 239
1-[3-(3-tert-butyl-phenyl)-piperidin-3-ylamino]4-(3,5-difluoro-phenyl)-but-
an-2-ol
[0570] 254
EXAMPLE 240
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidin-1-ol
[0571] 255
EXAMPLE 241
1-[3-(3-tert-butyl-phenyl)-1-methyl-piperidin-3-ylamino]-4-(3,5-difluoro-p-
henyl)-butan-2-ol
[0572] 256
EXAMPLE 242
1-{3-(3-tert-butyl-phenyl)-3-[4-3,5-difluoro-phenyl)-2-hydroxy-butylamino]-
-piperidin-1-yl}-ethanone
[0573] 257
EXAMPLE 243
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidine-1-carboxylic acid methylamide
[0574] 258
EXAMPLE 244
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidine-1-carboxylic acid dimethylamide
[0575] 259
EXAMPLE 245
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidine-1-carboxylic acid benzylamide
[0576] 260
EXAMPLE 246
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidine-1-carboxylic acid isopropylamide
[0577] 261
EXAMPLE 247
{3-(3-tert-butyl-phenyl)-3-[4-3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidin-1-yl}-piperidin-1-yl-methanone
[0578] 262
EXAMPLE 248
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidine-1-carboxylic acid methyl ester
[0579] 263
EXAMPLE 249
1-[3-(3-tert-butyl-phenyl)-1-methanesulfonyl-piperidin-3-ylamino]-4-(3,5-d-
ifluoro-phenyl-butan-2-ol
[0580] 264
EXAMPLE 250
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-p-
iperidine-1-carboxylic acid amide
[0581] 265
EXAMPLE 251
1-{3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino-
]-piperidin-1-yl}-3-phenyl-propan-1-one
[0582] 266
EXAMPLE 252
3-(3-tert-butyl-phenyl-3-[4-3,5-difluoro-phenyl)-2-hydroxy-butylamino]-pip-
eridine-1-carboxylic acid benzyl ester
[0583] 267
EXAMPLE 253
4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-6-(2,2-dimethyl-propyl)-3-
,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester
[0584] 268
EXAMPLE 254
1-[(adamantan-1-ylmethyl)-amino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0585] 269
EXAMPLE 255
4-(3,5-difluoro-phenyl)-1-(1-thiophen-3-yl-cyclohexylamino)-butan-2-ol
[0586] 270
EXAMPLE 256
4-(3,5-difluoro-phenyl)-1-[1-(5-ethyl-thiophen-3-yl)-cyclohexylamino]-buta-
n-2-ol
[0587] 271
EXAMPLE 257
4-(3,5-difluoro-phenyl)-1-[1-(5-isopropyl-thiophen-3-yl)-cyclohexylamino]--
butan-2-ol
[0588] 272
EXAMPLE 258
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-butane-
-2,3-diol
[0589] 273
EXAMPLE 259
1-(3,5-difluoro-phenyl-4-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-napht-
halen-1-ylamino]-butane-2,3-diol
[0590] 274
EXAMPLE 260
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-meth-
oxy-butan-2-ol
[0591] 275
EXAMPLE 261
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-phen-
oxy-butan-2-ol
[0592] 276
EXAMPLE 262
methyl-carbamic acid
3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-di-
fluoro-benzyl)-2-hydroxy-propyl ester
[0593] 277
EXAMPLE 263
{1-(3,5-difluoro-benzyl)-3-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-nap-
hthalen-1-ylamino]-2-hydroxy-propoxy}-methanesulfonamide
[0594] 278
EXAMPLE 264
2-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propyl]-2,3,4,5-tetrahydro-benzo[c]azepin-1-one
[0595] 279
EXAMPLE 265
1-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-h-
ydroxy-propyl]-pyrrolidin-2-one
[0596] 280
Experimental Procedures
[0597] The compounds and the methods of treatment of the present
invention can be prepared by one skilled in the art based on
knowledge of the compound's chemical structure. The chemistry for
the preparation of the compounds employed in the methods of
treatment of this invention is known to those skilled in the art.
In fact, there is more than one process to prepare the compounds
employed in the methods of treatment of the present invention.
Specific examples of methods of preparation can be found in the
art. For examples, see Zuccarello et al., J. Org. Chem. 1998, 63,
4898-4906; Benedetti et al., J. Org. Chem. 1997, 62, 9348-9353;
Kang et al., J. Org. Chem. 1996, 61, 5528-5531; Kempf et al., J.
Med. Chem. 1993, 36, 320-330; Lee et al., J. Am. Chem. Soc. 1999,
121, 1145-1155, and references cited therein; Chem. Pharm. Bull.
(2000), 48(11), 1702-1710; J. Am. Chem. Soc. (1974), 96(8),
2463-72; Ind. J. Chem., Section B: Organic Chemistry Including
Medicinal Chemistry (2003), 42B(4), 910-915; J. Chem. Soc.[Section]
C: Organic (1971), (9), 1658-60, and Tet. Lett. (1995), 36(11),
1759-1762. See also U.S. Pat. Nos. 6,150,530, 5,892,052, 5,696,270,
and 5,362,912, and references cited therein, which are incorporated
herein by reference.
EXAMPLE 266
.sup.1H, .sup.13C NMR, and Mass Spec Procedures
[0598] .sup.1H and .sup.13C NMR spectra were obtained on a Varian
400 MHz, Varian 300 MHz, or Bruker 300 MHz instrument. Mass spec
samples analyses were performed with electron spray ionization
(ESI).
EXAMPLE 267
Exemplary HPLC Procedures
[0599] Various High Pressure Liquid Chromatography (HPLC)
procedures employed the following methods:
[0600] Method [1] utilizes a 20% [B]:80% [A] to 70% [B]:30% [A]
gradient in 1.75 min, then hold, at 2 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0601] Method [2] utilizes a 50% [B]:50% [A] to 95% [B]:5% [A]
gradient in 2.5 min, then hold, at 2 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0602] Method [3] utilizes a 5% [B]:95% [A] to 20% [B]:80% [A]
gradient in 2.5 min, then hold, at 2 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0603] Method [4] utilizes a 20% [B]:80% [A] to 70% [B]:30% [A]
gradient in 2.33 min, then hold, at 1.5 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0604] Method [5] utilizes a 50% [B]:50% [A] to 95% [B]:5% [A]
gradient in 3.33 min, then hold, at 1.5 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0605] Method [6] utilizes a 5% [B]:95% [A] to 20% [B]:80% [A]
gradient in 3.33 min, then hold, at 1.5 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0606] Method [7] utilizes a 20% [B]:80% [A] to 70% [B]:30% [A]
gradient in 1.75 min, then hold, at 2 mL/min, where [A]=0.1%
trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in
acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm.times.30 cm
column, 3 micron packing, 210 nm detection, at 35.degree. C.
[0607] Method [8] utilizes a YMC ODS-AQ S-3 120 A 3.0.times.50 mm
cartridge, with a standard gradient from 5% acetonitrile containing
0.01% heptafluorobutyric acid (HFBA) and 1% isopropanol in water
containing 0.01% HFBA to 95% acetonitrile containing 0.01% HFBA and
1% isopropanol in water containing 0.01% HFBA over 5 min.
[0608] Method [9]: 20-70% Acetonitrile in 1.75 min; 2 ml/min;
35.degree. C.; Column=Luna C18(2) 30 cm.times.4.6 mm; SN 112046-8
API-ES.
[0609] Method [10]: Column dimensions: 150 mm(long).times.21.2
mm(i.d.), C-18 staionary phase, 5 micron particle size, 100
angstrom pore size. Mobile phases are 0.1% Trifluoroacetic acid in
water (solvent A), and 0.1% trifluoroacetic acid in acetonitrile
(solvent B). Chromatographic conditions are 25 mL/min.: 5% solvent
B from 0 to 4.0 minutes, 5% to 95% solvent B from 4.0 to 22.0
minutes, 95% solvent B from 22.0 to 24.0 minutes 95% to 5% solvent
B from 24.0 to 24.4 minutes, then 5% solvent B from 24.4 to 27.0
minutes.
[0610] Method [11]: Column dimensions: 50 mm(long).times.3
mm(i.d.), C-18 stationary phase, 5 micron particle size, 100
angstrom pore size. Mobile phases are 0.05% trifluoroacetic acid in
water (solvent A), and 0.05% trifluoroacetic acid in acetonitrile
(solvent B). Chromatographic conditions are 3 mL/min.: 5% solvent B
from 0 to 0.275 minutes, 5% to 95% solvent B from 0.275 to 2.75
minutes, then 95% solvent B from 2.75 to 3.50 minutes.
EXAMPLE 268
Preparation of Precursor (4) for Formula (I) compounds
[0611] 281
[0612] As described herein, one embodiment of the present invention
provides for compounds of formula (4) as shown above in Scheme 1.
These compounds can be made by methods known to those skilled in
the art from starting compounds that are also known to those
skilled in the art. The process chemistry is further well known to
those skilled in the art. A suitable process for the preparation of
compounds of formula (4) is set forth in Scheme 1 above.
EXAMPLE 269
Alternative Preparation of Precursors for Formula (I) compounds
[0613] 282
[0614] An alternative approach, shown in Scheme 2 above, was to use
a common advanced intermediate 8 by which a reactive group could be
converted to yield compounds (4). Epoxides (2) were treated with
1.5-5 equivalents of primary amine H.sub.2N--R.sub.C1, (5) in an
alcoholic solvent, such as ethanol, isopropanol, or sec-butanol to
effect ring opening of the epoxide. In an embodiment, this reaction
is prepared at elevated temperatures from 40.degree. C. to reflux.
In another embodiment, this reaction is performed at reflux in
isopropanol. The resulting amino alcohol (6) was then deprotected
to form the free amine (7). The subsequent substition of the free
amine (7) was followed by the protection of the --NH--R.sub.c1
moiety to give compound 8.
[0615] When R.sub.C1 contains a labile functional group, such as an
aryl iodide, aryl bromide, aryl trifluoromethanesulfonate, or aryl
boronic ester, which may be converted into R.sub.C via transition
metal-mediated coupling, this allows for the rapid synthesis of a
variety of analogs (4). Such conversions may include Suzuki (aryl
boronic acid or boronic ester and aryl halide), Negishi (arylzinc
and aryl or vinyl halide), and Sonogashira (arylzinc and alkynyl
halide) couplings. Subsequent to the coupling reaction, the
protecting group P.sub.2 is removed by methods known in the art to
yield compounds (4).
[0616] The example below provides an exemplary procedure for the
preparation of epoxides 2 above.
EXAMPLE 270
Preparation of [2-(3,5-difluoro-phenyl)-1-oxiranyl-ethyl]-carbamic
acid tert-butyl ester
[0617] 283
[0618] The synthesis of tert-butyl
(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxi- ranyl]ethylcarbamate (11)
was carried out using the procedure described by Reeder, M. R., WO
2002085877. (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5--
difluorophenyl)propionic acid (9) was purchased from Chem Impex and
converted to the methyl ester without incident. Conversion of the
methyl ester to the chloroketone 10 was carried out on a 50 g scale
and repeatedly gave yields between 60-65% of an impure product. The
chlorohydrin was obtained via a diastereoselective
Meerwein-Ponndorf-Verley reduction. The product was washed with
octane to remove some, but not all of the impurities. Conversion of
the chlorohydrin to the epoxide 11 occurred with potassium
hydroxide in ethanol with the product being isolated from the
reaction mixture by precipitation after the addition of water. The
epoxide 11 could be recrystallized from hexanes/isopropanol,
although some batches of epoxide contained an unidentified
impurity.
[0619] Step 1: Preparation of
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3,5-d-
ifluorophenyl)propionic acid methyl ester.
[0620] A solution of
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluoroph-
enyl)propionic acid (9) (138 g, 458 mmol) was dissolved in THF
(1000 mL) and cooled to 0.degree. C. Potassium carbonate (69.6 g,
503.8 mmol) was added followed by the dropwise addition of dimethyl
sulfate (45.5 mL, 480.9 mmol). The reaction was removed from the
ice bath and allowed to stir at room temperature overnight after
which HPLC analysis shows the complete consumption of starting
material. The reaction was quenched by the addition of 10% ammonium
hydroxide (150 mL). The aqueous layer was removed and extracted
with ethyl acetate (500 mL). The combined organics were washed with
brine (500 mL), dried over magnesium sulfate and concentrated to
give a yellow solid. The solid was recrystallized from hexanes to
give the product as an off white solid (140.3 g, 445.0 mmol,
97%).
[0621] Step 2: tert-Butyl
(1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropyl- carbamate:
[0622] A solution of LDA was prepared by adding n-BuLi (26 mL, 260
mmol) to a solution of diisopropylamine (26.3 g, 260 mmol) in THF
(200 mL) at -78.degree. C. After the addition was complete, the
reaction was allowed by warm to 0.degree. C. This light yellow
solution was added dropwise to a solution of
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)p-
ropionic acid methyl ester (40 g, 127 mmol) and chloroiodomethane
(11.1 mL, 152 mmol) keeping the temperature below -65.degree. C.
After the addition, the solution was stirred for 30 minutes at
-78.degree. C. n-BuLi (15 mL, 150 mmol) was added dropwise keeping
the internal temperature below -62.degree. .degree. C. The reaction
was stirred for 30 minutes at -78.degree. C then quenched into 500
mL of 1 N HCl at 0.degree. C. The product was extracted into EtOAc
(500 mL), washed with brine (300 mL), dried over magnesium sulfate
and concentrated. Octane (400 mL) was added to the product and the
resulting solid collected by filtration and dried. The octane was
cooled to -78.degree. C. then allowed to warm until the octane
melted. The resulting solid was collected and added to the
previously collected solid. Drying of the combined solid gave the
title compound 10 as an off-white solid (33.9 g, 101.5 mmol,
64.5%).
[0623] Step 3: tert-Butyl
(1S,2S)-3-chloro-1-(3,5-diflurorbenzyl)-2-hydrox-
ypropylcarbamate.
[0624] A solution of tert-butyl
(1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxo- propylcarbamate (67.4
g, 202 mmol) (10) was dissolved in DCM (500 mL) and cooled to
0.degree. C. Tri(sec-butoxy)aluminum (54.7 g, 222.1 mmol, 1.1 eq)
in DCM (50 mL) was added dropwise. After stirring for 2 h at
0.degree. C., the reaction was complete by HPLC. The reaction was
quenched with 1 N HCl (750 mL) and the product extracted into ethyl
acetate (2.times.400 mL). The combined organics were washed with
brine (500 mL), dried over magnesium sulfate and concentrated to
give an oily yellow solid. Octane (300 mL) was added and the
resulting solid was collected by filtration and washed with octane
(100 mL). Drying overnight gave a white solid. The octane layers
were collected and concentrated to about 100 mL of volume, then
placed in the freezer for 48 h to yield a second crop of the title
compound (35 g, 104 mmol, 51%).
[0625] Step 4: tert-Butyl
(1S)-2-(3,5-diflurorphenyl)-1-[(2S)-oxiranyl]eth- ylcarbamate.
[0626] A solution of tert-butyl (1S,
2S)-3-chloro-1-(3,5-diflurorbenzyl)-2- -hydroxypropylcarbamate in
ethanol (150 mL) was cooled to 0.degree. C. A solution of KOH in
EtOH (25 mL) was added. The reaction was removed from the ice bath
and stirred for 2 h. The reaction was diluted with 300 mL of water
and placed into an ice bath. The resulting solid was collected by
filtration and washed with cold water (100 mL). Drying overnight
gave an off-white solid (11) (6.74 g, 22.51 mmol, 90%).
EXAMPLE 271
Alternative Procedure for the Preparation of Formula (I)
compounds
[0627] 284
[0628] 1-But-3-enyl-3,5-difluorobenzene
[0629] 1-Bromomethyl-3,5-difluorobenzene (12) (10.75 g, 51.9 mmol)
was added dropwise slowly to a stirring solution of allylmagnesium
bromide (Aldrich, 1.0 M solution in diethyl ether, 78 mL, 78 mmol)
at rt. Upon complete addition, the reaction mixture was stirred at
rt for 2.5 h. The reaction was quenched by slow addition of 1 N HCl
(40 mL). Diethyl ether (30 mL) was added, and the organics were
separated, washed (brine), dried (MgSO.sub.4), filtered and
concentrated. Fractional distillation (55-60.degree. C. at 13 torr)
afforded product 13 as a clear, colorless liquid (5.3 g, 60%):
R.sub.f=0.77 (hexanes). 285
[0630] 2-[2-(3,5-Difluorophenyl)ethyl]oxirane
[0631] m-chloroperbenzoic acid (22 g, Lancaster, 50-55 wt %, 64
mmol) was dissolved in dichloromethane (150 mL), and cooled to
0.degree. C. 1-But-3-enyl-3,5-difluorobenzene (13) (5.3 g, 31.5
mmol) in dichloromethane (10 mL) was added, and the mixture was
allowed to warm to rt overnight. The reaction was quenched with
saturated Na.sub.2SO.sub.3 (70 mL) and saturated NaHCO.sub.3 (70
mL), and the resulting mixture was stirred for 2 h. The organics
were separated, washed with saturated NaHCO.sub.3 (40 mL), brine
(50 mL), dried (MgSO.sub.4), filtered and concentrated. The residue
was dissolved in minimal cold hexanes and filtered. The filtrate
was concentrated to give desired product 14 (4.0 g, 70%): retention
time (min)=1.977; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.162.9
(dd, J=246.4, 12.9 Hz, 2C), 145.0 (t, J=8.9 Hz, 1C), 111.0 (dd,
J=16.7, 7.4 Hz, 2C), 101.4 (t, J=25.1 Hz, 1C), 51.2, 47.0, 33.5,
31.9; MS (ESI) 167. 286
[0632] Amine 1 (1 eq.) and 2-[2-(3,5-Difluorophenyl)ethyl]oxirane
14 (1 eq.) were dissolved in isopropanol and the reaction mixture
heated at 80.degree. C. for 6 hours. The solvent was evaporated and
product 15 was purified by flash chromatography and further
purified by HPLC.
EXAMPLE 272
Preparation of
4(S)-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chrom-
an-4-ylamino]-butan-2-ol
[0633] 287
[0634] The title compound was prepared according to the method
described in EXAMPLE 271. Characterization: MH+ 426.1, retention
time=2.0 min, Method [9].
EXAMPLE 273
Preparation of
1-(2-bromo-9H-fluoren-9-ylamino)-4-(3,5-difluoro-phenyl)-bu-
tan-2-ol
[0635] 288
[0636] The title compound was prepared according to the method
described in EXAMPLE 271. Characterization: MH+ 446.0, retention
time=2.1 min, Method [9].
EXAMPLE 274
Preparation of
4-(3,5-difluoro-phenyl)-1-[2-(2,2-dimethyl-propyl)-9H-fluor-
en-9-ylamino]-butan-2-ol
[0637] 289
[0638] The title compound was prepared according to the method
described in EXAMPLE 271. Characterization: MH+ 422.1, retention
time=2.2 min, Method [9].
EXAMPLE 275
Preparation of
4-(3,5-difluoro-phenyl)-1-(6-isobutyl-1,1-dioxo-1.lambda..s-
up.6-thiochroman-4-ylamino)-butan-2-ol
[0639] 290
[0640] The title compound was prepared according to the method
described in EXAMPLE 271. Characterization: MH+ 437.8, retention
time=1.9 min, Method [9].
EXAMPLE 276
Preparation of
1-(6-bromo-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-
-4-3,5-difluoro-phenyl)-butan-2-ol
[0641] 291
[0642] The title compound was prepared according to the method
described in EXAMPLE 271. Characterization: MH+ 460.0, retention
time=1.6 min, Method [9].
EXAMPLE 277
Preparation of
4-(3,5-difluoro-phenyl)-1-(1,1-dioxo-1.lambda..sup.6-thioch-
roman-4-ylamino)-butan-2-ol
[0643] 292
[0644] The title compound was prepared according to the method
described in EXAMPLE 271. Characterization: MH+ 382.1, retention
time=1.4 min, Method [9].
EXAMPLE 278
Preparation of
1-[1-(3-tert-butyl-phenyl)-4-methylsulfanyl-cyclohexylamino-
]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0645] 293
Synthesis of 4-methylsulfanyl-cyclohexanone (20)
[0646] 294
[0647] 1,4-Dioxa-spiro[4.5]decan-8-ol (17) from 1,
4-Dioxa-spiro[4.5]decan- -8-one (16)
[0648] To a solution of 1,4-dioxa-spiro[4.5]decan-8-one (16)
(Aldrich, 10.0 g, 64.0 mmol) in anhydrous methanol (250 mL) at
0.degree. C. was added solid sodium borohydride (4.6 g, 121 mmol).
The reaction mixture was allowed to warm to rt over 1 h, whereupon
TLC analysis indicated complete reaction. Water (60 mL) was added,
and the methanol was removed under reduced pressure. The aqueous
residue was partitioned between ethyl acetate (200 mL) and
saturated aqueous brine (50 mL). The layers were separated, and the
aqueous extracted with addition ethyl acetate (200 mL). The
combined organic layers were dried (MgSO.sub.4), filtered and
concentrated under reduced pressure to afford the crude alcohol 17
(9.3 g, 92%): R.sub.f=0.2 (CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.3.95 (s, 4H), 3.85-3.75 (m, 1H), 2.00-1.75 (m,
4H), 1.75-1.50 (m, 4H).
[0649] 8-Methylsulfanyl-1,4-Dioxa-spiro[4.5]decane (18) from
1,4-Dioxa-spiro[4.5]decan-8-ol (17)
[0650] Ref.: J. Org. Chem. 1986, 51, 2386-2388. To a solution of
1,4-dioxa-spiro[4.5]decan-8-ol (17) (8.6 g, 54 mmol) in chloroform
(54 mL) at 0.degree. C. was added pyridine (13.2 mL, 163 mmol). To
this stirring solution was added P-toluenesulfonyl chloride (20.7
g, 108 mmol) in portions. This was stirred at 0.degree. C. for 7 h,
whereupon the mixture was partitioned between diethyl ether (150
mL) and water (50 mL). The organic layer was washed with 3 N HCl
(50 mL), saturated sodium bicarbonate (50 mL), and water (50 mL).
The organic layer was dried (MgSO.sub.4), filtered and concentrated
under reduced pressure to give crude toluene-4-sulfonic acid
1,4-dioxa-spiro[4.5]dec-8-yl ester. (18) as a crystalline solid,
contaminated with p-toluenesulfonic acid: R.sub.f=0.31
(CH.sub.2Cl.sub.2).
[0651] Crude toluene-4-sulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl
ester (18) (18 g) in ethanol (25 mL) was added to a solution of
sodium thiomethoxide (12.1 g, 173 mmol) in dry methanol (75 mL).
This mixture was heated to 80.degree. C for 4 h. The mixture was
partitioned between ethyl acetate (100 mL) and water (100 mL). The
aqueous layer was extracted with additional ethyl acetate (100 mL).
The combined organic layers were concentrated under reduced
pressure. The residue was partitioned between CH.sub.2Cl.sub.2: (75
mL) and saturated NaHCO.sub.3 (100 mL). The aqueous layer was
extracted with additional CH.sub.2Cl.sub.2 (50 mL). The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure to give crude
8-methylsulfanyl-1,4-dioxa-spiro[4.5]decane (19) (6.6 g, 77% over
two steps): R.sub.f=0.45 (CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.3.94 (s, 4H), 3.67-3.53 (m, 1H), 2.09 (s, 3H),
2.05-1.92 (m, 2H), 1.90-1.50 (m, 6H).
[0652] 4-Methylsulfanyl-cyclohexanone (20) from
8-Methylsulfanyl-1,4-dioxa- -spiro[4.5]decane (19).
[0653] 8-Methylsulfanyl-1,4-dioxa-spiro[4.5]decane (19) (6.6 g, 35
mmol) was combined with p-toluenesulfonic acid (6.65 g, 35 mmol) in
water (75 mL), and heated to reflux for 5 h, and was subsequently
allowed to stir at rt overnight. The aqueous reaction mixture was
extracted with Et.sub.2O (3.times.100 mL). The combined organic
layers were washed successively with 3 N HCl (2.times.25 mL),
saturated NaHCO.sub.3 (2.times.25 mL), and water (2.times.25 mL).
The organics were then dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography (CH.sub.2Cl.sub.2 elution) to give
4-methylsulfanyl-cyclohexanone (20) (3.0 g, 60%): R.sub.f=0.21 (3:1
CH.sub.2Cl.sub.2/hexanes); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.3.01-2.98 (m, 1H), 2.52-2.38 (m, 2H), 2.35-2.22 (m, 2H),
2.22-2.08 (m, 2H), 2.06 (s, 3H), 1.88-1.72 (m, 2H). 295
[0654] 1-(3-tert-Butyl-phenyl)-4-Methylsulfanyl-cyclohexylamine
from 4-methylsulfanyl-cyclohexanone
[0655] 4-Methylsulfanyl-cyclohexanone (20) was converted into
1-(3-tert-Butyl-phenyl)-4-methylsulfanyl-cyclohexylamine (21) in
the manner described in EXAMPLE 361 below, except using
1-bromo-3-tert-butyl-benzene in the first step. 296
[0656]
1-[1-(3-tert-Butyl-phenyl)-4-methylsulfanyl-cyclohexylamino]-4-(3,5-
-difluoro-phenyl)-butan-2-ol from
1-(3-tert-Butyl-phenyl)-4-methylsulfanyl- -cyclohexylamine
[0657]
1-[1-(3-tert-Butyl-phenyl)-4-methylsulfanyl-cyclohexylamino]-4-(3,5-
-difluoro-phenyl)-butan-2-ol (22) was synthesized from
1-(3-tert-Butyl-phenyl)-4-methylsulfanyl-cyclohexylamine (21)
according to the procedure described in EXAMPLE 271.
EXAMPLE 279
Preparation of
1-[1-(3-tert-butyl-phenyl)-4-methoxy-cyclohexylamino]-4-(3,-
5-difluoro-phenyl)-butan-2-ol
[0658] 297
[0659] 1-(3-tert-Butyl-phenyl)-4-methoxy-cyclohexylamine from
4-methoxycyclohexanone 298
[0660] 4-Methoxycyclohexanone was synthesized according to the
procedure described in Kaiho, T. et al. J. Med. Chem. 1989, 32,
351-357. The ketone was converted to the
1-(3-tert-Butyl-phenyl)-4-methoxy-cyclohexylamine in the manner
described in EXAMPLE 361, except using 1-bromo-3-tert-butyl-be-
nzene in the first step to give a 1:1 mixture of isomers: retention
time (min)=1.33 and 1.42 (diastereomers), method [1],
[0661] MS(ESI) 213.2 (M-NH.sub.2); MS(ESI) 213.2 (M-NH.sub.2).
299
[0662] The amine was converted into
1-[1-(3-tert-Butyl-phenyl)-4-methoxy-c-
yclohexylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol according to the
procedure described in EXAMPLE 271.
EXAMPLE 280
Preparation of
1-[1-(3-tert-butyl-phenyl)-4-trifluoromethyl-cyclohexylamin-
o]4-(3,5-difluoro-phenyl)-butan-2-ol
[0663] 300
[0664] 1-(3-tert-Butyl-phenyl)-4-trifluoromethyl-cyclohexylamine
from 4-Trifluoromethyl-cyclohexanone 301
[0665] 4-Trifluoromethylcyclohexanone (Matrix Scientific) was
converted to the titled amine by the method described in EXAMPLE
361: retention time (min)=1.64 and 1.69 (diastereomers), method
[1]; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.55 (s, 0.5H), 7.47
(s, 0.5H), 7.40-7.20 (m, 3H), 2.54 (d, J=13.2 Hz, 1H), 2.15 (br s,
2H), 2.00-1.80 (m, 4H), 1.75-1.50 (m, 4H), 1.34 (s, 9H); MS(ESI)
283.1 (M-NH.sub.2). 302
[0666]
1-[1-(3-tert-Butyl-phenyl)-4-trifluoromethyl-cyclohexylamino]-4-(3,-
5-difluoro-phenyl)-butan-2-ol from
1-(3-tert-Butyl-phenyl)-4-trifluorometh- yl-cyclohexylamine
[0667] The titled compound can be synthesized from the intermediate
amine by the route described in EXAMPLE 271.
EXAMPLE 281
Preparation of
1-[1-(6-tert-butyl-pyrimidin-4-yl)-cyclohexylamino]-4-(3,5--
difluoro-phenyl)-butan-2-ol
[0668] 303
[0669] Synthesis of 1-(6-tert-Butyl-pyrimidin-4-yl)-cyclohexylamine
304
[0670] 6-tert-Butyl-pyrimidin-4-ol from
6-tert-Butyl-2-mercapto-pyrimidin-- 4-ol
[0671] Procedure adapted from: J. Med. Chem. 2002, 45, 1918-1929.
6-tert-Butyl-2-mercapto-pyrimidin-4-ol (1.0 g, 5.4 mmol),
synthesized according to the procedure described in J. Am. Chem.
Soc. 1945, 67, 2197, was dissolved in boiling EtOH (30 mL). Raney
Ni 2800 slurry (Aldrich) was added to the mixture dropwise until
starting material had been determined by TLC to be completely
consumed (approx. 5 mL of slurry over 3 h). The mixture was
filtered through diatomaceous earth, washed with EtOH (50 mL). The
filtrate was concentrated under reduced pressure to give 794 mg,
96% of desired product: R.sub.f=0.13 (1:1 EtOAc/hexanes); .sup.1H
NMR (300 MHz, MeOD-d.sub.4) .delta.8.14 (s, 1H), 6.37 (s, 1H), 1.29
(s, 9H).
[0672] 4-Bromo-6-tert-butyl-pyrimidine from
6-tert-Butyl-pyrimidin-4-ol
[0673] Procedure adapted from: Kim, J. T. Org. Lett. 2002, 4,
4697-4699. Phosphorus oxybromide (14.9 g, 51.9 mmol) was added to a
solution of 6-tert-Butyl-pyrimidin-4-ol (5.2 g, 34 mmol) and
N,N-dimethylaniline (1.25 g, 10 mmol) in anhydrous benzene (150
mL). The mixture was then heated to reflux for 3 h. The reaction
mixture was then allowed to cool to rt, and saturated
Na.sub.2CO.sub.3 (200 mL) was added. The layers were separated, and
the aqueous further extracted with EtOAc (300 mL). The combined
organic layers were washed (sat'd NaCl), dried (Na.sub.2SO.sub.4),
filtered and concentrated under reduced pressure. Flash
chromatography (0-20% EtOAc/hexanes gradient elution) afforded pure
product (3 g, 40%): R.sub.f=0.84 (1:4 EtOAc/hexanes); .sup.1H NMR
(300 MHz, CDCl.sub.3), .delta.8.82 (d, J=0.6 Hz, 1H), 7.74 (d,
J=0.6 Hz, 1H), 1.35 (s, 9H).
[0674] 1-(6-tert-Butyl-pyrimidin-4-yl)-cyclohexylamine from
4-Bromo-6-tert-butyl-pyrimidine
[0675] The cyclohexylamine was synthesized from the aryl bromide
using 2-methylpropane-2-sulfinic acid cyclohexylideneamide as
prepared according to the method of Liu, G. et al. J. Org. Chem.
1999, 64, 1278-1284: retention time (min)=1.48, method [1]; MS
(ESI) 234.2. 305
[0676]
1-[1-(6-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino]-4-(3,5-difluoro-
-phenyl)-butan-2-ol from
1-(6-tert-Butyl-pyrimidin-4-yl)-cyclohexylamine
[0677] The title compound can be synthesized from the intermediate
amine according to methods described in EXAMPLE 271.
EXAMPLE 282
Preparation of
1-[1-(3-tert-butyl-5-fluoro-phenyl)-cyclohexylamino]-4-(3,5-
-difluoro-phenyl)-butan-2-ol
[0678] 306307
[0679] (4-tert-Butyl-2-fluoro-phenyl)-carbamic acid methyl
ester:
[0680] To a stirred solution of the carbamate (12.2 g, 72 mmol) in
144 mL 5 dichloromethane at 0.degree. C. under a drying tube was
added aluminum trichloride (28.85 gm, 216 mmol) carefully portion
wise as a solid (some exotherm). The suspension was allowed to cool
back to 0.degree. C. for about 5 minutes and then isobromobutane
(39.22 mL, 360 mmol) was added carefully by syringe at a rate that
avoided reflux. The reaction was stirred for 5 minutes. HPLC shows
near complete conversion at this time (retention time (min)=3.60,
method [8]). The reaction was carefully poured into rapidly
stirring ice water (500 mL) and diluted with 400 mL
CH.sub.2Cl.sub.2. The mixture was stirred for about 5 minutes and
the layers separated. The organics were washed 2.times.100 mL with
H.sub.2O, 1.times.200 mL with saturated NaHCO.sub.3 and 1.times.100
mL with brine. The organics were dried (MgSO.sub.4), filtered and
concentrated to a brown oil that was used crude in the next
reaction.
[0681] 4-tert-Butyl-2-fluoro-phenylamine:
[0682] To a stirred solution of the crude carbamate (18.4 gm, 81.7
mmol) in 163 mL MeOH at room temperature under nitrogen was added
2N NaOH (81.7 mL, 163.4 mmol). The reaction was warmed to
75.degree. C. and stirred overnight. 40 mL of 2N NaOH was added and
the reaction stirred at 75.degree. C. overnight again. HPLC showed
the reaction has gone to completion (retention time=3.59, 3.65,
method [8]). The reaction was cooled to room temperature and most
of the MeOH was removed by rotovap. The residual aqueous mixture
was cooled on ice and neutralized to pH=8 with conc. HCl. The
solution was then extracted 2.times.100 mL with CH.sub.2Cl.sub.2
and the organics combined, dried (MgSO.sub.4), filtered and
concentrated to a brown oil which was taken into the iodination as
is.
[0683] 4-tert-Butyl-2-fluoro-6-iodo-phenylamine:
[0684] To a stirred solution of the crude aniline (12.8 g, 76.54
mmol) in 240 mL CH.sub.2Cl.sub.2 and 80 mL MeOH at room temperature
under nitrogen was added calcium carbonate (15.32 gm, 153.1 mmol)
followed by the iodinating reagent, benzyltrimethylammonium
iododichloride (67.28 g, 153.1 mmol). The reaction was allowed to
proceed overnight at room temperature. HPLC showed complete
consumption of starting material and a new late eluting peak. The
reaction was diluted to 500 mL with CH.sub.2Cl.sub.2 and poured
into ice cold 10% NaHSO.sub.3 with rapid stirring. The layers were
separated and the organics washed 1.times.500 mL with 10%
NaHSO.sub.3, 1.times.500 mL with H.sub.2O and 1.times.500 mL with
saturated NaHCO.sub.3. The organics were dried (MgSO.sub.4),
filtered and concentrated to a brown oil which was diluted in
CH.sub.2Cl.sub.2 and absorbed onto silica gel. After rotovap and
thorough high vacuum drying the silica was loaded into a ZIF module
in line with a Biotage 75S column and eluted first with pure
hexanes and then 98/2 hexanes/Et.sub.2O. The product was isolated
and concentrated to a brown oil (11.72 gm, 52% for three steps):
retention time (min)=4.45, method [8]; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.7.38 (s, 1H), 7.00 (d, J=10.8 Hz, 1H), 3.99 (s,
2H), 1.25 (s, 9H).
[0685] 1-tert-Butyl-3-fluoro-5-iodo-benzene:
[0686] To a stirred solution of t-butyl nitrite 7.13 mL, 60 mmol)
in 80 mL DMF at 60.degree. C. under nitrogen was added a solution
of the iodoaniline (11.72 gm, 40 mmol) in 80 mL DMF dropwise by
cannulation. The reaction began to evolve gas. After complete
addition the reaction was stirred for 1 hour and then cooled to
room temperature. HPLC showed complete consumption of starting
material and a new late eluting peak. The reaction was diluted with
1 L EtOAc and washed 4.times.800 mL with H.sub.2O and then
1.times.800 mL with brine. The organics were dried (MgSO.sub.4),
filtered and concentrated to a brown oil that was loaded onto a
Biotage 65 column with hexane and eluted with the same solvent. The
product containing fractions were pooled and partially concentrated
to about 100 mL. The solution of combined fractions was washed
1.times.100 mL with 10% NaHSO.sub.3, 1.times.100 mL with H.sub.2O
and 1.times.100 mL with NaHCO.sub.3. The clear organics were dried
(MgSO.sub.4), filtered and concentrated to a clear oil (6.8 gm,
61%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.48 (s, 1H),
7.27-7.22 (m, 1H), 7.04 (d, J=10.5 Hz, 1H), 1.26 (s, 9H).
[0687] 1-(3-tert-Butyl-5-fluoro-phenyl)-cyclohexanol:
[0688] To a stirred solution of the iodobenzene derivative (2.3 gm,
8.27 mmol) in 16 mL THF at -78.degree. C. under nitrogen was added
n-BuLi (2.5 M in hexanes, 3.31 mL, 8.27 mmol) dropwise by syringe.
After 2 hours, a solution of cyclohexanone (1.03 mL, 9.92 mmol) in
8 mL THF was added dropwise by cannulation at -78.degree. C. After
1 hour TLC in 4/1 hexanes/EtOAc shows a major spot at rf=0.4. The
reaction was poured into 50 mL saturated NH.sub.4Cl. and then the
solution was extracted 3.times.50 mL with EtOAc. The combined
organics were dried (MgSO.sub.4), filtered and concentrated. The
crude product was loaded onto a. Biotage 40M column with hexanes
and eluted with 4/96 EtOAc/hexanes. Product containing fractions
were pooled and concentrated to a clear oil which solidified upon
storage in the freezer overnight (1.3 gm, 63%): R.sub.f=0.2 (9:1
hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.31 (s,
1H), 7.01 (d, J=10.5 Hz, 1H), 6.95 (d, J=10.4 Hz, 1H), 1.86-1.56
(m, 10H), 1.31 (s, 9H).
[0689] 1-(1-Azido-cyclohexyl)-3-tert-butyl-5-fluoro-benzene:
[0690] To a stirred solution of the tertiary alcohol (1.3 gm, 5.2
mmol) in 11 mL CH.sub.2Cl.sub.2 at 0.degree. C. under nitrogen was
added sodium azide (1.01 gm, 15.6 mmol) as a solid. A solution of
TFA (1.2 mL, 15.6 mmol) in 5 mL CH.sub.2Cl.sub.2 was then added
dropwise by syringe. Immediately a solid began to precipitate. The
cooling bath was removed and after 1 hour, TLC in 9/1 hexanes/EtOAc
showed near complete consumption of starting material. The reaction
was allowed to proceed overnight. The reaction was partitioned
between CH.sub.2Cl.sub.2 (50 mL) and H.sub.2O (50 mL) and the
organics washed 2.times.50 mL with 3N NH.sub.4OH and 1.times.50 mL
with brine. The organics were dried (MgSO.sub.4), filtered and
concentrated to a yellow oil. The material was taken crude into the
Staudinger Reduction.
[0691] 1-(3-tert-Butyl-5-fluoro-phenyl)-cyclohexylamine
hydrochloride salt:
[0692] To a stirred solution of the azide (800 mg, 2.9 mmol) in 9
mL 95% EtOH at room temperature was added Pearlman's Catalyst. The
suspension was put through a vacuum/purge cycle three times with
hydrogen gas and then held under 1 atm hydrogen. After 2 hours the
reaction appeared to be complete by TLC in 9/1 EtOAc/MeOH. The
suspension was filtered through GF/F filter paper with 95% EtOH and
the filtrate concentrated to a crude oil. The oil was loaded onto a
Biotage 40M cartridge with EtOAc and eluted on the Horizon system
with a gradient of EtOAc to 10% MeOH in EtOAc. Product containing
fractions were pooled and concentrated to a clear oil (540 mg,
75%). The free base was dissolved in 5 mL Et.sub.2O and cooled to
0.degree. C. and treated with 1M HCl in Et.sub.2O (2 eq). A white
precipitate formed that was filtered off with hexane rinse and
dried under high vacuum: retention time (min)=2.73, method [8];
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.44 (s, 2H), 7.49 (s,
1H), 7.28-7.20 (m, 2H), 2.32-2.20 (m, 2H), 1.99-1.87 (m, 2H),
1.79-1.65 (m, 2H), 1.50-1.27 (m, 4H), 1.30 (s, 9H); MS (ESI) 249.8.
308
[0693]
1-[1-(3-tert-Butyl-5-fluoro-phenyl)-cyclohexylamino]-4-(3,5-difluor-
o-phenyl)-butan-2-ol
[0694] The title compound can be synthesized from
1-(3-tert-Butyl-5-fluoro- -phenyl)-cyclohexylamine using methods
described in EXAMPLE 271.
EXAMPLE 283
Preparation of 4-amino-4-(3-tert-butyl-phenyl)-cyclohexanone
[0695] 309
[0696] This amine was synthesized from
8-(3-tert-Butyl-phenyl)-1,4-dioxa-s- piro[4.5]dec-8-ylamine, TsOH,
and ethylene glycol in refluxing benzene. Retention time
(min)=1.34, method [4]; MS (ESI) 229.1 (100), 246.1 (40).
EXAMPLE 284
Preparation of
1-[1-(3-tert-butyl-phenyl)-4,4-difluoro-cyclohexylamino]-4--
(3,5-difluoro-phenyl)-butan-2-ol from
1-(3-tert-butyl-phenyl)-4,4-difluoro- -cyclohexylamine
[0697] 310
[0698] To 4-amino-4-(3-tert-butyl-phenyl)-cyclohexanone (200 mg,
0.82 mmol) was added a solution of bis(2-methoxyethyl)amino-sulfur
trifluoride (360 mg, 1.6 mmol) and ethanol (12 .mu.L) in
CH.sub.2Cl.sub.2 (1 mL). This was stirred overnight at rt. The
reaction mixture was quenched with saturated NaHCO.sub.3 (5 mL),
and extracted with EtOAc (2.times.5 mL). The organic extracts were
dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (10%
MeOH/CH.sub.2Cl.sub.2 elution) to give 20 mg (9%) of material as an
oil: R.sub.f=0.33 (10% MeOH/CH.sub.2Cl.sub.2); retention time
(min)=1.51, method [1]; MS (ESI) 251.1. 311
[0699]
1-[1-(3-tert-Butyl-phenyl)-4,4-difluoro-cyclohexylamino]-4-(3,5-dif-
luoro-phenyl)-butan-2-ol
[0700] The title compound can be synthesized from
1-(3-tert-Butyl-phenyl)-- 4,4-difluoro-cyclohexylamine according to
the method described in EXAMPLE 271.
EXAMPLE 285
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid benzyl ester
[0701] 312
[0702]
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butyla-
mino]-piperidine-1-carboxylic acid benzyl ester from
3-amino-3-(3-tert-butyl-phenyl)-piperidine-1-carboxylic acid benzyl
ester
[0703] The titled compound was prepared according to the procedure
described in EXAMPLE 271 from
3-amino-3-(3-tert-butyl-phenyl)-piperidine-- 1-carboxylic acid
benzyl ester.
EXAMPLE 286
Preparation of
1-[3-(3-tert-butyl-phenyl)-1-methyl-piperidin-3-ylamino]-4--
(3,5-difluoro-phenyl)-butan-2-ol and
1-[3-(3-tert-butyl-phenyl)-piperidin--
3-ylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0704] 313
[0705] To a stirring solution of
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluor-
o-phenyl)-2-hydroxy-butylamino]-piperidine-1-carboxylic acid benzyl
ester in MeOH and HOAc was added 10% palladium-carbon. The
resulting mixture was stirred at room temperature under an
atmospheric pressure of hydrogen for 2 days. The mixture was then
filtered through a plug of Celite. The Celite plug was washed
several times with 10% MeOH/EtOAc. The filtrate was concentrated
under reduced pressure to give a crude mixture, which was subjected
to silica gel chromatography, and further purified via HPLC to give
the title compounds.
EXAMPLE 287
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid methyl ester
[0706] 314
[0707] To a stirring solution of
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluor-
o-phenyl)-2-hydroxy-butylamino]-piperidine-1-carboxylic acid benzyl
ester in EtOAc and HOAc was added 10% palladium-carbon. The
resulting mixture was stirred at room temperature under an
atmospheric pressure of hydrogen for 2 days. The mixture was then
filtered through a plug of Celite. The Celite plug was washed
several times with 10% MeOH/EtOAc. The filtrate was concentrated
under reduced pressure to give a crude mixture, which was subjected
to silica gel chromatography to give
1-[3-(3-tert-Butyl-phenyl)-piperidin-3-ylamino]-4-(3,5-difluoro-phenyl)-b-
utan-2-ol.
[0708] To a stirring solution of
1-[3-(3-tert-Butyl-phenyl)-piperidin-3-yl-
amino]-4-(3,5-difluoro-phenyl)-butan-2-ol in CH.sub.2Cl.sub.2 was
successively added pyridine, DMAP, and methyl chloroformate. The
resulting mixture was allowed to react overnight at room
temperature. The reaction was quenched with a saturated NaHCO.sub.3
solution and extracted with EtOAc (2.times.20 mL). The organic
layers were washed with brine, dried over Na.sub.2SO.sub.4, and
filtered. The combined organic layers were evaporated under reduced
pressure. The crude mixture was purified via silica gel
chromatography to give the title compound.
EXAMPLE 288
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid benzyl ester
[0709] 315 316
[0710] 1-Benzyl-3-(3-tert-butyl-phenyl)-piperidin-3-ol. Iodo
t-butyl benzene (2.46 g, 9.44 mmol) was taken up in 10 mL of THF,
placed under N.sub.2 and cooled to -78.degree. C. T-Butyl lithium
(11.06 mL, 1.7M solution, 18.8 mmol) was added dropwise over 5
minutes. The reaction was allowed to stir for 1 hour. The
1-benzyl-piperidin-3-one (1.5 g, 8.0 mmol) was added and the
reaction was stirred for 3 hours warming to r.t. The reaction was
quenched with water and extracted with ether. The ether layer was
dried over MgSO4, filtered and concentrated under reduced pressure.
The material was purified using a biotage 40M eluting with hexanes:
ethyl acetate (70:30) to yield 1.4 g (54% yield) of a clear oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.57 (t, J=1.3 Hz, 1H),
7.36-7.22 (m, 8H), 3.95 (s, 1H), 3.58. (s, 2H), 2.91 (d, J=10.4 Hz,
1H), 2.76 (d, J=10.8 Hz, 1H), 2.34 (d, J=10.8 Hz, 1H), 2.10-1.90
(m, 3H), 1.85-1.62 (m, 4H), 1.32 (s, 9H).
[0711]
N-[1-Benzyl-3-(3-tert-butyl-phenyl)-piperidin-3-yl]-2-chloro-acetam-
ide. To 1-benzyl-3-(3-tert-butyl-phenyl)-piperidin-3-ol (517 mg,
1.6 mmol) and chloroacetonitrile (241 mg, 3.2 mmol) was added 300
uL of AcOH. This mixture was placed under nitrogen and cooled to
0.degree. C. Sulfuric acid (300 uL) was added dropwise keeping the
temp below 10.degree. C. The reaction was stirred for 12 hours
warming to r.t. The reaction was diluted with ethyl acetate (75 mL)
and 10% aq sodium carbonate (75 mL). The layers were separated and
the organic layer was dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The material was purified
using a biotage 40S cartridge eluting with hexanes:ethyl acetate
(70:30) to afford 247 mg (40% yield) of a clear oil: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.7.73 (s, 1H), 7.37-7.20 (m, 7H), 7.12
(dt, J=7.1,1.8 Hz, 1H), 4.02 (s, 2H), 3.56 (d, J=13.4 Hz, 1H), 3.48
(d, J=13.4 Hz, 1H), 2.95 (d, J=9.8 Hz, 1H), 2.80 (d, J=11.8 Hz,
1H), 2.71 (d, J=9.9 Hz, 1H), 2.10-2.00 (m, 2H), 1.91 (dt, J=12.8,
4.6 Hz, 1H), 1.85-1.65 (m, 2H), 1.29 (s, 9H).
[0712]
3-(3-tert-Butyl-phenyl)-3-(2-chloro-acetylamino)piperidine-1-carbox-
ylic acid benzyl ester. To a stirred solution of
N-[1-Benzyl-3-(3-tert-but-
yl-phenyl)-piperidin-3-yl]-2-Chloro-acetamide (247 mg, 0.620 mmol)
in Toluene (2 mL) was added benzylchloroformate (177 uL, 1.24
mmol). The reaction was heated to 80.degree. C. and stirred for 4
hours. An additional 2 eq was added and the reaction was stirred at
r.t. for 3 days. The reaction was diluted with ethyl acetate (50
mL) and 10% aq sodium carbonate (50 mL). The layers were separated
and the organic layer was dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The material was purified
using a biotage 12i cartridge eluting with hexanes:ethyl acetate
(70:30) to afford 240 mg (84% yield) of a clear oil: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.7.45-7.22 (m, 9H), 5.23 (d, J=12.3 Hz,
1H), 5.17 (d, J=12.3 Hz, 1H), 4.44-4.30 (m, 1H), 4.30-4.10 (m, 1H),
3.95-3.80 (m, 2H), 3.20-3.00 (m, 1H), 3.00-2.80 (m, 2H), 2.10-1.90
(m, 1H), 1.80-1.60 (m, 2H), 1.30 (s, 9H).
[0713] 3-Amino-3-(3-tert-butyl-phenyl)-piperidine-1-carboxylic acid
benzyl ester. The
3-(3-tert-butyl-phenyl)-3-(2-chloro-acetylamino)-piperidine-1--
carboxylic acid benzyl ester (239 mg, 0.540 mmol) was taken up in
ethanol (1 mL) and AcOH (200 uL) followed by the addition of
thiourea (50 mg, 0.648 mmol). The reaction was heated to 80.degree.
C. and stirred for 12 hours. The reaction was diluted with ethyl
acetate (50 mL) and 10% aq sodium carbonate (50 mL). The layers
were separated and the organic layer was dried over MgSO4, filtered
and concentrated under reduced pressure. The material was purified
using a biotage 12i cartridge eluting with ethyl acetate: methanol
(92:8) to afford 166 mg (84% yield) of a clear oil: retention time
(min)=1.71, method [1];
[0714] MS(ESI) 367.4 (31), 350.4 (100). 317
[0715]
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butyla-
mino]-piperidine-1-carboxylic acid benzyl ester was synthesized
from 3-Amino-3-(3-tert-butyl-phenyl)-piperidine-1-carboxylic acid
benzyl ester according to the procedure described in EXAMPLE
271.
EXAMPLE 289
Preparation of
1-{3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hyd-
roxy-butylamino]-piperidin-1-yl}-ethanone
[0716] 318
[0717] The free amine was converted into
1-{3-(3-tert-Butyl-phenyl)-3-[4-(-
3,5-difluoro-phenyl)-2-hydroxy-butylamino]-piperidin-1-yl}-ethanone
according to EXAMPLE 288.
EXAMPLE 290
Preparation of
1-[3-(3-tert-butyl-phenyl)-1-methanesulfonyl-piperidin-3-yl-
amino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0718] 319
[0719] The free amine was converted into
1-[3-(3-tert-Butyl-phenyl)-1-meth-
anesulfonyl-piperidin-3-ylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol
according to EXAMPLE 288.
EXAMPLE 291
Preparation of
1-{3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hyd-
roxy-butylamino]-piperidin-1-yl}-3-phenyl-propan-1-one
[0720] 320
[0721] The free amine was converted into
1-{3-(3-tert-Butyl-phenyl)-3-[4-(-
3,5-difluoro-phenyl)-2-hydroxy-butylamino]-piperidin-1-yl}-3-phenyl-propan-
-1-one according to EXAMPLE 288.
EXAMPLE 292
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid amide
[0722] 321
[0723] To a stirring solution of the free amine (0.074 mmol) in
THF/H.sub.2O (0.6 mL each) was added pyridine, acetic acid (2 drops
each) and NaOCN (3.7 mmol). The resulting mixture was allowed to
react for 24 h. The mixture was then quenched with CH.sub.2Cl.sub.2
(10 mL) and saturated NaHCO.sub.3 solution (10 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
(2.times.10 mL). The layers were dried over NaSO.sub.4, filtered,
and concentrated under reduced pressure. The crude mixture was
purified via a silica gel chromatography to give
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]--
piperidine-1-carboxylic acid amide.
EXAMPLE 293
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid amide
[0724] 322
[0725] To a stirring mixture of the amine (0.158 mmol) and
NaHPO.sub.4 (0.80 mmol) in THF (1 mL) was added dibenzoylperoxide
(0.182 mmol) in THF (0.2 mL) dropwise. After 15 h of stirring, the
resulting mixture was then filtered and the solid was washed with
50 mL of CH.sub.2Cl.sub.2. The organic layer was then concentrated
under reduced pressure. The insoluble material was then dissolved
in 10% NaHCO.sub.3 and CH.sub.2Cl.sub.2 (20 mL, each). The layers
were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. This crude rmixture was directly taken to the next
reaction without any further purification.
[0726] To a stirring solution of N-OBz in THF (1 mL) was added
hydrazine (200 .mu.L) dropwise at room temperature. After 15 h of
stirring, the mixture was then concentrated under reduced pressure.
The crude mixture was purified via silica chromatography to give
3-(3-tert-Butyl-phenyl)-3--
[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-piperidine-1-carboxylic
acid amide.
EXAMPLE 294
Preparation of
{3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydro-
xy-butylamino]-piperidin-1-yl}-piperidin-1-yl-methanone
[0727] 323
[0728] To a stirring solution of the free amine (0.74 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added Et.sub.3N and
1-piperidinecarbonyl chloride (1.4 mmol). The resulting mixture was
allowed to react at room temperature overnight. The reaction
mixture was then quenched with a saturated NaHCO.sub.3 solution.
The layers were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.10 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The crude mixture was purified via silica gel
chromatography and then further purified via HPLC to give
{3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-
-piperidin-1-yl}-piperidin-1-yl-methanone.
EXAMPLE 295
Preparation of
3-3-tert-butyl-phenyl-3-[4-3,5-difluoro-phenyl)-2-hydroxy-b-
utylamino]-piperidine-1-carboxylic acid dimethylamide
[0729] 324
[0730]
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butyla-
mino]-piperidine-1-carboxylic acid dimethylamide was synthesized
analogous to EXAMPLE 294.
EXAMPLE 296
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid isopropylamide
[0731] 325
[0732]
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butyla-
mino]-piperidine-1-carboxylic acid isopropylamide was synthesized
analogous to EXAMPLE 294.
EXAMPLE 297
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid methylamide
[0733] 326
[0734]
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butyla-
mino]-piperidine-1-carboxylic acid methylamide was synthesized
analogous to EXAMPLE 294.
EXAMPLE 298
Preparation of
3-(3-tert-butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydrox-
y-butylamino]-piperidine-1-carboxylic acid benzylamide
[0735] 327
[0736] To a stirring solution of
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluor-
o-phenyl)-2-hydroxy-butylamino]-piperidine-1-carboxylic acid amide
(0.14 mmol) in THF (1 mL) at 0.degree. C. was added
Ti(O.sup.iPr).sub.4 (48 mmol), followed by the addition of
benzaldehyde (0.2 mmol) and NaBH.sub.4 (4 mg). The reaction was
then allowed to warm to room temperature overnight. After 48 h, the
reaction mixture was quenched with a saturated NH.sub.4Cl solution
(5 mL). The reaction mixture was then diluted with CH.sub.2Cl.sub.2
(10 mL). The layers were separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 (2.times.10 mL). The combined
organic layers were washed brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure to give crude
product. This crude mixture was then purified via silica gel
chromatography to give
3-(3-tert-Butyl-phenyl)-3-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]--
piperidine-1-carboxylic acid benzylamide which was further purified
by HPLC.
EXAMPLE 299
Preparation of
4-(3,5-difluoro-phenyl)-1-[7-(2,2-dimethyl-propyl)-1,2,3,4--
tetrahydro-naphthalen-1-ylamino]-butan-2-ol
[0737] 328
[0738] The amine (mono-trifluoroacetate salt, 0.25 mmol, 54.4 mg)
and epoxide (0.25 mmol, 46 mg) were dissolved in isopropanol (1 mL)
and heated at 80.degree. C. for 12 hours, when LCMS was performed.
The product was purified by injection of the reaction mixture onto
preparative RP-HPLC [Method 10].
[0739] LCMS: Column dimensions: 50 mm(long).times.3 mm(i.d.), C-18
stationary phase, 5 micron particle size, 100 angstrom pore size.
Mobile phases are 0.05% trifluoroacetic acid in water (solvent A),
and 0.05% trifluoroacetic acid in acetonitrile (solvent B). The
program gradient is 10% solvent B from 0 to 0.25 minutes, 10% to
90% solvent B from 0.25 to 9.50 minutes, then 90% solvent B from
9.50 to 10.25 minutes. Ret. time (min): 4.72; [M+H]=401.74.
EXAMPLE 300
Preparation of
4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-6-(2,2-dim-
ethyl-propyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl
ester
[0740] 329
[0741] The title compound was prepared according to the procedure
described in Example 299 from the amine prepared in EXAMPLE 383.
LCMS ret. time (min): 5.17; [M+H]=536.70.
EXAMPLE 301
Preparation of
1-[2-bromo-5-(2,2-dimethyl-propyl)-benzylamino]-4-(3,5-difl-
uoro-phenyl)-butan-2-ol
[0742] 330
[0743] The title compound was prepared according to the procedure
described in Example 299 from the amine prepared in Example 385.
LCMS ret. time (min): 4.68; [M+H]=439.86.
EXAMPLE 302
Preparation of
4-(3,5-difluoro-phenyl)-1-[5-(2,2-dimethyl-propyl)-2-imidaz-
ol-1-yl-benzylamino]-butan-2-ol
[0744] 331
[0745] The title compound was prepared according to the procedure
described in Example 299 from the amine prepared in EXAMPLE 369.
LCMS ret. time (min): 3.20; [M+H]=428.05.
EXAMPLE 303
4-(3,5-difluoro-phenyl)1-[5-(2,2-dimethyl-propyl)-2-(4-hydroxymethyl-imida-
zol-1-yl)-benzylamino]-butan-2-ol
[0746] 332
[0747] The title compound was prepared according to the procedure
described in Example 299. LCMS ret. time (min): 3.27;
[M+H]=457.95.
EXAMPLE 304
Representative Procedure for 4-Heteroaryl Compounds Made Via
Reductive Amination
[0748] 333
[0749] To 0.2 mmol of compound 23 in 1.5 mL of methanol is added
0.24 mmol of heteroaryl amine. The mixture is stirred for 15
minutes at room temperature. 0.15 mL of glacial acetic acid is then
added to the reaction mixture. The mixture is stirred for an
additional 30 minutes. 2.5 equivalents of Argonaut
MP-Cyanoborohydride is then added to the reaction vial. Each
reaction vial is placed on a J-Kem Orbit Shaker block. The reaction
temperature is raised to 60.degree. C. The reaction mixture is
stirred for 60 h. The resins are filtered out of the reaction
mixture. The reaction mixture is then concentrated and isolated via
preparative HPLC utilizing a Varian ProStar Preparative HPLC system
to leave compounds with general structure 24. LC/MS analysis is
conducted utilizing method [1].
EXAMPLE 305
Representative Procedure for Preparation of Heteroaryl Analogs Via
Nucleophilic Displacement
[0750] 334
[0751] To 0.1 mmol of
1-[4-Amino-1-(3-tert-butyl-phenyl)-cyclohexylamino]--
4-(3,5-difluoro-phenyl)-butan-2-ol (25) in 1 mL DMF is added 0.15
mmol of heteroaryl halide. 0.1 mL of diisopropylethylamine is added
to each reaction vial. Each reaction vial is placed on a J-Kem
Orbit Shaker block. The reaction temperature is then raised to
80.degree. C. The reaction mixture is then stirred for 16 h. The
reaction mixture is then concentrated and isolated via preparative
HPLC utilizing a Varian ProStar Preparative HPLC system to leave
compounds with general structure 26. LC/MS analysis is conducted
utilizing method [1].
EXAMPLE 306
Preparation of
1-[1-(3-tert-butyl-phenyl)-4-(pyridin-2-ylamino)-cyclohexyl-
amino]-4-(3,5-difluoro-phenyl)-butan-2-ol
[0752] 335
[0753] To 125 mgs (0.33 mmol) of
[1-(3-tert-Butyl-phenyl)-4-oxo-cyclohexyl- ]-carbamic acid
tert-butyl ester (27) in 1 mL methanol in a 4-mL reaction vial was
added 0.4 mmol of 2-aminopyridine. 0.1 mL of glacial acetic acid
was added to each reaction vial. 2.5 equivalents (0.825
mequivalents., 323 mgs) of MP-cyanoborohydride was then added to
the reaction vial. The reaction mixture was stirred for 16 hours at
60.degree. C. to yield
[1-(3-tert-Butyl-phenyl)-4-(pyridin-2-ylamino)-cyclohexyl]-carbamic
acid tert-butyl ester (28). 1.5 mL of 4 N HCl in dioxane was added
to remove the BOC-group. The reaction mixture was stirred for 1
hour at room temperature to yield
1-(3-tert-Butyl-phenyl)-N'-pyridin-2-yl-cyclohexane-- 1,4-diamine
(29).
[0754] To 0.25 mmol of 29 in 1 mL of isopropanol was added 1 eq
(0.25 mmol) of 2-[2-(3,5-Difluoro-phenyl)-ethyl]-oxirane (14). The
reaction mixture wass then stirred for 6 hours at 80.degree. C. to
yield
1-[1-(3-tert-Butyl-phenyl)-4-(pyridin-2-ylamino)-cyclohexylamino]-4-(3,5--
difluoro-phenyl)-butan-2-ol (30). Isolation of 30 was accomplished
via preparative HPLC utilizing a Varian ProStar Preparative HPLC.
LC/MS analysis is conducted utilizing method [1].
[0755]
1-[1-(3-tert-Butyl-phenyl)-4-(pyridin-2-ylamino)-cyclohexylamino]-4-
-(3,5-difluoro-phenyl)-butan-2-ol. .sup.1H NMR (CD.sub.3OD)
8.07-7.80 (m, 1H), 7.79-7.64 (m, 1H), 7.64-7.42 (m, 3H), 7.35-7.14
(m, 1H), 6.94-6.65 (m, 3H), 3.95-3.76 (m, 1H), 3.70-3.48 (m, 1H),
2.91-2.76 (m, 2H), 2.76-2.61 (m, 2H), 2.52-2.34 (m, 2H), 2.25-2.07
(m, 1H), 2.07-1.89 (m, 2H), 1.89-1.70 (m, 2H), 1.70-1.52 (m, 2H).
HPLC ret. time 1.662.
EXAMPLE 307
Preparation of
4-(6-tert-butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-yla-
mino)-1-(3,5-difluoro-phenyl)-3-hydroxy-butan-1-one
[0756] 336
EXAMPLE 308
Preparation of
1-(6-tert-butyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4--
ylamino)-3-methyl-4-phenyl-butan-2-ol
[0757] 337
[0758] Epoxidation of olefin 31 with m-chloroperbenzoic acid gives
epoxide 32. Nucleophilic opening of epoxide 32 with amine 33
affords 34.
EXAMPLE 309
Preparation of
4-(3,5-difluoro-phenyl)-1-(6-isobutyl-1,1-dioxo-1.lambda..s-
up.6-thiochroman-4-ylamino)-pentan-2-ol
[0759] 338
[0760] 1-(1-Bromo-ethyl)-3,5-difluoro-benzene (35) is treated with
allylmagnesium bromide (36) to give intermediate 37. Epoxidation of
intermediate 37 with m-chloroperbenzoic acid affords epoxide 38.
Nucleophilic opening of epoxide 38 with amine 39 affords
1-(6-tert-Butyl-1,1-dioxo-1.lambda..sup.6-thiochroman-4-ylamino)-4-(3,5-d-
ifluoro-5 phenyl)-pentan-2-ol (40).
[0761] Further examples of compounds that can be made according to
the present invention are found in Example 310 below.
EXAMPLE 310
General Procedure for the Preparation of Compounds of Formula (I)
Via Nucleophilic displacement
[0762]
1 339 340 Step 1 Step 2 Example Reagent X A Reagent Y B 310-1 341
342 H.sub.2/Pd/C 343 310-2 344 345 n/a n/a 310-3 346 347
H.sub.2/Pd/C 348 310-4 349 350 n/a/ n/a 310-5 351 352 H.sub.2/Pd/C
353 310-6 354 355 n/a n/a 310-7 356 357 n/a n/a 310-8 358 359 n/a
n/a 310-9 360 361 n/a n/a 310-10 n/a 362 TFA 363 310-11 364 365 n/a
n/a 310-12 366 367 H.sub.2/Pd/C 368 310-13 n/a 369 TFA 370 310-14
n/a 371 TFA 372 310-15 373 374 n/a n/a 310-16 375 376 n/a n/a
310-17 377 378 n/a n/a 310-18 379 380 n/a n/a 310-19 381 382 n/a
n/a 310-20 383 384 n/a n/a
Representative Procedure for Nucleophilic Displacement
[0763] 385
[0764] To 43 mgs (0.1 mmol) of
3-Amino-1-[1-(3-tert-butyl-phenyl)-cyclohex-
ylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol (41) in 1 mL of
ethoxyethanol in a 4-mL reaction vial is added 0.4 mmol of
diisopropylethylamine and 0.1 mmol of the halide. The reaction
mixture is stirred for 16 hours at various temperatures
(25-150.degree. C.) to yield compounds of general structure 42.
Isolation of final products is accomplished via preparative HPLC
utilizing a Varian ProStar Preparative HPLC system. LC/MS analysis
is conducted utilizing method (described below).
[0765] For compounds
3-(3-Bromo-[1,2,4]thiadiazol-5-ylamino)-4-(3,5-difluo-
ro-phenyl)-1-(6-ethyl-2,2-dioxo-2.vertline.6-isothiochroman-4-ylamino)-but-
an-2-ol and
3-(3-Bromo-[1,2,4]thiadiazol-5-ylamino)-4-(3,5-difluoro-phenyl-
)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol,
3-Amino-4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.vertline.6-isothio-
chroman-4-ylamino)-butan-2-ol and
3-Amino-4-(3,5-difluoro-phenyl)-1-(7-eth-
yl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol are used as
starting materials instead of 1.
[0766] LC/MS method Column dimensions: 50 mm (long).times.2 mm
(i.d.), C-18 stationary phase, 5 micron particle size, 100 angstrom
pore size. Mobile phases: 0.05% trifluoroacetic acid in water
(solvent A), 0.05% trifluoroacetic acid in acetonitrile (solvent
B).
[0767] Chromatographic conditions: 3 mL/min., 5% to 95% solvent B
from 0.00 to 2.40 minutes, 95% solvent B from 2.40 to 3.00 minutes,
95% to 5% solvent B from 3.00 to 3.10 minutes, 5% solvent B from
3.10 to 3.50 minutes.
[0768] The compounds in the chart below were made according to the
procedure above.
2 Ret. Compound M + H time 3-(3-Bromo-[1,2,4]thiadiazol- 588.7 1.55
5-ylamino)-4-(3,5-difluo- ro- phenyl)-1-(6-ethyl-2,2-dioxo-
2.lambda..sup.6-isothioc- hroman-4-ylamino)- butan-2-ol
3-(3-Bromo-[1,2,4]thiadiazol- - 538.6 1.67
5-ylamino)-4-(3,5-difluoro- phenyl)-1-(7-ethyl-1,2,3,4-
tetrahydro-naphthalen-1- ylamino)-butan-2-ol
3-(3-Bromo-[1,2,4]thiadiazol- 593.6 1.98
5-ylamino)-1-[1-(3-tert-butyl- phenyl)-cyclohexylamino]-4-
(3,5-difluoro-phenyl)-butan-2-ol 1-[1-(3-tert-Butyl-phenyl)- 514.8
1.89 cyclohexylamino]-4-(3,5-difluoro-
phenyl)-3-([1,2,4]thiadiazol- 5-ylamino)-butan-2-ol
3-[3-[1-(3-tert-Butyl- 540.7 1.84 phenyl)-cyclohexylamino]-1-(3,5-
- difluoro-benzyl)-2-hydroxy- propylamino]-4-methoxy-
cyclobut-3-ene-1,2-dione 1-[1-(3-tert-Butyl-phenyl)- 559.8 2.81
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(3-nitro-thiophen-2-
ylamino)-butan-2-ol 1-[1-(3-tert-Butyl-phenyl)- 571.8 2.79
cyclohexylamino]-4-(3,5-di- fluoro- phenyl)-3-(2,5-dimethyl-4-
nitro-2H-pyrazol-3-ylam- ino)- butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 557.7 2.76
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(3-methyl-5-nitr- o-
3H-imidazol-4-ylamino)-butan-2- ol 3-(Benzo[4,5]thieno[3,2- 614.9
2.64 d]pyrimidin-4-ylamino)-1-[1-(- 3-tert-
butyl-phenyl)-cyclohexylamino]- 4-(3,5-difluoro-phenyl)- butan-2-ol
5-[3-[1-(3-tert-Butyl- 606.8 2.15 phenyl)-cyclohexylamino]-1-(3,5-
- difluoro-benzyl)-2-hydroxy- propylamino]-4-chloro-
isothiazole-3-carboxylic acid methyl ester
1-[1-(3-tert-Butyl-phenyl)- 600.9 2.21 cyclohexylamino]-4-(3,5-di-
fluoro- phenyl)-3-(2-fluoro-4- trifluoromethyl-thiazol-5-y-
lamino)- butan-2-ol 1-[1-(3-tert-Butyl-phenyl)- 575.2 2.59
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(5-pyridin-4-- yl-
[1,3,4]oxadiazol-2-ylamino)-butan- 2-ol
3-(5-Amino-[1,3,4]thiadiazol- 529.8 1.71 2-ylamino)-1-[1-(3-tert--
butyl- phenyl)-cyclohexylamino]-4- (3,5-difluoro-phenyl)-b-
utan-2-ol 1-[1-(3-tert-Butyl-phenyl)- 574.8 2.83
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(1-phenyl-1H-tetrazol-
- 5-ylamino)-butan-2-ol 3-[3-[1-(3-tert-Butyl- 663.8 1.73
phenyl)-cyclohexylamino]-1-(3,5- difluoro-benzyl)-2-hydro- xy-
propylamino]-5-iodo-1-methyl- 1H-pyridin-4-one
3-[3-[1-(3-tert-Butyl- 649.8 1.74 phenyl)-cyclohexylamino]-1-(3,5-
- difluoro-benzyl)-2-hydroxy- propylamino]-5-iodo-pyridin-- 4-ol
1-[1-(3-tert-Butyl-phenyl)- 512.9 2.02
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(5-methyl-
[1,3,4]oxadiazol-2-ylamino)-butan-2-ol 1-[1-(3-tert-Butyl-phenyl)-
- 574.9 2.17 cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(5-phenyl-
[1,3,4]oxadiazol-2-ylamino)-butan-2-ol
EXAMPLE 311
Preparation of
4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.-
6-isothiochroman-4-ylamino)-3-([1,2,4]thiadiazol-5-ylamino)-butan-2-ol
[0769] 386
[0770] Combined
3-Amino-4-(3,5-difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lam-
bda..sup.6-isothiochroman-4-ylamino)-butan-2-ol (43) (0.1 mmol)
with diisopropylamine (0.4 mmol) in ethanol.
3-bromo-5-chloro-[1,2,4]-thiadiaz- ole (44) (0.1 mmol) was added.
The reaction mixture was allowed to stir at room temperature for 16
hours. Purification of the resulting reaction mixture by HPLC
afforded 3-(3-Bromo-[1,2,4]thiadiazol-5-ylamino)-4-(3,5-d-
ifluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochroman-4-ylam-
ino)-butan-2-ol (45), m/z=586.8. 45 was added to methanol, followed
by the addition of a catalytic amount of Pd on carbon, and
subjected to 50 psi of H.sub.2, affording
4-(3,5-Difluoro-phenyl)-1-(6-ethyl-2,2-dioxo-2.lamb-
da..sup.6-isothiochroman-4-ylamino)-3-([1,2,4]thiadiazol-5-ylamino)-butan--
2-ol (46), m/z=508.9.
Synthetic Procudures for Examples 312, 314-317, and 319-323
[0771] General Procedure A
[0772] The amine (1 mmol) and 2,4-dichloropyrimidine (1.5 mmol)
were dissolved in DMF (2 mL). DIPEA (5 mmol) was added and the
resulting mixture was stirred at 90.degree. C. for 20 h under an
atmosphere of N.sub.2. The solution was cooled to room temperature
and diluted with Et.sub.2O (10 mL). The solution was washed with
brine (2.times.5 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum.
[0773] General Procedure B
[0774] The amine (1 mmol), 1-methyl-4-iodopyrazole (1 mmol), CuI
(0.05 mmol) and KOH (4 mmol) were placed in a vial. The vial was
evacuated and purged with N.sub.2 three times. DMSO/H.sub.2O (2 mL,
1/1, v/v) was added and the resulting mixture was stirred at
90.degree. C. for 20 h under an atmosphere of N.sub.2. The solution
was cooled to room temperature, diluted with CH.sub.2Cl.sub.2 (10
mL) and washed with H.sub.2O (5 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated under vacuum.
[0775] General Procedure C
[0776] The amine (1 mmol), 2-(3-iodo-phenyl)-N,N-dipropyl-acetamide
(1 mmol), CuI (0.05 mmol) and KOH (4 mmol) were placed in a vial.
The vial was evacuated and purged with N.sub.2 three times.
DMSO/H.sub.2O (2 mL, 1/1, v/v) was added and the resulting mixture
was stirred at 90.degree. C. for 20 h under an atmosphere of
N.sub.2. The solution was cooled to room temperature, diluted with
CH.sub.2Cl.sub.2 (10 mL) and washed with H.sub.2O (5 mL). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum.
EXAMPLE 312
Preparation of
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(2-chloro-pyr-
imidin-4-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol
[0777] 387
[0778] Following procedure A,
3-Amino-1-[1-(3-tert-butyl-phenyl)-cyclohexy-
lamino]-4-(3,5-difluoro-phenyl)-butan-2-ol was converted to
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-3-(2-chloro-pyrimidin-4-ylami-
no)-4-(3,5-difluoro-phenyl)-butan-2-ol which was purified using
flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH,
98/2/0.2) and HPLC.
[0779] Retention time (min)=2.18, method [1], MS(ESI) 543.4 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.94 (d, J=5.9 Hz, 1H),
7.45 (s, 1H), 7.20-7.11 (m, 5H), 6.75-6.55 (m, 3H), 6.12 (bs, 1H),
5.32 (bs, 1H), 4.42 (bs, 1H), 3.41-3.32 (m, 1H), 2.85-2.71 (m, 2H),
2.45-2.21 (m, 2H), 2.05-1.83 (m, 4H), 1.77-1.50 (m, 5H), 1.34 (s,
9H); .sup.13 C NMR (75 MHz, CDCl.sub.3) .delta.150.9, 127.8, 123.5,
123.3, 123.2, 112.5, 112.0, 101.6, 77.1, 57.3, 42.9, 36.3, 36.2,
35.9, 34.6, 31.3, 25.6, 22.2
EXAMPLE 313
Preparation of
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-
-phenyl)-3-(pyrimidin-4-ylamino)-butan-2-ol
[0780] 388
[0781]
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-3-(2-chloro-pyrimidin-4-
-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol (101 mg, 0.186 mmol)
was dissolved in EtOAc (1 mL) containing Pd/C (20 mg) and
triethylamine (38 .mu.L, 0.279 mmol). The mixture was shaken under
a 45 psi hydrogen atmosphere for 40 hours. The mixture was filtered
through a pad of Celite and concentrated to give
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-4-(3- ,
5-difluoro-phenyl)-3-(pyrimidin-4-ylamino)-butan-2-ol which was
purified using flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH, 99/1/0.1) and HPLC.
[0782] Retention time (min)=1.68, method [1], MS(ESI) 509.5 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.33 (s, 1H), 7.81 (d,
J=5.2 Hz, 1H), 7.62 (s, 1H), 7.45-7.29 (m, 2 H), 7.29-7.20 (m, 1H),
6.65-6.53 (m, 3H), 4.45 (bs, 1H), 4.09 (bs, 1H), 2.81-2.79 (m, 2H),
2.70-2.61 (m, 4H), 2.13-2.03 (m, 4H), 1.80-1.59 (m, 4H), 1.35 (s,
9H).
EXAMPLE 314
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0783] 389
[0784] Following procedure B,
3-Amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1-
,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol was converted to
4-(3,5-Difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamin-
o)-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol which was purified
using flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH,
98/2/0.2) and HPLC.
[0785] Retention time (min)=1.64, method [1], MS(ESI) 455.4 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.30-6.95 (m, 5H),
6.60-6.51 (m, 1H), 6.50-6.42 (m, 2H), 4.51-4.29 (m, 2H), 3.85 (s,
3H), 3.45-3.30 (m, 1H), 3.08-2.91 (m, 2H), 2.84 (dd, J=14.4, 5.1
Hz, 1H), 2.71-2.65 (m, 3H), 2.55 (q, J=7.5 Hz, 2H), 2.15-1.70 (m,
4H), 1.18 (t, J=7.5 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta.142.9, 140.6, 135.4, 131.0, 129.7, 128.9, 128.2, 127.9,
111.9, 102.5 (t, J=25 Hz, 1C), 77.1, 66.7, 63.7, 55.7, 74.3, 39.2,
32.6, 28.1, 27.9, 25.1, 18.7, 15.2.
EXAMPLE 315
Preparation of
4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylam-
ino]-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0786] 390
[0787] Following procedure B,
3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethy-
l-phenyl)-cyclopropylamino]-butan-2-ol was converted to
4-(3,5-Difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-3-(1-meth-
yl-1H-pyrazol-4-ylamino)-butan-2-ol which was purified using flash
chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH, 98/2/0.2)
and HPLC.
[0788] Retention time (min)=1.57, method [1], MS(ESI) 441.4 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.30-7.05 (m, 6H),
6.71-6.41 (m, 3H), 4.10-4.01 (m, 1H), 3.82 (s, 3H), 3.32-3.20 (m,
1H), 3.10-2.75 (m, 4H), 2.67 (q, 7.5 Hz, 2H), 1.53 (bs, 2H), 1.23
(t, J=7.5 Hz, 3H), 1.20-1.09 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.145.5, 140.7, 140.6, 133.6, 130.6, 129.3, 129.0,
127.0, 120.9, 118.1, 114.3, 112.1, 111.9, 102.2 (t, J=25 Hz, 1 C),
77.1, 66.9, 62.9, 49.3, 44.1, 39.1, 33.4, 28.6, 15.1, 11.5,
10.8.
EXAMPLE 316
Preparation of
4-(3,5-difluoro-phenyl)-1-(3-ethyl-benzylamino)-3-(1-methyl-
-1H-pyrazol-4-ylamino)-butan-2-ol from
3-amino-4-(3,5-difluoro-phenyl)-1-(-
3-ethyl-benzylamino)-butan-2-ol
[0789] 391
[0790] Following procedure B,
3-Amino-4-(3,5-difluoro-phenyl)-1-(3-ethyl-b-
enzylamino)-butan-2-ol was converted to
4-(3,5-Difluoro-phenyl)-1-(3-ethyl-
-benzylamino)-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol which
was purified using flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4- OH, 98/2/0.2) and HPLC.
[0791] Retention time (min)=1.46, method [1], MS(ESI) 415.4 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.30-6.85 (m, 6H),
6.69-6.51 (m, 3H), 4.10-3.87 (m, 3H), 3.72 (s, 3H), 3.30-3.05 (m,
2H), 2.95-2.68 (m, 3H), 2.56 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz,
3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.145.5, 129.9, 129.7,
129.2, 129.2, 129.1, 126.8, 119.1, 112.2, 111.8, 102.4 (t, J=25 Hz,
1 C), 77.1, 67.2, 61.8, 51.5, 50.1, 38.9, 34.4, 28.3, 15.1.
EXAMPLE 317
Preparation of
4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chroman--
4-ylamino]-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0792] 392
[0793] Following procedure B,
3-amino-4-(3,5-difluoro-phenyl)-1-[6-(2,2-di-
methyl-propyl)-chroman-4-ylamino]-butan-2-ol was converted to
4-(3,5-Difluoro-phenyl)-1-[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-3-(-
1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol which was purified using
flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH,
99/1/0.1) and HPLC.
[0794] Retention time (min)=1.84, method [1], MS(ESI) 499.5 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.32-7.15 (m, 2H),
7.10-7.01 (m, 2H), 6.75 (d, J=8.3 Hz, 1H), 6.65 (t, J=8.9 Hz, 1H),
6.54 (d, J=5.9 Hz, 2H), 4.45-4.30 (m 2H), 4.18-4.08 (m, 2H), 3.84
(s, 3H), 3.43 (bs, 1H), 3.08-2.85 (m, 2H), 2.85 (dd, J=14.2, 5.3,
1H), 2.71 (dd, J=9.2, 5.3, 1H), 2.46-2.10 (m, 4H), 1.27 (s, 9H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta.153.5, 133.3, 130.7,
117.2, 113.4, 112.1, 111.8, 102.5, 77.3, 66.8, 63.0, 61.5, 51.6,
48.8, 47.9, 39.0, 33.3, 31.5, 29.6, 28.9, 24.6.
EXAMPLE 318
Preparation of
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-3-(2-diethylami-
no-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol
[0795] 393
[0796]
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-3-(2-diethylamino-pyrim-
idin-4-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol from
[0797]
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-3-(2-chloro-pyrimidin-4-
-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol (78 mg, 0.144 mmol)
was dissolved in DMF (0.5 mL) containing diethylamine (74 .mu.L,
0.718 mmol) and potassium carbonate (100 mg, 0.718 mmol). The
reaction mixture was heated in a sealed tube at 90.degree. C. for
48 h. The resulting solution was diluted with Et.sub.2O (10 mL),
washed with brine (3.times.5 mL), dried over Na.sub.2SO.sub.4 and
purified using flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH, 98/2/0.2) and HPLC to give
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-3-(2-diethylamino-pyrimidin-4-
-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol.
[0798] Retention time (min)=1.85, method [1], MS(ESI) 580.6 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.9.99 (bs, 1H), 8.56 (d,
J=8.2 Hz, 1H), 8.13 (bs, 1H), 7.67 (s, 1H), 4.43-7.25 (m, 3H), 7.11
(d, J=6.9 Hz, 1H), 6.65-6.50 (m, 3H), 5.95 (d, J=7.2 Hz, 1H),
4.30-4.15. (m, 2H), 3.59-3.30 (m, 5H), 2.89-2.48 (m, 7H), 2.18-1.99
(m, 4H), 1.85-4.52 (m, 2H), 1.35 (s, 9H), 1.15 (bs, 6H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.152.5, 151.6, 141.6, 139.8, 133.9,
128.6, 125.8, 124.8, 124.7, 111.5 (d, J=24 Hz), 101.6 (t, J=24 Hz),
97.7, 77.1, 67.9, 64.1, 54.5, 45.1, 42.6, 34.7, 34.6, 32.9, 31.0,
24.8, 21.9, 12.3.
EXAMPLE 319
Preparation of
2-(3-{1-(3,5-difluoro-benzyl)-3-[1-(3-ethyl-phenyl)-cyclopr-
opylamino]-2-hydroxy-propylamino}-phenyl)-N,N-dipropyl-acetamide
[0799] 394
[0800] Following procedure C,
3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethy-
l-phenyl)-cyclopropylamino]-butan-2-ol was converted to
2-(3-{1-(3,5-Difluoro-benzyl)-3-[1-(3-ethyl-phenyl)-cyclopropylamino]-2-h-
ydroxy-propylamino}-phenyl)-N,N-dipropyl-acetamide which was
purified using flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH, 99/1/0.1) and HPLC.
2-(3-{1-(3,5-Difluoro-benzyl)-3-[1-(3-ethyl-phenyl)-c-
yclopropylamino]-2-hydroxy-propylamino}-phenyl)-N,N-dipropyl-acetamide
retention time (min)=2.13, method [1], MS(ESI) 578.3 (M+H); .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta.7.22-6.98 (m, 5H), 6.80-6.60 (m,
3H), 6.48-6.32 (m, 3H), 3.65-3.45 (m, 3H), 3.29-3.15 (m, 3H), 3.04
(dd, J=13.7, 3.6, 1H), 2.87-2.54 (m, 5H), 1.62-1.39 (m, 4H), 1.18
(t, J=13.7 Hz, 3H), 0.99-0.78 (m, 10H); .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta.172.1, 148.2, 143.9, 143.8, 143.7, 143.6, 142.3,
135.7, 128.9, 127.7, 126.8, 125.5, 124.7, 116.0, 112.1, 1211.9,
111.8, 111.7, 110.8, 100.4 (t, J=24 Hz), 72.0, 56.8, 49.7, 49.3,
46.5, 41.8, 40.6, 35.8, 28.2, 21.3, 20.1, 14.7, 14.1, 13.3, 10.1,
9.8.
EXAMPLE 320
Preparation of
2-{3-[1-(3,5-difluoro-benzyl)-3-(3-ethyl-benzylamino)-2-hyd-
roxy-propylamino]-phenyl}-N,N-dipropyl-acetamide
[0801] 395
[0802] Following procedure C,
3-Amino-4-(3,5-difluoro-phenyl)-1-(3-ethyl-b-
enzylamino)-butan-2-ol was converted to
2-{3-[1-(3,5-Difluoro-benzyl)-3-(3-
-ethyl-benzylamino)-2-hydroxy-propylamino]-phenyl}-N,N-dipropyl-acetamide
which was purified using flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3O- H/NH.sub.4OH, 99/1/0.1) and HPLC.
[0803] Retention time (min)=2.03 min, method [1], MS(ESI) 552.3
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.36-7.18 (m, 4H),
6.98 (t, J=7.6 Hz, 1H), 6.81 (d, 6.4 Hz, 2H), 6.71-6.62 (m, 1H),
6.49-6.43 (m, 3H), 4.18 (s, 2H), 3.89-3.75 (m, 1H), 3.70-3.61 (m
1H), 3.58 (s, 2H), 3.30-3.08 (m, 6H), 3.01 (dd, J=14.2, 12.4, 1H),
2.75 (dd, J=8.8, 13.7 Hz, 1H), 2.71-2.62 (m, 2H), 1.60-1.41 (m,
4H), 1.22 (t, J=7.6 Hz, 3H), 0.92-0.75 (m, 6H); .sup.13C NMR (75
MHz, CD.sub.3OD) .delta.171.9, 147.7, 145.1, 143.0, 142.9, 142.8,
135.9, 130.6, 129.0, 128.7, 128.6, 126.8, 116.8, 112.7, 112.0,
111.7, 111.1, 100.7 (t, J=24 Hz), 69.0, 57.1, 50.6, 48.0, 40.4,
35.9, 28.1, 21.4, 20.2, 14.5, 10.1, 9.8.
EXAMPLE 321
Preparation of
3-(2-chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1--
[6-(2,2-dimethyl-propyl)-chroman-4-ylamino]-butan-2-ol
[0804] 396
[0805] Following procedure A,
3-Amino-4-(3,5-difluoro-phenyl)-1-[6-(2,2-di-
methyl-propyl)-chroman-4-ylamino]-butan-2-ol was converted to
3-(2-Chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1-[6-(2,2-dimeth-
yl-propyl)-chroman-4-ylamino]-butan-2-ol which was purified using
flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH,
98/2/0.2) and HPLC.
[0806] Retention time (min)=1.90, method [1], MS(ESI) 531.2 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.82 (d, J=6.1 Hz, 1H),
7.12-7.08 (m, 2H), 6.89-6.68 (m, 4H), 6.37 (d, J=6.1 Hz, 1H),
4.62-4.58 (m, 1H), 4.49-4.41 (bs, 1H), 4.30-4.25 (m, 2H), 3.97 (dd,
J=6.0, 7.3 Hz, 1H), 3.39-3.12 (m, 3H), 2.75 (dd, J=13.7, 11.3 Hz,
1H), 2.41-2.35 (m, 4H), 0.91 (s, 9H); .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta.154.8, 153.6, 142.3, 132.9, 131.9, 130.7, 116.6,
114.3, 111.7, 111.4, 101.5, 100.8 (t, J=24 Hz), 68.5, 61.1, 54.5,
51.5, 48.5, 35.3, 30.9, 28.2, 24.2.
EXAMPLE 322
Preparation of
3-(2-chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1--
(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0807] 397
[0808] Following procedure A,
3-Amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1-
,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol was converted to
3-(2-Chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3-
,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol which was purified
using flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH,
98/2/0.2) and HPLC.
[0809] Retention time (min)=1.79, method [1], MS(ESI) 487.4 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.81 (d, J=6.0 Hz, 1H),
7.27-7.09 (m, 3H), 6.82 (d, J=7.9 Hz, 2H), 6.71 (t, J=9.2 Hz), 1H),
6.38 (d, J=6.0 Hz, 1H), 4.55-4.40 (m, 1H), 4.40 (bs, 1H), 3.99 (dd,
J=7.1, 7.6, 1H), 3.30-3.21 (m, 2H), 3.05 (dd, J=10.8, 12.2, 1H),
2.90-2.71 (m, 3H), 2.60 (q, J=7.5, 2H), 2.21-2.07 (m, 2H),
2.01-1.87 (m, 2H), 1.98 (t, J=7.5 Hz, 3H); .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta.154.8, 142.4, 135.6, 129.5, 129.1, 128.5, 127.8,
111.7, 111.4, 104.3, 101.1 (t, J=24 Hz), 68.4, 55.3, 54.9, 47.6,
47.1, 27.8, 27.6, 24.7, 18.1, 14.5.
EXAMPLE 323
Preparation of
3-(2-chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1--
[1-(3-ethyl-phenyl)-cyclopropylamino]-butan-2-ol
[0810] 398
[0811] Following procedure A,
3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethy-
l-phenyl)-cyclopropylamino]-butan-2-ol was converted to
3-(2-Chloro-pyrimidin-4-ylamino)-4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-ph-
enyl)-cyclopropylamino]-butan-2-ol which was purified using flash
chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH, 98/2/0.2)
and HPLC.
[0812] Retention time (min)=1.72, method [1], MS(ESI) 473.4 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.80 (d, J=6.0 Hz, 1H),
7.42-7.21 (m, 4H), 6.81 (d, J=6.1 Hz, 2H), 6.72 (t, J=9.1 Hz, 1H),
6.28 (d, J=6.0 Hz, 1H), 4.38-4.25 (m, 1H), 3.19 (dd, J=3.2, 14.0
Hz, 1H), 3.15-3.08 (m, 1H), 2.95 (dd, J=10.2, 10.4, 1H), 2.81-2.58
(m, 4H), 1.60-1.25 (m, 4H), 1.21 (t, J=7.6 Hz, 3H); .sup.13C NMR
(75 MHz, CD.sub.3OD) .delta.154.5, 145.3, 133.6, 129.1, 128.8,
128.7, 127.0, 111.7, 111.4, 104.2, 101.1, 68.6, 54.3, 48.8, 43.2,
35.3, 28.1, 14.4, 10.7, 10.0.
EXAMPLE 324
Preparation of
2-{4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-di-
fluoro-benzyl)-2-hydroxy-propylamino]-pyrimidin-2-ylamino}-N,N-dipropyl-ac-
etamide
[0813] 399
[0814]
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-3-(2-chloro-pyrimidin-4-
-ylamino)-4-(3,5-difluoro-phenyl)-butan-2-ol (27 mg, 49.7 .mu.mol)
and 2-amino-N,N-dipropyl-acetamide (15 mg, 74.5 .mu.mol) were
dissolved in DMF (100 .mu.L) containing potassium carbonate (21 mg,
149.1 .mu.mol). The reaction mixture was heated at 90.degree. C.
for 48 h. The resulting solution was diluted with brine (5 mL),
extracted with Et.sub.2O (5 mL), dried over Na.sub.2SO.sub.4 and
purified using flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH, 98/2/0.2) and HPLC to give
2-{4-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-
-2-hydroxy-propylamino]-pyrimidin-2-ylamino}-N,N-dipropyl-acetamide.
[0815] Retention time (min)=1.95, method [1], MS(ESI) 665.6 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.64 (s, 1H), 7.58 (d,
J=7.2 Hz, 1H), 7.48-7.35 (m, 3H), 6.81-6.71 (m, 3H), 5.86 (d, J=7.1
Hz, 1H), 4.35-4.11 (m, 3H), 3.75 (bs, 1H), 3.18 (dd, J=14, 3.4 Hz,
1H), 2.95-2.51 (m, 8H), 2.05-1.59 (m, 12H), 1.34 (s, 9H), 1.01 (t,
J=7.5 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).
EXAMPLE 325
Preparation of
{4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difl-
uoro-benzyl)-2-hydroxy-propylamino]-phenyl}-acetic acid
[0816] 400
[0817]
3-Amino-1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-
-phenyl)-butan-2-ol dihydrochloride salt (1 mmol),
4-iodophenylacetic acid (1 mmol), and potassium hydroxide (5 mmol)
were added to around bottom flask equipped with stirbar. DMSO (5
mL) and H.sub.2O (5 mL) were added and the mixture dissolved.
Copper iodide (10%). was added and the mixture was heated for 16
hours at 90.degree. C. The reaction was extracted with DCM
(2.times.10 mL), then neutralized with 1M HCl and extracted with
4:1 CHCl.sub.3/IPA. Both organic fractions were combined, dried
with sodium sulfate, and concentrated to give a brown oil. This
residue was purified by reverse-phase HPLC.
[0818] Retention time (min)=2.274, method [1]; .sup.1H NMR (300
MHz, CD.sub.3OD) .delta.7.54 (s, 1H), 7.46-7.27 (m, 3H), 6.94 (d,
2H, J=7.8 Hz), 6.76-6.59 (m, 3H), 6.36 (d, 2H, J=7.8 Hz), 3.58-3.43
(m, 2H), 3.41 (s, 2H), 3.03 (d, 1H, J=13.7 Hz), 2.87 (d, 1H, J=13.7
Hz), 2.76-2.45 (m, 4H), 1.95-1.54 (m, 4H), 1.39-1.06 (m, 11H).
.sup.13C NMR (75 MHz, CD.sub.3OD) 174.7, 162.7 (dd, 2C, J=248.2,
13.5 Hz), 158.2, 152.2, 146.0, 142.6 (t, 1C, J=9.7 Hz), 133.1,
129.6, 128.9, 126.0, 124.6, 124.3, 123.0, 112.6, 111.8 (dd, 2C,
J=17.1, 7.4 Hz), 100.9 (t, 1C, J=25.7 Hz), 69.7, 64.0, 57.3, 45.1,
39.5, 35.9, 34.3, 32.6, 32.5, 30.0, 24.6, 21.7; MS (ESI) 565.2.
EXAMPLE 326
Preparation of
3-{4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-di-
fluoro-benzyl)-2-hydroxy-propylamino]-phenyl}-propionic acid
[0819] 401
[0820] The title compound was prepared in an identical manner to
Example 325 using 3-(4-iodo-phenyl)-propionic acid as the coupling
species. Retention time (min)=2.106, method [1]; .sup.1H NMR (300
MHz, CD.sub.3OD) 7.55 (s, 1H), 7.46-7.27 (m, 3H), 6.90 (d, 2H,
J=7.8 Hz), 6.76-6.59 (m, 3H), 6.36 (d, 2H, J=7.8 Hz), 3.58-3.43 (m,
2H), 3.02 (dd, 1H, J=14.0, 4.0 Hz), 2.88 (dd, 1H, J=13.0, 2.7 Hz),
2.76-2.46 (m, 6H), 1.95-1.54 (m, 4H), 1.39-1.06 (m, 11H). .sup.13C
NMR (75 MHz, CD.sub.3OD) 175.4, 162.7 (dd, 2C, J=248.2, 13.5 Hz),
159.4, 152.2, 147.5, 145.0, 142.6 (t, 1C, J=9.7 Hz), 133.3, 129.6,
128.9, 126.0, 124.6, 124.3, 123.0, 112.6, 111.8 (dd, 2C, J=17.1,
7.4 Hz), 100.9 (t, 1C, J=25.7 Hz), 69.7, 64.0, 57.3, 45.1, 39.5,
35.9, 35.5, 34.3, 32.6, 32.5, 30.1, 29.6, 24.6, 21.7; MS (ESI)
579.3.
EXAMPLE 327
Preparation of
2-{3-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-di-
fluoro-benzyl)-2-hydroxy-propylamino]-phenyl}-N,N-dipropyl-acetamide
[0821] 402
[0822] The title compound was prepared in an identical manner to
Example 325 using 2-(3-iodo-phenyl)-N,N-dipropyl-acetamide as the
coupling species. Retention time (min)=2.529, method [1]; .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta.7.56 (s, 1H), 7.46-7.27 (m, 3H),
6.96 (t, 1H, J=7.6 Hz), 6.76-6.59 (m, 3H), 6.46 (d, 1H, J=7.2 Hz),
6.33 (s, 1H), 6.29 (d, 1H, J=7.9 Hz), 3.57 (s, 2H), 3.55-3.45 (m,
2H), 3.31-3.17 (m, 5H), 3.01 (dd, 1H, J=13.8, 3.8), 2.87 (dd, 1H,
J=12.6, 2.1 Hz), 2.79-2.51 (m, 4H), 1.96-1.30 (m, 12H), 1.28 (s,
9H); MS (ESI) 648.3.
EXAMPLE 328
Preparation of
4-[3-[1-(3-tert-butyl-phentyl-cyclohexylamino]-1-(3,5-diflu-
oro-benzyl)-2-hydroxy-propylamino]-benzoic acid
[0823] 403
[0824] The title compound was prepared in an identical manner to
Example 325 using 4-iodo-benzoic acid as the coupling species.
Retention time (min)=1.966, method [1]; MS (ESI) 551.2.
EXAMPLE 329
Preparation of
4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-diflu-
oro-benzyl)-2-hydroxy-propylamino]-N-methyl-benzamide
[0825] 404
[0826] The title compound was prepared in an identical manner to
Example 325 using 4-iodo-N-methyl-benzamide as the coupling
species. Retention time (min)=1.949, method [1]; MS (ESI)
564.3.
EXAMPLE 330
Preparation of
4-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-diflu-
oro-benzyl)-2-hydroxy-propylamino]-benzamide
[0827] 405
[0828] The title compound was prepared in an identical manner to
Example 325 using 4-iodo-benzamide as the coupling species.
Retention time (min)=1.977, method [1]; MS (ESI) 551.2.
EXAMPLE 331
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(2-fluoro-phenylamino)-butan-2-ol
[0829] 406
[0830] Cuprous iodide (17 mg, 89.3 .mu.mol),
3-amino-4-(3,5-difluoro-pheny-
l)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
dihydrochloride (91 mg, 203 .mu.mol), 1-fluoro-2-iodo-benzene (56
mg, 252 .mu.mol), and powdered potassium hydroxide (48 mg, 855
umol) were placed into a culture tube, evacuated, and refilled with
nitrogen. Dimethylsulfoxide (0.20 mL) and water (0.10 mL) were
added and the heterogenous mixture was placed into a preheated oil
bath at 90.degree. C. After stirring for 20 h, the heterogeneous
mixture was flash chromatographed with 99:1:0.1, 49:1:0.1,
24:1:0.1, and 23:2:0.2, methylene chloride:methanol:concentrated
ammonium hydroxide as the eluant to yield
4-(3,5-Difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-
-1-ylamino)-3-(2-fluoro-phenylamino)-butan-2-ol. Method [4]
Retention time 2.99 min by HPLC and 3.08 min by MS (M+=469).
EXAMPLE 332
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(4-trifluoromethyl-phenylamino)-butan-2-ol
[0831] 407
[0832] The title compound was prepared according to the procedure
described in Example 331. Method [4] Retention time 3.22 min by
HPLC and 3.31 min by MS (M+=519).
EXAMPLE 333
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(3-trifluoromethyl-phenylamino)-butan-2-ol
[0833] 408
[0834] The title compound was prepared according to the procedure
described in Example 331. Method [4] Retention time 3.16 min by
HPLC and 3.24 min by MS (M+=519).
EXAMPLE 334
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(3-hydroxymethyl-phenylamino)-butan-2-ol
[0835] 409
[0836] The title compound was prepared according to the procedure
described in Example 331. Method [4] Retention time 2.64 min by
HPLC and 2.73 min by MS (M+=481).
EXAMPLE 335
Preparation of
3-(4-amino-phenylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl--
1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0837] 410
[0838] The title compound was prepared according to the procedure
described in Example 331. Method [1] Retention time 1.37 min by
HPLC and 1.43 min by MS (M+=466).
EXAMPLE 336
Preparation of
3-(3-amino-phenylamino)-4-(3,5-difluoro-phenyl)-1-(7-ethyl--
1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol
[0839] 411
[0840] The title compound was prepared according to the procedure
described in Example 331. Method [4] Retention time 2.19 min by
HPLC and 2.28 min by MS (M+=466).
EXAMPLE 337
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(pyridin-2-ylamino)-butan-2-ol
[0841] 412
[0842] The title compound was prepared according to the procedure
described in Example 331. Method [4] Retention time 2.32 min by
HPLC and 2.41 min by MS (M+=452).
EXAMPLE 338
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(pyridin-3-ylamino)-butan-2-ol
[0843] 413
[0844] The title compound was prepared according to the procedure
described in Example 331. Method [1] Retention time 1.35 min by
HPLC and 1.42 min by MS (M+=452).
EXAMPLE 339
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(pyridin-4-ylamino)-butan-2-ol
[0845] 414
[0846] The title compound was prepared according to the procedure
described in Example 331. Method [1] Retention time 1.34 min by
HPLC and 1.40 min by MS (M+=452).
EXAMPLE 340
Preparation of
{3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-n-
aphthalen-1-ylamino)-2-hydroxy-propylamino]-phenyl}-acetic acid
[0847] 415
[0848] The title compound was prepared according to the procedure
described in Example 331, except the product was not flash
chromatographed but was directly purified via preparative HPLC.
[0849] Method [1] Retention time 1.74 min by HPLC and 1.83 min by
MS (M+=509).
EXAMPLE 341
Preparation of
2-{3-[1-(3,5-difluoro-benzyl)-3-(7-ethyl-1,2,3,4-tetrahydro-
-naphthalen-1-ylamino)-2-hydroxy-propylamino]-phenyl}-N,N-dipropyl-acetami-
de
[0850] Step 1: Preparation of
2-(3-iodo-phenyl)-N,N-dipropyl-acetamide 416
[0851] Dipropylamine (0.18 mL, 1.31 mmol), 3-iodophenylacetic acid
(269 mg, 1.03 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (237 mg, 1.24 mmol), and 1-hydroxyazabenzotriazole
(22 mg, 162 umol) in methylene chloride (10 mL) were stirred for 20
h. The solution was concentrated and the residue was flash
chromatographed with 9:1, 4:1, and 7:3 hexane:ethyl acetate as the
eluant to afford 350 mg (99% yield) of
2-(3-iodo-phenyl)-N,N-dipropyl-acetamide as a colorless oil.
[0852] Step 2: Preparation of
2-{3-[1-(3,5-Difluoro-benzyl)-3-(7-ethyl-1,2-
,3,4-tetrahydro-naphthalen-1-ylamino)-2-hydroxy-propylamino]-phenyl}-N,N-d-
ipropyl-acetamide 417
[0853] The title compound was prepared according to the procedure
described in Example 331. Method [1] Retention time 2.18 min by
HPLC and 2.25 min by MS (M+=592).
EXAMPLE 342
Preparation of
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-
-phenyl)-3-(1-methyl-1H-pyrazol-4-ylamino)-butan-2-ol
[0854] 418
[0855] The title compound was prepared according to the procedure
described in Example 331. Method [1] Retention time 1.86 min by
HPLC and 1.92 min by MS (M+=511).
EXAMPLE 343
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(pyrimidin-2-ylamino)-butan-2-ol
[0856] 419
[0857] Powdered cesium carbonate (420 mg, 1.29 mmol),
3-amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen--
1-ylamino)-butan-2-ol dihydrochloride (93 mg, 208 .mu.mol),
1,4-bis(diphenylphosphino)butane (27 mg, 63.3 .mu.mol),
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (22 mg,
21.3 .mu.mol), and 2-bromopyrimidine (38 mg, 239 .mu.mol) were
placed into a flask. The flask was evacuated and refilled with
nitrogen three times. Toluene (2.0 mL) was added and the
heterogenous mixture was placed into a preheated oil bath at
80.degree. C. After stirring for 18 h, the heterogeneous mixture
was flash chromatographed with 49:1:0.1, 24:1:0.1, and 23:2:0.2,
methylene chloride:methanol:concentrated ammonium hydroxide as the
eluant to yield 4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahy-
dro-naphthalen-1-ylamino)-3-(pyrimidin-2-ylamino)-butan-2-ol.
Method [4] Retention time 2.50 min by HPLC and 2.58 min by MS
(M+=453).
EXAMPLE 344
Preparation of N-Substituted Compounds Via Reductive Amination
[0858] 420
[0859] To 50 mgs (0.12 mmol) of
3-Amino-1-[1-(3-tert-butyl-phenyl)-cyclohe-
xylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol (47) in 1.0 mL of
methanol in a 4-mL reaction vial was added 1 equivalent (0.12 mmol)
of R-aldehyde. The mixture was stirred for 15 minutes at room
temperature. After stirring, 2 equivalents (48 mg) of
polymer-supported borohydride was added to the reaction mixture.
The reaction mixture was allowed to stir overnight at room
temperature. The borohydride resins were filtered out of the
reaction mixture. The reaction mixture was then concentrated and
isolated via preparative HPLC utilizing a Varian ProStar
Preparative HPLC system to leave compounds with general structure
48. LC/MS analysis is conducted utilizing method [1].
[0860] The compounds in the chart below were made according to the
procedure above.
3 Ret. Compound M + H Time 1-[1-(3-tert-Butyl-phenyl)- 459.5 1.754
cyclohexylamino]-4-(3,5-d- ifluoro- phenyl)-3-ethylamino-butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 473.5 1.781 cyclohexylamino]-4-(3,5-d-
ifluoro- phenyl)-3-propylamino-butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 485.5 1.800 cyclohexylamino]-3-
(cyclopropylmethyl-amino)-4- (3,5-difluoro-phenyl)-butan-2- ol
1-[1-(3-tert-Butyl-phenyl)- 588.5 2.052
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-[(1-phenyl-1H-
[1,2,3]triazol-4-ylmethyl)-amino]- butan-2-ol
2-{[3-[1-(3-tert-Butyl- 537.5 1.852 phenyl)-cyclohexylamino]-1-(3-
,5- difluoro-benzyl)-2-hydroxy- propylamino]-methyl}-pheno- l
3-(2-Amino-ethylamino)-1- 474.5 1.633 [1-(3-tert-butyl-phenyl)-
cyclohexylamino]-4-(3,5- difluoro-phenyl)-butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 514.5 1.566
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-[(pyrrolidin-3-
ylmethyl)-amino]-butan-2-ol 1-[1-(3-tert-Butyl-phenyl)- 542.5 1.559
cyclohexylamino]-4-(3,5-d- ifluoro- phenyl)-3-(2-piperidin-4-yl-
ethylamino)-butan-2-ol 1-[1-(3-tert-Butyl-phenyl)- 528.5 1.560
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-[(piperidin-4-
ylmethyl)-amino]-butan-2-ol 3-Benzylamino-1-[1-(3-tert- 521.5 1.948
butyl-phenyl)-cyclohexylamino]- 4-(3,5-difluoro-phenyl)-butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 559.5 1.874
cyclohexylamino]-3-[(4-chloro-1- methyl-1H-pyrazol-3-ylmethyl)-
amino]-4-(3,5-difluoro- phenyl)-butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 511.5 1.861
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-[(furan-2-ylmethyl)-
amino]-butan-2-ol 4-{[3-[1-(3-tert-Butyl- 553.5 1.769
phenyl)-cyclohexylamino]-1-(3,5- difluoro-benzyl)-2-hydroxy-
propylamino]-methyl}-benzene- 1,3-diol 1-[1-(3-tert-Butyl-phenyl)-
511.5 1.701 cyclohexylamino]-4-(3,5-d- ifluoro-
phenyl)-3-[(1H-pyrazol-3- ylmethyl)-amino]-butan-- 2-ol
3-(1-Benzyl-1H-pyrazol-4- 587.5 2.227 ylamino)-1-[1-(3-tert-butyl-
phenyl)-cyclohexylamino]- 4-(3,5-difluoro-phenyl)-butan-2-ol
3-[3-[1-(3-tert-Butyl- 505.5 1.646 phenyl)-cyclohexylamino]-1-(3,5-
difluoro-benzyl)-2-hydroxy- propylamino]-propane-1,2-diol
1-[1-(3-tert-Butyl-phenyl)- 519.5 1.907 cyclohexylamino]-4-(3,5-d-
ifluoro- phenyl)-3-(3-methylsulfanyl- propylamino)-butan-2-ol
1-[1-(3-tert-Butyl-phenyl)- 517.5 1.815
cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(3-hydroxy-2,2-
dimethyl-propylamino)-butan-2-ol 1-[1-(3-tert-Butyl-pheny- l)-
475.5 1.649 cyclohexylamino]-4-(3,5-difluoro- phenyl)-3-(2-hydroxy-
ethylamino)-butan-2-ol
EXAMPLE 345
Preparation of
4-(3,5-difluoro-phenyl)-1-{1-[3-(2,2-dimethyl-propyl)-pheny-
l]-cyclohexylamino}-3-(2,2,2-trifluoro-ethylamino)-butan-2-ol
[0861] Step 1: 421
[0862] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride was added to a THF (anhydrous) solution (500 .mu.L)
of amine 49 (0.186 mmol, 80 mg), trifluoroacetic acid (0.186 mmol,
18 mg), diisopropylethylamine (0.386 mmol, 48 mg) and
hydroxybenzotriazole (0.2 mmol, 27.6 mg). The reaction was capped
and allowed to shake at room temperature for 12 hours at which time
LCMS indicated complete reaction. The reaction was evaporated of
THF by N.sub.2 stream, acidified with 1N HCl in ethanol (100
.mu.L), diluted (400 .mu.L ethanol), and filtered. The solution was
injected onto a preparative RP-HPLC [Method 10] for purification to
provide amide 50.
[0863] LCMS Method [11]: ret. time (min): 2.77; [M+H]=526.80.
[0864] Step 2: 422
[0865] Amide 50 (15 mg, 0.0285 mmol) was dissolved in BH.sub.3
dimethylsulfide complex (2M in THF, 100 .mu.L, 0.2 mmol), and the
reaction was capped and heated with shaking at 80.degree. C. for 4
hours. At this time, LCMS was performed showing a complete
reaction. The reaction was quenched with a few drops of
isopropanol, then evaporated of volatiles by N.sub.2 stream,
acidified with 1N HCl in ethanol (100 .mu.L), diluted (400 .mu.L
ethanol), and filtered. This solution was injected onto a
preparative RP-HPLC [Method 10] for purification to give
4-(3,5-Difluoro-phenyl)-1-{1-[3-(2,2-dimethyl-propyl)-phenyl]-cyclohexyla-
mino}-3-(2,2,2-trifluoro-ethylamino)-butan-2-ol (51).
[0866] LCMS Method [11]: Ret. time (min): 2.37; [M+H]=512.90.
EXAMPLE 346
Preparation of
3-(2,2-difluoro-ethylamino)-4-(3,5-difluoro-phenyl)-1-{1-[3-
-(2,2-dimethyl-propyl)-phenyl]-cyclohexylamino}-butan-2-ol
[0867] 423
[0868] The title compound was prepared according to the procedure
described in Example 345. LCMS ret. time (min): 2.03;
[M+H]=494.90.
EXAMPLE 347
Alternative Preparation of Formula (I) Compounds
[0869] Scheme 3. 424
[0870] As described above and below, an embodiment of the present
invention provides for compounds with structure 52 as shown above
in Scheme 4. These compounds can be made by methods known to those
skilled in the art from starting compounds that are also known to
those skilled in the art. The process chemistry is further well
known to those skilled in the art. A suitable process for the
preparation of compounds with structure 52 is set forth in EXAMPLE
348 below.
EXAMPLE 348
Preparation of
2-(3,5-difluoro-benzyl)-4-(6-ethyl-2,2-dioxo-2.lambda..sup.-
6-isothiochroman-4-ylamino)-3-hydroxy-n-methyl-butyramide
[0871] 425
[0872] Alkylation of ester 53 with bromide 54 affords the aryl
substituted ester 55. Intermediate 55 is epoxidized with
m-chloroperbenzoic acid to give epoxide 56. Nucleophilic opening of
epoxide 56 with amine 57 affords intermediate 58. Treatment of
intermediate 58 with methylamine affords
2-(3,5-Difluoro-benzyl)-4-(6-ethyl-2,2-dioxo-2.lambda..sup.6-isothiochrom-
an-4-ylamino)-3-hydroxy-N-methyl-butyramide (59).
[0873] Further examples of compounds that can be made according to
the present invention are found in the examples below.
EXAMPLE 349
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-oxazol-2-yl-butan-2-ol
[0874] 426
EXAMPLE 350
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-thiazol-2-yl-butan-2-ol
[0875] 427
EXAMPLE 351
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino-
)-3-(1H-imidazol-2-yl)-butan-2-ol
[0876] 428
EXAMPLE 352
Preparation of
4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-napht-
halen-1-ylamino)-3-(5-ethyl-2H-[1,2,4]triazol-3-yl)-butan-2-ol
[0877] 429
EXAMPLE 353
Preparation of
4-(3,5-difluoro-phenyl)-1(7-ethyl-1,2,3,4-tetrahydro-naphth-
alen-1-ylamino)-3-(5-methyl-2H-pyrazol-3-yl)-butan-2-ol
[0878] 430
EXAMPLE 354
Preparation of
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino)-4-(3,5-difluoro-
-phenyl)-3-tetrazol-1-yl-butan-2-ol
[0879] 431
EXAMPLE 355
Preparation of
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-
-phenyl)-3-[1,2,3]triazol-1-yl-butan-2-ol (3)
[0880] 432
[0881] Step 1: Preparation of
3-Azido-1-[1-(3-tert-butyl-phenyl)-cyclohexy-
lamino]-4-(3,5-difluoro-phenyl)-butan-2-ol (60)
[0882] Preparation of the Trifylazide Solution: NaN.sub.3 (0.262 g,
4.028 mmol., 9.8 eq) was added to a round bottom flask, and
dissolved in 0.68 mL of de-ionized water and 1.2 mL of
CH.sub.2Cl.sub.2. The reaction was cooled to 0.degree. C. using an
ice bath. To the round bottom flask was added Tf.sub.2O (0.231 g,
0.13 mL, 0.818 mmol., 1.99 eq.) slowly. The reaction stirred for 2
hours at 0.degree. C., and then was warmed to room temperature. The
CH.sub.2Cl.sub.2 layer was extracted and the water layer was rinsed
with CH.sub.2Cl.sub.2 (twice with 6 mL). All organic layers were
combined and washed with sat. NaHCO.sub.3.
[0883] To a separate round bottom flask,
3-Amino-1-[1-(3-tert-butyl-phenyl-
)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol (0.177 g,
0.411 mmol., 1 eq), K.sub.2CO.sub.3 (0.085 g, 0.6165 mmol., 1.5
eq), CuSO.sub.4 (0.001 g, 0.0041 mmol., 0.01 eq), de-ionized water
(1.35 mL), and methanol (2.7 mL) were added. The trifylazide
solution above was added to the round bottom flask and stirred at
room temperature over night. The organic layer was concentrated
under reduced pressure. The water layer was diluted with 7.5 mL
de-ionized water. The pH of the solution was lowered to about 6
using a pH 6.2 0.25M phosphate buffer. The water layer was
extracted with EtOAc (three times, 10 mL each). The pH of the water
layer was lowered to pH 2. The solution was rinsed with EtOAc
(three times, 10 mL each). The EtOAc layers were combined and dried
with MgSO.sub.4, filtered, and concentrated under reduced pressure
to provide 0.211 grams of compound 60. MS m/z 457.2 (M-H)
(retention time: 2.254, method: [1]).
[0884] Step 2: Preparation of
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]--
4-(3,5-difluoro-phenyl)-3-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)-butan-2-
-ol (61)
[0885] Compound 60 (0.211 grams, 0.463 mmol.) was dissolved in
trimethylsilylacetylene (5 mL) and stirred at room temperature for
fourteen days. The reaction gave 0.17 grams of compound 61. MS m/z
555.3 (M-H) (retention time: 2.385, method: [1]).
[0886] Step 3: Preparation of
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]--
4-(3,5-difluoro-phenyl)-3-[1,2,3]triazol-1-yl-butan-2-ol (62)
[0887] Compound 61 (0.17 g, 0.306 mmol., 1.0 eq) was dissolved in 5
mL dry THF and added to a round bottom flask.
Tetrabutylammoniumfluoride (1.0 M in THF) (0.46 mL, 0.460 mmol.)
was added slowly to the round bottom flask. The reaction was then
heated to reflux (70.degree. C.) for three hours. The reaction
mixture was then concentrated in vacuo and the product 62 isolated
after flash chromatographic purification.
[0888] .sup.1H NMR (CD.sub.3OD) .delta.7.68 (s, 1H), 7.54 (s, 1H),
7.45 (s, 1H), 7.27-7.22 (m, 3H), 6.69 (t, J=9 Hz, 1H), 6.56-6.54
(d, J=6 Hz, 2H), 3.99 (m, 1H), 3.37-3.20 (m, 5H), 2.16-2.05 (m,
4H), 1.81-1.66 (m, 4H), 1.51-1.40 (m, 2H), 1.30 (s, 9H) MS m/z
483.3 (M-H) (retention time: 2.045, method: [1]).
EXAMPLE 356
Preparation of 2-(3,5-difluorophenyl)-1-oxiranylethanol (67) and
2-[2-(3,5-difluorophenyl)-1-methoxyethyl]oxirane (68)
[0889] 433
[0890] The synthesis of 2-(3,5-Difluorophenyl)-1-oxiranylethanol
(67) followed that reported in Kurihara, M. et al. Tetrahedron
Lett. 1999, 40, 3183-3184 for the synthesis of
2-phenyl-1-oxiranylethanol.
2-(3,5-Difluorophenyl)-1-oxiranylethanol: R.sub.f=0.42 (30%
EtOAc/hexanes); retention time (min)=1.350 (method [1]); MS(ESI)
242.3 (84), 201.3 (26), 183.3 (100).
[0891] The synthesis of
2-[2-(3,5-Difluorophenyl)-1-methoxyethyl]oxirane (68) followed the
method of Boeckman, R. K. Jr.; Liu, X. Synthesis 2002, 2138-2142.
2-(3,5-Difluorophenyl)-1-oxiranylethanol (67) (411 mg, 2.05 mmol)
was combined with silver(I) oxide (1.934 g, 8.34 mmol) in
iodomethane (5.2 mL, 83.3 mmol), and heated to gentle reflux
(45.degree. C. bath) for 20 h. The mixture was then diluted with
diethyl ether, filtered through diatomaceous earth, and the
filtrate concentrated under reduced pressure to give 68. Flash
chromatography (10% EtOAc/hexanes elution) afforded 273 mg (63%) of
the product as an oil: R.sub.f=0.26 (10% EtOAc/hexanes); retention
time (min)=1.895 (major), 1.951 (minor), method [1]; MS (ESI) 256.3
(100), 237.3 (22), 215.3 (26).
EXAMPLE 357
Preparation of
1-[1-(3-tert-butylphenyl)cyclohexylamino]-4-(3,5-difluoroph-
enyl)-butane-2,3-diol
[0892] 434
[0893] A solution of 1-(3-tert-Butylphenyl)cyclohexylamine (266 mg,
1.15 mmol) in isopropanol (2 mL) was added to
2-(3,5-Difluorophenyl)-1-oxirany- lethanol (67) (209 mg, 1.05 mmol)
in a sealed tube. The flask was sealed and heated to 90.degree. C.
for 7 h. The reaction mixture was concentrated under vacuum, and
purified by flash chromatography (0-5% MeOH/CH.sub.2Cl.sub.2
elution) to give a white foam as product (260 mg, 57%):
R.sub.f=0.53 in 10% MeOH/CH.sub.2Cl.sub.2; retention time
(min)=1.95, method [1]; MS (ESI) 432.4.
EXAMPLE 358
Preparation of
1-[1-(3-tert-butylphenyl)cyclohexylamino]-4-(3,5-difluoroph-
enyl)-3-methoxy-butan-2-ol
[0894] 435
[0895] This procedure follows that for the synthesis of
1-[1-(3-tert-butylphenyl)cyclohexylamino]-4-(3,5-difluorophenyl)-butane-2-
,3-diol in EXAMPLE 357, except
2-[2-(3,5-Difluorophenyl)-1-methoxyethyl]ox- irane (68) is used
instead of 2-(3,5-Difluorophenyl)-1-oxiranylethanol (67) to give
the title compound. Yield: 166 mg (55%).
[0896] Retention time (min)=2.11, method [1]; MS (ESI) 446.5.
[0897] Other analogs of this type include: 436
[0898]
1-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-
-3-phenoxy-butan-2-ol 437
[0899]
1-(3,5-Difluoro-phenyl)-4-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahyd-
ro-naphthalen-1-ylamino]-butane-2,3-diol 438
[0900] Methyl-carbamic acid
3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1--
(3,5-difluoro-benzyl)-2-hydroxypropyl ester 439
[0901]
{1-(3,5-Difluoro-benzyl)-3-[7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahy-
dro-naphthalen-1-ylamino]-2-hydroxy-propoxy}-methanesulfonamide
EXAMPLE 359
Preparation of
1-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-diflu-
oro-benzyl)-2-hydroxy-propyl]-azepan-2-one (74) and
1-[3-[1]-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-
-hydroxy-propyl]-pyrrolidin-2-one (75)
[0902] 440
[0903] Preparation of ester (70):
[0904] The amine (68) (0.1 g, 0.23 mM), adipic semialdehyde methyl
ester (0.05 mL, 0.35 mM), and polymer supported borohydride (2.5
M/g, 0.19 g, 0.46 mM) in MeOH (10 mL) was stirred overnight at RT.
Polymer supported borohydride was filtered off, filtrate was
concentrated and purified on Biotage (eluted with 4% MeOH in
CH.sub.2Cl.sub.2). Yield 0.12 g (92%) of ester (70).
[0905] Retention time (min)=1.91, method [1]; MS (ESI) 559.5
[0906] Hydrolysis of Ester (70):
[0907] An ester (70) (0.12 g, 0.22 mM) treated with LiOH hydride
(0.05 g) in water (0.25 mL) and MeOH (0.25 mL) was stirred
overnight at RT. The solvent was stripped and aq. citric acid was
added until pH 3. The acid (72) was extracted with CH.sub.2Cl.sub.2
(4.times.). Yield 0.105 g.
[0908] Retention time (min)=4.20, Method [3]; MS (ESI) 545.5
[0909] Preparation of
1-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,-
5-difluoro-benzyl)-2-hydroxy-propyl]-azepan-2-one (74):
[0910] An acid (72) (0.10 g, 0.18 mM) in 10 mL of DMF was treated
with BOP (0.09 g, 0.20 mM) and NaHCO.sub.3 (0.09 g, 1.08 mM). The
reaction mixture was stirred o/n at RT and then poured into water
(100 mL) and extracted with EtOAc (3.times.20 mL). The organic
layer was combined, washed with brine, dried and concentrated.
Crude yield 0.08 g. The product was purified by HPLC. Final yield
0.009 g (9.4%).
[0911] Retention time (min)=2.28, method [1]; MS (ESI) 527.3.
[0912] Preparation of
1-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,-
5-difluoro-benzyl)-2-hydroxy-propyl]-pyrrolidin-2-one (75):
[0913] Lactam (75) was synthesized according to the procedure
described above for lactam (74).
[0914] Retention time (min)=2.06, method [1]; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.7.69 (s, 1H), 7.50-7.25 (m, 3H), 6.65 (m, 3H),
4.17 (m, 1H), 3.93 (m, 1H), 3.28 (m, 1H), 3.15 (m, 1H), 2.88 (m,
1H), 2.76-2.57 (m, 5H), 2.17-1.95 (m, 4H), 1.80-1.61 (m, 5H), 1.45
(m, 2H), 1.35 (s, 9H); .sup.13C NMR (75 MHz, CDCl.sub.3);
.delta.176.4, 152.8, 134.1, 128.7, 126.1, 124.6, 124.5, 11.1,
102.1, 67.5, 64.3, 54.5, 44.4, 44.0, 34.9, 34.0, 33.1, 32.3, 31.1,
30.7, 24.8, 21.9, 18.2; MS (ESI) 499.3.
EXAMPLE 360
Preparation of
2-[3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-diflu-
oro-benzyl)-2-hydroxy-propyl]-2,3,4,5-tetrahydro-benzo[C]azepin-1-one
(81)
[0915] 441442
[0916] Step 1: Preparation of 2-(3-Hydroxy-prop-1-ynyl)-benzoic
acid methyl ester (76)
[0917] 2-Iodo-benzoic acid methyl ester (2.0 g, 7.632 mmol., 1 eq)
with propargyl alcohol (0.513 g, 9.158 mmol., 1.2 eq),
triethylamine (25 mL), PdCl.sub.2(PPh.sub.3).sub.2 (0.121 g, 0.153
mmol., 0.02 eq), and copper(I) iodide (0.014 g, 0.076 mmol., 0.01
eq) were added to a round bottom flask. The reaction mixture was
heated to 75.degree. C. for three days. For the workup, the
reaction was filtered through Celite and concentrated. The crude
compound was purified by silica column: (10% EtOAc:Hexanes, (250
mL), then 50% EtOAc:Hexanes, (500 mL)). The reaction provided 0.59
grams of pure compound (76). MS m/z 173.3 (M-OH) (retention time:
1.349, method: [1]).
[0918] Step 2: Preparation of 2-(3-Hydroxy-propyl)-benzoic acid
methyl ester (77)
[0919] Compound (76) (0.59 g, 3.10 mmol.) was dissolved in 5 mL
EtOAc and placed in a hydrogenation bottle. To the bottle,
PtO.sub.2 (0.06 g, 10.2% of the grams of compound (76)) was added.
The bottle was sealed and 50 psi of hydrogen was added. It was then
placed on the shaker for 2 hours. The reaction mixture was filtered
with Celite and concentrated. The reaction provided 0.53 g of
compound (77).
[0920] .sup.1H NMR (CDCl.sub.3) .delta.7.88-7.86 (d, J=6 Hz, 1H),
7.44-7.41 (d, J=9 Hz, 1H), 7.28 (t, J=9 Hz 1H), 7.25 (t, J=6 Hz,
1H), 3.89 (s, 3H), 3.63 (t, J=9 Hz, 2H), 3.06 (t, J=9 Hz 2H),
1.96-1.85 (m, 2H).
[0921] Step 3: Preparation of 2-(3-Oxo-propyl)-benzoic acid methyl
ester (78)
[0922] Added to a round bottom flask was PCC (0.788 g, 3.66 mmol.,
1.3 eq) and CH.sub.2Cl.sub.2 (35 mL). The reaction was cooled to
0.degree. C. Compound (77) (0.53 g, 2.72 mmol.) dissolved in 5 mL
CH.sub.2Cl.sub.2, was added slowly to the round bottom flask. The
reaction stirred over night (0.degree. C. to room temperature), was
filtered through Celite, and was rinsed with 50 mL of diethyl
ether. The filtrate was concentrated under reduced pressure. The
reaction provided 0.79 g of compound (78). .sup.1H NMR (CDCl.sub.3)
.delta.9.58 (s, 1H), 7.97-7.94 (d, J=9 Hz, 1H), 7.47-7.45 (d, J=6
Hz, 1H), 7.30-7.25 (bs, 2H), 3.91 (s, 3H), 3.30 (t, J=6 Hz, 2H),
2.84 (t, J=6 Hz, 2H) MS m/z 161.1 (M-O .sub.2) (retention time:
1.665, method: [1]).
[0923] Step 4: Preparation of
2-{3-[3-[1-(3-tert-Butyl-phenyl)-cyclohexyla-
mino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-propyl}-benzoic
acid methyl ester (79)
[0924]
3-Amino-1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-
-phenyl)-butan-2-ol (0.1 g, 0.23 mmol, 1.0 eq), compound (78)
(0.066 g, 0.345 mmol, 1.5 eq), Borohydrate (polymer support, 2.5
mmol/g) (0.184 g, 0.46 mmol, 2.0 eq), and 10 mL methanol were added
to a round bottom flask. The reaction stirred at room temperature
over night. The reaction was then filtered through Celite and
rinsed with 5 mL methanol. The filtrate was concentrated under
reduced pressure to provide 0.136 g of crude product. The crude
material was purified using a silica column (100% EtOAc (150 mL),
then 10% methanol in CH.sub.2Cl.sub.2 (150 mL)) to provide 0.052 g
of pure compound (79). MS m/z 607.5 (M-H) (retention time: 2.21,
method: [1]).
[0925] Step 5: Preparation of
2-{3-[3-[1-(3-tert-Butyl-phenyl)-cyclohexyla-
mino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-propyl}-benzoic
acid (80)
[0926] Compound (79) (0.052 g, 0.0856, 1.0 eq), lithium hydroxide
monohydrate (0.0198 g, 0.471 mmol, 5.5 eq) and one mL each of water
and methanol were added to a round bottom flask, and stirred at
room temperature overnight. The reaction was then treated with 0.05
g of KOH, stirred at 40.degree. C. for one hour, and concentrated
under reduced pressure. The solution was treated with 0.5 M citric
acid until the pH was 3. The solution was rinsed four times with 3
mL CH.sub.2Cl.sub.2. All CH.sub.2Cl.sub.2 washes were combined and
dried with MgSO.sub.4. The MgSO.sub.4 was removed by filtration,
and the compound was concentrated by reduced pressure. The reaction
gave 0.036 grams of compound (80).
[0927] MS m/z 593.5 (M-H) (retention time: 1.92, method: [1]).
[0928] Step 6: Preparation of
2-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamin-
o]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-2,3,4,5-tetrahydro-benzo[c]az-
epin-1-one (81)
[0929] Compound (80) (0.036 g, 0.061 mmol, 1.0 eq) was added to a
round bottom flask with NaHCO.sub.3 (0.031 g, 0.3642 mmol, 6.0 eq),
(benzotriazol-1-yloxy)tris(dimethylamine) phosphonium
hexafluorophosphate (BOP) (0.0295 g, 0.067 mmol, 1.1 eq), and 5 mL
of DMF. The reaction stirred at room temperature overnight. The
reaction was poured into 25 mL water and extracted with EtOAc three
times, 20 mL each. The EtOAc was treated with brine (30 mL) and
dried with MgSO.sub.4. The MgSO.sub.4 was removed by filtration,
and the solvent was removed by reduced pressure. The reaction gave
0.04 g of crude product. The reaction was purified by reversed
phase HPLC providing 4.5 mg of pure compound (81).
[0930] .sup.1H NMR (CDCl.sub.3) .delta.7.68 (s, 1H), 7.40-7.32 (m,
6H), 7.05-7.03 (d, J=6 Hz, 1H), 6.75-6.72 (d, J=9 Hz, 2H), 6.63 (t,
J=9 Hz, 1H), 4.15-4.05 (bs, 2H), 3.55-3.35 (bs, 2H), 2.90-2.80 (m,
2H), 2.70-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.15-2.05 (m, 2H),
1.85-1.75 (m, 4H), 1.65-1.45 (m, 6H), 1.29 (s, 9H)
[0931] MS m/z 575.3 (M-H) (retention time: 2.40, method: [1]).
[0932] Various amines that may be used for the preparation of
compounds of formula (I) are described in the Examples below.
EXAMPLE 361
Preparation of 1-(3-isopropylphenyl)cyclo hexanamine
hydrochloride
[0933] 443
[0934] Step 1. Preparation of 1-(3-isopropylphenyl)cyclohexanol
(82).
[0935] To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF
is added a small crystal of iodine followed by 40 .mu.L of
dibromoethane. This mixture is placed in a water bath at 50.degree.
C. and 3-isopropylbromobenzene (5.0 g, 25 mmol) in 15 mL of dry
tetrahydrofuran (THF) is added dropwise over 20 min, while the bath
temperature is raised to 70.degree. C. The mixture is stirred and
refluxed for 40 additional min. The solution is cooled in an
ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry
THF is added dropwise over 15 min. The ice bath is removed and the
mixture is allowed to warm to ambient temperature over 1 h. The
solution is decanted into aqueous saturated NH.sub.4Cl and combined
with an ether wash of the residual magnesium turnings. The organic
phase is washed twice more with aqueous NH.sub.4Cl, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
Chromatography on silica gel, eluting with 10% ethyl acetate in
heptane, affords 2.7 g (12 mmol, 60%) of
1-(3-isopropylphenyl)cyclohexanol 82 as an oil: .sup.1H NMR
(CDCl.sub.3) .delta.7.39 (m, 1H), 7.3 (m, 2H), 7.12 (m, 1H), 2.92
(m, 1H), 1.84-1.54 (m, 10H), 1.26 (d, J=7 Hz, 6H).
[0936] Step 2. Preparation of 1-(3-isopropylphenyl)cyclohexylazide
(83).
[0937] To 3.20 g (14.7 mmol) of 1-(3-isopropylphenyl)cyclohexanol
82 in 60 mL of CH.sub.2Cl.sub.2 under nitrogen is added 2.10 g
(32.3 mmol) of sodium azide. The stirred suspension is cooled to
-5.degree. C. and a solution of trifluoroacetic acid (9.0 mL, 120
mmol) in 35 mL of dichloromethane is added dropwise over 1 h. The
resulting suspension is stirred at 0.degree. C. for an additional
hour. 10 mL of water is added dropwise to the cold, vigorously
stirred mixture, followed by dropwise addition of a mixture of 10
mL of water and 10 mL of concentrated ammonium hydroxide. After 30
min the mixture is poured into a separatory funnel containing 350
mL of a 1:1 mixture of heptane and ethyl acetate, and 100 mL of
water. The organic phase is washed with an additional portion of
water, followed successively by 1 N KH.sub.2PO.sub.4, water, and
brine. It is then dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to afford 3.6 g (14.7 mmol, 100%) of 83 as a pale
yellow oil: .sup.1H NMR (CDCl.sub.3) .delta.7.3 (m, 2H), 7.25 (m,
1H), 7.16 (m, 1H), 2.92 (m, 1H), 2.01 (m, 2H), 1.83 (m, 2H),
1.73-1.64 (m, 5H), 1.3 (m, 1H), 1.26 (d, J=7 Hz, 6H).
[0938] Step 3. Preparation of 1-(3-isopropylphenyl)cyclohexanamine
hydrochloride (84).
[0939] To 1-(3-isopropylphenyl)cyclohexylazide 83 (2.7 g, 11 mmol)
in 200 mL of ethanol is added, 20 mL of glacial acetic acid and
0.54 g of 10% palladium on carbon. The mixture is evacuated and
placed under 16 psi of hydrogen, with shaking, for 2.5 h. The
reaction mixture is filtered, the catalyst is washed with ethanol,
and the solvents are removed in vacuo. Residual acetic acid is
removed by chasing the residue with toluene. The acetate salt is
dissolved in ethyl acetate and 1 N NaOH is added. The organic phase
is washed with more 1 N NaOH and then with water, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue is
dissolved in ether and ethereal HCl (concentrated HCl in ether
which has been stored over MgSO.sub.4) is added to afford a white
solid. This is filtered, washed with ether, collected as a solution
in dichloromethane, and concentrated to afford 2.1 g (8.3 mmol,
75%) of hydrochloride 84 as a white solid: .sup.1H NMR (CDCl.sub.3)
.delta.8.42 (br s, 3H), 7.43 (m, 2H), 7.25 (m, 1H), 7.15 (m, 1H),
2.92 (hept, J=7 Hz, 1H), 2.26 (m, 2H), 2.00 (m, 2H), 1.69 (m, 2H),
1.45-1.3 (m, 4H), 1.24 (d, J=7 Hz, 6H); IR (diffuse reflectance)
2944, 2864, 2766, 2707, 2490, 2447, 2411, 2368, 2052, 1599, 1522,
1455, 1357, 796, 704 cm .sup.-1. MS (EI)m/z(relative intensity) 217
(M+,26), 200 (13), 175 (18), 174 (99), 157 (15), 146 (23), 132
(56), 131 (11), 130 (16), 129 (18). HRMS (ESI) calculated for
C.sub.15H.sub.23N+H.sub.1 218.1909, found 218.1910. Anal.
Calculated for C.sub.15H.sub.23N.HCl: C, 70.98; H, 9.53; N, 5.52;
Cl, 13.97. Found: C, 70.98; H, 9.38; N, 5.49.
EXAMPLE 362
Preparation of 1-(3-ethyl-phenyl)-cyclohexylamine from
1-(1-azido-cyclohexyl)-3-ethyl-benzene
[0940] 444
[0941] A solution of 1-(1-azido-cyclohexyl)-3-ethyl-benzene (1.94
g, 8.39 mmol) in Et.sub.2O (8 mL) was added dropwise to a
suspension of lithium aluminum hydride (0.31 g, 8.17 mmol) in THF
(30 mL). This was stirred at room temperature under N.sub.2 (g)
inlet for 3 h, whereupon the reaction was quenched with 1.0N NaOH.
The reaction mixture was then partitioned between EtO.sub.2 and 1N
HCl. The aqueous layer was collected and basified with 2N
NH.sub.4OH and extracted with CHCl.sub.3. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered, and concentrated
under reduced pressure. The crude product was used without further
purification: mass spec (CI) 187.1 (M-16).
[0942] Scheme 4. Preparation of
8-(3-isopropylphenyl)-1,4dioxa-spiro[4.5]d- ecane-8-amine acetate
445
[0943] Step 1. Preparation of
8-(3-isopropylphenyl)-1,4-dioxa-spiro[4.5]de- cane-8-alcohol
(85).
[0944] A solution of 3-bromoisopropylbenzene (25 mmol) in 20 mL of
dry THF is added dropwise over 20 min to 1.22 g (50 mmol) of
magnesium turnings in 10 mL of refluxing THF under nitrogen and the
mixture is refluxed for an additional 25 min to form the Grignard
reagent. The Grignard solution is cooled and added by cannula to a
suspension of CuBr-dimethylsulfide complex (0.52 g, 2.5 mmol) in
dry THF at -25.degree. C. The suspension is stirred at -25.degree.
C. for 20 min, and then a solution of 1,4 cyclohexanedione,
monoethylene ketal (3.9 g, 25 mmol) in 15 mL of THF is added
dropwise over 5 min. The mixture is allowed to gradually warm to
ambient temperature. After chromatography over silica gel, eluting
with 20% to 30% ethyl acetate in heptane, alcohol 85 (5.6 g, 20
mmol, 80%) as a colorless oil which crystallizes to a white solid
on cooling: .sup.1H NMR (CDCl.sub.3) .delta.7.39 (s, 1H), 7.33 (m,
1H), 7.28 (t, J=7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 4.0 (m, 4H),
2.91 (hept, J=7 Hz, 1H), 2.15 (m, 4H), 1.82 (br d, J=11.5 Hz, 2H),
1.70 (brd, J=11.5 Hz, 2H), 1.25 (d, J=7 Hz, 6H); MS (CI) m/z 259.2
(M-OH).
[0945] Step 2. Preparation of
8-(3-isopropylphenyl)-1,4-dioxa-spiro[4.5]de- cane-8-azide (86).
8-(3-isopropylphenyl)-1,4-dioxa-spiro[4.5]decane-8-alco- hol 85
(5.5 g, 20 mmol) is reacted with sodium azide (2.9 g, 45 mmol) and
trifluoroacetic acid (TFA, 13 mL, 170 mmol) in 120 mL of
CH.sub.2Cl.sub.2 at 0.degree. C., allowing the reaction to stir 2 h
after dropwise addition of the TFA. The reaction is quenched by
dropwise addition of 18 mL of concentrated NH.sub.4OH.
[0946] The mixture is taken up in water, ethyl acetate, and
heptane, and the organic phase is washed three more times with
water and once with brine. The solution is dried
(Na.sub.2SO.sub.4), filtered, concentrated, and chromatographed
over silica gel, eluting with 3% acetone in heptane. Concentration
of the product-containing fractions affords 2.2 g (7.3 mmol, 36%)
of 86 as a colorless oil: .sup.1H NMR (CDCl.sub.3) .delta.7.33-7.26
(m, 3H), 7.17 (m, 1H), 3.98 (m, 4H), 2.92 (hept, J=7 Hz, 1H),
2.2-2.12 (m, 2H), 2.07-1.95 (m, 4H), 1.72 (m, 2H), 1.26 (d, J=7 Hz,
6H).
[0947] Step 3. Preparation of
8-(3-isopropylphenyl)-1,4-dioxa-spiro[4.5]de- cane-8-amine acetate
(87).
[0948] 2.2 g (7.3 mmol) of
8-(3-isopropylphenyl)-1,4-dioxa-spiro[4.5]decan- e-8-azide 86 in
200 mL of ethanol is reduced under 16 psi of hydrogen in the
presence of 0.7 g of 10% palladium on carbon for 4.5 h. Filtration
and removal of solvents with a toluene azeotrope affords a white
solid which is triturated with pentane to yield 2.14 g (6.4 mmol,
87%) of 87 as a white solid: .sup.1H NMR (CDCl.sub.3)
.delta.7.37-7.33 (m, 2H), 7.30-7.26 (m, 1H), 7.13 (d, J=7.5 Hz,
1H), 5.91 (br, 3H), 3.96 (m, 4H), 2.90 (hept., J=7 Hz, 1H), 2.32
(m, 2H), 2.03 (s, 3H), 2.0-1.85 (m, 4H), 1.63 (m, 2H), 1.25 (d, J=7
Hz, 6H); MS (CI) m/z 259.2 (M-NH.sub.2).
EXAMPLE 363
Preparation of 1-tert-butyl-3-iodo-benzene from
3-(tert-butyl)aniline
[0949] 3-(tert-butyl)aniline (Oakwood, 6.0 g, 40.21 mmol) was
slowly added to a cold solution of 12 N HCl (24.5 mL) while
stirring over an ice/acetone bath in a three-neck round bottom
flask equipped with a thermometer. A 2.9 M solution of sodium
nitrite (16 mL) was added via addition funnel to the reaction flask
at a rate so as maintain the temperature below 2.degree. C. The
solution was stirred for 30 min prior to being added to a reaction
flask containing a 4.2 M solution of potassium iodide (100 mL). The
reaction mixture was allowed to stir overnight while warming to RT.
The mixture was then extracted with a hexane/ether solution (1:1)
followed by washing with H.sub.2O (2.times.), 0.2N citric acid
(2.times.) and sat. NaCl. The organic phase was separated, dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
residue was purified by flash chromatography (100% Hexane) to give
the desired iodo intermediate (8.33 g, 80%): .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.1.34 (s, 9H), 7.07 (t, J=8.0 Hz, 1H),
7.39 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.77 (t, J=2.0 Hz,
1H).
EXAMPLE 364
Preparation of 1-(3-tert-butyl-phenyl)-cyclo hexanol from
1-tert-butyl-3-iodo-benzene
[0950] 446
[0951] 1-tert-Butyl-3-iodo-benzene (8.19 g, 31.49 mmol) in
anhydrous THF (35 mL) was cooled to -78.degree. C. A solution of
1.7M tert-butyl lithium was added and the reaction mixture was
allowed to stir while under N.sub.2 (g) inlet for 2 h. A solution
of cyclohexanone in anhydrous THF (5 mL) was added and the reaction
mixture was stirred for 1 h before transferring to a 0.degree. C.
bath for 1 h and warming to room temperature for 1 h. The reaction
was quenched with H.sub.2O and extracted with ether. The organic
layer was separated, dried (NaSO.sub.4) and concentrated under
reduce pressure. The residue was purified by flash chromatography
(100% CHCl.sub.3) to give the desired alcohol (4.73 g, 65%): mass
spec (CI) 215.2 (M-OH).
EXAMPLE 365
Preparation of 1-(1-azido-cyclohexyl)3-tert-butyl-benzene from
1-(3-tert-butyl-phenyl)-cyclo hexanol
[0952] 1-(3-tert-Butyl-phenyl)-cyclohexanol (3.33 g, 14.34 mmol) in
dry chloroform (75 mL) was cooled to 0.degree. C. under N.sub.2 (g)
inlet. Sodium azide (2.89 g, 44.45 mmol) was added followed by
dropwise addition of trifluoroacetic acid (5.5 mL, 71.39 mmol). The
reaction mixture was allowed to stir at room temperature overnight
and then partitioned between H.sub.2O and ether. The aqueous layer
was removed and the mixture was washed with H.sub.2O followed by
1.0 N NH.sub.4OH. The organic layer was separated, dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (100% hexane) to give
the desired azide (0.50 g, 14%):mass spec (CI) 215.2
(M-N.sub.3).
EXAMPLE 366
Preparation of 1-(3-tert-butyl-phenyl)-cyclo hexylamine from
1-(1-azido-cyclohexyl)3-tert-butyl-benzene
[0953] 447
[0954] To a solution of 1-(1-Azido-cyclohexyl)-3-tert-butylbenzene
dissolved in ethanol (5 mL) was added acetic acid (0.5 mL) and 10%
palladium on carbon (0.10 g, 0.94 mmol). The reaction mixture was
placed on the hydrogenator at 19 psi for 3.5 h and then filtered
through Celite and rinsed with ethanol. The filtrate was collected
and concentrated under reduced pressure. This was then partitioned
between EtOAc and 1N NaOH. The aqueous layer was removed and the
mixture was washed with H.sub.2O. The organic layer was separated,
dried (Na.sub.2SO.sub.4), and concentrated under reduced pressure.
The crude product was used without further purification: mass spec
(CI) 215.2 (M-NH.sub.2).
EXAMPLE 367
Preparation of 1-(3-isopropylphenyl)cyclo hexanamine
hydrochloride
[0955] 448
[0956] Step 1. Preparation of 1-(3-isopropylphenyl)cyclohexanol
(88).
[0957] To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF
is added a small crystal of iodine followed by 40 .mu.L of
dibromoethane. This mixture is placed in a water bath at 50.degree.
C. and 3-isopropylbromobenzene (5.0 g, 25 mmol) in 15 mL of dry
tetrahydrofuran (THF) is added dropwise over 20 min, while the bath
temperature is raised to 70.degree. C. The mixture is stirred and
refluxed for 40 additional min. The solution is cooled in an
ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry
THF is added dropwise over 15 min. The ice bath is removed and the
mixture is allowed to warm to ambient temperature over 1 h. The
solution is decanted into aqueous saturated NH.sub.4Cl and combined
with an ether wash of the residual magnesium turnings. The organic
phase is washed twice more with aqueous NH.sub.4Cl, dried over
anhydrous sodium sulfate, filtered and concentrated. Chromatography
on silica gel, eluting with 10% ethyl acetate in heptane, affords
2.7 g (12 mmol, 60%) of 1-(3-isopropylphenyl)cyclohexanol 88 as an
oil: .sup.1H NMR (CDCl.sub.3) .delta.7.39 (m, 1H), 7.3 (m, 2H),
7.12 (m, 1H), 2.92 (m, 1H), 1.84-1.54 (m, 10H), 1.26 (d, J=7 Hz,
6H).
[0958] Step 2. Preparation of 1-(3-isopropylphenyl)cyclohexylazide
(89).
[0959] To 3.20 g (14.7 mmol) of 1-(3-isopropylphenyl)cyclohexanol
88 in 60 mL of CH.sub.2Cl.sub.2 under nitrogen is added 2.10 g
(32.3 mmol) of sodium azide. The stirred suspension is cooled to
-5.degree. C. and a solution of trifluoroacetic acid (9.0 mL, 120
mmol) in 35 mL of dichloromethane is added dropwise over 1 h. The
resulting suspension is stirred at 0.degree. C. for an additional 1
h. 10 mL of water is added dropwise to the cold, vigorously stirred
mixture, followed by dropwise addition of a mixture of 10 mL of
water and 10 mL of concentrated ammonium hydroxide. After 30 min
the mixture is poured into a separatory funnel containing 350 mL of
a 1:1 mixture of heptane and ethyl acetate, and 100 mL of water.
The organic phase is washed with an additional portion of water,
followed successively by 1 N KH.sub.2PO.sub.4, water, and brine. It
is then dried over anhydrous sodium sulfate, filtered and
concentrated to afford 3.6 g (14.7 mmol, 100%) of 89 as a pale
yellow oil: .sup.1H NMR (CDCl.sub.3) .delta.7.3 (m, 2H), 7.25 (m,
1H), 7.16 (m, 1H), 2.92 (m, 1H), 2.01 (m, 2H), 1.83 (m, 2H),
1.73-1.64 (m, 5H), 1.3 (m, 1H), 1.26 (d, J=7 Hz, 6H).
[0960] Step 3. Preparation of 1-(3-isopropylphenyl)cyclohexanamine
hydrochloride (90).
[0961] To 1-(3-isopropylphenyl)cyclohexylazide 89 (2.7 g, 11 mmol)
in 200 mL of ethanol is added 20 mL of glacial acetic acid and 0.54
g of 10% palladium on carbon. The mixture is evacuated and placed
under 16 psi of hydrogen, with shaking, for 2.5 h. The reaction
mixture is filtered, the catalyst is washed with ethanol, and the
solvents are removed in vacuo. Residual acetic acid is removed by
chasing the residue with toluene. The acetate salt is dissolved in
ethyl acetate and 1 N NaOH is added. The organic phase is washed
with more 1 N NaOH and then with water, dried over sodium sulfate,
filtered and concentrated. The residue is dissolved in ether and
ethereal HCl (concentrated HCl in ether which has been stored over
magnesium sulfate) is added to afford a white solid. This is
filtered, washed with ether, collected as a solution in
dichloromethane, and concentrated to afford 2.1 g (8.3 mmol, 75%)
of hydrochloride 90 as a white solid: .sup.1H NMR (CDCl.sub.3)
.delta.8.42 (br s, 3H), 7.43 (m, 2H), 7.25 (m, 1H), 7.15 (m, 1H),
2.92 (hept, J=7 Hz, 1H), 2.26 (m, 2H), 2.00 (m, 2H), 1.69 (m, 2H),
1.45-1.3 (m, 4H), 1.24 (d, J=7 Hz, 6H); IR (diffuse reflectance)
2944, 2864, 2766, 2707, 2490, 2447, 2411, 2368, 2052, 1599, 1522,
1455, 1357, 796, 704 cm .sup.-1. MS (EI)m/z(relative intensity) 217
(M+,26), 200 (13), 175 (18), 174 (99), 157 (15), 146 (23), 132
(56), 131 (11), 130 (16), 129 (18). HRMS (ESI) calculated for
C.sub.15H.sub.23N+H.sub.1 218.1909, found 218.1910. Anal.
Calculated for C.sub.15H.sub.23N.HCl: C, 70.98; H, 9.53; N, 5.52;
Cl, 13.97. Found: C, 70.98; H, 9.38; N, 5.49.
EXAMPLE 368
Preparation of
5-(2,2-dimethyl-propyl)-2-imidazol-1-yl-benzylamine
[0962] 449
[0963] Incorporation of the neopentyl group was performed using a
Negishi coupling with the neopentyl zinc species generated from the
commercially available neopentylmagnesium chloride. The in situ
generated neopentyl zinc reagent underwent cross-coupling reaction
with the aryl bromide using the Fu catalyst at room temperature.
Displacement of the aryl fluoride with imidazole occurred in DMF
with heating. Reduction of the nitrile was carried out with Raney
Ni. During the reduction, a significant amount of dimer was seen
when Boc anhydride was used instead of ammonia. The reaction was
found to proceed to completion at 200 psi of hydrogen at 60.degree.
C. Reduction of the temperature to either 20.degree. C. or
40.degree. C. or reducing the pressure of hydrogen significantly
reduced the rate of the reduction. The product was an oil, but
treating with hydrogen chloride in dioxane gave the salt as a free
flowing solid.
[0964] Step 1: Preparation of
5-neopentyl-2-fluoro-benzonitrile.
[0965] To a solution of zinc chloride (50 mL, 1.0M in diethyl
ether, 50 mmol) was added neopentylmagnesium chloride (50 mL, 1.0M
in THF, 50 mmol) dropwise at 0.degree. C. During the addition, the
generated magnesium salts formed a white precipitate. The reaction
was removed from the ice bath and allowed to stir for 1 h, then
1-bromo-2-fluorobenzonitrile (5 g, 25 mmol) was added followed by
bis(tri-tert-butylphosphine)palladium (0.127 g, 0.25 mmol, 1%). The
reaction began to reflux and was placed back into the ice bath.
After 1 h, the reaction was diluted with 200 mL of diethyl ether
and washed with 1N HCl (2.times.100 mL), brine (100 mL), dried over
magnesium sulfate and concentrated to give an oily solid (4.3 g, 22
mmol, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.38-7.30 (m,
2H), 7.11 (dt, J=8.5, 1.4 Hz, 1H), 2.49 (s, 2H), 0.90 (s, 9H).
[0966] Step 2: Preparation of
5-neopentyl-2-imidazol-1-yl-benzonitrile.
[0967] A solution of 5-neopentyl-2-fluoro-benzonitrile (4.3 g, 22.5
mmol), imidazole (1.68 g, 24.73 mmol) and potassium carbonate (6.25
g, 44.97 mmol) were stirred in DMF (50 mL) at 90.degree. C. The
reaction was stopped after 4 h and worked up, but LCMS and HNMR
show starting material remaining. The crude product was resubmitted
to reaction conditions and stirred overnight. The reaction was
diluted with ethyl acetate (100 mL) and washed with water
(2.times.75 mL) and brine (75 mL). The organic layer was dried over
magnesium sulfate and concentrated to give a white solid (4.16 g,
17.4 mmol, 77%); MH+240.2.
[0968] Step 3: Preparation of 5-neopentyl-2-fluoro-benzylamine.
[0969] To a solution 5-neopentyl-2-imidazol-1-yl-benzonitrile
(10.00 g, 41.79 mmol) in ammonia in methanol solution (.about.7N,
350 mL) was added a slurry of Raney nickel (10 mL). The reaction
was sealed in a parr bomb and placed under H.sub.2 (200 psi) then
heated to 60.degree. C. As the pressure dropped, H.sub.2 was added
to adjust the pressure to 200 psi. After 8 h, the pressure had
stabilized. The vessel was cooled, the hydrogen was removed and the
reaction was placed under N.sub.2(g). The reaction was filtered,
washed with methanol and concentrated. The resulting oil was dried
for 48 h. The oil was dissolved in 50 mL of diethyl ether and 4N
HCl in dioxane (32 mL) was added which caused a precipitate to
form. This precipitate was collected by filtration, washed with
diethyl ether (100 mL) and methylene chloride (100 mL). Drying
under high vacuum gave a white solid (12.1 g, 38.3 mmol, 92%);
MH+244.2.
EXAMPLE 369
Preparation of 1-(3-tert-butyl-phenyl)-4-methyl-cyclohexylamine
[0970] Step 1: 450
[0971] A 2.0M solution of trimethylsilyldiazomethane in hexanes
(11.0 mL, 22.0 mmol) was added to a solution of a mixture of
cis/trans isomers of 4-methyl-cyclohexanecarboxylic acid (2.0 mL,
14.1 mmol) in methanol (14 mL) and hexane (14 mL). The clear
solution turned yellow following the addition of the
trimethylsilyidiazomethane. The solution was concentrated to yield
a mixture of cis/trans isomers of 4-methyl-cyclohexanecarboxylic
acid methyl ester.
[0972] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.3.68 and 3.66 (s,
3H), 2.51 and 2.21 (m and tt, J=3.6 Hz, and 12.2 Hz, 1H), 1.96 (m,
3H), 1.74-1.15 (broad m, 6H), 0.89 (m, 3H).
[0973] Step 2: 451
[0974] A 1.6M solution of .sup.nbutyllithium (1.7 mL, 2.72 mmol)
was added to a solution of dicyclohexylamine (0.52 mL, 2.61 mmol)
in toluene (10 mL). After stirring for 5 min, a mixture of
cis/trans isomers of 4-methyl-cyclohexanecarboxylic acid methyl
ester (342 mg, 2.19 mmol) was added. After stirring for 10 min,
1-bromo-3-tert-butyl-benzene (428 mg, 2.01 mmol) and
bis(tri-tert-butylphosphine)palladium(0) (52 mg, 102 umol) was
sequentially added. After stirring for 20 h, the solution was
diluted with 10% aqueous hydrochloric acid, and extracted with
diethyl ether. The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated. The residue was
flash chromatographed with 49:1, 24:1, and 23:2 hexanes:ethyl
acetate as the eluant to yield 484 mg (84% yield) of a mixture of
cis/trans isomers of 1-(3-tert-butyl-phenyl)-4-methyl-cyc-
lohexanecarboxylic acid methyl ester as a light yellow oil.
[0975] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.51 and 7.40 (t
and m, J=1.9 Hz, 1H), 7.33-7.13 (m, 3H), 3.65 (s, 3H), 2.62 (m,
2H), 1.77-1.02 (broad m, 7H), 1.30 (s, 9H), 0.91 (d, J=6.5 Hz,
3H).
[0976] Step 3: 452
[0977] Barium hydroxide-octahydrate (968 mg, 3.07 mmol), and a
mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-4-methyl-cyclohexanedarboxyl- ic acid
methyl ester in ethanol (10 mL) and water (10 mL) was placed into a
preheated oil bath at 85.degree. C. After heating at reflux for 18
h, the solution was diluted with 10% aqueous hydrochloric acid, and
extracted with methylene chloride. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated to
yield 285 mg (69% yield) of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-- 4-methyl-cyclohexanecarboxylic acid as a
light yellow oil.
[0978] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.51 and 7.48 (t
and s, J=1.9 Hz, 1H), 7.33-7.14 (m, 3H), 2.65 (d, J=12.6 Hz, 2H),
1.77-1.10 (broad m, 7H), 1.31 (s, 9H), 0.92 and 0.88 (both d, both
J=6.4 Hz, 3H).
[0979] Step 4: 453
[0980] Diphenylphosphoryl azide (0.26 mL, 1.20 mmol) was added to a
solution of a mixture of cis/trans
1-(3-tert-butyl-phenyl)-4-methyl-cyclo- hexanecarboxylic acid (275
mg, 1.00 mmol) and triethylamine (0.19 mL, 1.36 mmol) in toluene (5
mL). After stirring at ambient temperature for 16 h, the solution
was placed into a preheated oil bath at 80.degree. C. Bubbling was
observed. After stirring for 1 h at 80.degree. C., the bubbling had
ceased and the solution was cooled to ambient temperature. Dioxane
(2.5 mL) and 10% aqueous hydrochloric acid (2.5 mL) was added and
stirred vigorously for 18 h. The aqueous layer was made alkaline
with aqueous 3N NaOH and extracted with methylene chloride. The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated. The residue was flash chromatographed
with 19:1:0.1, 9:1:0.1, 17:3:0.3, and 4:1:0.1 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 75 mg (30% yield) of a single isomer of
1-(3-tert-butyl-phenyl)-4-methyl-cyclohexylamine.
[0981] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.51 (d, J=1.9 Hz,
1H), 7.37-7.27 (m, 3H), 1.77-1.10 (broad m, 9H), 1.34 (s, 9H), 0.98
(d, J=5.7 Hz, 3H). Method [1] Retention time 1.55 min by HPLC and
1.62 min by MS (M-NH.sub.2=229).
EXAMPLE 370
Preparation of 1-thiophen-3-yl-cyclohexylamine
[0982] Step 1: 454
[0983] A 1.6M solution of .sup.nbutyllithium (25,0 mL, 40.0 mmol)
was added to a solution of dicyclohexylamine (7.8 mL, 39.1 mmol) in
toluene (60 mL). After stirring for 5 min, cyclohexanecarboxylic
acid methyl ester (4.8 mL, 33.6 mmol) was added. After stirring for
10 min, 1-bromo-thiophene (2.8 mL, 29.6 mmol) and
bis(tri-tert-butylphosphine)pal- ladium(0) (312 mg, 610 .mu.mol)
was sequentially added. After stirring for 24 h, the solution was
diluted with 10% aqueous hydrochloric acid, filtered through a
Buchner funnel, and the solid was washed with diethyl ether. The
aqueous layer was extracted with diethyl ether, the combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated. The residue was flash chromatographed with 99:1,
49:1, and 24:1 hexanes:ethyl acetate as the eluant to yield 4.93 g
(74% yield) of 1-thiophen-3-yl-cyclohexanecarboxylic acid methyl
ester as a light yellow oil.
[0984] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.24 (m, 1H), 7.10
(m, 2H), 3.65 (s, 3H), 2.46 (d, J=6.7 Hz, 2H), 1.78-1.26 (broad m,
8H).
[0985] Step 2: 455
[0986] A 3 N solution of aqueous sodium hydroxide (5.0 mL, 15.0
mmol) was added to a solution of
1-thiophen-3-yl-cyclohexanecarboxylic acid methyl ester (500 mg,
2.23 mmol) in methanol (10 mL) and was placed into a preheated oil
bath at 50.degree. C. After stirring for 18 h, the solution was
concentrated, diluted with 10% aqueous hydrochloric acid, and
extracted with methylene chloride. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated to
yield 450 mg (96% yield) of 1-thiophen-3-yl-cyclohexanecarboxylic
acid as a white solid.
[0987] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.24 (m, 1H), 7.10
(m, 2H), 2.46 (d, J=6.7 Hz, 2H), 1.78-1.26 (broad m, 8H).
[0988] Step 3: 456
[0989] Diphenylphosphoryl azide (1.0 mL, 4.63 mmol) was added to a
solution of 1-thiophen-3-yl-cyclohexanecarboxylic acid (450 mg,
2.14 mmol) and triethylamine (1.00 mL, 7.17 mmol) in toluene (10
mL). After stirring at ambient temperature for 16 h, the solution
was placed into a preheated oil bath at 80.degree. C. Bubbling was
observed. After stirring for 1 h at 80.degree. C., the bubbling had
ceased and the solution was cooled to ambient temperature. Dioxane
(5 mL) and 10% aqueous hydrochloric acid (5 mL) was added and
stirred vigorously for 18 h. The aqueous layer was made alkaline
with aqueous 3N NaOH and extracted with methylene chloride. The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated. The residue was flash chromatographed
with 19:1:0.1, 9:1:0.1, 17:3:0.3, and 4:1:0.1 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 1-thiophen-3-yl-cyclohexylamine as an impure product.
[0990] Method [1] Retention time 0.43 min by HPLC and 0.50 min by
MS (M-NH.sub.2=165).
EXAMPLE 371
Preparation of cis/trans
1-(3-tert-butyl-phenyl)-3methyl-cyclohexylamine
[0991] Step 1: 457
[0992] A mixture of cis/trans isomers of
3-methyl-cyclohexanecarboxylic acid (1.44 g, 10.1 mmol),
2-trimethylsilylethanol (1.30 g, 11.0 mmol),
4-dimethylaminopyridine (128 mg, 1.05 mmol), and
1-(3-dimethylaminopropyl- )-3-ethylcarbodiimide hydrochloride (2.12
g, 11.1 mmol) in methylene chloride (10 mL) was stirred for 36 h.
The solution was diluted with 10% aqueous hydrochloric acid and
extracted with methylene chloride. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated to
yield 2.45 g (100% yield) of a mixture of cis/trans isomers of
3-methyl-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester
as a clear oil.
[0993] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.4.15 (m, 2H), 2.59
and 2.26 (m and tt, J=3.5 Hz, and 12.1 Hz, 1H), 1.98-1.19 (broad m,
8H), 1.12-0.93 (broad m, 3H), 0.90 (d and d, J=6.5 Hz and 6.7 Hz,
3H), 0.04 (s, 9H).
[0994] Step 2: 458
[0995] A 1.6M solution of .sup.nbutyllithium (0.85 mL, 1.36 mmol)
was added to a solution of dicyclohexylamine (0.27 mL, 1.36 mmol)
in toluene (5 mL). After stirring for 5 min, a mixture of cis/trans
isomers of 3-methyl-cyclohexanecarboxylic acid
2-trimethylsilanyl-ethyl ester (269 mg, 1.11 mmol) was added. After
stirring for 30 min, 1-bromo-3-tert-butyl-benzene (250 mg, 1.17
mmol) was added followed by the simultaneous addition of
tri-tert-butylphosphonium tetrafluoroborate (31 mg, 107 .mu.mol)
and tris(dibenzylideneacetone)dipalladium(0)-chlorof- orm adduct
(54 mg, 52.2 .mu.mol). The solution was placed into a preheated oil
bath at 60.degree. C. After stirring for 20 h, the solution was
diluted with 10% aqueous hydrochloric acid, and extracted with
diethyl ether. The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated. The residue was
flash chromatographed with 49:1, 24:1, and 23:2 hexanes:ethyl
acetate as the eluant to yield 250 mg (62% yield) of a mixture of
cis/trans isomers of 1-(3-tert-butyl-phenyl)--
3-methyl-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester
as a yellow oil.
[0996] Method [2] Retention time 3.64 min by HPLC and 3.68 min by
MS (M+Na=397).
[0997] Step 3: 459
[0998] cis/trans
1-(3-tert-butyl-phenyl)-3-methyl-cyclohexanecarboxylic acid
[0999] A 1.0 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (2.5 mL, 2.5 mmol) was added to a solution of a
mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-3-methyl-cyclohexanecarboxylic acid
2-trimethylsilanyl-ethyl ester (500 mg, 1.34 mmol) in
tetrahydrofuran (10 mL). After stirring for 24 h, the solution was
diluted with 10% aqueous hydrochloric acid, and extracted with
diethyl ether. The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated to yield 419 mg
(impure) of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-3-methyl-cyclohexanecarboxylic acid as a
brown viscous oil.
[1000] Step 4: 460
[1001] Diphenylphosphoryl azide (0.34 mL, 1.57 mmol) was added to a
solution of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-3-m- ethyl-cyclohexanecarboxylic acid (ca.
1.34 mmol) and triethylamine (0.24 mL, 1.72 mmol) in toluene (6
mL). After stirring at ambient temperature for 16 h, the solution
was placed into a preheated oil bath at 80.degree. C. Bubbling was
observed. After stirring for 1 h at 80.degree. C., the bubbling had
ceased and the solution was cooled to ambient temperature.
Concentrated sulfuric acid was added and stirred vigorously for 2
min. The aqueous layer was made alkaline with aqueous 3N NaOH and
extracted with methylene chloride. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated. The
residue was flash chromatographed with 99:1:0.1, 49:1:0.1,
24:1:0.1, 23:2:0.2, 22:3:0.3, 21:4:0.4, and 4:1:0.1 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 185 mg (impure) of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-3-methyl-cyclohexylamine.
[1002] Method [1] Retention time 1.75 min by HPLC and 1.82 min by
MS (M-NH.sub.2=229).
EXAMPLE 372
Preparation of cis/trans
1-(3-tert-butyl-phenyl)-2-methyl-cyclohexylamine
[1003] 461
[1004] Step 1:
[1005] A mixture of cis/trans isomers of
2-methyl-cyclohexanecarboxylic acid (1.44 g, 10.1 mmol),
2-trimethylsilylethanol (1.31 g, 11.1 mmol),
4-dimethylaminopyridine (123 mg, 1.01 mmol), and
1-(3-dimethylaminopropyl- )-3-ethylcarbodiimide hydrochloride (2.11
g, 11.0 mmol) in methylene chloride (10 mL) was stirred for 36 h.
The solution was diluted with 10% aqueous hydrochloric acid and
extracted with methylene chloride. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated to
yield 2.45 g (100% yield) of a mixture of cis/trans isomers of
2-methyl-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester
as a clear oil.
[1006] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.4.16 (m, 2H), 2.47
(m, 1H), 2.14 (m, 1H), 1.77-1.20 (broad m, 8H), 0.98 (m, 5H), 0.04
(s, 9H).
[1007] Step 2: 462
[1008] A 1.6M solution of .sup.nbutyllithium (0.85 mL, 1.36 mmol)
was added to a solution of dicyclohexylamine (0.27 mL, 1.36 mmol)
in toluene (5 mL). After stirring for 5 min, a mixture of cis/trans
isomers of 2-methyl-cyclohexanecarboxylic acid
2-trimethylsilanyl-ethyl ester (269 mg, 1.11 mmol) was added. After
stirring for 30 min, 1-bromo-3-tert-butyl-benzene (248 mg, 1.16
mmol) was added followed by the simultaneous addition of
tri-tert-butylphosphonium tetrafluoroborate (31 mg, 107 umol) and
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (51 mg,
49.3 umol). The solution was placed into a preheated oil bath at
60.degree. C. After stirring for 20 h, the solution was diluted
with 10% aqueous hydrochloric acid, and extracted with diethyl
ether. The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated. The residue was flash
chromatographed with 49:1, 24:1, and 23:2 hexanes:ethyl acetate as
the eluant to yield 375 mg (90% yield) of a mixture of cis/trans
isomers of 1-(3-tert-butyl-phenyl)-2-methyl-cyc- lohexanecarboxylic
acid 2-trimethylsilanyl-ethyl ester as a yellow oil.
[1009] Method [2] Retention time 3.67 min by HPLC and 3.75 min by
MS (M+Na=397).
[1010] Method [2] Retention time 3.77 min by HPLC and 3.85 min by
MS (M+Na=397).
[1011] Step 3: 463
[1012] A 1.0 M solution of tetrabutylammonium fluoride in
tetrahydrofuran (4.0 mL, 4.00 mmol) was added to a solution of a
mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-2-methyl-cyclohexanecarboxylic acid
2-trimethylsilanyl-ethyl ester (610 mg, 1.63 mmol) in
tetrahydrofuran (10 mL). After stirring for 24 h, the solution was
diluted with 10% aqueous hydrochloric acid, and extracted with
diethyl ether. The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated to yield, 360 mg (80%
yield) of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-2-methyl-cyclohexanecarboxylic acid as a
yellow oil.
[1013] Step 4: 464
[1014] Diphenylphosphoryl azide (0.34 mL, 1.57 mmol) was added to a
solution of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-2-m- ethyl-cyclohexanecarboxylic acid (ca.
1.34 mmol) and triethylamine (0.24 mL, 1.72 mmol) in toluene (6
mL). After stirring at ambient temperature for 16 h, the solution
was placed into a preheated oil bath at 80.degree. C. Bubbling was
observed. After stirring for 1 h at 80.degree. C., the bubbling had
ceased and the solution was cooled to ambient temperature.
Concentrated sulfuric acid was added and stirred vigorously for 2
min. The aqueous layer was made alkaline with aqueous 3N NaOH and
extracted with methylene chloride. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated. The
residue was flash chromatographed with 99:1:0.1, 49:1:0.1,
24:1:0.1, 23:2:0.2, 22:3:0.3, 21:4:0.4, and 4:1:0.1 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 95 mg (30% yield) of a mixture of cis/trans isomers of
1-(3-tert-butyl-phenyl)-2-methyl-cyclohexylamine.
[1015] Method [1] Retention time 1.72 min by HPLC and 1.79 min by
MS (M+=229).
EXAMPLE 373
Preparation of 1-(5-ethyl-thiophen-3-yl)-cyclohexylamine
[1016] Step 1: 465
[1017] A solution of N-bromosuccinimde (5.58 g, 31.4 mmol) and
1-thiophen-3-yl-cyclohexanecarboxylic acid methyl ester (3.19 g,
14.2 mmol) in dimethylformamide (60 mL) was stirred for 72 h. The
solution was diluted with 10% aqueous hydrochloric acid and
extracted with diethyl ether. The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated. The
residue was flash chromatographed with 99:1, 49:1, and 24:1
hexanes:ethyl acetate as the eluant to yield 4.30 g (79% yield) of
1-(2,5-dibromo-thiophen-3-yl)-cyclohexanecarboxylic acid methyl
ester as a yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.6.93 (s, 1H), 3.67 (s, 3H), 2.34 (m, 2H), 1.90 (m, 2H), 1.60
(m, 5H), 1.36 (m, 1H).
[1018] Step 2: 466
[1019] Trimethylsilylacetylene (487 mg, 4.96 mmol), cuprous iodide
(55 mg, 289 umol), dichlororbis(triphenylphosphine)palladium(II)
(310 mg, 442 umol), and
1-(2,5-dibromo-thiophen-3-yl)-cyclohexanecarboxylic acid methyl
ester (1.71 g, 4.48 mmol) in triethylamine (20 mL) was placed into
a preheat oil bath at 45.degree. C. After stirring for 18 h, the
solution was diluted with 10% aqueous hydrochloric acid and
extracted with diethyl ether. The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated. The
residue was flash chromatographed with 99:1, 49:1, and 24:1
hexanes:ethyl acetate as the eluant to yield 1.66 g (93% yield) of
1-(2-bromo-5-trimethylsilanylethynyl-thiophen-3-yl)-cycloh-
exanecarboxylic acid methyl ester as a yellow solid.
[1020] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.09 (s, 1H), 3.67
(s, 3H), 2.34 (m, 2H), 1.93 (m, 2H), 1.58 (m, 5H), 1.35 (m, 1H),
0.23 (s, 9H).
[1021] Step 3: 467
[1022] A heterogeneous mixture of potassium carbonate (1.42 g, 10.3
mmol) and
1-(2-bromo-5-trimethylsilanylethynyl-thiophen-3-yl)-cyclohexanecarbox-
ylic acid methyl ester (1.66 g, 4.16 mmol) in methanol (10 mL) was
stirred for 24 h. The solution was diluted with water and extracted
with methylene chloride. The combined organic extracts were dried
over magnesium sulfate, filtered, and concentrated. The residue was
flash chromatographed with 99:1, 49:1, and 24:1 hexanes:ethyl
acetate as the eluant to yield 1.17 g (74% yield) of
1-(2-bromo-5-ethynyl-thiophen-3-yl)- -cyclohexanecarboxylic acid
methyl ester as a yellow oil.
[1023] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.12 (s, 1H), 3.68
(s, 3H), 3.36 (s, 1H), 2.34 (m, 2H), 1.92 (m, 2H), 1.53 (m, 5H),
1.37 (m, 1H).
[1024] Step 4: 468
[1025] A solution
1-(2-bromo-5-ethynyl-thiophen-3-yl)-cyclohexanecarboxyli- c acid
methyl ester (1.17 g, 3.58 mmol) of in ethyl acetate (20 mL) was
added to a heterogeneous mixture of 10% palladium on carbon (1.16
g) and triethylamine (1.5 mL, 10.8 mmol) in ethyl acetate (20 mL)
in a parr bottle. The parr bottle was filled with hydrogen (20 psi)
and evacuated three times. The parr bottle was refilled with
hydrogen (20 psi) and shook for 1.5 h, filtered through celite, and
concentrated. The residue was flash chromatographed with 49:1 and
24:1 hexanes:ethyl acetate to yield 813 mg (90% yield) of
1-(5-ethyl-thiophen-3-yl)-cyclohexanecarboxyl- ic acid methyl ester
as a clear oil.
[1026] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.6.86 (d, J=1.5 Hz,
1H), 6.76 (d, J=1.0 Hz, 1H), 3.66 (s, 3H), 2.79 (dq, J=1.0 Hz and
7.5 Hz, 2H), 2.44 (m, 2H), 1.78-1.19 (broad m, 8H), 1.28 (t, J=7.5
Hz, 3H).
[1027] Step 5: 469
[1028] A 3N solution of aqueous sodium hydroxide (6.0 mL, 18.0
mmol) was added to a solution of
1-(5-ethyl-thiophen-3-yl)-cyclohexanecarboxylic acid methyl ester
(813 mg, 3.22 mmol) in methanol (12 mL) and was placed into a
preheated oil bath at 75.degree. C. After heating at reflux for 24
h, the solution was concentrated, diluted with 10% aqueous
hydrochloric acid, and extracted with methylene chloride. The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated to yield 771 mg (100% yield) of
1-(5-ethyl-thiophen-3-yl)-cyclohexanecarboxy- lic acid as a white
solid.
[1029] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.6.92 (d, J=1.5 Hz,
1H), 6.82 (d, J=1.2 Hz, 1H), 2.81 (dq, J=1.2 Hz and 7.5 Hz, 2H),
2.42 (m, 2H), 1.61 (m, 8H), 1.29 (t, J=7.5 Hz, 3H).
[1030] Step 6: 470
[1031] Diphenylphosphoryl azide (0.83 mL, 3.85 mmol) was added to a
solution of a 1-(5-ethyl-thiophen-3-yl)-cyclohexanecarboxylic acid
and triethylamine (0.67 mL, 4.81 mmol) in toluene (6 mL). After
stirring at ambient temperature for 18 h, the solution was placed
into a preheated oil bath at 80.degree. C. Bubbling was observed.
After stirring for 3 h at 80.degree. C., the bubbling had ceased
and the solution was cooled to ambient temperature. Concentrated
sulfuric acid was added and stirred vigorously for 2 min. The
aqueous layer was made alkaline with aqueous 3N NaOH and extracted
with methylene chloride. The combined organic extracts were dried
over magnesium sulfate, filtered, and concentrated. The residue was
flash chromatographed with 49:1:0.1, 24:1:0.1, 23:2:0.2, and
22:3:0.3 methylene chloride:methanol:concentrated ammonium
hydroxide as the eluant to yield 105 mg of a
1-(5-ethyl-thiophen-3-yl)-cyclohexylamine- .
[1032] Method [1] Retention time 1.23 min by HPLC and 1.29 min by
MS (M-NH.sub.2=193).
EXAMPLE 374
Preparation of 1-(2,5-dibromo-thiophen-3-yl)-cyclohexylamine
[1033] Step 1: 471
[1034] A 3N solution of aqueous sodium hydroxide (10.0 mL, 30.0
mmol) was added to a solution of
1-(2,5-dibromo-thiophen-3-yl)-cyclohexanecarboxyli- c acid methyl
ester (1.23 g, 3.22 mmol) in methanol (30 mL) and was placed into a
preheated oil bath at 75.degree. C. After heating at reflux for 24
h, the solution was concentrated, diluted with 10% aqueous
hydrochloric acid, and extracted with methylene chloride. The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated to yield 1.18 mg (100% yield) of
1-(2,5-dibromo-thiophen-3-yl)-cyclohexaneca- rboxylic acid as a
yellow oil.
[1035] Step 2: 472
[1036] Diphenylphosphoryl azide (0.84 mL, 3.89 mmol) was added to a
solution of a 1-(2,5-dibromo-thiophen-3-yl)-cyclohexanecarboxylic
acid (1.18 g, 3.21 mmol) and triethylamine (0.68 mL, 4.88 mmol) in
toluene (6 mL). After stirring at ambient temperature for 18 h, the
solution was placed into a preheated oil bath at 80.degree. C.
Bubbling was observed. After stirring for 3 h at 80.degree. C., the
bubbling had ceased and the solution was cooled to ambient
temperature. Concentrated sulfuric acid was added and stirred
vigorously for 2 min. The aqueous layer was made alkaline with
aqueous 3N NaOH and extracted with methylene chloride. The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated. The residue was flash chromatographed with 49:1:0.1,
24:1:0.1, 23:2:0.2, and 22:3:0.3 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 610 mg (56% yield) of a
1-(2,5-dibromo-thiophen-3-yl)-cyclohexylamine as a brown oil.
[1037] Method [1] Retention time 1.31 min by HPLC and 1.37 min by
MS (M+=321, 323, and 325).
EXAMPLE 375
Preparation of 1-(5-isopropyl-thiophen-3-yl)-cyclohexylamine
[1038] Step 1: 473
[1039] Tetrakis(triphenylphosphine)palladium(0) (380 mg, 329 mmol)
was added to a solution of
1-(2,5-dibromo-thiophen-3-yl)-cyclohexanecarboxyli- c acid methyl
ester (1.21 g, 3.17 mmol) and tributyl-(1-ethoxy-vinyl)-stan- nane
(1.33 mg, 3.68 mmol) in dimethylformamide (15 mL) and placed into a
preheated oil bath at 90.degree. C. After stirring for 18 h, the
solution was cooled to ambient temperature and 10% aqueous
hydrochloric acid was added. After stirring for 4 h, the solution
was extracted with diethyl ether, the combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated. The
residue was flash chromatographed with 99:1, 49:1, 24:1, 23:2,
22:3, 21:4, and 4:1 hexanes:ethyl acetate as the eluant to yield
391 mg (impure) of 1-(5-acetyl-2-bromo-thiophen-3-yl)-cyc-
lohexanecarboxylic acid methyl ester.
[1040] Method [2] Retention time 2.53 min by HPLC and 2.59 min by
MS (M+=345 and 347).
[1041] Step 2: 474
[1042] A solution of 1.6M .sup.nbutyllithium in hexanes (2.0 mL,
3.2 mmol) was added to a heterogeneous mixture of
methyltriphenylphosphonium bromide (1.14 g, 3.19 mmol) in
tetrahydrofuran (10 mL) at -10.degree. C. After stirring for 30 min
at -10.degree. C., the yellow slurry was cooled to -78.degree. C.
and 1-(5-acetyl-2-bromo-thiophen-3-yl)-cyclohexanecarbo- xylic acid
methyl ester (391 mg, <1.13 mmol, impure) was added. After
stirring for 10 min at -78.degree. C., the dry ice/acetone bath was
removed and the heterogeneous mixture was stirred for 3 h, during
which time the solution warmed to ambient temperature. The
heterogeneous mixture was concentrated and the residue was flash
chromatographed with 99:1, 49:1, 24:1, and 23:2 hexanes:etheyl
acetate as the eluant to yield 268 mg (impure) of
1-(2-bromo-5-isopropenyl-thiophen-3-yl)-cyclohexanecar- boxylic
acid methyl ester.
[1043] Step 3: 475
[1044] A solution
1-(2-bromo-5-isopropenyl-thiophen-3-yl)-cyclohexanecarbo- xylic
acid methyl ester (268 mg g, <781 .mu.mol, impure) of in ethyl
acetate (5 mL) was added to a heterogeneous mixture of 10%
palladium on carbon (100 mg) in ethyl acetate (5 mL) in a parr
bottle. The parr bottle was filled with hydrogen (20 psi) and
evacuated three times. The parr bottle was refilled with hydrogen
(20 psi) and shook for 1.5 h, filtered through celite, and
concentrated. The residue was flash chromatographed with 49:1 and
24:1 hexanes:ethyl acetate to yield 220 mg (impure) of
1-(5-isopropyl-thiophen-3-yl)-cyclohexanecarboxylic acid methyl
ester as a clear oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.6.86
(d, J=1.5 Hz, 1H), 6.76 (m, 1H), 3.66 (s, 3H), 3.11 (m, 1H), 2.44
(m, 2H), 1.68 (m, 8H), 1.32 (d, J=6.8 Hz, 6H).
[1045] Step 4: 476
[1046] A 3N solution of aqueous sodium hydroxide (3.0 mL, 9.00
mmol) was added to a solution of
1-(5-isopropyl-thiophen-3-yl)-cyclohexanecarboxyli- c acid methyl
ester (212 mg, <796 .mu.mol, impure) in methanol (10 mL) and was
placed into a preheated oil bath at 75.degree. C. After heating at
reflux for 24 h, the solution was concentrated, diluted with 10%
aqueous hydrochloric acid, and extracted with methylene chloride.
The combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated to yield 204 mg (impure) of
1-(5-isopropyl-thiophen-3-yl- )-cyclohexanecarboxylic acid.
[1047] Step 5: 477
[1048] Diphenylphosphoryl azide (0.22 mL, 1.02 mmol) was added to a
solution of a 1-(5-isopropyl-thiophen-3-yl)-cyclohexanecarboxylic
acid (204 mg, <808 .mu.mol, impure) and triethylamine (0.17 mL,
1.22 mmol) in toluene (2 mL). After stirring at ambient temperature
for 18 h, the solution was placed into a preheated oil bath at
80.degree. C. Bubbling was observed. After stirring for 3 h at
80.degree. C., the bubbling had ceased and the solution was cooled
to ambient temperature. Concentrated sulfuric acid was added and
stirred vigorously for 2 min. The aqueous layer was made alkaline
with aqueous 3N NaOH and extracted with methylene chloride. The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated. The residue was flash chromatographed
with 49:1:0.1, 24:1:0.1, 23:2:0.2, and 22:3:0.3 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 28 mg (16% yield) of a
1-(5-isopropyl-thiophen-3-yl)-cyclohexylamine.
[1049] Method [1] Retention time 1.41 min by HPLC and 1.47 min by
MS (M-NH.sub.2=207).
EXAMPLE 376
Preparation of cis/trans
2-amino-2-(3-tert-butyl-phenyl)-cyclohexanol
[1050] Step 1: 478
[1051] A 1.7M solution of tert-butyllithium in pentane (2.60 mL,
4.42 mmol) was added to a solution of 1-bromo-3-tert-butyl-benzene
(426 mg, 2.00 mmol) in tetrahydrofuran (5 mL) at -78.degree. C.
After stirring for 1 h, tributyltin chloride (0.57 mL, 2.10 mmol)
was added at -78. C. After stirring for 18 h, during which time the
solution warmed to ambient temperature, the solution was diluted
with water and extracted with methylene chloride. The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated to yield 976 mg (115% yield) of
tributyl-(3-tert-butyl-phenyl)-stannane as a impure light yellow
oil.
[1052] Step 2: 479
[1053] Lead tetraacetate (902 mg, 2.03 mmol) and mercuric acetate
(15 mg, 47.1 mmol) was simultaneously added to a solution of
tributyl-(3-tert-butyl-phenyl)-stannane (ca. 2.00 mmol) in
methylene chloride (4 mL) and was placed into a preheated oil bath
at 45.degree. C. After heating at reflux for 24 h, the solution was
cooled to ambient temperature and filtered through celite. The
celite was washed with chloroform and the filtrate was concentrated
to yield the triacetoxy-(3-tert-butyl-phenyl)-lead as an off
white/light yellow solid.
[1054] Step 3: 480
[1055] Pyridine (1.8 mL, 22.3 mmol) and 2-nitro-cyclohexanone (630
mg, 4.40 mmol) in chloroform (5 mL) was stirred for 15 min.
Triacetoxy-(3-tert-butyl-phenyl)-lead (<2.00 mmol) in chloroform
(5 mL) was added and the solution was placed into a preheated oil
bath at 85.degree. C. After heating at reflux for 16 h, the
solution was concentrated and the residue was flash chromatographed
with 19:1, 9:1, and 17:3 hexanes:ethyl acetate as the eluant to
yield 160 mg (28% over three steps) of
2-(3-tert-butyl-phenyl)-2-nitro-cyclohexanone as a yellow oil.
[1056] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.48 (d, J=7.7 Hz,
1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 3.06 (m,
1H), 2.94 (m, 1H), 2.54 (m, 2H), 1.95 (m, 3H), 1.74 (m, 1H), 1.32
(s, 9H).
[1057] Method [2] Retention time 1.74 min by HPLC and 1.79 min by
MS (M+Na=298).
[1058] Step 4: 481
[1059] Raney 2800 nickel slurry in water (2 mL) was added to a
solution of 2-(3-tert-butyl-phenyl)-2-nitro-cyclohexanone (40 mg,
145 umol) in ethanol (10 mL) in a parr bottle. The parr bottle was
filled with hydrogen (12 psi) and evacuated three times. The parr
bottle was refilled with hydrogen (12 psi) and shook for 18 h. The
heterogeneous mixture was filtered through celite and concentrated
to yield a mixture of cis/trans isomers of
2-amino-2-(3-tert-butyl-phenyl)-cyclohexanol.
[1060] Method [1] Retention time 1.38 min by HPLC and 1.43 min by
MS (M-NH.sub.2=231).
EXAMPLE 377
Preparation of 1-(5-bromo-thiophen-2-yl)-cyclohexylamine
[1061] Step 1: 482
[1062] A solution of 1.7M tert-butyllithium in pentane (14.0 mL,
23.8 mmol) was added to a solution of 2,5-dibromothiophene (2.67 g,
11.0 mmol) in tetrahydrofuran (20 mL) at -78.degree. C. After
stirring for 1 h, cyclohexanone (1.4 mL, 13.5 mmol) was added.
After stirring for 18 h, during which time the solution warmed to
ambient temperature, the solution was diluted with saturated
aqueous ammonium chloride and extracted with methylene chloride.
The combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated. The residue was flash chromatographed
with 19:1, 9:1, 17:3, 4:1 and 3:1 hexanes:ethyl acetate as the
eluant to yield 2.58 g (90% yield) of
1-(5-bromo-thiophen-2-yl)-cyclohexanol as a light orange oil.
[1063] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.6.89 (d, J=3.8 Hz,
1H), 6.72 (d, J=3.8 Hz, 1H), 2.34 (m, 2H), 1.95-1.62 (m, 6H), 1.28
(m, 2H).
[1064] Step 2: 483
[1065] Borontrifluoride-etherate (1.3 mL, 10.3 mmol) was added to a
solution of 1-(5-bromo-thiophen-2-yl)-cyclohexanol (2.57 g, 9.84
mmol) and azidotrimethylsilane (2.6 mL, 19.6 mmol) in diethyl ether
(20 mL) and placed into a preheated oil bath at 45.degree. C. After
heating at reflux for 1.5 h, the solution was diluted with water
and extracted with diethyl ether. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated. The
residue was flash chromatographed with 99:1, 49:1, and 24:1
hexanes:ethyl acetate as the eluant to yield 1.29 g (46% yield) of
2-(1-Azido-cyclohexyl)-5-bromo-thiophene as a light yellow oil.
[1066] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.6.95 (d, J=3.8 Hz,
1H), 6.79 (d, J=3.8 Hz, 1H), 2.00 (m, 2H), 1.87 (m, 2H), 1.62 (m,
5H), 1.34(m, 1H).
[1067] Step 3: 484
[1068] 1-(5-bromo-thiophen-2-yl)-cyclohexylamine
[1069] A solution of triphenylphosphine (550 mg, 2.10 mmol) and
2-(1-Azido-cyclohexyl)-5-bromo-thiophene (289 mg, 1.01 mmol) in
tetrahydrofuran (5 mL) and water (1 mL) was placed into a preheated
oil bath at 60.degree. C. After stirring for 24 h, the solution was
concentrated and the residue was flash chromatographed w/49:1:0.1,
24:1:0.1, 23:2:0.2, and 22:3:0.3 methylene
chloride:methanol:concentrated ammonium hydroxide as the eluant to
yield 1-(5-bromo-thiophen-2-yl)-cyclo- hexylamine impure with
triphenylphosphine oxide.
[1070] Method [1] Retention time 1.20 min by HPLC and 1.26 min by
MS (M-NH.sub.2=243 and 245). 485
[1071] 8-methylene-1,4-dioxa-spiro[4.5]decane
[1072] A solution of 1.6M .sup.nbutyllithium in hexanes (46 mL,
73.6 mmol) was slowly added to a heterogeneous mixture of
methyltriphenylphosphonium bromide (28.07 g, 78.6 mmol) in
tetrahydrofuran (150 mL) at -10.degree. C. After stirring for 1 h,
1,4-dioxa-spiro[4.5]decan-8-one (8.01 g, 51.3 mmol) was added.
After stirring for 3 h, during which time the solution warmed to
ambient temperature, acetone was added and the heterogeneous
mixture was concentrated. The residue was diluted with 1:1
methylene chloride:ethyl ether, filtered and concentrated. The
residue was flash chromatographed with 49:1, 24:1, and 23:2
hexanes:etheyl acetate as the eluant to yield 6.22 g (79% yield) of
8-methylene-1,4-dioxa-spiro[4.5]dec- ane as a yellow oil.
[1073] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.4.67 (s, 2H), 3.96
(s, 4H), 2.29 (m, 4H), 1.70 (m, 4H).
EXAMPLE 378
Preparation of cis/trans
[4-amino-4-(3-tert-butyl-phenyl)-cyclohexyl]-meth- anol
[1074] Step 1: 486
[1075] A solution of 8-methylene-1,4-dioxa-spiro[4.5]decane (6.22
g, 40.3 mmol) was stirred in tetrahydrofuran (100 mL) and 10%
aqueous hydrochloric acid (100 mL) for 18 h. The solution was
extracted with ethyl ether and the combined organic extracts were
dried over magnesium sulfate. The combined organic extracts were
filtered and concentrated to yiled 3.89 g (88% yield) of
4-methylene-cyclohexanone as a yellow oil.
[1076] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.4.89 (s, 2H), 2.47
(m, 8H).
[1077] Step 2: 487
[1078] A solution of 1.7M tert-butyllithium in pentane (32.0 mL,
54.4 mmol) was added to a solution of 1-bromo-3-tert-butyl-benzene
(5.54 g, 26.0 mmol) in tetrahydrofuran (60 mL) at -78.degree. C.
After stirring for 1 h, cyclohexanone (2.00 g, 18.2 mmol) in
tetrahydrofuran (15 mL) was added. After stirring for 18 h, during
which time the solution warmed to ambient temperature, the solution
was diluted with saturated aqueous ammonium chloride and extracted
with methylene chloride. The combined organic extracts were dried
over magnesium sulfate, filtered, and concentrated. The residue was
flash chromatographed with 49:1, 24:1, 23:2 hexanes:ethyl acetate
as the eluant to yield 3.61 g (81% yield) of
1-(3-tert-butyl-phenyl)-4-methylene-cyclohexanol as a yellow
oil.
[1079] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.56 (s, 1H), 7.30
(m, 3H), 4.72 (s, 2H), 2.60 (m, 2H), 2.27 (m, 2H), 1.93 (m, 4H),
1.33 (s, 9H).
[1080] Step 3: 488
[1081] Borontrifluoride-etherate (2.0 mL, 15.7 mmol) was added to a
solution of 1-(3-tert-butyl-phenyl)-4-methylene-cyclohexanol (3.60
g, 14.7 mmol) and azidotrimethylsilane (4.0 mL, 30.1 mmol) in
diethyl ether (30 mL) and placed into a preheated oil bath at
45.degree. C. After heating at reflux for 4 h, the solution was
diluted with saturated aqueous ammonium chloride and extracted with
diethyl ether. The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated. The residue was
flash chromatographed with 99:1, 49:1, and 24:1 hexanes:ethyl
acetate as the eluant to yield 1.46 g (37% yield) of
1-(1-azido-4-methylene-cyclohexyl)-3-tert-butyl-benzene as a clear
oil.
[1082] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.47 (s, 1H),
7.36-7.23 (broad m, 3H), 4.72 (s, 2H), 2.48 (m, 2H), 2.28 (m, 2H),
2.13 (m, 2H), 1.96 (m, 2H), 1.34 (s, 9H).
[1083] Step 4: 489
[1084] A solution of 2.0 M borane-dimethyl sulfide complex in
toluene (1.1 mL, 2.2 mmol) was added to a solution of
1,5-cyclooctadiene (0.28 mL, 2.28 mmol) in tetrahydrofuran (5 mL)
and was placed into a preheated oil bath at 70.degree. C. After
heating at reflux for 1 h, the solution was cooled to ambient
temperature and 1-(1-azido-4-methylene-cyclohexyl)-3-te-
rt-butyl-benzene (559 mg, 2.08 mmol) was added. After stirring for
18 h, the solution was cooled to 0.degree. C. and 3N aqueous
solution of sodium hydroxide (5.0 mL, 15.0 mmol) was added followed
by the slow dropwise addition of 50% aqueous hydrogen peroxide (2.0
mL, 34.7 mmol). After stirring for 4 h, during which time the
biphasic solution warmed to ambient temperature, the biphasic
solution was extracted with methylene chloride. The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated. The residue was flash chromatographed with 9:1, 4:1,
and 7:3 hexanes:ethyl acetate as the eluant to yield 469 mg (79%
yield) of a mixture of cis/trans isomers of
[4-azido-4-(3-tert-butyl-phenyl)-cyclohexyl]-methanol as a clear
oil.
[1085] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.48 (s, 1H),
7.36-7.23 (broad m, 3H), 3.57 and 3.45 (t and m, J=5.5 Hz, 2H),
2.15 (m, 2H), 1.81 (m, 4H), 1.60-1.13 (broad m 3H), 1.34 (s,
9H).
[1086] Step 5: 490
[1087] A solution of a mixture of cis/trans isomers of
[4-azido-4-(3-tert-butyl-phenyl)-cyclohexyl]-methanol in ethyl
acetate (10 mL) was added to a heterogeneous mixture of 10%
palladium on carbon (400 mg) in ethyl acetate (10 mL) in a parr
bottle. The parr bottle was filled with hydrogen (20 psi) and
evacuated three times. The parr bottle was refilled with hydrogen
(20 psi) and shook for 1 h, filtered through celite, and
concentrated to yield a mixture of cis/trans isomers of
[4-amino-4-(3-tert-butyl-phenyl)-cyclohexyl]-methanol.
[1088] Method [1] Retention time 1.18 min by HPLC and 1.26 min by
MS (M-NH.sub.2=245).
[1089] Method [1] Retention time 1.28 min by HPLC and 1.37 min by
MS (M-NH.sub.2=245).
EXAMPLE 379
Preparation of
1-[2-aminomethyl-4-(2,2-dimethyl-propyl)-phenyl]-pyrrolidin-
-3-ol
[1090] 491
[1091] Step 1:
5-(2,2-Dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1-yl)-benzo-
nitrile
[1092] To 0.76g (4 mmole) of
5-(2,2-Dimethyl-propyl)-2-fluoro-benzonitrile in 15 mL of DMF was
added 1.11 g (8 mmole, 2 eq.) of potassium carbonate and 0.43 mL
(5.2 mmole, 1.3 eq.) of 3-pyrrolidinol and heated to 90-100.degree.
C. overnight. The reaction was monitored by HPLC/MS, Rt=1.349 min
(method[2]), m/e=259.2/281.2. The reaction was allowed to cool to
r. t., and quenched with ice/water/DCM, extracted and washed with
brine, dried, concentrated, and purified by flash column to give
0.82 g of
5-(2,2-Dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1-yl)-benzonitrile
(80% yield). Structure was confirmed by NMR.
[1093] TLC (30% EtOAc/Hexane). Rf=0.16 where s. m. at Rf=0.84.
[1094] LCMS m/e=259.2(M+H), Rt (retention time, minutes)=1.349
(method[2]).
[1095] Step 2:
1-[2-Aminomethyl-4-(2,2-dimethyl-propyl)-phenyl]-pyrrolidin-
-3-ol
[1096] To 0.8 g (3.1 mmole) of
5-(2,2-Dimethyl-propyl)-2-(3-hydroxy-pyrrol-
idin-1-yl)-benzonitrile in 27 mL of 7 M NH3/methanol was added 1 g
of Raney 2800 Ni/water in a Parr bottle, saturated with hydrogen to
65 psi and shaken overnight. The reaction mixture was filtered
through a cake of celite and solvents/ammonia stripped off to give
0.82 g of
1-[2-Aminomethyl-4-(2,2-dimethyl-propyl)-phenyl]-pyrrolidin-3-ol.
(99% yield) LCMS m/e=246.2(M-NH.sub.2), Rt (retention time,
minutes)=1.324 (method [1]).
EXAMPLE 380
Preparation of
5-(2,2-dimethyl-propyl)-2-pyrrolidin-1-yl-benzylamine
[1097] 492
[1098] Step A:
5-(2,2-Dimethyl-propyl)-2-pyrrolidin-1-yl-benzonitrile
[1099] The title compound was prepared according to the method in
EXAMPLE 379, Step 1. LCMS m/e=243.1/265.1 (M+H), Rt (retention
time, minutes)=2.436 (method [1]).
[1100] Step B:
5-(2,2-Dimethyl-propyl)-2-pyrrolidin-1-yl-benzylamine
[1101] The title compound was prepared according to the method in
EXAMPLE 379, STEP 2.
[1102] LCMS m/e=230.1/247.1 (M+H), Rt (retention time,
minutes)=1.528 (method [1]).
EXAMPLE 381
Preparation of
5-(2,2-dimethyl-propyl)-2-piperidin-1-yl-benzylamine
[1103] 493
[1104] Step 1:
5-(2,2-Dimethyl-propyl)-2-piperidin-1-yl-benzonitrile
[1105] The title compound was prepared according to the method in
EXAMPLE 379, STEP 1.
[1106] LCMS m/e=257.1/279.1 (M+H), Rt (retention time,
minutes)=2.599 (method [1]).
[1107] Step 2:
5-(2,2-Dimethyl-propyl)-2-piperidin-1-yl-benzylamine
[1108] The title compound was prepared according to the method in
EXAMPLE 379, STEP 2.
[1109] LCMS m/e=261.2/283.1 (M+H), Rt (retention time,
minutes)=1.358 (method [1]).
EXAMPLE 382
Preparation of
4-amino-6-(2,2-dimethyl-propyl)-3,4-dihydro-2H-quinoline-1--
carboxylic acid benzyl ester
[1110] 494
[1111] 1-(2,2-Dimethyl-propyl)-4-nitro-benzene and
1-(2,2-Dimethyl-propyl)- -2-nitro-benzene. To a stirred solution of
concentrated sulfuric acid (13.8 mL) at 0.degree. C. in an open
flask was added concentrated HNO.sub.3 (11.6 mL) dropwise by
addition funnel. The sulfuric/nitric acid mix was then transferred
to an addition funnel and added dropwise to a solution of neopentyl
benzene (17.2 g, 116 mmol) in nitromethane (90 mL) stirring at
0.degree. C. The temperature warmed to about 3.degree. C. during
the dropwise addition of the acid mixture. After complete addition,
TLC in 9/1 hexanes/EtOAc showed the nitrated materials had begun
forming. After warming to room temperature and stirring overnight
the reaction was poured into 400 mL ice water and extracted
3.times.150 mL with CH.sub.2Cl.sub.2. The combined organics were
washed 1.times.400 mL with H.sub.2O, 2.times.400 mL with saturated
NaHCO.sub.3, and 1.times.400 mL with brine. The organics were dried
(magnesium sulfate), filtered and concentrated to a yellow oil,
which appears to be about a 1:1 mixture of regioisomers. This
mixture was used crude in the subsequent reduction.
[1112] 4-(2,2-Dimethyl-propyl)-phenylamine. To a stirred solution
of the mixture of nitro compounds (22.4 g, 116 mmol) in 300 mL 95%
EtOH was added Pearlman's catalyst (4 g). The suspension was put
through a vacuum/purge cycle 3 times with hydrogen gas and then
held under 1 atm H.sub.2 overnight. TLC in 9/1 hexanes/EtOAc showed
two new lower rf spots. The nitro compounds had been completely
consumed. The reaction was filtered through GF/F filter paper with
95% EtOH and the filtrate concentrated. The crude material was
loaded onto a Biotage 75 L column with 5/95 EtOAc/hexanes and
eluted first with 5/95 EtOAc/hexanes (4 L) followed by 1/9
EtOAc/hexanes (6 L). The two regioisomeric anilines separated
nicely and were concentrated to give the undesired high rf aniline
as an orange oil and the desired lower rf aniline as a tan solid
(8.7 g, 46% from neopentyl benzene).
[1113] 3-Bromo-N-[4-(2,2-dimethyl-propyl)-phenyl]-propionamide. To
a stirred solution of the aniline (15.3 g, 93.78 mmol) in
CH.sub.2Cl.sub.2 (300 mL) at 0.degree. C. under nitrogen was added
dimethylaniline (12.5 g, 103 mmol) followed by
.beta.-bromopropionyl chloride (17.68 g, 103 mmol). After 2 h, the
reaction was diluted to 400 mL with CH.sub.2Cl.sub.2 and washed
3.times.300 mL with 2 N HCl, 3.times.300 mL with saturated
NaHCO.sub.3, and 1.times.300 mL with brine. The organics were dried
(magnesium sulfate), filtered and concentrated to a white solid
(27.5 g, 98%).
[1114] 1-[4-(2,2-Dimethyl-propyl)-phenyl]-azetidin-2-one. To a
stirred solution of DMF (115 mL) at 0.degree. C. under nitrogen was
added sodium hydride (60% oil dispersion, 4.61 g, 115 mmol). The
.beta.-bromoamide 27.5 g, 92 mmol) was then added dropwise by
cannulation in 270 mL THF. Gas evolution was observed and the
cooling bath was allowed to slowly melt and the reaction stirred at
room temperature overnight. The white suspension was then
partitioned between EtOAc (400 mL) and brine (300 mL). The organics
were isolated and washed 3.times.300 mL with brine. The organics
were dried (magnesium sulfate), filtered and concentrated to an off
white solid (20 g, 100%).
[1115] 6-(2,2-Dimethyl-propyl)-2,3-dihydro-1H-quinolin-4-one. To a
stirred solution of the .beta.-lactam (20.1 g, 92.5 mmol) in 300 mL
dichloroethane at 0.degree. C. under nitrogen was added triflic
acid (27.76 g, 185 mmol) dropwise by syringe. The reaction was
allowed to warm to room temperature and allowed to react for 4 h.
Afterward, the reaction mixture was poured into 1 L of rapidly
stirred 1:1 CH.sub.2Cl.sub.2:ice cold saturated NaHCO.sub.3. After
stirring for a few minutes the organics were isolated and the
aqueous solution extracted 1.times.200 mL with CH.sub.2Cl.sub.2.
The combined organics were dried (magnesium sulfate), filtered and
concentrated to a yellow oil (20.1 g, 100%).
[1116]
6-(2,2-Dimethyl-propyl)-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic
acid benzyl ester. To a stirred solution of the tetrahydroquinolone
(20.1 g, 92.5 mmol) in 300 mL CH.sub.2Cl.sub.2 at 0.degree. C.
under nitrogen was added DIEA (23.9 g, 185 mmol) by syringe
followed by benzyl chloroformate (23.7 g, 139 mmol) dropwise by
addition funnel. The reaction was allowed to warm to room
temperature overnight. TLC showed near complete consumption of
starting material. The reaction was transferred to a 1 L sep funnel
and washed 3.times.300 mL with 2 N HCl and 3.times.300 mL with
saturated NaHCO.sub.3. The organics were dried (magnesium sulfate),
filtered and concentrated to a brown oil which was loaded directly
onto a Biotage 75 L column and eluted with 9/1 hexanes/EtOAc.
Product containing fractions were pooled and concentrated to a pale
yellow oil that solidified upon standing (28.4 g, 87% from the
aniline).
[1117]
6-(2,2-Dimethyl-propyl)-4-(R)-hydroxy-3,4-dihydro-2H-quinoline-1-ca-
rboxylic acid benzyl ester. To a stirred solution of the ketone
(27.5 g, 79 mmol) in 79 mL THF at -25.degree. C. (CCl4/dry ice
bath) under nitrogen was added the CBS reagent (1 M in toluene, 7.9
mL, 7.9 mmol,) followed by dropwise addition of borane
dimethylsulfide complex (2 M in THF, 39.5 mL, 79 mmol) diluted with
95 mL THF by addition funnel, keeping the internal temperature
below -20.degree. C. After 1 h at -25.degree. C., TLC in 3/7
EtOAc/hexanes showed some residual starting material with a new
major lower rf spot dominating. The reaction was then allowed to
warm to room temperature and stirred overnight. TLC showed the
reaction had gone to completion. The reaction was recooled to
0.degree. C. and quenched by addition of 190 mL MeOH via addition
funnel. After removal of the cooling bath and stirring at room
temperature for 2 h, the reaction was concentrated to dryness by
rotovap and high vacuum and then loaded onto a Biotage 75 M column
with 4/1 hexanes/EtOAc and eluted. Product containing fractions
were pooled and concentrated to a pale yellow oil that solidified
upon standing (22.3 g, 80 mmol).
[1118]
4-(S)-Azido-6-(2,2-dimethyl-propyl)-3,4-dihydro-2H-quinoline-1-carb-
oxylic acid benzyl ester. To a stirred solution of the alcohol
(22.3 g, 63 mmol) in 126 mL toluene at 0.degree. C. under nitrogen
was added DPPA (20.84 g, 75.7 mmol) neat by syringe. DBU (11.53 g,
75.7 mmol) was then added dropwise by addition funnel in 100 mL
toluene. After complete addition the reaction was allowed to warm
to room temperature and stir overnight. The crude reaction looked
good by TLC in 4/1 hexanes/EtOAc with starting material completely
consumed and a clean new higher rf spot. The reaction was reduced
to about 100 mL by rotovap and was then loaded onto a Biotage 75 M
column with minimum CH.sub.2Cl.sub.2 and eluted with 5/95
EtOAc/hexanes. The product containing fractions were pooled and
concentrated to a clear oil which solidifed upon standing (22 g,
92%).
[1119]
4-(S)-Amino-6-(2,2-dimethyl-propyl)-3,4-dihydro-2H-quinoline-1-carb-
oxylic acid benzyl ester. To a stirred solution of the azide (22 g,
58 mmol) in 580 mL THF at room temperature under nitrogen was added
H.sub.2O (1.26 g, 70 mmol) followed by trimethylphosphine (1 M in
toluene, 67 mL, 67 mmol) dropwise by addition funnel. After
complete addition the reaction was allowed to stir overnight. TLC
in EtOAc showed a trace of starting azide left with the majority of
the material at the baseline. The reaction was concentrated to a
yellow oil by rotary evaporation followed by high vacuum. The crude
material was dissolved in EtOAc to load onto a column but a
precipitate formed. The precipitate was filtered off and was shown
to be not UV active on TLC and was thought to be trimethylphosphine
oxide and was discarded. The crude product filtrate was loaded onto
a Biotage 75M column with EtOAc and eluted with the same solvent.
Product containing fractions were pooled and concentrated to a pale
yellow oil (15.7 g, 77%).
EXAMPLE 383
Preparation of
4-(3-tert-butylphenyl)-tetrahydro-2H-pyran-4-amine
[1120] 495
[1121] 1-tert-Butyl-3-iodo-benzene. To a cooled (-40.degree. C.)
stirred solution of TiCl.sub.4 (11 mL of a 1.0 M sol in DCM, 11
mmol) in 5 mL of DCM was added dimethyl zinc (5.5 mL of a 2 N sol.
in toluene, 11 mmol). After stirring for 10 min Iodoacetophenone
(1.23 g, 5.0 mmol) was added. After 2 h the reaction was warmed to
0.degree. C. and stirred for an addtional 1 h. The reaction was
poured onto ice and extracted with ether. The organic phase was
washed with water and sat NaHCO.sub.3. The organic phase was dried
over magnesium sulfate, filtered, and dried under reduced pressure.
The material was distilled using a kugelrohr (80.degree. C. at 0.1
mm) to obtain 1.0 g (76% yield) of a clear oil; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.7.71 (t, J=2.0 Hz, 1H), 7.51 (dt, J=7.7,
1.3 Hz, 1H), 7.35 (app d, J=7.7 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H),
1.29 (s, 9H).
[1122] 2-Methyl-propane-2-sulfinic acid
(tetrahydro-pyran-4-ylidene)-amide- . To a stirred solution of
tetrahydro-pyran-4-one (1.2 g, 12 mmol) in 20 mL THF at room
temperature under nitrogen was added titanium (IV) ethoxide (4.8 g,
21 mmol) followed by 2-Methyl-propane-2-sulfinic acid amide (1.29
g, 10 mmol). The reaction was stirred at room temperature for 3 h.
The reaction was quenched by pouring it into 20 mL of saturated
sodium bicarb. stirring rapidly. The formed precipitate was
filtered off by filtration through GF/F filter paper and rinsed
with EtOAc. The aqueous layer was washed once with EtOAc. The
combined organics dried (magnesium sulfate), filtered and
concentrated to a yellow oil. The material was purified using a
biotage 40 M cartridge eluting with hexanes:ethyl acetate (60:40)
to yield 1.25 g (62% yield) of a clear oil.
2-Methyl-propane-2-sulfinic acid
[4-(3-tert-butyl-phenyl)-tetrahydro-pyra- n-4-yl]-amide. Iodo
t-butyl benzene (14 g, 54.6 mmol) was taken up in 50 mL of Toulene
under N.sub.2 and cooled to 0.degree. C. Butyl lithium (34 mL, 1.6
M sol. in hexanes) was added dropwise over 15 min. The reaction was
stirred at 0.degree. C. for 3 h. In a separate flask the imine
(5.28 g, 26 mmoles) was taken up in 30 mL of Toluene and cooled to
-78.degree. C. Trimethyl aluminum (14.3 mL, 2.0 mmol sol. in
toluene) was added dropwise over 10 min. The imine solution was
stirred for 10 min and then cannulated into the phenyl lithium over
30 min. The reaction was allowed to warm to room temperature and
stirred for 4 h. The reaction was quenched with sodium sulfate
decahydrate until the bubbling stopped. Magnesium sulfate was added
to the reaction and stirred for 30 min. The reaction was filtered,
rinsed with EtOAc and concentrated down onto silica gel. The
material was purified using a biotage 75S cartridge eluting with
ethyl acetate to yield 4.0 g (45% yield) of desired product.
[1123] 4-(3-tert-Butyl-phenyl)-tetrahydro-pyran-4-ylamine. To a
stirred solution of 2-methyl-propane-2-sulfinic acid
[4-(3-tert-butyl-phenyl)-tet- rahydro-pyran-4-yl]-amide (3.7 g,
11.0 mmol) in ether (10 mL) was added HCl (33 mL, 1 M sol. in
ether). The reaction was stirred for 30 min and then concentrated
under reduced pressure; LC rt=2.07 min; MS(ESI) 233.7.
EXAMPLE 384
Preparation of
4-amino-4-(3-tert-butylphenyl)-piperidine-1-carboxylic acid benzyl
ester
[1124] 496
[1125] 1-Benzyl-4-(3-tert-butylphenyl)-piperidin-4-ol. A solution
of bromo-tert-butylbenzene (4.62 g, 21.68 mmol) in THF (50 mL) was
cooled to -78.degree. C. then n-BuLi (2.5M, 9.1 mL) was added
dropwise. The reaction was stirred for 30 min then a solution of
1-benzyl-piperidin-4-one (3.69 g, 19.5 mmol) in THF (10 mL) was
added dropwise. After stirring for 30 min at -78.degree. C., the
reaction was warmed to 0.degree. C. then quenched with water (50
mL). The reaction was diluted with ethyl acetate (100 mL); the
organic layer was separated, washed with brine (50 mL), dried over
magnesium sulfate and concentrated to give an oil (6.94 g, 21.5
mmol), which was used in the next step without further
purification; LC rt=2.98 min; MS(ESI) 306.2.
[1126]
N-[1-Benzyl-4-(3-tert-butylphenyl)-piperidin-4-yl]-2-chloroacetamid-
e. To 1-benzyl-4-(3-tert-butylphenyl)-piperidin-4-ol (6.94 g, 21.45
mmol) and chloroacetonitrile (3.24 g, 75.50 mmol) was added acetic
acid (3.5 mL) then sulfuric acid (3.5 mL) and the reaction stirred
at room temperature overnight. The reaction was diluted with ethyl
acetate (100 mL), washed with ammonium chloride (100 mL), water (50
mL), brine (50 mL), then dried over magnesium sulfate and
concentrated. Silica gel chromatography eluting with 100% ethyl
acetate gave an oil (2.75 g, 6.89 mmol); MS(ESI) 399.3.
[1127]
4-(3-tert-Butylphenyl)-4-(2-chloroacetylamino)-piperidine-1-carboxy-
lic acid benzyl ester. To a solution of
N-[1-benzyl-4-(3-tert-butylphenyl)-
-piperidin-4-yl]-2-chloroacetamide (2.65 g, 6.664 mmol) in toluene
(20 mL) was added benzyl chloroformate (1.90 mL, 7.00 mmol) and the
reaction was heated to 80.degree. C. The reaction was concentrated,
placed onto silica gel and eluted with hexane/ethyl acetate (2:1).
Isolated an oil (2.82 g, 6.37 mmol); MS(ESI) 442.9.
[1128] 4-Amino-4-(3-tert-butylphenyl)-piperidine-1-carboxylic acid
benzyl ester. A solution of
4-(3-tert-butylphenyl)-4-(2-chloroacetylamino)-piper-
idine-1-carboxylic acid benzyl ester (2.82 g, 6.37 mmol) and
thiourea (0.53 g, 7.00 mmol) in 10 mL of ethanol and 2 mL of acetic
acid was heated to 80.degree. C. overnight. The reaction was
cooled, diluted with ethyl acetate (50 mL), washed with 1 N NaOH
(50 mL), brine (50 mL), dried over magnesium sulfate and
concentrated. Silica gel chromatography eluting with 5% MeOH/DCM
gave some product and some mixed fractions. The mixed fractions
were chromatographed over silica gel eluting with 3% MeOH/DCM and
again gave some product and some mixed fractions. Finally, the
mixed fractions were chromatographed over silica gel eluting with
8% MeOH/EtOAc and all impurities were removed. The batches of pure
product were combined and dried to give a colorless oil (1.60 g,
4.44 mmol, 69%); LC rt=3.15 min; MS(ESI) 350.0.
EXAMPLE 385
Preparation of 2-bromo-5-(2,2-dimethyl-propyl)-benzylamine
[1129] 497
[1130] To commercially available 2-bromo-5-iodobenzoic acid (76.5
mmol, 25 g), hydroxybenzotriazole (HOBt, 76.5mmol, 10.4 g),
triethylamine (TEA, 153 mmol, 21.3 mL) and ammonium chloride (84.1
mmol, 4.50 g), is added DMF (anhydrous, 300 mL). After dissolution
of solids by stirring,
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(EDC-HCl, 84.1 mmol, 16.08 g) is added. Stirring continues with the
reaction capped for 16 hours. The reaction is concentrated to half
the original volume via roto-evaporation, then 1 L ethyl acetate is
added and the subsequent solution is washed once with 1 M HCl (300
mL), then once with saturated NaHCO.sub.3 (300 mL), then twice with
H.sub.2O, and then once with saturated NaCl (100 mL). A white solid
resulted on drying the ethyl acetate phase with MgSO.sub.4,
filtering through celite, and evaporation of volitiles.
[1131] LCMS: Method [11]: Retention time at 220 nm detection is
1.51 minutes and [M=1].sup.+=325.8. LCMS shows nearly quantitative
product (i) at >95% purity.
[1132] To a THF (anhydrous, 300 mL) solution of amide ((i), 76.5
mmol) and tetrakis(triphenylphosphihe)palladium(0) (3.825 mmol,
4.42 g), is slowly added neopentylzinc iodide (commercially
available 0.5M in THF, 95.6 mmol, 190 mL). The mixture is capped
and allowed to stir at 40.degree. C. (in a temperature controlled
water bath) for 12 hours. The reaction solution is then quenched by
adding 1N HCl in ethanol (100 mL), and then evaporated of volitiles
via roto-evaporation. The resulting brown solid mass is partially
taken up in ethyl acetate (500 mL), filtered, and the filtrate
evaporated of volitiles via roto-evaporation. LCMS (method [11]) of
the crude residue shows a complex mixture, and the product can be
purified by passing a concentrated ethyl acetated solution through
a silica column with hexanes/ethyl acetate eluent and
fractionation. Pure fractions containing (ii) are determined by
LCMS (method [11], retention 2.19 minutes, [M+1]=269.83). The pure
fractions are evaporated of solvent via roto-evaporation and high
vacuum.
[1133] The bromo amide ((ii), 3.7 mmol, 1.0 g) is dissolved in a 2M
BH.sub.3 (dimethylsulfide complex) solution in THF (55 mmol, 27.8
mL) then refluxed (reaction flask equipped with a water cooled
condenser) for 24 h. At the end of reflux and after cooling, the
mixture is quenced with the slow addition of isopropanol (50 mL).
The reaction is removed of volitiles-via roto-evaporation, the
resulting oil is taken up in ethyl acetate (75 mL) and washed once
with aqueous HCl (1M, 25 mL), the organic layer is dried with
MgSO4, filtered, evaporated via roto-evaporation, and traces of
volitiles removed with high vacuum. LCMS (method [11]) of the crude
work-up residue shows 85% HPLC pure desired amine iii (retention
2.17 minutes, [M+1]=255.67).
EXAMPLE 386
NH.sub.2 Replacement of Hydroxyl Alpha to the --(CHR.sub.1)-- Group
of Compounds of Formula (I)
[1134] 498
EXAMPLE 387
SH Replacement of Hydroxyl Alpha to the --(CHR.sub.1)-- Group of
Compounds of Formula (I)
[1135] 499
Additional Exemplary Compounds
EXAMPLE 388
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-4-(3,5-difluoro-phenyl)-3-(2-m-
ethylamino-pyrimidin-4-ylamino)-butan-2-ol
[1136] 500
EXAMPLE 389
1-[1-(3-tert-butyl-phenyl)-cyclohexylamino]4-(3,5-difluoro-phenyl)-3-(4-me-
thoxy-benzyloxymethyl)-butan-2-ol
[1137] 501
[1138] Generally, the protection of amines is conducted, where
appropriate, by methods known to those skilled in the art. See, for
example, Protecting Groups in Organic Synthesis, John Wiley and
Sons, New York, N.Y., 1981, Chapter 7; Protecting Groups in Organic
Chemistry, Plenum Press, New York, N.Y., 1973, Chapter 2. When the
amino protecting group is no longer needed, it is removed by
methods known to those skilled in the art. By definition the amino
protecting group must be readily removable. A variety of suitable
methodologies are known to those skilled in the art, see also T. W.
Green and P. G. M. Wuts in Protective Groups in Organic Chemistry,
John Wiley and Sons, 3.sup.rd edition, 1999. Suitable amino
protecting groups include t-butoxycarbonyl, benzyl-oxycarbonyl,
formyl, trityl, phthalimido, trichloro-acetyl, chloroacetyl,
bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,
1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxy-carbonyl,
cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methyl-cyclohexanyloxycabonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxy-carbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonyl, 9-fluoroenylmethyl
carbonate, --CH--CH.dbd.CH.sub.2, and the like.
[1139] In an embodiment, the protecting group is t-butoxycarbonyl
(Boc) and/or benzyloxycarbonyl (CBZ). In another embodiment, the
protecting group is Boc. One skilled in the art will recognize
suitable methods of introducing a Boc or CBZ protecting group and
may additionally consult Protective Groups in Organic Chemistry,
for guidance.
[1140] The compounds of the present invention may contain geometric
or optical isomers as tautomers. Thus, the present invention
includes all tautomers and pure geometric isomers, such as the E
and Z geometric isomers, as mixtures thereof. Further, the present
invention includes pure enantiomers, diastereomers and/or mixtures
thereof, including racemic mixtures. The individual geometric
isomers, enantiomers or diastereomers may be prepared or isolated
by methods known to those in the art, including, for example chiral
chromatography, preparing diastereomers, separating the
diastereomers and then converting the diastereomers into
enantiomers.
[1141] Compounds of the present invention with designated
stereochemistry can be included in mixtures, including racemic
mixtures, with other enantiomers, diastereomers, geometric isomers
or tautomers. In a preferred embodiment, compounds of the present
invention are typically present in these mixtures in diastereomeric
and/or enantiomeric excess of at least 50%. Preferably, compounds
of the present invention are present in these mixtures in
diastereomeric and/or enantiomeric excess of at least 80%. More
preferably, compounds of the present invention with the desired
stereochemistry are present in diastereomeric and/or enantiomeric
excess of at least 90%. Even more preferably, compounds of the
present invention with the desired stereochemistry are present in
diastereomeric and/or enantiomeric excess of at least 99%.
Preferably the compounds of the present invention have the "S"
configuration at position 1. Also preferred are compounds that have
the "R" configuration at position 2. Most preferred are compounds
that have the "1S,2R" configuration. 502
[1142] Several of the compounds of formula (I) are amines, and as
such form salts when reacted with acids. Pharmaceutically
acceptable salts are preferred over the corresponding amines since
they produce compounds, which are more water soluble, stable and/or
more crystalline.
EXAMPLE 390
Biological Examples
[1143] Properties such as efficacy, oral bioavailability,
selectivity or blood-brain barrier penetration can be assessed by
techniques and assays known to one skilled in the art. Exemplary
assays for determining such properties are found below.
Inhibition of APP Cleavage
[1144] The methods of treatment and compounds of the present
invention inhibit cleavage of APP between Met595 and Asp596
numbered for the APP695 isoform, or a mutant thereof, or at a
corresponding site of a different isoform, such as APP751 or
APP770, or a mutant thereof (sometimes referred to as the "beta
secretase site"). While many theories exist, inhibition of
beta-secretase activity is thought to inhibit production of
A-beta.
[1145] Inhibitory activity is demonstrated in one of a variety of
inhibition assays, whereby cleavage of an APP substrate in the
presence of beta-secretase enzyme is analyzed in the presence of
the inhibitory compound, under conditions normally sufficient to
result in cleavage at the beta-secretase cleavage site. Reduction
of APP cleavage at the beta-secretase cleavage site compared with
an untreated or inactive control is correlated with inhibitory
activity. Assay systems that can be used to demonstrate efficacy of
the compounds of formula (I) are known. Representative assay
systems are described, for example, in U.S. Pat. Nos. 5,942,400 and
5,744,346, as well as in the Examples below.
[1146] The enzymatic activity of beta-secretase and the production
of A-beta can be analyzed in vitro or in vivo, using natural,
mutated, and/or synthetic APP substrates, natural, mutated, and/or
synthetic enzyme, and the compound employed in the particular
method of treatment. The analysis can involve primary or secondary
cells expressing native, mutant, and/or synthetic APP and enzyme,
animal models expressing native APP and enzyme, or can utilize
transgenic animal models expressing the substrate and enzyme.
Detection of enzymatic activity can be by analysis of at least one
of the cleavage products, for example, by immunoassay, fluorometric
or chromogenic assay, HPLC, or other means of detection. Inhibitory
compounds are determined as those able to decrease the amount of
beta-secretase cleavage product produced in comparison to a
control, where beta-secretase mediated cleavage in the reaction
system is observed and measured in the absence of inhibitory
compounds.
[1147] Efficacy reflects a preference for a target tissue. For
example, efficacy values yield information regarding a compound's
preference for a target tissue by comparing the compound's effect
on multiple (i.e., two) tissues. See, for example, Dovey et al., J.
Neurochemistry, 2001, 76:173-181. Efficacy reflects the ability of
compounds to target a specific tissue and create the desired result
(e.g., clinically). Efficacious compositions and corresponding
methods of treatment are needed to prevent or treat conditions and
diseases associated with amyloidosis.
[1148] Efficacious compounds of the present invention are those
able to decrease the amount of A-beta produced compared to a
control, where beta-secretase mediated cleavage is observed and
measured in the absence of the compounds. Detection of efficacy can
be by analysis of A-beta levels, for example, by immunoassay,
fluorometric or chromogenic assay, HPLC, or other means of
detection. The efficacy of the compounds of formula (I) was
determined as a percentage inhibition corresponding to A-beta
concentrations for tissue treated and untreated with compound.
Beta-Secretase
[1149] Various forms of beta-secretase enzyme are known, are
available, and useful for assaying enzymatic activity and
inhibition of enzyme activity. These include native, recombinant,
and synthetic forms of the enzyme. Human beta-secretase is known as
Beta Site APP Cleaving Enzyme (BACE), BACE1, Asp2, and memapsin 2,
and has been characterized, for example, in U.S. Pat. No. 5,744,346
and published PCT patent applications WO 98/22597, WO 00/03819, WO
01/23533, and WO 00/17369, as well as in literature publications
(Hussain et al., 1999, Mol. Cell. Neurosci., 14:419-427; Vassar et
al., 1999, Science, 286:735-741; Yan et al., 1999, Nature,
402:533-537; Sinha et al., 1999, Nature, 40:537-540; and Lin et
al., 2000, Proceedings Natl. Acad. Sciences USA, 97:1456-1460).
Synthetic forms of the enzyme have also been described in, for
example, WO 98/22597 and WO 00/17369. Beta-secretase can be
extracted and purified from human brain tissue and can be produced
in cells, for example mammalian cells expressing recombinant
enzyme.
APP Substrate
[1150] Assays that demonstrate inhibition of
beta-secretase-mediated cleavage of APP can utilize any of the
known forms of APP, including the 695 amino acid "normal" isotype
described by Kang et al., 1987, Nature, 325:733-6, the 770 amino
acid isotype described by Kitaguchi et. al., 1981, Nature,
331:530-532, and variants such as the Swedish Mutation (KM670-1 NL)
(APP-SW), the London Mutation (V7176F), and others. See, for
example, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature
Genet. 1:233-234, for a review of known variant mutations.
Additional useful substrates include the dibasic amino acid
modification, APP-KK, disclosed, for example, in WO 00/17369,
fragments of APP, and synthetic peptides containing the
beta-secretase cleavage site, wild type (WT) or mutated form,
(e.g., SW), as described, for example, in U.S. Pat. No. 5,942,400
and WO 00/03819.
[1151] The APP substrate contains the beta-secretase cleavage site
of APP (KM-DA or NL-DA) for example, a complete APP peptide or
variant, an APP fragment, a recombinant or synthetic APP, or a
fusion peptide. Preferably, the fusion peptide includes the
beta-secretase cleavage site fused to a peptide having a moiety
useful for enzymatic assay, for example, having isolation and/or
detection properties. A useful moiety can be an antigenic epitope
for antibody binding, a label or other detection moiety, a binding
substrate, and the like.
Antibodies
[1152] Products characteristic of APP cleavage can be measured by
immunoassay using various antibodies, as described, for example, in
Pirttila et al., 1999, Neuro. Lett., 249:21-4, and in U.S. Pat. No.
5,612,486. Useful antibodies to detect A-beta include, for example,
the monoclonal antibody 6E10 (Senetek, St. Louis, Mo.) that
specifically recognizes an epitope on amino acids 1-16 of the
A-beta peptide, antibodies 162 and 164 (New York State Institute
for Basic Research, Staten Island, N.Y.) that are specific for
human A-beta 1-40 and 1-42, respectively, and antibodies that
recognize the junction region of A-beta, the site between residues
16 and 17, as described in U.S. Pat. No. 5,593,846. Antibodies
raised against a synthetic peptide of residues 591 to 596 of APP
and SW192 antibody raised against 590-596 of the Swedish mutation
are also useful in immunoassay of APP and its cleavage products, as
described in U.S. Pat. Nos. 5,604,102 and 5,721,130.
Assay Systems
[1153] Assays for determining APP cleavage at the beta-secretase
cleavage site are well known in the art. Exemplary assays, are
described, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400,
and described in the Examples below.
Cell Free Assays
[1154] Exemplary assays that can be used to demonstrate the
inhibitory activity of the compounds of the present invention are
described, for example, in WO 00/17369, WO 00/03819, and U.S. Pat.
Nos. 5,942,400 and 5,744,346. Such assays can be performed in
cell-free incubations or in cellular incubations using cells
expressing A-beta-secretase and an APP substrate having
A-beta-secretase cleavage site.
[1155] An APP substrate containing the beta-secretase cleavage site
of APP, for example, a complete APP or variant, an APP fragment, or
a recombinant or synthetic APP substrate containing the amino acid
sequence KM-DA or NL-DA is incubated in the presence of
beta-secretase enzyme, a fragment thereof, or a synthetic or
recombinant polypeptide variant having beta-secretase activity and
effective to cleave the beta-secretase cleavage site of APP, under
incubation conditions suitable for the cleavage activity of the
enzyme. Suitable substrates optionally include derivatives that can
be fusion proteins or peptides that contain the substrate peptide
and a modification useful to facilitate the purification or
detection of the peptide or its beta-secretase cleavage products.
Useful modifications include the insertion of a known antigenic
epitope for antibody binding, the linking of a label or detectable
moiety, the linking of a binding substrate, and the like.
[1156] Suitable incubation conditions for a cell-free in vitro
assay include, for example, approximately 200 nM to 10 .mu.M
substrate, approximately 10 pM to 200 pM enzyme, and approximately
0.1 nM to 10 .mu.M inhibitor compound, in aqueous solution, at an
approximate pH of 4-7, at approximately 37.degree. C., for a time
period of approximately 10 min to 3 h.
[1157] These incubation conditions are exemplary only, and can be
varied as required for the particular assay components and/or
desired measurement system. Optimization of the incubation
conditions for the particular assay components should account for
the specific beta-secretase enzyme used and its pH optimum, any
additional enzymes and/or markers that might be used in the assay,
and the like. Such optimization is routine and will not require
undue experimentation.
[1158] One useful assay utilizes a fusion peptide having maltose
binding protein (MBP) fused to the C-terminal 125 amino acids of
APP-SW. The MBP portion is captured on an assay substrate by an
anti-MBP capture antibody. Incubation of the captured fusion
protein in the presence of beta-secretase results in cleavage of
the substrate at the beta-secretase cleavage site. Analysis of the
cleavage activity can be, for example, by immunoassay of cleavage
products. One such immunoassay detects a unique epitope exposed at
the carboxy terminus of the cleaved fusion protein, for example,
using the antibody SW192. This assay is described, for example, in
U.S. Pat. No. 5,942,400.
Cellular Assay
[1159] Numerous cell-based assays can be used to analyze
beta-secretase activity and/or processing of APP to release A-beta.
Contact of an APP substrate with A-beta-secretase enzyme within the
cell and in the presence or absence of a compound inhibitor of the
present invention can be used to demonstrate beta-secretase
inhibitory activity of the compound. It is preferred that the assay
in the presence of a useful inhibitory compound provides at least
about 10% inhibition of the enzymatic activity, as compared with a
non-inhibited control.
[1160] In an embodiment, cells that naturally express
beta-secretase are used. Alternatively, cells are modified to
express a recombinant beta-secretase or synthetic variant enzyme as
discussed above. The APP substrate can be added to the culture
medium and is preferably expressed in the cells. Cells that
naturally express APP, variant or mutant forms of APP, or cells
transformed to express an isoform of APP, mutant or variant APP,
recombinant or synthetic APP, APP fragment, or synthetic APP
peptide or fusion protein containing the beta-secretase APP
cleavage site can be used, provided that the expressed APP is
permitted to contact the enzyme and enzymatic cleavage activity can
be analyzed.
[1161] Human cell lines that normally process A-beta from APP
provide useful means to assay inhibitory activities of the
compounds employed in the methods of treatment of the present
invention. Production and release of A-beta and/or other cleavage
products into the culture medium can be measured, for example by
immunoassay, such as Western blot or enzyme-linked immunoassay
(EIA) such as by ELISA.
[1162] Cells expressing an APP substrate and an active
beta-secretase can be incubated in the presence of a compound
inhibitor to demonstrate inhibition of enzymatic activity as
compared with a control. Activity of beta-secretase can be measured
by analysis of at least one cleavage product of the APP substrate.
For example, inhibition of beta-secretase activity against the
substrate APP would be expected to decrease the release of specific
beta-secretase induced APP cleavage products such as A-beta.
[1163] Although both neural and non-neural cells process and
release A-beta, levels of endogenous beta-secretase activity are
low and often difficult to detect by EIA. The use of cell types
known to have enhanced beta-secretase activity, enhanced processing
of APP to A-beta, and/or enhanced production of A-beta are
therefore preferred. For example, transfection of cells with the
Swedish Mutant form of APP (APP-SW), with APP-KK, or with APP-SW-KK
provides cells having enhanced beta-secretase activity and
producing amounts of A-beta that can be readily measured.
[1164] In such assays, for example, the cells expressing APP and
beta-secretase are incubated in a culture medium under conditions
suitable for beta-secretase enzymatic activity at its cleavage site
on the APP substrate. On exposure of the cells to the compound
inhibitor employed in the methods of treatment, the amount of
A-beta released into the medium and/or the amount of CTF99
fragments of APP in the cell lysates is reduced as compared with
the control. The cleavage products of APP can be analyzed, for
example, by immune reactions with specific antibodies, as discussed
above.
[1165] Preferred cells for analysis of beta-secretase activity
include primary human neuronal cells, primary transgenic animal
neuronal cells where the transgene is APP, and other cells such as
those of a stable 293 cell line expressing APP, for example,
APP-SW.
In Vivo assays: Animal Models
[1166] Various animal models can be used to analyze beta-secretase
activity and/or processing of APP to release A-beta, as described
above. For example, transgenic animals expressing APP substrate and
beta-secretase enzyme can be used to demonstrate inhibitory
activity of the compounds of the present invention. Certain
transgenic animal models have been described, for example, in U.S.
Pat. Nos. 5,877,399, 5,612,486, 5,387,742, 5,720,936, 5,850,003,
5,877,015, and 5,811,633, and in Games et al., 1995, Nature,
373:523. Animals that exhibit characteristics associated with the
pathophysiology of Alzheimer's disease are preferred.
Administration of the compounds of the present invention to the
transgenic mice described herein provides an alternative method for
demonstrating the inhibitory activity of the compounds.
Administration of the compounds of the present invention in a
pharmaceutically effective carrier and via an administrative route
that reaches the target tissue in an appropriate therapeutic amount
is also preferred.
[1167] Inhibition of beta-secretase mediated cleavage of APP at the
beta-secretase cleavage site and of A-beta release can be analyzed
in these animals by measuring cleavage fragments in the animal's
body fluids such as cerebral fluid or tissues. Analysis of brain
tissues for A-beta deposits or plaques is preferred.
A: Enzyme Inhibition Assay
[1168] The methods of treatment and compounds of the present
invention are analyzed for inhibitory activity by use of the
MBP-C125 assay. This assay determines the relative inhibition of
beta-secretase cleavage of a model APP substrate, MBP-C125SW, by
the compounds assayed as compared with an untreated control. A
detailed description of the assay parameters can be found, for
example, in U.S. Pat. No. 5,942,400. Briefly, the substrate is a
fusion peptide formed of MBP and the carboxy terminal 125 amino
acids of APP-SW, the Swedish mutation. The beta-secretase enzyme is
derived from human brain tissue as described in Sinha et al., 1999,
Nature, 40:537-540 or recombinantly produced as the full-length
enzyme (amino acids 1-501), and can be prepared, for example, from
293 cells expressing the recombinant cDNA, as described in WO
00/47618.
[1169] Inhibition of the enzyme is analyzed, for example, by
immunoassay of the enzyme's cleavage products. One exemplary ELISA
uses an anti-MBP capture antibody that is deposited on precoated
and blocked 96-well high binding plates, followed by incubation
with diluted enzyme reaction supernatant, incubation with a
specific reporter antibody, for example, biotinylated anti-SW192
reporter antibody, and further incubation with
streptavidin/alkaline phosphatase. In the assay, cleavage of the
intact MBP-C125SW fusion protein results in the generation of a
truncated amino-terminal fragment, exposing a new SW-192
antibody-positive epitope at the carboxy terminus. Detection is
effected by a fluorescent substrate signal on cleavage by the
phosphatase. ELISA only-detects cleavage following Leu596 at the
substrate's APP-SW 751 mutation site.
Specific Assay Procedure
[1170] Compounds of formula (I) are diluted in a 1:1 dilution
series to a six-point concentration curve (two wells per
concentration) in one row of a 96-well plate per compound tested.
Each of the test compounds is prepared in DMSO to make up a 10 mM
stock solution. The stock solution is serially diluted in DMSO to
obtain a final compound concentration of 200 .mu.M at the high
point of a 6-point dilution curve. 10 .mu.L of each dilution is
added to each of two wells on row C of a corresponding V-bottom
plate to which 190 .mu.L of 52 mM NaOAc, 7.9% DMSO, pH 4.5 are
pre-added. The NaOAc diluted compound plate is spun down to pellet
precipitant and 20 .mu.L/well is transferred to a corresponding
flat-bottom plate to which 30 .mu.L of ice-cold enzyme-substrate
mixture (2.5 .mu.L MBP-C125SW substrate, 0.03 .mu.L enzyme and 24.5
.mu.L ice cold 0.09% TX100 per 30 .mu.L) is added. The final
reaction mixture of 200 .mu.M compound at the highest curve point
is in 5% DMSO, 20 mM NaOAc, 0.06% TX100, at pH 4.5.
[1171] Warming the plates to 37.degree. C. starts the enzyme
reaction. After 90 min at 37.degree. C., 200 .mu.L/well cold
specimen diluent is added to stop the reaction and 20 .mu.L/well
was transferred to a corresponding anti-MBP antibody coated ELISA
plate for capture, containing 80 .mu.L/well specimen diluent. This
reaction is incubated overnight at 4.degree. C. and the ELISA is
developed the next day after a 2 hour incubation with anti-192SW
antibody, followed by Streptavidin-AP conjugate and fluorescent
substrate. The signal is read on a fluorescent plate reader.
[1172] Relative compound inhibition potency is determined by
calculating the concentration of compound that showed a 50%
reduction in detected signal (IC.sub.50) compared to the enzyme
reaction signal in the control wells with no added compound. In
this assay, preferred compounds of the present invention exhibit an
IC.sub.50 of less than 50 .mu.M.
B: FP BACE Assay: Cell Free Inhibition Assay Utilizing a Synthetic
APP Substrate
[1173] A synthetic APP substrate that can be cleaved by
beta-secretase and having N-terminal biotin and made fluorescent by
the covalent attachment of Oregon green at the Cys residue is used
to assay beta-secretase activity in the presence or absence of the
inhibitory compounds employed in the present invention. Useful
substrates include
[1174] Biotin-SEVNL-DAEFRC[oregon green]KK,
[1175] Biotin-SEVKM-DAEFRC[oregon green]KK,
[1176] Biotin-GLNIKTEEISEISY-EVEFRC[oregon green]KK,
[1177] Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEFRC[oregon green]KK,
and
[1178] Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKAC[oregon
green]KK.
[1179] The enzyme (0.1 nM) and test compounds (0.001-100 .mu.M) are
incubated in pre-blocked, low affinity, black plates (384 well) at
37.degree. C. for 30 min. The reaction is initiated by addition of
150 mM substrate to a final volume of 30 .mu.L/well. The final
assay conditions are 0.001-100 .mu.M compound inhibitor, 0.1 molar
sodium acetate (pH 4.5), 150 nM substrate, 0.1 nM soluble
beta-secretase, 0.001% Tween 20, and 2% DMSO. The assay mixture is
incubated for 3 h at 37.degree. C., and the reaction is terminated
by the addition of a saturating concentration of immunopure
streptavidin. After incubation with streptavidin at room
temperature for 15 min, fluorescence polarization is measured, for
example, using a LJL Acqurest (Ex485 nm/Em530 nm).
[1180] The activity of the beta-secretase enzyme is detected by
changes in the fluorescence polarization that occur when the
substrate is cleaved by the enzyme. Incubation in the presence or
absence of compound inhibitor demonstrates specific inhibition of
beta-secretase enzymatic cleavage of its synthetic APP substrate.
In this assay, preferred compounds of the present invention exhibit
an IC.sub.50 of less than 50 .mu.M. More preferred compounds of the
present invention exhibit an IC.sub.50 of less than 10 .mu.M. Even
more preferred compounds of the present invention exhibit an
IC.sub.50 of less than 5 .mu.M.
C: Beta-Secretase Inhibition: P26-P4'SW Assay
[1181] Synthetic substrates containing the beta-secretase cleavage
site of APP are used-to assay beta-secretase activity, using the
methods described, for example, in published PCT application WO
00/47618. The P26-P4'SW substrate is a peptide of the sequence
(biotin)CGGADRGLTTRPGSGL- TNIKTEEISEVNLDAEF. The P26-P1 standard
has the sequence (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL.
[1182] Briefly, the biotin-coupled synthetic substrates are
incubated at a concentration of from about 0 to about 200 .mu.M in
this assay. When testing inhibitory compounds, a substrate
concentration of about 1.0 .mu.M is preferred. Test compounds
diluted in DMSO are added to the reaction mixture, with a final
DMSO concentration of 5%. Controls also contain a final DMSO
concentration of 5%. The concentration of beta secretase enzyme in
the reaction is varied, to give product concentrations with the
linear range of the ELISA assay, about 125 pM to 2000 pM, after
dilution.
[1183] The reaction mixture also includes 20 mM sodium acetate, pH
4.5, 0.06% Triton X100, and is incubated at 37.degree. C. for about
1 to 3 h. Samples are then diluted in assay buffer (for example,
145.4 nM sodium chloride, 9.51 mM sodium phosphate, 7.7 mM sodium
azide, 0.05% Triton X405, 6 g/L bovine serum albumin, pH 7.4) to
quench the reaction, then diluted further for immunoassay of the
cleavage products.
[1184] Cleavage products can be assayed by ELISA. Diluted samples
and standards are incubated in assay plates coated with capture
antibody, for example, SW192, for about 24 h at 4.degree. C. After
washing in TTBS buffer (150 mM sodium chloride, 25 mM Tris, 0.05%
Tween 20, pH 7.5), the samples are incubated with streptavidin-AP
according to the manufacturer's instructions. After a 1 h
incubation at room temperature, the samples are washed in TTBS and
incubated with fluorescent substrate solution A (31.2 g/L
2-amino-2-methyl-1-propanol, 30 mg/L, pH 9.5). Reaction with
streptavidin-alkaline phosphate permits detection by fluorescence.
Compounds that are effective inhibitors of beta-secretase activity
demonstrate reduced cleavage of the substrate as compared to a
control.
D: Assays using Synthetic Oligopeptide-Substrates
[1185] Synthetic oligopeptides are prepared incorporating the known
cleavage site of beta-secretase, and optionally include detectable
tags, such as fluorescent or chromogenic moieties. Examples of such
peptides, as well as their production and detection methods, are
described in U.S. Pat. No. 5,942,400. Cleavage products can be
detected using high performance liquid chromatography, or
fluorescent or chromogenic detection methods appropriate to the
peptide to be detected, according to methods well known in the
art.
[1186] By way of example, one such peptide has the sequence
SEVNL-DAEF, and the cleavage site is between residues 5 and 6.
Another preferred substrate has the sequence
ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF, and the cleavage site is between
residues 26 and 27.
[1187] These synthetic APP substrates are incubated in the presence
of beta-secretase under conditions sufficient to result in
beta-secretase mediated cleavage of the substrate. Comparison of
the cleavage results in the presence of a compound inhibitor to
control results provides a measure of the compound's inhibitory
activity.
E: Inhibition of Beta-Secretase Activity-Cellular Assay
[1188] An exemplary assay for the analysis of inhibition of
beta-secretase activity utilizes the human embryonic kidney cell
line HEKp293 (ATCC Accession No. CRL-1573) transfected with APP751
containing the naturally occurring double mutation Lys651 Met652 to
Asn651 Leu652 (numbered for APP751), commonly called the Swedish
mutation and shown to overproduce A-beta (Citron et al., 1992,
Nature, 360:672-674), as described in U.S. Pat. No. 5,604,102.
[1189] The cells are incubated in the presence/absence of the
inhibitory compound (diluted in DMSO) at the desired concentration,
generally up to 10 .mu.g/mL. At the end of the treatment period,
conditioned media is analyzed for beta-secretase activity, for
example, by analysis of cleavage fragments. A-beta can be analyzed
by immunoassay, using specific detection antibodies. The enzymatic
activity is measured in the presence and absence of the compound
inhibitors to demonstrate specific inhibition of beta-secretase
mediated cleavage of APP substrate.
F: Inhibition of Beta-Secretase in Animal Models of Alzheimer's
Disease
[1190] Various animal models can be used to screen for inhibition
of beta-secretase activity. Examples of animal models useful in the
present invention include mouse, guinea pig, dog, and the like. The
animals used can be wild type, transgenic, or knockout models. In
addition, mammalian models can express mutations in APP, such as
APP695-SW and the like described herein. Examples of transgenic
non-human mammalian models are described in U.S. Pat. Nos.
5,604,102, 5,912,410 and 5,811,633.
[1191] PDAPP mice, prepared as described in Games et al., 1995,
Nature, 373:523-527 are useful to analyze in vivo suppression of
A-beta release in the presence of putative inhibitory compounds. As
described in U.S. Pat. No. 6,191,166, 4 month old PDAPP mice are
administered a compound of formula (I) formulated in vehicle, such
as corn oil. The mice are dosed with compound (1-30 mg/mL,
preferably 1-10 mg/mL). After time, e.g., 3-10 h, the brains are
analyzed.
[1192] Transgenic animals are administered an amount of a compound
formulated in a carrier suitable for the chosen mode of
administration. Control animals are untreated, treated with
vehicle, or treated with an inactive compound. Administration can
be acute, (i.e., single dose or multiple doses in one day), or can
be chronic, (i.e. dosing is repeated daily for a period of days).
Beginning at time 0, brain tissue or cerebral fluid is obtained
from selected animals and analyzed for the presence of APP cleavage
peptides, including A-beta, for example, by immunoassay using
specific antibodies for A-beta detection. At the end of the test
period, brain tissue or cerebral fluid is analyzed for the presence
of A-beta and/or beta-amyloid plaques. The tissue is also analyzed
for necrosis.
[1193] Reduction of A-beta in brain tissues or cerebral fluids and
reduction of beta-amyloid plaques in brain tissue are assessed by
administering the compounds of formula (I), or pharmaceutical
compositions comprising compounds of formula (I) to animals and
comparing the data with that from non-treated controls.
G: Inhibition of A-Beta Production in Human Patients
[1194] Patients suffering from Alzheimer's disease demonstrate an
increased amount of A-beta in the brain. Alzheimer's disease
patients are subjected to a method of treatment of the present
invention, (i.e. administration of an amount of the compound
inhibitor formulated in a carrier suitable for the chosen mode of
administration). Administration is repeated daily for the duration
of the test period. Beginning on day 0, cognitive and memory tests
are performed, for example, once per month.
[1195] Patients administered the compounds of formula (I) are
expected to demonstrate slowing or stabilization of disease
progression as analyzed by a change in at least one of the
following disease parameters: A-beta present in cerebrospinal fluid
or plasma, brain or hippocampal volume, A-beta deposits in the
brain, amyloid plaque in the brain, or scores for cognitive and
memory function, as compared with control, non-treated
patients.
H: Prevention of A-Beta Production in Patients at Risk for
Alzheimer's Disease
[1196] Patients predisposed or at risk for developing Alzheimer's
disease can be identified either by recognition of a familial
inheritance pattern, for example, presence of the Swedish Mutation,
and/or by monitoring diagnostic parameters. Patients identified as
predisposed or at risk for developing Alzheimer's disease are
administered an amount of the compound inhibitor formulated in a
carrier suitable for the chosen mode of administration.
Administration is repeated daily for the duration of the test
period. Beginning on day 0, cognitive and memory tests are
performed, for example, once per month.
[1197] Patients subjected to a method of treatment of the present
invention (i.e., administration of a compound inhibitor) are
expected to demonstrate slowing or stabilization of disease
progression as analyzed by changes in at least one of the following
disease parameters: A-beta present in cerebrospinal fluid or
plasma, brain or hippocampal volume, amyloid plaque in the brain,
or scores for cognitive and memory function, as compared with
control, non-treated patients.
I: Efficacy of Compounds to Inhibit A-Beta Concentration
[1198] The invention encompasses compounds of formula (I) that are
efficacious. Efficacy is calculated as a percentage of
concentrations as follows:
Efficacy=(1-(total A-beta in dose group/total A-beta in vehicle
control)*100%
[1199] wherein the "total A-beta in dose group" equals the
concentration of A-beta in the tissue, (e.g., rat brain) treated
with the compound, and the "total A-beta in vehicle control" equals
the concentration of A-beta in the tissue, yielding a % inhibition
of A-beta production. Statistical significance is determined by
p-value <0.05 using the Mann Whitney t-test. See, for example,
Dovey et al., J. Neurochemistry, 2001, 76:173-181.
J: Selectivity of Compounds for Inhibiting BACE over Aspartyl
Proteases
[1200] The compounds of formula (I) can be selective for
beta-secretase versus catD. Wherein the ratio of catD:
beta-secretase is greater than 1, selectivity is calculated as
follows:
Selectivity=(IC.sub.50 for catD/IC.sub.50 for
beta-secretase)*100%
[1201] wherein IC.sub.50 is the concentration of compound necessary
to decrease the level of catD or beta-secretase by 50%. Selectivity
is reported as the ratio of IC.sub.50(catD):IC.sub.50(BACE).
[1202] The compounds of formula (I) can be selective for
beta-secretase versus catE. Wherein the ratio of
catE:beta-secretase is greater than 1, selectivity is calculated as
follows:
Selectivity=(IC.sub.50 for catE/IC.sub.50 for
beta-secretase)*100%
[1203] wherein IC.sub.50 is the concentration of compound necessary
to decrease the level of catE or beta-secretase by 50%. Selectivity
is reported as the ratio of IC.sub.50(catE):IC.sub.50(BACE).
[1204] Pharmacokinetic parameters were calculated by a
non-compartmental approach See, for example, Gibaldi, M. and
Perrier, D., Pharmacokinetics, Second Edition, 1982, Marcel Dekker
Inc., New York, N.Y., pp 409-418.
[1205] In the following examples, each value is an average of four
experimental runs. Unless otherwise indicated, specific formula (I)
compound examples represent a mixture of diastereomers.
EXAMPLE 391
Selectivity of Exemplary Formula (I) Compounds
[1206]
4 Example No. Compound IC.sub.50(catD):IC.sub.50(B- ACE) 391-1 503
3.8 3-(3-Bromo-[1,2,4]thiadiazol-5- ylamino)-4-(3,5-difluoro-
phenyl)-1-(6-ethyl- 2,2-dioxo-2.lambda..sup.6-isothio-
chroman-4-ylamino)-butan-2-ol 391-2 504 1.1
4-(3,5-Difluoro-phenyl)-1-[5- (2,2-dimethyl-propyl)-2-
imidazol-1-yl-benzylamino]- butan-2-ol
EXAMPLE 392
Selectivity of Exemplary Formula (I) Compounds
[1207]
5 Example No. Compound IC.sub.50(catD):IC.sub.50(B- ACE) 392-1 505
1.2 3-[3-[1-(3-tert-Butyl-phenyl)- cyclohexylamino]-1-(3,5-
difluoro-benzyl)-2-hydroxy- propylamino]- 5-iodo-pyridin-4-ol 392-2
506 1.9 3-[3-[1-(3-tert-Butyl-phenyl)- cyclohexylamino]-1-(3,5-
difluoro-benzyl)-2-hydroxy- propylamino]- pyridin-4-ol
K: Oral Bioavailability of Compounds for Inhibiting Amyloidosis
[1208] The invention encompasses compounds of formula (I) that are
orally bioavailable. Oral bioavailability can be determined
following both the an intravenous (IV) and oral (PO) administration
of a test compound.
[1209] Oral Bioavailability was determined in the male
Sprague-Dawley rat following both IV and PO administration of test
compound. Two month-old male rats (250-300 g) were surgically
implanted with polyethylene (PE-50) cannula in the jugular vein
while under isoflurane anesthesia the day before the in-life phase.
Animals were fasted overnight with water ad libitum, then dosed the
next day. The dosing regime consisted of either a 5 mg/kg (2.5
mL/kg) IV dose (N=3) administered to the jugular vein cannula, then
flushed with saline, or a 10 mg/kg (5 mL/kg) PO dose (N=3) by
esophageal gavage. Compounds were formulated with 10% Solutol in 5%
dextrose at 2 mg/mL. Subsequent to dosing, blood was collected at
0.016 (IV only), 0.083, 0.25, 0.5, 1, 3, 6, 9, and 24 h post
administration, and heparinized plasma was recovered following
centrifugation.
[1210] Compounds were extracted from samples following
precipitation of the plasma proteins by methanol. The resulting
supernatants were evaporated to dryness and reconstituted with
chromatographic mobile phase (35% acetonitrile in 0.1% formic acid)
and injected onto a reverse phase C18 column (2.times.50 mm, 5
.mu.m, BDS Hypersil). Detection was facilitated with a
multi-reaction-monitoring experiment on a tandem triple quadrupole
mass spectrometer (LC/MS/MS) following electrospray ionization.
Experimental samples were compared to calibration curves prepared
in parallel with aged match rat plasma and quantitated with a
weighted 1/x linear regression. The lower limit of quantization
(LOQ) for the assay was typically 0.5 ng/mL.
[1211] Oral bioavailability (% F) was calculated from the dose
normalized ratio of plasma exposure following oral administration
to the intravenous plasma exposure in the rat by the following
equation
%
F=(AUC.sub.po/AUC.sub.iv).times.(D.sub.iv/D.sub.po).times.100%
[1212] where D is the dose and AUC is the
area-under-the-plasma-concentrat- ion-time-curve from 0 to 24 h.
AUC subsequently calculated from the linear trapezoidal rule by
AUC=((C.sub.2+C.sub.1)/2).times.(T.sub.2-T.sub.1) where C is
concentration and T is time.
[1213] Pharmacokinetic parameters were calculated by a
non-compartmental approach See, for example, Gibaldi, M. and
Perrier, D., Pharmacokinetics, Second Edition, 1982, Marcel Dekker
Inc., New York, N.Y., pp 409-418.
L: Brain Uptake
[1214] The invention encompasses beta-secretase inhibitors that can
readily cross the blood-brain barrier. Factors that affect a
compound's ability to cross the blood-brain barrier include a
compound's molecular weight, Total Polar Surface Area (TPSA), and
log P (lipophilicity). See, e.g., Lipinski, C. A., et al., Adv.
Drug Deliv. Reviews, 23:3-25 (1997). One of ordinary skill in the
art will be aware of methods for determining characteristics
allowing a compound to cross the blood-brain barrier. See, for
example, Murcko et al., Designing Libraries with CNS Activity, J.
Med. Chem., 42 (24), pp. 4942-51 (1999). Calculations of logP
values were performed using the Daylight clogP program (Daylight
Chemical Information Systems, Inc.). See, for example, Hansch, C.,
et al., Substituent Constants for Correlation Analysis in Chemistry
and Biology, Wiley, New York (1979); Rekker, R., The Hydrophobic
Fragmental Constant, Elsevier, Amsterdam (1977); Fujita, T., et
al., J. Am. Chem. Soc., 86, 5157 (1964).
[1215] The following assay is employed to determine the brain
penetration of compounds encompassed by the present invention.
[1216] In-life phase: Test compounds are administered to CF-1
(20-30 g) mice at 10 .mu.mol/kg (4 to 7 mg/kg) following IV
administration in the tail vein. Two time-points, 5 and 60 minutes,
are collected post dose. Four mice are harvested for heparinized
plasma and non-perfused brains at each time-point for a total of 8
mice per compound.
[1217] Analytical phase: Samples are extracted and evaporated to
dryness, then reconstituted and injected onto a reverse phase
chromatographic column while monitoring the effluent with a triple
quadrupole mass spectrometer. Quantitation is then performed with a
1/x.sup.2 weighted fit of the least-squares regression from
calibration standards prepared in parallel with the in vivo
samples. The LOQ is generally 1 ng/mL and 0.5 ng/g for the plasma
and brain respectively. Data is reported in micromolar (.mu.M)
units. Brain levels are corrected for plasma volumes (16
.mu.L/g).
[1218] Results: Comparison of a compound's brain concentration
level to two marker compounds, Indinavir and Diazepam, demonstrates
the ability in which the compounds of the present invention can
cross the blood-brain barrier. Indinavir (HIV protease inhibitor)
is a poor brain penetrant marker and Diazepam is a blood flow
limited marker. The concentration levels of Indinavir in the brain
at 5 and 60 min were 0.165 .mu.M and 0.011 .mu.M, respectively. The
concentration levels of Diazepam at 5 and 60 min were 5.481 .mu.M
and 0.176 .mu.M, respectively.
[1219] The present invention has been described with reference to
various specific and preferred embodiments and techniques. However,
it should be understood that many variations and modifications may
be made while remaining within the spirit and scope of the present
invention.
[1220] Unless defined otherwise, all scientific and technical terms
used herein have the same meaning as commonly understood by one of
skill in the art to which this invention belongs. Although methods
and materials similar or equivalent to those described herein can
be used in the practice or testing of the present invention,
suitable methods and materials are described above. Additionally,
the materials, methods, and examples are illustrative only and not
intended to be limiting. All publications, patent applications,
patents, and other references mentioned herein are incorporated by
reference in their entirety. In case of conflict, the present
specification, including definitions, will control.
* * * * *